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Osteogenesis imperfecta | forms of osteoporosis, such as iatrogenic osteoporosis, idiopathic juvenile osteoporosis, disuse osteoporosis and exercise-related osteoporosis should also be considered as explanations when OI is suspected.: 255–256
Treatment
There is no cure for osteogenesis imperfecta. Maintaining a healthy lifestyle by exercising and avoiding smoking can help prevent fractures. Treatment may include care of broken bones, pain medication, physical therapy, mobility aids such as braces or wheelchairs, and surgery.Judging the success or failure of treatment can be difficult in OI patients, as decreased bone fracture rates may just be coincidental. While these rates are often used in medical studies to judge treatment efficacy, a Norwegian study of fifteen people with OI emphasized that they feel doctors should consider the whole patient and not just fracture rates.
Acute bone fracture care
Bone fractures are treated in individuals with osteogenesis imperfecta in much the same way as they are treated in the general population—OI bone heals at the same rate as non-OI bone.: 431 A greater emphasis is placed on using lightweight materials to immobilize the fracture, as in moderate or severe types of OI, using heavy casts, such as hip spica casts, can cause fractures at the bones at the boundaries of the cast, as well as generalized osteopenia.: 431 The lightweight cast or splint is then replaced with a removable orthosis after a few weeks and once evidence of union is seen on X-ray.: 431 In order to prevent a nonunion or malunion, all fractures should be immobilized, even if the fracture seems trivial (microfracture),: 439 as people with OI are at greater risk of nonunion.: 438 Bone infections secondary to fractures are treated as and when they occur with the appropriate antibiotics and antiseptics, as in the general population.: 424
Medications
Bisphosphonates
In 1998, an initial observational trial demonstrated the effectiveness of intravenous pamidronate, a bisphosphonate which had previously been used in adults to treat osteoporosis. In severe OI, this trial showed that pamidronate reduced bone pain, prevented new vertebral fractures, reshaped previously fractured vertebral bodies, and reduced the number of long-bone fractures.Although oral bisphosphonates are more convenient and cheaper, they are not absorbed as well, and intravenous bisphosphonates are generally more effective, although this is under study. Some studies have found oral and intravenous bisphosphonates, such as oral alendronate and intravenous pamidronate, equivalent. In a 2013 double-blind trial of children with mild OI, oral risedronate increased bone mineral densities, and reduced nonvertebral fractures. However, it did not decrease new vertebral fractures. A Cochrane review in 2016 concluded that though bisphosphonates seem to improve bone mineral density, it is uncertain whether this leads either to a reduction in bone fractures or improvement in the quality of life of individuals with osteogenesis imperfecta. Even in trials with as many as 125 children, no causal link has been found between bisphosphonates and decreased fracture rates; placebo controlled trials were also unable to prove that they brought about increased strength, motor control or lower pain levels.Bisphosphonates are not as effective at increasing the bone mineral density of adults.
Nutritional supplements
OI is a genetic disorder and is not caused by insufficient intake of any vitamin or mineral; supplementation cannot cure OI. With that said, people with OI tend to be severely deficient in vitamin D at much higher rates than the general population, and the cause of this is not well understood. The severity of the deficiency and the likelihood of its occurrence is thought to be related to severity of OI. Vitamin D supplementation may be recommended, at least until levels of 25(OH)D3 in blood return to normal. Below normal levels of vitamin D are also concerning as they may decrease the benefit of bisphosphanates.
Surgery
A surgery of any type inherently carries more risks when done on a patient who has (especially moderate to severe) OI. Skeletal deformities and dentinogenesis imperfecta may hinder access to the airway.: 333 Use of, and weaning off of, mechanical ventilation is also more challenging to carry out on patients with OI.: 333 During the procedure itself or the healing process, defective OI collagen may lead to bleeding diatheses.: 333 The safety of anesthesia is also of more concern among patients with OI,: 333 with anesthetic complications 5.6x more likely to occur when the patient has OI type III. A unique concern of anesthesia in OI is perioperative fracture—fractures sustained due to patient transfer and airway access techniques that, while routine when a patients bones are strong, may cause injury with brittle OI bones. As an example, due to a 1972 report of a humerus fracture from a sphygmomanometer cuff sustained in an OI patient during surgery, blood pressure monitoring protocols are often modified for patients with OI, with neonatal size cuffs and machine settings being used even in adults;: ¶11.72 further, the least deformed of the patients limbs is preferred to receive the cuff.: ¶14.23
Rodding
Metal rods can be surgically inserted in the long bones to improve strength, a procedure developed by Harold A. Sofield when he was Chief of Staff at Chicagos Shriners Hospitals for Children, a hospital that offers orthopedic care and surgery to children regardless of their familys ability to pay. Large numbers of children with OI came to Shriners, and Sofield experimented with various methods to strengthen their bones. In 1959, with Edward A. Millar [sic], Sofield wrote a seminal article describing a three-part surgery that seemed radical at the time: precisely breaking the bones ("fragmentation"), putting the resulting bone fragments in a straight line ("realignment"), then placing metal rods into the intramedullary canals of the long bones to stabilize and strengthen them ("rod fixation"). His treatment proved useful for increasing the mobility of people with OI, and it has been adopted throughout the world—it became standard surgical treatment for severe OI by 1979, in which year David Sillence found that ≈2⁄3 of the patients he surveyed with OI type III had undergone at least one rodding surgery.: 108 Rodding surgery is often done with the hope that it will offer a path to ambulation, walking, to patients with moderate or severe OI. A 2020 review in The Journal of Bone and Joint Surgery (JB&JS) found it remains broadly popular: ≈2⁄3 of people with OI types III and IV (severe OI) have undergone some form of rodding surgery in their lives, at a mean age of 4+1⁄10 and 7+1⁄2 years respectively;: Table I one possible explanation for a tendency towards earlier intervention in type III is that one half of affected children could not walk at all without the surgery, as their limbs were more bowed, so surgery was sought sooner.In those with type III OI who had undergone rodding surgery, 79.5% had the femurs and tibias of both legs rodded.: Table I The most common form of rods used are intramedullary (IM) rods, some of which, such as the Fassier–Duval IM rod, are telescoping, meaning that they are designed to grow as the child grows, in an attempt to avoid the necessity of revision surgeries. Telescoping IM rods are widely used, and the common Fassier–Duval IM rod is designed to be used to rod the femur, tibia, and humerus.: 1 The surgery involves breaking the long bones in between one and three (or more): Figure 4 places, then fixing the rod alongside the bone to keep it straight.: 11 While telescoping IM rods are intended to grow along with both the femur and tibia in developing children; surgeons have a preference to use non-telescoping IM rods, such as Rush rods, in the tibia, which grows less comparatively—the JB&JS review found that while 69.7% of femurs were treated with telescoping IM rods, only 36.9% of tibiae were.: Table IV While the review in the JB&JS was able to correlate receiving rodding surgery with greater mobility across all types of OI, in patients with type IV, the surgery did not decrease the incidence of broken bones as compared to non-rodded patients—while type IV patients with rodded tibiae experienced 0.93 tibia fractures per year, patients with natural tibiae experienced only 0.81. However, in patients with type III, rodding surgery decreased the average number of tibia fractures per year from 0.84 to 0.57.: Table V
Spinal
Spinal fusion can be performed either as a preventative measure or to correct existing scoliosis, although the inherent fragility of OI bone makes this operation more complex in OI patients than it does with patients who have adolescent idiopathic scoliosis, but normal bone density. Despite the risks, however, three Nemours–duPont orthopedic surgeons who specialize in surgical intervention for osteogenesis imperfecta recommend operating if the curve is greater than 50° after a child is past peak height velocity, as the spines curve can continue to worsen even into adulthood.: 104 Due to the risk involved, the same surgeons recommend that surgery for basilar impressions and basilar invaginations should only be carried out if the pressure being exerted on the spinal cord and brain stem is causing actual neurological symptoms.: 106–107 Once basilar invagination has become symptomatic, only surgery can halt or reverse the progression of neurological deficits.: 345
Physical therapy
Physical therapy is generally recommended, however individualized protocols are required due to the variability of OI.: 378 Physical therapy is used to strengthen muscles, improve motility, improve flexibility, and help with weight maintenance, although it must be done in a gentle manner to minimize the risk of bone fracture.: 378 In people with OI, exercise often involves water aerobics, light resistance exercises, and walking, if the patient is able.: 378 However, even in patients with mild OI, contact sports, as well as activities likely to put unnecessary stress on the joints, such as jumping, are contraindicated due to the risks they pose.: 378 Individuals with more limited mobility are encouraged to change positions regularly throughout the day; people who sit in a wheelchair most or all of the day are recommended to get out of it every two hours, as a form of exercise, to decrease stiffness, and to prevent pressure ulcers.: 378 Individuals with moderate to severe OI, who require assistive mobility devices and adapted vehicles, face significant barriers to access wheelchair-accessible pools or gyms—they either may not have any in their area, nor the means to get there.: 378 Obesity may be more likely to present among those with severe OI, (especially after the age of 20,) and can, in some, cause further declines in mobility.: 371, 373 Tilt table whole body vibration may also be done to increase the mobility of long-term immobilized (bedridden) patients with OI; in at least two cases it helped bedridden children to be able to sit upright.
Teeth
More than 1 in 2 people with OI also have dentinogenesis imperfecta (DI)—a congenital abnormality in the formation of dentin, one of the four major components of the human tooth. Dental treatment may pose as a challenge as a result of the various deformities, skeletal and dental, due to OI. Children with OI should go for a dental check-up as soon as their teeth erupt; this may minimize tooth structure loss as a result of abnormal dentine, and they should be monitored regularly to preserve their teeth and oral health.Many people with OI are treated with bisphosphonates, and there are several possible related complications with dental procedures, for example, medication-related osteonecrosis of the jaw (MRONJ). However, no report of bisphosphonate-related MRONJ in either a child or adult with OI was found in a 2016 Cochrane review of the safety and efficacy of bisphosphonates for OI.
In development
Monoclonal antibodies
Monoclonal antibodies have long been considered for OI, but as of 2021, such therapy has not been approved for OI, neither in the European Union nor in the United States. Thus, it is unclear whether they are safe or effective. Among the monoclonal antibodies that have been studied are romosozumab (targets sclerostin, by Amgen), fresolimumab (TGF-β, Sanofi), blosozumab (sclerostin, Lilly), and setrusumab (sclerostin, begun by Novartis).Setrusumab, formerly known as BPS-804, is a monoclonal antibody that targets sclerostin, and has been studied in OI specifically more than any of the others. In the body, sclerostin binds to the LRP5 and LRP6 receptors, resulting in inhibition of the Wnt signaling pathway. This decreases bone formation, and is not a problem when a person has healthy bones. It is thought, though, that decreasing the concentration of sclerostin in the body may lead to the formation of more bone, and that is the premise as to why monoclonal antibodies that reduce the concentrations of naturally occurring sclerostin may help strengthen OI bone. While setrusumab was first developed at the pharmaceutical company Novartis, Novartis sold its rights to patent the drug to Mereo Biopharma in 2015, who has continued its development in conjunction with Ultragenyx. In 2019, Mereo announced that it had concluded collecting data for its phase II-B trial of setrusumab; the study was completed on 12 November 2020. Despite the trial data failing to show improvements in bone density on QCT scans, its primary goal, there were improvements on DXA scans. In a September 2020 press release, Mereo said it was seeking to do a phase III trial in 2021, and had received a Rare Pediatric Disease (RPD) designation from the US Food and Drug Administration (FDA).Romosozumab, which also is a monoclonal antibody targeting sclerostin, is an approved drug in the US and EU for the treatment of osteoporosis. The pharmaceutical industry analyst Evercore has remarked that "it could wipe out setrusumabs economics", as romosozumab is priced more cheaply than a drug for a rare disease would be, claiming that it will be "vital" to Ultragenyxs profit margins to prove its setrusumab is more efficacious than romosozumab for OI. A clinical trial evaluating romosozumabs efficacy in OI began in September 2020 and as of September 2021 is ongoing. Ultragenyx predicts that its phase 2/3 trials for setrusumab will be completed in 2026.
Prevention
As a genetic disorder, the mainstay of twenty-first century prevention of osteogenesis imperfecta is based on preventing affected individuals from being born in the first place. Genetic counseling can help patients and their families determine what types of screening, if any, are right for their situation. Patients can consider preimplantation genetic diagnosis after in vitro fertilization to select fertilized embryos which are not affected.: 247–248 Common mutations which cause OI may be caught by exome sequencing and whole genome sequencing. If a pregnancy is already in progress, the procedure of amniocentesis may be undergone to see if the fetus is affected.: 247 If affected, it is up to the family to consider whether or not they want to terminate the pregnancy and try again—raising questions of medical ethics and a womans right to choose.Without intervention, patients with the most common mutations causing osteogenesis imperfecta have a 50% chance per gestation of passing on the disorder, as these mutations are inherited in an autosomal dominant pattern of Mendelian inheritance.: 247 Those with the rare autosomal recessive forms of OI have a 25% chance of passing on the disorder. Genetic testing of the affected members of the family can be used to determine which inheritance pattern applies.: 101 As OI type I may be difficult to detect in a newborn child, the cord blood of the child can be tested to determine if it has been passed on if the family has already rejected the more invasive genetic screening methods.: 247 In more severe cases, the diagnosis may be able to be done via ultrasound, especially if OI is already a possibility.: 248 An ethical concern with prenatal screening for OI often arises when parents inquire as to how severely affected their child will be—such questions are as yet difficult to answer conclusively.: 382 If a non-affected person has already had a child with OI, there is a greater likelihood (although still quite remote), that their future children will have OI due to genetic mosaicism.: 100, 1513 The disability rights critique of prenatal screening for OI, held by some bioethicists and some affected individuals, negatively compares it to eugenics, with even those not opposed to abortion opposing selective abortions on the ethical ground that their existence betrays the belief that the lives of those with OI are "less worth living [and] less valuable".: 388
Prognosis
The prognosis of osteogenesis imperfecta depends entirely on its type (see § Classification).
Life expectancy
In the mild form of the disorder, type I, the life expectancy of patients is near that of the general population.: 461 In type II, however, patients only very rarely live past the age of two, and typically die in their first weeks of life.: 1511 Assessment of the life expectancy of patients with types III and IV is more complicated, as lifestyle choices can cause fatally traumatic injuries that would not have otherwise occurred, or not been fatal in the general population. Life expectancy in type IV OI is thought to be close to normal, but in type III it is lower than in the general population.A 2016 study of data in Denmarks National Patient Register found that across all types of OI, all-cause mortality was three times higher, leading to a loss of around seven years in females and nine years in males. A 1996 study published in the British Medical Journal found that mortality in type III OI is significantly higher, with many patients dying in their 20s, 30s, and 40s; patients who survive to the age of 10 were further found to have longer life expectancy than newborns.
Mobility
People with mild (type I) OI as adults need few pieces of adaptive equipment, although in infancy they reach motor milestones at a significant delay compared to the general population.: 477 With adaptive equipment such as crutches, motorized wheelchairs, splints, reach extenders, and/or modifications to the home, many individuals with moderate to severe OI can achieve or maintain a significant degree of independence.: 488 With treatment and physical therapy, the maximum levels of mobility are expected to be unassisted community walking for type I, household or exercise walking for type III, and household or community walking for type IV; due to the variability of OI between individuals, mobility achieved varies and may be below this expected maximum.: 476
Epidemiology
In the United States, the incidence of osteogenesis imperfecta is estimated to be one per 20,000 live births. An estimated 20,000 to 50,000 people are affected by OI in the United States.The most common types are I, II, III, and IV, while the rest are very rare. Type I is the most common and has been reported to be around three times more common than type II. The prevalence of types III and IV is less certain. In a 1989 study in Denmark, type I was found to comprise 71% of cases and type II 12% of cases, with other types comprising the other 17%. In a 2015 study in Sweden, type I was nearly six times more common than type III and nearly four times more common than type IV.Most people with OI receive it from a parent, but in many cases, it is a brand new (de novo or "sporadic") mutation in a family. Among a study of patients with survivable types of OI, OI type III is most often de novo (85%), followed by type IV (50%) and type I (34%).: Table 1 Some populations can have a higher incidence of OI than would be otherwise expected if they have a larger than average number of carriers of the recessive forms of the disease.: 20–21
History
The condition, or types of it, has had various other names over the years and in different nations; "osteogenesis imperfecta" has, however, been the most widely accepted name for the condition since the late 20th century. Among some of the most common alternatives are "fragilitas ossium"; "Ekman–Lobstein syndrome", and "Vrolik syndrome", both eponyms; and, the colloquialism, "brittle bone disease".
Earliest recorded cases
OI has been identified in an ancient Egyptian infant mummified in around 1000 BC, originally dismissed by archaeologists as containing the remains of a monkey.: 161 The Norse king Ivar the Boneless, who lived c. 800 CE, is speculated to have had OI as well.Nicolas de Malebranche is oft credited as being the first person to describe the physical characteristics of OI in his 1688 book The Search after Truth, in which he describes a man who has had his "bones broken in the places a murderers would be" all his life. His confident description of the pathology of the disorder, however, which creates what he termed «enfants monstrueux» ("monstrous children"), is scientifically void—he wrote that it was due to the mothers antepartum viewership of a public execution by breaking wheel.: 683 : 165–168 The earliest modern scientific studies of OI began in 1788 by Olof Jakob Ekman, who described the condition, which he termed "osteomalacia congenital", in his doctoral thesis and mentioned cases of it going back to 1678, all in the same family, through three generations. Ekmans description of the condition mentioned dwarfism, bone fragility, and bowing of the long bones.: 763 In 1831, Edmund Axmann gave a detailed description of it in himself and his two brothers, being the first to mention blue sclerae as a characteristic sign of OI.: 683 Jean Lobstein first described the mild form of the condition, today known as type I, in 1833, calling it "osteopsathyrosis idiopathica".: 347 It was not until 1912 that hearing loss was positively recognized as a symptom of OI, first mentioned in a brief paper by the English physician Charles Allen Adair-Dighton.: 168–169
Of the term
Willem Vrolik, a Dutch anatomist who was also curator of the "Museum Vrolikianum", which made him privy to many specimens of bodies having birth defects, coined the term "osteogenesis imperfecta": 683 in his bilingual Latin and Dutch language book on teratology, Illustrations of Human and Mammalian Embryogenesis, first published in 1849.Included is a description of the remains of an infant who had what is now known as perinatally fatal OI type II: 347 : 5 (as verified in a 1998 re-examination of the remains by Baljet et al.). The remains were first given to Vroliks father, who could not make sense of them. Vrolik described poorly mineralized bones, bowed long bones, and fractures in various states of healing. Vrolik correctly determined that what he termed OI in the infant was not caused by secondary rickets, but a congenital abnomality causing primary osteopenia; he theorized this was due to a lack of "intrinsic generative energy".
Of its classification
Classification of OI has also evolved as scientific understanding of it has improved. Before the advent of modern genetic testing, OI was classified in two broad groups: osteogenesis imperfecta congenita, and osteogenesis imperfecta tarda, a division first proposed by the German physician E. Looser in 1906. Congenita was used to describe the modern clinical types II, III, and some cases of IV, where upon birth the condition was obvious, either due to bowing of the limbs or due to fractures sustained in utero. Tarda was used to classify the modern OI type I and some cases of type IV, where the inherent fragility of the bones did not become clear until long after birth. The idea that these "late" and "prenatal" forms were manifestations of the same disorder was first proposed in 1897 by Martin Benno Schmidt; by the 1950s this fact was well accepted.: 346 The modern system of four types (I, II, III, IV), meanwhile, were introduced in a paper by David Sillence, Alison Senn, and David Danks in the Journal of Medical Genetics in 1979, and have since become standard terms among doctors, patients, and researchers. The modern genetic types, (those with numbers greater than IV,) have come into use as more and more recessively inherited forms of OI have been discovered since the discovery of the first one by Roy Morello et al. in 2006. In 2010, the International Nomenclature Group for Constitutional Disorders of the Skeleton (INCDS) "freed" the Sillence types from molecular reference, acquiescing to their new clinical-first role in the wake of what was to them a "surprising" increase in the number of genetic causes of OI.Writing for the Annual Review of Genetics in 2012, Drs. Peter Byers and Shawna M. Pyott lamented how the expansion of the number of types to include genetic types has created a system that "grew like Topsy".: 492 They suggest that it may indeed be impossible to create a system which is useful for clinicians and which accurately describes the genetic cause of a persons OI, with attempts always prioritizing one use at the expense of the other.: 492
Society and culture
Much medical research has been done into the causes of osteogenesis imperfecta, benefiting not only those with OI but medicine more broadly; in the ten years between 2006 and 2016, the many discoveries of non-collagen related recessive gene mutations, which still led in those who have them to the clinical signs of OI, led to numerous breakthroughs in medical understanding of the process of healthy bone development.
Other animals
In dogs, OI is an autosomal recessive condition, meaning that dogs with two copies of the allele will be affected. Many breed organizations and veterinarians offer OI tests to tell if a dog is a carrier of OI. Dogs who are heterozygous for OI should only be bred to non-carriers. Homozygous carriers should never be bred, unless it is to a non-carrier.Naturally occurring mutations causing OI have been found in Golden Retrievers, Dachshunds, and Beagles. OI has also been identified in zebrafish and mice.Although dogs, mice, fish, and humans are not genetically identical, some of these animal models have been officially recognized to represent the varying types of OI in humans. For example, homozygous oim/oim mice experience spontaneous bone fractures, small body size, and kyphosis, making them a model of OI type III. Meanwhile, heterozygous oim/+ mice appear normal but have bones which are quite a bit weaker than wild mice, making them a model for OI type I |
Osteogenesis imperfecta | . As in human OI, the location on the gene which is mutated affects the severity of resulting disease—the G859C Col1a1 mouse is a model for OI type II as affected mice all die in the perinatal period.Animal testing on identified animal models may lead to human therapies for OI.
Explanatory notes
References
External links
"Osteogenesis Imperfecta Overview". NIH Osteoporosis and Related Bone Diseases — National Resource Center. National Institutes of Health, U.S. Department of Health and Human Services. |
Osteopetrosis | Osteopetrosis, literally "stone bone", also known as marble bone disease or Albers-Schönberg disease, is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle, or osteomalacia, in which the bones soften. Osteopetrosis can cause bones to dissolve and break.It is one of the hereditary causes of osteosclerosis. It is considered to be the prototype of osteosclerosing dysplasias. The cause of the disease is understood to be malfunctioning osteoclasts and their inability to resorb bone. Although human osteopetrosis is a heterogeneous disorder encompassing different molecular lesions and a range of clinical features, all forms share a single pathogenic nexus in the osteoclast. The exact molecular defects or location of the mutations taking place are unknown. Osteopetrosis was first described in 1903, by German radiologist Albers-Schönberg.
Signs and symptoms
Despite this excess bone formation, people with osteopetrosis tend to have bones that are more brittle than normal. Mild osteopetrosis may cause no symptoms, and present no problems.
However, serious forms can result in the following:
Stunted growth, deformity, and increased likelihood of fractures
Patients experience anemia, recurrent infections, and hepatosplenomegaly due to bone expansion leading to bone marrow narrowing and extramedullary hematopoiesis
It can also result in blindness, facial paralysis, and deafness, due to the increased pressure put on the nerves by the extra bone
Abnormal cortical bone morphology
Abnormal form of the vertebral bodies
Abnormality of temperature regulation
Abnormality of the ribs
Abnormality of vertebral epiphysis morphology
Bone pain
Cranial nerve paralysis
Craniosynostosis
Hearing impairment
Hypocalcemia
Malignant infantile osteopetrosis
Autosomal recessive osteopetrosis (ARO), also known as malignant infantile osteopetrosis or infantile malignant osteopetrosis (IMO), is a rare type of skeletal dysplasia characterized by a distinct radiographic pattern of overall increased density of the bones with fundamental involvement of the medullary portion. Infantile osteopetrosis typically manifests in infancy. Diagnosis is principally based on clinical and radiographic evaluation, confirmed by gene analysis where applicable. As a result of medullary canal obliteration and bony expansion, grave pancytopenia, cranial nerve compression, and pathologic fractures may ensue. The prognosis is poor if untreated. The classic radiographic features include endobone or "bone-within-bone" appearance in the spine, pelvis and proximal femora, upper limbs, and short tubular bones of the hand. Additionally, there is the Erlenmeyer flask deformity type 2 which is characterized by the absence of normal diaphysial metaphysical modeling of the distal femora with abnormal radiographic appearance of trabecular bone and alternating radiolucent metaphyseal bands.The precise and early diagnosis of infantile osteopetrosis is important for management of complications, genetic counselling, and timely institution of appropriate treatment, namely hematopoietic stem cell transplantation (HSCT), which offers a satisfactory treatment modality for a considerable percentage of infantile osteopetrosis. Amelioration of radiographic bone lesions after HSCT in infantile osteopetrosis has been proposed as an important indicator of success of the therapy. A few publications with limited study participants have demonstrated the resolution of skeletal radiographic pathology following HSCT.
Adult osteopetrosis
Autosomal dominant osteopetrosis (ADO) is also known as Albers-Schonberg disease. Most do not know they have this disorder because most individuals do not show any symptoms. However, the ones that do show symptoms will typically have a curvature of the spine (scoliosis), and multiple bone fractures. There are two types of adult osteopetrosis based on the basis of radiographic, biochemical, and clinical features.
Many patients will have bone pains. The defects are very common and include neuropathies due to cranial nerve entrapment, osteoarthritis, and carpal tunnel syndrome. About 40% of patients will experience recurrent fractures of their bones. 10% of patients will have osteomyelitis of the mandible.
Causes
The various types of osteopetrosis are caused by genetic changes (mutations) in one of at least ten genes. There is nothing a parent can do before, during or after a pregnancy to cause osteopetrosis in a child.The genes associated with osteopetrosis are involved in the development and/or function of osteoclasts, cells that break down bone tissue when old bone is being replaced by new bone (bone remodeling). This process is necessary to keep bones strong and healthy. Mutations in these genes can lead to abnormal osteoclasts, or having too few osteoclasts. If this happens, old bone cannot be broken down as new bone is formed, so bones become too dense and prone to breaking.
Mutations in the CLCN7 gene cause most cases of autosomal dominant osteopetrosis, 10-15% of cases of autosomal recessive osteopetrosis (the most severe form), and all known cases of intermediate autosomal osteopetrosis.
Mutations in the TCIRG1 gene cause about 50% of cases of autosomal recessive osteopetrosis.
Mutations in the IKBKG gene cause X-linked osteopetrosis.
Mutations in other genes are less common causes of osteopetrosis.
In about 30% percent of affected people, the cause is unknown.Normally, bone growth is a balance between osteoblasts (cells that create bone tissue) and osteoclasts (cells that destroy bone tissue). Those with osteopetrosis have a deficiency of osteoclasts, meaning too little bone is being resorbed, resulting in too much bone being created.
Gene variation
Mechanisms
Normal bone growth is achieved by a balance between bone formation by osteoblasts and bone resorption (breakdown of bone matrix) by osteoclasts. In osteopetrosis, the number of osteoclasts may be reduced, normal, or increased. Most importantly, osteoclast dysfunction mediates the pathogenesis of this disease.Osteopetrosis is caused by underlying mutations that interfere with the acidification of the osteoclast resorption pit, for example due to a deficiency of the carbonic anhydrase enzyme encoded by the CA2 gene. Carbonic anhydrase is required by osteoclasts for proton production. Without this enzyme hydrogen ion pumping is inhibited and bone resorption by osteoclasts is defective, as an acidic environment is needed to dissociate calcium hydroxyapatite from the bone matrix. As bone resorption fails while bone formation continues, excessive bone is formed.Mutations in at least nine genes cause the various types of osteopetrosis. Mutations in the CLCN7 gene are responsible for about 75 percent of cases of autosomal dominant osteopetrosis, 10 to 15 percent of cases of autosomal recessive osteopetrosis, and all known cases of intermediate autosomal osteopetrosis. TCIRG1 gene mutations cause about 50 percent of cases of autosomal recessive osteopetrosis. Mutations in other genes are less common causes of autosomal dominant and autosomal recessive forms of the disorder. The X-linked type of osteopetrosis, OL-EDA-ID, results from mutations in the IKBKG gene. In about 30 percent of all cases of osteopetrosis, the cause of the condition is unknown.The genes associated with osteopetrosis are involved in the formation, development, and function of specialized cells called osteoclasts. These cells break down bone tissue during bone remodeling, a normal process in which old bone is removed and new bone is created to replace it. Bones are constantly being remodeled, and the process is carefully controlled to ensure that bones stay strong and healthy.
Mutations in any of the genes associated with osteopetrosis lead to abnormal or missing osteoclasts. Without functional osteoclasts, old bone is not broken down as new bone is formed. As a result, bones throughout the skeleton become unusually dense. The bones are also structurally abnormal, making them prone to fracture. These problems with bone remodeling underlie all of the major features of osteopetrosis.
Diagnosis
The differential diagnosis of osteopetrosis includes other disorders that produce osteosclerosis. They constitute a wide array of disorders with clinically and radiologically diverse manifestations. Among the differential diagnosis are hereditary ostoesclerosing dysplasias such as; neuropathic infantile osteopetrosis, infantile osteopetrosis with renal tubular acidosis, infantile osteopetrosis with immunodeficiency, infantile osteopetrosis with leukocyte adhesion deficiency syndrome (LAD-III), pyknodysostosis (osteopetrosis acro-osteolytica), osteopoikilosis (Buschke–Ollendorff syndrome), osteopathia striata with cranial sclerosis, mixed sclerosing skeletal dysplasias, progressive diaphyseal dysplasia (Camurati–Engelmann disease), SOST-related sclerosing skeletal dysplasias. Besides, the differential diagnosis includes acquired conditions that induce osteosclerosis such as osteosclerotic metastasis notably carcinomas of the prostate gland and breast, Pagets disease of bone, myelofibrosis (primary disorder or secondary to intoxication or malignancy), Erdheim-Chester disease, osteosclerosing types of osteomyelitis, sickle cell disease, hypervitaminosis D, and hypoparathyroidism.
Treatment
It was the first genetic disease treated with hematopoietic stem cell transplantation (osteoclasts are derived from hematopoietic precursors). There is no cure, although curative therapy with bone marrow transplantion is being investigated in clinical trials. It is believed the healthy marrow will provide cells from which osteoclasts will develop. If complications occur in children, patients can be treated with vitamin D. Gamma interferon has also been shown to be effective, and it can be associated to vitamin D. Erythropoetin has been used to treat any associated anemia. Corticosteroids may alleviate both the anemia and stimulate bone resorption. Fractures and osteomyelitis can be treated as usual. Treatment for osteopetrosis depends on the specific symptoms present and the severity in each person. Therefore, treatment options must be evaluated on an individual basis. Nutritional support is important to improve growth and it also enhances responsiveness to other treatment options. A calcium-deficient diet has been beneficial for some affected people.Treatment is necessary for the infantile form:
Vitamin D (calcitriol) appears to stimulate dormant osteoclasts, which stimulates bone resorption
Gamma interferon can have long-term benefits. It improves white blood cell function (leading to fewer infections), decreases bone volume, and increases bone marrow volume.
Erythropoietin can be used for anemia, and corticosteroids can be used for anemia and to stimulate bone resorption.Bone marrow transplantation (BMT) improves some cases of severe, infantile osteopetrosis associated with bone marrow failure, and offers the best chance of longer-term survival for individuals with this type.In pediatric (childhood) osteopetrosis, surgery is sometimes needed because of fractures. Adult osteopetrosis typically does not require treatment, but complications of the condition may require intervention. Surgery may be needed for aesthetic or functional reasons (such as multiple fractures, deformity, and loss of function), or for severe degenerative joint disease.
Prognosis
The long-term-outlook for people with osteopetrosis depends on the subtype and the severity of the condition in each person. The severe infantile forms of osteopetrosis are associated with shortened life expectancy, with most untreated children not surviving past their first decade. Bone marrow transplantation seems to have cured some infants with early-onset disease. However, the long-term prognosis after transplantation is unknown. For those with onset in childhood or adolescence, the effect of the condition depends on the specific symptoms (including how fragile the bones are and how much pain is present). Life expectancy in the adult-onset forms is normal.
Prevalence
Approximately eight to 40 children are born in the United States each year with the malignant infantile type of osteopetrosis. One in every 100,000 to 500,000 individuals is born with this form of osteopetrosis. Higher rates have been found in Denmark and Costa Rica. Males and females are affected in equal numbers.The adult type of osteopetrosis affects about 1,250 individuals in the United States. One in every 200,000 individuals is affected by the adult type of osteopetrosis. Higher rates have been found in Brazil. Males and females are affected in equal numbers.Osteopetrosis affects one newborn out of every 20,000 to 250,000 worldwide, but the odds are much higher in the Russian region of Chuvashia (1 of every 3,500–4,000 newborns) due to genetic traits of the Chuvash people.
Recent research
Recent research demonstrated that the systematic administration of RANKL for one month to Rankl(-/-) mice, which closely resemble the human disease, significantly improved the bone phenotype and has beneficial effects on bone marrow, spleen and thymus; major adverse effects arise only when mice are clearly overtreated. Overall, it provided evidence that the pharmacological administration of RANKL represents the appropriate treatment option for RANKL-deficient ARO patients, to be validated in a pilot clinical trial.Interferon gamma-1b is FDA-approved to delay the time to disease progression in patients with severe, malignant osteopetrosis.
Notable cases
Laurel Burch
Lil Bub
References
Bibliography
== External links == |
Otitis externa | Otitis externa, also called swimmers ear, is inflammation of the ear canal. It often presents with ear pain, swelling of the ear canal, and occasionally decreased hearing. Typically there is pain with movement of the outer ear. A high fever is typically not present except in severe cases.Otitis externa may be acute (lasting less than six weeks) or chronic (lasting more than three months). Acute cases are typically due to bacterial infection, and chronic cases are often due to allergies and autoimmune disorders. the most common cause of Otitis externa is bacterial. Risk factors for acute cases include swimming, minor trauma from cleaning, using hearing aids and ear plugs, and other skin problems, such as psoriasis and dermatitis. People with diabetes are at risk of a severe form of malignant otitis externa. Diagnosis is based on the signs and symptoms. Culturing the ear canal may be useful in chronic or severe cases.Acetic acid ear drops may be used as a preventive measure. Treatment of acute cases is typically with antibiotic drops, such as ofloxacin or acetic acid. Steroid drops may be used in addition to antibiotics. Pain medications such as ibuprofen may be used for the pain. Antibiotics by mouth are not recommended unless the person has poor immune function or there is infection of the skin around the ear. Typically, improvement occurs within a day of the start of treatment. Treatment of chronic cases depends on the cause.Otitis externa affects 1–3% of people a year; more than 95% of cases are acute. About 10% of people are affected at some point in their lives. It occurs most commonly among children between the ages of seven and twelve and among the elderly. It occurs with near equal frequency in males and females. Those who live in warm and wet climates are more often affected.
Signs and symptoms
Tenderness of pinna is the predominant complaint and the only symptom directly related to the severity of acute external otitis. Unlike other forms of ear infections, we observe tenderness in outer ear i.e., the pain of acute external otitis is worsened when the outer ear is touched or pulled gently. Pushing the tragus, the tablike portion of the auricle that projects out just in front of the ear canal opening, also typically causes pain in this condition as to be diagnostic of external otitis on physical examination. People may also experience ear discharge and itchiness. When enough swelling and discharge in the ear canal is present to block the opening, external otitis may cause temporary conductive hearing loss.Because the symptoms of external otitis lead many people to attempt to clean out the ear canal (or scratch it) with slim implements, self-cleaning attempts generally lead to additional traumas of the injured skin, so rapid worsening of the condition often occurs.
Causes
The two factors that are required for external otitis to develop are (1) the presence of germs that can infect the skin and (2) impairments in the integrity of the skin of the ear canal that allow an infection to occur. If the skin is healthy and uninjured, only exposure to a high concentration of pathogens, such as submersion in a pond contaminated by sewage, is likely to set off an episode. However, if there are chronic skin conditions that affect the ear canal skin, such as atopic dermatitis, seborrheic dermatitis, psoriasis or abnormalities of keratin production, or if there has been a break in the skin from trauma, even the normal bacteria found in the ear canal may cause infection and full-blown symptoms of external otitis.Fungal ear canal infections, also known as otomycosis, range from inconsequential to extremely severe. Fungi can be saprophytic, in which there are no symptoms and the fungus simply co-exists in the ear canal in a harmless parasitic relationship with the host, in which case the only physical finding is the presence of a fungus. If the fungus begins active reproduction, the ear canal can fill with dense fungal debris, causing pressure and ever-increasing pain that is unrelenting until the fungus is removed from the canal and anti-fungal medication is used. Most antibacterial ear drops also contain a steroid to hasten resolution of canal edema and pain. Unfortunately, such drops make the fungal infection worse. Prolonged use of them promotes the growth of fungus in the ear canal. Antibacterial ear drops should be used for a maximum of one week, but 5 days is usually enough. Otomycosis responds more than 95% of the time to a three-day course of the same over-the-counter anti-fungal solutions used
for athletes foot.
Swimming
Swimming in polluted water is a common way to contract swimmers ear, but it is also possible to contract swimmers ear from water trapped in the ear canal after a shower, especially in a humid climate. Prolonged swimming can saturate the skin of the canal, compromising its barrier function and making it more susceptible to further damage if the ear is instrumented with cotton swabs after swimming. Constriction of the ear canal from bone growth (Surfers ear) can trap debris leading to infection. Saturation divers have reported otitis externa during occupational exposure.
Objects in ear
Even without exposure to water, the use of objects such as cotton swabs or other small objects to clear the ear canal is enough to cause breaks in the skin, and allow the condition to develop. Once the skin of the ear canal is inflamed, external otitis can be drastically enhanced by either scratching the ear canal with an object or by allowing water to remain in the ear canal for any prolonged length of time.
Infections
The majority of cases are due to Pseudomonas aeruginosa and Staphylococcus aureus, followed by a great number of other gram-positive and gram-negative species. Candida albicans and Aspergillus species are the most common fungal pathogens responsible for the condition.
Diagnosis
When the ear is inspected, the canal appears red and swollen in well-developed cases. The ear canal may also appear eczema-like, with scaly shedding of skin. Touching or moving the outer ear increases the pain, and this maneuver on physical exam is important in establishing the clinical diagnosis. It may be difficult to see the eardrum with an otoscope at the initial examination because of narrowing of the ear canal from inflammation and the presence of drainage and debris. Sometimes the diagnosis of external otitis is presumptive and return visits are required to fully examine the ear. The culture of the drainage may identify the bacteria or fungus causing infection, but is not part of the routine diagnostic evaluation. In severe cases of external otitis, there may be swelling of the lymph node(s) directly beneath the ear.The diagnosis may be missed in most early cases because the examination of the ear, with the exception of pain with manipulation, is nearly normal. In some early cases, the most striking visual finding is the lack of earwax. As a moderate or severe case of external otitis resolves, weeks may be required before the ear canal again shows a normal amount of it.
Classification
In contrast to the chronic otitis externa, acute otitis externa (AOE) is predominantly a bacterial infection, occurs suddenly, rapidly worsens, and becomes painful. The ear canal has an abundant nerve supply, so the pain is often severe enough to interfere with sleep. Wax in the ear can combine with the swelling of the canal skin and the associated pus to block the canal and dampen hearing, creating a temporary conductive hearing loss. In more severe or untreated cases, the infection can spread to the soft tissues of the face that surround the adjacent parotid gland and the jaw joint, making chewing painful. In its mildest forms, otitis externa is so common that some ear nose and throat physicians have suggested that most people will have at least a brief episode at some point in life.
The skin of the bony ear canal is unique, in that it is not movable but is closely attached to the bone, and it is almost paper-thin. For these reasons, it is easily abraded or torn by even minimal physical force. Inflammation of the ear canal skin typically begins with a physical insult, most often from injury caused by attempts at self-cleaning or scratching with cotton swabs, pen caps, fingernails, hair pins, keys, or other small implements. Another causative factor for acute infection is prolonged water exposure in the forms of swimming or exposure to extreme humidity, which can compromise the protective barrier function of the canal skin, allowing bacteria to flourish, hence the name "swimmers ear".
Prevention
The strategies for preventing acute external otitis are similar to those for treatment.
Avoid inserting anything into the ear canal: use of cotton buds or swabs is the most common event leading to acute otitis externa. Most normal ear canals have a self-cleaning and self-drying mechanism, the latter by simple evaporation.
After prolonged swimming, a person prone to external otitis can dry the ears using a small battery-powered ear dryer, available at many retailers, especially shops catering to watersports enthusiasts. Alternatively, drops containing dilute acetic acid (vinegar diluted 3:1) or Burows solution may be used. It is especially important not to instrument ears when the skin is saturated with water, as it is very susceptible to injury, which can lead to external otitis.
Avoid swimming in polluted water.
Avoid washing hair or swimming if very mild symptoms of acute external otitis begin
Although the use of earplugs, when swimming and shampooing hair, may help prevent external otitis, there are important details in the use of plugs. Hard and poorly fitting earplugs can scratch the ear canal skin and set off an episode. When earplugs are used during an acute episode, either disposable plugs are recommended, or used plugs must be cleaned and dried properly to avoid contaminating the healing ear canal with infected discharge.According to one source, the use of in-ear headphones during otherwise "dry" exercise in the summer has been associated with the development of swimmers ear since the plugs can create a warm and moist environment inside the ears. The source claims that on-ear or over-ear headphones can be a better alternative for preventing swimmers ear.
Treatment
Medications
Effective solutions for the ear canal include acidifying and drying agents, used either singly or in combination. When the ear canal skin is inflamed from the acute otitis externa, the use of dilute acetic acid may be painful.
Burows solution is a very effective remedy against both bacterial and fungal external otitis. This is a buffered mixture of aluminium sulfate and acetic acid, and is available without prescription in the United States.Ear drops are the mainstay of treatment for external otitis. Some contain antibiotics, either antibacterial or antifungal, and others are simply designed to mildly acidify the ear canal environment to discourage bacterial growth. Some prescription drops also contain anti-inflammatory steroids, which help to resolve swelling and itching. Although there is evidence that steroids are effective at reducing the length of treatment time required, fungal otitis externa (also called otomycosis) may be caused or aggravated by overly prolonged use of steroid-containing drops.Antibiotics by mouth should not be used to treat uncomplicated acute otitis externa. Antibiotics by mouth are not a sufficient response to bacteria which cause this condition and have significant side effects including increased risk of opportunistic infection. In contrast, topical products can treat this condition. Oral anti-pseudomonal antibiotics can be used in case of severe soft tissue swelling extending into the face and neck and may hasten recovery.Although the acute external otitis generally resolves in a few days with topical washes and antibiotics, complete return of hearing and cerumen gland function may take a few more days. Once healed completely, the ear canal is again self-cleaning. Until it recovers fully, it may be more prone to repeat infection from further physical or chemical insult.Effective medications include ear drops containing antibiotics to fight infection, and corticosteroids to reduce itching and inflammation. In painful cases, a topical solution of antibiotics such as aminoglycoside, polymyxin or fluoroquinolone is usually prescribed. Antifungal solutions are used in the case of fungal infections. External otitis is almost always predominantly bacterial or predominantly fungal so that only one type of medication is necessary and indicated.
Cleaning
Removal of debris (wax, shed skin, and pus) from the ear canal promotes direct contact of the prescribed medication with the infected skin and shortens recovery time. When canal swelling has progressed to the point where the ear canal is blocked, ear drops may not penetrate far enough into the ear canal to be effective. The physician may need to carefully insert a wick of cotton or other commercially available, pre-fashioned, absorbent material called an ear wick and then saturate that with the medication. The wick is kept saturated with medication until the canal opens enough that the drops will penetrate the canal without it. Removal of the wick does not require a health professional. Antibiotic ear drops should be dosed in a quantity that allows coating of most of the ear canal and used for no more than 4 to 7 days. The ear should be left open. It is imperative that visualization of an intact tympanic membrane (eardrum) is noted.
Use of certain medications with a ruptured tympanic membrane can cause tinnitus, vertigo, dizziness and hearing loss in some cases.
Prognosis
Otitis externa responds well to treatment, but complications may occur if it is not treated. Individuals with underlying diabetes, disorders of the immune system, or history of radiation therapy to the base of the skull are more likely to develop complications, including malignant otitis externa. In these individuals, rapid examination by an otolaryngologist (ear, nose, and throat physician) is very important.
Chronic otitis externa
Spread of infection to other areas of the body
Necrotizing external otitis
Otitis externa haemorhagica
Necrotizing external otitis
Necrotizing external otitis (malignant otitis externa) is an uncommon form of external otitis that occurs mainly in elderly diabetics, being somewhat more likely and more severe when the diabetes is poorly controlled. Even less commonly, it can develop due to a severely compromised immune system. Beginning as infection of the external ear canal, there is an extension of the infection into the bony ear canal and the soft tissues deep to the bony canal. Unrecognized and untreated, it may result in death. The hallmark of malignant otitis externa (MOE) is unrelenting pain that interferes with sleep and persists even after swelling of the external ear canal may have resolved with topical antibiotic treatment. It can also cause skull base osteomyelitis (SBO), manifested by multiple cranial nerve palsies, described below under the "Treatment" heading.
Natural history
MOE follows a much more chronic and indolent course than ordinary acute otitis externa. There may be granulation involving the floor of the external ear canal, most often at the bony-cartilaginous junction. Paradoxically, the physical findings of MOE, at least in its early stages, are often much less dramatic than those of ordinary acute otitis externa. In later stages, there can be soft tissue swelling around the ear, even in the absence of significant canal swelling. While fever and leukocytosis might be expected in response to bacterial infection invading the skull region, MOE does not cause fever or elevation of white blood count.
Treatment of MOE
Unlike ordinary otitis externa, MOE requires oral or intravenous antibiotics for cure. Pseudomonas is the most common offending pathogen. Diabetes control is also an essential part of treatment. When MOE goes unrecognized and untreated, the infection continues to smolder and over weeks or months can spread deeper into the head and involve the bones of the skull base, constituting skull base osteomyelitis (SBO). Multiple cranial nerve palsies can result, including the facial nerve (causing facial palsy), the recurrent laryngeal nerve (causing vocal cord paralysis), and the cochlear nerve (causing deafness).
The infecting organism is almost always pseudomonas aeruginosa, but it can instead be fungal (aspergillus or mucor). MOE and SBO are not amenable to surgery, but exploratory surgery may facilitate the culture of unusual organism(s) that are not responding to empirically used anti-pseudomonal antibiotics (ciprofloxacin being the drug of choice). The usual surgical finding is diffuse cellulitis without localized abscess formation. SBO can extend into the petrous apex of the temporal bone or more inferiorly into the opposite side of the skull base.The use of hyperbaric oxygen therapy as an adjunct to antibiotic therapy remains controversial.
Complications
As the skull base is progressively involved, the adjacent exiting cranial nerves and their branches, especially the facial nerve and the vagus nerve, may be affected, resulting in facial paralysis and hoarseness, respectively. If both of the recurrent laryngeal nerves are paralyzed, shortness of breath may develop and necessitate tracheotomy. Profound deafness can occur, usually later in the disease course due to relative resistance of the inner ear structures. Gallium scans are sometimes used to document the extent of the infection but are not essential to disease management. Skull base osteomyelitis is a chronic disease that can require months of IV antibiotic treatment, tends to recur, and has a significant mortality rate.
Epidemiology
The incidence of otitis externa is high. In the Netherlands, it has been estimated at 12–14 per 1000 population per year, and has been shown to affect more than 1% of a sample of the population in the United Kingdom over a 12-month period.
History
During the Tektite Project in 1969 there was a great deal of otitis externa. The Diving Medical Officer devised a prophylaxis that came to be known as, "Tektite Solution", equal parts of 15% tannic acid, 15% acetic acid and 50% isopropyl alcohol or ethanol. During Tektite ethanol was used because it was available in the lab for pickling specimens.
Other animals
References
== External links == |
Ovarian hyperstimulation syndrome | Ovarian hyperstimulation syndrome (OHSS) is a medical condition that can occur in some women who take fertility medication to stimulate egg growth, and in other women in very rare cases. Most cases are mild, but rarely the condition is severe and can lead to serious illness or death.
Signs and symptoms
Symptoms are set into 3 categories: mild, moderate, and severe. Mild symptoms include abdominal bloating and feeling of fullness, nausea, diarrhea, and slight weight gain. Moderate symptoms include excessive weight gain (weight gain of greater than 2 pounds per day), increased abdominal girth, vomiting, diarrhea, darker urine, decreased urine output, excessive thirst, and skin and/or hair feeling dry (in addition to mild symptoms). Severe symptoms are fullness/bloating above the waist, shortness of breath, pleural effusion, urination significantly darker or has ceased, calf and chest pains, marked abdominal bloating or distention, and lower abdominal pains (in addition to mild and moderate symptoms).
Complications
OHSS may be complicated by ovarian torsion, ovarian rupture, venous thromboembolism, acute respiratory distress syndrome, electrolytes imbalance, thrombophlebitis and chronic kidney disease. Symptoms generally resolve in 1 to 2 weeks, but will be more severe and persist longer if pregnancy occurs. This is due to human chorionic gonadotropin (hCG) from the pregnancy acting on the corpus luteum in the ovaries in sustaining the pregnancy before the placenta has fully developed. Typically, even in severe OHSS with a developing pregnancy, the duration does not exceed the first trimester.
Cause
Sporadic OHSS is very rare, and may have a genetic component. Clomifene citrate therapy can occasionally lead to OHSS, but the vast majority of cases develop after use of gonadotropin therapy (with administration of FSH), such as Pergonal, and administration of hCG to induce final oocyte maturation and/or trigger oocyte release, often in conjunction with IVF. The frequency varies and depends on a womans risk factors, management, and methods of surveillance. About 5% of treated women may encounter moderate to severe OHSS. Risk factors include polycystic ovary syndrome, young age, low BMI, high antral follicle count, the development of many ovarian follicles under stimulation, extreme elevated serum estradiol concentrations, the use of hCG for final oocyte maturation and/or release, the continued use of hCG for luteal support, and the occurrence of a pregnancy (resulting in hCG production).
Mortality is low, but several fatal cases have been reported.
Medications
Ovarian hyperstimulation syndrome is particularly associated with injection of a hormone called human chorionic gonadotropin (hCG) which is used for inducing final oocyte maturation and/or triggering oocyte release. The risk is further increased by multiple doses of hCG after ovulation and if the procedure results in pregnancy.Using a GnRH agonist instead of hCG for inducing final oocyte maturation and/or release results in an elimination of the risk of ovarian hyperstimulation syndrome, but a slight decrease of the delivery rate of approximately 6%.
Pathophysiology
OHSS has been characterized by the presence of multiple luteinized cysts within the ovaries leading to ovarian enlargement and secondary complications, but that definition includes almost all women undergoing ovarian stimulation. The central feature of clinically significant OHSS is the development of vascular hyperpermeability and the resulting shift of fluids into the third space.As hCG causes the ovary to undergo extensive luteinization, large amounts of estrogens, progesterone, and local cytokines are released. It is almost certain that vascular endothelial growth factor (VEGF) is a key substance that induces vascular hyperpermeability, making local capillaries "leaky", leading to a shift of fluids from the intravascular system to the abdominal and pleural cavity. Supraphysiologic production of VEGF from many follicles under the prolonged effect of hCG appears to be the specific key process underlying OHSS. Thus, while the woman accumulates fluid in the third space, primarily in the form of ascites, she actually becomes hypovolemic and is at risk for respiratory, circulatory (such as arterial thromboembolism since blood is now thicker), and renal problems. Women who are pregnant sustain the ovarian luteinization process through the production of hCG.Avoiding OHSS typically requires interrupting the pathological sequence, such as avoiding the use of hCG. One alternative is to use a GnRH agonist instead of hCG. While this has been repeatedly shown to "virtually eliminate" OHSS risk, there is some controversy regarding the effect on pregnancy rates if a fresh non-donor embryo transfer is attempted, almost certainly due to a luteal phase defect. There is no dispute that the GnRH agonist trigger is effective for oocyte donors and for embryo banking (cryopreservation) cycles.
Classification
OHSS is divided into the categories mild, moderate, severe, and critical.
In mild forms of OHSS the ovaries are enlarged (5–12 cm) and there may be additional accumulation of ascites with mild abdominal distension, abdominal pain, nausea, and diarrhea. In severe forms of OHSS there may be hemoconcentration, thrombosis, distension, oliguria (decreased urine production), pleural effusion, and respiratory distress. Early OHSS develops before pregnancy testing and late OHSS is seen in early pregnancy.
Criteria for severe OHSS include enlarged ovary, ascites, hematocrit > 45%, WBC > 15,000, oliguria, creatinine 1.0-1.5 mg/dl, creatinine clearance > 50 ml/min, liver dysfunction, and anasarca. Critical OHSS includes enlarged ovary, tense ascites with hydrothorax and pericardial effusion, hematocrit > 55%, WBC > 25,000, oligoanuria, creatinine > 1.6 mg/dl, creatinine clearance < 50 ml/min, kidney failure, thromboembolic phenomena, and ARDS.
Prevention
Physicians can reduce the risk of OHSS by monitoring of FSH therapy to use this medication judiciously, and by withholding hCG medication.
Cabergoline confers a significant reduction in the risk of OHSS in high risk women according to a Cochrane review of randomized studies, but the included trials did not report the live birth rates or multiple pregnancy rates. Cabergoline, as well as other dopamine agonists, might reduce the severity of OHSS by interfering with the VEGF system. A systematic review and meta-analysis concluded that prophylactic treatment with cabergoline reduces the incidence, but not the severity of OHSS, without compromising pregnancy outcomes.The risk of OHSS is smaller when using GnRH antagonist protocol instead of GnRH agonist protocol for suppression of ovulation during ovarian hyperstimulation. The underlying mechanism is that, with the GnRH antagonist protocol, initial follicular recruitment and selection is undertaken by endogenous endocrine factors prior to starting the exogenous hyperstimulation, resulting in a smaller number of growing follicles when compared with the standard long GnRH agonist protocol.A Cochrane review found administration of hydroxyethyl starch decreases the incidence of severe OHSS. There was insufficient evidence to support routine cryopreservation and insufficient evidence for the relative merits of intravenous albumin versus cryopreservation. Also, coasting, which is ovarian hyperstimulation without induction of final maturation, does not significantly decrease the risk of OHSS.Volume expanders such as albumin and hydroxyethyl starch solutions act providing volume to the circulatory system
Treatment
Treatment of OHSS depends on the severity of the hyperstimulation.
Mild OHSS can be treated conservatively with monitoring of abdominal girth, weight, and discomfort on an outpatient basis until either conception or menstruation occurs. Conception can cause mild OHSS to worsen in severity.Moderate OHSS is treated with bed rest, fluids, and close monitoring of labs such as electrolytes and blood counts. Ultrasound may be used to monitor the size of ovarian follicles. Depending on the situation, a physician may closely monitor a womens fluid intake and output on an outpatient basis, looking for increased discrepancy in fluid balance (over 1 liter discrepancy is cause for concern). Resolution of the syndrome is measured by decreasing size of the follicular cysts on 2 consecutive ultrasounds.Aspiration of accumulated fluid (ascites) from the abdominal/pleural cavity may be necessary, as well as opioids for the pain. If the OHSS develops within an IVF protocol, it can be prudent to postpone transfer of the pre-embryos since establishment of pregnancy can lengthen the recovery time or contribute to a more severe course. Over time, if carefully monitored, the condition will naturally reverse to normal – so treatment is typically supportive, although a woman may need to be treated or hospitalized for pain, paracentesis, and/or intravenous hydration.
References
Further reading
Delvigne A, Rozenberg S (2002). "Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review". Hum Reprod Update. 8 (6): 559–77. doi:10.1093/humupd/8.6.559. PMID 12498425.
Delvigne A, Rozenberg S (2003). "Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS)". Hum Reprod Update. 9 (1): 77–96. doi:10.1093/humupd/dmg005. PMID 12638783.
== External links == |
Overactive bladder | Overactive bladder (OAB) is a condition where there is a frequent feeling of needing to urinate to a degree that it negatively affects a persons life. The frequent need to urinate may occur during the day, at night, or both. If there is loss of bladder control then it is known as urge incontinence. More than 40% of people with overactive bladder have incontinence. Conversely, about 40% to 70% of urinary incontinence is due to overactive bladder. Overactive bladder is not life-threatening, but most people with the condition have problems for years.The cause of overactive bladder is unknown. Risk factors include obesity, caffeine, and constipation. Poorly controlled diabetes, poor functional mobility, and chronic pelvic pain may worsen the symptoms. People often have the symptoms for a long time before seeking treatment and the condition is sometimes identified by caregivers. Diagnosis is based on a persons signs and symptoms and requires other problems such as urinary tract infections or neurological conditions to be excluded. The amount of urine passed during each urination is relatively small. Pain while urinating suggests that there is a problem other than overactive bladder.Specific treatment is not always required. If treatment is desired pelvic floor exercises, bladder training, and other behavioral methods are initially recommended. Weight loss in those who are overweight, decreasing caffeine consumption, and drinking moderate fluids, can also have benefits. Medications, typically of the anti-muscarinic type, are only recommended if other measures are not effective. They are no more effective than behavioral methods; however, they are associated with side effects, particularly in older people. Some non-invasive electrical stimulation methods appear effective while they are in use. Injections of botulinum toxin into the bladder is another option. Urinary catheters or surgery are generally not recommended. A diary to track problems can help determine whether treatments are working.Overactive bladder is estimated to occur in 7-27% of men and 9-43% of women. It becomes more common with age. Some studies suggest that the condition is more common in women, especially when associated with loss of bladder control. Economic costs of overactive bladder were estimated in the United States at US$12.6 billion and 4.2 billion Euro in 2000.
Signs and symptoms
Overactive bladder is characterized by a group of four symptoms: urgency, urinary frequency, nocturia, and urge incontinence. Urge incontinence is not present in the "dry" classification.Urgency is considered the hallmark symptom of OAB, but there are no clear criteria for what constitutes urgency and studies often use other criteria. Urgency is currently defined by the International Continence Society (ICS), as of 2002, as "Sudden, compelling desire to pass urine that is difficult to defer." The previous definition was "Strong desire to void accompanied by fear of leakage or pain." The definition does not address the immediacy of the urge to void and has been criticized as subjective.Urinary frequency is considered abnormal if the person urinates more than eight times in a day. This frequency is usually monitored by having the person keep a voiding diary where they record urination episodes. The number of episodes varies depending on sleep, fluid intake, medications, and up to seven is considered normal if consistent with the other factors.Nocturia is a symptom where the person complains of interrupted sleep because of an urge to void and, like the urinary frequency component, is affected by similar lifestyle and medical factors. Individual waking events are not considered abnormal, one study in Finland established two or more voids per night as affecting quality of life.Urge incontinence is a form of urinary incontinence characterized by the involuntary loss of urine occurring for no apparent reason while feeling urinary urgency as discussed above. Like frequency, the person can track incontinence in a diary to assist with diagnosis and management of symptoms. Urge incontinence can also be measured with pad tests, and these are often used for research purposes. Some people with urge incontinence also have stress incontinence and this can complicate clinical studies.It is important that the clinician and the person with overactive bladder both reach a consensus on the term, urgency. Some common phrases used to describe OAB include, When Ive got to go, Ive got to go, or When I have to go, I have to rush, because I think I will wet myself. Hence the term, fear of leakage, is an important concept to people.
Causes
The cause of OAB is unclear, and indeed there may be multiple causes. It is often associated with overactivity of the detrusor urinae muscle, a pattern of bladder muscle contraction observed during urodynamics. It is also possible that the increased contractile nature originates from within the urothelium and lamina propria, and abnormal contractions in this tissue could stimulate dysfunction in the detrusor or whole bladder.
Catheter-related irritation
If bladder spasms occur or there is no urine in the drainage bag when a catheter is in place, the catheter may be blocked by blood, thick sediment, or a kink in the catheter or drainage tubing. Sometimes spasms are caused by the catheter irritating the bladder, prostate or penis. Such spasms can be controlled with medication such as butylscopolamine, although most people eventually adjust to the irritation and the spasms go away.
Diagnosis
Diagnosis of OAB is made primarily on the persons signs and symptoms and by ruling out other possible causes such as an infection. Urodynamics, a bladder scope, and ultrasound are generally not needed. Additionally, urine culture may be done to rule out infection. The frequency/volume chart may be maintained and cystourethroscopy may be done to exclude tumor and kidney stones. If there is an underlying metabolic or pathologic condition that explains the symptoms, the symptoms may be considered part of that disease and not OAB.Psychometrically robust self-completion questionnaires are generally recognized as a valid way of measuring a persons signs and symptoms, but there does not exist a single ideal questionnaire. These surveys can be divided into two groups: general surveys of lower urinary tract symptoms and surveys specific to overactive bladder. General questionnaires include: American Urological Association Symptom Index (AUASI), Urogenital Distress Inventory (UDI), Incontinence Impact Questionnaire (IIQ), and Bristol Female Lower Urinary Tract Symptoms (BFLUTS). Overactive bladder questionnaires include: Overactive Bladder Questionnaire (OAB-q), Urgency Questionnaire (UQ), Primary OAB Symptom Questionnaire (POSQ), and the International Consultation on Incontinence Questionnaire (ICIQ).
OAB causes similar symptoms to some other conditions such as urinary tract infection (UTI), bladder cancer, and benign prostatic hyperplasia (BPH). Urinary tract infections often involve pain and hematuria (blood in the urine) which are typically absent in OAB. Bladder cancer usually includes hematuria and can include pain, both not associated with OAB, and the common symptoms of OAB (urgency, frequency, and nocturia) may be absent. BPH frequently includes symptoms at the time of voiding as well as sometimes including pain or hematuria, and all of these are not usually present in OAB. Diabetes insipidus, which causes high frequency and volume, though not necessarily urgency.
Classification
There is some controversy about the classification and diagnosis of OAB. Some sources classify overactive bladder into two different variants: "wet" (i.e., an urgent need to urinate with involuntary leakage) or "dry" (i.e., an urgent need to urinate but no involuntary leakage). Wet variants are more common than dry variants. The distinction is not absolute; one study suggested that many classified as "dry" were actually "wet" and that people with no history of any leakage may have had other syndromes.OAB is distinct from stress urinary incontinence, but when they occur together, the condition is usually known as mixed incontinence.
Management
A recent (2019) systematic review of studies related to urinary incontinence in women found that behavioral therapy, alone or combined with other treatments, is generally more effective than any other single treatment alone. Behavioral therapy as a treatment has been used to improve or cure urgency urinary incontinence, including improving patient satisfaction.
Lifestyle
Treatment for OAB includes nonpharmacologic methods such as lifestyle modification (fluid restriction, avoidance of caffeine), bladder retraining, and pelvic floor muscle (PFM) exercise.
Timed voiding is a form of bladder training that uses biofeedback to reduce the frequency of accidents resulting from poor bladder control. This method is aimed at improving the persons control over the time, place and frequency of urination.
Timed voiding programs involve establishing a schedule for urination. To do this, a person fills in a chart of voiding and leaking. From the patterns that appear in the chart, the person can plan to empty his or her bladder before he or she would otherwise leak. Some individuals find it helpful to use a vibrating reminder watch to help them remember to use the bathroom. Vibrating watches can be set to go off at certain intervals or at specific times throughout the day, depending on the watch. Through this bladder training exercise, the person can alter their bladders schedule for storing and emptying urine.
Medications
A number of antimuscarinic drugs (e.g., darifenacin, hyoscyamine, oxybutynin, tolterodine, solifenacin, trospium, fesoterodine) are frequently used to treat overactive bladder. Long term use, however, has been linked to dementia. β3 adrenergic receptor agonists (e.g., mirabegron, vibegron), may be used, as well. However, both antimuscarinic drugs and β3 adrenergic receptor agonists constitute a second-line treatment due to the risk of side effects.Few people get complete relief with medications and all medications are no more than moderately effective.A typical person with overactive bladder may urinate 12 times per day. Medication may reduce this number by 2-3 and reduce urinary incontinence events by 1-2 per day.
Procedures
Various devices (Urgent PC Neuromodulation System) may also be used. Botulinum toxin A (Botox) is approved by the Food and Drug Administration in adults with neurological conditions, including multiple sclerosis and spinal cord injury. Botulinum Toxin A injections into the bladder wall can suppress involuntary bladder contractions by blocking nerve signals and may be effective for up to 9 months. The growing knowledge of pathophysiology of overactive bladder fuelled a huge amount of basic and clinical research in this field of pharmacotherapy. A surgical intervention involves the enlargement of the bladder using bowel tissues, although generally used as a last resort. This procedure can greatly enlarge urine volume in the bladder.OAB may be treated with electrical stimulation, which aims to reduce the contractions of the muscle that tenses around the bladder and causes urine to pass out of it. There are invasive and non-invasive electrical stimulation options. Non-invasive options include the introduction of a probe into the vagina or anus, or the insertion of an electrical probe into a nerve near the ankle with a fine needle. These non-invasive options appear to reduce symptoms while they are in use, and are better than no treatment, or treatment with drugs, or pelvic floor muscle treatment, but the quality of evidence is low. It is unknown which electrical stimulation option works best. Also, it is unknown whether the benefits last after treatment stops.
Prognosis
Many people with OAB symptoms had those symptoms subside within a year, with estimates as high as 39%, but most have symptoms for several years.
Epidemiology
Earlier reports estimated that about one in six adults in the United States and Europe had OAB. The number of people affected with OAB increases with age, thus it is expected that OAB will become more common in the future as the average age of people living in the developed world is increasing. However, a recent Finnish population-based survey suggested that the number of people affected had been largely overestimated due to methodological shortcomings regarding age distribution and low participation (in earlier reports). It is suspected, then, that OAB affects approximately half the number of individuals as earlier reported.The American Urological Association reports studies showing rates as low as 7% to as high as 27% in men and rates as low as 9% to 43% in women. Urge incontinence was reported as higher in women. Older people are more likely to be affected, and the number of symptoms increases with age.
See also
National Association For Continence
Underactive bladder
References
External links
Sacco E, Bientinesi R, Marangi F, DAddessi A, Racioppi M, Gulino G, Pinto F, Totaro A, Bassi P (2011). "[Overactive bladder syndrome: the social and economic perspective]". Urologia (in Italian). 78 (4): 241–56. doi:10.5301/RU.2011.8886. PMID 22237808. S2CID 36693916.
"Overactive Bladder". MedlinePlus. U.S. National Library of Medicine. |
Ovulation induction | Ovulation induction is the stimulation of ovulation by medication. It is usually used in the sense of stimulation of the development of ovarian follicles to reverse anovulation or oligoovulation.
Scope
The term ovulation induction can potentially also be used for:
Final maturation induction, in the sense of triggering oocyte release from relatively mature ovarian follicles during late follicular phase. In any case, ovarian stimulation (in the sense of stimulating the development of oocytes) is often used in conjunction with triggering oocyte release, such as for proper timing of artificial insemination.
Controlled ovarian hyperstimulation (stimulating the development of multiple follicles of the ovaries in one single cycle), has also appeared in the scope of ovulation induction. Controlled ovarian hyperstimulation is generally part of in vitro fertilization, and the aim is generally to develop multiple follicles (optimally between 11 and 14 antral follicles measuring 2–8 mm in diameter), followed by transvaginal oocyte retrieval, co-incubation, followed by embryo transfer of a maximum of two embryos at a time.
Also, where anovulation or oligovulation is secondary to another disease, the treatment for the underlying disease can be regarded as ovulation induction, by indirectly resulting in ovulation.However, this article focuses on medical ovarian stimulation, during early to mid-follicular phase, without subsequent in vitro fertilization, with the aim of developing one or two ovulatory follicles (the maximum number before recommending sexual abstinence).
Indications
Ovulation induction helps reversing anovulation or oligoovulation, that is, helping women who do not ovulate on their own regularly, such as those with polycystic ovary syndrome (PCOS).
Regimen alternatives
The main alternatives for ovulation induction medications are:
Antiestrogen, causing an inhibition of the negative feedback of estrogen on the pituitary gland, resulting in an increase in secretion of follicle-stimulating hormone. Medications in use for this effect are mainly clomifene citrate and tamoxifen (both being selective estrogen-receptor modulators), as well as letrozole (an aromatase inhibitor.
Follicle-stimulating hormone, directly stimulating the ovaries. In women with anovulation, it may be an alternative after 7 to 12 attempted cycles of antiestrogens (as evidenced by clomifene citrate), since the latter ones are less expensive and more easy to control.
Antiestrogens
Clomifene citrate
Clomifene citrate (or clomid) is the medication which is most commonly used to treat anovulation. It is a selective estrogen-receptor modulator, affecting the hypothalamic–pituitary–gonadal axis to respond as if there was an estrogen deficit in the body, in effect increasing the production of follicle-stimulating hormone. It is relatively easy and convenient to use. Clomifene appears to inhibit estrogen receptors in hypothalamus, thereby inhibiting negative feedback of estrogen on production of follicle-stimulating hormone. It may also result in direct stimulation of the hypothalamic-pituitary axis. It also has an effect on cervical mucus quality and uterine mucosa, which might affect sperm penetration and survival, hence its early administration during the menstrual cycle. Clomifene citrate is a very efficient ovulation inductor, and has a success rate of 67%. Nevertheless, it only has a 37% success rate in inducing pregnancy. This difference may be due to the anti-estrogenic effect which clomifene citrate has on the endometrium, cervical mucus, uterine blood flow, as well as the resulting decrease in the motility of the fallopian tubes and the maturation of the oocytes.
Letrozole
Letrozole has been used for ovarian stimulation by fertility doctors since 2001 because it has fewer side-effects than clomiphene and less chance of multiple gestation. A study of 150 babies following treatment with letrozole or letrozole and follicle-stimulating hormone presented at the American Society of Reproductive Medicine 2005 Conference found no difference in overall abnormalities but did find a significantly higher rate of locomotor and cardiac abnormalities among the group having taken letrozole compared to natural conception. A larger, follow-up study with 911 babies compared those born following treatment with letrozole to those born following treatment with clomiphene. That study also found no significant difference in the rate of overall abnormalities, but found that congenital cardiac anomalies was significantly higher in the clomiphene group compared to the letrozole group.
Dosage is generally 2.5 to 7.5 mg daily over 5 days. A higher dose of up to 12.5 mg per day results in increased follicular growth and a higher number of predicted ovulations, without a detrimental effect on endometrial thickness, and is considered in those who do not respond adequately to a lower dose.
Tamoxifen
Tamoxifen affects estrogen receptors in a similar fashion as clomifene citrate. It is often used in the prevention and treatment of breast cancer. It can therefore also be used to treat patients that have a reaction to clomifene citrate.
Follicle-stimulating hormone
Preparations of follicle-stimulating hormone mainly include those derived from the urine of menopausal women, as well as recombinant preparations. The recombinant preparations are more pure and more easily administered, but they are more expensive. The urinary preparations are equally effective and less expensive, but are not as convenient to administer as they are available in vials versus injection pens.
Gonadotropin-releasing hormone pump
The gonadotropin-releasing hormone pump is used to release doses in a pulsatile fashion. This hormone is synthesised by the hypothalamus and induces the secretion of follicle-stimulating hormone by the pituitary gland. Gonadotropin-releasing hormone must be delivered in a pulsatile fashion to imitate the random secretion of the hypothalamus in order to stimulate the pituitary into secreting luteinizing hormone and follicle-stimulating hormone. The gonadotropin-releasing hormone pump is the size of a cigarette box and has a small catheter. Unlike other treatments, using the gonadotropin-releasing hormone pump usually does not result in multiple pregnancies. Filicori from the University of Bologna suggests that this might be because gonadotrophins are absent when the treatment is initiated, and therefore the hormones released by the pituitary (luteinizing hormone and follicle-stimulating hormone) can still take part in the retro-control of gonadotrophin secretion, mimicking the natural cycle. This treatment can also be used for underweight and/or anorexic patients; it has also been used in certain cases of hyperprolactimenia.
National and regional usage
In the Nordic countries, letrozole is practically the standard initial regimen used for ovulation induction, since no formulation of clomifene is registered for use there.India banned the usage of letrozole in 2011, citing potential risks to infants. In 2012, an Indian parliamentary committee said that the drug controller office colluded with letrozoles makers to approve the drug for infertility in India.
Technique
Although there are many possible additional diagnostic and interventional techniques, protocols for ovulation induction generally consist of:
Determining the first day of the last menstruation, which is termed day 1. In case of amenorrhea, a period can be induced by intake of an oral progestin for 10 days.
Daily administration of the ovulation induction regimen, starting on day 3, 4, or 5, and it is usually taken for 5 days.
Sexual intercourse or artificial insemination by the time of ovulation.
Ultrasonography
During ovulation induction, it is recommended to start at a low dose and monitor the ovarian response with transvaginal ultrasound, including discernment of the number of developing follicles. Initial exam is most commonly started 4–6 days after last pill. Serial transvaginal ultrasound can reveal the size and number of developing follicles. It can also provide presumptive evidence of ovulation such as sudden collapse of the preovulatory follicle, and an increase in fluid volume in the rectouterine pouch. After ovulation, it may reveal signs of luteinization such as loss of clearly defined follicular margins and appearance of internal echoes.
Supernumerary follicles
A cycle with supernumerary follicles is usually defined as one where there are more than two follicles >16 mm in diameter. It is generally recommended to have such cycles cancelled because of the risk of multiple pregnancy (see also the "Risks and side effects" section below). In cancelled cycles, the woman or couple should be warned of the risks in case of supernumerary follicles, and should avoid sexual intercourse or use contraception until the next menstruation. Induction of final maturation (such as done with hCG) may need to be withheld because of increased risk of ovarian hyperstimulation syndrome. The starting dose of the inducing drug should be reduced in the next cycle.Alternatives to cancelling a cycle are mainly:
Aspiration of supernumerary follicles until one or two remain.
Converting the protocol to IVF treatment with embryo transfer of up to two embryos only.
Selective fetal reduction. This alternative confers a high risk of complications.
Proceeding with any multiple pregnancy without fetal reduction, with the ensuing risk of complications. This alternative is not recommended.
Lab tests
The following laboratory tests may be used to monitor induced cycles:
Serum estradiol levels, starting 4–6 days after last pill
Adequacy of luteinizing hormone surge LH surge by urine tests 3 to 4 days after last clomifene pill
Post-coital test 1–3 days before ovulation to check whether there are at least 5 progressive sperm per HPF
Mid-luteal progesterone, with at least 10 ng/ml 7–9 days after ovulation being regarded as adequate.
Final maturation induction
Final maturation induction and release, such as by human chorionic gonadotropin (HCG or hCG) or recombinant luteinizing hormone, results in a predictable time of ovulation, with the interval from drug administration to ovulation depending on the type of drug. This avails for sexual intercourse or intrauterine insemination to conveniently be scheduled at ovulation, the most likely time to achieve pregnancy.As evidenced by clomifene-induced cycles, however, triggering oocyte release has been shown to decrease pregnancy chances compared to frequent monitoring with LH surge tests. Therefore, in such cases, triggering oocyte release is best reserved for women who require intrauterine insemination and in whom luteinizing hormone monitoring proves difficult or unreliable. It may also be used when luteinizing hormone monitoring has no shown an luteinizing hormone surge by cycle day 18 (where cycle day 1 is the first day of the preceding menstruation) and there is an ovarian follicle of over 20 mm in size.
Repeat cycles
Ovulation induction can be repeated every menstrual cycle. For clomifene, the dosage may be increased by 50-mg increments in subsequent cycles until ovulation is achieved. However, at a dosage of 200 mg, further increments are unlikely to increase pregnancy chances.It is not recommended by the manufacturer of clomifene to use it for more than 6 consecutive cycles. In women with anovulation, 7 - 12 attempted cycles of pituitary feedback regimens (as evidenced by clomifene citrate) are recommended before switching to gonadotrophins, since the latter ones are more expensive and less easy to control.It is no longer recommended to perform an ultrasound examination to exclude any significant residual ovarian enlargement before each new treatment cycle.
Risks and side effects
Ultrasound and regular hormone checks mitigate risks throughout the process. However, there are still some risks with the procedure.
Ovarian hyperstimulation syndrome occurs in 5-10% of cases. Symptoms depend on whether the case is mild, moderate, or severe, and can range from bloating and nausea, through to shortness of breathe, pleural effusion, and excessive weight gain (more than 2 pounds per day).
Multiple pregnancy
There is also the risk that more than one egg is produced, leading to twins or triplets. Women with polycystic ovary syndrome may be particularly at risk. Multiple pregnancy occurs in approximately 15-20% of cases following cycles induced with gonadotrophins such as human menopausal gonadotropin and follicle-stimulating hormone. The risks associated with multiple pregnancy are much higher than singleton pregnancy; incidence of perinatal death is seven times higher in triplet births and five times higher in twin births than the risks associated with a singleton pregnancy. It is therefore important to adapt the treatment to each individual patient. If more than one or two ovulatory follicles are detected on ultrasonography, sexual abstinence is recommended.
Alternatives
In vitro fertilization, including controlled ovarian hyperstimulation.
In vitro maturation is letting ovarian follicles mature in vitro, and this technique can potentially be an alternative both to anovulation reversal and oocyte release triggering. Rather, oocytes can mature outside the body, such as prior to IVF. Hence, no (or at least a lower dose of) gonadotropins have to be injected in the body. However, there still isnt enough evidence to prove the effectiveness and security of the technique.
== References == |
Paracentesis | Paracentesis (from Greek κεντάω, "to pierce") is a form of body fluid sampling procedure, generally referring to peritoneocentesis (also called laparocentesis or abdominal paracentesis) in which the peritoneal cavity is punctured by a needle to sample peritoneal fluid.The procedure is used to remove fluid from the peritoneal cavity, particularly if this cannot be achieved with medication. The most common indication is ascites that has developed in people with cirrhosis.
Indications
It is used for a number of reasons:
to relieve abdominal pressure from ascites
to diagnose spontaneous bacterial peritonitis and other infections (e.g. abdominal TB)
to diagnose metastatic cancer
to diagnose blood in peritoneal space in trauma
For ascites
The procedure is often performed in a doctors office or an outpatient clinic. In an experts hands, it is usually very safe, although there is a small risk of infection, excessive bleeding or perforating a loop of bowel. These last two risks can be minimized greatly with the use of ultrasound guidance.The patient is requested to urinate before the procedure; alternately, a Foley catheter is used to empty the bladder. The patient is positioned in the bed with the head elevated at 45–60 degrees to allow fluid to accumulate in lower abdomen. After cleaning the side of the abdomen with an antiseptic solution, the physician numbs a small area of skin and inserts a large-bore needle with a plastic sheath 2 to 5 cm (1 to 2 in) in length to reach the peritoneal (ascitic) fluid. The needle is removed, leaving the plastic sheath to allow drainage of the fluid. The fluid is drained by gravity, a syringe, or by connection to a vacuum bottle. Several litres of fluid may be drained during the procedure; however, if more than two litres are to be drained, it will usually be done over the course of several treatments. After the desired level of drainage is complete, the plastic sheath is removed and the puncture site bandaged. The plastic sheath can be left in place with a flow control valve and protective dressing if further treatments are expected to be necessary.If fluid drainage in cirrhotic ascites is more than 5 litres, patients may receive intravenous serum albumin (25% albumin, 8g/L) to prevent hypotension (low blood pressure). There has been debate as to whether albumin administration confers benefit, but a recent 2016 meta-analysis concluded that it can reduce mortality after large-volume paracentesis significantly. However, for every end-point investigated, while albumin was favorable as compared to other agents (e.g., plasma expanders, vasoconstrictors), these were not statistically significant and the meta-analysis was limited by the quality of the studies — two of which that were in fact unsuitable — included in it.The procedure generally is not painful and does not require sedation. The patient is usually discharged within several hours following post-procedure observation provided that blood pressure is otherwise normal and the patient experiences no dizziness.
Fluid analysis
The serum-ascites albumin gradient can help determine the cause of the ascites.The ascitic white blood cell count can help determine if the ascites is infected. A count of 250 neutrophils per ml or higher is considered diagnostic for spontaneous bacterial peritonitis. Cultures of the fluid can be taken, but the yield is approximately 40% (72-90% if blood culture bottles are used).
Contraindications
Mild hematologic abnormalities do not increase the risk of bleeding. The risk of bleeding may be increased if:
prothrombin time > 21 seconds
international normalized ratio > 1.6
platelet count < 50,000 per cubic millimeter.Absolute contraindication is the acute abdomen that requires surgery.
Relative contraindications are:
Pregnancy
Distended urinary bladder
Abdominal wall cellulitis
Distended bowel
Intra-abdominal adhesions.
See also
Anterior chamber paracentesis
References
External links
WebMD: Patient guide |
Paroxysmal nocturnal hemoglobinuria | Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the bodys innate immune system. This destructive process occurs due to deficiency of the red blood cell surface protein DAF, which normally inhibits such immune reactions. Since the complement cascade attacks the red blood cells within the blood vessels of the circulatory system, the red blood cell destruction (hemolysis) is considered an intravascular hemolytic anemia. Other key features of the disease, such as the high incidence of venous blood clot formation, are incompletely understood.PNH is the only hemolytic anemia caused by an acquired (rather than inherited) intrinsic defect in the cell membrane (deficiency of glycophosphatidylinositol or GPI) leading to the absence of protective exterior surface proteins that normally attach via a GPI anchor. It may develop on its own ("primary PNH") or in the context of other bone marrow disorders such as aplastic anemia ("secondary PNH"). Only a minority of affected people have the telltale red urine in the morning that originally gave the condition its name.Allogeneic bone marrow transplantation is the only cure, but has significant rates of additional medical problems and death. The monoclonal antibody eculizumab reduces the need for blood transfusions and improves quality of life for those affected by PNH. Eculizumab dramatically alters the natural course of PNH, reducing symptoms and disease complications as well as improving survival to the extent that it may be equivalent to that of the general population. Eculizumab costs at least US$440,000 for a single year of treatment and has been reported as one of the worlds most expensive drugs.
Signs and symptoms
The classic sign of PNH is red discoloration of the urine due to the presence of hemoglobin and hemosiderin from the breakdown of red blood cells. As the urine is more concentrated in the morning, this is when the color is most pronounced. This phenomenon mainly occurs in those who have the primary form of PNH, who will notice this at some point in their disease course. The remainder mainly experience the symptoms of anemia, such as tiredness, shortness of breath, and palpitations.A small proportion of patients report attacks of abdominal pain, difficulty swallowing and pain during swallowing, as well as erectile dysfunction in men; this occurs mainly when the breakdown of red blood cells is rapid, and is attributable to spasm of smooth muscle due to depletion of nitric oxide by red cell breakdown products.Forty percent of people with PNH develop thrombosis (a blood clot) at some point in their illness. This is the main cause of severe complications and death in PNH. These may develop in common sites (deep vein thrombosis of the leg and resultant pulmonary embolism when these clots break off and enter the lungs), but in PNH blood clots may also form in more unusual sites: the hepatic vein (causing Budd-Chiari syndrome), the portal vein of the liver (causing portal vein thrombosis), the superior or inferior mesenteric vein (causing mesenteric ischemia) and veins of the skin. Cerebral venous thrombosis, an uncommon form of stroke, is more common in those with PNH.
Pathophysiology
All cells have proteins attached to their membranes, often serving as a mode of communication or signaling between the cell and the surrounding environment. These signaling proteins are physically attached to the cell membrane in various ways, commonly anchored by glycolipids such as glycosyl phosphatidylinositols (GPI). PNH occurs as a result of a defect in the assembling of these glycolipid-protein structures on the surface of blood cells.The most common defective enzyme in PNH is phosphatidylinositol glycan A (PIGA), one of several enzymes needed to make GPI. The gene that codes for PIGA is located on the X chromosome, which means that only one active copy of the gene for PIGA is present in each cell (initially, females have two copies, but one is silenced through X-inactivation). A mutation in the PIGA gene can lead to the absence of GPI anchors expressed on the cell membrane. When this mutation occurs in a hematopoietic stem cell in the bone marrow, all of the cells it produces will also have the defect.Several of the proteins that anchor to GPI on the cell membrane are used to protect the cell from destruction by the complement system, and, without these anchors, the cells are more easily targeted by the complement proteins. Although red blood cells, white blood cells, and platelets are targeted by complement, red blood cells are particularly vulnerable to lysis. The complement system is part of the innate immune system and has a variety of functions, from destroying invading microorganisms by opsonization to direct destabilization by the membrane attack complex. The main proteins that protect blood cells from destruction are decay-accelerating factor (DAF/CD55), which disrupts formation of C3-convertase, and protectin (CD59/MIRL/MAC-IP), which binds the membrane attack complex and prevents C9 from binding to the cell.The symptoms of esophageal spasm, erectile dysfunction, and abdominal pain are attributed to the fact that hemoglobin released during hemolysis binds with circulating nitric oxide, a substance that is needed to relax smooth muscle. This theory is supported by the fact that these symptoms improve on administration of nitrates or sildenafil (Viagra), which improves the effect of nitric oxide on muscle cells. There is a suspicion that chronic hemolysis causing chronically depleted nitric oxide may lead to the development of pulmonary hypertension (increased pressure in the blood vessels supplying the lung), which in turn puts strain on the heart and causes heart failure.Historically, the role of sleep and night in this disease (the "nocturnal" component of the name) has been attributed to acidification of the blood at night due to relative hypoventilation and accumulation of carbon dioxide in the blood during sleep. This hypothesis has been questioned by researchers who note that not all those with PNH have increased hemolysis during sleep, so it is uncertain how important a role sleep actually plays in this disease.
Diagnosis
Blood tests in PNH show changes consistent with intravascular hemolytic anemia: low hemoglobin, raised lactate dehydrogenase, raised bilirubin (a breakdown product of hemoglobin), and decreased levels of haptoglobin; there can be raised reticulocytes (immature red cells released by the bone marrow to replace the destroyed cells) if there is no iron deficiency present. The direct antiglobulin test (DAT, or direct Coombs test) is negative, as the hemolysis of PNH is not caused by antibodies. If the PNH occurs in the setting of known (or suspected) aplastic anemia, abnormal white blood cell counts and decreased platelet counts may be seen at this. In this case, anemia may be caused by insufficient red blood cell production in addition to the hemolysis.Historically, the sucrose lysis test, in which a patients red blood cells are placed in low-ionic-strength solution and observed for hemolysis, was used for screening. If this was positive, the Hams acid hemolysis test (after Dr Thomas Ham, who described the test in 1937) was performed for confirmation. The Ham test involves placing red blood cells in mild acid; a positive result (increased RBC fragility) indicates PNH or Congenital dyserythropoietic anemia. This is now an obsolete test for diagnosing PNH due to its low sensitivity and specificity.Today, the gold standard is flow cytometry for CD55 and CD59 on white and red blood cells. Based on the levels of these cell proteins, erythrocytes may be classified as type I, II, or III PNH cells. Type I cells have normal levels of CD55 and CD59; type II have reduced levels; and type III have absent levels. The fluorescein-labeled proaerolysin (FLAER) test is being used more frequently to diagnose PNH. FLAER binds selectively to the glycophosphatidylinositol anchor and is more accurate in demonstrating a deficit than simply for CD59 or CD55.
Classification
PNH is classified by the context under which it is diagnosed:
Classic PNH. Evidence of PNH in the absence of another bone marrow disorder.
PNH in the setting of another specified bone marrow disorder such as aplastic anemia and myelodysplastic syndrome (MDS).
Subclinical PNH. PNH abnormalities on flow cytometry without signs of hemolysis.
Screening
There are several groups where screening for PNH should be undertaken. These include patients with unexplained thrombosis who
are young, have thrombosis in an unusual site (e.g. intra-abdominal veins, cerebral veins, dermal veins), have any evidence of hemolysis (e.g. a raised LDH), or have a low red blood cell, white blood cell, or platelet count. Those who have a diagnosis of aplastic anemia should be screened annually.
Treatment
Acute attacks
There is disagreement as to whether steroids (such as prednisolone) can decrease the severity of hemolytic crises. Transfusion therapy may be needed; in addition to correcting significant anemia, this suppresses the production of PNH cells by the bone marrow, and indirectly the severity of the hemolysis. Iron deficiency develops with time, due to losses in urine, and may have to be treated if present. Iron therapy can result in more hemolysis as more PNH cells are produced.
Long-term
PNH is a chronic condition. In patients with only a small clone and few problems, monitoring of the flow cytometry every six months gives information on the severity and risk of potential complications. Given the high risk of thrombosis in PNH, preventive treatment with warfarin decreases the risk of thrombosis in those with a large clone (50% of white blood cells type III).Episodes of thrombosis are treated as they would in other patients, but, given that PNH is a persisting underlying cause, it is likely that treatment with warfarin or similar drugs needs to be continued long-term after an episode of thrombosis.
Eculizumab
In 2007, the drug eculizumab was approved for the treatment of PNH. Prior to eculizumab, the median life expectancy of an individual with PNH was approximately 10 years. Since that time, short and mid-term studies of patients on eculizumab demonstrate that the drug returns the patient to a normal life expectancy, improves quality of life, and decreases the need for blood transfusions.Eculizumab is controversial due to its high cost, as it is among the most expensive pharmaceuticals in the world, with a price of US$440,000 per person per year. Eculizumab is a humanized monoclonal antibody that acts as a terminal complement inhibitor. The drug interferes with the formation of the membrane attack complex in erythrocytes by binding to C5, compensating for the loss of protective function that results from CD59 deficiency. This alleviates the primary source of intravascular hemolysis, but it does not reduce the opsonization of erythrocytes caused by CD55 deficiency, so patients who receive this medication often still experience mild to moderate hemolysis. The U.S. Food and Drug Administration (FDA) has issued a black-box warning as those who take the medication have a 1,000 to 2,000-fold greater risk of invasive meningococcal disease. People on eculizumab are strongly advised to receive meningococcal vaccination at least two weeks prior to starting therapy and to consider preventative antibiotics for the duration of treatment.
Pegcetacoplan
Pegcetacoplan was approved for medical use in the United States in May 2021.
Epidemiology
PNH is rare, with an annual rate of 1-2 cases per million. The prognosis without disease-modifying treatment is 10–20 years. Many cases develop in people who have previously been diagnosed with aplastic anemia or myelodysplastic syndrome. The fact that PNH develops in MDS also explains why there appears to be a higher rate of leukemia in PNH, as MDS can sometimes transform into leukemia.25% of female cases of PNH are discovered during pregnancy. This group has a high rate of thrombosis, and the risk of death of both mother and child are significantly increased (20% and 8% respectively).
History
The first description of paroxysmal hemoglobinuria was by the German physician Paul Strübing (Greifswald, 1852–1915) during a lecture in 1881, later published in 1882. Later comprehensive descriptions were made by Ettore Marchiafava and Alessio Nazari in 1911, with further elaborations by Marchiafava in 1928 and Ferdinando Micheli in 1931.The Dutch physician Enneking coined the term "paroxysmal nocturnal hemoglobinuria" (or haemoglobinuria paroxysmalis nocturna in Latin) in 1928, which has since become the default description.
References
== External links == |
Patent ductus arteriosus | Patent ductus arteriosus (PDA) is a medical condition in which the ductus arteriosus fails to close after birth: this allows a portion of oxygenated blood from the left heart to flow back to the lungs by flowing from the aorta, which has a higher pressure, to the pulmonary artery. Symptoms are uncommon at birth and shortly thereafter, but later in the first year of life there is often the onset of an increased work of breathing and failure to gain weight at a normal rate. With time, an uncorrected PDA usually leads to pulmonary hypertension followed by right-sided heart failure.
The ductus arteriosus is a fetal blood vessel that normally closes soon after birth. In a PDA, the vessel does not close, but remains patent (open), resulting in an abnormal transmission of blood from the aorta to the pulmonary artery. PDA is common in newborns with persistent respiratory problems such as hypoxia, and has a high occurrence in premature newborns. Premature newborns are more likely to be hypoxic and have PDA due to underdevelopment of the heart and lungs.
If transposition of the great vessels is present in addition to a PDA, the PDA is not surgically closed since it is the only way that oxygenated blood can mix with deoxygenated blood. In these cases, prostaglandins are used to keep the PDA open, and NSAIDs are not administered until surgical correction of the two defects is completed.
Signs and symptoms
Common symptoms include:
dyspnea (shortness of breath)Signs include:
tachycardia (a heart rate exceeding the normal resting rate)
continuous "machine-like" (also described as "rolling-thunder" and "to-and-fro") heart murmur (usually from aorta to pulmonary artery, with higher flow during systole and lower flow during diastole)
cardiomegaly (enlarged heart, reflecting ventricular dilation and volume overload)
left subclavicular thrill
bounding pulse
widened pulse pressure
increased cardiac output
increased systolic pressure
poor growth
differential cyanosis, i.e. cyanosis of the lower extremities but not of the upper body.People with patent ductus arteriosus typically present in good health, with normal respirations and heart rate. If the PDA is moderate or large, widened pulse pressure and bounding peripheral pulses are frequently present, reflecting increased left ventricular stroke volume and diastolic run-off of blood into the (initially lower-resistance) pulmonary vascular bed. Eisenmenger physiology is pulmonary hypertension due to a left-to-right shunt. Prominent suprasternal and carotid pulsations may be noted secondary to increased left ventricular stroke volume.
Risk factors
Known risk factors include:
Preterm birth
Congenital rubella syndrome
Chromosomal abnormalities (e.g., Down syndrome)
Genetic conditions such as Loeys–Dietz syndrome (would also present with other heart defects), Wiedemann–Steiner syndrome, and CHARGE syndrome.
Fetal Alcohol Spectrum Disorder
Diagnosis
PDA is usually diagnosed using noninvasive techniques. Echocardiography (in which sound waves are used to capture the motion of the heart) and associated Doppler studies are the primary methods of detecting PDA. Electrocardiography (ECG), in which electrodes are used to record the electrical activity of the heart, is not particularly helpful as no specific rhythms or ECG patterns can be used to detect PDA.A chest X-ray may be taken, which reveals overall heart size (as a reflection of the combined mass of the cardiac chambers) and the appearance of blood flow to the lungs. A small PDA most often accompanies a normal-sized heart and normal blood flow to the lungs. A large PDA generally accompanies an enlarged cardiac silhouette and increased blood flow to the lungs.
Prevention
Some evidence suggests that intravenous NSAIDs, such as indomethacin, administration on the first day of life to all preterm infants reduces the risk of developing a PDA and the complications associated with PDA. Intravenous Indomethacin treatment in premature infants also may reduce the need for surgical intervention. Administering ibuprofen probably helps to prevent PDA and reduce the need for surgery but it also likely increases the risk of kidney complications.
Treatment
Symptomatic PDA can be treated with both surgical and non-surgical methods.
Conservative
Neonates without adverse symptoms may simply be monitored as outpatients.
Surgery
Surgically, the DA may be closed by ligation (though support in premature infants is mixed). This can either be performed manually and be tied shut, or with intravascular coils or plugs that leads to formation of a thrombus in the DA.Devices developed by Franz Freudenthal block the blood vessel with woven structures of nitinol wire.Newer procedures performed effectively in older, bigger children include catheter PDA occlusion and video-assisted thoracoscopic PDA clipping.
Prostaglandin inhibitors
Because prostaglandin E2 is responsible for keeping the DA open, NSAIDs (which can inhibit prostaglandin synthesis) such as indomethacin or a special form of ibuprofen have been used to initiate PDA closure. Findings from a 2015 systematic review concluded that, for closure of a PDA in preterm and/or low birth weight infants, ibuprofen is as effective as indomethacin. It also causes fewer side effects (such as transient acute kidney injury) and reduces the risk of necrotising enterocolitis. A review and meta-analysis showed that paracetamol may be effective for closure of a PDA in preterm infants. A 2018 network meta-analysis that compared indomethacin, paracetamol and ibuprofen at different doses and administration schemes among them found that a high dose of oral ibuprofen may offer the highest likelihood of closure in preterm infants. However, a 2020 systematic review found that early (≤7 days of life) or very early (≤72 hours of life) pharmacological treatment of symptomatic PDA does not reduce death or other poor clinical outcomes in preterm infants but instead increases their exposure to NSAIDS. Vasodilator therapy is suitable for people with Eisenmenger physiology. To assess improvement in people with Eisenmenger physiology, close monitory of toe oxygen saturation is required, for there exists a chance of reversal after a successful right-to-left shuntWhile indometacin can be used to close a PDA, some neonates require their PDA be kept open. Keeping a ductus arteriosus patent is indicated in neonates born with concurrent heart malformations, such as transposition of the great vessels. Drugs such as alprostadil, a PGE-1 analog, can be used to keep a PDA open until the primary defect is corrected surgically.
Prognosis
If left untreated, the disease may progress from left-to-right shunt (acyanotic heart) to right-to-left shunt (cyanotic heart), called Eisenmengers syndrome. Pulmonary hypertension is a potential long-term outcome, which may require a heart and/or lung transplant. Another complication of PDA is intraventricular hemorrhage.
History
Robert Edward Gross, MD performed the first successful ligation of a patent ductus arteriosus on a seven-year-old girl at Childrens Hospital Boston in 1938.
Adult
Since PDA is usually identified in infants, it is less common in adults, but it can have serious consequences, and is usually corrected surgically upon diagnosis.
See also
George Alexander Gibson
References
External links
Patent Ductus Arteriosus Causes from US Department of Health and Human Services
Patent Ductus Arteriosus from Merck
Patent ductus arteriosus information for parents. |
Head lice infestation | Head lice infestation, also known as pediculosis capitis, is the infection of the head hair and scalp by the head louse (Pediculus humanus capitis). Itching from lice bites is common. During a persons first infection, the itch may not develop for up to six weeks. If a person is infected again, symptoms may begin much more quickly. The itch may cause problems with sleeping. Generally, however, it is not a serious condition. While head lice appear to spread some other diseases in Africa, they do not appear to do so in Europe or North America.Head lice are spread by direct contact with the hair of someone who is infected. The cause of head lice infestations in children is not related to cleanliness. Other animals, such as cats and dogs, do not play a role in transmission. Head lice feed only on human blood and are only able to survive on human head hair. When adults, they are about 2 to 3 mm long. When not attached to a human, they are unable to live beyond three days. Humans can also become infected with two other lice – the body louse and the crab louse. To make the diagnosis, live lice must be found. Using a comb can help with detection. Empty eggshells (known as nits) are not sufficient for the diagnosis.Possible treatments include: combing the hair frequently with a fine tooth comb or shaving the head completely. A number of topical medications are also effective, including malathion, ivermectin, and dimethicone. Dimethicone, which is a silicone oil, is often preferred due to the low risk of side effects. Pyrethroids such as permethrin have been commonly used; however, they have become less effective due to increasing pesticide resistance. There is little evidence for alternative medicines.Head-lice infestations are common, especially in children. In Europe, they infect between 1 and 20% of different groups of people. In the United States, between 6 and 12 million children are infected a year. They occur more often in girls than boys. It has been suggested that historically, head lice infection were beneficial, as they protected against the more dangerous body louse. Infestations may cause stigmatization of the infected individual.
Epidemiology
Reliable data describing the usual incidence of infestation in the general public, in the average school community, or during specific times of the year are lacking.
The number of cases of human louse infestations (or pediculosis) has increased worldwide since the mid-1960s, reaching hundreds of millions annually. It is estimated between 1 and 20% of specific groups in Europe are infected.Despite improvements in medical treatment and prevention of human diseases during the 20th century, head louse infestation remains stubbornly prevalent. In 1997, 80% of American elementary schools reported at least one outbreak of lice. Lice infestation during that same period was more prevalent than chickenpox.About 6–12 million children between the ages of 3 and 11 are treated annually for head lice in the United States alone. High levels of louse infestations have also been reported from all over the world, including Israel, Denmark, Sweden, U.K., France, and Australia.The United Kingdoms National Health Service report that lice have no preference for any type of hair be it clean, dirty, or short. The number of children per family, the sharing of beds and closets, hair washing habits, local customs and social contacts, healthcare in a particular area (e.g. school), and socioeconomic status were found to be factors in head louse infestation in Iran. Other studies found no relationship between frequency of brushing or shampooing. The California Department of Public Health indicates that chronic head lice infestation may be a sign of socioeconomic or family problems. Children between 4 and 13 years of age are the most frequently infested group. In the U.S., African-American children have lower rates of infestation.Head lice (Pediculus humanus capitis) infestation is most frequent on children aged 3–10 and their families. Females get head lice twice as often as males, and infestation in persons of Afro-Caribbean or other black descent could be rare due to difference in hair shape or width. But these children may have nits that hatch and the live lice could be transferred by head contact to other children.
Signs and symptoms
Head lice are generally uncomfortable, but typically do not constitute a serious condition. The most common symptom is itching of the head, which normally worsens 3 to 4 weeks after the initial infestation. The bite reaction is very mild, and it can be rarely seen between the hairs. Bites can be seen, especially in the neck of long-haired individuals when the hair is pushed aside. Swelling of the local lymph nodes and fever are rare. Itching may cause skin breakdown and uncommonly result in a bacterial infection. Many individuals do not experience symptoms. Itching may take 2–6 weeks to develop upon first infestation, and sooner in subsequent infestations.In Ethiopia, head lice appear to be able to spread louse-born epidemic typhus and Bartonella quintana. In Europe, the head lice do not appear to carry these infections.
Transmission
Head lice spreads through direct contact of the head of an infested person with the head of a non-infested person. The presence of live lice indicates an active infestation while the presence of nits indicates a past or currently inactive infection with the potential to become active. Head lice do not leap or spring as a means to transfer to their hosts; instead, they move by crawling. Transmission by indirect contact (e.g. sharing bedding, clothing, headwear, the same comb) is much less common. The cause of head lice infestations is not related to cleanliness. Neither hair length nor how often the hair is brushed affects the risk of infection. Pets are not vectors for head lice.Other lice that infest humans are the body louse and the crab louse (aka pubic lice). The claws of these three species are adapted to attach to specific hair diameters. Pubic lice are most often spread by sexual contact with an infested person. Body lice can be found on clothing and they are not known to burrow into the skin.
Diagnosis
The condition is diagnosed by finding live lice and unhatched eggs in the hair. Finding empty eggs is not enough. Dandruff, lint, sand, hair casts, and dried hairspray, can be mistaken for eggs and nits. This is made easier by using a magnifying glass or running a comb through the childs wet hair, the latter of which is the most assured method of diagnosis and can be used to monitor treatment. In questionable cases, a child can be referred to a health professional. However, head lice infestation is commonly overdiagnosed, with extinct infestations being mistaken for active ones. Infestations are only considered extinct if nits are more than 0.25 inches away from the scalp and nymphs and adult lice are absent. As a result, lice-killing treatments are more often used on non-infested than infested children. The use of a louse comb is the most effective way to detect living lice. With both methods, special attention should be paid to the area near the ears and the nape of the neck. The use of a magnifying glass to examine the material collected between the teeth of the comb could prevent misdiagnosis.The presence of nits alone, however, is not an accurate indicator of an active head louse infestation. Generally, white nits are empty egg casings, while brown nits may still contain viable louse larva. One way of determining the nit is to squeeze it between two fingernails; it gives a characteristic snapping pop sound as the egg bursts. Children with nits on their hair have a 35–40% chance of also being infested with living lice and eggs. If lice are detected, the entire family needs to be checked (especially children up to the age of 13 years) with a louse comb, and only those who are infested with living lice should be treated. As long as no living lice are detected, the child should be considered negative for head louse infestation. Accordingly, a child should be treated with a pediculicide only when living lice are detected on their hair (not because he/she has louse eggs/nits on the hair and not because the scalp is itchy).
Prevention
Examination of the childs head at regular intervals using a louse comb allows the diagnosis of louse infestation at an early stage. Early diagnosis makes treatment easier and reduces the possibility of infesting others. In times and areas when louse infestations are common, weekly examinations of children, especially those 4–15 years old, carried out by their parents, will aid control. Additional examinations are necessary if the child came in contact with infested individuals, if the child frequently scratches his/her head, or if nits suddenly appear on the childs hair.
Clothes, towels, bedding, combs, and brushes, which came in contact with the infested individual, can be disinfected either by leaving them outside for at least two days or by washing them at 60 °C (140 °F) for 30 minutes. This is because adult lice can survive only one to two days without a blood meal and are highly dependent on human body warmth.
Treatment
There are a number of treatments effective for head lice. These methods include combs, shaving, medical creams, and hot air. Medical creams usually require two treatments a week apart. Head lice are not justification to keep children home from school as the risk of spread is low.
Mechanical measures
Wet combing (mechanical removal of lice through combing wet hair) can be used as treatment measure for those who are too young for pediculicide treatment, which is intended for 6 years of age or older. Wet combing a few times a day for a few weeks may also get rid of the infestation in half of people. This requires the use of a special lice comb with extra fine teeth. This is the recommended method for infants and women who are pregnant. Shaving the head can also effectively treat lice.
Another treatment is the use of heated air applied by a hair dryer. This can be of special use in the early stages of an infestation, since it has very high mortality for eggs.
Medications
There are many medications which can kill lice. Dimethicone is between 70 and 97% effective with a low rate of side effects, and thus is seen as the preferred treatment. It works by physical means and there is no evidence of pesticide resistance. Ivermectin is around 80% effective, but can cause local skin irritation. Malathion has an effectiveness around 90%, but theres the possibility of toxicity. Pyrethroids such as permethrin, while commonly used, have lower rates of effectiveness due to the resistance among lice. Effectiveness varies from 10 to 80%, depending on the population studied. Medications within a lotion appear to work better than those within a shampoo. Benzyl alcohol appears effective but it is unclear if it is better than standard treatments. Abametapir was approved for medical use in the United States in July 2020.Resistance to several commonly used treatments is increasing worldwide, with patterns of resistance varying by region. Head lice have demonstrated resistance to permethrin, malathion, phenothrin, and carbaryl in several countries around the world. A previous method used to delay resistance included utilizing a rotating list of recommended insecticides by health authorities. The mosaic model is the current recommendation, in which it is advised to use one product for a treatment course, followed by a different insecticide from another substance class if the first treatment fails.
Home Remedies
Tea tree oil has been promoted as a treatment for head lice; however, there is no clear evidence of its effectiveness. A 2012 review of head lice treatment recommended against the use of tea tree oil for children because it could cause skin irritation or allergic reactions, because of contraindications, and because of a lack of knowledge about the oils safety and effectiveness. Other home remedies, such as putting vinegar, isopropyl alcohol, olive oil, mayonnaise, or melted butter under a shower cap, have been disproven. The CDC states that swimming has no effect on drowning lice, and can decrease the effectiveness of some treatments.
Environment
After treatment, people are often instructed to wash all bedding and vacuum all areas the head may have been, such as car seats, coat hoods, and sofas, but this is not always necessary, since adult lice will die within 2 days without a blood meal, and newly hatched lice die within minutes of hatching. Combs and brushes may be deloused in boiling water for 5–10 minutes. Items may also be frozen for 24 hours well below the freezing point of water to ensure that ice crystals form within the cells of the lice.
Outbreak Management
In addition to environmental management, an outbreak of head lice infestation requires synchronous treatment of all who are infested and evaluation of those who have been exposed or are suspected to have head lice. Synchronous ovoidal dimethicone treatment has been shown to successfully manage and terminate outbreaks, and a single treatment is likely sufficient. Other treatment methods can be repeated 8–10 days following initial treatment, and may sometimes require a third treatment. Outbreak status and treatment effectiveness can be monitored using the wet combing method.
Stigma
Head lice infestations are notably common, as is the stigma associated with those who experience infestations. Such stigma is even evidenced in the English language as the term "lousy," an adjective that describes something as very poor, bad or disgusting. Misperceptions of those infected with head lice include that it is associated with low socioeconomic status, poor hygiene, unhealthiness, immigration status, and homelessness. Though these negative beliefs are unfounded, they can lead to consequences for both the caregivers and the affected individual, such as social exclusion and isolation from peers, victim-blaming, caregiver strain, inappropriate or unsafe treatment practices, and missed work or school.
Public Health Implications
Over-treatment or mismanagement of head lice, which can be driven by stigma, has important implications at the level of the individual and community. Though evidence-based guidelines from the CDC, American Academy of Pediatrics (AAP) and National Association of School Nurses (NASN) all recommend discontinuing "no-nit" policies in schools (meaning that a child does not need to be free of nits before returning to school), 80 percent of schools in the United States still maintain stringent policies that prevent children with infestations from attending. Thus, to foster a return to school in a timely fashion, these policies can encourage unsafe or harsh treatment practices, including chemicals like bleach or kerosene. Similarly, over-treatment of head-lice using pesticide-based pediculicides has been linked to increased resistance and declining efficacy of these treatments.
Society and culture
To a Louse (on a ladys bonnet). Perhaps the most widely known cultural reference to pediculosis capitis, occurring in a noted poem by Robert Burns.
Other animals
Lice infestation in general is known as pediculosis, and occurs in many mammalian and bird species. Lice infesting other host species are not the same organism as that which causes head lice infestations in humans, nor do the three louse species which infest humans infest any other host species.
References
External links
CDC: Head lice |
Pediculosis corporis | Pediculosis corporis is a cutaneous condition caused by body lice (specifically Pediculus humanus humanus) that lay their eggs in the seams of clothing.: 447
Signs and symptoms
Body lice are a nuisance in themselves and cause intense itching. They are also vectors (transmitters) of other diseases and can spread epidemic typhus, trench fever, and louse-borne relapsing fever.
Risk factors
Body lice are spread through prolonged direct physical contact with a person who has them or through contact with articles such as clothing, beds, bed linens, or towels that have been in contact with an infested person. In the United States, body lice infestations are rare, typically found mainly in homeless transient populations who do not have access to bathing and regular changes of clean clothes. Infestation is unlikely to persist on anyone who bathes regularly and who has at least weekly access to freshly laundered clothing and bedding.Although louse-borne (epidemic) typhus is no longer widespread, outbreaks of this disease still occur during times of war, civil unrest, natural or man-made disasters, and in prisons where people live together in unsanitary conditions. Louse-borne typhus still exists in places where climate, chronic poverty, and social customs or war and social upheaval prevent regular changes and laundering of clothing.
Pathophysiology
Body lice frequently lay their eggs on or near the seams of clothing. They must feed on blood and usually only move to the skin to feed. They exist worldwide and infest people of all races and can therefore spread rapidly under crowded living conditions where hygiene is poor (homeless, refugees, victims of war or natural disasters).
Treatment
A body lice infestation is treated by improving the personal hygiene of the infested person, including assuring a regular (at least weekly) change of clean clothes. Clothing, bedding, and towels used by the infested person should be laundered using hot water (at least 130 °F or 54 °C) and machine dried using the hot cycle.Sometimes the infested person also is treated with a pediculicide (a medicine that can kill lice); however, a pediculicide generally is not necessary if hygiene is maintained and items are laundered appropriately at least once a week. A pediculicide should be applied exactly as directed on the bottle or by a physician.Delousing can also be practically achieved by boiling all clothes and bedding, or washing them at a high temperature. A temperature of 130 °F or 54 °C for 5 minutes will kill most of the adults and prevent eggs from hatching. Leaving the clothes unwashed, but unworn for a full week, also results in the death of lice and eggs.Where this is not practical or possible, powder dusting with 10% DDT, 1% malathion or 1% permethrin is also effective. Oral ivermectin at a dose of 12 mg on days 0, 7 and 14 has been used in a small trial of 33 people in Marseilles, but did not result in complete eradication, although there was a significant fall in the number of parasites and proportion of people infected. At the moment, ivermectin cannot be routinely recommended for the treatment of body lice.
Medication, insecticide or burning of clothing and bedding is usually not necessary, as the problem normally goes away with daily bathing, and weekly (or more frequent) laundering and drying of clothing, bedding, towels, etc. in a hot clothes drier.
See also
List of cutaneous conditions
Pediculosis
Skin lesion
Vagabonds leukomelanoderma
== References == |
Pediculosis pubis | Pediculosis pubis (also known as "crabs" and "pubic lice") is an infestation by the pubic louse, Pthirus pubis, a wingless insect which feeds on blood and lays its eggs (nits) on mainly pubic hair. Less commonly, hair near the anus, armpit, beard, eyebrows, moustache, and eyelashes may be involved. It is usually acquired during sex, but can be spread via bedding, clothing and towels, and is more common in crowded conditions where there is close contact between people.The main symptom is an intense itch in the groin, particularly at night. There may be some grey-blue discolouration at the feeding site, and eggs and lice may be visible. Scratch marks, crusting and scarring may be seen, and there may be signs of secondary bacterial infection.Diagnosis is by visualising the nits or live lice, either directly or with a magnifying glass. Investigations for other sexually transmitted infections (STIs) are usually performed.First line treatment usually contains permethrin and is available over the counter. Two rounds of treatment at least a week apart are usually required to kill newly hatched nymphs. Washing bedding and clothing in hot water kills the lice, and transmission can be prevented by avoiding sexual contact until no signs of infestation exist. Eggs may be removed by combing pubic hair with a comb dipped in vinegar. Sexual partners should be evaluated and treated.Infestation with pubic lice is found in all parts of the world and occurs in all ethnic groups and all levels of society. Worldwide, the condition affects about 2% of the population.
Definition
Pediculosis pubis is an infestation by the pubic louse, Pthirus pubis, a wingless insect which feeds on blood and lays its eggs (nits) on mainly pubic hair. Less commonly, hair near the anus, armpit, beard, eyebrows, moustache, and eyelashes may be involved. Although the presence of pubic lice are associated with the presence of other sexually transmitted diseases, pubic lice do not spread infectious diseases.
Signs and symptoms
The onset of symptoms is typically three weeks after the first infestation of lice and is mainly an intense itch in the pubic area and groin, particularly at night, resulting from an allergic reaction to the saliva of feeding lice. In some infestations, a characteristic grey-blue or slate coloration macule appears (maculae caeruleae) at the feeding site, which may last for days. Nits or live lice may be seen crawling on the skin. Louse droppings may be noticed as a black powder in the underwear.Scratch marks, crusting, scarring, rust-colored faecal material, blood stained underwear and secondary bacterial infection may sometimes be seen. Large lymph nodes in the groin and armpits may be felt. Some people with pubic lice infestation may not have any symptoms.
Causes
Spread
Pubic lice are usually transmitted from one person to another during vaginal, oral or anal sex, whether a condom is used or not. One sexual encounter with an infected person carries a high risk of catching pubic lice. In some circumstances transmission can occur through kissing and hugging, and less likely via bedding, clothing and towels. The lice spread more easily in crowded conditions where the distance between people is close, allowing the lice to crawl from one person to another.Infestation on the eyebrows or eyelashes of a child may indicate sexual exposure or abuse.
Characteristics and life cycle
Pubic lice (Pthirus pubis) have three stages: the egg (also called a nit), the nymph, and the adult. They can be hard to see and are found firmly attached to the hair shaft. They are oval and usually yellow to white. Pubic lice nits take about 6–10 days to hatch. The nymph is an immature louse that hatches from the nit (egg). A nymph looks like an adult pubic louse but it is smaller. Pubic lice nymphs take about 2–3 weeks after hatching to mature into adults capable of reproducing. To live, a nymph must feed on blood. The adult pubic louse resembles a miniature crab when viewed through a strong magnifying glass. Pubic lice have six legs; their two front legs are very large and look like the pincher claws of a crab—thus the nickname "crabs". Pubic lice are tan to grayish-white in color. Females lay nits and are usually larger than males. To live, lice must feed on blood. If the louse falls off a person, it dies within 1–2 days. Eggs (nits) are laid on a hair shaft. Females will lay approximately 30 eggs during their 3–4 week life span. Eggs hatch after about a week and become nymphs, which look like smaller versions of the adults. The nymphs undergo three molts before becoming adults. Adults are 1.5–2.0 mm long and flattened. They are much broader in comparison to head and body lice. Adults are found only on the human host and require human blood to survive. Pubic lice are transmitted from person to person most-commonly via sexual contact, although fomites (bedding, clothing) may play a minor role in their transmission.
Diagnosis
Diagnosis is made by carefully looking at the pubic hair for nits, young lice and adult lice. Lice and nits can be removed either with forceps or by cutting the infested hair with scissors (with the exception of an infestation of the eye area). A magnifying glass, dermatoscope or a stereo-microscope can be used for identification. Testing for other sexually transmitted infections is recommended in those who are infested with pubic lice.
Treatment
Pubic lice can be treated at home. Available treatments may vary from country to country and include mainly permethrin-containing creams and lotions applied to cool dry skin.Treatment with medication is combined with combing pubic hair with a fine-toothed comb after applying vinegar directly to skin or dipping the comb in vinegar, to remove nits. It is recommended to wash bedding, clothing and towels in hot water or preferably in a washing machine at 50°C or higher. When this is not possible, the clothing can be stored in a sealed plastic bag for at least three days. Re-infestation can be prevented by wearing clean underwear at the start of treatment and after completing treatment. Shaving the affected hair is not essential.
First line
At first, treatment is usually with topical permethrin 1% cream, which can be bought over the counter without a prescription. It is applied to the areas affected by pubic lice and washed off after 10 minutes. Brands of permethrin include Lyclear, available in the UK as a creme rinse or dermal cream at 5% strengths.
In the US, permethrin may be familiar as NIX, Actin and ElimiteAn alternative is the combination of pyrethrins and piperonyl butoxide, in a topical application, which include the brands Licide, and A-200, Pronto and RID shampoos. These medications are safe and effective when used exactly according to the instructions in the package or on the label. To kill newly hatched lice, both treatments can be repeated within the following seven to ten days.European guidelines state alternatives to permethrin as including either the application of 0.2% phenothrin (washed off after two hours), or 0.5% malathion lotions (washed off after 12 hours). The CDC states alternatives as topical 0.5% malathion or oral ivermectin.
Other treatments
Lindane is still used in a shampoo form in some non-European countries. Its licence was withdrawn by the European Medicines Agency in 2008. It may be considered as a last resort in some people who show resistance to other treatments, but is not recommended to be used for a second round of treatment. Lindane is not recommended in pregnant and breastfeeding women, children under the age of two years, and people who have extensive dermatitis. The FDA warns against use in people with a history of uncontrolled seizure disorders and cautious use in infants, children, the elderly, and individuals with other skin conditions (e.g., atopic dermatitis, psoriasis) and in those who weigh less than 110 lbs (50 kg). Carbaryl has been used since 1976 but found to have the potential to cause cancer in rodents and not to be as effective as previously thought. It is either not used at all or its use is restricted.Sexual partners should be evaluated and treated, and sexual contact should be avoided until all partners are better. Because of the strong association between the presence of pubic lice and sexually transmitted infections (STIs), affected people require investigation for other STIs.
Eyes
Infestation of the eyes is treated differently than other parts of the body. Lice can be removed with forceps or by removing or trimming the lashes. Eyelashes may be treated with a gentle petroleum jelly for occlusion.
Complications
Complications are usually as a result of persistent scratching and include thickening of the skin, darkened skin, and secondary bacterial infection including impetigo, conjunctivitis and blepharitis.
Epidemiology
Infestation with pubic lice is found in all parts of the world, occurs in all ethnic groups and all levels of society.Current worldwide prevalence has been very approximately estimated at two percent of the human population. Accurate numbers are difficult to acquire, because pubic lice infestations are not considered a reportable condition by many governments. Many cases are self-treated or treated discreetly by personal physicians, which further adds to the difficulty of producing accurate statistics.It has been reported that the trend of pubic hair removal has led to the destruction of the natural habitat of the crab louse populations in some parts of the world, thereby reducing the incidence of the disease.
Etymology and history
Infestation with pubic lice is also called phthiriasis or phthiriasis pubis, while infestation of eyelashes with pubic lice is called phthiriasis palpebrarum or pediculosis ciliarum. Linnaeus was first to describe and name the pubic louse in 1758, when he called it Pediculus pubis. The disease is spelled with phth, but the scientific name of the louse Pthirus pubis is spelled with pth (an etymologically incorrect spelling that was nonetheless officially adopted in 1958).
Other animals
Humans are the only known hosts of this parasite, although a closely related species, Pthirus gorillae, infects gorilla populations.
References
External links
Crab louse on the UF / Institute of Food and Agriculture |
Pellagra | Pellagra is a disease caused by a lack of the vitamin niacin (vitamin B3). Symptoms include inflamed skin, diarrhea, dementia, and sores in the mouth. Areas of the skin exposed to either sunlight or friction are typically affected first. Over time affected skin may become darker, stiffen, peel, or bleed.There are two main types of pellagra, primary and secondary. Primary pellagra is due to a diet that does not contain enough niacin and tryptophan. Secondary pellagra is due to a poor ability to use the niacin within the diet. This can occur as a result of alcoholism, long-term diarrhea, carcinoid syndrome, Hartnup disease, and a number of medications such as isoniazid. Diagnosis is typically based on symptoms and may be assisted by urine testing.Treatment is with either niacin or nicotinamide supplementation. Improvements typically begin within a couple of days. General improvements in diet are also frequently recommended. Decreasing sun exposure via sunscreen and proper clothing is important while the skin heals. Without treatment death may occur. The disease occurs most commonly in the developing world, often as a disease of poverty associated with malnutrition, specifically sub-Saharan Africa.
Signs and symptoms
The classic symptoms of pellagra are diarrhea, dermatitis, dementia, and death ("the four Ds").
A more comprehensive list of symptoms includes:
Sensitivity to sunlight
Dermatitis (characteristic "broad collar" rash known as casal collar)
Hair loss
Swelling
Smooth, beefy red glossitis (tongue inflammation)
Trouble sleeping
Weakness
Mental confusion or aggression
Ataxia (lack of coordination), paralysis of extremities, peripheral neuritis (nerve damage)
Diarrhea
Dilated cardiomyopathy (enlarged, weakened heart)
Eventually dementiaJ. Frostigs and Tom Spies—according to Cleary and Cleary—described more specific psychological symptoms of pellagra as:
Psychosensory disturbances (impressions as being painful, annoying bright lights, odors intolerance causing nausea and vomiting, dizziness after sudden movements),
Psychomotor disturbances (restlessness, tense and a desire to quarrel, increased preparedness for motor action), as well as
Emotional disturbancesIndependently of clinical symptoms, blood level of tryptophan or urinary metabolites such as 2-pyridone/N-methylniacinamide ratio <2 or NAD/NADP ratio in red blood cells can diagnose pellagra. The diagnosis is confirmed by rapid improvements in symptoms after doses of niacin (250–500 mg/day) or niacin enriched food.
Pathophysiology
Pellagra can develop according to several mechanisms, classically as a result of niacin (vitamin B3) deficiency, which results in decreased nicotinamide adenine dinucleotide (NAD). Since NAD and its phosphorylated NADP form are cofactors required in many body processes, the pathological impact of pellagra is broad and results in death if not treated.
The first mechanism is simple dietary lack of niacin. Second, it may result from deficiency of tryptophan, an essential amino acid found in meat, poultry, fish, eggs, and peanuts that the body uses to make niacin. Third, it may be caused by excess leucine, as it inhibits quinolinate phosphoribosyl transferase (QPRT) and inhibits the formation of niacin or nicotinic acid to nicotinamide mononucleotide (NMN) causing pellagra like symptoms to occur.Some conditions can prevent the absorption of dietary niacin or tryptophan and lead to pellagra. Inflammation of the jejunum or ileum can prevent nutrient absorption, leading to pellagra, and this can in turn be caused by Crohns disease. Gastroenterostomy can also cause pellagra. Chronic alcoholism can also cause poor absorption which combines with a diet already low in niacin and tryptophan to produce pellagra. Hartnup disease is a genetic disorder that reduces tryptophan absorption, leading to pellagra.
Alterations in protein metabolism may also produce pellagra-like symptoms. An example is carcinoid syndrome, a disease in which neuroendocrine tumors along the GI tract use tryptophan as the source for serotonin production, which limits the available tryptophan for niacin synthesis. In normal patients, only one percent of dietary tryptophan is converted to serotonin; however, in patients with carcinoid syndrome, this value may increase to 70%. Carcinoid syndrome thus may produce niacin deficiency and clinical manifestations of pellagra. Anti-tuberculosis medication tends to bind to vitamin B6 and reduce niacin synthesis, since B6 (pyridoxine) is a required cofactor in the tryptophan-to-niacin reaction.
Several therapeutic drugs can provoke pellagra. These include the antibiotics isoniazid, which decreases available B6 by binding to it and making it inactive, so it cannot be used in niacin synthesis, and chloramphenicol; the anti-cancer agent fluorouracil; and the immunosuppressant mercaptopurine.
Treatment
If untreated, pellagra can kill within four or five years. Treatment is with nicotinamide, which has the same vitamin function as niacin and a similar chemical structure, but has lower toxicity. The frequency and amount of nicotinamide administered depends on the degree to which the condition has progressed.
Epidemiology
Pellagra can be common in people who obtain most of their food energy from corn, notably rural South America, where maize is a staple food. If maize is not nixtamalized, it is a poor source of tryptophan, as well as niacin. Nixtamalization corrects the niacin deficiency, and is a common practice in Native American cultures that grow corn, but most especially in Mexico and the countries of Central America. Following the corn cycle, the symptoms usually appear during spring, increase in the summer due to greater sun exposure, and return the following spring. Indeed, pellagra was once endemic in the poorer states of the U.S. South, such as Mississippi and Alabama, where its cyclical appearance in the spring after meat-heavy winter diets led to it being known as "spring sickness" (particularly when it appeared among more vulnerable children), as well as among the residents of jails and orphanages as studied by Dr. Joseph Goldberger.Pellagra is common in Africa, Indonesia, and China. In affluent societies, a majority of patients with clinical pellagra are poor, homeless, alcohol-dependent, or psychiatric patients who refuse food. Pellagra was common among prisoners of Soviet labor camps (the Gulags). In addition, pellagra, as a micronutrient deficiency disease, frequently affects populations of refugees and other displaced people due to their unique, long-term residential circumstances and dependence on food aid. Refugees typically rely on limited sources of niacin provided to them, often peanuts (which, in Africa, may be supplied in place of local groundnut staples, such as the Bambara or Hausa groundnut); the instability in the nutritional content and distribution of food aid can be the cause of pellagra in displaced populations. In the 2000s, there were outbreaks in countries such as Angola, Zimbabwe and Nepal. In Angola specifically, recent reports show a similar incidence of pellagra since 2002, with clinical pellagra in 0.3% of women and 0.2% of children and niacin deficiency in 29.4% of women and 6% of children related to high untreated corn consumption.In other countries such as the Netherlands and Denmark, even with sufficient intake of niacin, cases have been reported. In this case, deficiency might happen not just because of poverty or malnutrition but secondary to alcoholism, drug interaction (psychotropic, cytostatic, tuberculostatic or analgesics), HIV, vitamin B2 and B6 deficiency, or malabsorption syndromes such as Hartnup disease and carcinoid tumors.
History
Native American cultivators who first domesticated corn (maize) prepared it by nixtamalization, in which the grain is treated with a solution of alkali such as lime. Nixtamalization makes the niacin nutritionally available and prevents pellagra. When maize was cultivated worldwide, and eaten as a staple without nixtamalization, pellagra became common.
Pellagra was first described for its dermatological effect in Spain in 1735 by Gaspar Casal. He explained that the disease causes dermatitis in exposed skin areas such as hands, feet and neck and that the origin of the disease is poor diet and atmospheric influences. His work published in 1762 by his friend Juan Sevillano was titled Historia Natural y Medicina del Principado de Asturias or Natural and Medical History of the Principality of Asturias (1762). This led to the disease being known as "Asturian leprosy", and it is recognized as the first modern pathological description of a syndrome. It was an endemic disease in northern Italy, where it was named, from Lombard, as "pell agra" (agra = holly-like or serum-like; pell = skin) by Francesco Frapolli of Milan. With pellagra affecting over 100,000 people in Italy by the 1880s, debates raged as to how to classify the disease (as a form of scurvy, elephantiasis or as something new), and over its causation. In the 19th century, Roussel started a campaign in France to restrict consumption of maize and eradicated the disease in France, but it remained endemic in many rural areas of Europe. Because pellagra outbreaks occurred in regions where maize was a dominant food crop, the most convincing hypothesis during the late 19thcentury, as espoused by Cesare Lombroso, was that the maize either carried a toxic substance or was a carrier of disease. Louis Sambon, an Anglo-Italian doctor working at the London School of Tropical Medicine, was convinced that pellagra was carried by an insect, along the lines of malaria. Later, the lack of pellagra outbreaks in Mesoamerica, where maize is a major food crop, led researchers to investigate processing techniques in that region.
Pellagra was studied mostly in Europe until the late 19th century when it became epidemic especially in the southern United States. In the early 1900s, pellagra reached epidemic proportions in the American South. Between 1906 and 1940 more than 3 million Americans were affected by pellagra with more than 100,000 deaths, yet the epidemic resolved itself right after dietary niacin fortification. Pellagra deaths in South Carolina numbered 1,306 during the first ten months of 1915; 100,000 Southerners were affected in 1916. At this time, the scientific community held that pellagra was probably caused by a germ or some unknown toxin in corn. The Spartanburg Pellagra Hospital in Spartanburg, South Carolina, was the nations first facility dedicated to discovering the cause of pellagra. It was established in 1914 with a special Congressional appropriation to the U.S. Public Health Service (PHS) and set up primarily for research. In 1915, Dr. Joseph Goldberger, assigned to study pellagra by the Surgeon General of the United States, showed it was linked to diet by observing the outbreaks of pellagra in orphanages and mental hospitals. Goldberger noted that children between the ages of 6 and 12 (but not older or younger children at the orphanages) and patients at the mental hospitals (but not doctors or nurses) were the ones who seemed most susceptible to pellagra. Goldberger theorized that a lack of meat, milk, eggs, and legumes made those particular populations susceptible to pellagra. By modifying the diet served in these institutions with "a marked increase in the fresh animal and the leguminous protein foods," Goldberger was able to show that pellagra could be prevented. By 1926, Goldberger established that a diet that included these foods, or a small amount of brewers yeast, prevented pellagra.
Goldberger experimented on 11 prisoners (one was dismissed because of prostatitis). Before the experiment, the prisoners were eating the prison fare fed to all inmates at Rankin Prison Farm in Mississippi. Goldberger started feeding them a restricted diet of grits, syrup, mush, biscuits, cabbage, sweet potatoes, rice, collards, and coffee with sugar (no milk). Healthy white male volunteers were selected as the typical skin lesions were easier to see in Caucasians and this population was felt to be those least susceptible to the disease, and thus provide the strongest evidence that the disease was caused by a nutritional deficiency. Subjects experienced mild, but typical cognitive and gastrointestinal symptoms, and within five months of this cereal-based diet, 6 of the 11 subjects broke out in the skin lesions that are necessary for a definitive diagnosis of pellagra. The lesions appeared first on the scrotum. Goldberger was not given the opportunity to experimentally reverse the effects of diet-induced pellagra as the prisoners were released shortly after the diagnoses of pellagra were confirmed. In the 1920s, he connected pellagra to the corn-based diets of rural areas rather than infection as contemporary medical opinion would suggest. Goldberger believed that the root cause of pellagra amongst Southern farmers was limited diet resulting from poverty, and that social and land reform would cure epidemic pellagra. His reform efforts were not realized, but crop diversification in the Southern United States, and the accompanying improvement in diet, dramatically reduced the risk of pellagra. Goldberger is remembered as the "unsung hero of American clinical epidemiology". Though he identified that a missing nutritional element was responsible for pellagra, he did not discover the specific vitamin responsible.
In 1937, Conrad Elvehjem, a biochemistry professor at the University of Wisconsin-Madison, showed that the vitamin niacin cured pellagra (manifested as black tongue) in dogs. Later studies by Dr. Tom Spies, Marion Blankenhorn, and Clark Cooper established that niacin also cured pellagra in humans, for which Time Magazine dubbed them its 1938 Men of the Year in comprehensive science.Research conducted between 1900 and 1950 found the number of cases of women with pellagra was consistently double the number of cases of affected men. This is thought to be due to the inhibitory effect of estrogen on the conversion of the amino acid tryptophan to niacin. Some researchers of the time gave a few explanations regarding the difference.Gillman and Gillman related skeletal tissue and pellagra in their research in South Africans. They provide some of the best evidence for skeletal manifestations of pellagra and the reaction of bone in malnutrition. They claimed radiological studies of adult pellagrins demonstrated marked osteoporosis. A negative mineral balance in pellagrins was noted, which indicated active mobilization and excretion of endogenous mineral substances, and undoubtedly impacted the turnover of bone. Extensive dental caries were present in over half of pellagra patients. In most cases, caries were associated with "severe gingival retraction, sepsis, exposure of cementum, and loosening of teeth".
Etymology
The word pellagra comes from the Lombard words "pell" (skin) and "agra" (fem. sour).
United States
Pellagra was first reported in 1902 in the United States, and has "caused more deaths than any other nutrition-related disease in American history", reaching epidemic proportions in the American South during the early 1900s. Poverty and consumption of corn were the most frequently observed risk factors, but the exact cause was not known, until groundbreaking work by Joseph Goldberger. A 2017 National Bureau of Economic Research paper explored the role of cotton production in the emergence of disease; one prominent theory is that "widespread cotton production had displaced local production of niacin-rich foods and driven poor Southern farmers and mill workers to consume milled Midwestern corn, which was relatively cheap but also devoid of the niacin necessary to prevent pellagra." The study provided evidence in favor of the theory: there were lower pellagra rates in areas where farmers had been forced to abandon cotton production (a highly profitable crop) in favor of food crops (less profitable crops) due to boll weevil infestation of cotton crops (which occurred randomly).The whole dried corn kernel contains a nutritious germ and a thin seed coat that provides some fiber. There are two important considerations for using ground whole-grain corn.
The germ contains oil that is exposed by grinding, thus whole-grain cornmeal and grits turn rancid quickly at room temperature and should be refrigerated.
Whole-grain cornmeal and grits require extended cooking times as seen in the following cooking directions for whole-grain grits:"Place the grits in a pan and cover them with water. Allow the grits to settle a full minute, tilt the pan, and skim off and discard the chaff and hulls with a fine tea strainer. Cook the grits for 50 minutes if the grits were soaked overnight or else 90 minutes if not."
Most of the niacin in mature cereal grains is present as niacytin, which is niacin bound up in a complex with hemicellulose which is nutritionally unavailable. In mature corn this may be up to 90% of the total niacin content. The preparation method of nixtamalization using the whole dried corn kernel made this niacin nutritionally available and reduced the chance of developing pellagra. Niacytin is concentrated in the aleurone and germ layers which are removed by milling. The milling and degerming of corn in the preparation of cornmeal became feasible with the development of the Beall degerminator, which was originally patented in 1901 and was used to separate the grit from the germ in corn processing. However, this process of degermination reduces the niacin content of the cornmeal.
Casimir Funk, who helped elucidate the role of thiamin in the etiology of beriberi, was an early investigator of the problem of pellagra. Funk suggested that a change in the method of milling corn was responsible for the outbreak of pellagra, but no attention was paid to his article on this subject.Pellagra developed especially among the vulnerable populations in institutions such as orphanages and prisons, because of the monotonous and restricted diet. Soon pellagra began to occur in epidemic proportions in states south of the Potomac and Ohio rivers. The pellagra epidemic lasted for nearly four decades beginning in 1906. It was estimated that there were 3 million cases, and 100,000 deaths due to pellagra during the epidemic.
Popular culture
George Sessions Perrys 1941 novel Hold Autumn in Your Hand – and Jean Renoirs 1945 film adaptation of it, The Southerner – incorporates pellagra ("spring sickness") as a major plot element in the story of an impoverished Texas farm family.
See also
Central chromatolysis
Harriette Chick
Zeism
References
Further reading
External links
"Pellagra" . Encyclopædia Britannica. Vol. 21 (11th ed.). 1911. p. 69.
Pellagra – Food and Agriculture Organization (FAO) |
Pemphigus vulgaris | Pemphigus vulgaris is a rare chronic blistering skin disease and the most common form of pemphigus. Pemphigus was derived from the Greek word pemphix, meaning blister. It is classified as a type II hypersensitivity reaction in which antibodies are formed against desmosomes, components of the skin that function to keep certain layers of skin bound to each other. As desmosomes are attacked, the layers of skin separate and the clinical picture resembles a blister. These blisters are due to acantholysis, or breaking apart of intercellular connections through an autoantibody-mediated response. Over time the condition inevitably progresses without treatment: lesions increase in size and distribution throughout the body, behaving physiologically like a severe burn.
Before the advent of modern treatments, mortality for the disease was close to 90%. Today, the mortality rate with treatment is between 5-15% due to the introduction of corticosteroids as primary treatment. Nevertheless, in 1998, pemphigus vulgaris was the fourth most common cause of death due to a skin disorder.
The disease mainly affects middle-aged and older adults between 50–60 years old. There has historically been a higher incidence in women.
Signs and symptoms
Pemphigus vulgaris most commonly presents with oral blisters (buccal and palatine mucosa, especially), but also includes cutaneous blisters. Other mucosal surfaces, the conjunctiva, nose, esophagus, penis, vulva, vagina, cervix, and anus, may also be affected. Flaccid blisters over the skin are frequently seen with sparing of the skin covering the palms and soles.Blisters commonly erode and leave ulcerated lesions and erosions. A positive Nikolsky sign (induction of blistering in normal skin or at the edge of a blister) is indicative of the disease.Severe pain with chewing can lead to weight loss and malnutrition.
Pathophysiology
Pemphigus is an autoimmune disease caused by antibodies directed against both desmoglein 1 and desmoglein 3 present in desmosomes. Loss of desmosomes results in loss of cohesion between keratinocytes in the epidermis, and a disruption of the barrier function served by intact skin. The process is classified as a type II hypersensitivity reaction (in which antibodies bind to antigens on the bodys own tissues). On histology, the basal keratinocytes are usually still attached to the basement membrane leading to a characteristic appearance called "tombstoning". Transudative fluid accumulates in between the keratinocytes and the basal layer (suprabasal split), forming a blister and resulting in what is known as a positive Nikolskys sign. This is a contrasting feature from bullous pemphigoid, which is thought to be due to anti-hemidesmosome antibodies, and where the detachment occurs between the epidermis and dermis (subepidermal bullae). Clinically, pemphigus vulgaris is characterized by extensive flaccid blisters and mucocutaneous erosions. The severity of the disease, as well as the mucosal lesions, is believed to be directly proportional to the levels of desmoglein 3. Milder forms of pemphigus (like foliacious and erythematoses) are more anti-desmoglein 1 heavy.
The disease arises most often in middle-aged or older people, usually starting with a blister that ruptures easily. It can also start with blisters in the mouth. The lesions can become quite extensive.
Diagnosis
Because it is a rare disease, diagnosis is often complicated and takes a long time. Early in the disease patients may have erosions in the mouth or blisters on the skin. These blisters can be itchy or painful. Theoretically, the blisters should demonstrate a positive Nikolskys sign, in which the skin sloughs off from slight rubbing, but this is not always reliable. The gold standard for diagnosis is a punch biopsy from the area around the lesion that is examined by direct immunofluorescent staining, in which cells are acantholytic, that is, lacking the normal intercellular connections that hold them together. These can also be seen on a Tzanck smear. These cells are basically rounded, nucleated keratinocytes formed due to antibody mediated damage to cell adhesion protein desmoglein.
Pemphigus vulgaris is easily confused with impetigo and candidiasis. IgG4 is considered pathogenic. The diagnosis can be confirmed by testing for the infections that cause these other conditions, and by a lack of response to antibiotic treatment.
Treatment
Corticosteroids and other immunosuppressive medications have historically been employed to reduce pemphigus symptoms, yet steroids are associated with serious and long-lasting side effects and their use should be limited as much as possible. Intravenous immunoglobulin, mycophenolate mofetil, methotrexate, azathioprine, and cyclophosphamide have also been used with varying degrees of success.
An established alternative to steroids are monoclonal antibodies such as rituximab, which are increasingly being used as first-line treatment. In summer 2018, the FDA granted full approval to rituximab for this application, following successful fast track evaluation. In numerous case series, many patients achieve remission after one cycle of rituximab. Treatment is more successful if initiated early on in the course of disease, perhaps even at diagnosis. Rituximab treatment combined with monthly IV immunoglobulin infusions has resulted in long-term remission with no recurrence of disease in 10 years after treatment was halted. This was a small trial study of 11 patients with 10 patients followed to completion.
Rituximab demonstrated superior efficacy compared to mycophenolate mofetil in a Phase III clinical trial, results of which were published in 2021.
Epidemiology
Pemphigus vulgaris is a relatively rare disease that only affects about 1 to 5 people in 1 million in the United Kingdom, with an incidence of 1-10 cases per 1 million people across the world. There is an estimated prevalence of 30,000-40,000 cases in the United States. Cases of P. vulgaris usually dont develop until after the age of 50 or so. The disease is not contagious which means it cannot be spread from person to person. There is currently no way of knowing who will be affected with P. vulgaris in their life as it is usually not a genetic disorder and is usually triggered later in life by environmental factors. Men and women are both equally affected and the disease has been found to affect people of many different cultures and racial backgrounds, especially Ashkenazi Jews, people of Mediterranean, North Indian and Persian descent. There has been no found difference in the rate of disease when looking at socioeconomic factors as well.If left untreated, 8 of 10 people with the disease die within a year with a cause of death being infection or loss of fluids, which is very common for raw, open sores that are characteristic of P. vulgaris. With treatment, only about 1 in 10 people with the disease die, either from the condition, or side effects of the medicine.An effect of the disease being so rare is that there is not enough evidence to prove that the treatments currently being used are actually as effective as they could be. Doctors are trying to find effective steroid-sparing agents to use in the treatment, to decrease the side effects of long term steroid treatment. The small amount of case numbers make it hard to test statistical significance between the affected and the control groups when testing if these types of systematic treatments are effective.
Research
Research into using genetically modified T-cells to treat pemphigus vulgaris in mice was reported in 2016. Rituximab indiscriminately attacks all B cells, which reduces the bodys ability to control infections. In the experimental treatment, human T cells are genetically engineered to recognize only those B cells that produce antibodies to desmoglein. In PV, autoreactive B cells produce antibodies against Dsg3, disrupting its adhesive function and causing skin blistering. By expressing Dsg3 on their surfaces, the CAAR-T cells lure those B cells in and kill them. The Dsg 3 CAAR-T cells eliminated Dsg3-specific B cells in lab dishes and in mice, the researchers reported at the time.
Penns Aimee Payne, M.D., Ph.D., and Michael Milone, M.D., Ph.D., a co-inventor of Novartis’ CAR-T cancer therapy Kymriah, pioneered the CAAR-T idea and have founded biotech Cabaletta Bio, hoping to bring their therapies through clinical studies to the market. The MuSK-CAAR-T is the second candidate in its pipeline; the company has already received FDA clearance to test its lead project, DSG3-CAAR-T, in patients with mucosal pemphigus vulgaris (PV), and a phase 1 trial is expected to start in 2020.
See also
List of conditions caused by problems with junctional proteins
List of cutaneous conditions
List of immunofluorescence findings for autoimmune bullous conditions
References
External links
Pemphigus vulgaris - DermNet New Zealand |
Periodic paralysis | Periodic paralysis is a group of rare genetic diseases that lead to weakness or paralysis from common triggers such as cold, heat, high carbohydrate meals, not eating, stress or excitement and physical activity of any kind. The underlying mechanism of these diseases are malfunctions in the ion channels in skeletal muscle cell membranes that allow electrically charged ions to leak in or out of the muscle cell, causing the cell to depolarize and become unable to move.The symptoms of periodic paralysis can also be caused by hyperthyroidism, and are then labeled thyrotoxic periodic paralysis; however, if this is the underlying condition there are likely to be other characteristic manifestations, enabling a correct diagnosis.
Types
Periodic paralysis is an autosomal dominant myopathy with considerable variation in penetrance, leading to a spectrum of familial phenotypes (only one parent needs to carry the gene mutation to affect the children, but not all family members who share the gene are affected to the same degree). Specific diseases include:
Hypokalemic periodic paralysis (Online Mendelian Inheritance in Man (OMIM): 170400), where potassium leaks into the muscle cells from the bloodstream.
Hyperkalemic periodic paralysis (Online Mendelian Inheritance in Man (OMIM): 170500), where potassium leaks out of the cells into the bloodstream.
Paramyotonia congenita (Online Mendelian Inheritance in Man (OMIM): 168300), a form which often accompanies hyperkalemic periodic paralysis, but may present alone. The primary symptom of paramyotonia congenita is muscle contracture which develops during exercise or activity. Paramyotonia congenita attacks may also be triggered by a low level of potassium in the bloodstream. This means people with both hyperkalemic periodic paralysis and paramyotonia congenita can have attacks with fluctuations of potassium up or down.
Andersen-Tawil syndrome (Online Mendelian Inheritance in Man (OMIM): 170390), a form of periodic paralysis that includes significant heart rhythm problems, fainting and risk of sudden death. Potassium levels may be low, high, or normal during attacks of ATS. Patients with ATS may also have skeletal abnormalities like scoliosis (curvature of the spine), webbing between the second and third toes or fingers (syndactyly), crooked fingers (clinodactyly), a small jaw (micrognathia) and low-set ears. Patients need to have another form of periodic paralysis to have the Andersen-Tawil. If a patient has hypo or hyper periodic paralysis they have a 50% chance of getting Andersen-Tawil. They just have to have the gene that causes it. This is a rare occurrence of having this. Only around 100 people in the world are recorded to have it.
Cause
One of the most common descriptions of periodic paralysis are episodic attacks of muscle weakness, which are commonly associated with serum potassium levels. Physical activity and diet content (carbohydrates) have been identified as PP triggers. Unlike non-dystrophic myotonias, the periodic paralysis phenotype is triggered after resting following exercise. Voltage-gated sodium channel (Nav1.4) mutations are among the key causes behind periodic paralysis.Hyper-kalemic PP (hyperPP) is identified with high extracellular potassium levels which are typically greater than 5 mM during attacks; however, HyperPP attacks can also take place without rise in potassium concentrations. HyperPP has a prevalence rate of 1/100,000. Patients become symptomatic around the age of 10. The weakness attacks in hyperPP are relatively short lasting, and range from minutes to hours. The attacks can happen upwards of ten times per month.Hypo-kalemic PP (hypoPP) is associated with low potassium levels. The onset of hypoPP occurs between the ages of 15 and 35. The prevalence of hypoPP is estimated to 1/100,000. HypoPP can be triggered by many external factors such as stress, high-sugar diet, and rest after exercise. During hypoPP attacks, the serum potassium concentrations can drop to less than 3 mM. Furthermore, hypoPP attacks are considerably longer lasting than hyperPP. As exercise is a trigger for periodic paralysis attacks, recently there is more research going into the physiological changes that accompany exercise including changes in blood pH.
Diagnosis
This disease is unusually difficult to diagnose. Patients often report years of wrong diagnosis and treatments that made them worse instead of better. Part of this may be that migraines are present in up to 50% of patients and can cause a confusing array of symptoms including headaches, speech difficulties and visual, auditory or sensory auras. DNA testing is available for only a half dozen common gene mutations, while dozens of known mutations are possible but are not routinely tested. Electromyography (EMG) findings are not specific but the McManis Protocol, also called the Compound Muscle Amplitude Potential test (CMAP) can be used by a skilled neurologist capable of utilizing the EMG, which can give assistance in diagnosing several of these PP disorders. The old glucose/insulin provocative testing can cause life-threatening symptoms and should not be used.Also of note is that potassium levels do not have to range outside of normal limits to cause serious, even life-threatening paralysis. These diseases are not the same as having a very low level of potassium (hypokalemia) or high potassium (hyperkalemia) and must not be treated as such. The total body store of potassium is usually normal; it is just in the wrong place.
Treatment
Treatment of the periodic paralyses may include carbonic anhydrase inhibitors (such as acetazolamide, methazolamide or dichlorphenamide), taking supplemental oral potassium chloride and a potassium-sparing diuretic (for hypos) or avoiding potassium (for hypers), thiazide diuretics to increase the amount of potassium excreted by the kidneys (for hypers), and significant lifestyle changes including tightly controlled levels of exercise or activity. However, treatment should be tailored to the particular type of periodic paralysis.Treatment of periodic paralysis in Andersen-Tawil syndrome is similar to that for other types. However, pacemaker insertion or an implantable cardioverter-defibrillator may be required to control cardiac symptoms.
Prognosis
While the disability can range from minor, occasional weakness to permanent muscle damage, inability to hold a normal job and use of a powerchair, most people function fairly well with drugs and lifestyle changes.
References
Song, YW; Kim, SJ; Heo, TH; Kim, MH; Kim, JB (Dec 2012). "Normokalemic periodic paralysis is not a distinct disease". Muscle & Nerve. 46 (6): 908–913. doi:10.1002/mus.23441. PMID 22926674. S2CID 43821573.
External links
NIH information page on periodic paralysis |
Periodontal disease | Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main cause of tooth loss for adults worldwide. In its more serious form, called periodontitis, the gums can pull away from the tooth, bone can be lost, and the teeth may loosen or fall out. Bad breath may also occur.Periodontal disease is generally due to bacteria in the mouth infecting the tissue around the teeth. Factors that increase the risk of disease include smoking, diabetes, HIV/AIDS, family history, and certain medications. Diagnosis is by inspecting the gum tissue around the teeth both visually and with a probe and X-rays looking for bone loss around the teeth.Treatment involves good oral hygiene and regular professional teeth cleaning. Recommended oral hygiene include daily brushing and flossing. In certain cases antibiotics or dental surgery may be recommended. Clinical trials show that smoking cessation and dietary improvements improve disease outcomes. Globally 538 million people were estimated to be affected in 2015 and has been known to affect 10-15% of the population generally. In the United States nearly half of those over the age of 30 are affected to some degree, and about 70% of those over 65 have the condition. Males are affected more often than females.
Signs and symptoms
In the early stages, periodontitis has very few symptoms, and in many individuals the disease has progressed significantly before they seek treatment.
Symptoms may include:
Redness or bleeding of gums while brushing teeth, using dental floss or biting into hard food (e.g., apples) (though this may also occur in gingivitis, where there is no attachment loss gum disease )
Gum swelling that recurs
Spitting out blood after brushing teeth
Halitosis, or bad breath, and a persistent metallic taste in the mouth
Gingival recession, resulting in apparent lengthening of teeth (this may also be caused by heavy-handed brushing or with a stiff toothbrush)
Deep pockets between the teeth and the gums (pockets are sites where the attachment has been gradually destroyed by collagen-destroying enzymes, known as collagenases)
Loose teeth, in the later stages (though this may occur for other reasons, as well)Gingival inflammation and bone destruction are largely painless. Hence, people may wrongly assume painless bleeding after teeth cleaning is insignificant, although this may be a symptom of progressing periodontitis in that person.
Associated conditions
Periodontitis has been linked to increased inflammation in the body, such as indicated by raised levels of C-reactive protein and interleukin-6. It is associated with an increased risk of stroke, myocardial infarction, atherosclerosis and hypertension. It also linked in those over 60 years of age to impairments in delayed memory and calculation abilities. Individuals with impaired fasting glucose and diabetes mellitus have higher degrees of periodontal inflammation, and often have difficulties with balancing their blood glucose level owing to the constant systemic inflammatory state, caused by the periodontal inflammation. Although no causal association was proven, there is an association between chronic periodontitis and erectile dysfunction, inflammatory bowel disease, heart disease, and pancreatic cancer.
Diabetes and Periodontal Disease
A positive correlation between raised levels of glucose within the blood and the onset or progression of periodontal disease has been shown in the current literature.
Data has also shown that there is a significant increase in the incidence or progression of periodontitis in patients with uncontrolled diabetes compared to those who do not have diabetes or have well-controlled diabetes. In uncontrolled diabetes, the formation of reactive oxygen species can damage cells such as those in the connective tissue of the periodontal ligament, resulting in cell necrosis or apoptosis. Furthermore, individuals with uncontrolled diabetes mellitus who have frequent exposure to periodontal pathogens have a greater immune response to these bacteria. This can subsequently cause and/or accelerate periodontal tissue destruction leading to periodontal disease.Oral Cancer and Periodontal Disease
Current literature suggests a link between periodontal disease and oral cancer. Studies have confirmed an increase in systemic inflammation markers such as C-Reactive Protein and Interleukin-6 to be found in patients with advanced periodontal disease. The link between systemic inflammation and oral cancer has also been well established.
Both periodontal disease and cancer risk are associated with genetic susceptibility and it is possible that there is a positive association by a shared genetic susceptibility in the two diseases.
Due to the low incidence rate of oral cancer, studies have not been able to conduct quality studies to prove the association between the two, however future larger studies may aid in the identification of individuals at a higher risk.Systemic implications
Periodontal disease (PD) can be described as an inflammatory condition affecting the supporting structures of the teeth. Studies have shown that PD is associated with higher levels of systemic inflammatory markers such as Interleukin-6 (IL-6), C-Reactive Protein (CRP) and Tumor Necrosis Factor (TNF). To compare, elevated levels of these inflammatory markers are also associated with cardiovascular disease and cerebrovascular events such as ischemic strokes.The presence of a wide spectrum inflammatory oral diseases can increase the risk of an episode of stroke in an acute or chronic phase. Inflammatory markers, CRP, IL-6 are known risk factors of stroke. Both inflammatory markers are also biomarkers of PD and found to be an increased level after daily activities, such as mastication or toothbrushing, are performed. Bacteria from the periodontal pockets will enter the bloodstream during these activities and the current literature suggests that this may be a possible triggering of the aggravation of the stroke process.Other mechanisms have been suggested, PD is a known chronic infection. It can aid in the promotion of atherosclerosis by the deposition of cholesterol, cholesterol esters and calcium within the subendothelial layer of vessel walls. Atherosclerotic plaque that is unstable may rupture and release debris and thrombi that may travel to different parts of the circulatory system causing embolization and therefore, an ischemic stroke. Therefore, PD has been suggested as an independent risk factor for stroke.
A variety of cardiovascular diseases can also be associated with periodontal disease. Patients with higher levels of inflammatory markers such as TNF, IL-1, IL-6 and IL-8 can lead to progression of atherosclerosis and the development and perpetuation of atrial fibrillation, as it is associated with platelet and coagulation cascade activations, leading to thrombosis and thrombotic complications.
Experimental animal studies have shown a link between periodontal disease, oxidative stress and cardiac stress. Oxidative stress favours the development and progression of heart failure as it causes cellular dysfunction, oxidation of proteins and lipids, and damage to the deoxyribonucleic acid (DNA), stimulating fibroblast proliferation and metalloproteinases activation favouring cardiac remodelling.
Clinical Significance
Inadequate Nutrition and Periodontal Disease
Periodontal disease is multifactorial, and nutrition can significantly affect its prognosis. Studies have shown that a healthy and well-balanced diet is crucial to maintaining periodontal health. Nutritional deficiencies can lead to oral manifestations such as those in scurvy and rickets disease.
Different vitamins will play a different role in periodontal health:
Vitamin C: Deficiencies may lead to gingival inflammation and bleeding, subsequently advancing periodontal disease
Vitamin D: Deficiencies may lead to delayed post-surgical healing
Vitamin E: Deficiencies may lead to impaired gingival wound healing
Vitamin K: Deficiencies may lead to gingival bleedingNutritional supplements of vitamins have also been shown to positively affect healing after periodontal surgery and many of these vitamins can be found in a variety of food that we eat within a regular healthy diet.
Therefore, vitamin intakes (particularly vitamin C) and dietary supplements not only play a role in improving periodontal health, but also influence the rate of bone formation and periodontal regeneration. However, studies supporting the correlation between nutrition and periodontal health are limited, and more long-term research is required to confirm this.
Causes
Periodontitis is an inflammation of the periodontium, i.e., the tissues that support the teeth. The periodontium consists of four tissues:
gingiva, or gum tissue,
cementum, or outer layer of the roots of teeth,
alveolar bone, or the bony sockets into which the teeth are anchored, and
periodontal ligaments (PDLs), which are the connective tissue fibers that run between the cementum and the alveolar bone.
The primary cause of gingivitis is poor or ineffective oral hygiene, which leads to the accumulation of a mycotic and bacterial matrix at the gum line, called dental plaque. Other contributors are poor nutrition and underlying medical issues such as diabetes. Diabetics must be meticulous with their homecare to control periodontal disease. New finger prick tests have been approved by the Food and Drug Administration in the US, and are being used in dental offices to identify and screen people for possible contributory causes of gum disease, such as diabetes.
In some people, gingivitis progresses to periodontitis – with the destruction of the gingival fibers, the gum tissues separate from the tooth and deepened sulcus, called a periodontal pocket. Subgingival microorganisms (those that exist under the gum line) colonize the periodontal pockets and cause further inflammation in the gum tissues and progressive bone loss. Examples of secondary causes are those things that, by definition, cause microbic plaque accumulation, such as restoration overhangs and root proximity.
Smoking is another factor that increases the occurrence of periodontitis, directly or indirectly, and may interfere with or adversely affect its treatment. It is arguably the most important environmental risk factor for periodontitis. Research has shown that smokers have more bone loss, attachment loss and tooth loss compared to non-smokers. This is likely due to several effects of smoking on the immune response including decreased wound healing, suppression of antibody production, and the reduction of phagocytosis by neutrophilsEhlers–Danlos syndrome and Papillon–Lefèvre syndrome (also known as palmoplantar keratoderma) are also risk factors for periodontitis.
If left undisturbed, microbial plaque calcifies to form calculus, which is commonly called tartar. Calculus above and below the gum line must be removed completely by the dental hygienist or dentist to treat gingivitis and periodontitis. Although the primary cause of both gingivitis and periodontitis is the microbial plaque that adheres to the tooth surfaces, there are many other modifying factors. A very strong risk factor is ones genetic susceptibility. Several conditions and diseases, including Down syndrome, diabetes, and other diseases that affect ones resistance to infection, also increase susceptibility to periodontitis.
Periodontitis may be associated with higher stress. Periodontitis occurs more often in people from the lower end of the socioeconomic scale than people from the upper end of the socioeconomic scale.Genetics appear to play a role in determining the risk for periodontitis. It is believed genetics could explain why some people with good plaque control have advanced periodontitis, whilst some others with poor oral hygiene are free from the disease. Genetic factors which could modify the risk of a person developing periodontitis include:
Defects of phagocytosis: person may have hypo-responsive phagocytes.
Hyper-production of interleukins, prostaglandins and cytokines, resulting in an exaggerated immune response.
Interleukin 1 (IL-1) gene polymorphism: people with this polymorphism produce more IL-1, and subsequently are more at risk of developing chronic periodontitis.Diabetes appears to exacerbate the onset, progression, and severity of periodontitis. Although the majority of research has focused on type 2 diabetes, type 1 diabetes appears to have an identical effect on the risk for periodontitis. The extent of the increased risk of periodontitis is dependent on the level of glycaemic control. Therefore, in well managed diabetes there seems to be a small effect of diabetes on the risk for periodontitis. However, the risk increases exponentially as glycaemic control worsens. Overall, the increased risk of periodontitis in diabetics is estimated to be between two and three times higher. So far, the mechanisms underlying the link are not fully understood, but it is known to involve aspects of inflammation, immune functioning, neutrophil activity, and cytokine biology.
Mechanism
As dental plaque or biofilm accumulates on the teeth near and below the gums there is some dysbiosis of the normal oral microbiome. As of 2017 it was not certain what species were most responsible for causing harm, but gram-negative anaerobic bacteria, spirochetes, and viruses have been suggested; in individual people it is sometimes clear that one or more species is driving the disease. Research in 2004 indicated three gram negative anaerobic species: Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Bacteroides forsythus and Eikenella corrodens.Plaque may be soft and uncalcified, hard and calcified, or both; for plaques that are on teeth the calcium comes from saliva; for plaques below the gumline, it comes from blood via oozing of inflamed gums.The damage to teeth and gums comes from the immune system as it attempts to destroy the microbes that are disrupting the normal symbiosis between the oral tissues and the oral microbe community. As in other tissues, Langerhans cells in the epithelium take up antigens from the microbes, and present them to the immune system, leading to movement of white blood cells into the affected tissues. This process in turn activates osteoclasts which begin to destroy bone, and it activates matrix metalloproteinases that destroy ligaments. So, in summary, it is bacteria which initiates the disease, but key destructive events are brought about by the exaggerated response from the hosts immune system.
Classification
There were several attempts to introduce an agreed-upon classification system for periodontal diseases: in 1989, 1993, 1999, and 2017.
1999 classification
The 1999 classification system for periodontal diseases and conditions listed seven major categories of periodontal diseases, of which 2–6 are termed destructive periodontal disease, because the damage is essentially irreversible. The seven categories are as follows:
Gingivitis
Chronic periodontitis
Aggressive periodontitis
Periodontitis as a manifestation of systemic disease
Necrotizing ulcerative gingivitis/periodontitis
Abscesses of the periodontium
Combined periodontic-endodontic lesionsMoreover, terminology expressing both the extent and severity of periodontal diseases are appended to the terms above to denote the specific diagnosis of a particular person or group of people.
Severity
The "severity" of disease refers to the amount of periodontal ligament fibers that have been lost, termed "clinical attachment loss". According to the 1999 classification, the severity of chronic periodontitis is graded as follows:
Slight: 1–2 mm (0.039–0.079 in) of attachment loss
Moderate: 3–4 mm (0.12–0.16 in) of attachment loss
Severe: ≥ 5 mm (0.20 in) of attachment loss
Extent
The "extent" of disease refers to the proportion of the dentition affected by the disease in terms of percentage of sites. Sites are defined as the positions at which probing measurements are taken around each tooth and, generally, six probing sites around each tooth are recorded, as follows:
Mesiobuccal
Mid-buccal
Distobuccal
Mesiolingual
Mid-lingual
DistolingualIf up to 30% of sites in the mouth are affected, the manifestation is classified as "localized"; for more than 30%, the term "generalized" is used.
2017 classification
The 2017 classification of periodontal diseases is as follows:Periodontal health, gingival disease and conditions
Periodontal health and gingival health
Clinical gingival health on an intact periodontium
Clinical gingival health on an intact periodontium
Stable periodontitis
Non periodontitis person
Gingivitis - Dental biofilm induced
Associated with the dental biofilm alone
Mediated by systemic and local risk factors
Drug induced gingival enlargement.
Gingival diseases - Non dental biofilm induced
Genetic/developmental disorders
Specific infections
Inflammatory and immune conditions
Reactive processes
Neoplasms
Endocrine, nutritional and metabolic
Traumatic lesions
Gingival pigmentation.Periodontitis
Necrotizing periodontal diseases
Necrotizing Gingivitis
Necrotizing Periodontitis
Necrotizing Stomatitis
Periodontitis as a manifestation of systemic disease
PeriodontitisOther conditions affecting the periodontium
(Periodontal Manifestations of Systemic Diseases and Developmental and Acquired Conditions)
Systemic disease of conditions affecting the periodontal support tissues
Other Periodontal Conditions
Periodontal abscesses
Endodontic- periodontal lesions
Mucogingival deformities and conditions
Gingival Phenotype
Gingival/Soft Tissue Recession
Lack of Gingiva
Decreased Vestibular Depth
Aberrant Frenum/muscle position
Gingival Excess
Abnormal Color
Condition of the exposed root surface
Traumatic occlusal forces
Primary Occlusal Trauma
Secondary Occlusal Trauma
Tooth and prosthesis related factors
Localized tooth-related factors
Localized dental prostheses-related factorsPeri-implant diseases and conditions
Peri-implant health
Peri-implant mucositis
Peri-implantitis
Peri-implant soft and hard tissue deficiencies
Staging
The goals of staging periodontitis is to classify the severity of damage and assess specific factors that may affect management.According to the 2017 classification, periodontitis is divided into four stages; after considering a few factors such as:
Amount and percentage bone loss radiographically
Clinical attachment loss, probing depth
Presence of furcation
Vertical bony defects
History of tooth loss related to periodontitis
Tooth hypermobility due to secondary occlusal trauma
Grading
According to the 2017 classification, the grading system for periodontitis consists of three grades:
Grade A: Slow progression of disease; no evidence of bone loss over last five years
Grade B: Moderate progression; < 2mm of bone loss over last five years
Grade C: Rapid progression or future progression at high risk; ≥ 2mm bone loss over five yearsRisk factors affecting which grade a person is classified into include:
Smoking
Diabetes
Prevention
Daily oral hygiene measures to prevent periodontal disease include:
Brushing properly on a regular basis (at least twice daily), with the person attempting to direct the toothbrush bristles underneath the gumline, helps disrupt the bacterial-mycotic growth and formation of subgingival plaque.
Flossing daily and using interdental brushes (if the space between teeth is large enough), as well as cleaning behind the last tooth, the third molar, in each quarter
Using an antiseptic mouthwash: Chlorhexidine gluconate-based mouthwash in combination with careful oral hygiene may cure gingivitis, although they cannot reverse any attachment loss due to periodontitis.
Regular dental check-ups and professional teeth cleaning as required: Dental check-ups serve to monitor the persons oral hygiene methods and levels of attachment around teeth, identify any early signs of periodontitis, and monitor response to treatment.Clinical trials show that smoking cessation abd dietary improvements improve disease outcomes.Typically, dental hygienists (or dentists) use special instruments to clean (debride) teeth below the gumline and disrupt any plaque growing below the gumline. This is a standard treatment to prevent any further progress of established periodontitis. Studies show that after such a professional cleaning (periodontal debridement), microbial plaque tends to grow back to precleaning levels after about three to four months. Nonetheless, the continued stabilization of a persons periodontal state depends largely, if not primarily, on the persons oral hygiene at home, as well as on the go. Without daily oral hygiene, periodontal disease will not be overcome, especially if the person has a history of extensive periodontal disease.
Management
The cornerstone of successful periodontal treatment starts with establishing excellent oral hygiene. This includes twice-daily brushing with daily flossing. Also, the use of an interdental brush is helpful if space between the teeth allows. For smaller spaces, products such as narrow picks with soft rubber bristles provide excellent manual cleaning. Persons with dexterity problems, such as with arthritis, may find oral hygiene to be difficult and may require more frequent professional care and/or the use of a powered toothbrush. Persons with periodontitis must realize it is a chronic inflammatory disease and a lifelong regimen of excellent hygiene and professional maintenance care with a dentist/hygienist or periodontist is required to maintain affected teeth.
Initial therapy
Removal of microbial plaque and calculus is necessary to establish periodontal health. The first step in the treatment of periodontitis involves nonsurgical cleaning below the gum line with a procedure called "root surface instrumentation" or "RSI", this causes a mechanical disturbance to the bacterial biofilm below the gumline. This procedure involves the use of specialized curettes to mechanically remove plaque and calculus from below the gumline, and may require multiple visits and local anesthesia to adequately complete. In addition to initial RSI, it may also be necessary to adjust the occlusion (bite) to prevent excessive force on teeth that have reduced bone support. Also, it may be necessary to complete any other dental needs, such as replacement of rough, plaque-retentive restorations, closure of open contacts between teeth, and any other requirements diagnosed at the initial evaluation. It is important to note that RSI is different to scaling and root planing: RSI only removes the calculus, while scaling and root planing removes the calculus as well as underlying softened dentine, which leaves behind a smooth and glassy surface, which is not a requisite for periodontal healing. Therefore, RSI is now advocated over root planing.
Reevaluation
Nonsurgical scaling and root planing are usually successful if the periodontal pockets are shallower than 4–5 mm (0.16–0.20 in). The dentist or hygienist must perform a re-evaluation four to six weeks after the initial scaling and root planing, to determine if the persons oral hygiene has improved and inflammation has regressed. Probing should be avoided then, and an analysis by gingival index should determine the presence or absence of inflammation. The monthly reevaluation of periodontal therapy should involve periodontal charting as a better indication of the success of treatment, and to see if other courses of treatment can be identified. Pocket depths of greater than 5–6 mm (0.20–0.24 in) which remain after initial therapy, with bleeding upon probing, indicate continued active disease and will very likely lead to further bone loss over time. This is especially true in molar tooth sites where furcations (areas between the roots) have been exposed.
Surgery
If nonsurgical therapy is found to have been unsuccessful in managing signs of disease activity, periodontal surgery may be needed to stop progressive bone loss and regenerate lost bone where possible. Many surgical approaches are used in the treatment of advanced periodontitis, including open flap debridement and osseous surgery, as well as guided tissue regeneration and bone grafting. The goal of periodontal surgery is access for definitive calculus removal and surgical management of bony irregularities which have resulted from the disease process to reduce pockets as much as possible. Long-term studies have shown, in moderate to advanced periodontitis, surgically treated cases often have less further breakdown over time and, when coupled with a regular post-treatment maintenance regimen, are successful in nearly halting tooth loss in nearly 85% of diagnosed people.
Local drug delivery
Local drug deliveries in periodontology has gained acceptance and popularity compared to systemic drugs due to decreased risk in development of resistant flora and other side effects. A meta analysis of local tetracycline found improvement. Local application of statin may be useful.
Systemic drug delivery
Systemic drug delivery in conjunction with non-surgical therapy may be used as a means to reduce the percentage of the bacterial plaque load in the mouth. Many different antibiotics and also combinations of them have been tested; however, there is yet very low-certainty evidence of any significant difference in the short and long term compared to non-surgical therapy alone. It may be beneficial to limit the use of systemic drugs, since bacteria can develop antimicrobial resistance and some specific antibiotics might induce temporary mild adverse effects, such as nausea, diarrhoea and gastrointestinal disturbances.
Adjunctive systemic antimicrobial treatment
There is currently low-quality evidence suggesting if adjunctive systemic antimicrobials are beneficial for the non-surgical treatment of periodontitis. It is not sure whether some antibiotics are better than others when used alongside scaling and root planing).
Maintenance
Once successful periodontal treatment has been completed, with or without surgery, an ongoing regimen of "periodontal maintenance" is required. This involves regular checkups and detailed cleanings every three months to prevent repopulation of periodontitis-causing microorganisms, and to closely monitor affected teeth so early treatment can be rendered if the disease recurs. Usually, periodontal disease exists due to poor plaque control resulting from inappropriate brushing. Therefore, if the brushing techniques are not modified, a periodontal recurrence is probable.
Other
Most alternative "at-home" gum disease treatments involve injecting antimicrobial solutions, such as hydrogen peroxide, into periodontal pockets via slender applicators or oral irrigators. This process disrupts anaerobic micro-organism colonies and is effective at reducing infections and inflammation when used daily. A number of other products, functionally equivalent to hydrogen peroxide, are commercially available, but at substantially higher cost. However, such treatments do not address calculus formations, and so are short-lived, as anaerobic microbial colonies quickly regenerate in and around calculus.
Doxycycline may be given alongside the primary therapy of scaling (see § initial therapy). Doxycycline has been shown to improve indicators of disease progression (namely probing depth and attachment level). Its mechanism of action involves inhibition of matrix metalloproteinases (such as collagenase), which degrade the teeths supporting tissues (periodontium) under inflammatory conditions. To avoid killing beneficial oral microbes, only small doses of doxycycline (20 mg) are used.Phage therapy may be a new therapeutic alternative.
Prognosis
Dentists and dental hygienists measure periodontal disease using a device called a periodontal probe. This thin "measuring stick" is gently placed into the space between the gums and the teeth, and slipped below the gumline. If the probe can slip more than 3 mm (0.12 in) below the gumline, the person is said to have a gingival pocket if no migration of the epithelial attachment has occurred or a periodontal pocket if apical migration has occurred. This is somewhat of a misnomer, as any depth is, in essence, a pocket, which in turn is defined by its depth, i.e., a 2-mm pocket or a 6-mm pocket. However, pockets are generally accepted as self-cleansable (at home, by the person, with a toothbrush) if they are 3 mm or less in depth. This is important because if a pocket is deeper than 3 mm around the tooth, at-home care will not be sufficient to cleanse the pocket, and professional care should be sought. When the pocket depths reach 6 to 7 mm (0.24 to 0.28 in) in depth, the hand instruments and ultrasonic scalers used by the dental professionals may not reach deeply enough into the pocket to clean out the microbial plaque that causes gingival inflammation. In such a situation, the bone or the gums around that tooth should be surgically altered or it will always have inflammation which will likely result in more bone loss around that tooth. An additional way to stop the inflammation would be for the person to receive subgingival antibiotics (such as minoc |
Periodontal disease | ycline) or undergo some form of gingival surgery to access the depths of the pockets and perhaps even change the pocket depths so they become 3 mm or less in depth and can once again be properly cleaned by the person at home with his or her toothbrush.
If people have 7-mm or deeper pockets around their teeth, then they would likely risk eventual tooth loss over the years. If this periodontal condition is not identified and people remain unaware of the progressive nature of the disease, then years later, they may be surprised that some teeth will gradually become loose and may need to be extracted, sometimes due to a severe infection or even pain.
According to the Sri Lankan tea laborer study, in the absence of any oral hygiene activity, approximately 10% will experience severe periodontal disease with rapid loss of attachment (>2 mm/year). About 80% will experience moderate loss (1–2 mm/year) and the remaining 10% will not experience any loss.
Epidemiology
Periodontitis is very common, and is widely regarded as the second most common dental disease worldwide, after dental decay, and in the United States has a prevalence of 30–50% of the population, but only about 10% have severe forms.
Chronic periodontitis affects about 750 million people or about 10.8% of the world population as of 2010.Like other conditions intimately related to access to hygiene and basic medical monitoring and care, periodontitis tends to be more common in economically disadvantaged populations or regions. Its occurrence decreases with a higher standard of living. In Israeli population, individuals of Yemenite, North-African, South Asian, or Mediterranean origin have higher prevalence of periodontal disease than individuals from European descent. Periodontitis is frequently reported to be socially patterned, i.e. people from the lower end of the socioeconomic scale are affected more often than people from the upper end of the socioeconomic scale.
History
An ancient hominid from 3 million years ago had gum disease. Records from China and the Middle East, along with archaeological studies, show that mankind has had Periodontal disease for at least many thousands of years. In Europe and the Middle East archaeological research looking at ancient plaque DNA, shows that in the ancient hunter-gatherer lifestyle there was less gum disease, but that it became more common when more cereals were eaten. The Otzi Iceman was shown to have had severe gum disease. Furthermore, research has shown that in the Roman era in the UK, there was less periodontal disease than in modern times. The researchers suggest that smoking may be a key to this.
Society and culture
Etymology
The word "periodontitis" (Greek: περιοδοντίτις) comes from the Greek peri, "around", odous (GEN odontos), "tooth", and the suffix -itis, in medical terminology "inflammation". The word pyorrhea (alternative spelling: pyorrhoea) comes from the Greek pyorrhoia (πυόρροια), "discharge of matter", itself from pyon, "discharge from a sore", rhoē, "flow", and the suffix -ia. In English this term can describe, as in Greek, any discharge of pus; i.e. it is not restricted to these diseases of the teeth.
Economics
It is estimated that lost productivity due to severe periodontitis costs the global economy about US$54 billion each year.
Other animals
Periodontal disease is the most common disease found in dogs and affects more than 80% of dogs aged three years or older. Its prevalence in dogs increases with age, but decreases with increasing body weight; i.e., toy and miniature breeds are more severely affected. Recent research undertaken at the Waltham Centre for Pet Nutrition has established that the bacteria associated with gum disease in dogs are not the same as in humans. Systemic disease may develop because the gums are very vascular (have a good blood supply). The blood stream carries these anaerobic micro-organisms, and they are filtered out by the kidneys and liver, where they may colonize and create microabscesses. The microorganisms traveling through the blood may also attach to the heart valves, causing vegetative infective endocarditis (infected heart valves). Additional diseases that may result from periodontitis include chronic bronchitis and pulmonary fibrosis.
Footnotes
External links
Canadian Academy of Periodontology — What is periodontitis?
Periodontal disease and braces. Orthodontics Australia. |
Pernicious anemia | Pernicious anemia is a type of vitamin B12 deficiency anemia, a disease in which not enough red blood cells are produced due to the malabsorption of vitamin B12. Malabsorption in pernicious anemia results from the lack or loss of intrinsic factor needed for the absorption of vitamin B12. Anemia is defined as a condition in which the blood has a lower than normal amount of red blood cells or hemoglobin. The disease may come on slowly and insidiously.The most common initial symptoms are tiredness, and weakness. Other signs and symptoms of anemia include breathlessness, dizziness, a sore red tongue, lightheadedness, headaches, poor ability to exercise, cold hands and feet, low blood pressure, pale or yellow skin, chest pain, and an irregular heartbeat. The digestive tract may also be disturbed giving symptoms that can include nausea and vomiting, heartburn, upset stomach and loss of appetite. Pernicious anemia can cause osteoporosis and may lead to bone fractures. Symptoms of severe vitamin B12 deficiency can include tingling or numbness in the hands and feet, memory problems, blurred vision, unsteady walking, poor balance, muscle weakness, impaired sense of taste and smell, poor reflexes, clumsiness, depression, and confusion. Without treatment, some of these problems may become permanent.Pernicious anemia occurs due to an autoimmune response that produces antibodies that attack the parietal cells in the stomach lining and prevents them from creating intrinsic factor. Malabsorption may also result from the surgical removal of all or part of the stomach or small intestine; from an inherited disorder or from certain drugs or illnesses that damage the stomach lining. Other causes of low vitamin B12 include not enough dietary intake (which can be a risk in a vegan diet), celiac disease, or tapeworm infection. When suspected, diagnosis is made by blood tests initially a complete blood count, and occasionally, bone marrow tests. Blood tests may show fewer but larger red blood cells, low numbers of young red blood cells, low levels of vitamin B12, and antibodies to intrinsic factor.Pernicious anemia can be treated with intramuscular injections or pills of vitamin B12. Nasal sprays and gels are also available for those who have trouble swallowing pills. Treatment may need to be lifelong.Pernicious anemia due to autoimmune problems occurs in about one per 1000 people in the USA. Among those over the age of 60, about 2% have the condition. It more commonly affects people of northern European descent. Women are more commonly affected than men. With proper treatment, most people live normal lives. Due to a higher risk of stomach cancer, those with pernicious anemia should be checked regularly for this. The first clear description was by Thomas Addison in 1849. The term "pernicious" means "deadly", and this term came into use because before the availability of treatment the disease was often fatal.
Signs and symptoms
Pernicious anemia often presents slowly, and can cause harm insidiously and unnoticeably. Untreated, it can lead to neurological complications, and in serious cases, death. It can take several years for pernicious anemia to appear, and the disease often goes unrecognized, as the body becomes used to feeling unwell.
The onset may be vague and slow, as the same symptoms are often also present with anemia; in 81.1% of cases of cobalamin deficiency, pernicious anemia is not observed. Pernicious anemia may be present without a person experiencing symptoms at first, over time, feeling tired and weak, lightheadedness, dizziness, headaches, rapid or irregular heartbeat, breathlessness, glossitis (a sore red tongue), poor ability to exercise, low blood pressure, cold hands and feet, pale or yellow skin, easy bruising and bleeding, low-grade fevers, shakiness, cold sensitivity, chest pain, upset stomach, nausea, loss of appetite, heartburn, weight loss, diarrhea, constipation, severe joint pain, feeling abnormal sensations including tingling or numbness to the fingers and toes (pins and needles), and tinnitus, may occur. Anemia may present with a number of further common symptoms, including hair thinning and loss, early greying of the hair, mouth ulcers, bleeding gums, angular cheilitis, a look of exhaustion with pale and dehydrated or cracked lips and dark circles around the eyes, as well as brittle nails.In more severe or prolonged cases of pernicious anemia, nerve cell damage may occur, which can lead to more severe symptoms, including sense loss, difficulty in proprioception, neuropathic pain, unsteady walking (ataxia), poor balance, loss of sensation in the feet, muscle weakness, blurred vision (either due to retinopathy or optic neuropathy), impaired urination, fertility problems, decreased sense of taste and smell, decreased level of consciousness, changes in reflexes, memory loss, mood swings, depression, irritability, slurred speech, cognitive impairment, confusion, anxiety, clumsiness, psychosis, and, in more severe cases, dementia. Anemia may also lead to cardiac murmurs and/or altered blood pressure (low or high). The deficiency may also present with thyroid disorders. In severe cases, the anemia may cause congestive heart failure. A complication of severe chronic PA is subacute combined degeneration of spinal cord, which leads to distal sensory loss (posterior column), absent ankle reflex, increased knee reflex response, and extensor plantar response. Other than anemia, hematological symptoms may include cytopenias, intramedullary hemolysis, and pseudothrombotic microangiopathy. Vitamin B12 deficiency, which is reversible, is occasionally confused with acute myeloid leukemia, which is an irreversible autoimmune condition presenting with some of the same hematological symptoms, including hypercellular bone marrow with blastic differentiation and hypersegmented neutrophils. Pernicious anemia can contribute to a delay in physical growth in children, and may also be a cause for delay in puberty for adolescents.
Causes
Vitamin B12 cannot be produced by the human body, and must be obtained from the diet. When foods containing B12 are eaten, the vitamin is usually bound to protein and is released by proteases released by the pancreas into the small bowel. Following its release, most B12 is absorbed by the body in the small bowel (ileum) after binding to a protein known as intrinsic factor. Intrinsic factor is produced by parietal cells of the gastric mucosa (stomach lining) and the intrinsic factor-B12-complex is absorbed by enterocytes in the ileums cubam receptors. PA is characterised by B12 deficiency caused by the absence of intrinsic factor. Other disorders that can disrupt the absorption of vitamin B12 in the small intestine include celiac disease, surgical removal of crohns disease, and HIV.
PA may be considered as an end stage of autoimmune atrophic gastritis, a disease characterised by stomach atrophy and the presence of antibodies to parietal cells and intrinsic factor. Autoimmune atrophic gastritis, is localised to the body of the stomach, where parietal cells are located. Antibodies to intrinsic factor and parietal cells cause the destruction of the oxyntic gastric mucosa, in which the parietal cells are located, leading to the subsequent loss of intrinsic factor synthesis. Without intrinsic factor, the ileum can no longer absorb the B12. Atrophic gastritis is often a precursor to gastric cancer.Although the exact role of Helicobacter pylori infection in PA remains controversial, evidence indicates H. pylori is involved in the pathogenesis of the disease. A long-standing H. pylori infection may cause gastric autoimmunity by a mechanism known as molecular mimicry. Antibodies produced by the immune system can be cross-reactive and may bind to both H. pylori antigens and those found in the gastric mucosa. The antibodies are produced by activated B cells that recognise both pathogen and self-derived peptides. The autoantigens believed to cause the autoreactivity are the alpha and beta subunits of the sodium-potassium pump. In a study, B12 deficiency caused by Helicobacter pylori was positively correlated with CagA positivity and gastric inflammatory activity, rather than gastric atrophy. Less commonly, H. pylori and Zollinger-Ellison syndrome may cause a form of nonautoimmune gastritis that can lead to pernicious anemia.Impaired B12 absorption can also occur following gastric removal (gastrectomy) or gastric bypass surgery. In these surgeries, either the parts of the stomach that produce gastric secretions are removed or they are bypassed. This means intrinsic factor, as well as other factors required for B12 absorption, are not available. However, B12 deficiency after gastric surgery does not usually become a clinical issue. This is probably because the body stores many years worth of B12 in the liver and gastric surgery patients are adequately supplemented with the vitamin.Although no specific PA susceptibility genes have been identified, a genetic factor likely is involved in the disease. Pernicious anemia is often found in conjunction with other autoimmune disorders, suggesting common autoimmune susceptibility genes may be a causative factor. In spite of that, previous family studies and case reports focusing on PA have suggested that there is a tendency of genetic heritance of PA in particular, and close relatives of the PA patients seem to have higher incidence of PA and associated PA conditions. Moreover, it was further indicated that the formation of antibodies to gastric cells was autosomal dominant gene determined, and the presence of antibodies to the gastric cells might not be necessarily related to the occurrence of atrophic gastritis related to PA.
Pathophysiology
Although the healthy body stores three to five years worth of B12 in the liver, the usually undetected autoimmune activity in ones gut over a prolonged period of time leads to B12 depletion and the resulting anemia; pernicious anemia refers to one of the hematologic manifestations of chronic auto-immune gastritis, in which the immune system targets the parietal cells of the stomach or intrinsic factor itself, leading to decreased absorption of vitamin B12.
B12 is required by enzymes for two reactions: the conversion of methylmalonyl-CoA to succinyl-CoA, and the conversion of homocysteine to methionine. In the latter reaction, the methyl group of levomefolic acid is transferred to homocysteine to produce tetrahydrofolate and methionine. This reaction is catalyzed by the enzyme methionine synthase with B12 as an essential cofactor. During B12 deficiency, this reaction cannot proceed, which leads to the accumulation of levomefolic acid. This accumulation depletes the other types of folate required for purine and thymidylate synthesis, which are required for the synthesis of DNA. Inhibition of DNA replication in maturing red blood cells results in the formation of large, fragile megaloblastic erythrocytes. The neurological aspects of the disease are thought to arise from the accumulation of methylmalonyl- CoA due to the requirement of B12 as a cofactor to the enzyme methylmalonyl-CoA mutase.
Diagnosis
Pernicious anemia is thought mainly to be an autoimmune disorder that attacks the gastric parietal cells that produce intrinsic factor resulting in impaired absorption of B12. However, pernicious anemia may also have a genetic component, potentially running in families. Pernicious anemia may be suspected when a blood smear shows large, brittle, immature, erythrocytes, known as megaloblasts. To make a diagnosis a full blood count, and blood smear, with the following tests included is needed:
A complete blood count and blood smear evaluates the mean corpuscular volume (MCV) and the mean corpuscular hemoglobin concentration (MCHC) to demonstrate megaloblastic anemia. PA is identified with a high MCV (macrocytic anemia) and a normal MCHC (normochromic anemia). Ovalocytes are also typically seen on the blood smear, and a pathognomonic feature of megaloblastic anemias (which include PA and others) is hypersegmented neutrophils.
Vitamin B12 serum levels are used to detect its deficiency, but do not distinguish its causes. Vitamin B12 levels can be falsely high or low and data for sensitivity and specificity vary widely. Normal serum levels may be found in cases of deficiency where myeloproliferative disorders, liver disease, transcobalamin II deficiency, or small intestinal bacterial overgrowth are present.
Intrinsic factor and parietal cell antibodies – the blood is checked for antibodies against IF and parietal cells in the stomach. The presence of antibodies to gastric parietal cells and IF is common in PA. Parietal cell antibodies are found in other autoimmune disorders and also in up to 10% of healthy individuals. However, around 85% of PA patients have parietal cell antibodies, which means they are a sensitive marker for the disease. Intrinsic factor antibodies are much less sensitive than parietal cell antibodies, but they are much more specific. They are found in about half of PA patients and are very rarely found in other disorders. These antibody tests can distinguish between PA and food-B12 malabsorption.
Methylmalonic acid and/or homocysteine – vitamin B12 plays an important role in metabolic processes and cellular functions. Therefore, its deficiency leads to the accumulation of some metabolic products. Methylmalonic acid and/or homocysteine is one of the metabolic products that can be measured in the blood. as the increase in the levels of both helps differentiate between vitamin B12 deficiency and folic acid deficiency, because homocysteine alone increases in the latter.Elevated gastrin levels can be found in around 80–90% of PA cases, but they may also be found in other forms of gastritis. Decreased pepsinogen I levels or a decreased pepsinogen I to pepsinogen II ratio may also be found, although these findings are less specific to PA and can be found in food-B12 malabsorption and other forms of gastritis.The diagnosis of atrophic gastritis type A should be confirmed by gastroscopy and stepwise biopsy. About 90% of individuals with PA have antibodies for parietal cells; however, only 50% of all individuals in the general population with these antibodies have pernicious anemia.Forms of vitamin B12 deficiency other than PA must be considered in the differential diagnosis of megaloblastic anemia. For example, a B12-deficient state which causes megaloblastic anemia and which may be mistaken for classical PA may be caused by infection with the tapeworm Diphyllobothrium latum, possibly due to the parasites competition with host for vitamin B12.The classic test for PA, the Schilling test, is no longer widely used, as more efficient methods are available. This historic test consisted, in its first step, of taking an oral dose of radiolabelled vitamin B12, followed by quantitation of the vitamin in the patients urine over a 24-hour period via measurement of the radioactivity. A second step of the test repeats the regimen and procedure of the first step, with the addition of oral intrinsic factor. A patient with PA presents lower than normal amounts of intrinsic factor; hence, addition of intrinsic factor in the second step results in an increase in vitamin B12 absorption (over the baseline established in the first). The Schilling test distinguished PA from other forms of B12 deficiency, specifically, from Imerslund–Gräsbeck syndrome, a B12-deficiency caused by mutations in CUBN that codes for cubilin the cobalamin receptor.
Treatment
Pernicious anemia may not be diagnosed at first. More in-depth diagnosis may be required. Pernicious anemia caused by a loss of intrinsic factor cannot be prevented. If there are other, reversible causes of low vitamin B12 levels, the cause must be treated. Pernicious anemia is usually easily treated by providing the necessary level of vitamin B12 supplementation. Severe cases can be treated with intramuscular injections of vitamin B12. Less severe cases may be treated with high doses of oral supplemenation of vitamin B12. A nasal spray, gel, and sublingual preparation are also available for people who may have difficulty in swallowing. Folate supplementation may affect the course and treatment of pernicious anemia, therefore vitamin B12 replacement is often recommended initially. In some severe cases of anemia, a blood transfusion may be needed to resolves haematological effects. Often treatment will be needed for life.
Prognosis
A person with well-treated PA can live a healthy life. Failure to diagnose and treat in time, however, may result in permanent neurological damage, excessive fatigue, depression, memory loss, and other complications. In severe cases, the neurological complications of pernicious anemia can lead to death – hence the name, "pernicious", meaning deadly.There is an increased risk of gastric cancer in those with pernicious anemia linked to the common feature of atrophic gastritis.
Epidemiology
PA is estimated to affect 0.1% of the general population and 1.9% of those over 60, accounting for 20–50% of B12 deficiency in adults. A review of literature shows that the prevalence of PA is higher in Northern Europe, especially in Scandinavian countries, and among people of African descent, and that increased awareness of the disease and better diagnostic tools might play a role in apparently higher rates of incidence.
History
A case of anemia with a first recognition of associated atrophic gastritis a feature of pernicious anemia, was first described in 1824 by James Combe. This was fully investigated in 1849, by British physician Thomas Addison, from which it acquired the common name of Addisons anemia. In 1871, the first accurate description of the disease in Europe was by Michael Anton Biermer, a German physician who referred to the insidious course of the condition, and because it was untreatable and fatal at the time, he first referred to it as "pernicious" anemia. In 1900 Russell coined the term subacute combined degeneration of spinal cord.In 1907, Richard Clarke Cabot reported on a series of 1200 patients with PA; their average survival was between one and three years. Pernicious anemia was a fatal disease before about the year 1920, until the importance of the liver in hematopoiesis was recognized, the treatment of pernicious anemia was unsuccessful and arbitrary. It may have motivated George Whipple, who had a keen interest in liver diseases, to investigate the livers role in hematopoiesis. Whipple began evaluating the effects of treatments for anemia caused by chronic blood loss. Whipple, Huber, and Robchett have studied the effects on hemoglobin and blood regeneration of a variety of treatments – among which only raw liver has shown real promise. Serendipity is said to have played a role in this discovery. Whipple observed that blood regeneration was poor in dogs fed cooked liver after chronic blood loss, had it not been that a lazy laboratory technician had given the dogs raw liver, the much more dramatic response might not have been discovered at that point in history.
Around 1926, George Minot and William P. Murphy, who learned of Whipples discovery, sought raw liver as a treatment for pernicious anemia. They later suggested a high-protein diet with high amounts of raw liver. This caused a rapid improvement in symptoms and a simultaneous rise in red blood cell counts. Fruit and iron were also part of the diet, and it appears that at this point, Minot and Murphy were not quite sure that the liver was a very important factor. It was thought that iron in liver tissue, not liver juice-soluble factor, cured hemorrhagic anemia in dogs. Thus, the discovery of liver juice as a treatment for pernicious anemia had been by coincidence. However, Minot, Murphy, and Whipple received the joint Nobel Prize for discovering a cure for a previously fatal disease of unknown cause in 1934, becoming the first Americans to be awarded the Nobel Prize in Physiology and Medicine.It is not easy to eat uncooked liver, and extracts were developed as a concentrate of liver juice for intramuscular injection. In 1928, chemist Edwin Cohn prepared an extract that was 50 to 100 times stronger than obtained from raw liver. This became part of the standard management of pernicious anemia until the 1950s. The active ingredient in the liver remained unknown until 1948. The anti-pernicious anemia factor was only isolated from the liver by Smith, Rex and others. The substance was cobalamin, which the discoverers called "vitamin B12". They showed that giving a few micrograms could prevent relapse in the disease. Dorothy Hodgkin and co-workers went on to use X-ray crystallography to elucidate the structure of cobalamin for which she, too, was awarded a Nobel Prize.Understanding of the pathogenesis of pernicious anaemia increased over subsequent decades. It had long been known that the disease was associated with defects in the gastrointestinal tract: patients had chronic gastritis and lack of acid secretion (achlorhydria). It is known that transport of physiological amounts of vitamin B12 depends on the combined actions of gastric, ileal and pancreatic components. The gastric moiety was discovered and named intrinsic factor by William Castle in 1930. A further important advance was made in the early 1960s by Doniach with the recognition that pernicious anemia is an autoimmune disease. Pernicious anemia is eventually treated with either injections or large oral doses of B12, typically between 1 and 4 mg daily.
A medical author takes the view that Mary Todd Lincoln, the wife of American President Abraham Lincoln, had pernicious anemia for decades and died from it in 1882.
Research
Permeation enhancers
Treatment using oral drugs is an easier option in management but the bioavailabity of B12 is low. This is due to low absorption in the intestine, and breakdown by enzyme activity. Research continues to focus on the use of permeation enhancers or permeation absorbers in combination with the treatment. One of the better performing enhancers studied is salcoprozate sodium (SNAC). SNAC is able to form a noncovalent complex with cobalamin while preserving its chemical integrity and protect B12 from gastric acidity. This complex is much more lipophilic than the water-soluble vitamin B12, so is able to pass through cellular membranes with greater ease. Molecular dynamics are used in experiments to gain an understanding of the molecular interactions involved in the different molecules used and the degree of ease achieved in absorption across the gastric epithelium.
References
External links
Pernicious anemia at Curlie |
Peroxisomal disorder | Peroxisomal disorders represent a class of medical conditions caused by defects in peroxisome functions. This may be due to defects in single enzymes important for peroxisome function or in peroxins, proteins encoded by PEX genes that are critical for normal peroxisome assembly and biogenesis.
Peroxisome biogenesis disorders
Peroxisome biogenesis disorders (PBDs) include the Zellweger syndrome spectrum (PBD-ZSD) and rhizomelic chondrodysplasia punctata type 1 (RCDP1). PBD-ZSD represents a continuum of disorders including infantile Refsum disease, neonatal adrenoleukodystrophy, and Zellweger syndrome. Collectively, PBDs are autosomal recessive developmental brain disorders that also result in skeletal and craniofacial dysmorphism, liver dysfunction, progressive sensorineural hearing loss, and retinopathy.PBD-ZSD is most commonly caused by mutations in the PEX1, PEX6, PEX10, PEX12, and PEX26 genes. This results in the over-accumulation of very long chain fatty acids and branched chain fatty acids, such as phytanic acid. In addition, PBD-ZSD patients show deficient levels of plasmalogens, ether-phospholipids necessary for normal brain and lung function.RCDP1 is caused by mutations in the PEX7 gene, which encodes the PTS2 receptor. RCDP1 patients can develop large tissue stores of branched chain fatty acids, such as phytanic acid, and show reduced levels of plasmalogens.
Enzyme and transporter defects
Peroxisomal disorders also include:
References
External links
Peroxisomal+disorders at the US National Library of Medicine Medical Subject Headings (MeSH) |
PID | PID or Pid may refer to:
Medicine
Pelvic inflammatory disease or pelvic inflammatory disorder, an infection of the upper part of the female reproductive system
Primary immune deficiency, disorders in which part of the bodys immune system is missing or does not function properly
Prolapsed intervertebral disc, commonly called a herniated disc
Science, technology and engineering
BBC Programme Identifier, a unique identifier for a BBC television or radio programme brand, a season or series, or an individual episode
OBD-II PIDs (on-board diagnostics parameter IDs), requests for data through an OBD connector in automotive repair
Packet Identifier, a field in a MPEG transport stream packet
Passive infrared detector, a passive infrared sensor
Persistent identifier, a long-lasting reference to a document, file, web page, or other object
Phosphotyrosine-interacting domain, also known as phosphotyrosine-binding domain, a protein domain which bind to phosphotyrosine
Photoionization detector, measures volatile organic compounds and other gases
Physical Interface Device, a class of a USB device
PID controller (proportional-integral-derivative controller), a control concept used in automation
Piping and instrumentation diagram (P&ID), a diagram in the process industry which shows the piping of the process flow etc.
Principal ideal domain, an algebraic structure
Process identifier, a number used by many operating systems to identify a process
Organisations
Police Intelligence Department, a staff department of the Singapore Police Force
Political Intelligence Department (disambiguation), multiple organisations
Politieke Inlichtingen Dienst (Political Intelligence Department), was the main security agency for the Dutch East Indies
Prague Integrated Transport (Pražská integrovaná doprava – PID in Czech), an integrated public transport system in Prague
Other uses
Pathways into Darkness, a 1993 video game by Bungie
"Paul is dead", a 1960s urban legend that Paul McCartney was dead
Pid (video game), a 2012 video game by Might and Delight
Project Initiation Documentation, in project management
Party identification, the political party with which an individual identifies
Everett Pid Purdy (1904–1951), American athlete who played in both Major League Baseball and the National Football League
See also
PIDS (disambiguation) |
Pinworm infection | Pinworm infection (threadworm infection in the UK), also known as enterobiasis, is a human parasitic disease caused by the pinworm. The most common symptom is itching in the anal area. This can make sleeping difficult. The period of time from swallowing eggs to the appearance of new eggs around the anus is 4 to 8 weeks. Some people who are infected do not have symptoms.The disease is spread between people by pinworm eggs. The eggs initially occur around the anus and can survive for up to three weeks in the environment. They may be swallowed following contamination of the hands, food, or other articles. Those at risk are those who go to school, live in a health care institution or prison, or take care of people who are infected. Other animals do not spread the disease. Diagnosis is by seeing the worms which are about one centimetre long or the eggs under a microscope.Treatment is typically with two doses of the medications mebendazole, pyrantel pamoate, or albendazole two weeks apart. Everyone who lives with or takes care of an infected person should be treated at the same time. Washing personal items in hot water after each dose of medication is recommended. Good handwashing, daily bathing in the morning, and daily changing of underwear can help prevent reinfection.Pinworm infections commonly occur in all parts of the world. They are the most common type of worm infection in Western Europe and the United States. School-aged children are the most commonly infected. In the United States about 20% of children will develop pinworm at some point. Infection rates among high-risk groups may be as high as 50%. It is not considered a serious disease. Pinworms are believed to have affected humans throughout history.
Signs and symptoms
One-third of individuals with pinworm infection are totally asymptomatic. The main symptoms are itching in and around the anus and perineum. The itching occurs mainly during the night, and is caused by the female pinworms migrating to lay eggs around the anus. Both the migrating females and the clumps of eggs are irritating, as well as the sticky substance that is produced by the worms when the eggs are laid. The intensity of the itching varies, and it can be described as tickling, crawling sensations, or even acute pain. The itching leads to continuously scratching the area around the anus, which can further result in tearing of the skin and complications such as secondary bacterial infections, including bacterial skin inflammation, and hair follicle inflammation. General symptoms are trouble sleeping, and restlessness. A considerable proportion of children experience loss of appetite, weight loss, irritability, emotional instability, and bed wetting.Pinworms cannot damage the skin, and they do not normally migrate through tissues. However, they may move onto the vulva and into the vagina, from there moving to the external orifice of the uterus, and onwards to the uterine cavity, fallopian tubes, ovaries, and peritoneal cavity. This can cause inflammation of the vulva and vagina. This causes vaginal discharge and itchiness of the vulva. The pinworms can also enter the urethra, and presumably, they carry intestinal bacteria with them. According to Gutierrez (2000), a statistically significant correlation between pinworm infection and urinary tract infections has been shown; however, Burkhart & Burkhart (2005) maintain that the incidence of pinworms as a cause of urinary tract infections remains unknown. One report indicated that 36% of young girls with a urinary tract infection also had pinworms. Painful urination has been associated with pinworm infection.The relationship between pinworm infestation and appendicitis has been researched, but there is a lack of clear consensus on the matter: While Gutiérrez maintains that there exists a consensus that pinworms do not produce the inflammatory reaction, Cook (1994) states that it is controversial whether pinworms are causatively related to acute appendicitis, and Burkhart & Burkhart (2004) state that pinworm infection causes symptoms of appendicitis to surface.
Cause
The cause of a pinworm infection is the worm Enterobius vermicularis. The entire lifecycle – from egg to adult – takes place in the human gastrointestinal tract of a single human host. This process is two to eight weeks.
Spread
Pinworm infection spreads through human-to-human transmission, by swallowing infectious pinworm eggs. The eggs are hardy and can remain infectious in a moist environment for up to three weeks, though in a warm dry environment they usually last only 1–2 days. They do not tolerate heat well, but can survive in low temperatures: at −8 degrees Celsius (18 °F), two-thirds of the eggs are still viable after 18 hours.After the eggs have been initially deposited near the anus, they are readily transmitted to other surfaces through contamination. The surface of the eggs is sticky when laid, and the eggs are readily transmitted from their initial deposit near the anus to fingernails, hands, night-clothing and bed linen. From here, eggs are further transmitted to food, water, furniture, toys, bathroom fixtures and other objects. Household pets often carry the eggs in their fur, while not actually being infected. Dust containing eggs can become airborne and widely dispersed when dislodged from surfaces, for instance when shaking out bed clothes and linen. Consequently, the eggs can enter the mouth and nose through inhalation, and be swallowed later. Although pinworms do not strictly multiply inside the body of their human host, some of the pinworm larvae may hatch on the anal mucosa, and migrate up the bowel and back into the gastrointestinal tract of the original host. This process is called retroinfection. According to Burkhart (2005), when this retroinfection occurs, it leads to a heavy parasitic load and ensures that the pinworm infestation continues. This statement is contradictory to a statement by Caldwell, who contends that retroinfection is rare and not clinically significant. Despite the limited, 13-week lifespan of individual pinworms, autoinfection (infection from the original host to itself), either through the anus-to-mouth route or through retroinfection, causes the pinworms to inhabit the same host indefinitely.
Life cycle
The life cycle begins with eggs being ingested. The eggs hatch in the duodenum (first part of the small intestine). The emerging pinworm larvae grow rapidly to a size of 140 to 150 micrometres, and migrate through the small intestine towards the colon. During this migration they moult twice and become adults. Females survive for 5 to 13 weeks, and males about 7 weeks. The male and female pinworms mate in the ileum (last part of the small intestine), whereafter the male pinworms usually die, and are passed out with stool. The gravid female pinworms settle in the ileum, caecum (beginning of the large intestine), appendix and ascending colon, where they attach themselves to the mucosa and ingest colonic contents. Almost the entire body of a gravid female becomes filled with eggs. The estimations of the number of eggs in a gravid female pinworm ranges from about 11,000 to 16,000. The egg-laying process begins approximately five weeks after initial ingestion of pinworm eggs by the human host. The gravid female pinworms migrate through the colon towards the rectum at a rate of 12 to 14 centimetres per hour. They emerge from the anus, and while moving on the skin near the anus, the female pinworms deposit eggs either through (1) contracting and expelling the eggs, (2) dying and then disintegrating, or (3) bodily rupture due to the host scratching the worm. After depositing the eggs, the female becomes opaque and dies. The reason the female emerges from the anus is to obtain the oxygen necessary for the maturation of the eggs.
Diagnosis
Diagnosis relies on finding the eggs or the adult pinworms. Individual eggs are invisible to the naked eye, but they can be seen using a low-power microscope. On the other hand, the light-yellowish thread-like adult pinworms are clearly visually detectable, usually during the night when they move near the anus, or on toilet paper. Shining a flashlight on the infected individuals anus about one hour after they fall asleep is one form of detection and may show worms crawling out of the anus. Another form of detection is the use of transparent adhesive tape (e.g. Scotch Tape) applied on the anal area which will pick up deposited eggs, and diagnosis can be made by examining the tape with a microscope. This test is most successful if done every morning for several days, because the females do not lay eggs every day, and the number of eggs varies. A third method of diagnosis is examining a sample from under their fingernails under a microscope as itching around the anal area is common and therefore they may have collected some eggs under their nails as a result.Pinworms do not lay eggs in the feces, but sometimes eggs are deposited in the intestine. As such, routine examination of fecal material gives a positive diagnosis in only 5 to 15% of infected subjects, and is therefore of little practical diagnostic use. In a heavy infection, female pinworms may adhere to stools that pass out through the anus, and they may thus be detected on the surface on the stool. Adult pinworms are occasionally seen during colonoscopy. On a microscopic level, pinworms have an identifying feature of alae (i.e., protruding ridges) running the length of the worm.
Prevention
Pinworm infection cannot be totally prevented under most circumstances. This is due to the prevalence of the parasite and the ease of transmission through soiled night clothes, airborne eggs, contaminated furniture, toys and other objects. Infection may occur in the highest strata of society, where hygiene and nutritional status are typically high. The stigma associated with pinworm infection is hence considered a possible over-emphasis. Counselling is sometimes needed for upset parents who have discovered their children are infected, as they may not realize how prevalent the infection is.Preventive action revolves around personal hygiene and the cleanliness of the living quarters. The rate of reinfection can be reduced through hygienic measures, and this is recommended especially in recurring cases.The main measures are keeping fingernails short, and washing and scrubbing hands and fingers carefully, especially after defecation and before meals. Showering every morning is also highly recommended to wash off any eggs that may be still laying on the skin. Under ideal conditions, bed covers, sleeping garments, and hand towels should be changed daily and clothes and linens should be washed in hot water and then be placed in a hot dryer in order to kill off any eggs. Children can wear gloves while asleep, and the bedroom floor should be kept clean. Regular disinfection of kitchen and bathroom surfaces will help to prevent spread as well. Food should be covered to limit contamination with dust-borne parasite eggs. It is not recommended to shake clothes and bed linen as the eggs may detach and spread or to share clothes and towels. Nail biting and sucking on fingers is also discouraged.
Treatment
Medication is the primary treatment for pinworm infection. However, reinfection is frequent regardless of the medication used. Total elimination of the parasite in a household may require repeated doses of medication for up to a year or more. Because the drugs kill the adult pinworms, but not the eggs, the first retreatment is recommended in two weeks. Also, if one household member spreads the eggs to another, it will be a matter of two or three weeks before those eggs become adult worms and thus amenable to treatment. Asymptomatic infections, often in small children, can serve as reservoirs of infection, and therefore the entire household should be treated regardless of whether or not symptoms are present.The benzimidazole compounds albendazole (brand names e.g., Albenza, Eskazole, Zentel and Andazol) and mebendazole (brand names e.g., Ovex, Vermox, Antiox and Pripsen) are the most effective. They work by inhibiting the microtubule function in the pinworm adults, causing glycogen depletion, thereby effectively starving the parasite. A single 100 milligram dose of mebendazole with one repetition after two weeks, is considered the safest, and is usually effective with cure rate of 96%. Mebendazole has no serious side effects, although abdominal pain and diarrhea have been reported. Pyrantel pamoate (also called pyrantel embonate, brand names e.g., Reeses Pinworm Medicine, Pin-X, Combantrin, Anthel, Helmintox, and Helmex) kills adult pinworms through neuromuscular blockade, and is considered as effective as the benzimidazole compounds and is used as a second-line medication. Pyrantel pamoate is available over the counter and does not require a prescription. Pinworms located in the genitourinary system (in this case, female genital area) may require other drug treatments.
Treatment in Pregnancy and Breastfeeding
The available data on mebendazole, albendazole, and pyrantel pamoate use in pregnancy is limited and they are all assigned to pregnancy category level C. Treatment of a pinworm infection during pregnancy is only recommended for patients with significant symptoms that may be causing adverse effects to the pregnant person such as loss of sleep and weight loss. Pyrantel pamoate is the treatment of choice in pregnancy but should be used only after consultation with a health care practitioner rather than self-treatment. Treatment should be avoided in the first trimester, and if possible done in the third trimester. If the pregnant individual is asymptomatic, then they should be treated after the baby is delivered.Mebendazole has less than 10% of the oral dose absorbed into systemic circulation with a clinically insignificant amount of drug excreted in breastmilk, and therefore treatment should not be withheld during breastfeeding. There is limited data on the use of pyrantel pamoate and albendazole in breastfeeding but WHO also classifies them as compatible with breastfeeding. This is due to the drugs acting mainly in the intestinal system of the mother with only a very small amount of drug being absorbed into the systemic circulation.
Epidemiology
Pinworm infection occurs worldwide, and is the most common helminth (i.e., parasitic worm) infection in the United States and Western Europe. In the United States, a study by the Center of Disease Control reported an overall incidence rate of 11.4% among people of all ages. Pinworms are particularly common in children with approximately 30% of children being infected and most commonly seen in children between 7 and 11 years old. The prevalence rates in children having been reported as high as 61% in India, 50% in England, 39% in Thailand, 37% in Sweden, and 29% in Denmark. Finger sucking has been shown to increase both incidence and relapse rates, and nail biting has been similarly associated. Because it spreads from host to host through contamination, enterobiasis is common among people living in close contact, and tends to occur in all people within a household. The prevalence of pinworms is not associated with gender, nor with any particular social class, race, or culture. Pinworms are an exception to the tenet that intestinal parasites are uncommon in affluent communities.
History
The earliest known instance of pinworms is evidenced by pinworm eggs found in coprolite, carbon dated to 7837 BC at western Utah. Pinworm infection is not classified as a neglected tropical disease unlike many other parasitic worm infections.Garlic has been used as a treatment in the ancient cultures of China, India, Egypt, and Greece. Hippocrates (459–370 BC) mentioned garlic as a remedy against intestinal parasites. German botanist Lonicerus (1564) recommended garlic against parasitic worms.
Notes
References
External links
Brown MD (March 2006). "Images in clinical medicine. Enterobius vermicularis". The New England Journal of Medicine. 354 (13): e12. doi:10.1056/NEJMicm040931. PMID 16571876. |
Pleurodesis | Pleurodesis is a medical procedure in which part of the pleural space is artificially obliterated. It involves the adhesion of the visceral and the costal pleura. The mediastinal pleura is spared.
Uses
Pleurodesis is performed to prevent recurrence of spontaneous pneumothorax or pleural effusion, and can be done chemically or mechanically. It is generally avoided in patients with cystic fibrosis if possible, because lung transplantation becomes more difficult following this procedure. Previous pneumothorax with or without pleurodesis is not a contraindication to subsequent lung transplantation.
Chemical
Chemicals such as bleomycin, tetracycline (e.g., minocycline), povidone-iodine, or a slurry of talc can be introduced into the pleural space through a chest drain. The instilled chemicals cause irritation between the parietal and the visceral layers of the pleura which closes off the space between them and prevents further fluid from accumulating. Pharmacy-prepared chemicals for pleurodesis should be clearly labeled "NOT FOR IV ADMINISTRATION" to avoid potentially fatal wrong-site medication errors.Sterile talc powder, administered intrapleurally via a chest tube, is indicated as a sclerosing agent to decrease the recurrence of malignant pleural effusions in symptomatic patients. It is usually performed at the time of a diagnostic thoracoscopy.Povidone iodine is equally effective and safe as talc, and may be preferred because of easy availability and low cost.Chemical pleurodesis is a painful procedure, and so patients are often premedicated with a sedative and analgesics. A local anesthetic may be instilled into the pleural space, or an epidural catheter may be placed for anesthesia.
Surgical
Surgical pleurodesis, also known as mechanical or abrasive pleurodesis, may be performed via thoracotomy or thoracoscopy. This involves mechanically irritating the parietal pleura, often with a scratchpad (a small foam pad with coated abrasive) normally used for cleaning electrocautery blade tips. Moreover, surgical removal of parietal pleura is an effective way of achieving stable pleurodesis.Alternatively, tunneled pleural catheters (TPCs) may be placed in an outpatient setting and often result in auto-pleurodesis, whereby portable vacuum bottles are used to evacuate the pleural fluid. Routine evacuation keeps the pleura together, resulting in physical agitation by the catheter, which slowly causes the pleura to scar together. This method, though the minimally invasive and minimal cost solution, takes an average of about 30 days to achieve pleurodesis and is therefore the slowest means of achieving pleurodesis among other modalities.
References
External links
Media related to Pleurodesis at Wikimedia Commons |
Polycystic ovary syndrome | Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and not the underlying cause of the disorder.Women with PCOS may experience irregular menstrual periods, heavy periods, excess hair, acne, pelvic pain, difficulty getting pregnant, and patches of thick, darker, velvety skin. The primary characteristics of this syndrome include: hyperandrogenism, anovulation, insulin resistance, and neuroendocrine disruption.A review of the international evidence found that the prevalence of PCOS could be as high as 26% among some populations, though ranges between 4% and 18% are reported for general populations. Despite its high prevalence, the exact cause of PCOS remains uncertain and there is no known cure.
Definition
Two definitions are commonly used:
NIHIn 1990 a consensus workshop sponsored by the NIH/NICHD suggested that a person has PCOS if they have all of the following:oligoovulation
signs of androgen excess (clinical or biochemical)
exclusion of other disorders that can result in menstrual irregularity and hyperandrogenismRotterdamIn 2003 a consensus workshop sponsored by ESHRE/ASRM in Rotterdam indicated PCOS to be present if any 2 out of 3 criteria are met, in the absence of other entities that might cause these findings:
oligoovulation and/or anovulation
excess androgen activity
polycystic ovaries (by gynecologic ultrasound)The Rotterdam definition is wider, including many more women, the most notable ones being women without androgen excess. Critics say that findings obtained from the study of women with androgen excess cannot necessarily be extrapolated to women without androgen excess.
Androgen Excess PCOS SocietyIn 2006, the Androgen Excess PCOS Society suggested a tightening of the diagnostic criteria to all of the following:excess androgen activity
oligoovulation/anovulation and/or polycystic ovaries
exclusion of other entities that would cause excess androgen activity
Signs and symptoms
Signs and symptoms of PCOS include irregular or no menstrual periods, heavy periods, excess body and facial hair, acne, pelvic pain, difficulty getting pregnant, and patches of thick, darker, velvety skin. This metabolic, endocrine and reproductive disorder is not universally defined, but the most common symptoms are irregular or absent periods, ovarian cysts, enlarged ovaries, excess androgen, weight gain and hirsutism. Associated conditions include type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer. This disease is related to the number of follicles per ovary each month growing from the average range of 6 to 8 to double, triple or more. it is important to distinguish between PCOS (the syndrome) and a woman with PCO (polycystic ovaries): to have PCOS, a woman must have at least two of these three symptoms (PCO, anovulation/oligoovulation and hyperandrogenism). This means that a woman can have PCOS (displaying anovulation and hyperandrogenism) without having PCO. Conversely, having PCO does not indicate that a person necessarily has PCOS.
Common signs and symptoms of PCOS include the following:
Menstrual disorders: PCOS mostly produces oligomenorrhea (fewer than nine menstrual periods in a year) or amenorrhea (no menstrual periods for three or more consecutive months), but other types of menstrual disorders may also occur.
Infertility: This generally results directly from chronic anovulation (lack of ovulation).
High levels of masculinizing hormones: Known as hyperandrogenism, the most common signs are acne and hirsutism (male pattern of hair growth, such as on the chin or chest), but it may produce hypermenorrhea (heavy and prolonged menstrual periods), androgenic alopecia (increased hair thinning or diffuse hair loss), or other symptoms. Approximately three-quarters of women with PCOS (by the diagnostic criteria of NIH/NICHD 1990) have evidence of hyperandrogenemia.
Metabolic syndrome: This appears as a tendency towards central obesity and other symptoms associated with insulin resistance, including low energy levels and food cravings. Serum insulin, insulin resistance, and homocysteine levels are higher in women with PCOS.
Polycystic Ovaries: Ovaries might get enlarged and comprise follicles surrounding the eggs. As result, ovaries might fail to function regularly.Women with PCOS tend to have central obesity, but studies are conflicting as to whether visceral and subcutaneous abdominal fat is increased, unchanged, or decreased in women with PCOS relative to reproductively normal women with the same body mass index. In any case, androgens, such as testosterone, androstanolone (dihydrotestosterone), and nandrolone decanoate have been found to increase visceral fat deposition in both female animals and women.Although 80% of PCOS presents in women with obesity, 20% of women diagnosed with the disease are non-obese or "lean" women. However, obese women that have PCOS have a higher risk of adverse outcomes, such as hypertension, insulin resistance, metabolic syndrome, and endometrial hyperplasia.Even though most women with PCOS are overweight or obese, it is important to acknowledge that non-overweight women can also be diagnosed with PCOS. Up to 30% of women diagnosed with PCOS maintain a normal weight before and after diagnosis. "Lean" women still face the various symptoms of PCOS with the added challenges of having their symptoms properly addressed and recognized. Lean women often go undiagnosed for years, and usually are diagnosed after struggles to conceive. Lean women are likely to have a missed diagnosis of diabetes and cardiovascular disease. These women also have an increased risk of developing insulin resistance, despite not being overweight. Lean women are often taken less seriously with their diagnosis of PCOS, and also face challenges finding appropriate treatment options. This is because most treatment options are limited to approaches of losing weight and healthy dieting.Testosterone levels are usually elevated in women with PCOS. In a 2020 systematic review and meta-analysis of sexual dysfunction related to PCOS which included 5,366 women with PCOS from 21 studies, testosterone levels were analyzed and were found to be 2.34 nmol/L (67 ng/dL) in women with PCOS and 1.57 nmol/L (45 ng/dL) in women without PCOS. In a 1995 study of 1,741 women with PCOS, mean testosterone levels were 2.6 (1.1–4.8) nmol/L (75 (32–140) ng/dL). In a 1998 study which reviewed many studies and subjected them to meta-analysis, testosterone levels in women with PCOS were 62 to 71 ng/dL (2.2–2.5 nmol/L) and testosterone levels in women without PCOS were about 32 ng/dL (1.1 nmol/L). In a 2010 study of 596 women with PCOS which used liquid chromatography–mass spectrometry (LC–MS) to quantify testosterone, median levels of testosterone were 41 and 47 ng/dL (with 25th–75th percentiles of 34–65 ng/dL and 27–58 ng/dL and ranges of 12–184 ng/dL and 1–205 ng/dL) via two different labs. If testosterone levels are above 140 to 200 ng/dL (per different sources), other possible causes of hyperandrogenism such as congenital adrenal hyperplasia or an androgen-secreting tumor may be present and should be excluded.
Associated conditions
Many individuals arent under the impression that the first warning sign is usually a change in appearance. But there are also manifestations of mental health problems, such as anxiety, depression, and eating disorders.A diagnosis of PCOS suggests an increased risk of the following:
Endometrial hyperplasia and endometrial cancer (cancer of the uterine lining) are possible, due to overaccumulation of uterine lining, and also lack of progesterone, resulting in prolonged stimulation of uterine cells by estrogen. It is not clear whether this risk is directly due to the syndrome or from the associated obesity, hyperinsulinemia, and hyperandrogenism.
Insulin resistance/Type II diabetes. A review published in 2010 concluded that women with PCOS have an elevated prevalence of insulin resistance and type II diabetes, even when controlling for body mass index (BMI). PCOS also makes a woman at higher risk for diabetes.
High blood pressure, in particular if obese or during pregnancy
Depression and anxiety
Dyslipidemia – disorders of lipid metabolism — cholesterol and triglycerides. Women with PCOS show a decreased removal of atherosclerosis-inducing remnants, seemingly independent of insulin resistance/Type II diabetes.
Cardiovascular disease, with a meta-analysis estimating a 2-fold risk of arterial disease for women with PCOS relative to women without PCOS, independent of BMI.
Strokes
Weight gain
Miscarriage
Sleep apnea, particularly if obesity is present
Non-alcoholic fatty liver disease, particularly if obesity is present
Acanthosis nigricans (patches of darkened skin under the arms, in the groin area, on the back of the neck)
Autoimmune thyroiditis
Some studies report a higher incidence of PCOS among transgender men (prior to taking testosterone), though not all have not found the same association. People with PCOS in general are also reportedly more likely to see themselves as "sexually undifferentiated" or "androgynous" and "less likely to identify with a female gender scheme."The risk of ovarian cancer and breast cancer is not significantly increased overall.
Cause
PCOS is caused by a combination of genetic and environmental factors. Risk factors include obesity, a lack of physical exercise, and a family history of someone with the condition. Transgender men may also experience a higher than expected rate of PCOS. Diagnosis is based on two of the following three findings: anovulation, high androgen levels, and ovarian cysts. Cysts may be detectable by ultrasound. Other conditions that produce similar symptoms include adrenal hyperplasia, hypothyroidism, and high blood levels of prolactin.PCOS is a heterogeneous disorder of uncertain cause. There is some evidence that it is a genetic disease. Such evidence includes the familial clustering of cases, greater concordance in monozygotic compared with dizygotic twins and heritability of endocrine and metabolic features of PCOS. There is some evidence that exposure to higher than typical levels of androgens and the anti-Müllerian hormone (AMH) in utero increases the risk of developing PCOS in later life.
Genetics
The genetic component appears to be inherited in an autosomal dominant fashion with high genetic penetrance but variable expressivity in females; this means that each child has a 50% chance of inheriting the predisposing genetic variant(s) from a parent, and, if a daughter receives the variant(s), the daughter will have the disease to some extent. The genetic variant(s) can be inherited from either the father or the mother, and can be passed along to both sons (who may be asymptomatic carriers or may have symptoms such as early baldness and/or excessive hair) and daughters, who will show signs of PCOS. The phenotype appears to manifest itself at least partially via heightened androgen levels secreted by ovarian follicle theca cells from women with the allele. The exact gene affected has not yet been identified. In rare instances, single-gene mutations can give rise to the phenotype of the syndrome. Current understanding of the pathogenesis of the syndrome suggests, however, that it is a complex multigenic disorder.Due to the scarcity of large-scale screening studies, the prevalence of endometrial abnormalities in PCOS remains unknown, though women with the condition may be at increased risk for endometrial hyperplasia and carcinoma as well as menstrual dysfunction and infertility.
The severity of PCOS symptoms appears to be largely determined by factors such as obesity.
PCOS has some aspects of a metabolic disorder, since its symptoms are partly reversible. Even though considered as a gynecological problem, PCOS consists of 28 clinical symptoms.Even though the name suggests that the ovaries are central to disease pathology, cysts are a symptom instead of the cause of the disease. Some symptoms of PCOS will persist even if both ovaries are removed; the disease can appear even if cysts are absent. Since its first description by Stein and Leventhal in 1935, the criteria of diagnosis, symptoms, and causative factors are subject to debate. Gynecologists often see it as a gynecological problem, with the ovaries being the primary organ affected. However, recent insights show a multisystem disorder, with the primary problem lying in hormonal regulation in the hypothalamus, with the involvement of many organs. The term PCOS is used due to the fact that there is a wide spectrum of symptoms possible. It is common to have polycystic ovaries without having PCOS; approximately 20% of European women have polcystic ovaries, but most of those women do not have PCOS.
Environment
PCOS may be related to or worsened by exposures during the prenatal period, epigenetic factors, environmental impacts (especially industrial endocrine disruptors, such as bisphenol A and certain drugs) and the increasing rates of obesity.Endocrine disruptors are defined as chemicals that can interfere with the endocrine system by mimicking hormones such as estrogen. However, additional research is needed to assess the role that endocrine disruptors may play in disrupting reproductive health in women and possibly triggering or exacerbating PCOS and its related symptoms.
Pathogenesis
Polycystic ovaries develop when the ovaries are stimulated to produce excessive amounts of androgenic hormones, in particular testosterone, by either one or a combination of the following (almost certainly combined with genetic susceptibility):
the release of excessive luteinizing hormone (LH) by the anterior pituitary gland
through high levels of insulin in the blood (hyperinsulinaemia) in women whose ovaries are sensitive to this stimulusA majority of women with PCOS have insulin resistance and/or are obese, which is a strong risk factor for insulin resistance, although insulin resistance is a common finding among women with PCOS in normal-weight women as well. Elevated insulin levels contribute to or cause the abnormalities seen in the hypothalamic-pituitary-ovarian axis that lead to PCOS. Hyperinsulinemia increases GnRH pulse frequency, which in turn results in an increase in the LH/FSH ratio increased ovarian androgen production; decreased follicular maturation; and decreased SHBG binding. Furthermore, excessive insulin increases the activity of 17α-hydroxylase, which catalyzes the conversion of progesterone to androstenedione, which is in turn converted to testosterone. The combined effects of hyperinsulinemia contribute to an increased risk of PCOS.Adipose (fat) tissue possesses aromatase, an enzyme that converts androstenedione to estrone and testosterone to estradiol. The excess of adipose tissue in obese women creates the paradox of having both excess androgens (which are responsible for hirsutism and virilization) and excess estrogens (which inhibit FSH via negative feedback).The syndrome acquired its most widely used name due to the common sign on ultrasound examination of multiple (poly) ovarian cysts. These "cysts" are in fact immature ovarian follicles. The follicles have developed from primordial follicles, but this development has stopped ("arrested") at an early stage, due to the disturbed ovarian function. The follicles may be oriented along the ovarian periphery, appearing as a string of pearls on ultrasound examination.PCOS may be associated with chronic inflammation, with several investigators correlating inflammatory mediators with anovulation and other PCOS symptoms. Similarly, there seems to be a relation between PCOS and an increased level of oxidative stress.
Diagnosis
Not every person with PCOS has polycystic ovaries (PCO), nor does everyone with ovarian cysts have PCOS; although a pelvic ultrasound is a major diagnostic tool, it is not the only one. The diagnosis is fairly straightforward using the Rotterdam criteria, even when the syndrome is associated with a wide range of symptoms.
Differential diagnosis
Other causes of irregular or absent menstruation and hirsutism, such as hypothyroidism, congenital adrenal hyperplasia (21-hydroxylase deficiency), Cushings syndrome, hyperprolactinemia, androgen-secreting neoplasms, and other pituitary or adrenal disorders, should be investigated.
Assessment and testing
Standard assessment
History-taking, specifically for menstrual pattern, obesity, hirsutism and acne. A clinical prediction rule found that these four questions can diagnose PCOS with a sensitivity of 77.1% (95% confidence interval [CI] 62.7%–88.0%) and a specificity of 93.8% (95% CI 82.8%–98.7%).
Gynecologic ultrasonography, specifically looking for small ovarian follicles. These are believed to be the result of disturbed ovarian function with failed ovulation, reflected by the infrequent or absent menstruation that is typical of the condition. In a normal menstrual cycle, one egg is released from a dominant follicle – in essence, a cyst that bursts to release the egg. After ovulation, the follicle remnant is transformed into a progesterone-producing corpus luteum, which shrinks and disappears after approximately 12–14 days. In PCOS, there is a so-called "follicular arrest"; i.e., several follicles develop to a size of 5–7 mm, but not further. No single follicle reaches the preovulatory size (16 mm or more). According to the Rotterdam criteria, which are widely used for diagnosis of PCOS, 12 or more small follicles should be seen in a suspect ovary on ultrasound examination. More recent research suggests that there should be at least 25 follicles in an ovary to designate it as having polycystic ovarian morphology (PCOM) in women aged 18–35 years. The follicles may be oriented in the periphery, giving the appearance of a string of pearls. If a high-resolution transvaginal ultrasonography machine is not available, an ovarian volume of at least 10 ml is regarded as an acceptable definition of having polycystic ovarian morphology. rather than follicle count.
Laparoscopic examination may reveal a thickened, smooth, pearl-white outer surface of the ovary. (This would usually be an incidental finding if laparoscopy were performed for some other reason, as it would not be routine to examine the ovaries in this way to confirm a diagnosis of PCOS.)
Serum (blood) levels of androgens, including androstenedione and testosterone may be elevated. Dehydroepiandrosterone sulfate (DHEA-S) levels above 700–800 µg/dL are highly suggestive of adrenal dysfunction because DHEA-S is made exclusively by the adrenal glands. The free testosterone level is thought to be the best measure, with approximately 60 per cent of PCOS patients demonstrating supranormal levels.Some other blood tests are suggestive but not diagnostic. The ratio of LH (Luteinizing hormone) to FSH (Follicle-stimulating hormone), when measured in international units, is elevated in women with PCOS. Common cut-offs to designate abnormally high LH/FSH ratios are 2:1 or 3:1 as tested on Day 3 of the menstrual cycle. The pattern is not very sensitive; a ratio of 2:1 or higher was present in less than 50% of women with PCOS in one study. There are often low levels of sex hormone-binding globulin, in particular among obese or overweight women.Anti-Müllerian hormone (AMH) is increased in PCOS, and may become part of its diagnostic criteria.
Glucose tolerance testing
2-hour oral glucose tolerance test (GTT) in women with risk factors (obesity, family history, history of gestational diabetes) may indicate impaired glucose tolerance (insulin resistance) in 15–33% of women with PCOS. Frank diabetes can be seen in 65–68% of women with this condition. Insulin resistance can be observed in both normal weight and overweight people, although it is more common in the latter (and in those matching the stricter NIH criteria for diagnosis); 50–80% of people with PCOS may have insulin resistance at some level.
Fasting insulin level or GTT with insulin levels (also called IGTT). Elevated insulin levels have been helpful to predict response to medication and may indicate women needing higher doses of metformin or the use of a second medication to significantly lower insulin levels. Elevated blood sugar and insulin values do not predict who responds to an insulin-lowering medication, low-glycemic diet, and exercise. Many women with normal levels may benefit from combination therapy. A hypoglycemic response in which the two-hour insulin level is higher and the blood sugar lower than fasting is consistent with insulin resistance. A mathematical derivation known as the HOMAI, calculated from the fasting values in glucose and insulin concentrations, allows a direct and moderately accurate measure of insulin sensitivity (glucose-level x insulin-level/22.5).
Management
The primary treatments for PCOS include lifestyle changes and use of medications.Goals of treatment may be considered under four categories:
Lowering of insulin resistance
Restoration of fertility
Treatment of hirsutism or acne
Restoration of regular menstruation, and prevention of endometrial hyperplasia and endometrial cancerIn each of these areas, there is considerable debate as to the optimal treatment. One of the major factors undelying the debate is the lack of large-scale clinical trials comparing different treatments. Smaller trials tend to be less reliable and hence may produce conflicting results. General interventions that help to reduce weight or insulin resistance can be beneficial for all these aims, because they address what is believed to be the underlying cause. As PCOS appears to cause significant emotional distress, appropriate support may be useful.
Diet
Where PCOS is associated with overweight or obesity, successful weight loss is the most effective method of restoring normal ovulation/menstruation. The American Association of Clinical Endocrinologists guidelines recommend a goal of achieving 5 to 15% weight loss or more, which improves insulin resistance and all hormonal disorders. Still, many women find it very difficult to achieve and sustain significant weight loss. Insulin resistance itself can cause increased food cravings and lower energy levels, which can make it difficult to lose weight on a regular weight-loss diet. A scientific review in 2013 found similar improvements in weight, body composition and pregnancy rate, menstrual regularity, ovulation, hyperandrogenism, insulin resistance, lipids, and quality of life to occur with weight loss, independent of diet composition. Still, a low GI diet, in which a significant portion of total carbohydrates is obtained from fruit, vegetables, and whole-grain sources, has resulted in greater menstrual regularity than a macronutrient-matched healthy diet.Vitamin D deficiency may play some role in the development of the metabolic syndrome, and treatment of any such deficiency is indicated. However, a systematic review of 2015 found no evidence that vitamin D supplementation reduced or mitigated metabolic and hormonal dysregulations in PCOS. As of 2012, interventions using dietary supplements to correct metabolic deficiencies in people with PCOS had been tested in small, uncontrolled and nonrandomized clinical trials; the resulting data are insufficient to recommend their use.
Medications
Medications for PCOS include oral contraceptives and metformin. The oral contraceptives increase sex hormone binding globulin production, which increases binding of free testosterone. This reduces the symptoms of hirsutism caused by high testosterone and regulates return to normal menstrual periods. Metformin is a medication commonly used in type 2 diabetes mellitus to reduce insulin resistance, and is used off label (in the UK, US, AU and EU) to treat insulin resistance seen in PCOS. In many cases, metformin also supports ovarian function and return to normal ovulation. Spironolactone can be used for its antiandrogenic effects, and the topical cream eflornithine can be used to reduce facial hair. A newer insulin resistance medication class, the thiazolidinediones (glitazones), have shown equivalent efficacy to metformin, but metformin has a more favorable side effect profile. The United Kingdoms National Institute for Health and Clinical Excellence recommended in 2004 that women with PCOS and a body mass index above 25 be given metformin when other therapy has failed to produce results. Metformin may not be effective in every type of PCOS, and therefore there is some disagreement about whether it should be used as a general first line therapy. In addition to this, metformin is associated with several unpleasant side effects: including abdominal pain, metallic taste in the mouth, diarrhoea and vomiting. The use of statins in the management of underlying metabolic syndrome remains unclear.It can be difficult to become pregnant with PCOS because it causes irregular ovulation. Medications to induce fertility when trying to conceive include the ovulation inducer clomiphene or pulsatile leuprorelin. Evidence from randomised controlled trials suggests that in terms of live birth, metformin may be better than placebo, and metform plus clomiphene may be better than clomiphene alone, but that in both cases women may be more likely to experience gastrointestinal side effects with metformin.Metformin is thought to be safe to use during pregnancy (pregnancy category B in the US). A review in 2014 concluded that the use of metformin does not increase the risk of major birth defects in women treated with metformin during the first trimester. Liraglutide may reduce weight and waist circumference in people with PCOS more than other medications.
Infertility
Not all women with PCOS have difficulty becoming pregnant. But some women with PCOS may have difficulty getting pregnant since their body does not produce the hormones necessary for regular ovulation. PCOS might also increase the risk of miscarriage or premature delivery. However, it is possible to have a normal pregnancy. Including medical care and a healthy lifestyle to follow.
For those that do, anovulation or infrequent ovulation is a common cause and PCOS is the main cause of anovulatory infertility. Other factors include changed levels of gonadotropins, hyperandrogenemia, and hyperinsulinemia. Like women without PCOS, women with PCOS that are ovulating may be infertile due to other causes, such as tubal blockages due to a history of sexually transmitted diseases.For overweight anovulatory women with PCOS, weight loss and diet adjustments, especially to reduce the intake of simple carbohydrates, are associated with resumption of natural ovulation. Digital health interventions have been shown to be particularly effective in providing combined therapy to manage PCOS through both lifestyle changes and medication.For those women that after weight loss still are anovulatory or for anovulatory lean women, then the medications letrozole and clomiphene citrate are the principal treatments used to promote ovulation. Previously, the anti-diabetes medication metformin was recommended treatment for anovulation, but it appears less effective than letrozole or clomiphene.For women not responsive to letrozole or clomiphene and diet and lifestyle modification, there are options available including assisted reproductive technology procedures such as controlled ovarian hyperstimulation with follicle-stimulating hormone (FSH) injections followed by in vitro fertilisation (IVF).Though surgery is not commonly performed, the polycystic ovaries can be treated with a laparoscopic procedure called "ovarian drilling" (puncture of 4–10 small follicles with electrocautery, laser, or biopsy needles), which often results in either resumption of spontaneous ovulations or ovulations after adjuvant treatment with clomiphene or FSH. (Ovarian wedge resection is no longer used as much due to complications such as adhesions and the presence of frequently effective medications.) There are, however, concerns about the long-term effects |
Polycystic ovary syndrome | of ovarian drilling on ovarian function.
Mental Health
Although women with PCOS are far more likely to have depression than women without, the evidence for anti-depressant use in women with PCOS remains inconclusive. However, the pathophysiology of depression and mental stress during PCOS is linked to various changes including psychological changes such as high activity of pro-inflammatory markers and immune system during stress.PCOS is associated with other mental health related conditions besides depression such as Anxiety, Bipolar disorder, and Obsessive–compulsive disorder.
Hirsutism and acne
When appropriate (e.g., in women of child-bearing age who require contraception), a standard contraceptive pill is frequently effective in reducing hirsutism. Progestogens such as norgestrel and levonorgestrel should be avoided due to their androgenic effects. Metformin combined with an oral contraceptive may be more effective than either metformin or the oral contraceptive on its own.Other medications with anti-androgen effects include flutamide, and spironolactone, which can give some improvement in hirsutism. Metformin can reduce hirsutism, perhaps by reducing insulin resistance, and is often used if there are other features such as insulin resistance, diabetes, or obesity that should also benefit from metformin. Eflornithine (Vaniqa) is a medication that is applied to the skin in cream form, and acts directly on the hair follicles to inhibit hair growth. It is usually applied to the face. 5-alpha reductase inhibitors (such as finasteride and dutasteride) may also be used; they work by blocking the conversion of testosterone to dihydrotestosterone (the latter of which responsible for most hair growth alterations and androgenic acne).
Although these agents have shown significant efficacy in clinical trials (for oral contraceptives, in 60–100% of individuals), the reduction in hair growth may not be enough to eliminate the social embarrassment of hirsutism, or the inconvenience of plucking or shaving. Individuals vary in their response to different therapies. It is usually worth trying other medications if one does not work, but medications do not work well for all individuals.
Menstrual irregularity
If fertility is not the primary aim, then menstruation can usually be regulated with a contraceptive pill. The purpose of regulating menstruation, in essence, is for the womans convenience, and perhaps her sense of well-being; there is no medical requirement for regular periods, as long as they occur sufficiently often.If a regular menstrual cycle is not desired, then therapy for an irregular cycle is not necessarily required. Most experts say that, if a menstrual bleed occurs at least every three months, then the endometrium (womb lining) is being shed sufficiently often to prevent an increased risk of endometrial abnormalities or cancer. If menstruation occurs less often or not at all, some form of progestogen replacement is recommended.
Alternative medicine
A 2017 review concluded that while both myo-inositol and D-chiro-inositols may regulate menstrual cycles and improve ovulation, there is a lack of evidence regarding effects on the probability of pregnancy. A 2012 and 2017 review have found myo-inositol supplementation appears to be effective in improving several of the hormonal disturbances of PCOS. Myo-inositol reduces the amount of gonadotropins and the length of controlled ovarian hyperstimulation in women undergoing in vitro fertilization. A 2011 review found not enough evidence to conclude any beneficial effect from D-chiro-inositol. There is insufficient evidence to support the use of acupuncture, current studies are inconclusive and theres a need for additional randomized controlled trials.
Treatment
PCOS has no cure, as of 2020. Treatment may involve lifestyle changes such as weight loss and exercise. Birth control pills may help with improving the regularity of periods, excess hair growth, and acne. Metformin and anti-androgens may also help. Other typical acne treatments and hair removal techniques may be used. Efforts to improve fertility include weight loss, clomiphene, or metformin. In vitro fertilization is used by some in whom other measures are not effective.
Epidemiology
PCOS is the most common endocrine disorder among women between the ages of 18 and 44. It affects approximately 2% to 20% of this age group depending on how it is defined. When someone is infertile due to lack of ovulation, PCOS is the most common cause and could guide to patients diagnosis. The earliest known description of what is now recognized as PCOS dates from 1721 in Italy.
The prevalence of PCOS depends on the choice of diagnostic criteria. The World Health Organization estimates that it affects 116 million women worldwide as of 2010 (3.4% of women). Another estimate indicates that 7% of women of reproductive age are affected. Another study using the Rotterdam criteria found that about 18% of women had PCOS, and that 70% of them were previously undiagnosed. Prevalence also varies across countries due to lack of large-scale scientific studies; India, for example, has a purported rate of 1 in 5 women having PCOS.There are few studies that have investigated the racial differences in cardiometabolic factors in women with PCOS. There is also limited data on the racial differences in the risk of metabolic syndrome and cardiovascular disease in adolescents and young adults with PCOS. The first study to comprehensively examine racial differences discovered notable racial differences in risk factors for cardiovascular disease. African American women were found to be significantly more obese, with a significantly higher prevalence of metabolic syndrome compared to white adult women with PCOS. It is important for the further research of racial differences among women with PCOS, to ensure that every woman that is affected by PCOS has the available resources for management.
Ultrasonographic findings of polycystic ovaries are found in 8–25% of women non-affected by the syndrome. 14% women on oral contraceptives are found to have polycystic ovaries. Ovarian cysts are also a common side effect of levonorgestrel-releasing intrauterine devices (IUDs).There are few studies that have investigated the racial differences in cardiometabolic factors in women with PCOS.
History
The condition was first described in 1935 by American gynecologists Irving F. Stein, Sr. and Michael L. Leventhal, from whom its original name of Stein–Leventhal syndrome is taken. Stein and Leventhal first described PCOS as an endocrine disorder in the United States, and since then, it has become recognized as one of the most common causes of oligo ovulatory infertility among women.The earliest published description of a person with what is now recognized as PCOS was in 1721 in Italy. Cyst-related changes to the ovaries were described in 1844.
Etymology
Other names for this syndrome include polycystic ovarian syndrome, polycystic ovary disease, functional ovarian hyperandrogenism, ovarian hyperthecosis, sclerocystic ovary syndrome, and Stein–Leventhal syndrome. The eponymous last option is the original name; it is now used, if at all, only for the subset of women with all the symptoms of amenorrhea with infertility, hirsutism, and enlarged polycystic ovaries.Most common names for this disease derive from a typical finding on medical images, called a polycystic ovary. A polycystic ovary has an abnormally large number of developing eggs visible near its surface, looking like many small cysts.
Society and culture
In 2005, 4 million cases of PCOS were reported in the US, costing $4.36 billion in healthcare costs. In 2016 out of the National Institute Healths research budget of $32.3 billion for that year, 0.1% was spent on PCOS research. Among those aged between 14 and 44, PCOS is conservatively estimated to cost $4.37 billion per year.As opposed to women in the general population, women with PCOS experience higher rates of depression and anxiety. International guidelines and Indian guidelines suggest psychosocial factors should be considered in women with PCOS, as well as screenings for depression and anxiety. Globally, this aspect has been increasingly focused on because it reflects the true impact of PCOS on the lives of patients. Research shows that PCOS adversely impacts a patients quality of life.
Public figures
A number of celebrities and public figures have spoken about their experiences with PCOS, including:
Victoria Beckham
Harnaam Kaur
Chrisette Michele
Keke Palmer
Frankie Bridge
Daisy Ridley
Romee Strijd
Jaime King
Sasha Pieterse
Lea Michele
See also
Androgen-dependent syndromes
PCOS Challenge (reality television series)
References
Further reading
== External links == |
Porphyria | Porphyria is a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are rapid in onset and short in duration. Symptoms of an attack include abdominal pain, chest pain, vomiting, confusion, constipation, fever, high blood pressure, and high heart rate. The attacks usually last for days to weeks. Complications may include paralysis, low blood sodium levels, and seizures. Attacks may be triggered by alcohol, smoking, hormonal changes, fasting, stress, or certain medications. If the skin is affected, blisters or itching may occur with sunlight exposure.Most types of porphyria are inherited from one or both of a persons parents and are due to a mutation in one of the genes that make heme. They may be inherited in an autosomal dominant, autosomal recessive, or X-linked dominant manner. One type, porphyria cutanea tarda, may also be due to hemochromatosis (increased iron in the liver), hepatitis C, alcohol, or HIV/AIDS. The underlying mechanism results in a decrease in the amount of heme produced and a build-up of substances involved in making heme. Porphyrias may also be classified by whether the liver or bone marrow is affected. Diagnosis is typically made by blood, urine, and stool tests. Genetic testing may be done to determine the specific mutation.Treatment depends on the type of porphyria and the persons symptoms. Treatment of porphyria of the skin generally involves the avoidance of sunlight, while treatment for acute porphyria may involve giving intravenous heme or a glucose solution. Rarely, a liver transplant may be carried out.The precise prevalence of porphyria is unclear, but it is estimated to affect between 1 and 100 per 50,000 people. Rates are different around the world. Porphyria cutanea tarda is believed to be the most common type. The disease was described as early as 370 BC by Hippocrates. The underlying mechanism was first described by German physiologist and chemist Felix Hoppe-Seyler in 1871. The name porphyria is from the Greek πορφύρα, porphyra, meaning "purple", a reference to the color of the urine that may be present during an attack.
Signs and symptoms
Acute porphyrias
Acute intermittent porphyria (AIP), variegate porphyria (VP), aminolevulinic acid dehydratase deficiency porphyria (ALAD) and hereditary coproporphyria (HCP). These diseases primarily affect the nervous system, resulting in episodic crises known as acute attacks. The major symptom of an acute attack is abdominal pain, often accompanied by vomiting, hypertension (elevated blood pressure), and tachycardia (an abnormally rapid heart rate).The most severe episodes may involve neurological complications: typically motor neuropathy (severe dysfunction of the peripheral nerves that innervate muscle), which leads to muscle weakness and potentially to quadriplegia (paralysis of all four limbs) and central nervous system symptoms such as seizures and coma. Occasionally, there may be short-lived psychiatric symptoms such as anxiety, confusion, hallucinations, and, very rarely, overt psychosis. All these symptoms resolve once the acute attack passes.Given the many presentations and the relatively low occurrence of porphyria, patients may initially be suspected to have other, unrelated conditions. For instance, the polyneuropathy of acute porphyria may be mistaken for Guillain–Barré syndrome, and porphyria testing is commonly recommended in those situations. Elevation of aminolevulinic acid from lead-induced disruption of heme synthesis results in lead poisoning having symptoms similar to acute porphyria.
Chronic porphyrias
The non-acute porphyrias are X-linked dominant protoporphyria (XLDPP), congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), and erythropoietic protoporphyria (EPP). None of these are associated with acute attacks; their primary manifestation is with skin disease. For this reason, these four porphyrias—along with two acute porphyrias, VP and HCP, that may also involve skin manifestations—are sometimes called cutaneous porphyrias.
Skin disease is encountered where excess porphyrins accumulate in the skin. Porphyrins are photoactive molecules, and exposure to light results in promotion of electrons to higher energy levels. When these return to the resting energy level or ground state, energy is released. This accounts for the property of fluorescence typical of the porphyrins. This causes local skin damage.
Two distinct patterns of skin disease are seen in porphyria:
Immediate photosensitivity. This is typical of XLDPP and EPP. Following a variable period of sun exposure—typically about 30 minutes—patients complain of severe pain, burning, and discomfort in exposed areas. Typically, the effects are not visible, though occasionally there may be some redness and swelling of the skin.
Vesiculo-erosive skin disease. This—a reference to the characteristic blistering (vesicles) and open sores (erosions) noted in patients—is the pattern seen in CEP, PCT, VP, and HCP. The changes are noted only in sun-exposed areas such as the face and back of the hands. Milder skin disease, such as that seen in VP and HCP, consists of increased skin fragility in exposed areas with a tendency to form blisters and erosions, particularly after minor knocks or scrapes. These heal slowly, often leaving small scars that may be lighter or darker than normal skin. More severe skin disease is sometimes seen in PCT, with prominent lesions, darkening of exposed skin such as the face, and hypertrichosis: abnormal hair growth on the face, particularly the cheeks. The most severe disease is seen in CEP and a rare variant of PCT known as hepatoerythropoietic porphyria (HEP); symptoms include severe shortening of digits, loss of skin appendages such as hair and nails, and severe scarring of the skin with progressive disappearance of ears, lips, and nose. Patients may also show deformed, discolored teeth or gum and eye abnormalities.
Cause
The porphyrias are generally considered genetic in nature.
Genetics
Subtypes of porphyrias depend on which enzyme is deficient.
X-linked dominant protoporphyria is a rare form of erythropoietic protoporphyria caused by a gain-of-function mutation in ALAS2 characterized by severe photosensitivity.In the autosomal recessive types, if a person inherits a single gene they may become a carrier. Generally they do not have symptoms, but may pass the gene onto offspring.
Triggers
Acute porphyria can be triggered by a number of drugs, most of which are believed to trigger it by interacting with enzymes in the liver which are made with heme. Such drugs include:
Sulfonamides, including sulfadiazine, sulfasalazine and trimethoprim/sulfamethoxazole.
Sulfonylureas like glibenclamide, gliclazide and glimepiride, although glipizide is thought to be safe.
Barbiturates including thiopental, phenobarbital, primidone, etc.
Systemic treatment with antifungals including fluconazole, griseofulvin, ketoconazole and voriconazole. (Topical use of these agents is thought to be safe due to minimal systemic absorption.)
Certain antibiotics like rifapentine, rifampicin, rifabutine, isoniazid, nitrofurantoin and, possibly, metronidazole.
Ergot derivatives including dihydroergotamine, ergometrine, ergotamine, methysergide, etc.
Certain antiretroviral medications (e.g. indinavir, nevirapine, ritonavir, saquinavir, etc.)
Progestogens
Some anticonvulsants including: carbamazepine, ethosuximide, phenytoin, topiramate, valproate.
Some painkillers like dextropropoxyphene, ketorolac, metamizole, pentazocine
Some cancer treatments like bexarotene, busulfan, chlorambucil, estramustine, etoposide, flutamide, idarubicin, ifosfamide, irinotecan, ixabepilone, letrozole, lomustine, megestrol, mitomycin, mitoxantrone, paclitaxel, procarbazine, tamoxifen, topotecan
Some antidepressants like imipramine, phenelzine, trazodone
Some antipsychotics like risperidone, ziprasidone
Some retinoids used for skin conditions like acitretin and isotretinoin
Miscellaneous others including: cocaine, methyldopa, fenfluramine, disulfiram, orphenadrine, pentoxifylline, and sodium aurothiomalate.
Pathogenesis
In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, catalase, peroxidase, and P450 liver cytochromes.The body requires porphyrins to produce heme, which is used to carry oxygen in the blood among other things, but in the porphyrias there is a deficiency (inherited or acquired) of the enzymes that transform the various porphyrins into others, leading to abnormally high levels of one or more of these substances. Porphyrias are classified in two ways, by symptoms and by pathophysiology. Physiologically, porphyrias are classified as liver or erythropoietic based on the sites of accumulation of heme precursors, either in the liver or in the bone marrow and red blood cells.Deficiency in the enzymes of the porphyrin pathway leads to insufficient production of heme. Heme function plays a central role in cellular metabolism. This is not the main problem in the porphyrias; most heme synthesis enzymes—even dysfunctional enzymes—have enough residual activity to assist in heme biosynthesis. The principal problem in these deficiencies is the accumulation of porphyrins, the heme precursors, which are toxic to tissue in high concentrations. The chemical properties of these intermediates determine the location of accumulation, whether they induce photosensitivity, and whether the intermediate is excreted (in the urine or feces).There are eight enzymes in the heme biosynthetic pathway, four of which—the first one and the last three—are in the mitochondria, while the other four are in the cytosol. Defects in any of these can lead to some form of porphyria. The hepatic porphyrias are characterized by acute neurological attacks (seizures, psychosis, extreme back and abdominal pain, and an acute polyneuropathy), while the erythropoietic forms present with skin problems, usually a light-sensitive blistering rash and increased hair growth.Variegate porphyria (also porphyria variegata or mixed porphyria), which results from a partial deficiency in PROTO oxidase, manifests itself with skin lesions similar to those of porphyria cutanea tarda combined with acute neurologic attacks. Hereditary coproporphyria, which is characterized by a deficiency in coproporphyrinogen oxidase, coded for by the CPOX gene, may also present with both acute neurologic attacks and cutaneous lesions. All other porphyrias are either skin- or nerve-predominant.
Diagnosis
Porphyrin studies
Porphyria is diagnosed through biochemical analysis of blood, urine, and stool. In general, urine estimation of porphobilinogen (PBG) is the first step if acute porphyria is suspected. As a result of feedback, the decreased production of heme leads to increased production of precursors, PBG being one of the first substances in the porphyrin synthesis pathway. In nearly all cases of acute porphyria syndromes, urinary PBG is markedly elevated except for the very rare ALA dehydratase deficiency or in patients with symptoms due to hereditary tyrosinemia type I. In cases of
mercury- or arsenic poisoning-induced porphyria, other changes in porphyrin profiles appear, most notably elevations of uroporphyrins I & III, coproporphyrins I & III, and pre-coproporphyrin.Repeat testing during an attack and subsequent attacks may be necessary in order to detect a porphyria, as levels may be normal or near-normal between attacks. The urine screening test has been known to fail in the initial stages of a severe, life-threatening attack of acute intermittent porphyria.Up to 90% of the genetic carriers of the more common, dominantly inherited acute hepatic porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria) have been noted in DNA tests to be latent for classic symptoms and may require DNA or enzyme testing. The exception to this may be latent post-puberty genetic carriers of hereditary coproporphyria.As most porphyrias are rare conditions, general hospital labs typically do not have the expertise, technology, or staff time to perform porphyria testing. In general, testing involves sending samples of blood, stool, and urine to a reference laboratory. All samples to detect porphyrins must be handled properly. Samples should be taken during an acute attack; otherwise a false negative result may occur. Samples must be protected from light and either refrigerated or preserved.If all the porphyrin studies are negative, one must consider pseudoporphyria. A careful medication review often will find the cause of pseudoporphyria.
Additional tests
Further diagnostic tests of affected organs may be required, such as nerve conduction studies for neuropathy or an ultrasound of the liver. Basic biochemical tests may assist in identifying liver disease, hepatocellular carcinoma, and other organ problems.
Management
Acute porphyria
Carbohydrate administration
Often, empirical treatment is required if the diagnostic suspicion of a porphyria is high since acute attacks can be fatal. A high-carbohydrate diet is typically recommended; in severe attacks, a dextrose 10% infusion is commenced, which may aid in recovery by suppressing heme synthesis, which in turn reduces the rate of porphyrin accumulation. However, this can worsen cases of low blood sodium levels (hyponatraemia) and should be done with extreme caution as it can prove fatal.
Heme analogs
Hematin (trade name Panhematin) and heme arginate (trade name NormoSang) are the drugs of choice in acute porphyria, in the United States and the United Kingdom, respectively. These drugs need to be given very early in an attack to be effective; effectiveness varies amongst individuals. They are not curative drugs but can shorten attacks and reduce the intensity of an attack. Side effects are rare but can be serious. These heme-like substances theoretically inhibit ALA synthase and hence the accumulation of toxic precursors. In the United Kingdom, supplies of NormoSang are kept at two national centers; emergency supply is available from St Thomass Hospital, London. In the United States, Lundbeck manufactures and supplies Panhematin for infusion.Heme arginate (NormoSang) is used during crises but also in preventive treatment to avoid crises, one treatment every 10 days.Any sign of low blood sodium (hyponatremia) or weakness should be treated with the addition of hematin, heme arginate, or even tin mesoporphyrin, as these are signs of impending syndrome of inappropriate antidiuretic hormone (SIADH) or peripheral nervous system involvement that may be localized or severe, progressing to bulbar paresis and respiratory paralysis.
Cimetidine
Cimetidine has also been reported to be effective for acute porphyric crisis and possibly effective for long-term prophylaxis.
Symptom control
Pain is severe, frequently out of proportion to physical signs, and often requires the use of opiates to reduce it to tolerable levels. Pain should be treated as early as medically possible. Nausea can be severe; it may respond to phenothiazine drugs but is sometimes intractable. Hot baths and showers may lessen nausea temporarily, though caution should be used to avoid burns or falls.
Early identification
It is recommended that patients with a history of acute porphyria, and even genetic carriers, wear an alert bracelet or other identification at all times. This is in case they develop severe symptoms, or in case of accidents where there is a potential for drug exposure, and as a result they are unable to explain their condition to healthcare professionals. Some drugs are absolutely contraindicated for patients with any form of porphyria.
Neurologic and psychiatric disorders
Patients who experience frequent attacks can develop chronic neuropathic pain in extremities as well as chronic pain in the abdomen. Intestinal pseudo-obstruction, ileus, intussusception, hypoganglionosis, and encopresis in children have been associated with porphyrias. This is thought to be due to axonal nerve deterioration in affected areas of the nervous system and vagal nerve dysfunction. Pain treatment with long-acting opioids, such as morphine, is often indicated, and, in cases where seizure or neuropathy is present, gabapentin is known to improve outcome.Seizures often accompany this disease. Most seizure medications exacerbate this condition. Treatment can be problematic: barbiturates especially must be avoided. Some benzodiazepines are safe and, when used in conjunction with newer anti-seizure medications such as gabapentin, offer a possible regimen for seizure control. Gabapentin has the additional feature of aiding in the treatment of some kinds of neuropathic pain. Magnesium sulfate and bromides have also been used in porphyria seizures; however, development of status epilepticus in porphyria may not respond to magnesium alone. The addition of hematin or heme arginate has been used during status epilepticus.Depression often accompanies the disease and is best dealt with by treating the offending symptoms and if needed the judicious use of antidepressants. Some psychotropic drugs are porphyrinogenic, limiting the therapeutic scope. Other psychiatric symptoms such as anxiety, restlessness, insomnia, depression, mania, hallucinations, delusions, confusion, catatonia, and psychosis may occur.
Underlying liver disease
Some liver diseases may cause porphyria even in the absence of genetic predisposition. These include hemochromatosis and hepatitis C. Treatment of iron overload may be required.Patients with the acute porphyrias (AIP, HCP, VP) are at increased risk over their life for hepatocellular carcinoma (primary liver cancer) and may require monitoring. Other typical risk factors for liver cancer need not be present.
Hormone treatment
Hormonal fluctuations that contribute to cyclical attacks in women have been treated with oral contraceptives and luteinizing hormones to shut down menstrual cycles. However, oral contraceptives have also triggered photosensitivity and withdrawal of oral contraceptives has triggered attacks. Androgens and fertility hormones have also triggered attacks. In 2019, givosiran was approved in the United States for the treatment of acute hepatic porphyria.
Erythropoietic porphyria
These are associated with accumulation of porphyrins in erythrocytes and are rare.
The pain, burning, swelling, and itching that occur in erythropoietic porphyrias generally require avoidance of bright sunlight. Most kinds of sunscreen are not effective, but SPF-rated long-sleeve shirts, hats, bandanas, and gloves can help. Chloroquine may be used to increase porphyrin secretion in some EPs. Blood transfusion is occasionally used to suppress innate heme production.The rarest is congenital erythropoietic porphyria (CEP), otherwise known as Gunthers disease. The signs may present from birth and include severe photosensitivity, brown teeth that fluoresce in ultraviolet light due to deposition of Type 1 porphyrins, and later hypertrichosis. Hemolytic anemia usually develops. Pharmaceutical-grade beta carotene may be used in its treatment. A bone marrow transplant has also been successful in curing CEP in a few cases, although long-term results are not yet available.In December 2014, afamelanotide received authorization from the European Commission as a treatment for the prevention of phototoxicity in adult patients with EPP.
Epidemiology
Rates of all types of porphyria taken together have been estimated to be approximately one in 25,000 in the United States. The worldwide prevalence has been estimated to be between one in 500 and one in 50,000 people.Porphyrias have been detected in all races and in multiple ethnic groups on every continent. There are high incidence reports of AIP in areas of India and Scandinavia. More than 200 genetic variants of AIP are known, some of which are specific to families, although some strains have proven to be repeated mutations.
History
The underlying mechanism was first described by Felix Hoppe-Seyler in 1871, and acute porphyrias were described by the Dutch physician Barend Stokvis in 1889.The links between porphyrias and mental illness have been noted for decades. In the early 1950s, patients with porphyrias (occasionally referred to as "porphyric hemophilia") and severe symptoms of depression or catatonia were treated with electroshock therapy.
Vampires and werewolves
Porphyria has been suggested as an explanation for the origin of vampire and werewolf legends, based upon certain perceived similarities between the condition and the folklore.
In January 1964, L. Illiss 1963 paper, "On Porphyria and the Aetiology of Werewolves," was published in Proceedings of the Royal Society of Medicine. Later, Nancy Garden argued for a connection between porphyria and the vampire belief in her 1973 book, Vampires. In 1985, biochemist David Dolphins paper for the American Association for the Advancement of Science, "Porphyria, Vampires, and Werewolves: The Aetiology of European Metamorphosis Legends," gained widespread media coverage, popularizing the idea.The theory has been rejected by a few folklorists and researchers as not accurately describing the characteristics of the original werewolf and vampire legends or the disease, and as potentially stigmatizing people with porphyria.A 1995 article from the Postgraduate Medical Journal (via NIH) explains:
As it was believed that the folkloric vampire could move about freely in daylight hours, as opposed to the 20th century variant, congenital erythropoietic porphyria cannot readily explain the folkloric vampire but may be an explanation of the vampire as we know it in the 20th century. In addition, the folkloric vampire, when unearthed, was always described as looking quite healthy ("as they were in life"), while due to disfiguring aspects of the disease, sufferers would not have passed the exhumation test. Individuals with congenital erythropoietic porphyria do not crave blood. The enzyme (hematin) necessary to alleviate symptoms is not absorbed intact on oral ingestion, and drinking blood would have no beneficial effect on the sufferer. Finally, and most important, the fact that vampire reports were literally rampant in the 18th century, and that congenital erythropoietic porphyria is an extremely rare manifestation of a rare disease, makes it an unlikely explanation of the folkloric vampire.
Notable cases
King George III. The mental illness exhibited by George III in the regency crisis of 1788 has inspired several attempts at retrospective diagnosis. The first, written in 1855, thirty-five years after his death, concluded that he had acute mania. M. Guttmacher, in 1941, suggested manic-depressive psychosis as a more likely diagnosis. The first suggestion that a physical illness was the cause of King Georges mental derangement came in 1966, in a paper called "The Insanity of King George III: A Classic Case of Porphyria", with a follow-up in 1968, "Porphyria in the Royal Houses of Stuart, Hanover and Prussia". The papers, by a mother/son psychiatrist team, were written as though the case for porphyria had been proven, but the response demonstrated that many experts, including those more intimately familiar with the manifestations of porphyria, were unconvinced. Many psychiatrists disagreed with the diagnosis, suggesting bipolar disorder as far more probable. The theory is treated in Purple Secret, which documents the ultimately unsuccessful search for genetic evidence of porphyria in the remains of royals suspected to have had it. In 2005, it was suggested that arsenic (which is known to be porphyrogenic) given to George III with antimony may have caused his porphyria. This study found high levels of arsenic in King Georges hair. In 2010, one analysis of historical records argued that the porphyria claim was based on spurious and selective interpretation of contemporary medical and historical sources. The mental illness of George III is the basis of the plot in The Madness of King George, a 1994 British film based upon the 1991 Alan Bennett play, The Madness of George III. The closing credits of the film include the comment that the Kings symptoms suggest that he had porphyria and notes that the disease is "periodic, unpredictable, and hereditary". The traditional argument that George III did NOT have porphyria, but rather bipolar disorder, is thoroughly defended by Andrew Roberts in his new biography, "The Last King of America."
Descendants of George III. Among other descendants of George III theorized by the authors of Purple Secret to have had porphyria (based on analysis of their extensive and detailed medical correspondence) were his great-great-granddaughter Princess Charlotte of Prussia (Emperor William IIs eldest sister) and her daughter Princess Feodora of Saxe-Meiningen. They uncovered better evidence that George IIIs great-great-great-grandson Prince William of Gloucester was reliably diagnosed with variegate porphyria.
Mary, Queen of Scots. It is believed that Mary, Queen of Scots, King George IIIs ancestor, also had acute intermittent porphyria, although this is subject to much debate. It is assumed she inherited the disorder, if indeed she had it, from her father, James V of Scotland. Both father and daughter endured well-documented attacks that could fall within the constellation of symptoms of porphyria.
Maria I of Portugal. Maria I—known as "Maria the Pious" or "Maria the Mad" because of both her religious fervor and her acute mental illness, which made her incapable of handling state affairs after 1792 – is also thought to have had porphyria. Francis Willis, the same physician who treated George III, was even summoned by the Portuguese court but returned to England after the court limited the treatments he could oversee. Contemporary sources, such as Secretary of State for Foreign Affairs Luís Pinto de Sousa Coutinho, noted that the queen had ever-worsening stomach pains and abdominal spasms: hallmarks of porphyria.
Vlad III Dracula, “The Impaler.” Vlad III was also said to have had acute porphyria, which may have started the notion that vampires were allergic to sunlight.
Vincent van Gogh. Other commentators have suggested that Vincent van Gogh may have had acute intermittent porphyria.
King Nebuchadnezzar of Babylon. The description of this king in Daniel 4 suggests to some that he had porphyria.
Physician Archie Cochrane. He was born with porphyria, which caused health problems throughout his life.
Paula Frías Allende. The daughter of the Chilean novelist Isabel Allende. She fell into a porphyria-induced coma in 1991, which inspired Isabel to write the memoir Paula, dedicated to her.
Uses in Literature
Stated or implied references to porphyria are included in some literature, particularly gothic literature. These include the following:
The condition is the name of the title character in the gothic poem "Porphyrias |
Porphyria | Lover," by Robert Browning.
The condition is heavily implied to be the cause of the symptoms suffered by the narrator in the gothic short story "Lusus Naturae," by Margaret Atwood. Some of the narrators symptoms resemble those of porphyria, and one passage of the story states that the name of the narrators disease "had some Ps and Rs in it."
References
External links
Porphyria at Curlie
The Drug Database for Acute Porphyria - comprehensive database on drug porphyrinogenicity
Orphanets disease page on Porphyria |
Postherpetic neuralgia | Postherpetic neuralgia (PHN) is neuropathic pain that occurs due to damage to a peripheral nerve caused by the reactivation of the varicella zoster virus (herpes zoster, also known as shingles). Typically, the nerve pain (neuralgia) is confined to an area of skin innervated by a single sensory nerve, which is known as a dermatome. PHN is defined as dermatomal nerve pain that persists for more than 90 days after an outbreak of herpes zoster affecting the same dermatome. Several types of pain may occur with PHN including continuous burning pain, episodes of severe shooting or electric-like pain, and a heightened sensitivity to gentle touch which would not otherwise cause pain (mechanical allodynia) or to painful stimuli (hyperalgesia). Abnormal sensations and itching may also occur.The nerve pain of PHN is thought to result from damage in a peripheral nerve that was affected by the reactivation of the varicella zoster virus or troubles after chemotherapy. PHN typically begins when the herpes zoster vesicles have crusted over and begun to heal, but can begin in the absence of herpes zoster—a condition called zoster sine herpete.There is no treatment that modifies the disease course of PHN; therefore, controlling the affected persons symptoms is the main goal of treatment. Medications applied to the skin such as capsaicin or topical anesthetics (e.g., lidocaine) are used for mild pain and can be used in combination with oral medications for moderate to severe pain. Oral anticonvulsant medications such as gabapentin and pregabalin are also approved for treatment of PHN. Tricyclic antidepressants reduce PHN pain, but their use is limited by side effects. Opioid medications are not generally recommended for treatment except in specific circumstances. Such cases should involve a pain specialist in patient care due to mixed evidence of efficacy and concerns about potential for abuse and addiction.PHN is the most common long-term complication of herpes zoster. The incidence and prevalence of PHN are uncertain due to varying definitions. Approximately 20% of people affected by herpes zoster report pain in the affected area three months after the initial episode of herpes zoster, and 15% of people similarly report this pain two years after the herpes zoster rash. Since herpes zoster occurs due to reactivation of the varicella zoster virus, which is more likely to occur with a weakened immune system, both herpes zoster and PHN occur more often in the elderly and in people with diabetes mellitus. Risk factors for PHN include older age, a severe herpes-zoster rash, and pain during the herpes zoster episode. PHN is often very painful and can be quite debilitating. Affected individuals often experience a decrease in their quality of life.
Signs and symptoms
Symptoms:
With resolution of the herpes zoster eruption, pain that continues for three months or more is defined as postherpetic neuralgia.
Pain is variable, from discomfort to very severe, and may be described as burning, stabbing, or gnawing.Signs:
Area of previous herpes zoster may show evidence of cutaneous scarring.
Sensation may be altered over the areas involved, in the form of either hypersensitivity or decreased sensation.
In rare cases, the patient might also experience muscle weakness, tremor, or paralysis if the nerves involved also control muscle movement.
Pathophysiology
Postherpetic neuralgia is thought to be due to nerve damage caused by herpes zoster. The damage causes nerves in the affected dermatomic area of the skin to send abnormal electrical signals to the brain. These signals may convey excruciating pain, and may persist or recur for months, years, or for life.A key factor in the neural plasticity underlying neuropathic pain is altered gene expression in sensory dorsal root ganglia neurons. Injury to sensory nerves induces neurochemical, physiological, and anatomical modifications to afferent and central neurons, such as afferent terminal sprouting and inhibitory interneuron loss. Following nerve damage, NaCl channel accumulation causes hyperexcitability, and downregulation of the TTX-resistant Nav1.8 (sensory neuron specific, SNS1) channel and upregulation of TTX-sensitive Nav1.3 (brain type III) and TRPV1 channels. These changes contribute to increased NMDA glutamate receptor-dependent excitability of spinal dorsal horn neurons and are restricted to the ipsilateral (injured) side. A combination of these factors could contribute to the neuropathic pain state of postherpetic neuralgia.
Diagnosis
Lab Studies:
No laboratory work is usually necessary.
Results of cerebrospinal fluid evaluation are abnormal in 61%.
Pleocytosis is observed in 46%, elevated protein in 26%, and VZV DNA in 22%.
These findings are not predictive of the clinical course of postherpetic neuralgia.
Viral culture or immunofluorescence staining may be used to differentiate herpes simplex from herpes zoster in cases that are difficult to distinguish clinically.
Antibodies to herpes zoster can be measured. A 4-fold increase has been used to support the diagnosis of subclinical herpes zoster (zoster sine herpete). However, a rising titer secondary to viral exposure rather than reactivation cannot be ruled out.Imaging studies:
Magnetic resonance imaging lesions attributable to herpes zoster were seen in the brain stem and cervical cord in 56% (9/16) of patients.
At three months after onset of herpes zoster, 56% (5/9) of patients with an abnormal magnetic resonance image had developed postherpetic neuralgia.
Of the seven patients who had no herpes-zoster-related lesions on the magnetic resonance image, none had residual pain.
Prevention
Primary prevention
In 1995, the Food and Drug Administration (FDA) approved the Varicella vaccine to prevent chickenpox. Its effect on postherpetic neuralgia is still unknown. The vaccine—made from a weakened form of the varicella-zoster virus—may keep chickenpox from occurring in nonimmune children and adults, or at least lessen the risk of the varicella zoster virus lying dormant in the body and reactivating later as shingles. If shingles could be prevented, postherpetic neuralgia could be completely avoided.In May 2006 the Advisory Committee on Immunization Practices approved a new vaccine by Merck (Zostavax) against shingles. This vaccine is a more potent version of the chickenpox vaccine, and evidence shows that it reduces the incidence of postherpetic neuralgia. The CDC recommends use of this vaccine in all persons over 60 years old.The most effective means of preventing PHN from a herpes zoster infection is prior vaccination with the varicella vaccine. Vaccination decreases the overall incidence of virus reactivation but also decreases the severity of disease development and incidence of PHN if reactivation does occur.
Secondary prevention
A 2013 Cochrane meta-analysis of 6 randomized controlled trials (RCTs) investigating oral antiviral medications given within 72 hours after the onset of herpes zoster rash in immunocompetent people for preventing postherpetic neuralgia (PHN) found no significant difference between placebo and acyclovir.
Additionally, there was no significant difference in preventing the incidence of PHN found in the one RCT included in the meta-analysis that compared placebo to oral famciclovir treatment within 72 hours of HZ rash onset. Studies using valacyclovir treatment were not included in the meta-analysis.
PHN was defined as pain at the site of the dermatomic rash at 120 days after the onset of rash, and incidence was evaluated at 1, 4, and 6 months after rash onset. Patients who are prescribed oral antiviral agents after the onset of rash should be informed that their chances of developing PHN are no different than those not taking oral antiviral agents.
Treatment
The pain from postherpetic neuralgia can be very severe and requires immediate treatment. There is no treatment which modifies the course of the disease and management primarily aims to control symptoms.
Medications
Topical medications
Medications applied to the skin can be used alone if the pain from PHN is mild or in combination with oral medications if the pain is moderate to severe. Topical medications for PHN include low-dose (0.075%) and high-dose (8%) capsaicin and anesthetics such as lidocaine patches. Lidocaine patches (5% concentration) are approved in the United States and Europe to treat PHN though evidence supporting their use is limited. A meta-analysis of multiple small placebo-controlled randomized controlled trials found that for every two people treated with topical lidocaine, one person experienced at least a 50% reduction in their PHN-associated pain (number needed to treat (NNT)=2).Low-dose capsaicin may be useful for reducing PHN-associated pain but is limited by side effects (redness and a burning or stinging sensation with application) and the need to apply it four times daily. Approximately three people must be treated with low-dose capsaicin cream for one person to experience significant pain relief (number needed to treat =3.3). A single topical application of a high-dose capsaicin patch over the affected area after numbing the area with a topical anesthetic has also been found to relieve PHN-associated pain. For every eleven people treated with a high-dose capsaicin patch for up to 12 weeks, one person experienced a significant improvement in their pain. (number needed to treat=11). Due to the need for topical anesthesia before application of the high-dose capsaicin patch, referral to a pain specialist is generally recommended if this approach is being considered.
Oral medications
Multiple oral medications have demonstrated efficacy in relieving postherpetic neuralgia pain. Tricyclic antidepressants (TCAs), such as nortriptyline or desipramine, are effective in reducing postherpetic neuralgia pain but are limited by their numerous side effects. For every three people treated with a tricyclic antidepressant, one person is expected to have a clinically significant reduction in their pain (NNT=3). Additionally, of every sixteen people treated with a TCA, one person is expected to stop the medication due to a bothersome side effect, such as dry mouth, constipation, or urinary retention (number needed to harm=16). The anticonvulsant medications pregabalin and gabapentin also effectively relieve postherpetic neuralgia pain. Treatment with pregabalin leads to a reduction in pain intensity of 50% or more in one person out of every 4–5 people treated (NNT=4–5). Similarly, treatment with gabapentin also leads to a 50% reduction in pain intensity in one person out of every 7-8 people treated (NNT=7.5).Opioids such as tramadol, methadone, oxycodone, and morphine have not been well-studied for postherpetic neuralgia treatment. Acetaminophen and nonsteroidal anti-inflammatory drugs are thought to be ineffective and have not undergone rigorous study for PHN.
Prognosis
The natural history of postherpetic neuralgia involves slow resolution of the pain syndrome. A subgroup of affected individuals may develop severe, long-lasting pain that does not respond to medical therapy.
Epidemiology
In the United States each year approximately 1,000,000 individuals develop herpes zoster. Of those individuals, approximately 10–18% develop postherpetic neuralgia.Fewer than 10 percent of people younger than 60 develop postherpetic neuralgia after a bout of herpes zoster, while about 40 percent of people older than 60 do.
References
Further reading
Hempenstall K, Nurmikko TJ, Johnson RW, AHern RP, Rice AS (July 2005). "Analgesic therapy in postherpetic neuralgia: a quantitative systematic review". PLOS Medicine. 2 (7): e164. doi:10.1371/journal.pmed.0020164. PMC 1181872. PMID 16013891.
== External links == |
Post-traumatic stress disorder | Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats on a persons life. Symptoms may include disturbing thoughts, feelings, or dreams related to the events, mental or physical distress to trauma-related cues, attempts to avoid trauma-related cues, alterations in the way a person thinks and feels, and an increase in the fight-or-flight response. These symptoms last for more than a month after the event. Young children are less likely to show distress but instead may express their memories through play. A person with PTSD is at a higher risk of suicide and intentional self-harm.Most people who experience traumatic events do not develop PTSD. People who experience interpersonal violence such as rape, other sexual assaults, being kidnapped, stalking, physical abuse by an intimate partner, and incest or other forms of childhood sexual abuse are more likely to develop PTSD than those who experience non-assault based trauma, such as accidents and natural disasters. Those who experience prolonged trauma, such as slavery, concentration camps, or chronic domestic abuse, may develop complex post-traumatic stress disorder (C-PTSD). C-PTSD is similar to PTSD but has a distinct effect on a persons emotional regulation and core identity.Prevention may be possible when counselling is targeted at those with early symptoms but is not effective when provided to all trauma-exposed individuals whether or not symptoms are present. The main treatments for people with PTSD are counselling (psychotherapy) and medication. Antidepressants of the SSRI or SNRI type are the first-line medications used for PTSD and are moderately beneficial for about half of people. Benefits from medication are less than those seen with counselling. It is not known whether using medications and counselling together has greater benefit than either method separately. Medications, other than some SSRIs or SNRIs, do not have enough evidence to support their use and, in the case of benzodiazepines, may worsen outcomes.In the United States, about 3.5% of adults have PTSD in a given year, and 9% of people develop it at some point in their life. In much of the rest of the world, rates during a given year are between 0.5% and 1%. Higher rates may occur in regions of armed conflict. It is more common in women than men.Symptoms of trauma-related mental disorders have been documented since at least the time of the ancient Greeks. A few instances of evidence of post-traumatic illness have been argued to exist from the seventeenth and eighteenth centuries, such as the diary of Samuel Pepys, who described intrusive and distressing symptoms following the 1666 Fire of London. During the world wars, the condition was known under various terms, including shell shock, war nerves, neurasthenia and combat neurosis. The term "post-traumatic stress disorder" came into use in the 1970s in large part due to the diagnoses of U.S. military veterans of the Vietnam War. It was officially recognized by the American Psychiatric Association in 1980 in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III).
Symptoms
Symptoms of PTSD generally begin within the first three months after the inciting traumatic event, but may not begin until years later. In the typical case, the individual with PTSD persistently avoids either trauma-related thoughts and emotions or discussion of the traumatic event and may even have amnesia of the event. However, the event is commonly relived by the individual through intrusive, recurrent recollections, dissociative episodes of reliving the trauma ("flashbacks"), and nightmares (50 to 70%). While it is common to have symptoms after any traumatic event, these must persist to a sufficient degree (i.e., causing dysfunction in life or clinical levels of distress) for longer than one month after the trauma to be classified as PTSD (clinically significant dysfunction or distress for less than one month after the trauma may be acute stress disorder). Some following a traumatic event experience post-traumatic growth.
Associated medical conditions
Trauma survivors often develop depression, anxiety disorders, and mood disorders in addition to PTSD.Substance use disorder, such as alcohol use disorder, commonly co-occur with PTSD. Recovery from post-traumatic stress disorder or other anxiety disorders may be hindered, or the condition worsened, when substance use disorders are comorbid with PTSD. Resolving these problems can bring about improvement in an individuals mental health status and anxiety levels.In children and adolescents, there is a strong association between emotional regulation difficulties (e.g. mood swings, anger outbursts, temper tantrums) and post-traumatic stress symptoms, independent of age, gender, or type of trauma.Moral injury the feeling of moral distress such as a shame or guilt following a moral transgression is associated with PTSD but is distinguished from it. Moral injury is associated with shame and guilt while PTSD is associated with anxiety and fear.: 2,8,11
Risk factors
Persons considered at risk include combat military personnel, survivors of natural disasters, concentration camp survivors, and survivors of violent crime. Persons employed in occupations that expose them to violence (such as soldiers) or disasters (such as emergency service workers) are also at risk. Other occupations that are at higher risk include police officers, firefighters, ambulance personnel, health care professionals, train drivers, divers, journalists, and sailors, in addition to people who work at banks, post offices or in stores.
Trauma
PTSD has been associated with a wide range of traumatic events. The risk of developing PTSD after a traumatic event varies by trauma type and is highest following exposure to sexual violence (11.4%), particularly rape (19.0%). Men are more likely to experience a traumatic event (of any type), but women are more likely to experience the kind of high-impact traumatic event that can lead to PTSD, such as interpersonal violence and sexual assault.Motor vehicle collision survivors, both children and adults, are at an increased risk of PTSD. Globally, about 2.6% of adults are diagnosed with PTSD following a non-life-threatening traffic accident, and a similar proportion of children develop PTSD. Risk of PTSD almost doubles to 4.6% for life-threatening auto accidents. Females were more likely to be diagnosed with PTSD following a road traffic accident, whether the accident occurred during childhood or adulthood.Post-traumatic stress reactions have been studied in children and adolescents. The rate of PTSD might be lower in children than adults, but in the absence of therapy, symptoms may continue for decades. One estimate suggests that the proportion of children and adolescents having PTSD in a non-wartorn population in a developed country may be 1% compared to 1.5% to 3% of adults. On average, 16% of children exposed to a traumatic event develop PTSD, varying according to type of exposure and gender. Similar to the adult population, risk factors for PTSD in children include: female gender, exposure to disasters (natural or manmade), negative coping behaviours, and/or lacking proper social support systems.Predictor models have consistently found that childhood trauma, chronic adversity, neurobiological differences, and familial stressors are associated with risk for PTSD after a traumatic event in adulthood. It has been difficult to find consistently aspects of the events that predict, but peritraumatic dissociation has been a fairly consistent predictive indicator of the development of PTSD. Proximity to, duration of, and severity of the trauma make an impact. It has been speculated that interpersonal traumas cause more problems than impersonal ones, but this is controversial. The risk of developing PTSD is increased in individuals who are exposed to physical abuse, physical assault, or kidnapping. Women who experience physical violence are more likely to develop PTSD than men.
Intimate partner violence
An individual that has been exposed to domestic violence is predisposed to the development of PTSD. There is a strong association between the development of PTSD in mothers that experienced domestic violence during the perinatal period of their pregnancy.Those who have experienced sexual assault or rape may develop symptoms of PTSD. PTSD symptoms include re-experiencing the assault, avoiding things associated with the assault, numbness, and increased anxiety and an increased startle response. The likelihood of sustained symptoms of PTSD is higher if the rapist confined or restrained the person, if the person being raped believed the rapist would kill them, the person who was raped was very young or very old, and if the rapist was someone they knew. The likelihood of sustained severe symptoms is also higher if people around the survivor ignore (or are ignorant of) the rape or blame the rape survivor.
War-related trauma
Military service is a risk factor for developing PTSD. Around 78% of people exposed to combat do not develop PTSD; in about 25% of military personnel who develop PTSD, its appearance is delayed.Refugees are also at an increased risk for PTSD due to their exposure to war, hardships, and traumatic events. The rates for PTSD within refugee populations range from 4% to 86%. While the stresses of war affect everyone involved, displaced persons have been shown to be more so than others.Challenges related to the overall psychosocial well-being of refugees are complex and individually nuanced. Refugees have reduced levels of well-being and a high rates of mental distress due to past and ongoing trauma. Groups that are particularly affected and whose needs often remain unmet are women, older people and unaccompanied minors. Post-traumatic stress and depression in refugee populations also tend to affect their educational success.
Unexpected death of a loved one
Sudden, unexpected death of a loved one is the most common traumatic event type reported in cross-national studies. However, the majority of people who experience this type of event will not develop PTSD. An analysis from the WHO World Mental Health Surveys found a 5.2% risk of developing PTSD after learning of the unexpected death of a loved one. Because of the high prevalence of this type of traumatic event, unexpected death of a loved one accounts for approximately 20% of PTSD cases worldwide.
Life-threatening illness
Medical conditions associated with an increased risk of PTSD include cancer, heart attack, and stroke. 22% of cancer survivors present with lifelong PTSD like symptoms. Intensive-care unit (ICU) hospitalization is also a risk factor for PTSD. Some women experience PTSD from their experiences related to breast cancer and mastectomy. Loved ones of those who experience life-threatening illnesses are also at risk for developing PTSD, such as parents of child with chronic illnesses.
Pregnancy-related trauma
Women who experience miscarriage are at risk of PTSD. Those who experience subsequent miscarriages have an increased risk of PTSD compared to those experiencing only one. PTSD can also occur after childbirth and the risk increases if a woman has experienced trauma prior to the pregnancy. Prevalence of PTSD following normal childbirth (that is, excluding stillbirth or major complications) is estimated to be between 2.8 and 5.6% at six weeks postpartum, with rates dropping to 1.5% at six months postpartum. Symptoms of PTSD are common following childbirth, with prevalence of 24–30.1% at six weeks, dropping to 13.6% at six months. Emergency childbirth is also associated with PTSD.
Genetics
There is evidence that susceptibility to PTSD is hereditary. Approximately 30% of the variance in PTSD is caused from genetics alone. For twin pairs exposed to combat in Vietnam, having a monozygotic (identical) twin with PTSD was associated with an increased risk of the co-twins having PTSD compared to twins that were dizygotic (non-identical twins). Women with a smaller hippocampus might be more likely to develop PTSD following a traumatic event based on preliminary findings. Research has also found that PTSD shares many genetic influences common to other psychiatric disorders. Panic and generalized anxiety disorders and PTSD share 60% of the same genetic variance. Alcohol, nicotine, and drug dependence share greater than 40% genetic similarities.Several biological indicators have been identified that are related to later PTSD development. Heightened startle responses and, with only preliminary results, a smaller hippocampal volume have been identified as possible biomarkers for heightened risk of developing PTSD. Additionally, one study found that soldiers whose leukocytes had greater numbers of glucocorticoid receptors were more prone to developing PTSD after experiencing trauma.
Pathophysiology
Neuroendocrinology
PTSD symptoms may result when a traumatic event causes an over-reactive adrenaline response, which creates deep neurological patterns in the brain. These patterns can persist long after the event that triggered the fear, making an individual hyper-responsive to future fearful situations. During traumatic experiences, the high levels of stress hormones secreted suppress hypothalamic activity that may be a major factor toward the development of PTSD.PTSD causes biochemical changes in the brain and body, that differ from other psychiatric disorders such as major depression. Individuals diagnosed with PTSD respond more strongly to a dexamethasone suppression test than individuals diagnosed with clinical depression.Most people with PTSD show a low secretion of cortisol and high secretion of catecholamines in urine, with a norepinephrine/cortisol ratio consequently higher than comparable non-diagnosed individuals. This is in contrast to the normative fight-or-flight response, in which both catecholamine and cortisol levels are elevated after exposure to a stressor.Brain catecholamine levels are high, and corticotropin-releasing factor (CRF) concentrations are high. Together, these findings suggest abnormality in the hypothalamic-pituitary-adrenal (HPA) axis.
The maintenance of fear has been shown to include the HPA axis, the locus coeruleus-noradrenergic systems, and the connections between the limbic system and frontal cortex. The HPA axis that coordinates the hormonal response to stress, which activates the LC-noradrenergic system, is implicated in the over-consolidation of memories that occurs in the aftermath of trauma. This over-consolidation increases the likelihood of ones developing PTSD. The amygdala is responsible for threat detection and the conditioned and unconditioned fear responses that are carried out as a response to a threat.The HPA axis is responsible for coordinating the hormonal response to stress. Given the strong cortisol suppression to dexamethasone in PTSD, HPA axis abnormalities are likely predicated on strong negative feedback inhibition of cortisol, itself likely due to an increased sensitivity of glucocorticoid receptors.
PTSD has been hypothesized to be a maladaptive learning pathway to fear response through a hypersensitive, hyperreactive, and hyperresponsive HPA axis.Low cortisol levels may predispose individuals to PTSD: Following war trauma, Swedish soldiers serving in Bosnia and Herzegovina with low pre-service salivary cortisol levels had a higher risk of reacting with PTSD symptoms, following war trauma, than soldiers with normal pre-service levels. Because cortisol is normally important in restoring homeostasis after the stress response, it is thought that trauma survivors with low cortisol experience a poorly contained—that is, longer and more distressing—response, setting the stage for PTSD.
It is thought that the locus coeruleus-noradrenergic system mediates the over-consolidation of fear memory. High levels of cortisol reduce noradrenergic activity, and because people with PTSD tend to have reduced levels of cortisol, it has been proposed that individuals with PTSD cannot regulate the increased noradrenergic response to traumatic stress. Intrusive memories and conditioned fear responses are thought to be a result of the response to associated triggers. Neuropeptide Y (NPY) has been reported to reduce the release of norepinephrine and has been demonstrated to have anxiolytic properties in animal models. Studies have shown people with PTSD demonstrate reduced levels of NPY, possibly indicating their increased anxiety levels.Other studies indicate that people with PTSD have chronically low levels of serotonin, which contributes to the commonly associated behavioral symptoms such as anxiety, ruminations, irritability, aggression, suicidality, and impulsivity. Serotonin also contributes to the stabilization of glucocorticoid production.
Dopamine levels in a person with PTSD can contribute to symptoms: low levels can contribute to anhedonia, apathy, impaired attention, and motor deficits; high levels can contribute to psychosis, agitation, and restlessness.Several studies described elevated concentrations of the thyroid hormone triiodothyronine in PTSD. This kind of type 2 allostatic adaptation may contribute to increased sensitivity to catecholamines and other stress mediators.
Hyperresponsiveness in the norepinephrine system can also be caused by continued exposure to high stress. Overactivation of norepinephrine receptors in the prefrontal cortex can be connected to the flashbacks and nightmares frequently experienced by those with PTSD. A decrease in other norepinephrine functions (awareness of the current environment) prevents the memory mechanisms in the brain from processing the experience, and emotions the person is experiencing during a flashback are not associated with the current environment.There is considerable controversy within the medical community regarding the neurobiology of PTSD. A 2012 review showed no clear relationship between cortisol levels and PTSD. The majority of reports indicate people with PTSD have elevated levels of corticotropin-releasing hormone, lower basal cortisol levels, and enhanced negative feedback suppression of the HPA axis by dexamethasone.
Neuroanatomy
A meta-analysis of structural MRI studies found an association with reduced total brain volume, intracranial volume, and volumes of the hippocampus, insula cortex, and anterior cingulate. Much of this research stems from PTSD in those exposed to the Vietnam War.People with PTSD have decreased brain activity in the dorsal and rostral anterior cingulate cortices and the ventromedial prefrontal cortex, areas linked to the experience and regulation of emotion.The amygdala is strongly involved in forming emotional memories, especially fear-related memories. During high stress, the hippocampus, which is associated with placing memories in the correct context of space and time and memory recall, is suppressed. According to one theory this suppression may be the cause of the flashbacks that can affect people with PTSD. When someone with PTSD undergoes stimuli similar to the traumatic event, the body perceives the event as occurring again because the memory was never properly recorded in the persons memory.The amygdalocentric model of PTSD proposes that the amygdala is very much aroused and insufficiently controlled by the medial prefrontal cortex and the hippocampus, in particular during extinction. This is consistent with an interpretation of PTSD as a syndrome of deficient extinction ability.The basolateral nucleus (BLA) of the amygdala is responsible for the comparison and development of associations between unconditioned and conditioned responses to stimuli, which results in the fear conditioning present in PTSD. The BLA activates the central nucleus (CeA) of the amygdala, which elaborates the fear response, (including behavioral response to threat and elevated startle response). Descending inhibitory inputs from the medial prefrontal cortex (mPFC) regulate the transmission from the BLA to the CeA, which is hypothesized to play a role in the extinction of conditioned fear responses. While as a whole, amygdala hyperactivity is reported by meta analysis of functional neuroimaging in PTSD, there is a large degree of heterogeniety, more so than in social anxiety disorder or phobic disorder. Comparing dorsal (roughly the CeA) and ventral(roughly the BLA) clusters, hyperactivity is more robust in the ventral cluster, while hypoactivity is evident in the dorsal cluster. The distinction may explain the blunted emotions in PTSD (via desensitization in the CeA) as well as the fear related component.In a 2007 study Vietnam War combat veterans with PTSD showed a 20% reduction in the volume of their hippocampus compared with veterans who did not have such symptoms. This finding was not replicated in chronic PTSD patients traumatized at an air show plane crash in 1988 (Ramstein, Germany).Evidence suggests that endogenous cannabinoid levels are reduced in PTSD, particularly anandamide, and that cannabinoid receptors (CB1) are increased in order to compensate. There appears to be a link between increased CB1 receptor availability in the amygdala and abnormal threat processing and hyperarousal, but not dysphoria, in trauma survivors.
A 2020 study found no evidence for conclusions from prior research that suggested low IQ is a risk factor for developing PTSD.
Diagnosis
PTSD can be difficult to diagnose, because of:
the subjective nature of most of the diagnostic criteria (although this is true for many mental disorders);
the potential for over-reporting, e.g., while seeking disability benefits, or when PTSD could be a mitigating factor at criminal sentencing
the potential for under-reporting, e.g., stigma, pride, fear that a PTSD diagnosis might preclude certain employment opportunities;
symptom overlap with other mental disorders such as obsessive compulsive disorder and generalized anxiety disorder;
association with other mental disorders such as major depressive disorder and generalized anxiety disorder;
substance use disorders, which often produce some of the same signs and symptoms as PTSD; and
substance use disorders can increase vulnerability to PTSD or exacerbate PTSD symptoms or both; and
PTSD increases the risk for developing substance use disorders.
the differential expression of symptoms culturally (specifically with respect to avoidance and numbing symptoms, distressing dreams, and somatic symptoms)
Screening
There are a number of PTSD screening instruments for adults, such as the PTSD Checklist for DSM-5 (PCL-5) and the Primary Care PTSD Screen for DSM-5 (PC-PTSD-5).There are also several screening and assessment instruments for use with children and adolescents. These include the Child PTSD Symptom Scale (CPSS), Child Trauma Screening Questionnaire, and UCLA Post-traumatic Stress Disorder Reaction Index for DSM-IV.In addition, there are also screening and assessment instruments for caregivers of very young children (six years of age and younger). These include the Young Child PTSD Screen, the Young Child PTSD Checklist, and the Diagnostic Infant and Preschool Assessment.
Assessment
Evidence-based assessment principles, including a multimethod assessment approach, form the foundation of PTSD assessment.
Diagnostic and statistical manual
PTSD was classified as an anxiety disorder in the DSM-IV, but has since been reclassified as a "trauma- and stressor-related disorder" in the DSM-5. The DSM-5 diagnostic criteria for PTSD include four symptom clusters: re-experiencing, avoidance, negative alterations in cognition/mood, and alterations in arousal and reactivity.
International classification of diseases
The International Classification of Diseases and Related Health Problems 10 (ICD-10) classifies PTSD under "Reaction to severe stress, and adjustment disorders." The ICD-10 criteria for PTSD include re-experiencing, avoidance, and either increased reactivity or inability to recall certain details related to the event.The ICD-11 diagnostic description for PTSD contains three components or symptom groups (1) re-experiencing, (2) avoidance, and (3) heightened sense of threat. ICD-11 no longer includes verbal thoughts about the traumatic event as a symptom. There is a predicted lower rate of diagnosed PTSD using ICD-11 compared to ICD10 or DSM-5. ICD-11 also proposes identifying a distinct group with complex post-traumatic stress disorder (CPTSD), who have more often experienced several or sustained traumas and have greater functional impairment than those with PTSD.
Differential diagnosis
A diagnosis of PTSD requires that the person has been exposed to an extreme stressor. Any stressor can result in a diagnosis of adjustment disorder and it is an appropriate diagnosis for a stressor and a symptom pattern that does not meet the criteria for PTSD.
The symptom pattern for acute stress disorder must occur and be resolved within four weeks of the trauma. If it lasts longer, and the symptom pattern fits that characteristic of PTSD, the diagnosis may be changed.Obsessive compulsive disorder may be diagnosed for intrusive thoughts that are recurring but not related to a specific traumatic event.In extreme cases of prolonged, repeated traumatization where there is no viable chance of escape, survivors may develop complex post-traumatic stress disorder. This occurs as a result of layers of trauma rather than a single traumatic event, and includes additional symptomatology, such as the loss of a coherent sense of self.
Prevention
Modest benefits have been seen from early access to cognitive behavioral therapy. Critical incident stress management has been suggested as a means of preventing PTSD, but subsequent studies suggest the likelihood of its producing negative outcomes. A 2019 Cochrane review did not find any evidence to support the use of an intervention offered to everyone", and that "multiple session interventions may result in worse outcome than no intervention for some individuals." The World Health Organization recommends against the use of benzodiazepines and antidepressants in for acute stress (symptoms lasting less than one month). Some evidence supports the use of hydrocortisone for prevention in adults, although there is limited or no evidence supporting propranolol, escitalopram, temazepam, or gabapentin.
Psychological debriefing
Trauma-exposed individuals often receive treatment called psychological debriefing in an effort to prevent PTSD, which consists of interviews that are meant to allow individuals to directly confront the event and share their feelings with the counselor and to help structure their memories of the event. However, several meta-analyses find that psychological debriefing is unhelpful and is potentially harmful. This is true for both single-session debriefing and multiple session interventions. As of 2017 the American Psychological Association assessed psychological debriefing as No Research Support/Treatment is Potentially Harmful.
Risk-targeted interventions
Risk-targeted interventions are those that attempt to mitigate specific formative information or events. It can target modeling normal behaviors, instruction on a task, or giving information on the event.
Management
Reviews of studies have found that combination therapy (psychological and pharmacotherapy) is no more effective than psychological therapy alone.
Counselling
The approaches with the strongest evidence include behavioral and cognitive-behavioral therapies such as prolonged exposure therapy, cognitive processing therapy, and eye movement desensitization and reprocessing (EMDR). There is some evidence for brief eclectic psychotherapy (BEP), narrative exposure therapy (NET), and written exposure therapy.A 2019 Cochrane review evaluated couples and family therapies compared to no care and individual and group therapies for the treatment of PTSD. There were too few studies on couples therapies to determine if substantive benefits were derived but preliminary RCTs suggested that couples therapies may be beneficial for reducing PTSD symptoms.A meta-analytic comparison of EMDR and cognitive behavioral therapy (CBT) found both protocols indistinguishable in terms of effectiveness in treating PTSD; however, "the contribution of the eye movement component in EMDR to treatment outcome" is unclear. A meta-analysis in children and adolescents also found that EMDR was as efficacious as CBT.Children with PTSD are far more likely to pursue treatment at school (because of its proximity and ease) than at a free clinic.
Cognitive behavioral therapy
CBT seeks to change the way a person feels and acts by changing the patterns of thinking or behavior, or both, responsible for negative emotions. Results from a 2018 systematic review found high strength of evidence that supports CBT-exposure therapy efficacious for a reduction in PTSD and depression symptoms, as well as the loss of PTSD diagnosis. CBT has been proven to be an effective treatment for PTSD and is currently considered the standard of care for PTSD by the United States Department of Defense. In CBT, individuals learn to identify thoughts that make them feel afraid or upset and replace them with less distressing thoughts. The goal is to understand how certain thoughts about events cause PTSD-related stress. The provision of CBT in an Internet-based format has also been studied in a 2018 Cochrane review. This review did find similar beneficial effects for Internet-based settings as in face-to-face but the quality of the evidence was low due to the small number of trials reviewed.Exposure therapy is a type of cognitive behavioral therapy that involves assisting trauma survivors to re-experience distressing trauma-related memories and reminders in order to facilitate habituation and successful emotional processing of the trauma memory. Most exposure therapy programs include both imaginal confrontation with the traumatic memories and real-life exposure to trauma reminders; this therapy modality is well supported by clinical evidence. The success of exposure-based therapies has raised the question of whether exposure is a necessary ingredient in the treatment of PTSD. Some organizations have endorsed the need for exposure. The U.S. Department of Veterans Affairs has been actively training mental health treatment staff in prolonged exposure therapy and Cognitive Processing Therapy in an effort to better treat U.S. veterans with PTSD.
Recent research on contextually based third-generation behavior therapies suggests that they may produce results comparable to some of the better validated therapies. Many of these therapy methods have a significant element of exposure and have demonstrated success in treating the primary problems of PTSD and co-occurring depressive symptoms.
Eye movement desens |
Post-traumatic stress disorder | itization and reprocessing
Eye movement desensitization and reprocessing (EMDR) is a form of psychotherapy developed and studied by Francine Shapiro. She had noticed that, when she was thinking about disturbing memories herself, her eyes were moving rapidly. When she brought her eye movements under control while thinking, the thoughts were less distressing.In 2002, Shapiro and Maxfield published a theory of why this might work, called adaptive information processing. This theory proposes that eye movement can be used to facilitate emotional processing of memories, changing the persons memory to attend to more adaptive information. The therapist initiates voluntary rapid eye movements while the person focuses on memories, feelings or thoughts about a particular trauma. The therapists uses hand movements to get the person to move their eyes backward and forward, but hand-tapping or tones can also be used. EMDR closely resembles cognitive behavior therapy as it combines exposure (re-visiting the traumatic event), working on cognitive processes and relaxation/self-monitoring. However, exposure by way of being asked to think about the experience rather than talk about it has been highlighted as one of the more important distinguishing elements of EMDR.There have been several small controlled trials of four to eight weeks of EMDR in adults as well as children and adolescents. There is moderate strength of evidence to support the efficacy of EMDR "for reduction in PTSD symptoms, loss of diagnosis, and reduction in depressive symptoms" according to a 2018 systematic review update. EMDR reduced PTSD symptoms enough in the short term that one in two adults no longer met the criteria for PTSD, but the number of people involved in these trials was small and thus results should be interpreted with caution pending further research. There was not enough evidence to know whether or not EMDR could eliminate PTSD in adults. In children and adolescents, a recent meta-analysis of randomized controlled trials using MetaNSUE to avoid biases related to missing information found that EMDR was at least as efficacious as CBT, and superior to waitlist or placebo. There was some evidence that EMDR might prevent depression. There were no studies comparing EMDR to other psychological treatments or to medication. Adverse effects were largely unstudied. The benefits were greater for women with a history of sexual assault compared with people who had experienced other types of traumatizing events (such as accidents, physical assaults and war). There is a small amount of evidence that EMDR may improve re-experiencing symptoms in children and adolescents, but EMDR has not been shown to improve other PTSD symptoms, anxiety, or depression.The eye movement component of the therapy may not be critical for benefit. As there has been no major, high quality randomized trial of EMDR with eye movements versus EMDR without eye movements, the controversy over effectiveness is likely to continue. Authors of a meta-analysis published in 2013 stated, "We found that people treated with eye movement therapy had greater improvement in their symptoms of post-traumatic stress disorder than people given therapy without eye movements.... Secondly we found that in laboratory studies the evidence concludes that thinking of upsetting memories and simultaneously doing a task that facilitates eye movements reduces the vividness and distress associated with the upsetting memories."
Interpersonal psychotherapy
Other approaches, in particular involving social supports, may also be important. An open trial of interpersonal psychotherapy reported high rates of remission from PTSD symptoms without using exposure. A current, NIMH-funded trial in New York City is now (and into 2013) comparing interpersonal psychotherapy, prolonged exposure therapy, and relaxation therapy.
Medication
While many medications do not have enough evidence to support their use, four (sertraline, fluoxetine, paroxetine, and venlafaxine) have been shown to have a small to modest benefit over placebo. With many medications, residual PTSD symptoms following treatment is the rule rather than the exception.
Antidepressants
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) may have some benefit for PTSD symptoms. Tricyclic antidepressants are equally effective but are less well tolerated. Evidence provides support for a small or modest improvement with sertraline, fluoxetine, paroxetine, and venlafaxine. Thus, these four medications are considered to be first-line medications for PTSD.
Benzodiazepines
Benzodiazepines are not recommended for the treatment of PTSD due to a lack of evidence of benefit and risk of worsening PTSD symptoms. Some authors believe that the use of benzodiazepines is contraindicated for acute stress, as this group of drugs can cause dissociation. Nevertheless, some use benzodiazepines with caution for short-term anxiety and insomnia. While benzodiazepines can alleviate acute anxiety, there is no consistent evidence that they can stop the development of PTSD and may actually increase the risk of developing PTSD 2–5 times. Additionally, benzodiazepines may reduce the effectiveness of psychotherapeutic interventions, and there is some evidence that benzodiazepines may actually contribute to the development and chronification of PTSD. For those who already have PTSD, benzodiazepines may worsen and prolong the course of illness, by worsening psychotherapy outcomes, and causing or exacerbating aggression, depression (including suicidality), and substance use. Drawbacks include the risk of developing a benzodiazepine dependence, tolerance (i.e., short-term benefits wearing off with time), and withdrawal syndrome; additionally, individuals with PTSD (even those without a history of alcohol or drug misuse) are at an increased risk of abusing benzodiazepines. Due to a number of other treatments with greater efficacy for PTSD and less risks (e.g., prolonged exposure, cognitive processing therapy, eye movement desensitization and reprocessing, cognitive restructuring therapy, trauma-focused cognitive behavioral therapy, brief eclectic psychotherapy, narrative therapy, stress inoculation training, serotonergic antidepressants, adrenergic inhibitors, antipsychotics, and even anticonvulsants), benzodiazepines should be considered relatively contraindicated until all other treatment options are exhausted. For those who argue that benzodiazepines should be used sooner in the most severe cases, the adverse risk of disinhibition (associated with suicidality, aggression and crimes) and clinical risks of delaying or inhibiting definitive efficacious treatments, make other alternative treatments preferable (e.g., inpatient, residential, partial hospitalization, intensive outpatient, dialectic behavior therapy; and other fast-acting sedating medications such as trazodone, mirtazapine, amitripytline, doxepin, prazosin, propranolol, guanfacine, clonidine, quetiapine, olanzapine, valproate, gabapentin).
Prazosin
Prazosin, an alpha-1 adrenergic antagonist, has been used in veterans with PTSD to reduce nightmares. Studies show variability in the symptom improvement, appropriate dosages, and efficacy in this population.
Glucocorticoids
Glucocorticoids may be useful for short-term therapy to protect against neurodegeneration caused by the extended stress response that characterizes PTSD, but long-term use may actually promote neurodegeneration.
Cannabinoids
Cannabis is not recommended as a treatment for PTSD because scientific evidence does not currently exist demonstrating treatment efficacy for cannabinoids. However, use of cannabis or derived products is widespread among U.S. veterans with PTSD.The cannabinoid nabilone is sometimes used for nightmares in PTSD. Although some short-term benefit was shown, adverse effects are common and it has not been adequately studied to determine efficacy. An increasing number of states permit and have legalized the use of medical cannabis for the treatment of PTSD.
Other
Exercise, sport and physical activity
Physical activity can influence peoples psychological and physical health. The U.S. National Center for PTSD recommends moderate exercise as a way to distract from disturbing emotions, build self-esteem and increase feelings of being in control again. They recommend a discussion with a doctor before starting an exercise program.
Play therapy for children
Play is thought to help children link their inner thoughts with their outer world, connecting real experiences with abstract thought. Repetitive play can also be one way a child relives traumatic events, and that can be a symptom of trauma in a child or young person. Although it is commonly used, there have not been enough studies comparing outcomes in groups of children receiving and not receiving play therapy, so the effects of play therapy are not yet understood.
Military programs
Many veterans of the wars in Iraq and Afghanistan have faced significant physical, emotional, and relational disruptions. In response, the United States Marine Corps has instituted programs to assist them in re-adjusting to civilian life, especially in their relationships with spouses and loved ones, to help them communicate better and understand what the other has gone through. Walter Reed Army Institute of Research (WRAIR) developed the Battlemind program to assist service members avoid or ameliorate PTSD and related problems. Wounded Warrior Project partnered with the US Department of Veterans Affairs to create Warrior Care Network, a national health system of PTSD treatment centers.
Nightmares
In 2020, the United States Food and Drug Administration granted marketing approval for an Apple Watch app call NightWare. The app aims to improve sleep for people suffering from PTSD-related nightmares, by vibrating when it detects a nightmare in progress based on monitoring heart rate and body movement.
Epidemiology
There is debate over the rates of PTSD found in populations, but, despite changes in diagnosis and the criteria used to define PTSD between 1997 and 2013, epidemiological rates have not changed significantly. Most of the current reliable data regarding the epidemiology of PTSD is based on DSM-IV criteria, as the DSM-5 was not introduced until 2013.
The United Nations World Health Organization publishes estimates of PTSD impact for each of its member states; the latest data available are for 2004. Considering only the 25 most populated countries ranked by overall age-standardized Disability-Adjusted Life Year (DALY) rate, the top half of the ranked list is dominated by Asian/Pacific countries, the US, and Egypt. Ranking the countries by the male-only or female-only rates produces much the same result, but with less meaningfulness, as the score range in the single-sex rankings is much-reduced (4 for women, 3 for men, as compared with 14 for the overall score range), suggesting that the differences between female and male rates, within each country, is what drives the distinctions between the countries.As of 2017, the cross-national lifetime prevalence of PTSD was 3.9%, based on a survey were 5.6% had been exposed to trauma. The primary factor impacting treatment-seeking behavior, which can help to mitigate PTSD development after trauma was income, while being younger, female, and having less social status (less education, lower individual income, and being unemployed) were all factors associated with less treatment-seeking behaviour.
United States
The National Comorbidity Survey Replication has estimated that the lifetime prevalence of PTSD among adult Americans is 6.8%, with women (9.7%) more than twice as likely as men (3.6%) to have PTSD at some point in their lives. More than 60% of men and more than 60% of women experience at least one traumatic event in their life. The most frequently reported traumatic events by men are rape, combat, and childhood neglect or physical abuse. Women most frequently report instances of rape, sexual molestation, physical attack, being threatened with a weapon and childhood physical abuse. 88% of men and 79% of women with lifetime PTSD have at least one comorbid psychiatric disorder. Major depressive disorder, 48% of men and 49% of women, and lifetime alcohol use disorder or dependence, 51.9% of men and 27.9% of women, are the most common comorbid disorders.
Military combat
The United States Department of Veterans Affairs estimates that 830,000 Vietnam War veterans had symptoms of PTSD. The National Vietnam Veterans Readjustment Study (NVVRS) found 15% of male and 9% of female Vietnam veterans had PTSD at the time of the study. Life-time prevalence of PTSD was 31% for males and 27% for females. In a reanalysis of the NVVRS data, along with analysis of the data from the Matsunaga Vietnam Veterans Project, Schnurr, Lunney, Sengupta, and Waelde found that, contrary to the initial analysis of the NVVRS data, a large majority of Vietnam veterans had PTSD symptoms (but not the disorder itself). Four out of five reported recent symptoms when interviewed 20–25 years after Vietnam.A 2011 study from Georgia State University and San Diego State University found that rates of PTSD diagnosis increased significantly when troops were stationed in combat zones, had tours of longer than a year, experienced combat, or were injured. Military personnel serving in combat zones were 12.1 percentage points more likely to receive a PTSD diagnosis than their active-duty counterparts in non-combat zones. Those serving more than 12 months in a combat zone were 14.3 percentage points more likely to be diagnosed with PTSD than those having served less than one year. Experiencing an enemy firefight was associated with an 18.3 percentage point increase in the probability of PTSD, while being wounded or injured in combat was associated with a 23.9 percentage point increase in the likelihood of a PTSD diagnosis. For the 2.16 million U.S. troops deployed in combat zones between 2001 and 2010, the total estimated two-year costs of treatment for combat-related PTSD are between $1.54 billion and $2.69 billion.As of 2013, rates of PTSD have been estimated at up to 20% for veterans returning from Iraq and Afghanistan. As of 2013 13% of veterans returning from Iraq were unemployed.
Man-made disasters
The September 11 attacks took the lives of nearly 3,000 people, leaving 6,000 injured. First responders (police, firefighters, and emergency medical technicians), sanitation workers, and volunteers were all involved in the recovery efforts. The prevalence of probable PTSD in these highly exposed populations was estimated across several studies using in-person, telephone, and online interviews and questionnaires. Overall prevalence of PTSD was highest immediately following the attacks and decreased over time. However, disparities were found among the different types of recovery workers. The rate of probable PTSD for first responders was lowest directly after the attacks and increased from ranges of 4.8-7.8% to 7.4-16.5% between the 5-6 year follow-up and a later assessment. When comparing traditional responders to non-traditional responders (volunteers), the probable PTSD prevalence 2.5 years after the initial visit was greater in volunteers with estimates of 11.7% and 17.2% respectively. Volunteer participation in tasks atypical to the defined occupational role was a significant risk factor for PTSD. Other risk factors included exposure intensity, earlier start date, duration of time spent on site, and constant, negative reminders of the trauma. Additional research has been performed to understand the social consequences of the September 11 attacks. Alcohol consumption was assessed in a cohort of World Trade Center workers using the cut-annoyed-guilty-eye (CAGE) questionnaire for alcohol use disorder. Almost 50% of World Trade Center workers who self-identified as alcohol users reported drinking more during the rescue efforts. Nearly a quarter of these individuals reported drinking more following the recovery. If determined to have probable PTSD status, the risk of developing an alcohol problem was double compared to those without psychological morbidity. Social disability was also studied in this cohort as a social consequence of the September 11 attacks. Defined by the disruption of family, work, and social life, the risk of developing social disability increased 17-fold when categorized as having probable PTSD.
Anthropology
Cultural and medical anthropologists have questioned the validity of applying the diagnostic criteria of PTSD cross-culturally. Trauma (and resulting PTSD) is often experienced through the outermost limits of suffering, pain and fear. The images and experiences relived through PTSD often defy easy description through language. Therefore, the translation of these experiences from one language to another is problematic, and the primarily Euro-American research on trauma is necessarily limited. The Sapir-Whorf hypothesis suggests that people perceive the world differently according to the language they speak: language and the world it exists within reflect back on the perceptions of the speaker. For example, ethnopsychology studies in Nepal have found that cultural idioms and concepts often don’t translate to western terminologies: piDaa is a term that may align to trauma/suffering, but also people who suffer from this are considered paagal (mad) and are subject to negative social stigma, indicating the need for culturally appropriate and carefully tailored support interventions. In summary, different cultures remember past experiences within different linguistic and cultural paradigms. As such, cultural and medical anthropologists have questioned the validity of applying the diagnostic criteria of PTSD cross-culturally, as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-III), and constructed through the Euro-American paradigm of psychology.There remains a dearth of studies into the conceptual frameworks that surround trauma in non-Western cultures. There is little evidence to suggest therapeutic benefit in synthesizing local idioms of distress into a culturally constructed disorder of the post-Vietnam era, a practice anthropologist believe contributes to category fallacy. For many cultures there is no single linguistic corollary to PTSD, psychological trauma being a multi-faceted concept with corresponding variances of expression. Designating the effects of trauma as an affliction of the spirit is common in many non-Western cultures where idioms such as “soul loss” and “weak heart” indicate a preference to confer suffering to a spirit-body or heart-body diametric. These idioms reflect the emphasis that collectivist cultures place on healing trauma through familial, cultural and religious activities while avoiding the stigma that accompanies a mind-body approach. Prescribing PTSD diagnostics within these communities is ineffective and often detrimental. For trauma that extends beyond the individual such as the effects of war, anthropologists believe applying the term “social suffering” or “cultural bereavement” to be more beneficial.Every facet of society is affected by conflict; the prolonged exposure to mass violence can lead to a ‘continuous suffering’ among civilians, soldiers, and bordering countries. Entered into the DSM in 1980, clinicians and psychiatrists based the diagnostic criteria for PTSD around American veterans of the Vietnam war. Though the DSM (in its fifth edition at the time of writing) gets reviewed and updated regularly, it is unable to fully encompass the disorder due to its Americanization (or Westernization). That is, what may be considered characteristics of PTSD in western society, may not directly translate across to other cultures around the world. Displaced people of the African country Burundi experienced symptoms of depression and anxiety, though little symptoms of PTSD were noted. In a similar review, Sudanese refugees relocated in Uganda were ‘concerned with material [effects]’ (lack of food, shelter, and healthcare), rather than psychological distress. In this case, many refugees didn’t present symptoms at all, with a minor few developing anxiety and depression. War-related stresses and traumas will be ingrained in the individual, however they will be affected differently from culture to culture, and the “clear-cut” rubric for diagnosing PTSD doesn’t allow for culturally contextual reactions to take place.
Veterans
United States
The United States provides a range of benefits for veterans that the VA has determined have PTSD, which developed during, or as a result of, their military service. These benefits may include tax-free cash payments, free or low-cost mental health treatment and other healthcare, vocational rehabilitation services, employment assistance, and independent living support.
Iraq
Young Iraqis have high rates of post-traumatic stress disorder due to the 2003 invasion of Iraq.
United Kingdom
In the UK, there are various charities and service organisations dedicated to aiding veterans in readjusting to civilian life. The Royal British Legion and the more recently established Help for Heroes are two of Britains more high-profile veterans organisations which have actively advocated for veterans over the years. There has been some controversy that the NHS has not done enough in tackling mental health issues and is instead "dumping" veterans on charities such as Combat Stress.
Canada
Veterans Affairs Canada offers a new program that includes rehabilitation, financial benefits, job placement, health benefits program, disability awards, peer support and family support.
History
The 1952 edition of the DSM-I includes a diagnosis of "gross stress reaction", which has similarities to the modern definition and understanding of PTSD. Gross stress reaction is defined as a normal personality using established patterns of reaction to deal with overwhelming fear as a response to conditions of great stress. The diagnosis includes language which relates the condition to combat as well as to "civilian catastrophe".A USAF study carried out in 1979 focused on individuals (civilian and military) who had worked to recover or identify the remains of those who died in Jonestown. The bodies had been dead for several days, and a third of them had been children. The study used the term "dysphoria" to describe PTSD-like symptoms.Early in 1978, the diagnosis term "post-traumatic stress disorder" was first recommended in a working group finding presented to the Committee of Reactive Disorders. The condition was described in the DSM-III (1980) as posttraumatic stress disorder. In the DSM-IV, the spelling "posttraumatic stress disorder" is used, while in the ICD-10, the spelling is "post-traumatic stress disorder".The addition of the term to the DSM-III was greatly influenced by the experiences and conditions of U.S. military veterans of the Vietnam War. Owing to its association with the war in Vietnam, PTSD has become synonymous with many historical war-time diagnoses such as railway spine, stress syndrome, nostalgia, soldiers heart, shell shock, battle fatigue, combat stress reaction, or traumatic war neurosis. Some of these terms date back to the 19th century, which is indicative of the universal nature of the condition. In a similar vein, psychiatrist Jonathan Shay has proposed that Lady Percys soliloquy in the William Shakespeare play Henry IV, Part 1 (act 2, scene 3, lines 40–62), written around 1597, represents an unusually accurate description of the symptom constellation of PTSD.
The correlations between combat and PTSD are undeniable; according to Stéphane Audoin-Rouzeau and Annette Becker, "One-tenth of mobilized American men were hospitalized for mental disturbances between 1942 and 1945, and, after thirty-five days of uninterrupted combat, 98% of them manifested psychiatric disturbances in varying degrees." In fact, much of the available published research regarding PTSD is based on studies done on veterans of the war in Vietnam. A study based on personal letters from soldiers of the 18th-century Prussian Army concludes that combatants may have had PTSD. Aspects of PTSD in soldiers of ancient Assyria have been identified using written sources from 1300 to 600 BCE. These Assyrian soldiers would undergo a three-year rotation of combat before being allowed to return home, and were reported to have faced immense challenges in reconciling their past actions in war with their civilian lives. Connections between the actions of Viking berserkers and the hyperarousal of post-traumatic stress disorder have also been drawn.The researchers from the Grady Trauma Project highlight the tendency people have to focus on the combat side of PTSD: "less public awareness has focused on civilian PTSD, which results from trauma exposure that is not combat related... " and "much of the research on civilian PTSD has focused on the sequelae of a single, disastrous event, such as the Oklahoma City bombing, September 11th attacks, and Hurricane Katrina". Disparity in the focus of PTSD research affects the already popular perception of the exclusive interconnectedness of combat and PTSD. This is misleading when it comes to understanding the implications and extent of PTSD as a neurological disorder. Dating back to the definition of Gross stress reaction in the DSM-I, civilian experience of catastrophic or high stress events is included as a cause of PTSD in medical literature. The 2014 National Comorbidity Survey reports that "the traumas most commonly associated with PTSD are combat exposure and witnessing among men and rape and sexual molestation among women."
Because of the initial overt focus on PTSD as a combat related disorder when it was first fleshed out in the years following the war in Vietnam, in 1975 Ann Wolbert Burgess and Lynda Lytle Holmstrom defined rape trauma syndrome (RTS) in order to draw attention to the striking similarities between the experiences of soldiers returning from war and of rape victims. This paved the way for a more comprehensive understanding of causes of PTSD.
After PTSD became an official psychiatric diagnosis with the publication of DSM-III (1980), the number of personal injurylawsuits (tort claims) asserting the plaintiff had PTSD increased rapidly. However, triers of fact (judges and juries) often regarded the PTSD diagnostic criteria as imprecise, a view shared by legal scholars, trauma specialists, forensic psychologists, and forensic psychiatrists. Professional discussions and debates in academic journals, at conferences, and between thought leaders, led to a more clearly-defined set of diagnostic criteria in DSM-IV, particularly the definition of a "traumatic event".The DSM-IV classified PTSD under anxiety disorders, but the DSM-5 created a new category called "trauma and stressor-related disorders", in which PTSD is now classified.
Terminology
The Diagnostic and Statistical Manual of Mental Disorders does not hyphenate "post" and "traumatic", thus, the DSM-5 lists the disorder as posttraumatic stress disorder. However, many scientific journal articles and other scholarly publications do hyphenate the name of the disorder, viz., "post-traumatic stress disorder". Dictionaries also differ with regard to the preferred spelling of the disorder with the Collins English Dictionary – Complete and Unabridged using the hyphenated spelling, and the American Heritage Dictionary of the English Language, Fifth Edition and the Random House Kernerman Websters College Dictionary giving the non-hyphenated spelling.Some authors have used the terms "post-traumatic stress syndrome" or "post-traumatic stress symptoms" ("PTSS"), or simply "post-traumatic stress" ("PTS") in the case of the U.S. Department of Defense, to avoid stigma associated with the word "disorder".
The comedian George Carlin criticized the euphemism treadmill which led to progressive change of the way PTSD was referred to over the course of the 20th century, from "shell shock" in the First World War to the "battle fatigue" in the Second World War, to "operational exhaustion" in the Korean War, to the current "post-traumatic stress disorder", coined during the Vietnam War, which "added a hyphen" and which, he commented, "completely burie[s] [the pain] under jargon". He also stated that the name given to the condition has had a direct effect on the way veteran soldiers with PTSD were treated and perceived by civilian populations over time.
Research
Most knowledge regarding PTSD comes from studies in high-income countries.To recapitulate some of the neurological and neurobehavioral symptoms experienced by the veteran population of recent conflicts in Iraq and Afghanistan, researchers at the Roskamp Institute and the James A Haley Veterans Hospital (Tampa) have developed an animal model to study the consequences of mild traumatic brain injury (mTBI) and PTSD. In the laboratory, the researchers exposed mice to a repeated session of unpredictable stressor (i.e. predator odor while restrained), and physical trauma in the form of inescapable foot-shock, and this was also combined with a mTBI. In this study, PTSD animals demonstrated recall of traumatic memories, anxiety, and an impaired social behavior, while animals subject to both mTBI and PTSD had a pattern of disinhibitory-like behavior. mTBI abrogated both contextual fear and impairments in social behavior seen in PTSD animals. In comparison with other animal studies, examination of neuroendocrine and neuroimmune responses in plasma revealed a trend toward increase in corticosterone in PTSD and combination groups.
Stellate ganglion block is an experimental procedure for the treatment of PTSD.Researchers are investigating a number of experimental FAAH and MAGL-inhibiting drugs of hopes of finding a better treatment for anxiety and stress-related illnesses. In 2016, the FAAH-inhibitor drug BIA 10-2474 was withdrawn from human trials in France due to adverse effects.Preliminary evidence suggests that MDMA-assisted psychotherapy might be an effective treatment for PTSD. However, it is important to note that the results in clinical trials of MDMA-assisted psychotherapy |
Post-traumatic stress disorder | might be substantially influenced by expectancy effects given the unblinding of participants. Furthermore, there is a conspicuous lack of trials comparing MDMA-assisted psychotherapy to existent first-line treatments for PTSD, such as trauma-focused psychological treatments, which seems to achieve similar or even better outcomes than MDMA-assisted psychotherapy.
Psychotherapy
Trauma-focused psychotherapies for PTSD (also known as "exposure-based" or "exposure" psychotherapies), such as prolonged exposure therapy (PE), eye movement desensitization and reprocessing (EMDR), and cognitive-reprocessing therapy (CPT) have the most evidence for efficacy and are recommended as first-line treatment for PTSD by almost all clinical practice guidelines. Exposure-based psychotherapies demonstrate efficacy for PTSD caused by different trauma "types", such as combat, sexual-assault, or natural disasters. At the same time, many trauma-focused psychotherapies evince high drop-out rates.Most systematic reviews and clinical guidelines indicate that psychotherapies for PTSD, most of which are trauma-focused therapies, are more effective than pharmacotherapy (medication), although there are reviews that suggest exposure-based psychotherapies for PTSD and pharmacotherapy are equally effective. Interpersonal psychotherapy shows preliminary evidence of probable efficacy, but more research is needed to reach definitive conclusions.
Notes
References
This article incorporates text from a free content work. Licensed under CC BY-SA 3.0 IGO Text taken from A Lifeline to learning: leveraging mobile technology to support education for refugees, UNESCO, UNESCO. UNESCO. To learn how to add open license text to Wikipedia articles, please see this how-to page. For information on reusing text from Wikipedia, please see the terms of use.
External links
Post-traumatic stress disorder at Curlie
Post traumatic stress disorder information from The National Child Traumatic Stress Network
Information resources from The University of Queensland School of Medicine
APA practice parameters for assessment and treatment for PTSD (Updated 2017)
Resources for professionals from the VA National PTSD Center
Psychiatry portal |
Precocious puberty | In medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. In a minority of children with precocious puberty, the early development is triggered by a disease such as a tumor or injury of the brain. Even when there is no disease, unusually early puberty can have adverse effects on social behavior and psychological development, can reduce adult height potential, and may shift some lifelong health risks. Central precocious puberty can be treated by suppressing the pituitary hormones that induce sex steroid production. The opposite condition is delayed puberty.The term is used with several slightly different meanings that are usually apparent from the context. In its broadest sense, and often simplified as early puberty, "precocious puberty" sometimes refers to any physical sex hormone effect, due to any cause, occurring earlier than the usual age, especially when it is being considered as a medical problem. Stricter definitions of "precocity" may refer only to central puberty starting before a statistically specified age based on percentile in the population (e.g., 2.5 standard deviations below the population mean), on expert recommendations of ages at which there is more than a negligible chance of discovering an abnormal cause, or based on opinion as to the age at which early puberty may have adverse effects. A common definition for medical purposes is onset before 8 years in girls or 9 years in boys.
Causes
Early pubic hair, breast, or genital development may result from natural early maturation or from several other conditions.
Central
If the cause can be traced to the hypothalamus or pituitary, the cause is considered central. Other names for this type are complete or true precocious puberty.Causes of central precocious puberty can include:
hypothalamic hamartoma produces pulsatile gonadotropin-releasing hormone (GnRH)
Langerhans cell histiocytosis
McCune–Albright syndromeCentral precocious puberty can also be caused by brain tumors, infection (most commonly tuberculous meningitis, especially in developing countries), trauma, hydrocephalus, and Angelman syndrome. Precocious puberty is associated with advancement in bone age, which leads to early fusion of epiphyses, thus resulting in reduced final height and short stature.Adrenocortical oncocytomas are rare with mostly benign and nonfunctioning tumors. There have been only three cases of functioning adrenocortical oncocytoma that have been reported up until 2013. Children with adrenocortical oncocytomas will present with "premature pubarche, clitoromegaly, and increased serum dehydroepiandrosterone sulfate and testosterone" which are some of the presentations associated with precocious puberty.Precocious puberty in girls begins before the age of 8. The youngest mother on record is Lina Medina, who gave birth at the age of either 5 years, 7 months and 17 days or 6 years 5 months as mentioned in another report."Central precocious puberty (CPP) was reported in some patients with suprasellar arachnoid cysts (SAC), and SCFE (slipped capital femoral epiphysis) occurs in patients with CPP because of rapid growth and changes of growth hormone secretion."If no cause can be identified, it is considered idiopathic or constitutional.
Peripheral
Secondary sexual development induced by sex steroids from other abnormal sources is referred to as peripheral precocious puberty or precocious pseudopuberty. It typically presents as a severe form of disease with children. Symptoms are usually as a sequelae from adrenal hyperplasia (because of 21-hydroxylase deficiency or 11-beta hydroxylase deficiency, the former being more common), which includes but is not limited to hypertension, hypotension, electrolyte abnormalities, ambiguous genitalia in females, signs of virilization in females. Blood tests will typically reveal high level of androgens with low levels of cortisol.
Causes can include:
Endogenous sources
Gonadal tumors (such as arrhenoblastoma)
Adrenal tumors
Germ cell tumor
Congenital adrenal hyperplasia
McCune–Albright syndrome
Silver–Russell syndrome
Familial male-limited precocious puberty (testotoxicosis)
Exogenous hormones
Environmental exogenous hormones
As treatment for another condition
Isosexual and heterosexual
Generally, patients with precocious puberty develop phenotypically appropriate secondary sexual characteristics. This is called isosexual precocity.In some cases, a patient may develop characteristics of the opposite sex. For example, a male may develop breasts and other feminine characteristics, while a female may develop a deepened voice and facial hair. This is called heterosexual or contrasexual precocity. It is very rare in comparison to isosexual precocity and is usually the result of unusual circumstances. As an example, children with a very rare genetic condition called aromatase excess syndrome – in which exceptionally high circulating levels of estrogen are present – usually develop precocious puberty. Males and females are hyper-feminized by the syndrome. The "opposite" case would be the hyper-masculinisation of both male and female patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, in which there is an excess of androgens. Thus, in the aromatase excess syndrome the precocious puberty is isosexual in females and heterosexual in males, whilst in the CAH its isosexual in males and heterosexual in females.
Research
Although the causes of early puberty are still somewhat unclear, girls who have a high-fat diet and are not physically active or are obese are more likely to physically mature earlier. "Obese girls, defined as at least 10 kilograms (22 pounds) overweight, had an 80 percent chance of developing breasts before their ninth birthday and starting menstruation before age 12 – the western average for menstruation is about 12.7 years." In addition to diet and exercise habits, exposure to chemicals that mimic estrogen (known as xenoestrogens) is another possible cause of early puberty in girls. Bisphenol A, a xenoestrogen found in hard plastics, has been shown to affect sexual development. "Factors other than obesity, however, perhaps genetic and/or environmental ones, are needed to explain the higher prevalence of early puberty in black versus white girls." While more girls are increasingly entering puberty at younger ages, new research indicates that some boys are actually starting later (delayed puberty). "Increasing rates of obese and overweight children in the United States may be contributing to a later onset of puberty in boys, say researchers at the University of Michigan Health System."High levels of beta-hCG in serum and cerebrospinal fluid observed in a 9-year-old boy suggest a pineal gland tumor. The tumor is called a chorionic gonadotropin secreting pineal tumor. Radiotherapy and chemotherapy reduced tumor and beta-hCG levels normalized.In a study using neonatal melatonin on rats, results suggest that elevated melatonin could be responsible for some cases of early puberty.Familial cases of idiopathic central precocious puberty (ICPP) have been reported, leading researchers to believe there are specific genetic modulators of ICPP. Mutations in genes such as LIN28, and LEP and LEPR, which encode leptin and the leptin receptor, have been associated with precocious puberty. The association between LIN28 and puberty timing was validated experimentally in vivo, when it was found that mice with ectopic over-expression of LIN28 show an extended period of pre-pubertal growth and a significant delay in puberty onset.Mutations in the kisspeptin (KISS1) and its receptor, KISS1R (also known as GPR54), involved in GnRH secretion and puberty onset, are also thought to be the cause for ICPP However, this is still a controversial area of research, and some investigators found no association of mutations in the LIN28 and KISS1/KISS1R genes to be the common cause underlying ICPP.The gene MKRN3, which is a maternally imprinted gene, was first cloned by Jong et al. in 1999. MKRN3 was originally named Zinc finger protein 127. It is located on human chromosome 15 on the long arm in the Prader-Willi syndrome critical region2, and has since been identified as a cause of premature sexual development or CPP. The identification of mutations in MKRN3 leading to sporadic cases of CPP has been a significant contribution to better understanding the mechanism of puberty. MKRN3 appears to act as a "brake" on the central hypothalamic-pituitary access. Thus, loss of function mutations of the protein allow early activation of the GnRH pathway and cause phenotypic CPP. Patients with a MKRN3 mutation all display the classic signs of CCP including early breast and testes development, increased bone aging and elevated hormone levels of GnRH and LH.
Diagnosis
Studies indicate that breast development in girls and the appearance of pubic hair in both girls and boys are starting earlier than in previous generations. As a result, "early puberty" in children as young as 9 and 10 is no longer considered abnormal, particularly with girls. Although it is not considered as abnormal, it may be upsetting to parents and can be harmful to children who mature physically at a time when they are immature mentally.No age reliably separates normal from abnormal processes in children, but the following age thresholds for evaluation are thought to minimize the risk of missing a significant medical problem:
Breast development in boys before appearance of pubic hair or testicular enlargement
Pubic hair or genital enlargement (gonadarche) in boys with onset before 9 years
Pubic hair (pubarche) before 8 or breast development (thelarche) in girls with onset before 7 years
Menstruation (menarche) in girls before 10 yearsMedical evaluation is sometimes necessary to recognize the few children with serious conditions from the majority who have entered puberty early but are still medically normal. Early sexual development warrants evaluation because it may:
induce early bone maturation and reduce eventual adult height
indicate the presence of a tumour or other serious problem
cause the child, particularly a girl, to become an object of adult sexual interest.
Treatment
One possible treatment is with anastrozole. GnRH agonists, including histrelin, triptorelin, or leuprorelin, are other possible treatments. Non-continuous use of GnRH agonists stimulates the pituitary gland to release follicle stimulating hormone (FSH) and luteinizing hormone (LH).
Prognosis
Early puberty is posited to put girls at higher risk of sexual abuse; however, a causal relationship is, as yet, inconclusive. Early puberty also puts girls at a higher risk for teasing or bullying, mental health disorders and short stature as adults. Girls as young as 8 are increasingly starting to menstruate, develop breasts and grow pubic and underarm hair; these "biological milestones" typically occurred only at 13 or older in the past. African-American girls are especially prone to early puberty.Though boys face fewer problems from early puberty than girls do, early puberty is not always positive for boys. Early sexual maturation in boys can be accompanied by increased aggressiveness due to the surge of pubertal hormones. Because they appear older than their peers, pubescent boys may face increased social pressure to conform to adult norms; society may view them as more emotionally advanced, although their cognitive and social development may lag behind their physical development. Studies have shown that early-maturing boys are more likely to be sexually active and are more likely to participate in risky behaviors.
History
Pubertas praecox is the Latin term used by physicians from the 1790s onward. Various hypotheses and inferences on pubertal (menstrual, procreative) timing are attested since ancient times, which, well into early modernity were explained on the basis of temperamental, humoral and Jungian "complexional" causes, or general or local "plethora" (blood excess). Endocrinological (hormonal) theories and discoveries are a twentieth-century development.
See also
List of youngest birth mothers
List of youngest birth fathers
Premature menopause
Premature ovarian failure
References
== External links == |
Abortion | Abortion is the termination of a pregnancy by removal or expulsion of an embryo or fetus. An abortion that occurs without intervention is known as a miscarriage or "spontaneous abortion"; these occur in approximately 30% to 40% of pregnancies. When deliberate steps are taken to end a pregnancy, it is called an induced abortion, or less frequently "induced miscarriage". The unmodified word abortion generally refers to an induced abortion. The reasons why women have abortions are diverse and vary across the world. Reasons include maternal health, an inability to afford a child, domestic violence, lack of support, feeling they are too young, wishing to complete education or advance a career, and not being able or willing to raise a child conceived as a result of rape or incest.When properly done, induced abortion is one of the safest procedures in medicine.: 1 In the United States, the risk of maternal mortality is 14 times lower after induced abortion than after childbirth. Unsafe abortions—those performed by people lacking the necessary skills, or in inadequately resourced settings—are a major cause of maternal death, especially in the developing world, though self-managed medication abortions are highly effective and safe. Public health data shows that making safe abortion legal and accessible reduces maternal deaths.Modern methods use medication or surgery for abortions. The drug mifepristone in combination with prostaglandin appears to be as safe and effective as surgery during the first and second trimester of pregnancy. The most common surgical technique involves dilating the cervix and using a suction device. Birth control, such as the pill or intrauterine devices, can be used immediately following abortion. When performed legally and safely on a woman who desires it, induced abortions do not increase the risk of long-term mental or physical problems. In contrast, unsafe abortions performed by unskilled individuals, with hazardous equipment, or in unsanitary facilities cause 47,000 deaths and 5 million hospital admissions each year. The World Health Organization states that "access to legal, safe and comprehensive abortion care, including post-abortion care, is essential for the attainment of the highest possible level of sexual and reproductive health".Around 73 million abortions are performed each year in the world, with about 45% done unsafely. Abortion rates changed little between 2003 and 2008, before which they decreased for at least two decades as access to family planning and birth control increased. As of 2018, 37% of the worlds women had access to legal abortions without limits as to reason. Countries that permit abortions have different limits on how late in pregnancy abortion is allowed. Abortion rates are similar between countries that ban abortion and countries that allow it.Historically, abortions have been attempted using herbal medicines, sharp tools, forceful massage, or through other traditional methods. Abortion laws and cultural or religious views of abortions are different around the world. In some areas, abortion is legal only in specific cases such as rape, fetal defects, poverty, risk to a womans health, or incest. There is debate over the moral, ethical, and legal issues of abortion. Those who oppose abortion often argue that an embryo or fetus is a person with a right to life, and thus equate abortion with murder. Those who support the legality of abortion often argue that it is part of a womans right to make decisions about her own body. Others favor legal and accessible abortion as a public health measure.
Types
Induced
Approximately 205 million pregnancies occur each year worldwide. Over a third are unintended and about a fifth end in induced abortion. Most abortions result from unintended pregnancies. In the United Kingdom, 1 to 2% of abortions are done due to genetic problems in the fetus. A pregnancy can be intentionally aborted in several ways. The manner selected often depends upon the gestational age of the embryo or fetus, which increases in size as the pregnancy progresses. Specific procedures may also be selected due to legality, regional availability, and doctor or a womans personal preference.
Reasons for procuring induced abortions are typically characterized as either therapeutic or elective. An abortion is medically referred to as a therapeutic abortion when it is performed to save the life of the pregnant woman; to prevent harm to the womans physical or mental health; to terminate a pregnancy where indications are that the child will have a significantly increased chance of mortality or morbidity; or to selectively reduce the number of fetuses to lessen health risks associated with multiple pregnancy. An abortion is referred to as an elective or voluntary abortion when it is performed at the request of the woman for non-medical reasons. Confusion sometimes arises over the term "elective" because "elective surgery" generally refers to all scheduled surgery, whether medically necessary or not.
Spontaneous
Miscarriage, also known as spontaneous abortion, is the unintentional expulsion of an embryo or fetus before the 24th week of gestation. A pregnancy that ends before 37 weeks of gestation resulting in a live-born infant is a "premature birth" or a "preterm birth". When a fetus dies in utero after viability, or during delivery, it is usually termed "stillborn". Premature births and stillbirths are generally not considered to be miscarriages, although usage of these terms can sometimes overlap.Studies of pregnant women in the US and China have shown that between 40% and 60% of embryos do not progress to birth. The vast majority of miscarriages occur before the woman is aware that she is pregnant, and many pregnancies spontaneously abort before medical practitioners can detect an embryo. Between 15% and 30% of known pregnancies end in clinically apparent miscarriage, depending upon the age and health of the pregnant woman. 80% of these spontaneous abortions happen in the first trimester.The most common cause of spontaneous abortion during the first trimester is chromosomal abnormalities of the embryo or fetus, accounting for at least 50% of sampled early pregnancy losses. Other causes include vascular disease (such as lupus), diabetes, other hormonal problems, infection, and abnormalities of the uterus. Advancing maternal age and a womans history of previous spontaneous abortions are the two leading factors associated with a greater risk of spontaneous abortion. A spontaneous abortion can also be caused by accidental trauma; intentional trauma or stress to cause miscarriage is considered induced abortion or feticide.
Methods
Medical
Medical abortions are those induced by abortifacient pharmaceuticals. Medical abortion became an alternative method of abortion with the availability of prostaglandin analogs in the 1970s and the antiprogestogen mifepristone (also known as RU-486) in the 1980s.The most common early first-trimester medical abortion regimens use mifepristone in combination with misoprostol (or sometimes another prostaglandin analog, gemeprost) up to 10 weeks (70 days) gestational age, methotrexate in combination with a prostaglandin analog up to 7 weeks gestation, or a prostaglandin analog alone. Mifepristone–misoprostol combination regimens work faster and are more effective at later gestational ages than methotrexate–misoprostol combination regimens, and combination regimens are more effective than misoprostol alone. This regimen is effective in the second trimester. Medical abortion regimens involving mifepristone followed by misoprostol in the cheek between 24 and 48 hours later are effective when performed before 70 days gestation.In very early abortions, up to 7 weeks gestation, medical abortion using a mifepristone–misoprostol combination regimen is considered to be more effective than surgical abortion (vacuum aspiration), especially when clinical practice does not include detailed inspection of aspirated tissue. Early medical abortion regimens using mifepristone, followed 24–48 hours later by buccal or vaginal misoprostol are 98% effective up to 9 weeks gestational age; from 9 to 10 weeks efficacy decreases modestly to 94%. If medical abortion fails, surgical abortion must be used to complete the procedure.Early medical abortions account for the majority of abortions before 9 weeks gestation in Britain, France, Switzerland, United States, and the Nordic countries.Medical abortion regimens using mifepristone in combination with a prostaglandin analog are the most common methods used for second-trimester abortions in Canada, most of Europe, China and India, in contrast to the United States where 96% of second-trimester abortions are performed surgically by dilation and evacuation.A 2020 Cochrane Systematic Review concluded that providing women with medications to take home to complete the second stage of the procedure for an early medical abortion results in an effective abortion. Further research is required to determine if self-administered medical abortion is as safe as provider-administered medical abortion, where a health care professional is present to help manage the medical abortion. Safely permitting women to self-administer abortion medication has the potential to improve access to abortion. Other research gaps that were identified include how to best support women who choose to take the medication home for a self-administered abortion.
Surgical
Up to 15 weeks gestation, suction-aspiration or vacuum aspiration are the most common surgical methods of induced abortion. Manual vacuum aspiration (MVA) consists of removing the fetus or embryo, placenta, and membranes by suction using a manual syringe, while electric vacuum aspiration (EVA) uses an electric pump. These techniques can both be used very early in pregnancy. MVA can be used up to 14 weeks but is more often used earlier in the U.S. EVA can be used later.MVA, also known as "mini-suction" and "menstrual extraction" or EVA can be used in very early pregnancy when cervical dilation may not be required. Dilation and curettage (D&C) refers to opening the cervix (dilation) and removing tissue (curettage) via suction or sharp instruments. D&C is a standard gynecological procedure performed for a variety of reasons, including examination of the uterine lining for possible malignancy, investigation of abnormal bleeding, and abortion. The World Health Organization recommends sharp curettage only when suction aspiration is unavailable.Dilation and evacuation (D&E), used after 12 to 16 weeks, consists of opening the cervix and emptying the uterus using surgical instruments and suction. D&E is performed vaginally and does not require an incision. Intact dilation and extraction (D&X) refers to a variant of D&E sometimes used after 18 to 20 weeks when removal of an intact fetus improves surgical safety or for other reasons.Abortion may also be performed surgically by hysterotomy or gravid hysterectomy. Hysterotomy abortion is a procedure similar to a caesarean section and is performed under general anesthesia. It requires a smaller incision than a caesarean section and can be used during later stages of pregnancy. Gravid hysterectomy refers to removal of the whole uterus while still containing the pregnancy. Hysterotomy and hysterectomy are associated with much higher rates of maternal morbidity and mortality than D&E or induction abortion.First-trimester procedures can generally be performed using local anesthesia, while second-trimester methods may require deep sedation or general anesthesia.
Labor induction abortion
In places lacking the necessary medical skill for dilation and extraction, or where preferred by practitioners, an abortion can be induced by first inducing labor and then inducing fetal demise if necessary. This is sometimes called "induced miscarriage". This procedure may be performed from 13 weeks gestation to the third trimester. Although it is very uncommon in the United States, more than 80% of induced abortions throughout the second trimester are labor-induced abortions in Sweden and other nearby countries.Only limited data are available comparing this method with dilation and extraction. Unlike D&E, labor-induced abortions after 18 weeks may be complicated by the occurrence of brief fetal survival, which may be legally characterized as live birth. For this reason, labor-induced abortion is legally risky in the United States.
Other methods
Historically, a number of herbs reputed to possess abortifacient properties have been used in folk medicine. Among these are: tansy, pennyroyal, black cohosh, and the now-extinct silphium.: 44–47, 62–63, 154–55, 230–31 In 1978, one woman in Colorado died and another developed organ damage when they attempted to terminate their pregnancies by taking pennyroyal oil.
Because the indiscriminant use of herbs as abortifacients can cause serious—even lethal—side effects, such as multiple organ failure, such use is not recommended by physicians.
Abortion is sometimes attempted by causing trauma to the abdomen. The degree of force, if severe, can cause serious internal injuries without necessarily succeeding in inducing miscarriage. In Southeast Asia, there is an ancient tradition of attempting abortion through forceful abdominal massage. One of the bas reliefs decorating the temple of Angkor Wat in Cambodia depicts a demon performing such an abortion upon a woman who has been sent to the underworld.Reported methods of unsafe, self-induced abortion include misuse of misoprostol and insertion of non-surgical implements such as knitting needles and clothes hangers into the uterus. These and other methods to terminate pregnancy may be called "induced miscarriage". Such methods are rarely used in countries where surgical abortion is legal and available.
Safety
The health risks of abortion depend principally upon whether the procedure is performed safely or unsafely. The World Health Organization (WHO) defines unsafe abortions as those performed by unskilled individuals, with hazardous equipment, or in unsanitary facilities. Legal abortions performed in the developed world are among the safest procedures in medicine. In the United States as of 2012, abortion was estimated to be about 14 times safer for women than childbirth. CDC estimated in 2019 that US pregnancy-related mortality was 17.2 maternal deaths per 100,000 live births, while the US abortion mortality rate is 0.7 maternal deaths per 100,000 procedures. In the UK, guidelines of the Royal College of Obstetricians and Gynaecologists state that "Women should be advised that abortion is generally safer than continuing a pregnancy to term." Worldwide, on average, abortion is safer than carrying a pregnancy to term. A 2007 study reported that "26% of all pregnancies worldwide are terminated by induced abortion," whereas "deaths from improperly performed [abortion] procedures constitute 13% of maternal mortality globally." In Indonesia in 2000 it was estimated that 2 million pregnancies ended in abortion, 4.5 million pregnancies were carried to term, and 14-16 percent of maternal deaths resulted from abortion.In the US from 2000 to 2009, abortion had a mortality rate lower than plastic surgery, lower or similar to running a marathon, and about equivalent to traveling 760 miles (1,220 km) in a passenger car. Five years after seeking abortion services, women who gave birth after being denied an abortion reported worse health than women who had either first or second trimester abortions. The risk of abortion-related mortality increases with gestational age, but remains lower than that of childbirth. Outpatient abortion is as safe from 64 to 70 days gestation as it before 63 days.There is little difference in terms of safety and efficacy between medical abortion using a combined regimen of mifepristone and misoprostol and surgical abortion (vacuum aspiration) in early first trimester abortions up to 10 weeks gestation. Medical abortion using the prostaglandin analog misoprostol alone is less effective and more painful than medical abortion using a combined regimen of mifepristone and misoprostol or surgical abortion.Vacuum aspiration in the first trimester is the safest method of surgical abortion, and can be performed in a primary care office, abortion clinic, or hospital. Complications, which are rare, can include uterine perforation, pelvic infection, and retained products of conception requiring a second procedure to evacuate. Infections account for one-third of abortion-related deaths in the United States. The rate of complications of vacuum aspiration abortion in the first trimester is similar regardless of whether the procedure is performed in a hospital, surgical center, or office. Preventive antibiotics (such as doxycycline or metronidazole) are typically given before abortion procedures, as they are believed to substantially reduce the risk of postoperative uterine infection; however, antibiotics are not routinely given with abortion pills. The rate of failed procedures does not appear to vary significantly depending on whether the abortion is performed by a doctor or a mid-level practitioner.Complications after second-trimester abortion are similar to those after first-trimester abortion, and depend somewhat on the method chosen. The risk of death from abortion approaches roughly half the risk of death from childbirth the farther along a woman is in pregnancy; from one in a million before 9 weeks gestation to nearly one in ten thousand at 21 weeks or more (as measured from the last menstrual period). It appears that having had a prior surgical uterine evacuation (whether because of induced abortion or treatment of miscarriage) correlates with a small increase in the risk of preterm birth in future pregnancies. The studies supporting this did not control for factors not related to abortion or miscarriage, and hence the causes of this correlation have not been determined, although multiple possibilities have been suggested.Some purported risks of abortion are promoted primarily by anti-abortion groups,
but lack scientific support. For example, the question of a link between induced abortion and breast cancer has been investigated extensively. Major medical and scientific bodies (including the WHO, National Cancer Institute, American Cancer Society, Royal College of OBGYN and American Congress of OBGYN) have concluded that abortion does not cause breast cancer.In the past even illegality has not automatically meant that the abortions were unsafe. Referring to the U.S., historian Linda Gordon states: "In fact, illegal abortions in this country have an impressive safety record.": 25 According to Rickie Solinger,
A related myth, promulgated by a broad spectrum of people concerned about abortion and public policy, is that before legalization abortionists were dirty and dangerous back-alley butchers.... [T]he historical evidence does not support such claims.: 4
Authors Jerome Bates and Edward Zawadzki describe the case of an illegal abortionist in the eastern U.S. in the early 20th century who was proud of having successfully completed 13,844 abortions without any fatality.: 59
In 1870s New York City the famous abortionist/midwife Madame Restell (Anna Trow Lohman) appears to have lost very few women among her more than 100,000 patients—a lower mortality rate than the childbirth mortality rate at the time. In 1936, the prominent professor of obstetrics and gynecology Frederick J. Taussig wrote that a cause of increasing mortality during the years of illegality in the U.S. was that
With each decade of the past fifty years the actual and proportionate frequency of this accident [perforation of the uterus] has increased, due, first, to the increase in the number of instrumentally induced abortions; second, to the proportionate increase in abortions handled by doctors as against those handled by midwives; and, third, to the prevailing tendency to use instruments instead of the finger in emptying the uterus.: 223
Mental health
Current evidence finds no relationship between most induced abortions and mental health problems other than those expected for any unwanted pregnancy. A report by the American Psychological Association concluded that a womans first abortion is not a threat to mental health when carried out in the first trimester, with such women no more likely to have mental-health problems than those carrying an unwanted pregnancy to term; the mental-health outcome of a womans second or greater abortion is less certain. Some older reviews concluded that abortion was associated with an increased risk of psychological problems; however, they did not use an appropriate control group.Although some studies show negative mental-health outcomes in women who choose abortions after the first trimester because of fetal abnormalities, more rigorous research would be needed to show this conclusively. Some proposed negative psychological effects of abortion have been referred to by anti-abortion advocates as a separate condition called "post-abortion syndrome", but this is not recognized by medical or psychological professionals in the United States.A 2020 long term-study among US women found that about 99% of women felt that they made the right decision five years after they had an abortion. Relief was the primary emotion with few women feeling sadness or guilt. Social stigma was a main factor predicting negative emotions and regret years later.
Unsafe abortion
Women seeking an abortion may use unsafe methods, especially when it is legally restricted. They may attempt self-induced abortion or seek the help of a person without proper medical training or facilities. This can lead to severe complications, such as incomplete abortion, sepsis, hemorrhage, and damage to internal organs.Unsafe abortions are a major cause of injury and death among women worldwide. Although data are imprecise, it is estimated that approximately 20 million unsafe abortions are performed annually, with 97% taking place in developing countries. Unsafe abortions are believed to result in millions of injuries. Estimates of deaths vary according to methodology, and have ranged from 37,000 to 70,000 in the past decade; deaths from unsafe abortion account for around 13% of all maternal deaths. The World Health Organization believes that mortality has fallen since the 1990s. To reduce the number of unsafe abortions, public health organizations have generally advocated emphasizing the legalization of abortion, training of medical personnel, and ensuring access to reproductive-health services.A major factor in whether abortions are performed safely or not is the legal standing of abortion. Countries with restrictive abortion laws have higher rates of unsafe abortion and similar overall abortion rates compared to those where abortion is legal and available. For example, the 1996 legalization of abortion in South Africa had an immediate positive impact on the frequency of abortion-related complications, with abortion-related deaths dropping by more than 90%. Similar reductions in maternal mortality have been observed after other countries have liberalized their abortion laws, such as Romania and Nepal. A 2011 study concluded that in the United States, some state-level anti-abortion laws are correlated with lower rates of abortion in that state. The analysis, however, did not take into account travel to other states without such laws to obtain an abortion. In addition, a lack of access to effective contraception contributes to unsafe abortion. It has been estimated that the incidence of unsafe abortion could be reduced by up to 75% (from 20 million to 5 million annually) if modern family planning and maternal health services were readily available globally. Rates of such abortions may be difficult to measure because they can be reported variously as miscarriage, "induced miscarriage", "menstrual regulation", "mini-abortion", and "regulation of a delayed/suspended menstruation".Forty percent of the worlds women are able to access therapeutic and elective abortions within gestational limits, while an additional 35 percent have access to legal abortion if they meet certain physical, mental, or socioeconomic criteria. While maternal mortality seldom results from safe abortions, unsafe abortions result in 70,000 deaths and 5 million disabilities per year. Complications of unsafe abortion account for approximately an eighth of maternal mortalities worldwide, though this varies by region. Secondary infertility caused by an unsafe abortion affects an estimated 24 million women. The rate of unsafe abortions has increased from 44% to 49% between 1995 and 2008. Health education, access to family planning, and improvements in health care during and after abortion have been proposed to address this phenomenon.
Incidence
There are two commonly used methods of measuring the incidence of abortion:
Abortion rate – number of abortions annually per 1,000 women between 15 and 44 years of age; some sources use a range of 15–49.
Abortion percentage – number of abortions out of 100 known pregnancies; pregnancies include live births, abortions, and miscarriages.In many places, where abortion is illegal or carries a heavy social stigma, medical reporting of abortion is not reliable. For this reason, estimates of the incidence of abortion must be made without determining certainty related to standard error. The number of abortions performed worldwide seems to have remained stable in recent years, with 41.6 million having been performed in 2003 and 43.8 million having been performed in 2008. The abortion rate worldwide was 28 per 1000 women per year, though it was 24 per 1000 women per year for developed countries and 29 per 1000 women per year for developing countries. The same 2012 study indicated that in 2008, the estimated abortion percentage of known pregnancies was at 21% worldwide, with 26% in developed countries and 20% in developing countries.On average, the incidence of abortion is similar in countries with restrictive abortion laws and those with more liberal access to abortion. Restrictive abortion laws are associated with increases in the percentage of abortions performed unsafely. The unsafe abortion rate in developing countries is partly attributable to lack of access to modern contraceptives; according to the Guttmacher Institute, providing access to contraceptives would result in about 14.5 million fewer unsafe abortions and 38,000 fewer deaths from unsafe abortion annually worldwide.The rate of legal, induced abortion varies extensively worldwide. According to the report of employees of Guttmacher Institute it ranged from 7 per 1000 women per year (Germany and Switzerland) to 30 per 1000 women per year (Estonia) in countries with complete statistics in 2008. The proportion of pregnancies that ended in induced abortion ranged from about 10% (Israel, the Netherlands and Switzerland) to 30% (Estonia) in the same group, though it might be as high as 36% in Hungary and Romania, whose statistics were deemed incomplete.An American study in 2002 concluded that about half of women having abortions were using a form of contraception at the time of becoming pregnant. Inconsistent use was reported by half of those using condoms and three-quarters of those using the birth control pill; 42% of those using condoms reported failure through slipping or breakage. The Guttmacher Institute estimated that "most abortions in the United States are obtained by minority women" because minority women "have much higher rates of unintended pregnancy". In a 2022 analysis by the Kaiser Family Foundation, while people of color comprise 44% of the population in Mississippi, 59% of the population in Texas, 42% of the population in Louisiana (by the state Health Department), and 35% of the population in Alabama, they comprise 80%, 74%, 72%, and 70% of those receiving abortions.The abortion rate may also be expressed as the average number of abortions a woman has during her reproductive years; this is referred to as total abortion rate (TAR).
Gestational age and method
Abortion rates also vary depending on the stage of pregnancy and the method practiced. In 2003, the Centers for Disease Control and Prevention (CDC) reported that 26% of reported legal induced abortions in the United States were known to have been obtained at less than 6 weeks gestation, 18% at 7 weeks, 15% at 8 weeks, 18% at 9 through 10 weeks, 10% at 11 through 12 weeks, 6% at 13 through 15 weeks, 4% at 16 through 20 weeks and 1% at more than 21 weeks. 91% of these were classified as having been done by "curettage" (suction-aspiration, dilation and curettage, dilation and evacuation), 8% by "medical" means (mifepristone), >1% by "intrauterine instillation" (saline or prostaglandin), and 1% by "other" (including hysterotomy and hysterectomy). According to the CDC, due to data collection difficulties the data must be viewed as tentative and some fetal deaths reported beyond 20 weeks may be natural deaths erroneously classified as abortions if the removal of the dead fetus is accomplished by the same procedure as an induced abortion.The Guttmacher Institute estimated there were 2,200 intact dilation and extraction procedures in the US during 2000; this accounts for <0.2% of the total number of abortions performed that year. Similarly, in England and Wales in 2006, 89% of terminations occurred at or under 12 weeks, 9% between 13 and 19 weeks, and 2% at or over 20 weeks. 64% of those reported were by vacuum aspiration, 6% by D&E, and 30% were medical. There are more second trimester abortions in developing countries such as China, India and Vietnam than in developed countries.
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Abortion | Motivation
Personal
The reasons why women have abortions are diverse and vary across the world. Some of the reasons may include an inability to afford a child, domestic violence, lack of support, feeling they are too young, and the wish to complete education or advance a career. Additional reasons include not being able or willing to raise a child conceived as a result of rape or incest.
Societal
Some abortions are undergone as the result of societal pressures. These might include the preference for children of a specific sex or race, disapproval of single or early motherhood, stigmatization of people with disabilities, insufficient economic support for families, lack of access to or rejection of contraceptive methods, or efforts toward population control (such as Chinas one-child policy). These factors can sometimes result in compulsory abortion or sex-selective abortion.
Maternal and fetal health
An additional factor is maternal health which was listed as the main reason by about a third of women in 3 of 27 countries and about 7% of women in a further 7 of these 27 countries.In the U.S., the Supreme Court decisions in Roe v. Wade and Doe v. Bolton: "ruled that the states interest in the life of the fetus became compelling only at the point of viability, defined as the point at which the fetus can survive independently of its mother. Even after the point of viability, the state cannot favor the life of the fetus over the life or health of the pregnant woman. Under the right of privacy, physicians must be free to use their "medical judgment for the preservation of the life or health of the mother." On the same day that the Court decided Roe, it also decided Doe v. Bolton, in which the Court defined health very broadly: "The medical judgment may be exercised in the light of all factors—physical, emotional, psychological, familial, and the womans age—relevant to the well-being of the patient. All these factors may relate to health. This allows the attending physician the room he needs to make his best medical judgment.": 1200–01 Public opinion shifted in America following television personality Sherri Finkbines discovery during her fifth month of pregnancy that she had been exposed to thalidomide. Unable to obtain a legal abortion in the United States, she traveled to Sweden. From 1962 to 1965, an outbreak of German measles left 15,000 babies with severe birth defects. In 1967, the American Medical Association publicly supported liberalization of abortion laws. A National Opinion Research Center poll in 1965 showed 73% supported abortion when the mothers life was at risk, 57% when birth defects were present and 59% for pregnancies resulting from rape or incest.
Cancer
The rate of cancer during pregnancy is 0.02–1%, and in many cases, cancer of the mother leads to consideration of abortion to protect the life of the mother, or in response to the potential damage that may occur to the fetus during treatment. This is particularly true for cervical cancer, the most common type of which occurs in 1 of every 2,000–13,000 pregnancies, for which initiation of treatment "cannot co-exist with preservation of fetal life (unless neoadjuvant chemotherapy is chosen)". Very early stage cervical cancers (I and IIa) may be treated by radical hysterectomy and pelvic lymph node dissection, radiation therapy, or both, while later stages are treated by radiotherapy. Chemotherapy may be used simultaneously. Treatment of breast cancer during pregnancy also involves fetal considerations, because lumpectomy is discouraged in favor of modified radical mastectomy unless late-term pregnancy allows follow-up radiation therapy to be administered after the birth.Exposure to a single chemotherapy drug is estimated to cause a 7.5–17% risk of teratogenic effects on the fetus, with higher risks for multiple drug treatments. Treatment with more than 40 Gy of radiation usually causes spontaneous abortion. Exposure to much lower doses during the first trimester, especially 8 to 15 weeks of development, can cause intellectual disability or microcephaly, and exposure at this or subsequent stages can cause reduced intrauterine growth and birth weight. Exposures above 0.005–0.025 Gy cause a dose-dependent reduction in IQ. It is possible to greatly reduce exposure to radiation with abdominal shielding, depending on how far the area to be irradiated is from the fetus.The process of birth itself may also put the mother at risk. According to Li et al., "[v]aginal delivery may result in dissemination of neoplastic cells into lymphovascular channels, haemorrhage, cervical laceration and implantation of malignant cells in the episiotomy site, while abdominal delivery may delay the initiation of non-surgical treatment."
History and religion
Since ancient times, abortions have been done using a number of methods, including herbal medicines acting as abortifacients, sharp tools through the use of force, or through other traditional medicine methods. Induced abortion has a long history and can be traced back to civilizations as varied as ancient China (abortifacient knowledge is often attributed to the mythological ruler Shennong), ancient India since its Vedic age, ancient Egypt with its Ebers Papyrus (c. 1550 BCE), and the Roman Empire in the time of Juvenal (c. 200 CE). One of the earliest known artistic representations of abortion is in a bas relief at Angkor Wat (c. 1150). Found in a series of friezes that represent judgment after death in Hindu and Buddhist culture, it depicts the technique of abdominal abortion.In Judaism (Genesis 2:7), the fetus is not considered to have a human soul until it is safely outside of the woman, is viable, and has taken its first breath. The fetus is considered valuable property of the woman and not a human life while in the womb (Exodus 21:22–23). While Judaism encourages people to be fruitful and multiply by having children, abortion is allowed and is deemed necessary when a pregnant womans life is in danger. Several religions, including Judaism, which disagree that human life begins at conception, support the legality of abortion on religious freedom grounds.Some medical scholars and abortion opponents have suggested that the Hippocratic Oath forbade physicians in Ancient Greece from performing abortions; other scholars disagree with this interpretation, and state that the medical texts of Hippocratic Corpus contain descriptions of abortive techniques right alongside the Oath. The physician Scribonius Largus wrote in 43 CE that the Hippocratic Oath prohibits abortion, as did Soranus of Ephesus, although apparently not all doctors adhered to it strictly at the time. According to Soranus 1st or 2nd century CE work Gynaecology, one party of medical practitioners banished all abortives as required by the Hippocratic Oath; the other party to which he belonged was willing to prescribe abortions only for the sake of the mothers health. In Politics (350 BCE), Aristotle condemned infanticide as a means of population control. He preferred abortion in such cases, with the restriction that it "must be practised on it before it has developed sensation and life; for the line between lawful and unlawful abortion will be marked by the fact of having sensation and being alive."In the Catholic Church, opinion was divided on how serious abortion was in comparison with such acts as contraception, oral sex, and sex in marriage for pleasure rather than procreation.: 155–167 The Catholic Church did not begin vigorously opposing abortion until the 19th century. As early as ~100 A.D., the Didache taught that abortion was sinful. Several historians argue that prior to the 19th century most Catholic authors did not regard termination of pregnancy before quickening or ensoulment as an abortion. Among these authors were the Doctors of the Church, such as St. Augustine, St. Thomas Aquinas, and St. Alphonsus Liguori. Pope Sixtus V (r. 1585–90) was the only Pope before Pope Pius IX (in his 1869 bull, Apostolicae Sedis) to institute a Church policy labeling all abortion as homicide and condemning abortion regardless of the stage of pregnancy.: 362–364 : 157–158 Sixtus V 1588 pronouncement was reversed in 1591 by Pope Gregory XIV. In the recodification of 1917 Code of Canon Law, Apostolicae Sedis was strengthened, in part to remove a possible reading that excluded excommunication of the mother. Statements made in the Catechism of the Catholic Church, the codified summary of the Churchs teachings, considers abortion from the moment of conception as homicide and called for the end of legal abortion.A 2014 Guttmacher survey of abortion patients in the United States found that many reported a religious affiliation: 24% were Catholic while 30% were Protestant. A 1995 survey reported that Catholic women are as likely as the general population to terminate a pregnancy, Protestants are less likely to do so, and evangelical Christians are the least likely to do so. A 2019 Pew Research Center study found that most Christian denominations were against overturning Roe v. Wade, which in the United States legalized abortion, at around 70%, except White Evangelicals at 35%.In Islam, abortion is traditionally permitted until a point in time when Muslims believe the soul enters the fetus, considered by various theologians to be at conception, 40 days after conception, 120 days after conception, or quickening. Abortion is largely heavily restricted or forbidden in areas of high Islamic faith such as the Middle East and North Africa.
Abortion has been a fairly common practice, and was not always illegal or controversial until the 19th century. Under common law, including early English common law dating back to Edward Coke in 1648, abortion was generally permitted before quickening (14–26 weeks after conception, or betweeth the fourth and sixth month), and at womens discretion; it was whether abortion was performed after quickening that determined if it was a crime. In Europe and North America, abortion techniques advanced starting in the 17th century; the conservatism of most in the medical profession with regards to sexual matters prevented the wide expansion of abortion techniques. Other medical practitioners in addition to some physicians advertised their services, and they were not widely regulated until the 19th century when the practice, sometimes called restellism, was banned in both the United States and the United Kingdom.Church groups, as well as physicians, were highly influential in anti-abortion movements, and religious groups more so since the 20th century. Some of the early anti-abortion laws punished only the doctor or abortionist, and while women could be criminally tried for a self-induced abortion, they were rarely prosecuted in general. In the United States, some argued that abortion was more dangerous than childbirth until about 1930 when incremental improvements in abortion procedures relative to childbirth made abortion safer. Others maintain that in the 19th century early abortions under the hygienic conditions in which midwives usually worked were relatively safe. Several scholars argue that, despite improved medical procedures, the period from the 1930s until the 1970s saw more zealous enforcement of anti-abortion laws, and concomitantly an increasing control of abortion providers by organized crime.Soviet Russia (1919), Iceland (1935), and Sweden (1938) were among the first countries to legalize certain or all forms of abortion. In Nazi Germany (1935), a law permitted abortions for those deemed "hereditarily ill", while women considered of German stock were specifically prohibited from having abortions. Preceding the Nazi German example was that of some 19th-century physicians, one of the most famous and consequential being Horatio Storer, who argued for anti-abortion laws on racist and pseudoscientific grounds. Beginning in the second half of the 20th century, abortion was legalized in a greater number of countries.
Society and culture
Abortion debate
Induced abortion has long been the source of considerable debate. Ethical, moral, philosophical, biological, religious and legal issues surrounding abortion are related to value systems. Opinions of abortion may be about fetal rights, governmental authority, and womens rights.
In both public and private debate, arguments presented in favor of or against abortion access focus on either the moral permissibility of an induced abortion, or justification of laws permitting or restricting abortion. The World Medical Association Declaration on Therapeutic Abortion notes, "circumstances bringing the interests of a mother into conflict with the interests of her unborn child create a dilemma and raise the question as to whether or not the pregnancy should be deliberately terminated." Abortion debates, especially pertaining to abortion laws, are often spearheaded by groups advocating one of these two positions. Groups who favor greater legal restrictions on abortion, including complete prohibition, most often describe themselves as "pro-life" while groups who are against such legal restrictions describe themselves as "pro-choice".
Modern abortion law
Current laws pertaining to abortion are diverse. Religious, moral, and cultural factors continue to influence abortion laws throughout the world. The right to life, the right to liberty, the right to security of person, and the right to reproductive health are major issues of human rights that sometimes constitute the basis for the existence or absence of abortion laws.
In jurisdictions where abortion is legal, certain requirements must often be met before a woman may obtain a legal abortion (an abortion performed without the womans consent is considered feticide). These requirements usually depend on the age of the fetus, often using a trimester-based system to regulate the window of legality, or as in the U.S., on a doctors evaluation of the fetus viability. Some jurisdictions require a waiting period before the procedure, prescribe the distribution of information on fetal development, or require that parents be contacted if their minor daughter requests an abortion. Other jurisdictions may require that a woman obtain the consent of the fetus father before aborting the fetus, that abortion providers inform women of health risks of the procedure—sometimes including "risks" not supported by the medical literature—and that multiple medical authorities certify that the abortion is either medically or socially necessary. Many restrictions are waived in emergency situations. China, which has ended their one-child policy, and now has a two child policy, has at times incorporated mandatory abortions as part of their population control strategy.Other jurisdictions ban abortion almost entirely. Many, but not all, of these allow legal abortions in a variety of circumstances. These circumstances vary based on jurisdiction, but may include whether the pregnancy is a result of rape or incest, the fetus development is impaired, the womans physical or mental well-being is endangered, or socioeconomic considerations make childbirth a hardship. In countries where abortion is banned entirely, such as Nicaragua, medical authorities have recorded rises in maternal death directly and indirectly due to pregnancy as well as deaths due to doctors fears of prosecution if they treat other gynecological emergencies. Some countries, such as Bangladesh, that nominally ban abortion, may also support clinics that perform abortions under the guise of menstrual hygiene. This is also a terminology in traditional medicine. In places where abortion is illegal or carries heavy social stigma, pregnant women may engage in medical tourism and travel to countries where they can terminate their pregnancies. Women without the means to travel can resort to providers of illegal abortions or attempt to perform an abortion by themselves.The organization Women on Waves has been providing education about medical abortions since 1999. The NGO created a mobile medical clinic inside a shipping container, which then travels on rented ships to countries with restrictive abortion laws. Because the ships are registered in the Netherlands, Dutch law prevails when the ship is in international waters. While in port, the organization provides free workshops and education; while in international waters, medical personnel are legally able to prescribe medical abortion drugs and counseling.
Sex-selective abortion
Sonography and amniocentesis allow parents to determine sex before childbirth. The development of this technology has led to sex-selective abortion, or the termination of a fetus based on its sex. The selective termination of a female fetus is most common.
Sex-selective abortion is partially responsible for the noticeable disparities between the birth rates of male and female children in some countries. The preference for male children is reported in many areas of Asia, and abortion used to limit female births has been reported in Taiwan, South Korea, India, and China. This deviation from the standard birth rates of males and females occurs despite the fact that the country in question may have officially banned sex-selective abortion or even sex-screening. In China, a historical preference for a male child has been exacerbated by the one-child policy, which was enacted in 1979.Many countries have taken legislative steps to reduce the incidence of sex-selective abortion. At the International Conference on Population and Development in 1994 over 180 states agreed to eliminate "all forms of discrimination against the girl child and the root causes of son preference", conditions also condemned by a PACE resolution in 2011. The World Health Organization and UNICEF, along with other United Nations agencies, have found that measures to reduce access to abortion are much less effective at reducing sex-selective abortions than measures to reduce gender inequality.
Anti-abortion violence
In a number of cases, abortion providers and these facilities have been subjected to various forms of violence, including murder, attempted murder, kidnapping, stalking, assault, arson, and bombing. Anti-abortion violence is classified by both governmental and scholarly sources as terrorism. In the U.S. and Canada, over 8,000 incidents of violence, trespassing, and death threats have been recorded by providers since 1977, including over 200 bombings/arsons and hundreds of assaults. The majority of abortion opponents have not been involved in violent acts.
In the United States, four physicians who performed abortions have been murdered: David Gunn (1993), John Britton (1994), Barnett Slepian (1998), and George Tiller (2009). Also murdered, in the U.S. and Australia, have been other personnel at abortion clinics, including receptionists and security guards such as James Barrett, Shannon Lowney, Lee Ann Nichols, and Robert Sanderson. Woundings (e.g., Garson Romalis) and attempted murders have also taken place in the United States and Canada. Hundreds of bombings, arsons, acid attacks, invasions, and incidents of vandalism against abortion providers have occurred. Notable perpetrators of anti-abortion violence include Eric Robert Rudolph, Scott Roeder, Shelley Shannon, and Paul Jennings Hill, the first person to be executed in the United States for murdering an abortion provider.Legal protection of access to abortion has been brought into some countries where abortion is legal. These laws typically seek to protect abortion clinics from obstruction, vandalism, picketing, and other actions, or to protect women and employees of such facilities from threats and harassment.
Far more common than physical violence is psychological pressure. In 2003, Chris Danze organized anti-abortion organizations throughout Texas to prevent the construction of a Planned Parenthood facility in Austin. The organizations released the personal information online of those involved with construction, sent them up to 1200 phone calls a day and contacted their churches. Some protestors record women entering clinics on camera.
Non-human examples
Spontaneous abortion occurs in various animals. For example, in sheep it may be caused by stress or physical exertion, such as crowding through doors or being chased by dogs. In cows, abortion may be caused by contagious disease, such as brucellosis or Campylobacter, but can often be controlled by vaccination. Eating pine needles can also induce abortions in cows.
Several plants, including broomweed, skunk cabbage, poison hemlock, and tree tobacco, are known to cause fetal deformities and abortion in cattle: 45–46 and in sheep and goats.: 77–80 In horses, a fetus may be aborted or resorbed if it has lethal white syndrome (congenital intestinal aganglionosis). Foal embryos that are homozygous for the dominant white gene (WW) are theorized to also be aborted or resorbed before birth. In many species of sharks and rays, stress-induced abortions occur frequently on capture.Viral infection can cause abortion in dogs. Cats can experience spontaneous abortion for many reasons, including hormonal imbalance. A combined abortion and spaying is performed on pregnant cats, especially in trap–neuter–return programs, to prevent unwanted kittens from being born.
Female rodents may terminate a pregnancy when exposed to the smell of a male not responsible for the pregnancy, known as the Bruce effect.Abortion may also be induced in animals, in the context of animal husbandry. For example, abortion may be induced in mares that have been mated improperly, or that have been purchased by owners who did not realize the mares were pregnant, or that are pregnant with twin foals. Feticide can occur in horses and zebras due to male harassment of pregnant mares or forced copulation, although the frequency in the wild has been questioned. Male gray langur monkeys may attack females following male takeover, causing miscarriage.
See also
Abortion doula
Forced abortion
Notes
References
Bibliography
External links
First-trimester abortion in women with medical conditions. US Department of Health and Human Services
Safe abortion: Technical & policy guidance for health systems, World Health Organization (2015) |
Premenstrual dysphoric disorder | Premenstrual dysphoric disorder (PMDD) is a mood disorder characterized by emotional, cognitive, and physical symptoms that cause significant distress or impairment in menstruating women during the luteal phase of the menstrual cycle. The symptoms occur in the luteal phase, (between ovulation and menses), improve within a few days after the onset of menses, and are minimal or absent in the week after menses. PMDD has a profound impact on a persons quality of life and dramatically increases the risk of suicidal ideation and even suicide attempts. Many females of reproductive age experience discomfort or mild mood changes prior to menstruation. However, 5-8% experience severe premenstrual syndrome causing significant distress or functional impairment. Within this population of reproductive age, some women will meet the criteria for PMDD. PMDD is most common from age 25–35, but can occur anytime during a womans reproductive years.The exact cause of PMDD is currently unknown. However, because the symptoms are only present during ovulatory cycles and resolve after menses, it is believed to be caused by fluctuations in gonadal sex hormones or variations in sensitivity to sex hormones.In 2017, researchers at the National Institutes of Health discovered that women with PMDD have genetic changes that make their emotional regulatory pathways more sensitive to estrogen and progesterone, as well as their chemical derivatives. The researchers believe that this increased sensitivity may be responsible for PMDD symptoms.Some studies have suggested that those with PMDD are more at risk of developing postpartum depression after pregnancy, but other evidence has been found to suggest against that notion. PMDD was added to the list of depressive disorders in the Diagnostic and Statistical Manual of Mental Disorders in 2013. It has 11 main symptoms, and a woman has to exhibit at least five to be diagnosed with PMDD. Roughly 20% of women have some symptoms of PMDD, but either have less than five or do not have functional impairment.First line treatment for PMDD is with selective serotonin reuptake inhibitors (SSRIs). Hormonal therapy with oral contraceptives that contain drospirenone have demonstrated efficiency in reducing PMDD symptoms as well. Cognitive behavioral therapy, whether in combination with SSRIs or alone, has shown to be effective in reducing impairment. Dietary modifications and exercise may also be helpful, but studies investigating these treatments have not demonstrated efficacy in reducing PMDD symptoms.
Signs and symptoms
Clinicians consider mood symptoms, physical symptoms and impact on the patients life in making the diagnosis of PMDD. Mood symptoms include emotional lability (rapidly changing emotions, sensitivity to rejection, etc.), irritability and anger that may lead to conflict, anxiety, feeling on edge, hopelessness, difficulty concentrating, appetite changes, sleeping more or less than usual, or feeling out of control. The physical symptoms are similar to the symptoms of PMS. These include breast tenderness or swelling, joint pain, muscle pain, gaining weight, or feeling bloated.Because of the broad variety in clinical presentation, the onset of symptoms only during or around the luteal phase is key for diagnosing someone with PMDD rather than any other mood disorders. PMDD follows a predictable, cyclic pattern. Symptoms begin in the late luteal phase of the menstrual cycle (after ovulation) and end or are markedly reduced shortly after menstruation begins. On average, the symptoms last six days but can start up to two weeks before menses, meaning symptoms can be felt for up to three weeks out of a cycle. Severe symptoms can begin and worsen until the onset of menstruation, with many not feeling relief until a few days after menstruation ends. The most intense symptoms occurring in the week and days leading up to the first day of menstrual blood flow. The symptoms usually cease shortly after the start of the menstrual period or a few days after it ends. Various symptom and severity tracking questionnaires exist to document presence and severity of symptoms throughout consecutive menstrual cycles.The International Society for the Study of Premenstrual Disorders (ISPMD) defines two categories of premenstrual disorders: core PMD and variant PMD.
Core PMD has six characteristics, all mainly focusing on the cyclical nature of PMDD and its typical onset pre-menses tracked over the course of more than two menstrual cycles. The four classified Variant PMDs involve more unexpected variables that cause the onset of premenstrual distress; such as, PMD with absent menstruation or premenstrual exacerbation, wherein the symptoms of another preexisting psychological disorder may be heightened as a result of PMDD onset.
Epidemiology
About 5-8% of women of reproductive age experience severe premenstrual syndrome; most of these women also meet criteria for PMDD. PMDD is most common from age 25–35, but can occur anytime during a womans reproductive years.Among females of reproductive age living in India, the prevalence of PMDD is 8%.
Pathophysiology
PMDD mood symptoms are only present in menstruating women. Thus, symptoms do not occur during pregnancy, after menopause, or in women who have anovulatory cycles. Other mood disorders typically persist across all reproductive life events and are independent of a womans menstrual cycle.The current consensus on the cause of PMDD is a combination of heightened sensitivity to fluctuating levels of certain hormones (i.e. the reproductive hormones), environmental stress, and genetic predisposition. The sex steroids—estrogen and progesterone—are neuroactive; they have been noted in rat models to be involved in serotonin pathways. Serotonin is involved in mood regulation alongside estrogen, whose receptors are found in the prefrontal cortex and hippocampus—the regions most known for their involvement in regulating ones mood and cognition overall.While the timing of symptoms suggests hormonal fluctuations as the cause of PMDD, a demonstrable hormonal imbalance in women with PMDD has not been identified. In fact, levels of reproductive hormones and their metabolites in women with and without PMDD are indistinguishable. It is instead hypothesized that women with PMDD are more sensitive to normal levels of hormone fluctuations, predominantly estrogen and progesterone, which produces biochemical events in the nervous system that cause the premenstrual symptoms. These symptoms are more predominant in women who have a predisposition to the disorder.It is apparent that the premenstrual disorders are biologically driven and are not only psychological or cultural phenomena. PMDD has been reported by menstruating women worldwide, indicating a biological basis that is not geographically selective. Most psychologists infer that this disorder is caused by both a reaction to hormone flux and also genetic components. There is evidence of heritability of (retrospectively-reported) premenstrual symptoms from several twin and family studies done in the 1990s, with the heritability of PMDD proving to be about 56%.
Genetic factors
While whether or not this disorder has a specific genetic basis is still being discussed in the academic community and the possible genetic factors contributing to PMDD have yet to be thoroughly researched, there has recently been multiple genetic factors identified that contribute to the moodiness, depression, irritability, increased appetite, trouble sleeping, acne, fluid retention, headaches, nausea, and other symptoms that are all associated with this disorder.
Many studies have noted that a polymorphism of the brain-derived neurotrophic factor gene (BDNF), a gene that helps support neurons in their function and survival in the brain by creating a protein that helps in the growth, maturation, and maintenance of these cells, may play a role in causing PMDD symptoms. This is because the result of this polymorphism mimics the hallmarks of PMDD: volatile moods, depression and irritability centered around the menstrual cycle. This gene has been studied extensively in its association with depression and, promisingly for PMDD research, mice homozygous for the BDNF polymorphism exhibited anxiety-like traits that fluctuated and changed around the mices estrus, analogous to the humans menstruation, therefore mimicking some of the symptoms of PMDD.
Risk Factors
Environmental stressors have also been found to prospectively increase risk for PMDD symptoms. Environmental components such as stress, hormonal fluctuation, and epigenetics play a key role in the pathology and onset of the disorder. Some studies have noted evidence of interpersonal trauma (domestic violence, physical or emotional trauma, or substance abuse) or seasonal changes (making PMDD potentially comorbid with Seasonal Affective Disorder) having an impact on PMDD risk. But the most common pre-existing disorder found in those diagnosed with PMDD is major depression, wherein they either actually had it or were misdiagnosed when they should have only been diagnosed with PMDD. Finally, an easily modifiable risk factor for PMDD is cigarette smoking. One meta-analysis found dramatically increased risk of developing PMDD in menstruating women who smoke.
Relationship to pregnancy and menopause
Women with PMDD usually see their symptoms disappear while they are pregnant. Premenstrual dysphoric disorder is primarily a mood disorder that is associated with onset of menstruation; pregnancy, menopause, and hysterectomies all cause menstruation to cease, thereby stopping the proposed sex steroid-/serotonin-caused symptoms from occurring. Although one might expect a higher rate of postpartum depression among those with PMDD, a large study of women with prospectively-confirmed PMDD did not find a higher prevalence of postpartum depression than in controls. If a woman had experienced PPD beforehand, there was found to be a less-than 12% chance of PMDD pathology emerging—hardly any differentiation from the regular population of those who have never experienced postpartum depression. However, PMDD symptoms can get worse following pregnancy, or other associated events such as birth and miscarriage.
Mental Health Comorbidities in PMDD
The lifetime incidence of other psychiatric disorders is high among women with PMDD. An older review article (2002) utilizing the previous edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) used studies from 1966 to 2002 on PMS and mental health disorders and selected for patients who retrospectively met the diagnostic criteria for PMDD and found that Major Depressive Disorder, Seasonal affective disorder, and generalized anxiety disorder often co-occur in PMDD. Another systematic review study suggests that patients with bipolar disorder, type I or II, have a higher incidence of PMDD. While the diagnosis of PMDD requires a mental health provider to determine that the symptoms a woman is facing is not due to an underlying mental or physical health condition, it is important to note that other conditions often co-occur and impact the quality of life and treatment plan for people with PMDD.
Suicidality in Premenstrual Dysphoric Disorder
Previous links to suicidality and PMS have been made, but women with PMDD are more likely still to consider and attempt suicide even when controlling for mental health comorbidities. Despite the increase in suicidal ideation and attempts in this population, the data currently suggests that suicidal ideation or action is not more likely to occur during the late luteal phase when PMDD symptoms would occur. It is difficult to study whether treatment reduces suicidality because of the multifaceted reasons provided for suicidal ideation. However, treatment has been well documented to reduce physical and emotional symptoms of PMDD.
Diagnosis
Diagnostic criteria for PMDD are provided by a number of expert medical guides. Diagnosis can be supported by having women who are seeking treatment for PMDD use a daily charting method to record their symptoms. Daily charting helps to distinguish when mood disturbances are experienced and allows PMDD to be more easily distinguished from other mood disorders. With PMDD, mood symptoms are present only during the luteal phase, or last two weeks, of the menstrual cycle. While PMDD mood symptoms are of a cyclical nature, other mood disorders are variable or constant over time. Although there is a lack of consensus on the most efficient instrument by which to confirm a PMDD diagnosis, several validated scales for recording premenstrual symptoms include the Calendar of Premenstrual Experiences (COPE), Daily Record of Severity of Problems (DRSP), and Prospective Record of the Severity of Menstruation (PRISM). In the context of research, standardized numerical cutoffs are often applied to verify the diagnosis. The difficulty of diagnosing PMDD is one reason that it can be challenging for lawyers to cite the disorder as a defense of crime, in the very rare cases where PMDD is allegedly associated with criminal violence.
DSM-5
The DSM-5 which established seven criteria (A through G) for the diagnosis of PMDD which is paraphrased below. There is overlap between the criteria for PMDD in the DSM-5 and the criteria found in the Daily Record of Severity of Problems (DRSP).According to the DSM-5, a diagnosis of PMDD requires the presence of at least five of these symptoms with one of the symptoms being numbers 1–4. These symptoms should occur during the week before menses and remit after initiation of menses. In order to meet criteria for the diagnosis, the symptoms should be charted prospectively for two consecutive ovulation cycles in order to confirm a temporal and cyclical nature of the symptoms. The symptoms should also be severe enough to affect normal work, school, social activities, and/or relationships with others.
The symptoms of Criteria A-C must have been met for most menstrual cycles that occurred in the preceding year, and have to have cause significant impairment in family, work, school, or social functioning. (Criterion D).
Timing
Criterion A: During most menstrual cycles throughout the past year, at least 5 of the symptoms outlined in Criterion B and Criterion C must be present in the final week before the onset of menses, must start to improve within a few days after the onset of menses, and become minimal or absent in the week post-menses.
Symptoms
Criterion B: One (or more) of the following symptoms must be present:
Marked affective lability (e.g., mood swings, feeling suddenly sad or tearful, or increased sensitivity to rejection)
Marked irritability or anger or increased interpersonal conflicts
Marked depressed mood, feelings of hopelessness, or self-deprecating thoughts
Marked anxiety, tension, and/or feelings of being keyed up or on edgeCriterion C: One (or more) of the following symptoms must be present additionally, to reach a total of 5 symptoms when combined with present symptoms from Criterion B above:
Decreased interest in usual activities (e.g., work, school, friends, hobbies).
Subjective difficulty in concentration.
Lethargy, easy fatigability, or marked lack of energy.
Marked change in appetite; overeating; or specific food cravings.
Hypersomnia or insomnia.
A sense of being overwhelmed or out of control.
Physical symptoms such as breast tenderness or swelling, joint or muscle pain, a sensation of "bloating," or weight gain.Severity
Criterion D: The symptoms observed in Criteria A-C are associated with clinically significant distress or interference with work, school, usual social activities, or relationships with others (e.g., avoidance of social activities; decreased productivity and efficiency at work, school, or home).
Consideration of Other Psychiatric Disorders
Criterion E: The disturbance is not merely an exacerbation of the symptoms of another disorder, such as major depressive disorder, panic disorder, persistent depressive disorder (Dysthymia), or a personality disorder—although it may co-occur with any of these disorders.Confirmation of the Disorder
Criterion F: Criterion A should be confirmed by prospective daily ratings during at least two symptomatic cycles. The diagnosis may be made provisionally prior to this confirmation.
Criterion G: The symptoms are not attributable to the physiological effects of a substance (e.g., drug abuse, a medication, other treatments) or another medical condition (e.g., hyperthyroidism).
Clinically significant distress is not defined explicitly by the DSM-IV, where it has been critiqued by multiple scholars as being too vague, and potentially detrimental for those who have symptoms of depression, anxiety, or other mood disorders because they do not meet the clinical significance requirement.
ICD 11
Diagnostic criteria for PMDD are also provided by the 2016 World Health Organizations International Classification of Diseases (ICD-11-CM):
GA34.41 Premenstrual dysphoric disorder
Description
During a majority of menstrual cycles within the past year, a pattern of mood symptoms (depressed mood, irritability), somatic symptoms (lethargy, joint pain, overeating), or cognitive symptoms (concentration difficulties, forgetfulness) that begin several days before the onset of menses, start to improve within a few days after the onset of menses, and then become minimal or absent within approximately 1 week following the onset of menses. The temporal relationship of the symptoms and luteal and menstrual phases of the cycle may be confirmed by a prospective symptom diary. The symptoms are severe enough to cause significant distress or significant impairment in personal, family, social, educational, occupational or other important areas of functioning and do not represent the exacerbation of a mental disorder.
Royal College of Obstetricians and Gynecologists and the International Society for the Study of Premenstrual Disorders
Other organizations that have published diagnostic criteria for PMDD include the Royal College of Obstetricians and Gynecologists and the International Society for the Study of Premenstrual Disorders (ISPMD). The ISPMD was a consensus group established by an international multidisciplinary group of experts. The groups diagnostic criteria for PMDD focuses on the cyclic nature of the symptoms occurring during the luteal phase of the menstrual cycle, as well as the symptoms being absent after menstruation and before ovulation and causing significant impairment. The ISPMD diagnostic criteria for PMDD do not specify symptom characteristics or number of symptoms.
Differential diagnosis
A critical part of diagnosing PMDD is ruling out underlying psychiatric disorder or physical illness that can cause similar symptoms. That exhibits premenstrual exacerbation, the menopausal transition, hyperthyroidism, hypothyroidism, as well as other mood disorders. Furthermore, many medical disorders are worsened prior to ordering menses, but these typically do not present strictly during the luteal phase.
Mood disorders – there is potential for patients to have psychiatric disorders with superimposed PMDD or psychiatric disorders. In order to establish the timeline of symptoms required for a diagnosis of PMDD symptoms need to be tracked using scales like the Calendar of Premenstrual Experiences or the Daily Record of Severity of Problems.Menopausal transition – affective symptoms associated with the menopausal transition most commonly start when menstrual cycle starts to become irregular or anovulatory whereas PMDD symptoms occur during the luteal phase of ovulatory cycles.
Thyroid disorders—patients with both hyperthyroidism and hypothyroidism may present with affective symptoms. The patients history is very important to determine whether the provider should suspect thyroid disorders. Patients should also have thyroid hormone levels checked to ensure no underlying thyroid disorder is present.
Treatment
Medication
Several medications have been shown to effectively reduce the physical and emotional symptoms of PMDD.
Antidepressant Treatment
Selective serotonin reuptake inhibitors (SSRIs) are the first-line medication. Women taking SSRIs to ease PMDD generally report >50% alleviation in symptoms, which was significant improvement compared to placebo. Two approaches to dosing have been studied: continuous dosing (daily) and luteal dosing (14 days before menstruation and discontinuing at the onset of menses). Both dosing schedules have similar effectiveness with some recent studies demonstrating greater symptom control with continuous dosing. This gives patients control of how they want to dose their medication in alliance with their mental health provider.
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) have also been studied in the treatment of PMDD and shown efficacy in reducing symptoms. These are an alternative for patients who do not respond to SSRIs. However, they are more likely to be dosed continuously due to SNRI discontinuation syndrome - a flu-like feeling caused by dropping blood levels of SNRI.
Anxiolytics
Two medications typically given to reduce acute anxiety have been studied in treatment for PMDD: alprazolam (Xanax) and buspirone. Alprazolam carries a risk of abuse and causes central nervous system depression and results of clinical trials have not shown benefit to treatment. Buspirone showed lower efficacy than SSRI, but may be used as an adjunctive treatment or alternative if SSRI side effects are intolerable to the patient.
Psychotherapy
Cognitive behavioral therapy (CBT) has been shown to be effective for reducing premenstrual symptoms in women with (retrospectively-reported) PMS. CBT is an evidence-based approach for treating depression and focuses on the link between mood, thoughts, and actions to help women address current issues and symptoms. When CBT was compared to SSRI alone or in combination with SSRI, groups receiving CBT had significant improvement of PMS symptoms. Through the practice of CBT, women are better able to recognize and modify recurrent issues as well as thought and behavior patterns that interfere with functioning well or that make depressive symptoms worse. However, a recent meta-analysis suggests that existing psychotherapies may be primarily useful for reducing impairment (rather than symptom severity) in PMDD.
Hormonal Treatment
Oral contraceptives have been effective in reducing PMS symptoms, but only certain formulations have proven to be modestly effective in the treatment of PMDD. Transdermal estrogen and intrauterine devices containing levonorgestrel have also had modest efficacy.Another FDA approved treatment for PMDD is the oral contraceptive with ethinylestradiol and drospirenone (a novel progestin) taken on a 24-4 schedule (24 active pills, 4 inactive pills). It has been shown that hormonal birth control containing drospirenone and low levels of estrogen helps relieve severe PMDD symptoms, for at least the first three months that it is used. The idea behind using oral contraceptives is to suppress ovulation, therefore suppressing sex hormone fluctuations.
Another treatment, typically used when other options have failed, is injection of a gonadotropin-releasing hormone(GnRH) agonist with adjunctive estrogen and progesterone or tibolone. This is a last resort because GnRH antagonists can cause medical menopause by shutting down the bodys pathway for reproductive hormones called the hypothalamic, pituitary, gonadal axis. As a result, GnRH therapy presents increased risk of osteopenia (decreased bone density) and cardiovascular disease. This therapy is often reserved for patients considering surgical menopause to test the outcome of the surgery.
Surgical Menopause
In a minority of patient who meet specific criteria and drug-based treatments are ineffective or produce significant side effects, hysterectomy and bilateral oophorectomy followed by estrogen replacement therapy is an option Typically, the uterus is removed during the same surgery, and the women is prescribed a low-dose estrogen patch to reduce the symptoms produced by surgically induced menopause. There are five guidelines that should be considered before undergoing a surgical treatment. The vast majority of women with PMDD will not require surgical treatment to experience resolution of symptoms.
The diagnosis of PMDD must be confirmed
GnRH agonist therapy must be the only medical therapy that has been effective and it must have been effective continuously for a minimum of six months
Tolerance of estrogen replacement therapy has been tested
The woman does not desire further children
The womans age warrants several more years of therapy
Adjunctive and Alternative Treatments
Other proposed treatments include dietary modification, herbal remedies including St Johns Wort and chasteberry, acupuncture, and exercise. Some evidence suggests caffeine, sugar and alcohol intake may increase PMS symptoms. A review article claimed significant improvement of PMS symptoms with herbal treatments and acupuncture but the studies selected for review did not stratify severity of symptoms. Finally, the American College of Obstetricians and Gynecologists recommends regular aerobic exercise to reduce PMS symptoms.
History
In the 18th century, there were early accounts of weeping and other symptoms recurring almost every month, and in 1822 Prichard gave this description: "Many women … display a degree of excitement and irritation … at the period of menstruation; these are chiefly females of very irritable habits. In such instances, … an unusual vehemence of feeling and expression is observed … or there is torpor and dejection of mind with a despondent disposition". In 1827 a German mother was acquitted of infanticide on the grounds of menstrual mood disorder. Premenstrual tension was also described in the French literature of the early 19th century. Nearly one hundred years later, there were American descriptions of a cyclic personality change appearing 10–14 days before, and ending dramatically at the menses.The diagnostic category was discussed in the DSM-IIIR (1987), in which the proposed condition was named "Late Luteal Phase Dysphoric Disorder" and was included in the appendix as a proposed diagnostic category needing further study. Preparations for the DSM-IV led to debate about whether to keep the category at all, only keep it in the appendix, or remove it entirely; the reviewers determined that the condition was still too poorly studied and defined, so it was kept in the appendix but elaborated with diagnostic criteria to aid further study.As preparations were underway in 1998 for the DSM-IV-TR, the conversation changed, as Eli Lilly and Company paid for a large clinical trial of fluoxetine as a potential treatment for the condition that was then conducted by Canadian academics and published in the New England Journal of Medicine in 1995. Other studies have been conducted as well, wherein all found that approximately 60% of women with PMDD in the trials improved with the drug; representatives from Lilly & Co. and the FDA participated in the discussion.Various strong stances were taken in said discussion. Sally Severino, a psychiatrist, argued that because symptoms were more prevalent in the United States, PMDD was a culture-bound syndrome and not a biological condition; she also claimed it unnecessarily pathologized the hormonal changes of the menstrual cycle. Jean Endicott, another psychiatrist and chair of the committee, has argued that it was a valid condition from which women suffer and should be diagnosed and treated, and has claimed that if the symptoms were felt by males, far more effort and research would have been done by that moment. In the end the committee kept PMDD in the appendix.The decision has been criticized as being driven by Lillys financial interests, and possibly by financial interests of members of the committee who had received funding from Lilly. Paula Caplan, a psychologist who had served on the committee for the DSM-IV, noted at the time of the DSM-IV-TR decision that there was evidence that calcium supplements could treat PMDD but the committee gave it no attention. She had also claimed that the diagnostic category is harmful to women with PMDD, leading them to believe they are mentally ill, and potentially leading others to mistrust them in situations as important as job promotions or child custody cases. She has called PMDD a fake disorder. Nada Stotland has expressed concern that women with PMDD may actually have a more serious condition like major depressive disorder or may be facing difficult circumstances—such domestic abuse—and therefore may have their true issues remain undiagnosed and mismanaged if their gynecologist diagnoses them with PMDD and gives them drugs to treat it.The validity of PMDD was once more heavily debated when it came time to create the DSM-5 in 2008. In the end it was moved out of the appendix and into the main text as a formal category. A review in the Journal of Clinical Psychiatry published in 2014 examined the arguments against inclusion, which it summarized as:
the PMDD label will harm women economically, politically, legally, and domestically;
there is no equivalent hormone-based medical label for males;
the research on PMDD is faulty;
PMDD is a culture-bound condition;
PMDD is due to situational, rather than biological, factors; and
PMDD was fabricated by pharmaceutical companies for financial gain.Each argument was addressed and researchers found:
No evidence of harm;
no equivalent hormone-driven disorder has been discovered in men despite research seeking it;
the research base has matured and many more reputable studies have been performed;
several cases of PMDD have been reported or identified;
a small minority of women do have the condition; and
while there has been financial conflict of interest, it has not made the available research unusable.It concluded that women have historically been under-treated and told that they were making their symptoms up, and that the formal diagnostic criteria would spur more funding, research, diagnosis and treatment for women with PMDD.
References
External links
Premenstrual dysphoric disorder at Curlie
Bhatia SC, Bhatia SK ( |
Premenstrual dysphoric disorder | October 2002). "Diagnosis and treatment of premenstrual dysphoric disorder". American Family Physician. 66 (7): 1239–48. PMID 12387436.
International Association for Premenstrual Disorders (IAPMD) |
Premenstrual syndrome | Premenstrual syndrome (PMS) refers to emotional and physical symptoms that regularly occur in the one to two weeks before the start of each menstrual period. Symptoms resolve around the time menstrual bleeding begins. Different women experience different symptoms. The common emotional symptoms include irritability and mood changes. The common physical symptoms include acne, tender breasts, bloating, and feeling tired. These are nonspecific symptoms and may be seen in women without PMS. Often PMS-related symptoms are present for about six days. An individuals pattern of symptoms may change over time. Symptoms do not occur during pregnancy or following menopause.Diagnosis requires a consistent pattern of emotional and physical symptoms occurring after ovulation and before menstruation to a degree that interferes with normal life. Emotional symptoms must not be present during the initial part of the menstrual cycle. A daily list of symptoms over a few months may help in diagnosis. Other disorders that cause similar symptoms need to be excluded before a diagnosis is made.The cause of PMS is unknown, but the underlying mechanism is believed to involve changes in hormone levels. Reducing salt, alcohol, caffeine, and stress along with increasing exercise is typically all that is recommended in those with mild symptoms. Calcium and vitamin D supplementation may be useful in some. Anti-inflammatory drugs such as ibuprofen or naproxen may help with physical symptoms. In those with more significant symptoms birth control pills or the diuretic spironolactone may be useful.Up to 80% of women report having some symptoms after ovulation and before the beginning of menstruation, but these symptoms generally do not cause substantial disruption. These symptoms qualify as PMS in approximately 20 to 30% of pre-menopausal women. Premenstrual dysphoric disorder (PMDD) is a more severe form of PMS that has greater psychological symptoms. PMDD affects 3 to 8% of pre-menopausal individuals. Antidepressant medication of the selective serotonin reuptake inhibitors class may be used for PMDD in addition to the usual measures for PMS.
Signs and symptoms
More than 200 different symptoms have been associated with PMS. Common emotional and non-specific symptoms include stress, anxiety, difficulty with sleep, headache, feeling tired, mood swings, increased emotional sensitivity, and changes in interest in sex. Problems with concentration and memory may occur. There may also be depression or anxiety.Physical symptoms associated with the menstrual cycle – but not necessarily with PMS, which is symptoms that appear before menstruation, rather than during menstruation – include bloating, lower back pain, cramps in the pelvic area, constipation/diarrhea, swelling or tenderness in the breasts, cyclic acne (acne that appears and disappears at predictable times during the menstrual cycle), joint or muscle pain, and food cravings. The exact symptoms and their intensity vary significantly from person to person, and even somewhat from cycle to cycle and over time. Most people with premenstrual syndrome experience only a few of the possible symptoms, in a relatively predictable pattern.Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome affecting 3–8% of menstruating women.
Causes
While PMS is linked to the luteal phase, the causes of PMS are not clear, but several factors may be involved. Changes in hormones during the menstrual cycle seem to be an important factor, with changing hormone levels affecting some more than others. PMS occurs more often in those who are in their late 20s and early 40s, have at least one child, have a family history of depression, and have a past medical history of either postpartum depression or a mood disorder.
Diagnosis
There are no laboratory tests or unique physical findings to verify the diagnosis of PMS. The three key features are:
The chief complaint is one or more of the emotional symptoms associated with PMS. Irritability, tension, or unhappiness are typical emotional symptoms.
Symptoms appear predictably during the luteal (premenstrual) phase, reduce or disappear predictably shortly before or during menstruation, and remain absent during the follicular (preovulatory) phase.
The symptoms must be severe enough to interfere with the person’s everyday life.Mild PMS is common, and more severe symptoms would qualify as PMDD. PMS is not listed in the DSM-IV, unlike PMDD. To document a pattern and determine if it is PMDD, potentially affected women may keep a prospective record of their symptoms on a calendar for at least two menstrual cycles. This will help to establish if the symptoms are, indeed, limited to the premenstrual time, predictably recurring, and disruptive to normal functioning. A number of standardized instruments have been developed to describe PMS, including the Calendar of Premenstrual syndrome Experiences (COPE), the Prospective Record of the Impact and Severity of Menstruation (PRISM), and the Visual Analogue Scales (VAS).Other conditions that may better explain symptoms must be excluded. A number of medical conditions are subject to exacerbation at menstruation, a process called menstrual magnification. These conditions may lead women who do not have PMS to incorrectly believe that they have PMS, when the underlying disorder is some other medical problem, such as anemia, hypothyroidism, eating disorders and substance abuse. A key feature is that these conditions may also be present outside of the luteal phase. Conditions that can be magnified perimenstrually include depression or other affective disorders, migraine, seizure disorders, fatigue, irritable bowel syndrome, asthma, and allergies. Problems with other aspects of the female reproductive system must be excluded, including dysmenorrhea (pain during the menstrual period, rather than before it), endometriosis, perimenopause, and adverse effects produced by oral contraceptive pills.The National Institute of Mental Health research definition compares the intensity of symptoms from cycle days 5 to 10 to the six-day interval before the onset of the menstrual period. To qualify as PMS, symptom intensity must increase at least 30% in the six days before menstruation. Additionally, this pattern must be documented for at least two consecutive cycles.
Management
Many treatments have been tried in PMS. Reducing salt, caffeine, and stress along with increasing exercise is typically all that is recommended in those with mild symptoms. Calcium and vitamin D supplementation may be useful in some. Anti-inflammatories such as naproxen may help with physical symptoms. A healthy diet, reduced consumption of salt, caffeine and alcohol, and regular exercise may be effective for women in controlling water retention. In those with more significant symptoms birth control pills may be useful.Diuretics have been used to handle water retention. Spironolactone has been shown in some studies to be useful.
Antidepressants
SSRIs like fluoxetine, sertraline can be used to treat severe PMS. Those with PMS may be able to take medication only on the days when symptoms are expected to occur. Although intermittent therapy might be more acceptable to some, this might be less effective than continuous regimens. Side effect such as nausea and weakness are however relatively common.
Hormonal medications
Hormonal contraception is commonly used; common forms include the combined oral contraceptive pill and the contraceptive patch. This class of medication may cause PMS-related symptoms in some and may reduce physical symptoms in others. They do not relieve emotional symptoms.Progesterone support has been used for many years but evidence of its efficacy is inadequate.Gonadotropin-releasing hormone agonists can be useful in severe forms of PMS but have their own set of significant potential side effects.
Alternative medicine
Tentative evidence supports vitamin B6 and chasteberry. Data are insufficient to determine an effect of St. Johns wort, soy, vitamin E, and saffron. Evening primrose oil may be useful.There is tentative evidence that acupressure and acupuncture may help to reduce PMS symptoms and improve women quality of life.
Prognosis
PMS is generally a stable diagnosis, with susceptible individuals experiencing the same symptoms at the same intensity near the end of each cycle for years. Treatment for specific symptoms is usually effective.
Even without treatment, symptoms tend to decrease in perimenopausal women. However, those who experience PMS or PMDD are more likely to have significant symptoms associated with menopause, such as hot flashes.
Epidemiology
PMS, in which mild to moderate symptoms affect some facet of the persons life, occurs in about 20 to 30% of premenopausal women; the more severe symptoms of PMDD affect 3 to 8% of premenopausal women.Among females of reproductive age living in India, the prevalence of PMS is 43%; the prevalence among adolescents is even higher.
History
PMS was originally seen as an imagined disease. Women who reported its symptoms were often told it was "all in their head". Womans reproductive organs were thought to have complete control over them. Women were warned not to divert needed energy away from the uterus and ovaries. This view of limited energy very quickly ran up against a reality in 19th century America that young girls worked extremely long and hard hours in factories; newspapers in the 19th century were peppered with remedies to help in the "tyrannous processes" of the menstrual cycle. In 1873 Edward Clarke published an influential book titled Sex in Education. Clarke came to the conclusion that female operatives suffer less than schoolgirls because they "work their brain less". This suggested that they have stronger bodies and a reproductive "apparatus more normally constructed". Feminists later took opposition to Clarkes argument that women should not leave the private sphere by showing that women could function in the world outside the home in spite of natural body functions.The formal medical description of premenstrual syndrome (PMS) and the more severe, related diagnosis of premenstrual dysphoric disorder (PMDD) goes back at least 70 years to a paper presented at the New York Academy of Medicine by Robert T. Frank titled "Hormonal Causes of Premenstrual Tension". The specific term premenstrual syndrome appears to date from an article published in 1953 by Dalton and Greene in the British Medical Journal. Since then, PMS has been a continuous presence in popular culture, occupying a place that is larger than the research attention accorded it as a medical diagnosis. Some have argued that women are partially responsible for the medicalization of PMS. They claim that women are partially responsible for legitimizing this disorder and have thus contributed to the social construction of PMS as an illness. It has also been suggested that the public debate over PMS and PMDD was impacted by organizations who had a stake in the outcome including feminists, the American Psychiatric Association, physicians and scientists. Until the 1950s, there was little research done surrounding PMS and it was not seen as a social problem. By the 1980s, however, viewing PMS in a social context had begun to take place.
Alternative views
Some supporters of PMS as a social construct believe PMDD and PMS to be unrelated issues: according to them, PMDD is a product of brain chemistry, and PMS is a product of a hypochondriatic culture, i.e. a culture-bound syndrome. Most studies on PMS and PMDD rely solely on self-reporting. According to sociologist Carol Tavris, Western women are socially conditioned to expect PMS or to at least know of its existence, and they, therefore, report their symptoms accordingly. The anthropologist Emily Martin argues that PMS is a cultural phenomenon that continues to grow in a positive feedback loop, and thus is a social construction that contributes to learned helplessness or convenient excuse. Tavris says that PMS is blamed as an explanation for rage or sadness. The decision to call PMDD an illness has been criticized as inappropriate medicalization. In both cases, they are referring to the emotional aspects, not the normal physical symptoms that are present.
See also
Menstrual leave
References
External links
U.S. Department of Health & Human Services
Direct Online Health Encyclopaedia: Premenstrual syndrome (UK) at NHS
"Premenstrual Syndrome (PMS) (Premenstrual Tension)" at Merck Manual |
Primary biliary cholangitis | Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Further slow damage to the liver tissue can lead to scarring, fibrosis, and eventually cirrhosis.
Common symptoms are tiredness, itching, and in more advanced cases, jaundice. In early cases, the only changes may be those seen in blood tests.PBC is a relatively rare disease, affecting up to one in 3,000–4,000 people. It is much more common in women, with a sex ratio of at least 9:1 female to male.The condition has been recognised since at least 1851, and was named "primary biliary cirrhosis" in 1949. Because cirrhosis is a feature only of advanced disease, a change of its name to "primary biliary cholangitis" was proposed by patient advocacy groups in 2014.
Signs and symptoms
People with PBC experience fatigue (80%); this is a nonspecific symptom and can be debilitating, with a huge impact on quality of life. Its pathogenesis is still unknown, and is quite challenging to explore its specificity and to treat. Comorbidities that could contribute or worsen fatigue, such as depression, hypothyroidism, anaemia, obesity, or medication side effects, should be promptly identified and treated. Dry skin and dry eyes are also common. Itching (pruritus) occurs in 20–70% of cases, and can develop at any stage of the disease; it does not correlate with progression of liver disease, and may even improve or disappear as the disease advances. It is typically mild-to-moderate in intensity. Given the impact on quality of life and night sleep, pruritus is correlated with fatigue. It can rarely be severe, nonresponsive to medical therapy, and requiring liver transplant. Pruritus is characteristically intermittent, worse at night, and improves during summer.
People with more severe PBC may have jaundice (yellowing of the eyes and skin). PBC impairs bone density and the risk of fracture increases. Xanthelasma (skin lesions around the eyes) or other xanthoma may be present as a result of increased cholesterol levels.PBC can eventually progress to cirrhosis of the liver. This, in turn, may lead to a number of symptoms or complications, including:
Fluid retention in the abdomen (ascites) in more advanced disease
Enlarged spleen in more advanced disease
Oesophageal varices in more advanced disease
Hepatic encephalopathy, including coma in extreme cases in more advanced disease.People with PBC may also sometimes have the findings of an associated extrahepatic autoimmune disorder such as thyroid disease or rheumatoid arthritis or Sjögrens syndrome (in up to 80% of cases).
Causes
PBC has an immunological basis, and is classified as an autoimmune disorder. It results from a slow, progressive destruction of the small bile ducts of the liver, with the intralobular ducts and the canals of Hering (intrahepatic ductules) being affected early in the disease.
Most people with PBC (more than 90%) have antimitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex found in the mitochondria. People who are negative for AMAs are usually found to be positive when more sensitive methods of detection are used.People with PBC may also have been diagnosed with another autoimmune disease, such as a rheumatological, endocrinological, gastrointestinal, pulmonary, or dermatological condition, suggesting shared genetic and immune abnormalities.
Common associations include Sjögrens syndrome, systemic sclerosis, rheumatoid arthritis, lupus, hypothyroidism, and coeliac disease.A genetic predisposition to disease has been thought to be important for some time. Evidence for this includes cases of PBC in family members, identical twins both having the condition (concordance), and clustering of PBC with other autoimmune diseases. In 2009, a Canadian-led group of investigators reported in the New England Journal of Medicine results from the first PBC genome-wide association study. This research revealed parts of the IL12 signaling cascade, particularly IL12A and IL12RB2 polymorphisms, to be important in the aetiology of the disease in addition to the HLA region. In 2012, two independent PBC association studies increased the total number of genomic regions associated to 26, implicating many genes involved in cytokine regulation such as TYK2, SH2B3 and TNFSF11.A study of over 2,000 patients identified a gene, POGLUT1, that appeared to be associated with this condition. Earlier studies have also suggested that this gene may be involved. The implicated protein is an endoplasmic reticulum O-glucosyltransferase.
An environmental Gram-negative Alphaproteobacterium — Novosphingobium aromaticivorans has been associated with this disease, with several reports suggesting an aetiological role for this organism. The mechanism appears to be a cross-reaction between the proteins of the bacterium and the mitochondrial proteins of the liver cells. The gene encoding CD101 may also play a role in host susceptibility to this disease.A failure of immune tolerance against the mitochondrial pyruvate dehydrogenase complex (PDC-E2) is a primary cause, with shedding of the antigen into apoptotic bodies or "apotopes" leading to the anatomic localization. Such autoreactivity may also be the case with other proteins, including the gp210 and p62 nuclear pore proteins. Gp210 has increased expression in the bile duct of anti-gp210 positive patients, and these proteins may be associated with prognosis.
Diagnosis
Most patients are currently diagnosed when asymptomatic, having been referred to the hepatologist for abnormal liver function tests (mostly raised GGT or alkaline phosphatase) performed for annual screening blood tests. Other frequent scenarios include screening of patients with nonliver autoimmune diseases, e.g. rheumatoid arthritis, or investigation of elevated cholesterol, evaluation of itch or unresolved cholestasis post partum. Diagnosing PBC is generally straightforward. The basis for a definite diagnosis are:
Abnormalities in liver enzyme tests are usually present and elevated gamma-glutamyl transferase and alkaline phosphatase are found in early disease. Elevations in bilirubin occur in advanced disease.
Antimitochondrial antibodies are the characteristic serological marker for PBC, being found in 90–95% of patients and only 1% of controls. PBC patients have AMA against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in the mitochondria. Those people who are AMA negative but with disease similar to PBC have been found to have AMAs when more sensitive detection methods are employed.
Other auto-antibodies may be present:Antinuclear antibody measurements are not diagnostic for PBC because they are not specific, but may have a role in prognosis.
Anti-glycoprotein-210 antibodies, and to a lesser degree anti-p62 antibodies, correlate with the diseases progression toward end-stage liver failure. Anti-gp210 antibodies are found in 47% of PBC patients.
Anti-centromere antibodies often correlate with developing portal hypertension.
Anti-np62 and anti-sp100 are also found in association with PBC.Abdominal ultrasound, magnetic resonance cholangiopancreatography or a CT scan is usually performed to rule out blockage to the bile ducts. This may be needed if a condition causing secondary biliary cirrhosis, such as other biliary duct disease or gallstones, needs to be excluded. A liver biopsy may help, and if uncertainty remains as in some patients, an endoscopic retrograde cholangiopancreatography, an endoscopic investigation of the bile duct, may be performed.Given the high specificity of serological markers, liver biopsy is not necessary for the diagnosis of PBC; however, it is still necessary when PBC-specific antibodies are absent, or when co-existent autoimmune hepatitis or nonalcoholic steatohepatitis is suspected. Liver biopsy can be useful to stage the disease for fibrosis and ductopenia. Finally, it may also be appropriate in the presence of other extrahepatic comorbidities.
Liver biopsy
On microscopic examination of liver biopsy specimens, PBC is characterized by chronic, nonsuppurative inflammation, which surrounds and destroys interlobular and septal bile ducts. These histopathologic findings in primary biliary cholangitis include:
Inflammation of the bile ducts, characterized by intraepithelial lymphocytes
Periductal epithelioid granulomas.
Proliferation of bile ductules
Fibrosis (scarring)The Ludwig and Scheuer scoring systems have historically been used to stratify four stages of PBC, with stage 4 indicating the presence of cirrhosis. In the new system of Nakanuma, the stage of disease is based on fibrosis, bile duct loss, and features of cholestasis, i.e. deposition of orcein-positive granules, whereas the grade of necroinflammatory activity is based on cholangitis and interface hepatitis. The accumulation of orcein-positive granules occurs evenly across the PBC liver, which means that staging using the Nakanuma system is more reliable regarding sampling variability.
Liver biopsy for the diagnosis and staging of PBC lost favour after the evidence of a patchy distribution of the duct lesions and fibrosis across the organ. The widespread availability of noninvasive measures of fibrosis means that liver biopsy for staging of PBC is somewhat obsolete.
Liver biopsy does, however, remain useful in certain settings. The main indications are to confirm the diagnosis of PBC when PBC-specific antibodies are absent and confirm a diagnosis of PBC with AIH features (i.e. overlap PBC-AIH). Liver biopsy is also useful to assess the relative contribution of each liver injury when a comorbid liver disease is present, such as non-alcoholic steatohepatitis. In patients with inadequate response to UDCA, liver biopsy may provide the explanation and could undoubtedly inform risk stratification. For example, it may identify a previously unsuspected variant syndrome, steatohepatitis, or interface hepatitis of moderate or greater severity. It is also useful in AMA and ANA-specific antibody negative cholestatic patients to indicate an alternative process, e.g. sarcoidosis, small duct PSC, adult idiopathic ductopenia.
Histopathology stages (by Ludwig and Scheuer systems)
Stage 1 – portal stage: Normal-sized triads, portal inflammation, subtle bile duct damage: Granulomas are often detected in this stage.
Stage 2 – periportal stage: Enlarged triads, periportal fibrosis and/or inflammation, typically characterized by the finding of a proliferation of small bile ducts
Stage 3 – septal stage: Active and/or passive fibrous septa
Stage 4 – biliary cirrhosis: Nodules present, garland or jigsaw puzzle pattern
Treatment
Cholestasis
Medical therapy of PBC targets disease progression and symptom control. The first-line treatment for PBC is ursodeoxycholic acid (UDCA). UDCA has been the only drug available for two decades and more recently obeticholic acid (OCA), a semi-synthetic hydrophobic bile acid analogue, has been licensed in patients failing UDCA response or intolerant to UDCA. Several other agents have been studied, including immunosuppressants, but robust evidence of benefit is lacking.UDCA improves liver enzyme levels, slows down histological progression, and improves liver transplant-free survival. UDCA also reduces the need for liver transplantation. UDCA should be taken at a dose of 13 to 15 mg per kg of body weight per day, usually in two divided doses each day. Liver chemistries usually improve within a few weeks of starting UDCA, and 90% of any benefit is observed after 6–9 months of therapy. Liver chemistries should be re-evaluated after 1 year of treatment. UDCA is usually continued lifelong. Up to 40% of people do not respond to treatment with UDCA. Patients with PBC who have an inadequate response to UDCA or those few (less than 3%) who are intolerant to UDCA are candidates for second-line therapies.
Obeticholic acid (OCA) is FDA-approved for the treatment of PBC in individuals intolerant or unresponsive to UDCA. OCA is a farnesoid X receptor agonist, and results in increased bile flow (choleresis). OCA is started at 5 mg daily, and liver chemistries should be rechecked after 3 months of treatment. If the liver chemistries remain elevated, then the dose of OCA may be increased to 10 mg per day. The most common side effect of OCA is pruritus.
Fibric acid derivatives, or fibrates, are agonists of the peroxisome proliferator activator receptor (PPAR), a nuclear receptor involved in several metabolic pathways. While fibrates are approved for the treatment of hypertriglyceridemia, they exert anticholestatic effects and have been studied for the treatment of PBC. Among the fibrates, bezafibrate and fenofibrate, PPAR-alpha selective agonists, have been extensively studied as therapeutic agents because of their potential ability to decrease bile acid synthesis and bile acid-related hepatic inflammation. A randomized, controlled trial in 2018 showed its efficacy in patients with inadequate response to UDCA. While fibrates can be considered as off-label treatment for PBC that does not respond to UDCA, they should not be used in decompensated cirrhosis.Several additional medications have been investigated as potential treatments for PBC, and found to be ineffective as single agents (monotherapy), including: chlorambucil, colchicine, cyclosporine, corticosteroids, azathioprine, malotilate, methotrexate, mycophenolate mofetil, penicillamine, and thalidomide. Budesonide may be used as an off-label treatment for PBC, although its efficacy is controversial.
Itching
Pruritus is a common symptom in people with PBC. First-line treatment of pruritus consists of anion-exchange resins, such as cholestyramine, colestipol, or colesevalam. These anion-exchange resins are nonabsorbed, highly positively charged substances that bind bile acids, which are negatively charged anions. Anion-exchange resins relieve itching caused by excess bile acids in circulation by binding bile acids in the gut and facilitating elimination. Bloating or constipation may occur with anion-exchange resins. Cholestyramine may affect absorption of UDCA; if cholestyramine is necessary, it should be taken at least 60 minutes before or 4 hours after UDCA is taken.Treatment options for pruritus that does not improve with anion-exchange resins include: rifampicin, naltrexone, or sertraline. Rifampicin may rarely cause drug induced liver injury and should be avoided if serum bilirubin is elevated (greater than 2.5 mg/dL). Liver enzymes should be monitored after starting rifampin. Rifampicin induces enzymes, resulting in numerous potential drug-drug interactions. Opioid antagonists may cause a self-limited opioid withdrawal like reaction, with abdominal pain, elevated blood pressure, tachycardia, goose bumps, nightmares, and depersonalization. To avoid such reactions, the dose should start low and gradually be increased.
Other therapies
Fatigue is a nonspecific but often-reported symptom in PBC, and represents an unmet need since no therapies are licensed. A structured approach to management, quantifying fatigue and its impacts (through the use of disease-specific tools such as the PBC-40 quality-of-life measures), addressing contributing and exacerbating factors, and supporting patients to cope with its impact is effective. Drugs such as coenzyme Q and rituximab have been shown to be ineffective. A graded programme of exercise helps some individuals.
People with PBC may have poor lipid-dependent absorption of oil-soluble vitamins (A, D, E, and K). Appropriate supplementation is recommended when bilirubin is elevated.
People with PBC are at elevated risk of developing osteoporosis as compared to the general population and others with liver disease. Screening and treatment of this complication is an important part of the management of PBC.
As in all liver diseases, consumption of alcohol should be restricted or eliminated.
In patients with advanced liver disease, the only curative therapy is liver transplant. Outcomes are favourable, with five-year patient survival rates better than for most other indications for LT (80–85%).
Prognosis
The introduction of UDCA has dramatically changed the pattern and the course of the disease. Numerous trials and observational studies have demonstrated its efficacy on liver biochemistry, histological progression, and transplant-free survival.Among the UDCA-treated patients, the degree of the liver biochemistry improvement, i.e. the UDCA-response, identifies patients with different long-term prognosis. In the absence of cirrhosis, people who experience an improvement of liver enzymes to the normal range on treatment with UDCA have excellent survival, which may be similar to the general population. Survival is significantly reduced though, in those with abnormal liver biochemistry on treatment.
The two most important parameters in evaluating response to UDCA are alkaline phosphatase and total bilirubin. Qualitative and quantitative definitions of UDCA-response have been developed, based on changes of bilirubin, transaminases and ALP, after a period of 6 to 24 months of treatment with UDCA at 13–15 mg/kg/day.Patients at diagnosis can be risk-stratified based on the probability of UDCA-response. This is relevant to identify patients who would be eligible for second-line therapies before waiting for the treatment failure under UDCA, with potential impact on disease course.Hepatocellular carcinoma (HCC) is infrequent in PBC. Recent large-scale cohort studies highlighted that the lack of UDCA-response after 12 months of therapy and male sex are associated with increased future risk of developing HCC in PBC.
After liver transplant, the recurrence of disease may be as high as 18% at five years, and up to 30% at 10 years. No consensus exists on risk factors for recurrence of the disease.
Epidemiology
Epidemiologic studies report heterogeneous incidence rates of 0.33 to 5.8 per 100,000 inhabitants per year, and prevalence rates of 1.9 to 40.2 per 100,000 inhabitants. Such figures, in particular the prevalence, have shown some increase in the last decades. Improvement of diagnostic tools, increasing disease awareness, and digitised patient registration with facilitation of case-findings, along with improved survival, likely contributed to the rising prevalence rates.
The disease has been described worldwide, though North America and Northern Europe have shown the highest incidence and prevalence rates. Whether a true variation in disease prevalence exists among populations of different geographical areas and of different ethnicity or if this is a consequence of a difference in study quality is unknown. PBC is more common in women, with a female:male ratio of at least 9:1. The peak incidence of PBC is in the fifth decade of life. In some areas of the US and UK, the prevalence is estimated to be as high as one in 4,000. This is much more common than in South America or Africa, which may be due to better recognition in the US and UK. First-degree relatives may have as much as a 500 times increase in prevalence, but if this risk is greater in the same-generation relatives or the one that follows is debated.
PBC is considered a prime example of the female preponderance in autoimmunity with a female to male ratio of up to 9:1, confirmed by large cohort studies, although some recent data, using administrative registries, suggest an increasing male prevalence. Major defects of sex chromosomes, i.e. enhanced monosomy X in female patients and an enhanced Y chromosome loss in male patients, have been described and might well explain the greater female predisposition to develop PBC.An association of a greater incidence of PBC at latitudes more distant from the Equator is similar to the pattern seen in multiple sclerosis.Typical disease onset is between 30 and 60 years, though cases have been reported of patients diagnosed at the ages of 15 and 93. Prevalence of PBC in women over the age of 45 years could exceed one in an estimated 800 individuals.
History
The first report of the disease dates back 1851 by Addison and Gull, who described a clinical picture of progressive jaundice in the absence of mechanical obstruction of the large bile ducts. Ahrens et al. in 1950 published the first detailed description of 17 patients with this condition, and coined the term "primary biliary cirrhosis". In 1959, Dame Sheila Sherlock reported a further series of PBC patients and recognised that the disease could be diagnosed in a precirrhotic stage and proposed the term "chronic intrahepatic cholestasis" as more appropriate description of this disease, but this nomenclature failed to gain acceptance, and the term "primary biliary cirrhosis" lasted for decades. In 2014, to correct the inaccuracy and remove the social stigmata of cirrhosis, as well as all the misunderstanding, disadvantages, and discrimination emanating from this misnomer in daily life for patients, international liver associations agreed to rename the disease "primary biliary cholangitis", as it is now known.
Society and culture
Support groups
PBC Foundation
The PBC Foundation is a UK-based international charity offering support and information to people with PBC and their families and friends. It campaigns for increasing recognition of the disorder, improved diagnosis, and treatments, and estimates over 8,000 people are undiagnosed in the UK. The Foundation has supported research into PBC including the development of the PBC-40 quality of life measure published in 2004 and helped establish the PBC Genetics Study. It was founded by Collette Thain in 1996, after she was diagnosed with the condition. Thain was awarded an MBE Order of the British Empire in 2004 for her work with the Foundation. The PBC Foundation helped initiate the name change campaign in 2014.
PBCers Organization
The PBCers Organization is a US-based nonprofit patient support group that was founded by Linie Moore in 1996; it advocates for greater awareness of the disease and new treatments. It supported the name change initiative.
References
External links
Primary Biliary Cirrhosis page from the National Digestive Diseases Information Clearinghouse
Alagille syndrome |
Primary biliary cholangitis | Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Further slow damage to the liver tissue can lead to scarring, fibrosis, and eventually cirrhosis.
Common symptoms are tiredness, itching, and in more advanced cases, jaundice. In early cases, the only changes may be those seen in blood tests.PBC is a relatively rare disease, affecting up to one in 3,000–4,000 people. It is much more common in women, with a sex ratio of at least 9:1 female to male.The condition has been recognised since at least 1851, and was named "primary biliary cirrhosis" in 1949. Because cirrhosis is a feature only of advanced disease, a change of its name to "primary biliary cholangitis" was proposed by patient advocacy groups in 2014.
Signs and symptoms
People with PBC experience fatigue (80%); this is a nonspecific symptom and can be debilitating, with a huge impact on quality of life. Its pathogenesis is still unknown, and is quite challenging to explore its specificity and to treat. Comorbidities that could contribute or worsen fatigue, such as depression, hypothyroidism, anaemia, obesity, or medication side effects, should be promptly identified and treated. Dry skin and dry eyes are also common. Itching (pruritus) occurs in 20–70% of cases, and can develop at any stage of the disease; it does not correlate with progression of liver disease, and may even improve or disappear as the disease advances. It is typically mild-to-moderate in intensity. Given the impact on quality of life and night sleep, pruritus is correlated with fatigue. It can rarely be severe, nonresponsive to medical therapy, and requiring liver transplant. Pruritus is characteristically intermittent, worse at night, and improves during summer.
People with more severe PBC may have jaundice (yellowing of the eyes and skin). PBC impairs bone density and the risk of fracture increases. Xanthelasma (skin lesions around the eyes) or other xanthoma may be present as a result of increased cholesterol levels.PBC can eventually progress to cirrhosis of the liver. This, in turn, may lead to a number of symptoms or complications, including:
Fluid retention in the abdomen (ascites) in more advanced disease
Enlarged spleen in more advanced disease
Oesophageal varices in more advanced disease
Hepatic encephalopathy, including coma in extreme cases in more advanced disease.People with PBC may also sometimes have the findings of an associated extrahepatic autoimmune disorder such as thyroid disease or rheumatoid arthritis or Sjögrens syndrome (in up to 80% of cases).
Causes
PBC has an immunological basis, and is classified as an autoimmune disorder. It results from a slow, progressive destruction of the small bile ducts of the liver, with the intralobular ducts and the canals of Hering (intrahepatic ductules) being affected early in the disease.
Most people with PBC (more than 90%) have antimitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex found in the mitochondria. People who are negative for AMAs are usually found to be positive when more sensitive methods of detection are used.People with PBC may also have been diagnosed with another autoimmune disease, such as a rheumatological, endocrinological, gastrointestinal, pulmonary, or dermatological condition, suggesting shared genetic and immune abnormalities.
Common associations include Sjögrens syndrome, systemic sclerosis, rheumatoid arthritis, lupus, hypothyroidism, and coeliac disease.A genetic predisposition to disease has been thought to be important for some time. Evidence for this includes cases of PBC in family members, identical twins both having the condition (concordance), and clustering of PBC with other autoimmune diseases. In 2009, a Canadian-led group of investigators reported in the New England Journal of Medicine results from the first PBC genome-wide association study. This research revealed parts of the IL12 signaling cascade, particularly IL12A and IL12RB2 polymorphisms, to be important in the aetiology of the disease in addition to the HLA region. In 2012, two independent PBC association studies increased the total number of genomic regions associated to 26, implicating many genes involved in cytokine regulation such as TYK2, SH2B3 and TNFSF11.A study of over 2,000 patients identified a gene, POGLUT1, that appeared to be associated with this condition. Earlier studies have also suggested that this gene may be involved. The implicated protein is an endoplasmic reticulum O-glucosyltransferase.
An environmental Gram-negative Alphaproteobacterium — Novosphingobium aromaticivorans has been associated with this disease, with several reports suggesting an aetiological role for this organism. The mechanism appears to be a cross-reaction between the proteins of the bacterium and the mitochondrial proteins of the liver cells. The gene encoding CD101 may also play a role in host susceptibility to this disease.A failure of immune tolerance against the mitochondrial pyruvate dehydrogenase complex (PDC-E2) is a primary cause, with shedding of the antigen into apoptotic bodies or "apotopes" leading to the anatomic localization. Such autoreactivity may also be the case with other proteins, including the gp210 and p62 nuclear pore proteins. Gp210 has increased expression in the bile duct of anti-gp210 positive patients, and these proteins may be associated with prognosis.
Diagnosis
Most patients are currently diagnosed when asymptomatic, having been referred to the hepatologist for abnormal liver function tests (mostly raised GGT or alkaline phosphatase) performed for annual screening blood tests. Other frequent scenarios include screening of patients with nonliver autoimmune diseases, e.g. rheumatoid arthritis, or investigation of elevated cholesterol, evaluation of itch or unresolved cholestasis post partum. Diagnosing PBC is generally straightforward. The basis for a definite diagnosis are:
Abnormalities in liver enzyme tests are usually present and elevated gamma-glutamyl transferase and alkaline phosphatase are found in early disease. Elevations in bilirubin occur in advanced disease.
Antimitochondrial antibodies are the characteristic serological marker for PBC, being found in 90–95% of patients and only 1% of controls. PBC patients have AMA against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in the mitochondria. Those people who are AMA negative but with disease similar to PBC have been found to have AMAs when more sensitive detection methods are employed.
Other auto-antibodies may be present:Antinuclear antibody measurements are not diagnostic for PBC because they are not specific, but may have a role in prognosis.
Anti-glycoprotein-210 antibodies, and to a lesser degree anti-p62 antibodies, correlate with the diseases progression toward end-stage liver failure. Anti-gp210 antibodies are found in 47% of PBC patients.
Anti-centromere antibodies often correlate with developing portal hypertension.
Anti-np62 and anti-sp100 are also found in association with PBC.Abdominal ultrasound, magnetic resonance cholangiopancreatography or a CT scan is usually performed to rule out blockage to the bile ducts. This may be needed if a condition causing secondary biliary cirrhosis, such as other biliary duct disease or gallstones, needs to be excluded. A liver biopsy may help, and if uncertainty remains as in some patients, an endoscopic retrograde cholangiopancreatography, an endoscopic investigation of the bile duct, may be performed.Given the high specificity of serological markers, liver biopsy is not necessary for the diagnosis of PBC; however, it is still necessary when PBC-specific antibodies are absent, or when co-existent autoimmune hepatitis or nonalcoholic steatohepatitis is suspected. Liver biopsy can be useful to stage the disease for fibrosis and ductopenia. Finally, it may also be appropriate in the presence of other extrahepatic comorbidities.
Liver biopsy
On microscopic examination of liver biopsy specimens, PBC is characterized by chronic, nonsuppurative inflammation, which surrounds and destroys interlobular and septal bile ducts. These histopathologic findings in primary biliary cholangitis include:
Inflammation of the bile ducts, characterized by intraepithelial lymphocytes
Periductal epithelioid granulomas.
Proliferation of bile ductules
Fibrosis (scarring)The Ludwig and Scheuer scoring systems have historically been used to stratify four stages of PBC, with stage 4 indicating the presence of cirrhosis. In the new system of Nakanuma, the stage of disease is based on fibrosis, bile duct loss, and features of cholestasis, i.e. deposition of orcein-positive granules, whereas the grade of necroinflammatory activity is based on cholangitis and interface hepatitis. The accumulation of orcein-positive granules occurs evenly across the PBC liver, which means that staging using the Nakanuma system is more reliable regarding sampling variability.
Liver biopsy for the diagnosis and staging of PBC lost favour after the evidence of a patchy distribution of the duct lesions and fibrosis across the organ. The widespread availability of noninvasive measures of fibrosis means that liver biopsy for staging of PBC is somewhat obsolete.
Liver biopsy does, however, remain useful in certain settings. The main indications are to confirm the diagnosis of PBC when PBC-specific antibodies are absent and confirm a diagnosis of PBC with AIH features (i.e. overlap PBC-AIH). Liver biopsy is also useful to assess the relative contribution of each liver injury when a comorbid liver disease is present, such as non-alcoholic steatohepatitis. In patients with inadequate response to UDCA, liver biopsy may provide the explanation and could undoubtedly inform risk stratification. For example, it may identify a previously unsuspected variant syndrome, steatohepatitis, or interface hepatitis of moderate or greater severity. It is also useful in AMA and ANA-specific antibody negative cholestatic patients to indicate an alternative process, e.g. sarcoidosis, small duct PSC, adult idiopathic ductopenia.
Histopathology stages (by Ludwig and Scheuer systems)
Stage 1 – portal stage: Normal-sized triads, portal inflammation, subtle bile duct damage: Granulomas are often detected in this stage.
Stage 2 – periportal stage: Enlarged triads, periportal fibrosis and/or inflammation, typically characterized by the finding of a proliferation of small bile ducts
Stage 3 – septal stage: Active and/or passive fibrous septa
Stage 4 – biliary cirrhosis: Nodules present, garland or jigsaw puzzle pattern
Treatment
Cholestasis
Medical therapy of PBC targets disease progression and symptom control. The first-line treatment for PBC is ursodeoxycholic acid (UDCA). UDCA has been the only drug available for two decades and more recently obeticholic acid (OCA), a semi-synthetic hydrophobic bile acid analogue, has been licensed in patients failing UDCA response or intolerant to UDCA. Several other agents have been studied, including immunosuppressants, but robust evidence of benefit is lacking.UDCA improves liver enzyme levels, slows down histological progression, and improves liver transplant-free survival. UDCA also reduces the need for liver transplantation. UDCA should be taken at a dose of 13 to 15 mg per kg of body weight per day, usually in two divided doses each day. Liver chemistries usually improve within a few weeks of starting UDCA, and 90% of any benefit is observed after 6–9 months of therapy. Liver chemistries should be re-evaluated after 1 year of treatment. UDCA is usually continued lifelong. Up to 40% of people do not respond to treatment with UDCA. Patients with PBC who have an inadequate response to UDCA or those few (less than 3%) who are intolerant to UDCA are candidates for second-line therapies.
Obeticholic acid (OCA) is FDA-approved for the treatment of PBC in individuals intolerant or unresponsive to UDCA. OCA is a farnesoid X receptor agonist, and results in increased bile flow (choleresis). OCA is started at 5 mg daily, and liver chemistries should be rechecked after 3 months of treatment. If the liver chemistries remain elevated, then the dose of OCA may be increased to 10 mg per day. The most common side effect of OCA is pruritus.
Fibric acid derivatives, or fibrates, are agonists of the peroxisome proliferator activator receptor (PPAR), a nuclear receptor involved in several metabolic pathways. While fibrates are approved for the treatment of hypertriglyceridemia, they exert anticholestatic effects and have been studied for the treatment of PBC. Among the fibrates, bezafibrate and fenofibrate, PPAR-alpha selective agonists, have been extensively studied as therapeutic agents because of their potential ability to decrease bile acid synthesis and bile acid-related hepatic inflammation. A randomized, controlled trial in 2018 showed its efficacy in patients with inadequate response to UDCA. While fibrates can be considered as off-label treatment for PBC that does not respond to UDCA, they should not be used in decompensated cirrhosis.Several additional medications have been investigated as potential treatments for PBC, and found to be ineffective as single agents (monotherapy), including: chlorambucil, colchicine, cyclosporine, corticosteroids, azathioprine, malotilate, methotrexate, mycophenolate mofetil, penicillamine, and thalidomide. Budesonide may be used as an off-label treatment for PBC, although its efficacy is controversial.
Itching
Pruritus is a common symptom in people with PBC. First-line treatment of pruritus consists of anion-exchange resins, such as cholestyramine, colestipol, or colesevalam. These anion-exchange resins are nonabsorbed, highly positively charged substances that bind bile acids, which are negatively charged anions. Anion-exchange resins relieve itching caused by excess bile acids in circulation by binding bile acids in the gut and facilitating elimination. Bloating or constipation may occur with anion-exchange resins. Cholestyramine may affect absorption of UDCA; if cholestyramine is necessary, it should be taken at least 60 minutes before or 4 hours after UDCA is taken.Treatment options for pruritus that does not improve with anion-exchange resins include: rifampicin, naltrexone, or sertraline. Rifampicin may rarely cause drug induced liver injury and should be avoided if serum bilirubin is elevated (greater than 2.5 mg/dL). Liver enzymes should be monitored after starting rifampin. Rifampicin induces enzymes, resulting in numerous potential drug-drug interactions. Opioid antagonists may cause a self-limited opioid withdrawal like reaction, with abdominal pain, elevated blood pressure, tachycardia, goose bumps, nightmares, and depersonalization. To avoid such reactions, the dose should start low and gradually be increased.
Other therapies
Fatigue is a nonspecific but often-reported symptom in PBC, and represents an unmet need since no therapies are licensed. A structured approach to management, quantifying fatigue and its impacts (through the use of disease-specific tools such as the PBC-40 quality-of-life measures), addressing contributing and exacerbating factors, and supporting patients to cope with its impact is effective. Drugs such as coenzyme Q and rituximab have been shown to be ineffective. A graded programme of exercise helps some individuals.
People with PBC may have poor lipid-dependent absorption of oil-soluble vitamins (A, D, E, and K). Appropriate supplementation is recommended when bilirubin is elevated.
People with PBC are at elevated risk of developing osteoporosis as compared to the general population and others with liver disease. Screening and treatment of this complication is an important part of the management of PBC.
As in all liver diseases, consumption of alcohol should be restricted or eliminated.
In patients with advanced liver disease, the only curative therapy is liver transplant. Outcomes are favourable, with five-year patient survival rates better than for most other indications for LT (80–85%).
Prognosis
The introduction of UDCA has dramatically changed the pattern and the course of the disease. Numerous trials and observational studies have demonstrated its efficacy on liver biochemistry, histological progression, and transplant-free survival.Among the UDCA-treated patients, the degree of the liver biochemistry improvement, i.e. the UDCA-response, identifies patients with different long-term prognosis. In the absence of cirrhosis, people who experience an improvement of liver enzymes to the normal range on treatment with UDCA have excellent survival, which may be similar to the general population. Survival is significantly reduced though, in those with abnormal liver biochemistry on treatment.
The two most important parameters in evaluating response to UDCA are alkaline phosphatase and total bilirubin. Qualitative and quantitative definitions of UDCA-response have been developed, based on changes of bilirubin, transaminases and ALP, after a period of 6 to 24 months of treatment with UDCA at 13–15 mg/kg/day.Patients at diagnosis can be risk-stratified based on the probability of UDCA-response. This is relevant to identify patients who would be eligible for second-line therapies before waiting for the treatment failure under UDCA, with potential impact on disease course.Hepatocellular carcinoma (HCC) is infrequent in PBC. Recent large-scale cohort studies highlighted that the lack of UDCA-response after 12 months of therapy and male sex are associated with increased future risk of developing HCC in PBC.
After liver transplant, the recurrence of disease may be as high as 18% at five years, and up to 30% at 10 years. No consensus exists on risk factors for recurrence of the disease.
Epidemiology
Epidemiologic studies report heterogeneous incidence rates of 0.33 to 5.8 per 100,000 inhabitants per year, and prevalence rates of 1.9 to 40.2 per 100,000 inhabitants. Such figures, in particular the prevalence, have shown some increase in the last decades. Improvement of diagnostic tools, increasing disease awareness, and digitised patient registration with facilitation of case-findings, along with improved survival, likely contributed to the rising prevalence rates.
The disease has been described worldwide, though North America and Northern Europe have shown the highest incidence and prevalence rates. Whether a true variation in disease prevalence exists among populations of different geographical areas and of different ethnicity or if this is a consequence of a difference in study quality is unknown. PBC is more common in women, with a female:male ratio of at least 9:1. The peak incidence of PBC is in the fifth decade of life. In some areas of the US and UK, the prevalence is estimated to be as high as one in 4,000. This is much more common than in South America or Africa, which may be due to better recognition in the US and UK. First-degree relatives may have as much as a 500 times increase in prevalence, but if this risk is greater in the same-generation relatives or the one that follows is debated.
PBC is considered a prime example of the female preponderance in autoimmunity with a female to male ratio of up to 9:1, confirmed by large cohort studies, although some recent data, using administrative registries, suggest an increasing male prevalence. Major defects of sex chromosomes, i.e. enhanced monosomy X in female patients and an enhanced Y chromosome loss in male patients, have been described and might well explain the greater female predisposition to develop PBC.An association of a greater incidence of PBC at latitudes more distant from the Equator is similar to the pattern seen in multiple sclerosis.Typical disease onset is between 30 and 60 years, though cases have been reported of patients diagnosed at the ages of 15 and 93. Prevalence of PBC in women over the age of 45 years could exceed one in an estimated 800 individuals.
History
The first report of the disease dates back 1851 by Addison and Gull, who described a clinical picture of progressive jaundice in the absence of mechanical obstruction of the large bile ducts. Ahrens et al. in 1950 published the first detailed description of 17 patients with this condition, and coined the term "primary biliary cirrhosis". In 1959, Dame Sheila Sherlock reported a further series of PBC patients and recognised that the disease could be diagnosed in a precirrhotic stage and proposed the term "chronic intrahepatic cholestasis" as more appropriate description of this disease, but this nomenclature failed to gain acceptance, and the term "primary biliary cirrhosis" lasted for decades. In 2014, to correct the inaccuracy and remove the social stigmata of cirrhosis, as well as all the misunderstanding, disadvantages, and discrimination emanating from this misnomer in daily life for patients, international liver associations agreed to rename the disease "primary biliary cholangitis", as it is now known.
Society and culture
Support groups
PBC Foundation
The PBC Foundation is a UK-based international charity offering support and information to people with PBC and their families and friends. It campaigns for increasing recognition of the disorder, improved diagnosis, and treatments, and estimates over 8,000 people are undiagnosed in the UK. The Foundation has supported research into PBC including the development of the PBC-40 quality of life measure published in 2004 and helped establish the PBC Genetics Study. It was founded by Collette Thain in 1996, after she was diagnosed with the condition. Thain was awarded an MBE Order of the British Empire in 2004 for her work with the Foundation. The PBC Foundation helped initiate the name change campaign in 2014.
PBCers Organization
The PBCers Organization is a US-based nonprofit patient support group that was founded by Linie Moore in 1996; it advocates for greater awareness of the disease and new treatments. It supported the name change initiative.
References
External links
Primary Biliary Cirrhosis page from the National Digestive Diseases Information Clearinghouse
Alagille syndrome |
CD30+ cutaneous T-cell lymphoma | CD30+ cutaneous T-cell lymphoma, also known as primary cutaneous anaplastic large cell lymphoma, is a cutaneous (skin) condition characterized by solitary or localized skin lesions that have a tendency to ulcerate.: 738
See also
Cutaneous T-cell lymphoma
Secondary cutaneous CD30+ large cell lymphoma
List of cutaneous conditions
References
== External links == |
Proctitis | Proctitis is an inflammation of the anus and the lining of the rectum, affecting only the last 6 inches of the rectum.
Signs and symptoms
A common symptom is a continual urge to have a bowel movement—the rectum could feel full or have constipation. Another is tenderness and mild irritation in the rectum and anal region. A serious symptom is pus and blood in the discharge, accompanied by cramps and pain during the bowel movement. If there is severe bleeding, anemia can result, showing symptoms such as pale skin, irritability, weakness, dizziness, brittle nails, and shortness of breath.Symptoms are ineffectual straining to empty the bowels, diarrhea, rectal bleeding and possible discharge, a feeling of not having adequately emptied the bowels, involuntary spasms and cramping during bowel movements, left-sided abdominal pain, passage of mucus through the rectum, and anorectal pain.
Sexually transmitted proctitis
Gonorrhea (Gonococcal proctitis)
This is the most common cause. Strongly associated with anal intercourse. Symptoms include soreness, itching, bloody or pus-like discharge, or diarrhea. Other rectal problems that may be present are anal warts, anal tears, fistulas, and hemorrhoids.Chlamydia (chlamydia proctitis)
Accounts for twenty percent of cases. People may show no symptoms, mild symptoms, or severe symptoms. Mild symptoms include rectal pain with bowel movements, rectal discharge, and cramping. With severe cases, people may have discharge containing blood or pus, severe rectal pain, and diarrhea. Some people have rectal strictures, a narrowing of the rectal passageway. The narrowing of the passageway may cause constipation, straining, and thin stools.Herpes Simplex Virus 1 and 2 (herpes proctitis)
Symptoms may include multiple vesicles that rupture to form ulcers, tenesmus, rectal pain, discharge, hematochezia. The disease may run its natural course of exacerbations and remissions but is usually more prolonged and severe in patients with immunodeficiency disorders. Presentations may resemble dermatitis or decubitus ulcers in debilitated, bedridden patients. A secondary bacterial infection may be present.Syphilis (syphilitic proctitis)
The symptoms are similar to other causes of infectious proctitis; rectal pain, discharge, and spasms during bowel movements, but some people may have no symptoms. Syphilis occurs in three stages.
The primary stage: One painless sore, less than an inch across, with raised borders found at the site of sexual contact, and during acute stages of infection, the lymph nodes in the groin become diseased, firm, and rubbery.
The secondary stage: A contagious diffuse rash that may appear over the entire body, particularly on the hands and feet.
The third stage: Occurs late in the course of syphilis and affects mostly the heart and nervous system.
Causes
Proctitis has many possible causes. It may occur idiopathically (idiopathic proctitis, that is, arising spontaneously or from an unknown cause). Other causes include damage by irradiation (for example in radiation therapy for cervical cancer and prostate cancer) or as a sexually transmitted infection, as in lymphogranuloma venereum and herpes proctitis. Studies suggest a celiac disease-associated "proctitis" can result from an intolerance to gluten.
A common cause is engaging in anal sex with partner(s) infected with sexual transmitted diseases in men who have sex with men. Shared enema usage has been shown to facilitate the spread of Lymphogranuloma venereum proctitis.
Diagnosis
Doctors can diagnose proctitis by looking inside the rectum with a proctoscope or a sigmoidoscope. A biopsy is taken, in which the doctor scrapes a tiny piece of tissue from the rectum, and this tissue is then examined by microscopy. The physician may also take a stool sample to test for infections or bacteria. If the physician suspects that the patient has Crohns disease or ulcerative colitis, colonoscopy or barium enema X-rays are used to examine areas of the intestine.
Treatment
Treatment for proctitis varies depending on severity and the cause. For example, the physician may prescribe antibiotics for proctitis caused by bacterial infection. If the proctitis is caused by Crohns disease or ulcerative colitis, the physician may prescribe the drug 5-aminosalicyclic acid (5ASA) or corticosteroids applied directly to the area in enema or suppository form, or taken orally in pill form. Enema and suppository applications are usually more effective, but some patients may require a combination of oral and rectal applications.
Another treatment available is that of fiber supplements such as Metamucil. Taken daily these may restore regularity and reduce pain associated with proctitis.
Chronic radiation proctitis is usually treated first-line with sucralfate enemas. These are non-invasive and are effective in diffuse, distal disease. Other treatments may include mesalamine suppositories, vitamin E, hyperbaric oxygen, or short chain fatty acid enemas; however these treatments are only supported by observational or anecdotal evidence.
See also
Paraproctitis
References
External links
eMedicine |
Prostatitis | Prostatitis is inflammation of the prostate gland. Prostatitis is classified into acute, chronic, asymptomatic inflammatory prostatitis, and chronic pelvic pain syndrome.
In the United States, prostatitis is diagnosed in 8% of all male urologist visits and 1% of all primary care physician visits for male genitourinary symptoms.
Classification
The term prostatitis refers to inflammation of the tissue of the prostate gland. It may occur as an appropriate physiological response to an infection, or it may occur in the absence of infection.In 1999, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) devised a new classification system. For more specifics about each type of prostatitis, including information on symptoms, treatment, and prognosis, follow the links to the relevant full articles.
In 1968, Meares and Stamey determined a classification technique based upon the culturing of bacteria. This classification is no longer used.
The conditions are distinguished by the different presentation of pain, white blood cells (WBCs) in the urine, duration of symptoms and bacteria cultured from the urine. To help express prostatic secretions that may contain WBCs and bacteria, prostate massage is sometimes used.
See also
Interstitial cystitis — a related disease
Granulomatous prostatitis
IgG4-related prostatitis
Male accessory gland infection (MAGI)
References
External links
Prostatitis Self Assessment Calculator |
Pruritus ani | Pruritus ani is the irritation of the skin at the exit of the rectum, known as the anus, causing the desire to scratch. The intensity of anal itching increases from moisture, pressure, and rubbing caused by clothing and sitting. At worst, anal itching causes intolerable discomfort that often is accompanied by burning and soreness. It is estimated that up to 5% of the population of the United States experiences this type of discomfort daily.
Causes
If a specific cause for pruritus ani is found it is classified as "secondary pruritus ani". If a specific cause is not found it is classified as "idiopathic pruritus ani". The irritation can be caused by intestinal parasites, anal perspiration, frequent liquid stools, diarrhea, residual stool deposits, or the escape of small amounts of stool as a result of incontinence or flatulence. Another cause is yeast infection or candidiasis. Some diseases increase the possibility of yeast infections, such as diabetes mellitus or HIV infection. Treatment with antibiotics can bring about a disturbance of the natural balance of intestinal flora, and lead to perianal thrush, a yeast infection affecting the anus. Psoriasis also can be present in the anal area and cause irritation. Abnormal passageways (fistulas) from the small intestine or colon to the skin surrounding the anus can form as a result of disease (such as Crohns disease), acting as channels which may allow leakage of irritating fluids to the anal area. Other problems that can contribute to anal itching include pinworms, hemorrhoids, tears of the anal skin near the mucocutaneous junction (fissures), and skin tags (abnormal local growth of anal skin). Aside from diseases relative to the condition, a common view suggests that the initial cause of the itch may have passed, and that the illness is in fact prolonged by what is known as an itch-scratch-itch cycle. It states that scratching the itch encourages the release of inflammatory chemicals, which worsen redness, intensifies itchiness and increases the area covered by dry skin, thereby causing a snowball effect.
Some authorities describe “psychogenic pruritus” or "functional itch disorder", where psychological factors may contribute to awareness of itching.
Ingestion of pinworm eggs leads to enterobiasis, indicative of severe itching around the anus from migration of gravid females from the bowel. Severe cases of enterobiasis result in hemorrhage and eczema.
Diagnosis
Diagnosis is usually done with a careful examination of the anus and the patients history. If the presentation or physical findings are atypical, biopsies can be done.In case of long-lasting symptoms, above all in patients over 50 years of age, a colonoscopy is useful to rule out a colonic polyp or tumor, that can show pruritus ani as first symptom.
Treatment
The goal of treatment is asymptomatic, intact, dry, clean perianal skin with reversal of morphological changes. For pruritus ani of unknown cause (idiopathic pruritus ani) treatment typically begins with measures to reduce irritation and trauma to the perianal area. Stool softeners can help prevent constipation. If this is not effective topical steroids or injected methylene blue may be tried. Another treatment option that has been met with success in small-scale trials is the application of a very mild (.006) topical capsaicin cream. This strength cream is not typically commercially available and therefore must be diluted by a pharmacist or end-user. If the itchiness is secondary to another condition such as infection or psoriasis these are typically treated.A successful treatment option for chronic idiopathic pruritus ani has been documented using a clean, dry and apply (if necessary) method. The person is instructed to follow this procedure every time the urge to scratch occurs. The treatment makes the assumption that there is an unidentified bacteria in the feces that causes irritation and itching when the feces makes contact with the anal and perianal skin during defecation, flatulation or anal leakage (particularly during sleep).
Cleaning the area with warm water, avoiding all soaps and even baby wipes, then drying the area, ideally with a hair dryer to avoid irritation or failing that simply patting gently with a clean, dry, towel. If persons with pruritus ani do not need to scratch after these steps they are instructed to do nothing else. If the urge to scratch is still present they are instructed to apply a topical steroid cream which has antibiotic and antifungal properties. This will address a skin condition which may have become infected. Apply such a cream as directed by your medical professional but usually twice a day for one to two weeks. After this, they must maintain their clean and dry regime and apply an emollient ointment (not cream) to moisturize the skin. This should be applied after each bowel movement and at night. Continue until no longer needed. At any time, persons may use antihistamine treatments orally, to control the itching.
See also
Pruritus scroti
Pruritus vulvae
Perianal candidiasis
References
External links
Siddiqi S, Vijay V, Ward M, Mahendran R, Warren S (September 2008). "Pruritus ani". Annals of the Royal College of Surgeons of England. 90 (6): 457–463. doi:10.1308/003588408X317940. PMC 2647235. PMID 18765023. |
Pseudobulbar affect | Pseudobulbar affect (PBA), or emotional incontinence, is a type of emotional disturbance characterized by uncontrollable episodes of crying, laughing, anger or other emotional displays. PBA occurs secondary to a neurologic disorder or brain injury. Patients may find themselves crying uncontrollably at something that is only moderately sad, being unable to stop themselves for several minutes. Episodes may also be mood-incongruent: a patient may laugh uncontrollably when angry or frustrated, for example. Sometimes, the episodes may switch between emotional states, resulting in the patient crying uncontrollably before dissolving into fits of laughter.
The pseudobulbar affect, also referred to as emotional lability, should not be confused with labile mood or labile emotions that stem from emotional instability – affective dysregulation – commonly seen in mental illnesses and certain personality disorders.
Signs and symptoms
The cardinal feature of the disorder is a pathologically lowered threshold for exhibiting the behavioral response of laughter, crying, anger or all of the above. An affected individual exhibits episodes of laughter, crying, anger or a combination of these without an apparent motivating stimulus or in response to stimuli that would not have elicited such an emotional response before the onset of their underlying neurologic disorder. In some patients, the emotional response is exaggerated in intensity but is provoked by a stimulus with an emotional valence congruent with the character of the emotional display. For example, a sad stimulus provokes a pathologically exaggerated weeping response instead of a sigh, which the patient normally would have exhibited in that particular instance.
However, in some other patients, the character of the emotional display can be incongruent with, and even contradictory to, the emotional valence of the provoking stimulus or may be incited by a stimulus with no clear valence. For example, a patient may laugh in response to sad news or cry in response to stimuli with no emotional undertone, or, once provoked, the episodes may switch from laughing to crying or vice versa.The symptoms of PBA can be severe, with persistent and unremitting episodes. Characteristics include:
The onset can be sudden and unpredictable, and has been described by some patients as coming on like a seizure;
The outbursts have a typical duration of a few seconds to several minutes; and,
The outbursts may happen several times a day.Many people with neurologic disorders exhibit uncontrollable episodes of laughing, crying, or anger that are either exaggerated or contradictory to the context in which they occur. Where patients have significant cognitive deficits (e.g., Alzheimers) it can be unclear whether it is true PBA as opposed to a grosser form of emotional dysregulation, but patients with intact cognition often report the symptom as disturbing. Patients report that their episodes are at best only partially amenable to voluntary control, and unless they experience a severe change of mental status, as in traumatic brain injury they often have insight into their problem and judge their emotional displays as inappropriate and out of character. The clinical effect of PBA can be severe, with unremitting and persistent symptoms that can be disabling to patients, and may significantly affect quality of life for caregivers.
Social impact
While not as profoundly disabling as the physical symptoms of these diseases, PBA may significantly influence individuals social functioning and their relationships with others. Such sudden, frequent, extreme, uncontrollable emotional outbursts may lead to social withdrawal and interfere with activities of daily living, social and professional pursuits, and reduce overall healthcare. For example, patients with ALS and MS are often cognitively normal. However, the appearance of uncontrollable emotions is commonly associated with many additional neurological disorders such as attention deficit/hyperactivity disorder, Parkinsons disease, cerebral palsy, autism, epilepsy, and migraines. This may lead to avoidance of social interactions for the patient, which in turn impairs their coping mechanisms and their careers.
Depression
PBA may often be misdiagnosed as clinical depression or bipolar disorder; however, many clear distinctions exist.
In depressive and bipolar disorders, crying, anger or laughter are typically indicative of mood, whereas the pathological displays of crying which occur in PBA are often in contrast to the underlying mood, or greatly in excess of the mood or eliciting stimulus. In addition, a key to differentiating depression from PBA is duration: PBA episodes are sudden, occurring in an episodic manner, while crying in depression is a more sustained presentation and closely relates to the underlying mood state. The level of control that one has over the crying, anger or other emotional displays in PBA is minimal or nonexistent, whereas for those with depression, the emotional expression (typically crying) can be modulated by the situation. Similarly, the trigger for episodes of crying in patients with PBA may be nonspecific, minimal or inappropriate to the situation, but in depression the stimulus is specific to the mood-related condition. These differences are outlined in the adjacent Table.
In some cases, depressed mood and PBA may co-exist. Since depression is one of the most common emotional changes in patients with neurodegenerative disease or post-stroke sequelae, it is often comorbid with PBA. Comorbidity implies that depression is distinct from PBA and is not necessary for, nor does it exclude, a diagnosis of PBA.
Causes
The specific pathophysiology involved in this frequently debilitating condition is still under investigation; the primary pathogenic mechanisms of PBA remain controversial. One hypothesis, established by early researchers such as Wilson and Oppenheim, placed emphasis on the role of the corticobulbar pathways in modulating emotional expression in a top-down model, and theorized that PBA occurs when bilateral lesions in the descending corticobulbar tract cause failure of voluntary control of emotion, which leads to the disinhibition, or release, of laughing/crying centers in the brainstem. Other theories implicate the prefrontal cortex.
Secondary condition
PBA is a condition that occurs secondary to neurological disease or brain injury, and is thought to result from disruptions of neural networks that control the generation and regulation of motor output of emotions. PBA is most commonly observed in people with neurologic injuries such as traumatic brain injury (TBI) and stroke, and neurologic diseases such as dementias including Alzheimers disease, attention deficit/hyperactivity disorder (ADHD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Parkinsons disease (PD). It has been reported as a symptom of hyperthyroidism, Graves disease, or hypothyroidism in combination with depression.PBA has also been observed in association with a variety of other brain disorders, including brain tumors, Wilsons disease, syphilitic pseudobulbar palsy, and various encephalitides. Rarer conditions associated with PBA include gelastic epilepsy, dacrystic epilepsy, central pontine myelinolysis, olivopontinocerebellar atrophy, lipid storage diseases, chemical exposure (e.g., nitrous oxide and insecticides), fou rire prodromique, and Angelman syndrome.
It is hypothesized that these primary neurologic injuries and diseases affect chemical signaling in the brain, which in turn disrupts the neurologic pathways that control emotional expression.
Stroke
PBA is one of the most frequently reported post-stroke behavioral disorders, with a range of reported prevalence rates from 28% to 52%. The higher prevalence rates tend to be reported in stroke patients who are older or who have a history of prior stroke. The relationship between post-stroke depression and PBA is complicated, because the depressive syndrome also occurs with high frequency in stroke survivors. Post-stroke patients with PBA are more depressed than post-stroke patients without PBA, and the presence of a depressive syndrome may exacerbate the weeping side of PBA symptoms.
Multiple sclerosis
Recent studies suggest that approximately 10% of patients with multiple sclerosis (MS) will experience at least one episode of emotional lability. PBA is generally associated with later stages of the disease (chronic progressive phase). PBA in MS patients is associated with more severe intellectual deterioration, physical disability, and neurological disability.
Amyotrophic lateral sclerosis
A study designed specifically to survey for prevalence found that 49% of patients with amyotrophic lateral sclerosis (ALS) also had PBA. PBA does not appear to be associated with duration of ALS. It is a symptom of ALS that many patients are unaware of and do not receive information about from their physician.
Traumatic brain injury
One study of 301 consecutive cases in a clinic setting reported a 5% prevalence. PBA occurred in patients with more severe head injury, and coincided with other neurological features suggestive of pseudobulbar palsy.The Brain Injury Association of America (BIAA) indicates that approximately 80% of survey respondents experience symptoms of PBA. Results from a recent investigation estimate the prevalence of PBA associated with traumatic brain injury to exceed more than 55% of survivors.
Treatment
Education of patients, families, and caregivers is an important component of the appropriate treatment of PBA. Crying associated with PBA may be incorrectly interpreted as depression; laughter may be embarrassing, anger can be debilitating. It is therefore critical for families and caregivers to recognize the pathological nature of PBA and the reassurance that this is an involuntary syndrome that is manageable.
Traditionally, antidepressants such as sertraline, fluoxetine, citalopram, nortriptyline and amitriptyline have been prescribed with some efficacy.
Medication
Dextromethorphan hydrobromide affects the signals in the brain that trigger the cough reflex. It is used as a cough suppressant, although it can sometimes be used, medicinally, as a pain reliever, and is also used as a recreational drug.Quinidine sulfate affects the way the heart beats, and is generally used in people with certain heart rhythm disorders. It is also used to treat malaria. Quinidine sulfate, as a metabolic inhibitor, "increases plasma levels of dextromethorphan by competitively inhibiting cytochrome P450 2D6, which catalyzes a major biotransformation pathway for dextromethorphan," enabling therapeutic dextromethorphan concentrations.Dextromethorphan/quinidine is a combination of these two generic drugs, and is the first FDA-approved drug for the treatment of PBA, approved on October 29, 2010.For this multicenter study, the "Objectives...[were] to evaluate the safety, tolerability, and efficacy of two different doses of AVP-923 [Dextromethorphan/quinidine combination]...when compared to placebo." The conditions and results of that study are as follows:
At one study site, a total of 326 participants received one of three dose options. "METHODS: In a 12-week randomized, double-blind trial, ALS and MS patients with clinically significant PBA" were given a twice-daily dose of one of the following:
placebo (N=109)
dextromethorphan hydrobromide 30 mg/quinidine sulfate 10 mg (N=110)
Nuedexta – dextromethorphan hydrobromide 20 mg/quinidine sulfate 10 mg (N=107)283 patients (86.8%) completed the study. The number of PBA episodes (laughing, crying or aggressive outbursts) were 47% and 49% lower (based on the trials outcome measures), respectively, for the drug-combination options than for the placebo. The "mean CNS-LS scores" decreased by 8.2 points for both drug-combination options, vs a decrease of 5.7 points for the placebo.
Overall, the trial showed a statistically significant benefit from taking a combination of dextromethorphan and quinidine, with both dosages being safe and well tolerated. For a secondary objective measuring a participants "perceived health status...measuring eight health concepts: vitality, physical functioning, bodily pain, general health perceptions, physical role-, emotional role-, social role functioning, and mental health," the higher dosage showed improvement, especially on measures of social functioning and mental health.
Epidemiology
Prevalence estimates place the number of people with PBA between 1.5 and 2 million in the United States alone, which would be less than 1% of the U.S. population even at the high end of the estimate. Some argue that the number is probably higher and that clinicians underdiagnose PBA. However, the prevalence estimate of 2 million is based on an online survey. Self-selected computer-savvy patients in at-risk groups evaluated their own symptoms and submitted their self-diagnoses. No doctor or clinic confirmed the data. Motivation to participate could have been influenced by the presence of symptoms, which would have skewed the results. The actual prevalence could very well be quite a bit lower than estimated.
History
The Expression of the Emotions in Man and Animals by Charles Darwin was published in 1872. In Chapter VI, "Special Expressions of Man: Suffering and Weeping", Darwin discusses cultural variations in the acceptability of weeping and the wide differences in individual responses to suffering. The chapter contains the following sentence:
We must not, however, lay too much stress on the copious shedding of tears by the insane, as being due to the lack of all restraint; for certain brain-diseases, as hemiplegia, brain-wasting, and senile decay, have a special tendency to induce weeping.
Terminology
Historically, there have been a variety of terms used for the disorder, including pseudobulbar affect, pathological laughter and crying, emotional lability, emotionalism, emotional dysregulation, or more recently, involuntary emotional expression disorder. The term pseudobulbar (pseudo- + bulbar) came from the idea that the symptoms seemed similar to those caused by a bulbar lesion (that is, a lesion in the medulla oblongata).
Terms such as forced crying, involuntary crying, pathological emotionality, and emotional incontinence have also been used, although less frequently.
In popular culture
Arthur Fleck, the central character of the 2019 film Joker, displays signs of pseudobulbar affect, which are said to be what Joaquin Phoenix used as inspiration for his characters signature laugh.
In the 2019 movie Parasite, the character Ki-woo sustains head trauma, and although it is not clearly mentioned that hes affected by pseudobulbar affect, he mentions not being able to stop laughing when thinking about all the events that occur in the movie.
In the medical television show House, season 7, episode 8 ("Small Sacrifices"), the character Ramon Silva, played by Kuno Becker displays pseudobulbar affect, with uncontrollable incongruent laughter, while having the Marburg variety of multiple sclerosis.
In season 3, episode 9 of The Good Fight, the character Brenda DeCarlo, an external auditor, displays pseudobulbar affect, with uncontrollable incongruent laughter.
See also
Affect (psychology)
Affect display
References
External links
"Pseudobulbar affect and stroke" on the National Stroke Association website |
Pud | Pud may refer to:
Pudding, a typically sweet food
Comic strip mascot for Dubble Bubble
A nickname of Albert Kent, a Canadian football coach and olympic rower
A nickname of Philip J. Kaplan, an American entrepreneur
Pud Galvin, a Hall of Fame Major League Baseball pitcher
Pood or pud, an old Russian unit of weight
slang shortened version of "pudendum"PUD can be an acronym for
Planned Unit Development
Public Utility District, a consumer co-op owned utility
Peptic Ulcer Disease |
Pulmonary hypertension | Pulmonary hypertension (PH or PHTN) is a condition of increased blood pressure in the arteries of the lungs. Symptoms include shortness of breath, fainting, tiredness, chest pain, swelling of the legs, and a fast heartbeat. The condition may make it difficult to exercise. Onset is typically gradual.A patient is deemed to have pulmonary hypertension if the pulmonary mean arterial pressure is greater than 25mmHg at rest, or greater than 30mmHg during exercise.The cause is often unknown. Risk factors include a family history, prior blood clots in the lungs, HIV/AIDS, sickle cell disease, cocaine use, chronic obstructive pulmonary disease, sleep apnea, living at high altitudes, and problems with the mitral valve. The underlying mechanism typically involves inflammation and subsequent remodeling of the arteries in the lungs. Diagnosis involves first ruling out other potential causes.There is currently no cure for pulmonary hypertension, although research on a cure is ongoing. Treatment depends on the type of disease. A number of supportive measures such as oxygen therapy, diuretics, and medications to inhibit blood clotting may be used. Medications specifically used to treat pulmonary hypertension include epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, macitentan, and sildenafil. Lung transplantation may be an option in severe cases.The frequency of occurrence is estimated at 1,000 new cases per year in the United States. Females are more often affected than males. Onset is typically between 20 and 60 years of age. Pulmonary hypertension was identified by Ernst von Romberg in 1891.
Classification
According to WHO classification there are 5 groups of PH, where Group I (pulmonary arterial hypertension) is further subdivided into Group I and Group I classes. The most recent WHO classification system (with adaptations from the more recent ESC/ERS guidelines shown in italics) can be summarized as follows:WHO Group I – Pulmonary arterial hypertension (PAH)
Idiopathic
Heritable (BMPR2, ALK1, SMAD9, caveolin 1, KCNK3 mutations)
Drug- and toxin-induced (e.g., methamphetamine, amphetamine, or cocaine use )
Associated conditions:Connective tissue disease, HIV infection, Portal hypertension, Congenital heart diseases, SchistosomiasisWHO Group I – Pulmonary veno-occlusive disease (PVOD), pulmonary capillary hemangiomatosis (PCH)
Idiopathic
Heritable (EIF2AK4 mutations)
Drugs, toxins and radiation-induced
Associated conditions:connective tissue disease, HIV infectionWHO Group I" – Persistent pulmonary hypertension of the newborn
WHO Group II – Pulmonary hypertension secondary to left heart disease
Left ventricular systolic dysfunction
Left ventricular diastolic dysfunction
Valvular heart disease
Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathy
Congenital/acquired pulmonary venous stenosisWHO Group III – Pulmonary hypertension due to lung disease, chronic hypoxia
Chronic obstructive pulmonary disease (COPD)
Interstitial lung disease
Mixed restrictive and obstructive pattern pulmonary diseases
Sleep-disordered breathing
Alveolar hypoventilation disorders
Chronic exposure to high altitude
Developmental abnormalitiesWHO Group IV – chronic arterial obstruction
Chronic thromboembolic pulmonary hypertension (CTEPH)
Other pulmonary artery obstructions
Angiosarcoma or other tumor within the blood vessels
Arteritis
Congenital pulmonary artery stenosis
Parasitic infection (hydatidosis)WHO Group V – Pulmonary hypertension with unclear or multifactorial mechanisms
Hematologic diseases: chronic hemolytic anemia (including sickle cell disease)
Systemic diseases: sarcoidosis, pulmonary Langerhans cell histiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis
Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid diseases
Others: pulmonary tumoral thrombotic microangiopathy, fibrosing mediastinitis, chronic kidney failure, segmental pulmonary hypertension (pulmonary hypertension restricted to one or more lobes of the lungs)
Signs and symptoms
The symptoms of pulmonary hypertension include the following:
Less common signs/symptoms include non-productive cough and exercise-induced nausea and vomiting. Coughing up of blood may occur in some patients, particularly those with specific subtypes of pulmonary hypertension such as heritable pulmonary arterial hypertension, Eisenmenger syndrome and chronic thromboembolic pulmonary hypertension. Pulmonary venous hypertension typically presents with shortness of breath while lying flat or sleeping (orthopnea or paroxysmal nocturnal dyspnea), while pulmonary arterial hypertension (PAH) typically does not.Other typical signs of pulmonary hypertension include an accentuated pulmonary component of the second heart sound, a right ventricular third heart sound, and parasternal heave indicating a hypertrophied right ventricle. Signs of systemic congestion resulting from right-sided heart failure include jugular venous distension, ascites, and hepatojugular reflux. Evidence of tricuspid insufficiency and pulmonic regurgitation is also sought and, if present, is consistent with the presence of pulmonary hypertension.
Causes
Pulmonary hypertension is a pathophysiologic condition with many possible causes. Indeed, this condition frequently accompanies severe heart or lung conditions. A 1973 World Health Organization meeting was the first attempt to classify pulmonary hypertension by its cause, and a distinction was made between primary PH (resulting from a disease of the pulmonary arteries) and secondary PH (resulting secondary to other, non-vascular causes). Further, primary PH was divided into the "arterial plexiform", "veno-occlusive" and "thromboembolic" forms. In 1998, a second conference at Évian-les-Bains addressed the causes of secondary PH. Subsequent third, fourth, and fifth (2013) World Symposia on PAH have further defined the classification of PH. The classification continues to evolve based on improved understanding of the disease mechanisms.Most recently in 2015, the WHO guidelines were updated by the European Society of Cardiology (ESC) and European Respiratory Society (ERS). These guidelines are endorsed by the International Society for Heart and Lung Transplantation, and provide the current framework for understanding and treatment of pulmonary hypertension.
Genetics
Mutations in several genes have been associated with this condition these include bone morphogenetic protein receptor type 2 (BMPR2) and eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4).
Pathogenesis
The pathogenesis of pulmonary arterial hypertension (WHO Group I) involves the narrowing of blood vessels connected to and within the lungs. This makes it harder for the heart to pump blood through the lungs, as it is much harder to make water flow through a narrow pipe as opposed to a wide one. Over time, the affected blood vessels become stiffer and thicker, in a process known as fibrosis. The mechanisms involved in this narrowing process include vasoconstriction, thrombosis, and vascular remodeling (excessive cellular proliferation, fibrosis, and reduced apoptosis/programmed cell death in the vessel walls, caused by inflammation, disordered metabolism and dysregulation of certain growth factors). This further increases the blood pressure within the lungs and impairs their blood flow. In common with other types of pulmonary hypertension, these changes result in an increased workload for the right side of the heart. The right ventricle is normally part of a low pressure system, with systolic ventricular pressures that are lower than those that the left ventricle normally encounters. As such, the right ventricle cannot cope as well with higher pressures, and although right ventricular adaptations (hypertrophy and increased contractility of the heart muscle) initially help to preserve stroke volume, ultimately these compensatory mechanisms are insufficient; the right ventricular muscle cannot get enough oxygen to meet its needs and right heart failure follows. As the blood flowing through the lungs decreases, the left side of the heart receives less blood. This blood may also carry less oxygen than normal. Therefore, it becomes harder and harder for the left side of the heart to pump to supply sufficient oxygen to the rest of the body, especially during physical activity. During the end-systolic volume phase of the cardiac cycle, the Gaussian curvature and the mean curvature of right ventricular endocardial wall of PH patients was found to be significantly different as compared to controls.In PVOD (WHO Group I), pulmonary blood vessel narrowing occurs preferentially (though not exclusively) in post-capillary venous blood vessels. PVOD shares several characteristics with PAH, but there are also some important differences, for example differences in prognosis and response to medical therapy.Persistent pulmonary hypertension of the newborn occurs when the circulatory system of a newborn baby fails to adapt to life outside the womb; it is characterized by high resistance to blood flow through the lungs, right-to-left cardiac shunting and severe hypoxemia.Pathogenesis in pulmonary hypertension due to left heart disease (WHO Group II) is completely different in that constriction or damage to the pulmonary blood vessels is not the issue. Instead, the left heart fails to pump blood efficiently, leading to pooling of blood in the lungs and back pressure within the pulmonary system. This causes pulmonary edema and pleural effusions. In the absence of pulmonary blood vessel narrowing, the increased back pressure is described as isolated post-capillary pulmonary hypertension (older terms include passive or proportionate pulmonary hypertension or pulmonary venous hypertension). However, in some patients, the raised pressure in the pulmonary vessels triggers a superimposed component of vessel narrowing, which further increases the workload of the right side of the heart. This is referred to as post-capillary pulmonary hypertension with a pre-capillary component or combined post-capillary and pre-capillary pulmonary hypertension (older terms include reactive or out-of-proportion pulmonary hypertension).In pulmonary hypertension due to lung diseases and/or hypoxia (WHO Group III), low levels of oxygen in the alveoli (due to respiratory disease or living at high altitude) cause constriction of the pulmonary arteries. This phenomenon is called hypoxic pulmonary vasoconstriction and it is initially a protective response designed to stop too much blood flowing to areas of the lung that are damaged and do not contain oxygen. When the alveolar hypoxia is widespread and prolonged, this hypoxia-mediated vasoconstriction occurs across a large portion of the pulmonary vascular bed and leads to an increase in pulmonary arterial pressure, with thickening of the pulmonary vessel walls contributing to the development of sustained pulmonary hypertension. Prolonged hypoxia also induces the transcription factor HIF1A, which directly activates downstream growth factor signaling that causes irreversible proliferation and remodeling of pulmonary arterial endothelial cells, leading to chronic pulmonary arterial hypertension.In CTEPH (WHO Group IV), the initiating event is thought to be blockage or narrowing of the pulmonary blood vessels with unresolved blood clots; these clots can lead to increased pressure and shear stress in the rest of the pulmonary circulation, precipitating structural changes in the vessel walls (remodeling) similar to those observed in other types of severe pulmonary hypertension. This combination of vessel occlusion and vascular remodeling once again increases the resistance to blood flow and so the pressure within the system rises.
Molecular pathology
The molecular mechanism of pulmonary arterial hypertension (PAH) is not known yet, but it is believed that the endothelial dysfunction results in a decrease in the synthesis of endothelium-derived vasodilators such as nitric oxide and prostacyclin. Moreover, there is a stimulation of the synthesis of vasoconstrictors such as thromboxane and vascular endothelial growth factor (VEGF). These result in a severe vasoconstriction and vascular smooth muscle and adventitial hypertrophy characteristic of patients with PAH.
Nitric oxide-soluble guanylate cyclase pathway
In normal conditions, the vascular endothelial nitric oxide synthase produces nitric oxide from L-arginine in the presence of oxygen.This nitric oxide diffuses into neighboring cells (including vascular smooth muscle cells and platelets), where it increases the activity of the enzyme soluble guanylate cyclase, leading to increased formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). The cGMP then activates cGMP-dependent kinase or PKG (protein kinase G). Activated PKG promotes vasorelaxation (via a reduction of intracellular calcium levels), alters the expression of genes involved in smooth muscle cell contraction, migration and differentiation, and inhibits platelet activation. Nitric oxide–soluble guanylate cyclase signaling also leads to anti-inflammatory effects.Phosphodiesterase type 5 (PDE5), which is abundant in the pulmonary tissue, hydrolyzes the cyclic bond of cGMP. Consequently, the concentration of cGMP (and thus PKG activity) decreases.
Endothelin
Endothelin-1 is a peptide (comprising 21 amino acids) that is produced in endothelial cells. It acts on the endothelin receptors ETA and ETB in various cell types including vascular smooth muscle cells and fibroblasts, leading to vasoconstriction, hypertrophy, proliferation, inflammation, and fibrosis. It also acts on ETB receptors in endothelial cells; this leads to the release of both vasoconstrictors and vasodilators from those cells, and clears endothelin-1 from the system.
Prostacyclin (and thromboxane)
Prostacyclin is synthesized from arachidonic acid in endothelial cells. In vascular smooth muscle cells, prostacyclin binds mainly to the prostaglandin I receptor. This sends a signal to increase adenylate cyclase activity, which leads to increased synthesis of cyclic adenosine monophosphate (cAMP). This in turn leads to increased cAMP-dependent protein kinase or PKA (protein kinase A) activity, ultimately promoting vasodilation and inhibiting cell proliferation. Prostacyclin signaling also leads to anti-thrombotic, anti-fibrotic, and anti-inflammatory effects. Levels of cAMP (which mediates most of the biological effects of prostacyclin) are reduced by phosphodiesterases 3 and 4.
The vasoconstrictor thromboxane is also synthesized from arachidonic acid. In PAH, the balance is shifted away from synthesis of prostacyclin towards synthesis of thromboxane.
Other pathways
The three pathways described above are all targeted by currently available medical therapies for PAH. However, several other pathways have been identified that are also altered in PAH and are being investigated as potential targets for future therapies. For example, the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) is pathologically activated in PAH, causing a metabolic shift from oxidative phosphorylation to glycolysis and leading to increased cell proliferation and impaired apoptosis. Expression of vasoactive intestinal peptide, a potent vasodilator with anti-inflammatory and immune-modulatory roles, is reduced in PAH, while expression of its receptor is increased.
Plasma levels of serotonin, which promotes vasoconstriction, hypertrophy and proliferation, are increased in patients with PAH, although the role played by serotonin in the pathogenesis of PAH remains uncertain. The expression or activity of several growth factors (including platelet-derived growth factor, basic fibroblast growth factor, epidermal growth factor, and vascular endothelial growth factor) is increased and contributes to vascular remodeling in PAH. Other factors underlying the proliferative state of pulmonary vascular smooth muscle cells include OPG and TRAIL. Focusing only on the pulmonary vasculature provides an incomplete picture of PAH; the ability of the right ventricle to adapt to the increased workload varies between patients and is an important determinant of survival. The molecular pathology of PAH in the right ventricle is therefore also being investigated, and recent research has shifted to consider the cardiopulmonary unit as a single system rather than two separate systems. Importantly, right ventricular remodeling is associated with increased apoptosis; this is in contrast to pulmonary vascular remodeling which involves inhibition of apoptosis.
Diagnosis
In terms of the diagnosis of pulmonary hypertension, it has five major types, and a series of tests must be performed to distinguish pulmonary arterial hypertension from venous, hypoxic, thromboembolic, or unclear multifactorial varieties. PAH is diagnosed after exclusion of other possible causes of pulmonary hypertension.
Physical examination
A physical examination is performed to look for typical signs of pulmonary hypertension (described above), and a detailed family history is established to determine whether the disease might be heritable. A history of exposure to drugs such as benfluorex (a fenfluramine derivative), dasatinib, cocaine, methamphetamine, ethanol leading to cirrhosis, and tobacco leading to emphysema is considered significant. Use of selective serotonin reuptake inhibitors during pregnancy (particularly late pregnancy) is associated with an increased risk of the baby developing persistent pulmonary hypertension of the newborn.
Echocardiography
If pulmonary hypertension is suspected based on the above assessments, echocardiography is performed as the next step. A meta-analysis of Doppler echocardiography for predicting the results of right heart catheterization reported a sensitivity and specificity of 88% and 56%, respectively. Thus, Doppler echocardiography can suggest the presence of pulmonary hypertension, but right heart catheterization (described below) remains the gold standard for diagnosis of PAH.
Echocardiography can also help to detect congenital heart disease as a cause of pulmonary hypertension.
Exclude other diseases
If the echocardiogram is compatible with a diagnosis of pulmonary hypertension, common causes of pulmonary hypertension (left heart disease and lung disease) are considered and further tests are performed accordingly. These tests generally include electrocardiography (ECG), pulmonary function tests including lung diffusion capacity for carbon monoxide and arterial blood gas measurements, X-rays of the chest and high-resolution computed tomography (CT) scanning.
Ventilation/perfusion scintigraphy
If heart disease and lung disease have been excluded, a ventilation/perfusion scan is performed to rule out CTEPH. If unmatched perfusion defects are found, further evaluation by CT pulmonary angiography, right heart catheterization, and selective pulmonary angiography is performed.
CT scan
Signs of pulmonary hypertension on CT scan of the chest are:
Enlargement of the pulmonary trunk (measured at its bifurcation). It is, however, a poor predictor of pulmonary hypertension in patients with interstitial lung disease.A diameter of more than 27 mm for women and 29 mm for men is suggested as a cutoff.
A cutoff of 31.6 mm may be a more statistically robust in individuals without interstitial lung disease.Increased ratio of the diameter of the main pulmonary artery (pulmonary trunk) to the ascending aorta (measured at its bifurcation).A ratio of 1.0 is suggested as a cutoff in adults.
Cutoff ~1.09 in children.Increased diameter ratio of segmental arteries to bronchi. This finding in three or four lobes, in the presence of a dilated pulmonary trunk (≥29 mm), and absence of significant structural lung disease confers a specificity of 100% for pulmonary hypertension.
Mural calcification in central pulmonary arteries is most frequently seen in patients with Eisenmengers syndrome.
Right heart catheterization
Although pulmonary arterial pressure (PAP) can be estimated on the basis of echocardiography, pressure measurements with a Swan-Ganz catheter inserted through the right side of the heart provide the most definite assessment.[42] Pulmonary hypertension is defined as a mean PAP of at least 20 mm Hg (3300 Pa) at rest, and PAH is defined as precapillary pulmonary hypertension (i.e. mean PAP ≥ 20 mm Hg with pulmonary arterial occlusion pressure [PAOP] ≤ 15 mm Hg and pulmonary vascular resistance [PVR] > 3 Wood Units). PAOP and PVR cannot be measured directly with echocardiography. Therefore, diagnosis of PAH requires right-sided cardiac catheterization. A Swan-Ganz catheter can also measure the cardiac output; this can be used to calculate the cardiac index, which is far more important in measuring disease severity than the pulmonary arterial pressure.Mean PAP (mPAP) should not be confused with systolic PAP (sPAP), which is often reported on echocardiogram reports. A systolic pressure of 40 mm Hg typically implies a mean pressure of more than 25 mm Hg. Roughly, mPAP = 0.61•sPAP + 2. Due to the invasive nature of this procedure, the use of computational fluid dynamics based hemodynamic indices have been postulated.
Other
For people considered likely to have PAH based on the above tests, the specific associated condition is then determined based on the physical examination, medical/family history and further specific diagnostic tests (for example, serological tests to detect underlying connective tissue disease, HIV infection or hepatitis, ultrasonography to confirm the presence of portal hypertension, echocardiography/cardiac magnetic resonance imaging for congenital heart disease, laboratory tests for schistosomiasis, and high-resolution CT for PVOD and pulmonary capillary hemangiomatosis). Routine lung biopsy is discouraged in patients with PAH, because of the risk to the patient and because the findings are unlikely to alter the diagnosis and treatment.
Treatment
Treatment of pulmonary hypertension is determined by whether the PH is arterial, venous, hypoxic, thromboembolic, or miscellaneous. If it is caused by left heart disease, the treatment is to optimize left ventricular function by the use of medication or to repair/replace the mitral valve or aortic valve. Patients with left heart failure or hypoxemic lung diseases (groups II or III pulmonary hypertension) should not routinely be treated with vasoactive agents including prostanoids, phosphodiesterase inhibitors, or endothelin antagonists, as these are approved for the different condition called primary pulmonary arterial hypertension. To make the distinction, doctors at a minimum will conduct cardiac catheterization of the right heart, echocardiography, chest CT, a six-minute walk test, and pulmonary function testing. Using treatments for other kinds of pulmonary hypertension in patients with these conditions can harm the patient and wastes substantial medical resources.High-dose calcium channel blockers are useful in only 5% of IPAH patients who are vasoreactive by Swan-Ganz catheter. Unfortunately, calcium channel blockers have been largely misused, being prescribed to many patients with non-vasoreactive PAH, leading to excess morbidity and mortality. The criteria for vasoreactivity have changed. Only those patients whose mean pulmonary artery pressure falls by more than 10 mm Hg to less than 40 mm Hg with an unchanged or increased cardiac output when challenged with adenosine, epoprostenol, or nitric oxide are considered vasoreactive. Of these, only half of the patients are responsive to calcium channel blockers in the long term.A number of agents have recently been introduced for primary and secondary PAH. The trials supporting the use of these agents have been relatively small, and the only measure consistently used to compare their effectivity is the "six-minute walk test". Many have no data on mortality benefit or time to progression.
Vasoactive substances
Many pathways are involved in the abnormal proliferation and contraction of the smooth muscle cells of the pulmonary arteries in patients with pulmonary arterial hypertension. Three of these pathways are important since they have been targeted with drugs — endothelin receptor antagonists, phosphodiesterase type 5 (PDE-5) inhibitors, and prostacyclin derivatives.
Prostaglandins
Prostacyclin (prostaglandin I2) is commonly considered the most effective treatment for PAH. Epoprostenol (synthetic prostacyclin) is given via continuous infusion that requires a semi-permanent central venous catheter. This delivery system can cause sepsis and thrombosis. Prostacyclin is unstable, and therefore has to be kept on ice during administration. Since it has a half-life of 3 to 5 minutes, the infusion has to be continuous, and interruption can be fatal. Other prostanoids have therefore been developed. Treprostinil can be given intravenously or subcutaneously, but the subcutaneous form can be very painful. An increased risk of sepsis with intravenous Remodulin has been reported by the CDC. Iloprost is also used in Europe intravenously and has a longer half life. Iloprost was the only inhaled form of prostacyclin approved for use in the US and Europe, until the inhaled form of treprostinil was approved by the FDA in July 2009.
Endothelin receptor antagonists
Moderate quality evidence suggests that endothelin receptor antagonists improve exercise capacity and decrease symptoms severity. The dual (ETA and ETB) endothelin receptor antagonist bosentan was approved in 2001. Sitaxentan (Thelin) was approved for use in Canada, Australia, and the European Union, but not in the United States. In 2010, Pfizer withdrew Thelin worldwide because of fatal liver complications. A similar drug, ambrisentan is marketed as Letairis in the U.S. by Gilead Sciences. s
Phosphodiesterase type 5 inhibitors
The U.S. FDA approved sildenafil, a selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5), for the treatment of PAH in 2005. It is marketed for PAH as Revatio. In 2009, they also approved tadalafil, another PDE5 inhibitor, marketed under the name Adcirca. PDE5 inhibitors are believed to increase pulmonary artery vasodilation, and inhibit vascular remodeling, thus lowering pulmonary arterial pressure and pulmonary vascular resistance.Tadalafil is taken orally, as well as sildenafil, and it is rapidly absorbed (serum levels are detectable at 20 minutes). The T1/2 (biological half-life) hovers around 17.5 hours in healthy subjects. Moreover, if we consider pharmacoeconomic implications, patients that take tadalafil would pay two-thirds of the cost of sildenafil therapy. However, there are some adverse effects of this drug such as headache, diarrhea, nausea, back pain, dyspepsia, flushing and myalgia.
Activators of soluble guanylate cyclase
Soluble guanylate cyclase (sGC) is the intracellular receptor for NO. As of April 2009, the sGC activators cinaciguat and riociguat were undergoing clinical trials for the treatment of PAH.
Surgical
Atrial septostomy is a surgical procedure that creates a communication between the right and left atria. It relieves pressure on the right side of the heart, but at the cost of lower oxygen levels in blood (hypoxia). Lung transplantation replaces a chronic condition with the ongoing need for treatment. There is a post-surgical median survival of just over five years.Pulmonary thromboendarterectomy (PTE) is a surgical procedure that is used for chronic thromboembolic pulmonary hypertension. It is the surgical removal of an organized thrombus (clot) along with the lining of the pulmonary artery; it is a very difficult, major procedure that is currently performed in a few select centers.
Monitoring
Established clinical practice guidelines dictate the frequency of pulmonary nodule evaluation and surveillance,
patients are normally monitored through commonly available tests such as:
Prognosis
PAH is considered a universally fatal illness, although survival time may vary between individuals. The prognosis of pulmonary arterial hypertension (WHO Group I) has an untreated median survival of 2–3 years from time of diagnosis, with the cause of death usually being right ventricular failure (cor pulmonale). The survival time is variable and depends on many factors. A recent outcome study of those patients who had started treatment with bosentan (Tracleer) showed that 89% of patients were alive at 2 years. With new therapies, survival rates are increasing. For 2,635 patients enrolled in The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) from March 2006 to December 2009, 1-, 3-, 5-, and 7-year survival rates were 85%, 68%, 57%, and 49%, respectively. For patients with idiopathic/familial PAH, survival rates were 91%, 74%, 65%, and 59%. Levels of mortality are very high in pregnant women with severe pulmonary arterial hypertension (WHO Group I). Pregnancy is sometimes described |
Pulmonary hypertension | as contraindicated in these women.
Epidemiology
The epidemiology of IPAH is about 125–150 deaths per year in the U.S., and worldwide the incidence is similar at 4 cases per million. However, in parts of Europe (France), indications are 6 cases per million of IPAH. Females have a higher incidence rate than males (2–9:1).Other forms of PH are far more common. In systemic scleroderma, the incidence has been estimated to be 8 to 12% of all patients; in rheumatoid arthritis it is rare. However, in systemic lupus erythematosus it is 4 to 14%, and in sickle cell disease, it ranges from 20 to 40%. Up to 4% of people who develop a pulmonary embolism go on to develop chronic thromboembolic disease including pulmonary hypertension. A small percentage of patients with COPD develop pulmonary hypertension with no other disease to explain the high pressure. On the other hand, obesity-hypoventilation syndrome is very commonly associated with right heart failure due to pulmonary hypertension.
Research
For people that inherited the disease, gene therapy is being studied.
Notable cases
Elaine Kaufman, American restaurateur
Ina Balin, American Broadway and TV actress
Chloe Temtchine, American singer-songwriter
Natalie Cole, American singer
See also
Pulmonary Hypertension Association
Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)
References
Further reading
Rubin LJ, Badesch DB (August 2005). "Evaluation and management of the patient with pulmonary arterial hypertension". Annals of Internal Medicine. 143 (4): 282–92. CiteSeerX 10.1.1.463.8466. doi:10.7326/0003-4819-143-4-200508160-00009. PMID 16103472. S2CID 28841269.
Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, et al. (November 2015). "Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society". Circulation. 132 (21): 2037–99. doi:10.1161/CIR.0000000000000329. PMID 26534956. S2CID 7412370.
External links
The Merck Manual Home Edition: Pulmonary Hypertension |
Ventricular tachycardia | Ventricular tachycardia (V-tach or VT) is a fast heart rate arising from the lower chambers of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple episodes over a short period of time are referred to as an electrical storm. Short periods may occur without symptoms, or present with lightheadedness, palpitations, or chest pain. Ventricular tachycardia may result in ventricular fibrillation (VF) and turn into cardiac arrest. This conversion of the VT into VF is called the degeneration of the VT. It is found initially in about 7% of people in cardiac arrest.Ventricular tachycardia can occur due to coronary heart disease, aortic stenosis, cardiomyopathy, electrolyte problems, or a heart attack. Diagnosis is by an electrocardiogram (ECG) showing a rate of greater than 120 beats per minute and at least three wide QRS complexes in a row. It is classified as non-sustained versus sustained based on whether it lasts less than or more than 30 seconds. The term ventricular arrhythmia refers to the group of abnormal cardiac rhythms originating from the ventricle, which includes ventricular tachycardia, ventricular fibrillation, and torsades de pointes.In those who have normal blood pressure and strong pulse, the antiarrhythmic medication procainamide may be used. Otherwise, immediate cardioversion is recommended, preferably with a biphasic DC shock of 200 joules. In those in cardiac arrest due to ventricular tachycardia, cardiopulmonary resuscitation (CPR) and defibrillation is recommended. Biphasic defibrillation may be better than monophasic. While waiting for a defibrillator, a precordial thump may be attempted (However reserved to those who have the prior experience of doing so) in those on a heart monitor who are seen going into an unstable ventricular tachycardia. In those with cardiac arrest due to ventricular tachycardia, survival is about 45%. An implantable cardiac defibrillator or medications such as calcium channel blockers or amiodarone may be used to prevent recurrence.
Signs and symptoms
While a few seconds may not result in problems, longer periods are dangerous. Short periods may occur without symptoms or present with lightheadedness, palpitations, or chest pain. Ventricular tachycardia may turn into ventricular fibrillation and can result in cardiac arrest.
Cause
Ventricular tachycardia can occur due to coronary heart disease, aortic stenosis, cardiomyopathy, electrolyte problems (e.g., low blood levels of magnesium or potassium), inherited channelopathies (e.g., long-QT syndrome), catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia, alcohol withdrawal syndrome (typically following atrial fibrillation), or a myocardial infarction.
Pathophysiology
The morphology of the tachycardia depends on its cause and the origin of the re-entry electrical circuit in the heart.In monomorphic ventricular tachycardia, the shape of each heart beat on the ECG looks the same because the impulse is either being generated from increased automaticity of a single point in either the left or the right ventricle, or due to a reentry circuit within the ventricle. The most common cause of monomorphic ventricular tachycardia is scarring of the heart muscle from a previous myocardial infarction (heart attack). This scar cannot conduct electrical activity, so there is a potential circuit around the scar that results in the tachycardia. This is similar to the re-entrant circuits that are the cause of atrial flutter and the re-entrant forms of supraventricular tachycardia. Other rarer congenital causes of monomorphic VT include right ventricular dysplasia, and right and left ventricular outflow tract VT.Polymorphic ventricular tachycardia, on the other hand, is most commonly caused by abnormalities of ventricular muscle repolarization. The predisposition to this problem usually manifests on the ECG as a prolongation of the QT interval. QT prolongation may be congenital or acquired. Congenital problems include long QT syndrome and catecholaminergic polymorphic ventricular tachycardia. Acquired problems are usually related to drug toxicity or electrolyte abnormalities, but can occur as a result of myocardial ischemia. Class III anti-arrhythmic drugs such as sotalol and amiodarone prolong the QT interval and may in some circumstances be pro-arrhythmic. Other relatively common drugs including some antibiotics and antihistamines may also be a danger, in particular in combination with one another. Problems with blood levels of potassium, magnesium and calcium may also contribute. High-dose magnesium is often used as an antidote in cardiac arrest protocols.
Diagnosis
The diagnosis of ventricular tachycardia is made based on the rhythm seen on either a 12-lead ECG or a telemetry rhythm strip. It may be very difficult to differentiate between ventricular tachycardia and a wide-complex supraventricular tachycardia in some cases. In particular, supraventricular tachycardias with aberrant conduction from a pre-existing bundle branch block are commonly misdiagnosed as ventricular tachycardia. Other rarer phenomena include Ashman beats and antidromic atrioventricular re-entry tachycardias.Various diagnostic criteria have been developed to determine whether a wide complex tachycardia is ventricular tachycardia or a more benign rhythm. In addition to these diagnostic criteria, if the individual has a history of a myocardial infarction, congestive heart failure, or recent angina, the wide complex tachycardia is much more likely to be ventricular tachycardia.The proper diagnosis is important, as the misdiagnosis of supraventricular tachycardia when ventricular tachycardia is present is associated with worse prognosis. This is particularly true if calcium channel blockers, such as verapamil, are used to attempt to terminate a presumed supraventricular tachycardia. Therefore, it is wisest to assume that all wide complex tachycardia is VT until proven otherwise.ECG features of Ventricular Tachycardia in addition to the increased Heart rate are:
i) A wide QRS Complex ( Because the ectopics for the generation of the cardiac impulse originates in the Ventricular Myocyte and propagated via the intermyocyte conduction, which is a delayed conduction)
ii) A Josephsons sign where there is the notch in the downsloping of the S wave near its nadir.(Considered very specific for the VT).
iii) Capture beats (Normal QRS complex in between when the Heart pick up the sinus rhythm from the impulses generated by the SA node), fusion beats ( due to the fusion of the Abnormal and the Normal QRS complexes) which has a unique morphology .
iv) Positive or negative concordance.
v) Extreme Axis deviation or NORTH WEST axis . ( Axis between -90 to +180 degrees)
Classification
Ventricular tachycardia can be classified based on its morphology:
Monomorphic ventricular tachycardia means that the appearance of all the beats match each other in each lead of a surface electrocardiogram (ECG).
Scar-related monomorphic ventricular tachycardia is the most common type and a frequent cause of death in patients having survived a heart attack, especially if they have weak heart muscle.
Right ventricular outflow tract (RVOT) tachycardia is a type of monomorphic ventricular tachycardia originating in the right ventricular outflow tract. RVOT morphology refers to the characteristic pattern of this type of tachycardia on an ECG.
The source of the re-entry circuit can be identified by evaluating the morphology of the QRS complex in the V1 lead of a surface ECG. If the R wave is dominant (consistent with a right bundle branch block morphology), this indicates the origin of the VT is the left ventricle. Conversely, if the S wave is dominant (consistent with a left bundle branch block morphology, this is consistent with VT originating from the right ventricle or interventricular septum.
Polymorphic ventricular tachycardia, on the other hand, has beat-to-beat variations in morphology. This may appear as a cyclical progressive change in cardiac axis, previously referred to by its French name torsades de pointes ("twisting of the spikes"). However, at the current time, the term torsades de pointes is reserved for polymorphic VT occurring in the context of a prolonged resting QT interval.Another way to classify ventricular tachycardias is the duration of the episodes: Three or more beats in a row on an ECG that originate from the ventricle at a rate of more than 120 beats per minute constitute a ventricular tachycardia.
If the fast rhythm self-terminates within 30 seconds, it is considered a non-sustained ventricular tachycardia.
If the rhythm lasts more than 30 seconds, it is known as a sustained ventricular tachycardia (even if it terminates on its own after 30 seconds).A third way to classify ventricular tachycardia is on the basis of its symptoms: Pulseless VT is associated with no effective cardiac output, hence, no effective pulse, and is a cause of cardiac arrest (see also: pulseless electrical activity [PEA]). In this circumstance, it is best treated the same way as ventricular fibrillation (VF), and is recognized as one of the shockable rhythms on the cardiac arrest protocol. Some VT is associated with reasonable cardiac output and may even be asymptomatic. The heart usually tolerates this rhythm poorly in the medium to long term, and patients may certainly deteriorate to pulseless VT or to VF.Occasionally in ventricular tachycardia, supraventricular impulses are conducted to the ventricles, generating QRS complexes with normal or aberrant supraventricular morphology (ventricular capture). Or, those impulses can be merged with complexes that are originated in the ventricle and produce a summation pattern (fusion complexes).Less common is ventricular tachycardia that occurs in individuals with structurally normal hearts. This is known as idiopathic ventricular tachycardia and in the monomorphic form coincides with little or no increased risk of sudden cardiac death. In general, idiopathic ventricular tachycardia occurs in younger individuals diagnosed with VT. While the causes of idiopathic VT are not known, in general it is presumed to be congenital, and can be brought on by any number of diverse factors.
Treatment
Therapy may be directed either at terminating an episode of the abnormal heart rhythm or at reducing the risk of another VT episode. The treatment for stable VT is tailored to the specific person, with regard to how well the individual tolerates episodes of ventricular tachycardia, how frequently episodes occur, their comorbidities, and their wishes. Individuals with pulseless VT or unstable VT are hemodynamically compromised and require immediate electric cardioversion to shock them out of the VT rhythm.
Cardioversion
If a person still has a pulse, it is usually possible to terminate the episode using electric cardioversion. This should be synchronized to the heartbeat if the waveform is monomorphic if possible, in order to avoid degeneration of the rhythm to ventricular fibrillation. An initial energy of 100J is recommended. If the waveform is polymorphic, then higher energies and an unsynchronized shock should be provided (also known as defibrillation).
Defibrillation
A person with pulseless VT is treated the same as ventricular fibrillation with high-energy (360J with a monophasic defibrillator, or 200J with a biphasic defibrillator) unsynchronised cardioversion (defibrillation). They will be unconscious.
The shock may be delivered to the outside of the chest using the two pads of an external defibrillator, or internally to the heart by an implantable cardioverter-defibrillator (ICD) if one has previously been inserted.An ICD may also be set to attempt to overdrive pace the ventricle. Pacing the ventricle at a rate faster than the underlying tachycardia can sometimes be effective in terminating the rhythm. If this fails after a short trial, the ICD will usually stop pacing, charge up and deliver a defibrillation grade shock.
Medication
For those who are stable with a monomorphic waveform the medications procainamide or sotalol may be used and are better than lidocaine. Evidence does not show that amiodarone is better than procainamide.As a low magnesium level in the blood is a common cause of VT, magnesium sulfate can be given for torsades de pointes or if a low blood magnesium level is found/suspected.Long-term anti-arrhythmic therapy may be indicated to prevent recurrence of VT. Beta-blockers and a number of class III anti-arrhythmics are commonly used, such as the beta-blockers carvedilol, metoprolol, and bisoprolol, and the Potassium-Channel-Blockers amiodarone, dronedarone, bretylium, sotalol, ibutilide, and dofetilide. Angiotensin-converting-enzyme (ACE) inhibitors and aldosterone antagonists are also sometimes used in this setting.
Invasive treatment
An ICD (implantable cardioverter defibrillator ) is more effective than drug therapy for prevention of sudden cardiac death due to VT and VF, but does not prevent these rhythm from happening.
Catheter ablation is a potentially definitive treatment option for those with recurrent VT. Remote magnetic navigation is one effective method to do the procedure.In the past, ablation was often not considered until pharmacological options had been exhausted, often after the patient had developed substantial morbidity from recurrent episodes of VT and ICD shocks. Antiarrhythmic medications can reduce the frequency of ICD therapies, but have efficacy varies and side effects can be significant. Advances in technology and understanding of VT substrates now allow ablation of multiple and unstable VTs with acceptable safety and efficacy, even in patients with advanced heart disease.
References
== External links == |
Pyogenic granuloma | A pyogenic granuloma or lobular capillary hemangioma is a vascular tumor that occurs on both mucosa and skin, and appears as an overgrowth of tissue due to irritation, physical trauma, or hormonal factors. It is often found to involve the gums, skin, or nasal septum, and has also been found far from the head, such as in the thigh.Pyogenic granulomas may be seen at any age, and are more common in females than males. In pregnant women, lesions may occur in the first trimester with an increasing incidence until the seventh month, and are often seen on the gums.
Signs and symptoms
The appearance of pyogenic granuloma is usually a color ranging from red/pink to purple, grows rapidly, and can be smooth or mushroom-shaped. Younger lesions are more likely to be red because of their high number of blood vessels. Older lesions begin to change into a pink color. Size commonly ranges from a few millimeters to centimeters, though smaller or larger lesions may occur. A pyogenic granuloma can be painful, especially if located in an area of the body where it is constantly disturbed. Pyogenic granulomas can grow rapidly and often bleed profusely with little or no trauma. They may exude an oil-like substance, causing the surface to be damp. This is especially true if the granuloma is located on the scalp.Epulis granulomatosum is a variant of pyogenic granuloma that forms only on gingiva, and is often seen forming in a recent extraction socket. Pyogenic granulomas appear on the gingiva in 75% of cases, more often in the maxillary than mandibular jaw. Anterior areas are more often affected than posterior areas. It can also be found on the lips, tongue, and inner cheek. Poor oral hygiene or trauma are usually precipitating factors.One study has suggested a correlation between pyogenic granulomas and Bartonella seropositivity. However, this association has been questioned by others. The microscopic appearance of a pyogenic granuloma consists of highly vascular granulation tissue. Inflammation is present. The lesion may have a fibrous character if it is older, and the surface may have ulcerations. Pyogenic granulomas rarely occur in the conjunctiva, cornea, or connective tissue of the eye following minor local trauma. Grossly, these mass lesions resemble those occurring at more common sites. The relationship of these lesions to lobular capillary hemangiomas of skin and oropharyngeal mucosa commonly referred to as pyogenic granuloma is uncertain.
Associated conditions
Due to its overwhelming incidence on the gingiva, the condition is often associated with two other diseases, though not because they occur together. Instead, the three are associated with each other because they appear frequently on gingiva—peripheral giant cell granuloma and peripheral ossifying fibroma. Detailed analysis can be used to distinguish these conditions.
Cause
Pyogenic granulomas are caused by proliferation of capillaries and are not caused by infection or cancer.
Diagnosis
A doctor likely can diagnose a pyogenic granuloma based on its appearance, and might perform a biopsy to make a more accurate diagnosis. A biopsy also helps rule out malignant (cancerous) medical conditions that can cause a similar kind of growth. These conditions include squamous-cell carcinoma, basal-cell carcinoma, and melanoma.Histopathological examination shows multiple capillaries (due to the vascular nature of the tumor), neutrophils (pyogenic), and necrotic tissue.
Management
Although pyogenic granulomas are not infectious or cancer, treatment may be considered because of bleeding or ulceration. Frequently, they are treated with electrodesiccation (cauterization) and curettage (excision), though laser treatment using pulsed dye laser or CO2 laser is often effective.Several reports have demonstrated the efficacy of topical application of the beta-adrenergic antagonist timolol in the treatment of pediatric pyogenic granuloma.Usually, no treatment is used if the pyogenic granuloma occurs during pregnancy, since the lesion may heal spontaneously. Recurrent bleeding in either oral or nasal lesions may necessitate excision and cauterization sooner, however. If aesthetics are a concern, then treatment may be pursued, as well. Usually, only minor surgery may be needed, along with a dental cleaning for oral lesions to remove any calculus or other source of irritation. For nasal lesions, nose-picking should be discouraged.
History
Pyogenic granulomas were first described in 1897 by two French surgeons, Antonin Poncet and Dor, who named these lesions botryomycosis hominis.
Terminology
The name "pyogenic granuloma" is misleading, as it is neither pyogenic or a true granuloma. In actuality, it is a capillary hemangioma of lobular subtype, which is why such a lesion is prone to bleeding. It is also not truly pyogenic (pus-producing), as the cause is hormonal or traumatic and has no association with infection or pus production.
See also
Trumpeters wart
List of cutaneous conditions
References
== External links == |
Vitamin B6 | Vitamin B6 is one of the B vitamins, and thus an essential nutrient. The term refers to a group of six chemically similar compounds, i.e., "vitamers", which can be interconverted in biological systems. Its active form, pyridoxal 5′-phosphate, serves as a coenzyme in more than 140 enzyme reactions in amino acid, glucose, and lipid metabolism.Plants synthesize pyridoxine as a means of protection from the ultraviolet-B radiation of sunlight and to participate in synthesis of chlorophyll. Animals cannot synthesize any of the various forms of the vitamin, and hence must obtain it via diet, either of plants, or of other animals. There is some absorption of the vitamin produced by intestinal bacteria, but this is not sufficient to meet needs. For adult humans, recommendations from various countries food regulatory agencies are in the range of 1.0 to 2.0 milligrams (mg) per day. These same agencies also recognize ill effects from intakes that are too high, and so set safe upper limits, ranging from as low as 25 mg/day to as high as 100 mg/day depending on the country. Beef, pork, fowl and fish are generally good sources; dairy, eggs, mollusks and crustaceans also contain vitamin B6, but at lower levels. There is enough in a wide variety of plant foods so that a vegetarian or vegan diet does not put consumers at risk for deficiency.Dietary deficiency is rare. Classic clinical symptoms include rash and inflammation around the mouth and eyes, plus neurological effects that include drowsiness and peripheral neuropathy affecting sensory and motor nerves in the hands and feet. In addition to dietary shortfall, deficiency can be the result of anti-vitamin drugs. There are also rare genetic defects that can trigger vitamin B6 deficiency-dependent epileptic seizures in infants. These are responsive to pyridoxal 5-phosphate therapy.
Definition
Vitamin B6 is a water-soluble vitamin, one of the B vitamins. The vitamin actually comprises a group of six chemically related compounds, i.e., vitamers, that all contain a pyridine ring as their core. These are pyridoxine, pyridoxal, pyridoxamine, and their respective phosphorylated derivatives pyridoxine 5-phosphate, pyridoxal 5-phosphate and pyridoxamine 5-phosphate. Pyridoxal 5-phosphate has the highest biological activity, but the others are convertible to that form. Vitamin B6 serves as a co-factor in more than 140 cellular reactions, mostly related to amino acid biosynthesis and catabolism, but is also involved in fatty acid biosynthesis and other physiological functions.
Forms
Because of its chemical stability, pyridoxine hydrochloride is the form most commonly given as vitamin B6 dietary supplement. Absorbed pyridoxine (PN) is converted to pyridoxamine 5-phosphate (PMP) by the enzyme pyridoxal kinase, with PMP further converted to pyridoxal 5-phosphate (PLP), the metabolically active form, by the enzymes pyridoxamine-phosphate transaminase or pyridoxine 5-phosphate oxidase, the latter of which also catalyzes the conversion of pyridoxine 5′-phosphate (PNP) to PLP. Pyridoxine 5-phosphate oxidase is dependent on flavin mononucleotide (FMN) as a cofactor produced from riboflavin (vitamin B2). For degradation, in a non-reversible reaction, PLP is catabolized to 4-pyridoxic acid, which is excreted in urine.
Synthesis
Biosynthesis
Two pathways for PLP are currently known: one requires deoxyxylulose 5-phosphate (DXP), while the other does not, hence they are known as DXP-dependent and DXP-independent. These pathways have been studied extensively in Escherichia coli and Bacillus subtilis, respectively. Despite the disparity in the starting compounds and the different number of steps required, the two pathways possess many commonalities. The DXP-dependent pathway:
Commercial synthesis
The starting material is either the amino acid alanine, or propionic acid converted into alanine via halogenation and amination. Then, the procedure accomplishes the conversion of the amino acid into pyridoxine through the formation of an oxazole intermediate followed by a Diels–Alder reaction, with the entire process referred to as the "oxazole method". The product used in dietary supplements and food fortification is pyridoxine hydrochloride, the chemically stable hydrochloride salt of pyridoxine. Pyridoxine is converted in the liver into the metabolically active coenzyme form pyridoxal 5-phosphate. At present, while the industry mainly utilizes the oxazole method, there is research exploring means of using less toxic and dangerous reagents in the process. Fermentative bacterial biosynthesis methods are also being explored, but are not yet scaled up for commercial production.
Functions
PLP is involved in many aspects of macronutrient metabolism, neurotransmitter synthesis, histamine synthesis, hemoglobin synthesis and function, and gene expression. PLP generally serves as a coenzyme (cofactor) for many reactions including decarboxylation, transamination, racemization, elimination, replacement, and beta-group interconversion.
Amino acid metabolism
Transaminases break down amino acids with PLP as a cofactor. The proper activity of these enzymes is crucial for the process of moving amine groups from one amino acid to another. To function as a transaminase coenzyme, PLP bound to a lysine of the enzyme then binds to a free amino acid via formation of a Schiffs base. The process then dissociates the amine group from the amino acid, releasing a keto acid, then transfers the amine group to a different keto acid to create a new amino acid.
Serine racemase which synthesizes the neuromodulator D-serine from its enantiomer is a PLP-dependent enzyme.
PLP is a coenzyme needed for the proper function of the enzymes cystathionine synthase and cystathionase. These enzymes catalyze reactions in the catabolism of methionine. Part of this pathway (the reaction catalyzed by cystathionase) also produces cysteine.
Selenomethionine is the primary dietary form of selenium. PLP is needed as a cofactor for the enzymes that allow selenium to be used from the dietary form. PLP also plays a cofactor role in releasing selenium from selenohomocysteine to produce hydrogen selenide, which can then be used to incorporate selenium into selenoproteins.
PLP is required for the conversion of tryptophan to niacin, so low vitamin B6 status impairs this conversion.
Neurotransmitters
PLP is a cofactor in the biosynthesis of five important neurotransmitters: serotonin, dopamine, epinephrine, norepinephrine, and gamma-aminobutyric acid.
Glucose metabolism
PLP is a required coenzyme of glycogen phosphorylase, the enzyme necessary for glycogenolysis. Glycogen serves as a carbohydrate storage molecule, primarily found in muscle, liver and brain. Its breakdown frees up glucose for energy. PLP also catalyzes transamination reactions that are essential for providing amino acids as a substrate for gluconeogenesis, the biosynthesis of glucose.
Lipid metabolism
PLP is an essential component of enzymes that facilitate the biosynthesis of sphingolipids. Particularly, the synthesis of ceramide requires PLP. In this reaction, serine is decarboxylated and combined with palmitoyl-CoA to form sphinganine, which is combined with a fatty acyl-CoA to form dihydroceramide. This compound is then further desaturated to form ceramide. In addition, the breakdown of sphingolipids is also dependent on vitamin B6 because sphingosine-1-phosphate lyase, the enzyme responsible for breaking down sphingosine-1-phosphate, is also PLP-dependent.
Hemoglobin synthesis and function
PLP aids in the synthesis of hemoglobin, by serving as a coenzyme for the enzyme aminolevulinic acid synthase. It also binds to two sites on hemoglobin to enhance the oxygen binding of hemoglobin.
Gene expression
PLP has been implicated in increasing or decreasing the expression of certain genes. Increased intracellular levels of the vitamin lead to a decrease in the transcription of glucocorticoids. Vitamin B6 deficiency leads to the increased gene expression of albumin mRNA. Also, PLP influences expression of glycoprotein IIb by interacting with various transcription factors; the result is inhibition of platelet aggregation.
In plants
Plant synthesis of vitamin B6 contributes to protection from sunlight. Ultraviolet-B radiation (UV-B) from sunlight stimulates plant growth, but in high amounts can increase production of tissue-damaging reactive oxygen species (ROS), i.e., oxidants. Using Arabidopsis thaliana (common name: thale cress), researchers demonstrated that UV-B exposure increased pyridoxine biosynthesis, but in a mutant variety, pyridoxine biosynthesis capacity was not inducible, and as a consequence, ROS levels, lipid peroxidation, and cell proteins associated with tissue damage were all elevated. Biosynthesis of chlorophyll depends on aminolevulinic acid synthase, a PLP-dependent enzyme that uses succinyl-CoA and glycine to generate aminolevulinic acid, a chlorophyll precursor. In addition, plant mutants with severely limited capacity to synthesize vitamin B6 have stunted root growth, because synthesis of plant hormones such as auxin require the vitamin as an enzyme cofactor.
Medical uses
Isoniazid is an antibiotic used for the treatment of tuberculosis. Common side effect include numbness in the hands and feet, also known as peripheral neuropathy. Co-treatment with vitamin B6 alleviates the numbness.Overconsumption of seeds from Ginkgo biloba can deplete vitamin B6, because the ginkgotoxin is an anti-vitamin (vitamin antagonist). Symptoms include vomiting and generalized convulsions. Ginkgo seed poisoning can be treated with vitamin B6.
Dietary recommendations
The US National Academy of Medicine updated Dietary Reference Intakes for many vitamins in 1998. Recommended Dietary Allowances (RDAs), expressed as milligrams per day, increase with age from 1.2 to 1.5 mg/day for women and from 1.3 to 1.7 mg/day for men. The RDA for pregnancy is 1.9 mg/day, for lactation, 2.0 mg/day. For children ages 1–13 years the RDA increases with age from 0.5 to 1.0 mg/day. As for safety, Tolerable upper intake levels (ULs) for vitamins and minerals are identified when evidence is sufficient. In the case of vitamin B6 the adult UL is set at 100 mg/day.The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA. For women and men ages 15 and older the PRI is set at 1.6 and 1.7 mg/day, respectively; for pregnancy 1.8 mg/day, for lactation 1.7 mg/day. For children ages 1–14 years the PRIs increase with age from 0.6 to 1.4 mg/day. The EFSA also reviewed the safety question and set its UL at 25 mg/day.The Japanese Ministry of Health, Labour and Welfare updated its vitamin and mineral recommendations in 2015. The adult RDAs are at 1.2 mg/day for women 1.4 mg/day for men. The RDA for pregnancy is 1.4 mg/day, for lactation is 1.5 mg/day. For children ages 1–17 years the RDA increases with age from 0.5 to 1.5 mg/day. The adult UL was set at 40–45 mg/day for women and 50–60 mg/day for men, with the lower values in those ranges for adults over 70 years of age.
Safety
Adverse effects have been documented from vitamin B6 dietary supplements, but never from food sources. Even though it is a water-soluble vitamin and is excreted in the urine, doses of pyridoxine in excess of the dietary upper limit (UL) over long periods cause painful and ultimately irreversible neurological problems. The primary symptoms are pain and numbness of the extremities. In severe cases, motor neuropathy may occur with "slowing of motor conduction velocities, prolonged F wave latencies, and prolonged sensory latencies in both lower extremities", causing difficulty in walking. Sensory neuropathy typically develops at doses of pyridoxine in excess of 1,000 mg per day, but adverse effects can occur with much less, so intakes over 200 mg/day are not considered safe. Trials with amounts equal to or less than 200 mg/day established that as a "No-observed-adverse-effect level", meaning the highest amount at which no adverse effects were observed. This was divided by two to allow for people who might be extra sensitive to the vitamin, referred to as an "uncertainty factor", resulting in the aforementioned adult UL of 100 mg/day.
Labeling
For US food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value. For vitamin B6 labeling purposes 100% of the Daily Value was 2.0 mg, but as of May 27, 2016 it was revised to 1.7 mg to bring it into agreement with the adult RDA. A table of the old and new adult daily values is provided at Reference Daily Intake.
Sources
Bacteria residing in the large intestine are known to synthesize B-vitamins, including B6, but the amounts are not sufficient to meet host requirements, in part because the vitamins are competitively taken up by non-synthesizing bacteria.Vitamin B6 is found in a wide variety of foods. In general, meat, fish and fowl are good sources, but dairy foods and eggs are not (table). Crustaceans and mollusks contain about 0.1 mg/100 grams. Fruit (apples, oranges, pears) contain less than 0.1 mg/100g.Bioavailability from a mixed diet (containing animal- and plant-sourced foods) is estimated at being 75% – higher for PLP from meat, fish and fowl, lower from plants, as those are mostly in the form of pyridoxine glucoside, which has approximately half the bioavailability of animal-sourced B6 because removal of the glucoside by intestinal cells is not 100% efficient. Given lower amounts and lower bioavailability of the vitamin from plants there was a concern that a vegetarian or vegan diet could cause a vitamin deficiency state. However, the results from a population-based survey conducted in the U.S. demonstrated that despite a lower vitamin intake, serum PLP was not significantly different between meat-eaters and vegetarians, suggesting that a vegetarian diet does not pose a risk for vitamin B6 deficiency.Cooking, storage, and processing losses vary, and in some foods may be more than 50% depending on the form of vitamin present in the food. Plant foods lose less during processing, as they contain pyridoxine, which is more stable than the pyridoxal or pyridoxamine forms found in animal-sourced foods. For example, milk can lose 30–70% of its vitamin B6 content when dried. The vitamin is found in the germ and aleurone layer of grains, so there is more in whole wheat bread compared to white bread wheat, and more in brown rice compared to white rice.Most values shown in the table are rounded to nearest tenth of a milligram:
Fortification
As of 2019, fourteen countries require food fortification of wheat flour, maize flour or rice with vitamin B6 as pyridoxine hydrochloride. Most of these are in southeast Africa or Central America. The amounts stipulated range from 3.0 to 6.5 mg/kg. An additional seven countries, including India, have a voluntary fortification program. India stipulates 2.0 mg/kg.
Dietary supplements
In the US, multi-vitamin/mineral products typically contain 2 to 4 mg of vitamin B6 per daily serving as pyridoxine hydrochloride, but a few contain more than 25 mg. Many US dietary supplement companies also market a B6-only dietary supplement with 100 mg per daily serving. While the US National Academy of Medicine sets an adult safety UL at 100 mg/day, the European Food Safety Authority sets its UL at 25 mg/day.
Health claims
The Japanese Ministry of Health, Labour, and Welfare (MHLW) set up the Foods for Specified Health Uses (特定保健用食品; FOSHU) regulatory system in 1991 to individually approve the statements made on food labels concerning the effects of foods on the human body. The regulatory range of FOSHU was later broadened to allow for the certification of capsules and tablets. In 2001, MHLW enacted a new regulatory system, Foods with Health Claims (保健機能食品; FHC), which consists of the existing FOSHU system and the newly established Foods with Nutrient Function Claims (栄養機能表示食品; FNFC), under which claims were approved for any product containing a specified amount per serving of 12 vitamins, including vitamin B6, and two minerals. To make a health claim based on a foods vitamin B6 content, the amount per serving must be in the range of 0.3–25 mg. The allowed claim is: "Vitamin B6 is a nutrient that helps produce energy from protein and helps maintain healthy skin and mucous membranes."In 2010, the European Food Safety Authority (EFSA) published a review of proposed health claims for vitamin B6, disallowing claims for bone, teeth, hair skin and nails, and allowing claims that the vitamin provided for normal homocysteine metabolism, normal energy-yielding metabolism, normal psychological function, reduced tiredness and fatigue, and provided for normal cysteine synthesis.The US Food and Drug Administration (FDA) has several processes for permitting health claims on food and dietary supplement labels. There are no FDA-approved Health Claims or Qualified Health Claims for vitamin B6. Structure/Function Claims can be made without FDA review or approval as long as there is some credible supporting science. Examples for this vitamin are "Helps support nervous system function" and "Supports healthy homocysteine metabolism."
Absorption, metabolism and excretion
Vitamin B6 is absorbed in the jejunum of the small intestine by passive diffusion. Even extremely large amounts are well absorbed. Absorption of the phosphate forms involves their dephosphorylation catalyzed by the enzyme alkaline phosphatase. Most of the vitamin is taken up by the liver. There, the dephosphorylated vitamins are converted to the phosphorylated PLP, PNP and PMP, with the two latter converted to PLP. In the liver, PLP is bound to proteins, primarily albumin. The PLP-albumin complex is what is released by the liver to circulate in plasma. Protein-binding capacity is the limiting factor for vitamin storage. Total body stores, the majority in muscle, with a lesser amount in liver, have been estimated to be in the range of 61 to 167 mg.Enzymatic processes utilize PLP as a phosphate-donating cofactor. PLP is restored via a salvage pathway that requires three key enzymes, pyridoxal kinase, pyridoxine 5-phosphate oxidase, and phosphatases. Inborn errors in the salvage enzymes are known to cause inadequate levels of PLP in the cell, particularly in neuronal cells. The resulting PLP deficiency is known to cause or implicated in several pathologies, most notably infant epileptic seizures.The end-product of vitamin B6 catabolism is 4-pyridoxic acid, which makes up about half of the B6 compounds in urine. 4-Pyridoxic acid is formed by the action of aldehyde oxidase in the liver. Amounts excreted increase within 1–2 weeks with vitamin supplementation and decrease as rapidly after supplementation ceases. Other vitamin forms excreted in the urine include pyridoxal, pyridoxamine and pyridoxine, and their phosphates. When large doses of pyridoxine are given orally, the proportion of these other forms increases. A small amount of vitamin B6 is also excreted in the feces. This may be a combination of unabsorbed vitamin and what was synthesized by large intestine microbiota.
Deficiency
Signs and symptoms
The classic clinical syndrome for vitamin B6 deficiency is a seborrhoeic dermatitis-like eruption, atrophic glossitis with ulceration, angular cheilitis, conjunctivitis, intertrigo, and neurologic symptoms of somnolence, confusion, and neuropathy (due to impaired sphingosine synthesis) and microcytic anemia (due to impaired heme synthesis).Less severe cases present with metabolic disease associated with insufficient activity of the coenzyme PLP. The most prominent of the lesions is due to impaired tryptophan–niacin conversion. This can be detected based on urinary excretion of xanthurenic acid after an oral tryptophan load. Vitamin B6 deficiency can also result in impaired transsulfuration of methionine to cysteine. The PLP-dependent transaminases and glycogen phosphorylase provide the vitamin with its role in gluconeogenesis, so deprivation of vitamin B6 results in impaired glucose tolerance.
Diagnosis
The assessment of vitamin B6 status is essential, as the clinical signs and symptoms in less severe cases are not specific. The three biochemical tests most widely used are plasma PLP concentrations, the activation coefficient for the erythrocyte enzyme aspartate aminotransferase, and the urinary excretion of vitamin B6 degradation products, specifically urinary PA. Of these, plasma PLP is probably the best single measure, because it reflects tissue stores. Plasma PLP of less than 10 nmol/l is indicative of vitamin B6 deficiency. A PLP concentration greater than 20 nmol/l has been chosen as a level of adequacy for establishing Estimated Average Requirements and Recommended Daily Allowances in the USA. Urinary PA is also an indicator of vitamin B6 deficiency; levels of less than 3.0 mmol/day is suggestive of vitamin B6 deficiency. Other methods of measurement, including UV spectrometric, spectrofluorimetric, mass spectrometric, thin-layer and high-performance liquid chromatographic, electrophoretic, electrochemical, and enzymatic, have been developed.The classic clinical symptoms for vitamin B6 deficiency are rare, even in developing countries. A handful of cases were seen between 1952 and 1953, particularly in the United States, having occurred in a small percentage of infants who were fed a formula lacking in pyridoxine.
Causes
A deficiency of vitamin B6 alone is relatively uncommon and often occurs in association with other vitamins of the B complex. Evidence exists for decreased levels of vitamin B6 in women with type 1 diabetes and in patients with systemic inflammation, liver disease, rheumatoid arthritis, and those infected with HIV. Use of oral contraceptives and treatment with certain anticonvulsants, isoniazid, cycloserine, penicillamine, and hydrocortisone negatively impact vitamin B6 status. Hemodialysis reduces vitamin B6 plasma levels.
Genetic defects
Genetically confirmed diagnoses of diseases affecting vitamin B6 metabolism (ALDH7A1 deficiency, pyridoxine-5-phosphate oxidase deficiency, PLP binding protein deficiency, hyperprolinaemia type II and hypophosphatasia) can trigger vitamin B6 deficiency-dependent epileptic seizures in infants. These are responsive to pyridoxal 5-phosphate therapy.
History
An overview of the history was published in 2012. In 1934, the Hungarian physician Paul György discovered a substance that was able to cure a skin disease in rats (dermatitis acrodynia). He named this substance vitamin B6, as numbering of the B vitamins was chronological, and pantothenic acid had been assigned vitamin B5 in 1931. In 1938, Richard Kuhn was awarded the Nobel Prize in Chemistry for his work on carotenoids and vitamins, specifically B2 and B6. Also in 1938, Samuel Lepkovsky isolated vitamin B6 from rice bran. A year later, Stanton A. Harris and Karl August Folkers determined the structure of pyridoxine and reported success in chemical synthesis, and then in 1942 Esmond Emerson Snell developed a microbiological growth assay that led to the characterization of pyridoxamine, the aminated product of pyridoxine, and pyridoxal, the formyl derivative of pyridoxine. Further studies showed that pyridoxal, pyridoxamine, and pyridoxine have largely equal activity in animals and owe their vitamin activity to the ability of the organism to convert them into the enzymatically active form pyridoxal-5-phosphate.Following a recommendation of IUPAC-IUB in 1973, vitamin B6 is the official name for all 2-methyl,3-hydroxy,5-hydroxymethylpyridine derivatives exhibiting the biological activity of pyridoxine. Moreover, pyridoxine alone should not to be used as a synonym of vitamin B6.
Research
Observational studies suggested an inverse correlation between a higher intake of vitamin B6 and all cancers, with the strongest evidence for gastrointestinal cancers. However, evidence from a review of randomized clinical trials did not support a protective effect. The authors noted that high B6 intake may be an indicator of higher consumption of other dietary protective micronutrients. A review and two observational trials reporting lung cancer risk reported that serum vitamin B6 was lower in people with lung cancer compared to people without lung cancer, but did not incorporate any intervention or prevention trials.According to a prospective cohort study the long-term use of vitamin B6 from individual supplement sources at greater than 20 mg per day, which is more than ten times the adult male RDA of 1.7 mg/day, was associated with an increased risk for lung cancer among men. Smoking further elevated this risk. However, a more recent review of this study suggested that a causal relationship between supplemental vitamin B6 and an increased lung cancer risk cannot be confirmed yet.For coronary heart disease, a meta-analysis reported lower relative risk for a 0.5 mg/day increment in dietary vitamin B6 intake. As of 2021, there were no published reviews of randomized clinical trials for coronary heart disease or cardiovascular disease. In reviews of observational and intervention trials, neither higher vitamin B6 concentrations nor treatment showed any significant benefit on cognition and dementia risk. Low dietary vitamin B6 correlated with a higher risk of depression in women but not in men. When treatment trials were reviewed, no meaningful treatment effect for depression was reported, but a subset of trials in pre-menopausal women suggested a benefit, with a recommendation that more research was needed. The results of several trials with children diagnosed as having autism spectrum disorder (ASD) treated with high dose vitamin B6 and magnesium did not result in treatment effect on the severity of symptoms of ASD.
References
External links
The B6 database A database of B6-dependent enzymes at University of Parma
Vitamin+B6 at the US National Library of Medicine Medical Subject Headings (MeSH) |
Rapid eye movement sleep behavior disorder | Rapid eye movement sleep behavior disorder or REM behavior disorder (RBD) is a sleep disorder in which people act out their dreams. It involves abnormal behavior during the sleep phase with rapid eye movement (REM) sleep. The major feature of RBD is loss of muscle atonia (i.e., the loss of paralysis) during otherwise intact REM sleep (during which paralysis is not only normal but necessary). The loss of motor inhibition leads to sleep behaviors ranging from simple limb twitches to more complex integrated movements that can be violent or result in injury to either the individual or their bedmates.RBD is a very strong predictor of progression to a synucleinopathy (usually Parkinsons disease or dementia with Lewy bodies). Melatonin is useful in the treatment of RBD. RBD was first described in 1986.
Classification
RBD is a parasomnia. It is categorized as either idiopathic or symptomatic. Idiopathic RBD is the term used when RBD is not associated with another ongoing neurological condition. When it results from an identifiable cause, RBD is referred to as symptomatic RBD (and considered a symptom of the underlying disorder).
Characteristics
RBD is characterized by the dreamer acting out their dreams, with complex behaviors. These dreams often involve screaming, shouting, laughing, crying, arm flailing, kicking, punching, choking, and jumping out of bed. The actions in an episode can result in injuries to oneself or ones bedmate. The sleeping person may be unaware of these movements. Dreams often involve violent or aggressive actions, and an attack theme like being chased by people or animals. Because violence in dreams is more likely to be recalled, this could be an artifact of recall bias or selection bias. The individual with RBD may not be aware of having it. When awakened, people may be able to recall the dream they were having, which will match the actions they were performing.As the first indication of an underlying neurodegenerative disorder or synucleinopathy, symptoms of RBD may begin years or decades before the onset of another condition. Abnormal sleep behaviors may begin decades before any other symptoms, often as the first clinical indication if another condition.Symptomatic RBD can also be associated with narcolepsy, Guillain–Barré syndrome, limbic encephalitis, and Morvans syndrome.Other symptoms found in patients with RBD are reduced motor abilities, posture and gait changes, mild cognitive impairment, alterations in the sense of smell, impairments in color vision, autonomic dysfunction (orthostatic hypotension, constipation, urinary problems and sexual dysfunction), and depression.
Causes
Rapid eye movement behavior disorder occurs when there is a loss of normal voluntary muscle atonia during REM sleep resulting in motor behavior in response to dream content. It can be caused by adverse reactions to certain drugs or during drug withdrawal; however, it is most often associated with the elderly and in those with neurodegenerative disorders such as Parkinsons disease and other neurodegenerative diseases, for example multiple system atrophy and the Lewy body dementias.The underlying cause of RBD is not well understood, but it is likely that RBD is an early symptom of synucleinopathy rather than a separate disorder. Brainstem circuits that control atonia during REM sleep may be damaged, including those in the pontomedullary brainstem. REM sleep circuits are located in caudal brainstem structures—the same structures that are known to lead to be implicated in the synucleinopathies. Motor deficits like those seen in RBD are known to result from lesions in those circuits.Risk factors for developing RBD are a family history of acting out dreams, prior head injury, farming, exposure to pesticides, low education level, depression, and use of antidepressants.RBD may be acute and sudden in onset if associated with drug treatment or withdrawal (particularly with alcohol withdrawal). Antidepressant medications can induce or aggravate RBD symptoms.
Diagnosis
There are two ways to diagnose RBD: by documenting a history of complex, dream-enactment sleep behaviors, or by polysomnography recording of these behaviors along with REM sleep atonia loss.RBD may be established from clinical interview as well as several validated questionnaires, when sleep studies cannot be performed. Questionnaires such as the Rapid Eye Movement (REM) sleep Behavior Disorder Screening Questionnaire (RBDSQ), the REM Sleep Behavior Questionnaires – Hong-Kong (RBD-HK), the Mayo Sleep Questionnaire (MSQ) and the Innsbruck REM Sleep Behavior Disorder Inventory are well-validated.
Individuals with RBD may not be able to provide a history of dream enactment behavior, so bed partners are also consulted. The REM Sleep Behavior Disorder Single-Question Screen offers diagnostic sensitivity and specificity in the absence of polysomnography with one question: "Have you ever been told, or suspected yourself, that you seem to act out your dreams while asleep (for example, punching, flailing your arms in the air, making running movements, etc.)?"
Diagnostic criteria for RBD from the International Classification of Sleep Disorders (ICSD-3) are:
Repetition of vocalizations and/or complex motor behaviors during sleep
Polysomnography (PSG) show that these behaviors occur during REM sleep
If documentation of these behaviors by PSG is not possible, they must at least be assumed to take place during REM sleep based on records of dream enactment
REM sleep without atonia (RWA) can be seen in polysomnographic recordings
Episodes cannot be explained by another mental disorder, sleep disorder, substance abuse or medication
Differential
Other conditions are similar to RBD in that individuals exhibit excessive sleep movement and potentially violent behavior. Such disorders include non-REM parasomnias (sleepwalking, sleep terrors), periodic limb movement disorder, severe obstructive sleep apnea, and dissociative disorders. Because of the similarities between the conditions, polysomnography plays an important role in confirming RBD diagnosis.
Treatment
RBD is treatable (even when the underlying synucleinopathies are not). Melatonin and clonazepam are the most frequently used, and are comparably effective, but melatonin offers a safer alternative, because clonazepam can produce undesirable side effects. Other medications and treatments are available, but have only anecdotal evidence.Medications that may worsen RBD and should be stopped if possible are tramadol, mirtazapine, antidepressants, and beta blockers.In addition to medication, it is wise to secure the sleepers environment by removing potentially dangerous objects from the bedroom and either place a cushion around the bed or move the mattress to the floor for added protection against injuries. In extreme cases, an affected individual has slept in a sleeping bag zipped up to their neck, wearing mittens so they cannot unzip it until they awake.Patients are advised to maintain a normal sleep schedule, avoid sleep deprivation, and keep track of any sleepiness they may have. Treatment includes regulating neurologic symptoms and treating any other sleep disorders that might interfere with sleep. Sleep deprivation, alcohol, certain medications, and other sleep disorders can all increase RBD and should be avoided if possible.
Prognosis
Patients with RBD are at risk for sleep-related injury.Almost 92% of patients with idiopathic RBD will go on to develop a neurodegenerative disorder. The disorders most strongly associated with RBD are the synucleinopathies, particularly Parkinsons disease, dementia with Lewy bodies, and to a lesser extent, multiple system atrophy. Most people with RBD will convert to a synucleinopathy—usually Parkinsons disease or dementia with Lewy bodies—within 4 to 9 years from diagnosis of RBD, and 11 to 16 years from onset of symptoms.
Epidemiology
RBD prevalence as of 2017 is estimated to be 0.5–2% overall, and 5–13% of those aged 60 to 99. It is more common in males overall, but equally frequent among men and women below the age of 50. This may partially be due to a referral bias, as violent activity carried out by men is more likely to result in harm and injury and is more likely to be reported than injury to male bed partners by women, or it may reflect a true difference in prevalence as a result of genetic or androgenic factors. Typical onset is in the 50s or 60s.Almost half of those with Parkinsons, at least 88% of those with multiple system atrophy, and about 80% of people with Lewy body dementia have RBD. RBD is a very strong predictor of progression to a synucleinopathy (for example, the Lewy body dementias). On autopsy, up to 98% of individuals with polysomnography-confirmed RBD are found to have a synucleinopathy.
History
In the 1960s and 1970s, Michel Jouvet described brain lesions in cats that led to loss of atonia in REM sleep. Carlos Schenck and Mark Mahowald and their team in Minnesota first described RBD in 1986.
In animals
RBD has also been diagnosed in animals; specifically dogs.
See also
Sleepwalk with Me
Pseudobulbar affect
Gelastic seizure
References
Further reading
Roguski A, Rayment D, Whone AL, Jones MW, Rolinski M (2020). "A Neurologists Guide to REM Sleep Behavior Disorder". Front Neurol (Review). 11: 610. doi:10.3389/fneur.2020.00610. PMC 7360679. PMID 32733361. |
Rapid sequence induction | In advanced airway management, rapid sequence induction (RSI) – also referred to as rapid sequence intubation or as rapid sequence induction and intubation (RSII) or as crash induction – is a special process for endotracheal intubation that is used where the patient is at a high risk of pulmonary aspiration. It differs from other techniques for inducing general anesthesia in that several extra precautions are taken to minimize the time between giving the induction drugs and securing the tube, during which period the patients airway is essentially unprotected.First described by William Stept and Peter Safar in 1970, "classical" or "traditional" RSI involves pre-filling the patients lungs with a high concentration of oxygen gas; applying cricoid pressure to occlude the esophagus; administering pre-determined doses of rapid-onset sedative and neuromuscular-blocking drugs (traditionally thiopentone and suxamethonium) that induce prompt unconsciousness and paralysis; avoiding any artificial positive-pressure ventilation by mask after the patient stops breathing (to minimize insufflation of air into the stomach, which might otherwise provoke regurgitation); inserting a cuffed endotracheal tube with minimal delay; and then releasing the cricoid pressure after the cuff is inflated, with ventilation being started through the tube. There is no consensus around the precise definition of the term "modified RSI", but it is used to refer to various modifications that deviate from the classic sequence – usually to improve the patients physiological stability during the procedure, at the expense of theoretically increasing the risk of regurgitation. Examples of such modifications include using various alternative drugs, omitting the cricoid pressure, or applying ventilation before the tube has been secured.The procedure is used where general anesthesia must be induced before the patient has had time to fast long enough to empty the stomach; where the patient has a condition that makes aspiration more likely during induction of anesthesia, regardless of how long they have fasted (such as gastroesophageal reflux disease or advanced pregnancy); or where the patient has become unable to protect their own airway even before anesthesia (such as after a traumatic brain injury).
The induction drugs classically used for RSI have short durations of action, wearing off after only minutes. This confers a degree of fault tolerance on the procedure when it is used in elective or semi-elective settings: if intubation is unsuccessful, and if the clinical condition allows it, the procedure may be abandoned and the patient should regain the ability to protect their own airway sooner than would be the case under routine methods of induction. Conversely, in emergency settings where the patients condition does not allow for them to be woken up immediately, a failed intubation under RSI places them at very high risk for respiratory compromise.
Common medications
Premedication
Premedication is used to reduce anxiety of those who are going to be intubated and to reduce the anticipated physiological response of the patient during intubation.
Midazolam – It is a fast-acting and the most lipophilic of all benzodiazepine and rapidly crosses the blood–brain barrier. It is a gamma-aminobutyric acid (GABA) agonist. Usual doses for midazolam are 1 mg to 2 mg where the older people receive smaller doses and obese people receive higher doses. Midazolam is metabolised in the liver and is excreted through the kidneys. When midazolam is used alone, it has few side effects, but can cause respiratory depression if being used together with fentanyl.
Fentanyl – It is a synthetic, centrally-acting opioid. It suppresses pain and sympathetic stimulation. Sympathetic stimulation can cause further injury to those with heart disease, aortic dissection, and aortic aneurysm. Fentanyl is ideal because of its rapid onset, lack of histamine release, high lipophilicity, and short duration of action. The dosage is between 1 and 3 μg/kg. It is metabolised by liver. The most significant side effect is respiratory depression.
Atropine – The process of intubation can cause massive stimulation to vagus nerve, causing bradycardia (low heart rate). The people who are at increased risk of bradycardia are neonates and children. This does not happen in adults because sympathetic stimulation overpowers the vagal response. However, for those adults who have received drugs such as beta blocker, calcium channel blocker, and digoxin have an increased risk of developing bradycardia. Atropine is a muscarinic receptor antagonist, thus blocking the vagal response. The dose is 0.01 mg/kg. It has quick onset of action, and common side effects are: increased heart rate, dry mouth, flushing, and urinary retention.
Lidocaine – It is used to reduce the sympathetic response in those who have suspected raised intracranial pressure (ICP) or those who received succinylcholine which also causes increase ICP or those with underlying asthma that have bronchospasm. Administration of lidocaine can causes reduction in mean arterial pressure (MAP). The dosage is 1.5 mg/kg. This drug is metabolised by liver. The side effects are: hypotension, arrythmia (irregular heart beat). Lidocaine can further interact with other drugs such as amiodarone and monoamine oxidase inhibitor to cause hypotension, and dronedarone to cause arrhythmia.
Induction agents
Administration of induction agents followed by neuromuscular blockade agents helps to achieve optimal conditions for intubation.
Etomidate – It is an imidazole-derivative that stimulates GABA receptors. The dosage is between 0.2 and 0.6 mg/kg (commonly 20 to 50 mg doses). Dose reduction may be required in those with hypotension. Etomidate has minimal cardiovascular side effects, reduces intracerebral pressure (by reducing cerebral blood flow), and does not cause histamine release. It has quick onset of action, short duration of action, and undergoes hepatic elimination. Myoclonus, pain at the site of the injection, post-operative nausea and vomiting are common. It can also suppresses the production of cortisol and aldosterone.
Ketamine – It is highly lipophilic and crosses the blood-brain barrier. It inhibits the binding of glutamine to N-Methyl-D-aspartic acid (NMDA) receptors in Thalamocortical radiations and limbic system, causing amnesia. Through the same blockade of NMDA receptor, ketamine is also effective as a painkiller. The dosage is 1 to 2 mg/kg, usually given at 100 mg. Ketamine is metabolised by liver and excreted through kidneys. The drug lessen the reuptake of the catecholamine, increases heart rate, blood pressure, and cardiac output, thus suitable for those with hypotension. However, it can worsen the cardiac depression and hypotension for those with depletion of catecholamines. Thus, maximum dose of 1.5 mg/kg is need for this situation. For those with head injuries, ketamine does not appear to increase intracranial pressure, while able to maintain the mean arterial pressure. Ketamine also relieves bronchospasm by relaxing bronchiolar smooth muscles. However, it increases oral secretions during intubation. Ketamine is associated with nightmares, delirium, and hallucinations.
Propofol – It is a highly lipid-soluble, GABA agonist. The dosage is 1.5 mg/kg (usually 100 to 200 mg). It has quick onset of action, can cross the blood-brain barrier, wide tissue distribution, and can be cleared by the body quickly. In the elderly, the rate of propofol clearance is low. Therefore, lower doses of propofol (50 to 100 mg) should be given. It is suitable in those with kidney or liver impairment and decreases intra-cranial pressure. For those with bronchospasm, propofol also has mild bronchodilating effect. However, propofol can induce hypotension and bradycardia due to its calcium channel blocker and beta blocker properties. At prolonged high propofol dosages, it can induce propofol infusion syndrome. Pain during peripheral administration of propofol can be reduced by using a large bore cannula.
Midazolam – Apart as a premedication, midazolam can be used as an induction agent at the dose of 0.2 to 0.3 mg/kg. It has slow onset of action when used alone, but the onset can be improved when using together with an opioid. However, for those with hypotension, midazolam can further reduce the blood pressure and has cardiac depressive effects. Therefore, dose reduction is required for the elderly, and for those with heart and liver failure.
Methohexital – This is a GABA agonist. It works by reducing the dissociation of GABA from its receptors. The dosage is 1.5 mg/kg. It is metabolised in liver. However, methohexital can cause respiratory depression, venodilatation, myocardial depression, and hypotension. Additionally, it can also cause reduced cerebral blood flow and histamine release. It can cause distal thrombosis and tissue necrosis if given into the arterial system.
Paralytics
Paralytics are also known as neuromuscular-blocking drugs (NMB). NMB can reduce the complication rates of rapid sequence induction such as inadequate oxygenation of the blood, airway complications, and instability of the cardiovascular system. NMB can be divided into two types: depolarising and non-depolarising blockers. Depolarising blockers resembles the acetylcholine and activates the motor end-plate of the neuromuscular junction (NMJ). Meanwhile, non-depolarising blockers competitively blocks the NMJ without activating the motor end plate.
Depolarising blockers
Succinylcholine – This drug has rapid onset of action and fast duration. Its dosages are between 1 and 2 mg/kg body weight with common dosage of 100 mg. The drug can only be kept under room temperature for 14 days. Therefore, for longer shelf life, it has to be kept under temperatures from 3.3 °C (37.9 °F) to 8.7 °C (47.7 °F). When the intravenous access is not obtainable, the 3 to 4 mg/kg of intramuscular doses can be given (usual dose of 300 mg). However, duration of onset will be delayed to 3 to 4 minutes. Repetitive dosages of succinylcholine are discouraged to prevent vagal stimulation which leads to bradycardia.
Non-depolarising blockers
Rocuronium – The dosage of rocuronium is between 0.6 and 1.2 mg/kg. Since rocuronium has longer duration of onset, caution should be taken for those who are difficult to bag-mask ventilate.
Vecuronium – The dosage of this drug is between 0.08 and 0.1 mg/kg. Vecuronium is only used when there is a shortage of drugs such as succinylcholine and rocuronium.
Reversal agents
Sugammadex – It is used as a reversal agent for rocuronium and vecuronium. It works by encapsulating the paralytic drug thus preventing it from acting on the binding sites. The dose of 16 mg/kg is used for immediate reversal after administration such as during RSI. Doses of 2 mg/kg and 4 mg/kg are used if the patient has twitches evident on a twitch monitor and terminates the rocuronium action within 3 minutes. The FDA initially did not approve Sugammadex due to concerns over potential allergic reactions, however it was subsequently approved on December 15, 2015 for use in the United States.
Neostigmine – It can be used to reverse nondepolarizing neuromuscular blocking agents which cannot be reversed with sugammadex, although its onset is much slower. It works by competing with acetylcholine for the binding sites of acetylcholinesterase, which in turn prevents the breaking down of acetylcholine. The dosage is between 0.03 and 0.07 mg/kg. The side effect of this drug is bradycardia. Therefore, glycopyrrolate should be given together with neostigmine to prevent bradycardia.
Other medications
Thiopental
Metaraminol or ephedrine, where hypotension may occur secondary to the sedating drugs.
Phenylephrine – This drug is administered to those with hypotension post intubation as a result of lidocaine, midazolam, fentanyl, propofol, and ketamine. The dosages range from 50 to 200 μg in adults. It has quick onset and quick elimination. The common side effect is reflex bradycardia.
Technique
Rapid sequence intubation refers to the pharmacologically induced sedation and neuromuscular paralysis prior to intubation of the trachea. The technique is a quicker form of the process normally used to induce general anesthesia. A useful framework for describing the technique of RSI is the "seven Ps".
Preparation
The patient is assessed to predict the difficulty of intubation. Continuous physiological monitoring such as ECG and pulse oximetry is put on the patient. The equipment and drugs for the intubation are planned, including the endotracheal tube size, the laryngoscope size, and drug dosage. Drugs are prepared in syringes. Intravenous access is obtained to deliver the drugs, usually by placing one or two IV cannulae.
Preoxygenation
The aim of preoxygenation is to replace the nitrogen that forms the majority of the functional residual capacity with oxygen. This provides an oxygen reservoir in the lungs that will delay the depletion of oxygen in the absence of ventilation (after paralysis). For a healthy adult, this can lead to maintaining a blood oxygen saturation of at least 90% for up to 8 minutes. This time will be significantly reduced in obese patients, ill patients and children. Preoxygenation is usually performed by giving 100% oxygen via a tightly fitting face mask. Preoxygenation or a maximum of eight deep breaths over 60 seconds resulting in blood oxygenation is not different from that of quiet breathing volume for 3 minutes.Newer methods of preoxygenation include the use of a nasal cannula placed on the patient at 15 LPM at least 5 minutes prior to the administration of the sedation and paralytic drugs. High flow nasal oxygen has been shown to flush the nasopharynx with oxygen, and then when patients inspire they inhale a higher percentage of inspired oxygen. Small changes in FiO2 create dramatic changes in the availability of oxygen at the alveolus, and these increases result in marked expansion of the oxygen reservoir in the lungs prior to the induction of apnea. After apnea created by RSI the same high flow nasal cannula will help maintain oxygen saturation during efforts securing the tube (oral intubation). The use of nasal oxygen during pre-oxygenation and continued during apnea can prevent hypoxia before and during intubation, even in extreme clinical cases.
Pretreatment
Pretreatment consists of the medications given to specific groups of high-risk patients 3 minutes before the paralysis stage with the aim of protecting the patient from the adverse effects of introducing the laryngoscope and endotracheal tube. Intubation causes increased sympathetic activity, an increase in intracranial pressure and bronchospasm. Patients with reactive airway disease, increased intracranial pressure, or cardiovascular disease may benefit from pretreatment. Two common medications used in the pretreatment of RSI include Lidocaine and Atropine. Lidocaine has the ability to suppress the cough reflex which in turn may mitigate increased intracranial pressure. For this reason Lidocaine is commonly used as a pretreatment for trauma patients who are suspected of already having an increase in intracranial pressure. Although there is not yet definitive evidence to support this, if proper dosing is used it is safe. The typical dose is 1.5 mg/kg IV given three minutes prior to intubation. Atropine may also be used as a premedication agent in pediatrics to prevent bradycardia caused by hypoxia, laryngoscopy, and succinylcholine. Atropine is a parasympathetic blocker. The common premedication dose for atropine is 0.01–0.02 mg/kg.
Paralysis with induction
With standard intravenous induction of general anesthesia, the patient typically receives an opioid, and then a hypnotic medication. Generally the patient will be manually ventilated for a short period of time before a neuromuscular blocking agent is administered and the patient is intubated. During rapid sequence induction, the person still receives an IV opioid. However, the difference lies in the fact that the induction drug and neuromuscular blocking agent are administered in rapid succession with no time allowed for manual ventilation.Commonly used hypnotics include thiopental, propofol and etomidate. The neuromuscular blocking agents paralyze all of the skeletal muscles, most notably and importantly in the oropharynx, larynx, and diaphragm. Opioids such as fentanyl may be given to attenuate the responses to the intubation process (accelerated heart rate and increased intracranial pressure). This is supposed to have advantages in patients with ischemic heart disease and those with brain injury (e.g. after traumatic brain injury or stroke). Lidocaine is also theorized to blunt a rise in intracranial pressure during laryngoscopy, although this remains controversial and its use varies greatly. Atropine may be used to prevent a reflex bradycardia from vagal stimulation during laryngoscopy, especially in young children and infants. Despite their common use, such adjunctive medications have not been demonstrated to improve outcomes.
Positioning
Positioning involves bringing the axes of the mouth, pharynx, and larynx into alignment, leading to whats called the "sniffing" position. The sniffing position can be achieved by placing a rolled towel underneath the head and neck, effectively extending the head and flexing the neck. You are at proper alignment when the ear is inline with the sternum.As described by Brian Arthur Sellick in 1961, cricoid pressure (alternatively known as Sellicks maneuver) may be used to occlude the esophagus with the goal of preventing aspiration.
Placement of tube
During this stage, laryngoscopy is performed to visualize the glottis. Modern practice involves the passing of a ‘Bougie’, a thin tube, past the vocal cords and over which the endotracheal tube is then passed. The bougie is then removed and an inbuilt cuff at the end of the tube is inflated, (via a thin secondary tube and a syringe), to hold it in place and prevent aspiration of stomach contents.
The position of the tube in the trachea can be confirmed in a number of ways, including observing increasing end tidal carbon dioxide, auscultation of both lungs and stomach, chest movement, and misting of the tube.
Postintubation management
Malpositioning of the endotracheal tube (in a bronchus, above the glottis, or in the esophagus) should be excluded by confirmation of end tidal CO2, auscultation and observation of bilateral chest rise.
One important difference between RSI and routine tracheal intubation is that the practitioner does not typically manually assist the ventilation of the lungs after the onset of general anesthesia and cessation of breathing, until the trachea has been intubated and the cuff has been inflated.
Additional considerations
Age can play a role in whether or not the procedure is warranted, and is commonly needed in younger persons. The clinician that performs RSI must be skilled in tracheal intubation and also in bag valve mask ventilation. Alternative airway management devices must be immediately available, in the event the trachea cannot be intubated using conventional techniques. Such devices include the combitube and the laryngeal mask airway. Invasive techniques such as cricothyrotomy must also be available in the event of inability to intubate the trachea by conventional techniques.
RSI is mainly used to intubate patients at high risk of aspiration, mostly due to a full stomach as commonly seen in a trauma setting. Bag ventilation causes distention of stomach which can induce vomiting, so this phase must be quick. The patient is given a sedative and paralytic agent, usually midazolam / suxamethonium / propofol and intubation is quickly attempted with minimal or no manual ventilation. The patient is assessed for predictable intubation difficulties. Laryngoscope blades and endotracheal tubes smaller than would be used in a non-emergency setting are selected.
If the patient on initial assessment is found to have a difficult airway, RSI is contraindicated since a failed RSI attempt will leave no option but to ventilate the patient on bag and mask which can lead to vomiting. For these challenging cases, awake fiberoptic intubation is usually preferred.
Controversy
Since the introduction of RSI, there has been controversy regarding virtually every aspect of this technique, including:
choice of intravenous hypnotic agents as well as their dosage and timing of administration
dosage and timing of administration of neuromuscular blocking agents
avoidance of manual ventilation before tracheal intubation
optimal position and whether the head-up, head-down, or horizontal supine position is the safest for induction of anesthesia in full-stomach patients
application of cricoid pressure, which is also referred to as the Sellick maneuver.
References
External links
Rapid Sequence Intubation at eMedicine |
Rat-bite fever | Rat-bite fever (RBF) is an acute, febrile human illness caused by bacteria transmitted by rodents, in most cases, which is passed from rodent to human by the rodents urine or mucous secretions. Alternative names for rat-bite fever include streptobacillary fever, streptobacillosis, spirillary fever, bogger, and epidemic arthritic erythema. It is a rare disease spread by infected rodents and caused by two specific types of bacteria:
Streptobacillus moniliformis, the only reported bacteria that causes RBF in North America (streptobacillary RBF)
Spirillum minus, common in Asia (spirillary RBF, also known as sodoku). Most cases occur in Japan, but specific strains of the disease are present in the United States, Europe, Australia, and Africa.Some cases are diagnosed after patients were exposed to the urine or bodily secretions of an infected animal. These secretions can come from the mouth, nose, or eyes of the rodent. The majority of cases are due to the animals bite. It can also be transmitted through food or water contaminated with rat feces or urine. Other animals can be infected with this disease, including weasels, gerbils, and squirrels. Household pets such as dogs or cats exposed to these animals can also carry the disease and infect humans. If a person is bitten by a rodent, it is important to quickly wash and cleanse the wound area thoroughly with antiseptic solution to reduce the risk of infection.
Symptoms and signs
Symptoms are different for every person depending on the type of rat-bite fever with which the person is infected. Both spirillary and streptobacillary rat-bite fever have a few individual symptoms, although most symptoms are shared. Streptobacillosis is most commonly found in the United States and spirillary rat-bite fever is generally diagnosed in Africa. Rat-bite symptoms are visually seen in most cases and include inflammation around the open sore. A rash can also spread around the area and appear red or purple. Other symptoms associated with streptobacillary rat-bite fever include chills, fever, vomiting, headaches, and muscle aches. Joints can also become painfully swollen and pain can be experienced in the back. Skin irritations such as ulcers or inflammation can develop on the hands and feet. Wounds heal slowly, so symptoms possibly come and go over the course of a few months.
Symptoms associated with spirillary rat-bite fever include issues with the lymph nodes, which often swell or become inflamed as a reaction to the infection. The most common locations of lymph node swelling are in the neck, groin, and underarm. Symptoms generally appear within two to ten days of exposure to the infected animal. It begins with the fever and progresses to the rash on the hands and feet within two to four days. The rash appears all over the body with this form but rarely causes joint pain.
Causes
Two types of Gram-negative, facultatively anaerobic bacteria can cause the infection.
Spirillosis
Rat-bite fever transmitted by the Gram-negative coiled rod Spirillum minus (also known as Spirillum minor) is rarer, and is found most often in Asia. In Japan, the disease is called sodoku. Symptoms do not manifest for two to four weeks after exposure to the organism, and the wound through which it entered exhibits slow healing and marked inflammation. The fever lasts longer and is recurring, for months in some cases. Rectal pain and gastrointestinal symptoms are less severe or are absent. Penicillin is the most common treatment.
Streptobacillosis
The streptobacillosis form of rat-bite fever is known by the alternative names Haverhill fever and epidemic arthritic erythema. It is a severe disease caused by Streptobacillus moniliformis, transmitted either by rat bite or ingestion of contaminated products (Haverhill fever). After an incubation period of 2–10 days, Haverhill fever begins with high prostrating fevers, rigors (shivering), headache, and polyarthralgia (joint pain). Soon, an exanthem (widespread rash) appears, either maculopapular (flat red with bumps) or petechial (red or purple spots) and arthritis of large joints can be seen. The organism can be cultivated in blood or articular fluid. The disease can be fatal if untreated in 20% of cases due to malignant endocarditis, meningoencephalitis, or septic shock. Treatment is with penicillin, tetracycline, or doxycycline.
Diagnosis
This condition is diagnosed by detecting the bacteria in skin, blood, joint fluid, or lymph nodes. Blood antibody tests may also be used. To get a proper diagnosis for rat-bite fever, different tests are run depending on the symptoms being experienced.
To diagnosis streptobacillary rat-bite fever, blood or joint fluid is extracted and the organisms living in it are cultured. Diagnosis for spirillary rat bite fever is by direct visualization or culture of spirilla from blood smears or tissue from lesions or lymph nodes.
Prevention
Eliminating exposure is very important when it comes to disease prevention. When handling rodents or cleaning areas where rodents have been, contact between hand and mouth should be avoided. Hands and face should be washed after contact and any scratches both cleaned and antiseptics applied. The effect of chemoprophylaxis following rodent bites or scratches on the disease is unknown. No vaccines are available for these diseases.
Improved conditions to minimize rodent contact with humans are the best preventive measures. Animal handlers, laboratory workers, and sanitation and sewer workers must take special precautions against exposure. Wild rodents, dead or alive, should not be touched and pets must not be allowed to ingest rodents.
Those living in the inner cities where overcrowding and poor sanitation cause rodent problems are at risk from the disease. Half of all cases reported are children under 12 living in these conditions.
Treatment
Treatment with antibiotics is the same for both types of infection. The condition responds to penicillin, and where allergies to it occur, erythromycin or tetracyclines are used.
Prognosis
When proper treatment is provided for patients with rat-bite fever, the prognosis is positive. Without treatment, the infection usually resolves on its own, although it may take up to a year to do so. A particular strain of rat-bite fever in the United States can progress and cause serious complications that can be potentially fatal. Before antibiotics were used, many cases resulted in death. If left untreated, streptobacillary rat-bite fever can result in infection in the lining of the heart, covering over the spinal cord and brain, or in the lungs. Any tissue or organ throughout the body may develop an abscess.
Epidemiology
Rat-bite fever (RBF) is a zoonotic disease. It can be directly transmitted by rats, gerbils, and mice (the vectors) to humans by either a bite or scratch or it can be passed from rodent to rodent. The causative bacterial agent of RBF has also been observed in squirrels, ferrets, dogs, and pigs. The most common reservoir of the disease is rats because nearly all domestic and wild rats are colonized by the causative bacterial agent, Streptobacillus moniliformis. Most notably, the Black rat (Rattus rattus) and the Norwegian rat (Rattus norvegicus) are recognized as potential reservoirs due to their common use as laboratory animals or kept as pets. The bacteria Streptobacillus moniliformis is found in the rats upper respiratory tract. Most rats harbor the disease asymptomatically, and signs and symptoms rarely develop. It is estimated that 1 in 10 bites from a rat will result in developing RBF. A person is also at risk of acquiring the bacteria through touching contaminated surfaces with an open wound or mucous membrane or ingestion of contaminated water or food by rodent feces, though this is referred to as Haverhill Fever (epidemic arthritic erythema). RBF is not a contagious disease. That is, it cannot be transferred directly from person to person.Researchers are challenged in understanding the prevalence of RBF. One factor that limits the known number of cases of RBF in the United States is that it is not a reportable disease there. RBF is classified as a notifiable disease, which means it is required by the state to be reported, however, the state is not mandated to provide that information to the United States Centers for Disease Control. Identification of RBF is also hindered due to the presence of two different etiological bacterial agents, Streptobacillus moniliformis and Spirillum minus. RBF caused by Sp. minus is more commonly found in Asia and is termed Sodoku, whereas St. moniliformis is found more often in the United States and in the Western Hemisphere. Although cases of RBF have been reported all over the world, the majority of cases that have been documented are caused by St. moniliformis primarily in the United States, where approximately 200 cases have been identified and reported. Due to increasing population density, this illness is being seen more frequently, as humans have increased their contact with animals and the zoonotic diseases they carry. Most cases of the disease have been reported from densely populated regions, such as big cities. The populations at risk have broadened due to the fact that domestic rats have become a common household pet. In the United States it is estimated that children 5 years and younger are the most at risk, receiving 50% of the total exposure, followed by laboratory personnel and then pet store employees. Other groups at increased risk are people over 65 years old, immunocompromised individuals, and pregnant women.Symptoms of RBF include sudden high temperature fevers with rigors, vomiting, headaches, painful joints/arthritis. A red, bumpy rash develops in about 75% of subjects. Symptoms of RBF can develop between 3 days and 3 weeks after exposure. While symptoms differ between Streptobacillary and Spirillary RBF, both types exhibit an incubation period before symptoms manifest. Due to its symptoms, RBF is often misdiagnosed by clinicians, leading to lingering symptoms and worsening conditions in patients; left untreated the mortality rate (death rate) of RBF is 13%. Even when treated, RBF can lead to migratory polyarthralgia, persistent rash, and fatigue which can persist for weeks to years after initial infection and treatment.
See also
Pasteurellosis
List of cutaneous conditions
Zoonosis
References
Rat Bite Fever (RBF) | CDC
Further reading
"Rat-bite Fever (RBF)". Centers for Disease Control and Prevention. Retrieved 28 February 2014.
Centers for Disease Control Prevention (CDC) (January 2005). "Fatal rat-bite fever—Florida and Washington, 2003". MMWR Morb. Mortal. Wkly. Rep. 53 (51): 1198–202. PMID 15635289.
Rat-bite fever (MyOptumHealth.com)
Tandon, R; Lee, M; Curran, E; Demierre, MF; Sulis, CA (Dec 15, 2006). "A 26-year-old woman with a rash on her extremities". Clinical Infectious Diseases. 43 (12): 1585–6, 1616–7. doi:10.1086/509574. PMID 17109293.
Centers for Disease Control, (CDC) (Jun 8, 1984). "Rat-bite fever in a college student--California". MMWR. Morbidity and Mortality Weekly Report. 33 (22): 318–20. PMID 6427575.
== External links == |
Raynaud syndrome | Raynaud syndrome, also known as Raynauds phenomenon, eponymously named after the physician Auguste Gabriel Maurice Raynaud, who first described it in his doctoral thesis in 1862, is a medical condition in which the spasm of small arteries causes episodes of reduced blood flow to end arterioles. Typically, the fingers, and less commonly, the toes, are involved. Rarely, the nose, ears, or lips are affected. The episodes classically result in the affected part turning white and then blue. Often, numbness or pain occurs. As blood flow returns, the area turns red and burns. The episodes typically last minutes but can last several hours.Episodes are typically triggered by cold or emotional stress. Primary Raynauds, also known as idiopathic, means that it is spontaneous, of unknown cause, and unrelated to another disease. Secondary Raynauds occurs as a result of another condition and has an older age at onset; episodes are intensely painful and can be asymmetric and associated with skin lesions. Secondary Raynauds can occur due to a connective-tissue disorder such as scleroderma or lupus, injuries to the hands, prolonged vibration, smoking, thyroid problems, and certain medications, such as birth control pills. Diagnosis is typically based on the symptoms.The primary treatment is avoiding the cold. Other measures include the discontinuation of nicotine or stimulant use. Medications for treatment of cases that do not improve include calcium channel blockers and iloprost. Little evidence supports alternative medicine. Severe disease may in rare cases lead to complications, specifically skin sores or gangrene.About 4% of people have the condition. Onset of the primary form is typically between ages 15 and 30 and occurs more frequently in females. The secondary form usually affects older people. Both forms are more common in cold climates.
Signs and symptoms
The condition can cause localized pain, discoloration (paleness), and sensations of cold and/or numbness.
When exposed to cold temperatures, the blood supply to the fingers or toes, and in some cases the nose or earlobes, is markedly reduced; the skin turns pale or white (called pallor) and becomes cold and numb.
These events are episodic, and when the episode subsides or the area is warmed, the blood flow returns, and the skin color first turns red (rubor), and then back to normal, often accompanied by swelling, tingling, and a painful "pins and needles" sensation. All three color changes are observed in classic Raynauds. However, not all patients see all of the aforementioned color changes in all episodes, especially in milder cases of the condition. The red flush is due to reactive hyperemia of the areas deprived of blood flow.In pregnancy, this sign normally disappears due to increased surface blood flow. Raynauds has occurred in breastfeeding mothers, causing nipples to turn white and painful.
Causes
Primary
Raynauds disease, or primary Raynauds, is diagnosed if the symptoms are idiopathic, that is, if they occur by themselves and not in association with other diseases. Some refer to primary Raynauds disease as "being allergic to coldness". It often develops in young women in their teens and early adulthood. Primary Raynauds is thought to be at least partly hereditary, although specific genes have not yet been identified.Smoking increases frequency and intensity of attacks, and a hormonal component exists. Caffeine, estrogen, and nonselective beta-blockers are often listed as aggravating factors, but evidence that they should be avoided is not solid.
Secondary
Raynauds phenomenon, or secondary Raynauds, occurs secondary to a wide variety of other conditions.
Secondary Raynauds has a number of associations:
Connective tissue disorders:
Scleroderma
Systemic lupus erythematosus
Rheumatoid arthritis
Sjögrens syndrome
Dermatomyositis
Polymyositis
Mixed connective tissue disease
Cold agglutinin disease
Ehlers-Danlos syndrome
Eating disorders:
Anorexia nervosa
Obstructive disorders:
Atherosclerosis
Buergers disease
Takayasus arteritis
Subclavian aneurysms
Thoracic outlet syndrome
Drugs:
Beta-blockers
Cytotoxic drugs – particularly chemotherapeutics and most especially bleomycin
Cyclosporin
Bromocriptine
Ergotamine
Sulfasalazine
Anthrax vaccines whose primary ingredient is the Anthrax Protective Antigen
Stimulant medications, such as those used to treat ADHD (amphetamine and methylphenidate)
OTC pseudoephedrine medications (Chlor-Trimeton, Sudafed, others)
Occupation:
Jobs involving vibration, particularly drilling and prolonged use of a string trimmer (weed whacker), experience vibration white finger
Exposure to vinyl chloride, mercury
Exposure to the cold (e.g., by working as a frozen food packer)
Others:
Physical trauma to the extremities
Lyme disease
Hypothyroidism
Cryoglobulinemia
Cancer
Chronic fatigue syndrome
Reflex sympathetic dystrophy
Carpal tunnel syndrome
Magnesium deficiency
Multiple sclerosis
Erythromelalgia (clinically presenting as the opposite of Raynauds, with hot and warm extremities, often co-exists in patients with Raynauds)
Chilblains (also clinically presenting as the opposite of Raynauds, with hot and itchy extremities, however it affects smaller areas than erythromelalgia, for instance the tip of a toe rather than the whole foot)Raynauds can precede these other diseases by many years, making it the first presenting symptom. This may be the case in the CREST syndrome, of which Raynauds is a part.Patients with secondary Raynauds can also have symptoms related to their underlying diseases. Raynauds phenomenon is the initial symptom that presents for 70% of patients with scleroderma, a skin and joint disease.When Raynauds phenomenon is limited to one hand or one foot, it is referred to as unilateral Raynauds. This is an uncommon form, and it is always secondary to local or regional vascular disease. It commonly progresses within several years to affect other limbs as the vascular disease progresses.
Mechanism
Its pathophysiology includes hyperactivation of the sympathetic nervous system causing extreme vasoconstriction of the peripheral blood vessels, leading to tissue hypoxia.
Diagnosis
Distinguishing Raynauds disease (primary Raynauds) from Raynauds phenomenon (secondary Raynauds) is important. Looking for signs of arthritis or vasculitis, as well as a number of laboratory tests, may separate them. Nail fold capillary examination or "capillaroscopy" is one of the most sensitive methods to diagnose RS with connective tissue disorders, i.e. distinguish a secondary from a primary form objectively.If suspected to be secondary to systemic sclerosis, one tool which may help aid in the prediction of systemic sclerosis is thermography.A careful medical history will seek to identify or exclude possible secondary causes.
Digital artery pressures are measured in the arteries of the fingers before and after the hands have been cooled. A decrease of at least 15 mmHg is diagnostic (positive).
Doppler ultrasound to assess blood flow
Full blood count may reveal a normocytic anaemia suggesting the anaemia of chronic disease or kidney failure.
Blood test for urea and electrolytes may reveal kidney impairment.
Thyroid function tests may reveal hypothyroidism.
Tests for rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein, and autoantibody screening may reveal specific causative illnesses or an inflammatory process. Anti-centromere antibodies are common in limited systemic sclerosis (CREST syndrome).
Nail fold vasculature (capillaroscopy) can be examined under a microscope.To aid in the diagnosis of Raynauds phenomenon, multiple sets of diagnostic criteria have been proposed. Table 1 below provides a summary of these various diagnostic criteria.Recently, International Consensus Criteria were developed for the diagnosis of primary Raynauds phenomenon by a panel of experts in the fields of rheumatology and dermatology.
Management
Secondary Raynauds is managed primarily by treating the underlying cause, and as primary Raynauds, avoiding triggers, such as cold, emotional and environmental stress, vibrations and repetitive motions, and avoiding smoking (including passive smoking) and sympathomimetic drugs.
Medications
Medications can be helpful for moderate or severe disease.
Vasodilators – calcium channel blockers, such as the dihydropyridines nifedipine or amlodipine, preferably slow-release preparations – are often first-line treatment. They have the common side effects of headache, flushing, and ankle edema, but these are not typically of sufficient severity to require cessation of treatment. The limited evidence available shows that calcium-channel blockers are only slightly effective in reducing how often the attacks happen. Although, other studies also reveal that CCBs may be effective at decreasing severity of attacks, pain and disability associated with Raynauds phenomenon. People whose disease is secondary to erythromelalgia often cannot use vasodilators for therapy, as they trigger flares causing the extremities to become burning red due to too much blood supply.
People with severe disease prone to ulceration or large artery thrombotic events may be prescribed aspirin.
Sympatholytic agents, such as the alpha-adrenergic blocker prazosin, may provide temporary relief to secondary Raynauds phenomenon.
Losartan can, and topical nitrates may, reduce the severity and frequency of attacks, and the phosphodiesterase inhibitors sildenafil and tadalafil may reduce their severity.
Angiotensin receptor blockers or ACE inhibitors may aid blood flow to the fingers, and some evidence shows that angiotensin receptor blockers (often losartan) reduce frequency and severity of attacks, and possibly better than nifedipine.
The prostaglandin iloprost is used to manage critical ischemia and pulmonary hypertension in Raynauds phenomenon, and the endothelin receptor antagonist bosentan is used to manage severe pulmonary hypertension and prevent finger ulcers in scleroderma.
Statins have a protective effect on blood vessels, and SSRIs such as fluoxetine may help symptoms, but the data is weak.
PDE5 inhibitors are used off-label to treat severe ischemia and ulcers in fingers and toes for people with secondary Raynauds phenomenon; as of 2016, their role more generally in Raynauds was not clear.
Surgery
In severe cases, an endoscopic thoracic sympathectomy procedure can be performed. Here, the nerves that signal the blood vessels of the fingertips to constrict are surgically cut. Microvascular surgery of the affected areas is another possible therapy, but this procedure should be considered as a last resort.
A more recent treatment for severe Raynauds is the use of botulinum toxin. The 2009 article studied 19 patients ranging in age from 15 to 72 years with severe Raynauds phenomenon of which 16 patients (84%) reported pain reduction at rest; 13 patients reported immediate pain relief, three more had gradual pain reduction over 1–2 months. All 13 patients with chronic finger ulcers healed within 60 days. Only 21% of the patients required repeated injections. A 2007 article describes similar improvement in a series of 11 patients. All patients had significant relief of pain.
Alternative medicine
Evidence does not support the use of alternative medicine, including acupuncture and laser therapy.
Prognosis
The prognosis of primary Raynaud syndrome is often very favorable, with no mortality and little morbidity. However, a minority develops gangrene. The prognosis of secondary Raynaud is dependent on the underlying disease, and how effective blood flow-restoring maneuvers are.
References
External links
What Is Raynauds Disease at National Heart, Lung, and Blood Institute
Questions and Answers about Raynauds Phenomenon at National Institutes of Health
Bakst R, Merola JF, Franks AG, Sanchez M (October 2008). "Raynauds phenomenon: pathogenesis and management". Journal of the American Academy of Dermatology. 59 (4): 633–53. doi:10.1016/j.jaad.2008.06.004. PMID 18656283. |
Refractive surgery | Refractive eye surgery is optional eye surgery used to improve the refractive state of the eye and decrease or eliminate dependency on glasses or contact lenses. This can include various methods of surgical remodeling of the cornea (keratomileusis), lens implantation or lens replacement. The most common methods today use excimer lasers to reshape the curvature of the cornea. Refractive eye surgeries are used to treat common vision disorders such as myopia, hyperopia, presbyopia and astigmatism.
History
The first theoretical work on the potential of refractive surgery was published in 1885 by Hjalmar August Schiøtz, an ophthalmologist from Norway. In 1930, the Japanese ophthalmologist Tsutomu Sato made the first attempts at performing this kind of surgery, hoping to correct the vision of military pilots. His approach was to make radial cuts in the cornea, correcting effects by up to 6 diopters. The procedure unfortunately produced a high rate of corneal degeneration, however, and was soon rejected by the medical community.
The first proficient refractive surgery technique was developed in the Barraquer ophthalmologic clinic (Bogotá, Colombia), in 1963, by Jose Barraquer. His technique, called keratomileusis, meaning corneal reshaping (from Greek κέρας (kéras: horn) and σμίλευσις (smileusis: carving)), enabled the correction, not only of myopia, but also of hyperopia. It involves removing a corneal layer, freezing it so that it could be manually sculpted into the required shape, and finally reimplanting the reshaped layer into the eye. In 1980, Swinger performed first keratomileusis surgery in US. In 1985, Krumeich and Swinger introduced non-freeze keratomileusis technique, it remained a relatively imprecise technique.
In 1974 a refractive procedure called Radial Keratotomy (RK) was developed in the USSR by Svyatoslav Fyodorov and later introduced to the United States. RK involves making a number of cuts in the cornea to change its shape and correct refractive errors. The incisions are made with a diamond knife. Following the introduction of RK, doctors routinely corrected nearsightedness, farsightedness, and astigmatism using various applications of incisions on the cornea.
Meanwhile, experiments in 1970 using a xenon dimer and in 1975 using noble gas halides resulted in the invention of a type of laser called an excimer laser. While excimer lasers were initially used for industrial purposes, in 1980, Rangaswamy Srinivasan, a scientist of IBM who was using an excimer laser to make microscopic circuits in microchips for informatics equipment, discovered that the excimer could also be used to cut organic tissues with high accuracy without significant thermal damage. The discovery of an effective biological cutting laser, along with the development of computers to control it, enabled the development of new refractive surgery techniques.
In 1983, Stephen Trokel, a scientist at Columbia University, in collaboration with Theo Seiler and Srinivasan, performed the first Photorefractive Keratectomy (PRK), or keratomileusis in situ (without separation of corneal layer) in Germany. The first patent for this approach, which later became known as LASIK surgery, was granted by the US Patent Office to Gholam Ali. Peyman, MD on June 20, 1989. It involves cutting a flap in the cornea and pulling it back to expose the corneal bed, then using an excimer laser to ablate the exposed surface to the desired shape, and then replacing the flap. The name LASIK was coined in 1991 by University of Crete and the Vardinoyannion Eye.
The patents related to so-called broad-beam LASIK and PRK technologies were granted to US companies including Visx and Summit during 1990–1995 based on the fundamental US patent issued to IBM (1983) which claimed the use of UV laser for the ablation of organic tissues.
In 1991, J.T. Lin, Ph.D. (a Chinese Physicist) was granted a US patent for a new technology using a flying-spot for customized LASIK currently used worldwide. The first US patent using an eye-tracking device to prevent decentration in LASIK procedures was granted to another Chinese Physicist, Dr. S. Lai in 1993.
Techniques
Flap procedures
Excimer laser ablation is done under a partial-thickness lamellar corneal flap.
Automated lamellar keratoplasty (ALK): The surgeon uses an instrument called a microkeratome to cut a thin flap of the corneal tissue. The flap is lifted like a hinged door, targeted tissue is removed from the corneal stroma, again with the microkeratome, and then the flap is replaced.
Laser-assisted in situ Keratomileusis (LASIK): The surgeon uses either a microkeratome or a femtosecond laser to cut a flap of the corneal tissue (usually with a thickness of 100–180 micrometres). The flap is lifted like a hinged door, but in contrast to ALK, the targeted tissue is removed from the corneal stroma with an excimer laser. The flap is subsequently replaced. When the flap is created using an IntraLase brand femtosecond laser, the method is called IntraLASIK; other femtosecond lasers such as the Ziemer create a flap similarly. Femtosecond lasers have numerous advantages over mechanical microkeratome based procedure. Microkeratome related flap complications like incomplete flaps, buttonholes or epithelial erosion are eliminated with femtosecond laser procedure. Absence of microscopic metal fragments from the blade will reduce the risk of lamellar keratitis also.Customized aspheric treatment zone (CATz) is a topography-guided LASIK treatment developed by NIDEK Co. Ltd which ablates the cornea based on patient-specific geometry to address certain disadvantages in conventional wavefront spherocylindrical ablation. The treatment is effective for myopia with astigmatism or otherwise irregular corneas, and reduces symptoms such as glare, halos, and night driving difficulty.
Refractive Lenticule Extraction (ReLEx):
ReLEx "FLEx" (Femtosecond Lenticule Extraction): A femtosecond laser cuts a lenticule within the corneal stroma. Afterwards, a LASIK-like flap is cut which can be lifted to access the lenticule. This is removed through manual dissection using a blunt spatula and forceps.
ReLEx "SMILE" (Small Incision Lenticule Extraction): A newer technique without a flap, a femtosecond laser cuts a lenticule within the corneal stroma. The same laser is used to cut a small incision along the periphery of the lenticlue about 1/5th the size of a standard LASIK flap incision. The surgeon then uses a specially designed instrument to separate and remove the lenticule through the incision, leaving the anterior lamellae of the cornea intact. No excimer laser is used in the "ReLEx-procedures".
Surface procedures
The excimer laser is used to ablate the most anterior portion of the corneal stroma. These procedures do not require a partial thickness cut into the stroma. Surface ablation methods differ only in the way the epithelial layer is handled.
Photorefractive keratectomy (PRK) is an outpatient procedure generally performed with local anesthetic eye drops (as with LASIK/LASEK). It is a type of refractive surgery which reshapes the cornea by removing microscopic amounts of tissue from the corneal stroma, using a computer-controlled beam of light (excimer laser). The difference from LASIK is that the top layer of the epithelium is removed (and a bandage contact lens is used), so no flap is created. Recovery time is longer with PRK than with LASIK, though the outcome (after 3 months) is about the same (very good). More recently, customized ablation has been performed with LASIK, LASEK, and PRK.
Transepithelial photorefractive keratectomy (TransPRK) is a laser-assisted eye surgery to correct refraction errors of human eye cornea. It employs excimer laser to ablate outer layer of cornea, epithelium, as well its connective tissue, stroma, to correct eye optical power.
Laser Assisted Sub-Epithelium Keratomileusis (LASEK) is a procedure that also changes the shape of the cornea using an excimer laser to ablate the tissue from the corneal stroma, under the corneal epithelium, which is kept mostly intact to act as a natural bandage. The surgeon uses an alcohol solution to loosen then lift a thin layer of the epithelium with a trephine blade (usually with a thickness of 50 micrometres). During the weeks following LASEK, the epithelium heals, leaving no permanent flap in the cornea. This healing process can involve discomfort comparable to that with PRK.
EPI-LASIK is a new technique similar to LASEK that uses an epi-keratome (rather than a trephine blade and alcohol), to remove the top layer of the epithelium (usually with thickness of 50 micrometres), which is subsequently replaced. For some people it can provide better results than regular LASEK in that it avoids the possibility of negative effects from the alcohol, and recovery may involve less discomfort.
Customized Transepithelial No-touch (C-TEN) is an innovative strategy for corneal surgery that avoids any corneal manipulation via a complete laser-assisted trans-epithelial approach. Since C-TEN is planned on the morphology of each individual eye, it can treat a large variety of corneal pathologies from refractive to therapeutic. C-TEN is sometimes referred to as Advanced Surface Ablation (ASA)
Corneal incision procedures
Radial keratotomy (RK), developed by Russian ophthalmologist Svyatoslav Fyodorov in 1974, uses spoke-shaped incisions, always made with a diamond knife, to alter the shape of the cornea and reduce myopia or astigmatism; this technique is, in medium to high diopters, usually replaced by other refractive methods.
Arcuate keratotomy (AK), also known as Astigmatic keratotomy, uses curvilinear incisions at the periphery of the cornea to correct high levels of non-pathological astigmatism, up to 13 diopters. AK is often used for the correction of high post-keratoplasty astigmatism or post-cataract surgery astigmatism.
Limbal relaxing incisions (LRI) are incisions near the outer edge of the iris, used to correct minor astigmatism (typically less than 2 diopters). This is often performed in conjunction with an Intraocular Lens implantation.
Other procedures
Radial Keratocoagulation, also known as Radial Thermokeratoplasty, was invented in 1985 by Svyatoslav Fyodorov and is used to correct hyperopia by putting a ring of 8 or 16 small burns surrounding the pupil, and steepen the cornea with a ring of collagen constriction. It can also be used to treat selected types of astigmatism. It is now generally replaced by laser thermal keratoplasty/laser thermokeratoplasty.
Laser thermal keratoplasty (LTK) is a non-touch thermal keratoplasty performed with a Holmium laser, while conductive keratoplasty (CK) is thermal keratoplasty performed with a high-frequency electric probe. Thermal keratoplasty can also be used to improve presbyopia or reading vision after age 40.
Intrastromal corneal ring segments (Intacs) are approved by FDA for treatment of low degrees of myopia.
Phakic intraocular lens (PIOL) implantation inside the eye can also be used to change refractive errors. The newest type of intervention is a type of PIOL called the implantable collamer lens (ICL) which uses a biocompatible flexible lens which can be inserted in the eye via a 3 mm incision. The ICL is used to correct myopia ranging from −0.5 to −18 diopters, and +0.5 cylinder power to +6.0 for the Toric ICL models.
Generally refractive surgery can be broadly divided into: corneal surgery, scleral surgery, lens related surgery (including phakic IOL implantation, clear lens extraction, photophacoreduction and photophacomodulation for correction of presbyopia)
For presbyopia correction, a corneal inlay consisting of a porous black ring surrounding a small clear aperture was originally developed by D. Miller, H. Grey PhD and a group at Acufocus. The inlay is placed under a LASIK flap or in a stromal pocket.Using mid-IR and UV lasers for the treatment of presbyopia by scleral tissue ablation was first proposed and patented by J.T. Lin, Ph.D. in US patents #6,258,082 (in 2001) and #6,824,540 (in 2004).
Expectations
Research conducted by the Magill Research Center for Vision Correction, Medical University of South Carolina, showed that the overall patient satisfaction rate after primary LASIK surgery was 95.4%. They further differentiated between myopic LASIK (95.3%) and hyperopic LASIK (96.3%). They concluded that the vast majority (95.4%) of patients were satisfied with their outcome after LASIK surgery.Ophthalmologists use various approaches to analyze the results of refractive surgery, and alter their techniques to provide better results in the future. Some of these approaches are programmed into the devices ophthalmologists use to measure the refraction of the eye and the shape of the cornea, such as corneal topography.
Risks
While refractive surgery is becoming more affordable and safe, it may not be recommended for everybody. People with certain eye diseases involving the cornea or retina, pregnant women, and patients who have medical conditions such as glaucoma, diabetes, uncontrolled vascular disease, or autoimmune disease are not good candidates for refractive surgery. Keratoconus, a progressive thinning of the cornea, is a common corneal disorder. Keratoconus occurring after refractive surgery is called Corneal Ectasia. It is believed that additional thinning of the cornea via refractive surgery may contribute to advancement of the disease that may lead to the need for a corneal transplant. Therefore, keratoconus is a contraindication to refractive surgery. Corneal topography and pachymetry are used to screen for abnormal corneas. Furthermore, some peoples eye shape may not permit effective refractive surgery without removing excessive amounts of corneal tissue. Those considering laser eye surgery should have a full eye examination.
Although the risk of complications is decreasing compared to the early days of refractive surgery, there is still a small chance for serious problems. These include vision problems such as ghosting, halos, starbursts, double-vision, and dry-eye syndrome. With procedures that create a permanent flap in the cornea (such as LASIK), there is also the possibility of accidental traumatic flap displacement years after the surgery, with potentially disastrous results if not given prompt medical attention.For patients with strabismus, risks of complications such as diplopia and/or increased strabismus angle need to be evaluated carefully. In case both refractive surgery and strabismus surgery are to be performed, it is recommended that the refractive surgery be done first.
Children
Pediatric refractive surgery involves other risks than refractive surgery on adults, yet it may be indicated especially for children whose cognitive or visual development is failing due to refractive error, in particular in cases of bilateral high refractive error, anisometropia, anisometric amblyopia or accommodative esotropia.Interventions on young children may require general anaesthesia in order to avoid risks due to involuntary movement, and children have a higher risk of rubbing or manipulating their eyes post-surgically. Changes to refractive error occurring during normal age development need to be accounted for, and children have a higher risk of developing postoperative corneal haze. This risk is particularly relevant with relation to myopic children.One study evaluated the outcome of LASEK interventions on 53 children aged 10 months to 16 years who had anisometropic amblyopia. The choice of LASEK was made as it was felt it would give fewer complications than LASIK and less post-operative pain than PRK. In the intervention, which was performed under general anaesthesia, the refractive error in the weaker eye was corrected to balance the refractive error of the other eye. Strabismus surgery was performed later if required. After one year, over 60% had improved in best corrected visual acuity (BCVA) in the weaker eye. Notably, over 80% showed stereopsis post-operatively whereas less than 40% had showed stereopsis before.In addition to corneal refractive procedures (LASIK, PRK and LASEK), intraocular refractive procedures (phakic intraocular lenses, refractive lens exchange and clear lens extraction) are also performed on children.
See also
Orthokeratology – contact lenses worn only at night to reshape the eye.
References
External links
DJO|Digital Journal of Ophthalmology |
Renal colic | Renal colic is a type of abdominal pain commonly caused by obstruction of ureter from dislodged kidney stones. The most frequent site of obstruction is the vesico-ureteric junction (VUJ), the narrowest point of the upper urinary tract. Acute obstruction and the resultant urinary stasis (disruption of urine flow) can distend the ureter (hydroureter) and cause a reflexive peristaltic smooth muscle spasm, which leads to a very intense visceral pain transmitted via the ureteric plexus.
Signs and symptoms
Renal colic typically begins in the flank and often radiates to below the ribs or the groin. It typically comes in waves due to ureteric peristalsis, but may be constant. It is often described as one of the most severe pains.Although this condition can be very painful, most ureteric stones under 5 mm size will eventually pass into the bladder without needing treatments, and cause no permanent physical damage. The experience is said to be traumatizing due to the severe pain, and the experience of passing blood and clots as well as pieces of stone. In most cases, people with renal colic are advised to drink more water to facilitate passing; in other instances, lithotripsy or endoscopic surgery may be needed. Preventive treatment can be instituted to minimize the likelihood of recurrence.
Diagnosis
The diagnosis of renal colic is the same as the diagnosis for renal calculus and ureteric stones.
Differential diagnosis
A renal colic must be differentiated from the following conditions:
biliary colic and cholecystitis
aortic and iliac aneurysms (in older patients with left-side pain, hypertension or atherosclerosis)
interstitial: appendicitis, diverticulitis or peritonitis (in this case patients prefer to lie still rather than being restless)
gynaecological: endometriosis, ovarian torsion and ectopic pregnancy
testicular torsion
Treatment
Most small stones are passed spontaneously and only pain management is required. Above 5 mm (0.20 in) the rate of spontaneous stone passage decreases. NSAIDs (non-steroidal anti-inflammatory drugs), such as diclofenac or ibuprofen, and antispasmodics like butylscopolamine are used. Although morphine may be administered to assist with emergency pain management, it is often not recommended as morphine is addictive and raises ureteral pressure, worsening the condition. Vomiting is also considered an important adverse effect of opioids, mainly with pethidine. Oral narcotic medications are also often used.There is typically no antalgic position for the patient (lying down on the non-aching side and applying a hot bottle or towel to the area affected may help). Larger stones may require surgical intervention for their removal, such as shockwave lithotripsy, laser lithotripsy, ureteroscopy or percutaneous nephrolithotomy. Patients can also be treated with alpha blockers in cases where the stone is located in the ureter.
References
== External links == |
Rhabdomyosarcoma | Rhabdomyosarcoma (RMS) is a highly aggressive form of cancer that develops from mesenchymal cells that have failed to fully differentiate into myocytes of skeletal muscle. Cells of the tumor are identified as rhabdomyoblasts.There are four subtypes – embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma. Embryonal, and alveolar are the main groups, and these types are the most common soft tissue sarcomas of childhood and adolescence. The pleomorphic type is usually found in adults.It is generally considered to be a disease of childhood, as the vast majority of cases occur in those below the age of 18. It is commonly described as one of the small-blue-round-cell tumors of childhood due to its appearance on an H&E stain. Despite being relatively rare, it accounts for approximately 40% of all recorded soft tissue sarcomas.
RMS can occur in any soft tissue site in the body, but is primarily found in the head, neck, orbit, genitourinary tract, genitals, and extremities. There are no clear risk factors, but the disease has been associated with some congenital abnormalities. Signs and symptoms vary according to tumor site, and prognosis is closely tied to the location of the primary tumor. Common sites of metastasis include the lungs, bone marrow, and bones. There are many classification systems for RMS and a variety of defined histological types. Embryonal rhabdomyosarcoma is the most common type and comprises about 60% of cases.Outcomes vary considerably, with 5 years survival rates between 35% and 95% depending on the type of RMS involved, so clear diagnosis is critical for effective treatment and management. Accurate and quick diagnosis is often difficult due to the heterogeneity of RMS tumors and a lack of strong genetic markers of the disease, although recent research by UVA Health researchers discovered “multiple lines of evidence supporting [the gene] AVIL is powerful driver for both major types of rhabdomyosarcoma,” according to researcher Hui Li, PhD, of the University of Virginia School of Medicine’s Department of Pathology and UVA Cancer Center. (.) Malfunctions in AVIL, Li and his team found, play an essential role in the development of the two main subtypes of rhabdomyosarcoma. In a scientific paper outlining the findings, he and his colleagues describe rhabdomyosarcoma as “addicted” to the gene’s excess activity. They ultimately label AVIL a “bona fide oncogene” for rhabdomyosarcoma.
Treatment usually involves a combination of surgery, chemotherapy, and radiation. Sixty percent to 70% of newly diagnosed patients with nonmetastatic disease can be cured using this combined approach to therapy. Despite aggressive multimodality treatment, less than 20% of patients with metastatic RMS are able to be cured of their disease.
Types
Given the difficulty in diagnosing rhabdomyosarcoma, definitive classification of subtypes has proven difficult. As a result, classification systems vary by institute and organization. However, rhabdomyosarcoma in the 2020 WHO classification is listed as four histological subtypes: embryonal, alveolar, pleomorphic, and spindle cell/sclerosing.
Embryonal
Embryonal rhabdomyosarcoma (ERMS) is the most common histological variant, comprising approximately 60–70% of childhood cases. It is most common in children 0–4 years old, with a maximum reported incidence of 4 cases per 1 million children. ERMS is characterized by spindle-shaped cells with a stromal-rich appearance, and the morphology is similar to the developing muscle cells of a 6- to 8-week-old embryo. Tumors often present in the head and neck as well as the genitourinary tract.
Embryonal subtype
Botryoid rhabdomyosarcoma is almost always found in mucosal lined organs including the vagina, bladder, and nasopharynx (although presentation in the nasopharynx typically affects older children). It often presents in infants younger than a year old, as a round, grape-like mass on the affected organ. Histologically, cells of the botryoid variant are defined by a dense tumor layer under an epithelium (cambium layer). This subtype has a good prognosis.Botryoid rhabdomyosarcoma is also sometimes present in adult women, found in the cervix or uterus.
Alveolar
Alveolar rhabdomyosarcoma (ARMS) is the second most common type. ARMS comprises approximately 20–25% of RMS-related tumors, and it is equally distributed among all age groups with an incidence of about 1 case per 1 million people ages 0 to 19. For this reason, it is the most common form of RMS observed in young adults and teenagers, who are less prone to the embryonal variant. This type of RMS is characterized by densely-packed, round cells that arrange around spaces similar in shape to pulmonary alveoli, although variants have been discovered without these characteristic alveolar spacings. ARMS tends to form more often in the extremities, trunk, and peritoneum. It is also typically more aggressive than ERMS.
Pleomorphic
Pleomorphic rhabdomyosarcoma (undifferentiated) rhabdomyosarcoma), also known as anaplastic rhabdomyosarcoma, is defined by the presence of pleomorphic cells with large, lobate hyperchromatic nuclei and multipolar mitotic figures. These tumors display high heterogeneity and extremely poor differentiation. The pleomorphic cells may be diffuse or localized, with the diffuse variation correlating to a worse prognosis. It occurs most often in adults, rarely in children, and is often discovered in the extremities. Due to the lack of discernible separation among cancers of this type, clinicians will often label undiagnosed sarcomas with little to no discernible features as anaplastic RMS. It is the most aggressive type of RMS, and will often require intensive treatment.
Spindle cell/sclerosing
Spindle cell/sclerosing rhabdomyosarcoma is an added subtype listed in the 2020 WHO classification of soft tissue sarcomas.This subtype is very similar to that of leiomyosarcoma (cancer of the smooth muscle tissue), and it has a fascicular, spindled, and leiomyomatous growth pattern with notable rhabdomyoblastic differentiation . It occurs most commonly in the paratesticular region, and the prognosis for this particular form of RMS is excellent with a reported five-year survival rate of 95%. The sclerosing aspect of this subtype has a hyaline sclerosis and pseudovascular development.Multiple classification systems have been proposed for guiding management and treatment, and the most recent and widely used classification system is the "International Classification of Rhabdomyosarcoma" or ICR. It was created by the IRSG in 1995 after their series of four multi-institutional trials aimed at studying the presentation, histology, epidemiology, and treatment of RMS (IRSG I–IV). The ICR system is based on prognostic indicators identified in IRSG I–IV. Pleomorphic rhabdomyosarcoma usually occurs in adults rather than children, and is therefore not included in this system.
Signs and symptoms
RMS can occur in almost any soft-tissue site in the body; the most common primary sites are genitourinary (24%), parameningeal (16%), extremity (19%), orbit (9%), other head and neck (10%), and miscellaneous other sites (22%). RMS often presents as a mass, but signs and symptoms can vary widely depending on the site of the primary tumor. Genitourinary tumors may present with hematuria, urinary tract obstruction, and/or a scrotal or vaginal mass. Tumors that arise in the retroperitoneum and mediastinum can become quite large before producing signs and symptoms. Parameningeal tumors may present with cranial nerve dysfunction, symptoms of sinusitis, ear discharge, headaches, and facial pain. Orbital tumors often present with orbital swelling and proptosis. Extremity tumors generally present as a rapidly enlarging, firm mass in the relevant tissue. The cancers prevalence in the head, face, and neck will often allow for earlier signs of the disease simply due to the obvious nature of tumors in these locations. Despite the varying presentation and typically aggressive nature of the disease, RMS has the potential to be diagnosed and treated early. The fourth IRSG study found that 23% of patients were diagnosed in time for a complete resection of their cancer, and 15% had resection with only minimal remnants of the diseased cells.
Risk factors
Rhabdomyosarcoma is difficult to diagnose. Risk factors that increase the likelihood of this cancer include inherited disorders such as Li-Fraumeni syndrome, Neurofibromatosis type 1, Beckwith-Wiedemann syndrome, Costello syndrome, Noonan syndrome, and DICER1 syndrome.
Genetic
There are multiple genetic lesions associated with rhabdomyosarcoma, but there has been little consistent data demonstrating an association between specific genetic abnormalities and outcome. However, alveolar and embryonal types of RMS can be distinguished cytogenetically, and identification of specific genetic lesions can allow for accurate classification of the ARMS subtype when the histopathological findings are equivocal or unclear. This is valuable for clinical practice as the alveolar type presents a higher risk to the patient and will often require more aggressive treatment than the embryonal type. Thus, ARMS is also referred to as Fusion Positive rhabdomyosarcoma (FP-RMS). Up to 90% of alveolar RMS cases present with a translocations of t(2;13)(q35, q14) or, less commonly, t(1;13)(p36, q15). Both involve the translocation of a DNA binding domain of either PAX3 or PAX7, a member of the Paired Box family of transcription factors, to a transactivation site on FOXO1 (previously known as FKHR), a member of the forkhead/HNF-3 transcription factor family. The t(2;13) translocation results in a fusion of the PAX3 gene with FOXO1, while the t(1;13) translocation involves the fusion of PAX7 with FOXO1. PAX3 has a demonstrated role in muscle cell development, which supports its potential role in RMS. The t(2;13) translocation can result in the PAX3-FKHR fusion product, which is indicative of classic cystic ARMS. Cases of FP-RMS are associated with a poorer prognosis than fusion-negative RMS.The fusion protein presents a potential therapeutic target, and in recent years more research has been conducted to clarify the role of PAX3-FOXO1 in FP-RMS. PAX3-FOXO1 is now known to drive key oncogenes such as MYC and MYCN by creating long-distance genetic interactions by super enhancers. In this context, PAX3-FOXO1 both (1) drives the expression of MYC, MYCN and even MYOD1 (a transcription factor highly expressed in all RMS subtypes) but also (2) co-binds with these master transcription factors at super enhancers to support cancer growth. Furthermore, it was demonstrated that FP-RMS subtypes were especially sensitive to inhibitors (such as JQ1) of a super enhancer bound protein BRD4.Embryonal RMS usually presents with a loss of heterozygosity (LOH) in the short arm of chromosome 11 (p11,15.5). This region is associated with multiple oncogenes, and the potential loss-of-function of this region is likely associated with the loss of a tumor suppressor. However, the specific consequences of this LOH at (p11,15.5) have yet to be determined. The short arm of chromosome 11 is also the site of the insulin-like growth factor 2 gene (IGF-2), which is often over-expressed in RMS.The loss-of-function of tumor suppressor p53 is associated with many cancers including rhabdomyosarcoma, and approximately 50% of RMS cases have been shown to carry some form of mutation to the P53 gene. Other oncogenes often associated with rhabdomyosarcoma, albeit with less frequency, include NMYC, NRAS, KRAS, P16, and c-Met. One study showed that 35% of embryonal RMS tumors contained activating mutations in either NRAS or KRAS and it is worth noting that ras activation has been shown to block myogenic differentiation, which could help explain its potential role in rhabdomyosarcogenesis. More recently, a mechanistic and epigenetic link between mutant RAS isoforms and a block of myogenic differentiation has been demonstrated. Furthermore, it has been shown that this differentiation block can be overcome with a clinical stage inhibitor of the MAP kinase pathway known as a MEK inhibitor.
Diagnosis
Rhabdomyosarcoma is often difficult to diagnose due to its similarities to other cancers and varying levels of differentiation. It is loosely classified as one of the small-blue-round-cell tumors due to its appearance on an H&E stain. Other cancers that share this classification include neuroblastoma, Ewing sarcoma, and lymphoma, and a diagnosis of RMS requires confident elimination of these morphologically similar diseases. The defining diagnostic trait for RMS is confirmation of malignant skeletal muscle differentiation with myogenesis (presenting as a plump, pink cytoplasm) under light microscopy. Cross striations may or may not be present. Accurate diagnosis is usually accomplished through immunohistochemical staining for muscle-specific proteins such as myogenin, muscle-specific actin, desmin, D-myosin, and myoD1. Myogenin, in particular, has been shown to be highly specific to RMS, although the diagnostic significance of each protein marker may vary depending on the type and location of the malignant cells. The alveolar type of RMS tends to have stronger muscle-specific protein staining. Electron microscopy may also aid in diagnosis, with the presence of actin and myosin or Z bands pointing to a positive diagnosis of RMS. Classification into types and subtypes is accomplished through further analysis of cellular morphology (alveolar spacings, presence of cambium layer, aneuploidy, etc.) as well as genetic sequencing of tumor cells. Some genetic markers, such as the PAX3-FKHR fusion gene expression in alveolar RMS, can aid in diagnosis. Open biopsy is usually required to obtain sufficient tissue for accurate diagnosis. All findings must be considered in context, as no one trait is a definitive indicator for RMS.
Staging
Following diagnosis and histopathological analysis, various imaging techniques may be used, including MRI, ultrasound, and a bone scan in order to determine the extent of local invasion and any metastasis. Further investigational techniques may be necessary depending on tumor sites. A parameningeal presentation of RMS will often require a lumbar puncture to rule out metastasis to the meninges. A paratesticular presentation will often require an abdominal CT to rule out local lymph node involvement, and so on. Outcomes are strongly tied to the extent of the disease, and its early mapping is important for treatment planning.The current staging system for rhabdomyosarcoma is unusual relative to most cancers. It utilizes a modified TNM (tumor-nodes-metastasis) system originally developed by the IRSG. This system accounts for tumor size (> or <5 cm), lymph node involvement, tumor site, and presence of metastasis. It grades on a scale of 1 to 4 based on these criteria. In addition, patients are sorted by clinical group (from the clinical groups from the IRSG studies) based on the success of their first surgical resection. The current Childrens Oncology Group protocols for the treatment of RMS categorize patients into one of four risk categories based on tumor grade and clinical group, and these risk categories have been shown to be highly predictive of outcome.
Treatment
Treatment of rhabdomyosarcoma is a multidisciplinary practice involving the use of surgery, chemotherapy, radiation, and possibly immunotherapy. Surgery is generally the first step in a combined therapeutic approach. Resectability varies depending on tumor site, and RMS often presents in sites that dont allow for full surgical resection without significant morbidity and loss of function. Less than 20% of RMS tumors are fully resected with negative margins. Rhabdomyosarcomas are highly chemosensitive, with approximately 80% of cases responding to chemotherapy. In fact, multi-agent chemotherapy is indicated for all patients with rhabdomyosarcoma. Before the use of adjuvant and neoadjuvant therapy involving chemotherapeutic agents, treatment solely by surgical means had a survival rate of <20%. Modern survival rates with adjuvant therapy are approximately 60–70%.There are two main methods of chemotherapy treatment for RMS. There is the VAC regimen, consisting of vincristine, actinomycin D, and cyclophosphamide, and the IVA regimen, consisting of ifosfamide, vincristine, and actinomycin D. These drugs are administered in 9–15 cycles depending on the staging of the disease and other therapies used. Other drug and therapy combinations may also show additional benefit. Addition of doxorubicin and cisplatin to the VAC regimen was shown to increase survival rates of patients with alveolar-type, early-stage RMS in IRS study III, and this same addition improved survival rates and doubled bladder salvage rates in patients with stage III RMS of the bladder. In children and young adults with stage IV metastatic rhabdomyoscarcoma, a Cochrane review has found no evidence to support the use of high-dose chemotherapy as a standard therapy.Radiation therapy, which kill cancer cells with focused doses of radiation, is often indicated in the treatment of rhabdomyosarcoma, and the exclusion of this treatment from disease management has been shown to increase recurrence rates. Radiation therapy is used when resecting the entirety of the tumor would involve disfigurement or loss of important organs (eye, bladder, etc.). Generally, in any case where a lack of complete resection is suspected, radiation therapy is indicated. Administration is usually following 6–12 weeks of chemotherapy if tumor cells are still present. The exception to this schedule is the presence of parameningeal tumors that have invaded the brain, spinal cord, or skull. In these cases radiation treatment is started immediately. In some cases, special radiation treatment may be required. Brachytherapy, or the placement of small, radioactive "seeds" directly inside the tumor or cancer site, is often indicated in children with tumors of sensitive areas such as the testicles, bladder, or vagina. This reduces scattering and the degree of late toxicity following dosing. Radiation therapy is more often indicated in higher stage classifications.
Immunotherapy is a more recent treatment modality that is still in development. This method involves recruiting and training the patients immune system to target the cancer cells. This can be accomplished through administering small molecules designed to pull immune cells towards the tumors, taking immune cells pulled from the patient and training to attack tumors through presentation with tumor antigen, or other experimental methods. A specific example here would be presenting some of the patients dendritic cells, which direct the immune system to foreign cells, with the PAX3-FKHR fusion protein in order to focus the patients immune system to the malignant RMS cells. All cancers, including rhabdomyosarcoma, could potentially benefit from this new, immune-based approach.
Prognostic
Prognosis in rhabdomyosarcoma patients has been shown to be dependent on age, tumor site, resectability of tumor, tumor size, regional lymph node involvement, presence of metastasis, site and extent of metastasis, and biological and histopathological characteristics of the tumor cells. Survival after recurrence is poor, and new salvage therapy strategies are needed.
Epidemiology
Rhabdomyosarcoma is the most common soft-tissue sarcoma in children as well as the third most common solid tumor in children. Recent estimates place the incidence of the disease at approximately 4.5 case per 1 million children/adolescents with approximately 250 new cases in the United States each year. With the vast majority of cases of RMS occurring in children or adolescents, two-thirds of reported cases occur in youths under the age of 10. RMS also occurs slightly more often in males than in females, with a ratio of approximately 1.3–1.5:1. In addition, slightly lower prevalence of the disease has been reported in black and Asian children relative to white children. In most cases, there are no clear predisposing risk factors for the development of RMS. It tends to occur sporadically with no obvious cause. However, RMS has been correlated with familial cancer syndromes and congenital abnormalities including neurofibromatosis type 1, Beckwith-Wiedemann syndrome, Li–Fraumeni syndrome, cardio-facio-cutaneous syndrome, and Costello syndrome. It has also been associated with parental use of cocaine and marijuana.
History
Rhabdomyosarcoma was first described by Weber, a German physician, in 1845, but it wasnt until the paper by Arthur Stout in 1946 that RMS was formally classified. The first thirty years of investigation were conducted by the Intergroup Rhabdomyosarcoma Study Group (IRSG), an independent National Cancer Institute (NCI)-funded cooperative that has become a part of the Childrens Oncology Group.
Research
Cancer stem cells of rhabdomyosarcoma have been identified and fibroblast growth factor receptor 3 has been suggested as their marker. Preclinical animal studies that try to use conditionally replicating adenoviruses against such cells are in progress.
Epigenetic Therapy for rhabdomyosarcoma is becoming more important. A recent study by Bharathy et al. found that deacetylase inhibitor, entinostat works in aggressive subtype, alveolar rhabdomyosarcoma (aRMS) by specifically blocking the activity of HDAC3, thereby preventing epigenetic suppression of a microRNA that inhibits PAX3:FOXO1 translation. These findings and ongoing clinical trials (ADVL1513) shows promise for an effective therapy for some patients with aRMS.
See also
Rhabdomyoma
References
Saboo, S. S.; Krajewski, K. M.; Zukotynski, K.; Howard, S.; Jagannathan, J. P.; Hornick, J. L.; Ramaiya, N. (2012). "Imaging Features of Primary and Secondary Adult Rhabdomyosarcoma". American Journal of Roentgenology. 199 (6): W694–W703. doi:10.2214/AJR.11.8213. PMID 23169742.
== External links == |
Rheumatic fever | Rheumatic fever (RF) is an inflammatory disease that can involve the heart, joints, skin, and brain. The disease typically develops two to four weeks after a streptococcal throat infection. Signs and symptoms include fever, multiple painful joints, involuntary muscle movements, and occasionally a characteristic non-itchy rash known as erythema marginatum. The heart is involved in about half of the cases. Damage to the heart valves, known as rheumatic heart disease (RHD), usually occurs after repeated attacks but can sometimes occur after one. The damaged valves may result in heart failure, atrial fibrillation and infection of the valves.Rheumatic fever may occur following an infection of the throat by the bacterium Streptococcus pyogenes. If the infection is left untreated, rheumatic fever occurs in up to three percent of people. The underlying mechanism is believed to involve the production of antibodies against a persons own tissues. Due to their genetics, some people are more likely to get the disease when exposed to the bacteria than others. Other risk factors include malnutrition and poverty. Diagnosis of RF is often based on the presence of signs and symptoms in combination with evidence of a recent streptococcal infection.Treating people who have strep throat with antibiotics, such as penicillin, decreases the risk of developing rheumatic fever. In order to avoid antibiotic misuse this often involves testing people with sore throats for the infection; however, testing might not be available in the developing world. Other preventive measures include improved sanitation. In those with rheumatic fever and rheumatic heart disease, prolonged periods of antibiotics are sometimes recommended. Gradual return to normal activities may occur following an attack. Once RHD develops, treatment is more difficult. Occasionally valve replacement surgery or valve repair is required. Otherwise complications are treated as usual.Rheumatic fever occurs in about 325,000 children each year and about 33.4 million people currently have rheumatic heart disease. Those who develop RF are most often between the ages of 5 and 14, with 20% of first-time attacks occurring in adults. The disease is most common in the developing world and among indigenous peoples in the developed world. In 2015 it resulted in 319,400 deaths down from 374,000 deaths in 1990. Most deaths occur in the developing world where as many as 12.5% of people affected may die each year. Descriptions of the condition are believed to date back to at least the 5th century BCE in the writings of Hippocrates. The disease is so named because its symptoms are similar to those of some rheumatic disorders.
Signs and symptoms
The disease typically develops two to four weeks after a throat infection. Symptoms include: fever, painful joints with those joints affected changing with time, involuntary muscle movements, and occasionally a characteristic non-itchy rash known as erythema marginatum. The heart is involved in about half of the cases. Damage to the heart valves usually occurs only after multiple attacks but may occasionally occur after a single case of RF. The damaged valves may result in heart failure and also increase the risk of atrial fibrillation and infection of the valves.
Pathophysiology
Rheumatic fever is a systemic disease affecting the connective tissue around arterioles, and can occur after an untreated strep throat infection, specifically due to group A streptococcus (GAS), Streptococcus pyogenes. The similarity between antigens of Streptococcus pyogenes and multiple cardiac proteins can cause a life-threatening type II hypersensitivity reaction. Usually, self reactive B cells remain anergic in the periphery without T cell co-stimulation. During a streptococcal infection, mature antigen-presenting cells such as B cells present the bacterial antigen to CD4+T cells which differentiate into helper T2 cells. Helper T2 cells subsequently activate the B cells to become plasma cells and induce the production of antibodies against the cell wall of Streptococcus. However the antibodies may also react against the myocardium and joints, producing the symptoms of rheumatic fever. S. pyogenes is a species of aerobic, cocci, gram-positive bacteria that are non-motile, non-spore forming, and forms chains and large colonies.S. pyogenes has a cell wall composed of branched polymers which sometimes contain M protein, a virulence factor that is highly antigenic. The antibodies which the immune system generates against the M protein may cross-react with heart muscle cell protein myosin, heart muscle glycogen and smooth muscle cells of arteries, inducing cytokine release and tissue destruction. However, the only proven cross-reaction is with perivascular connective tissue. This inflammation occurs through direct attachment of complement and Fc receptor-mediated recruitment of neutrophils and macrophages. Characteristic Aschoff bodies, composed of swollen eosinophilic collagen surrounded by lymphocytes and macrophages can be seen on light microscopy. The larger macrophages may become Anitschkow cells or Aschoff giant cells. Rheumatic valvular lesions may also involve a cell-mediated immunity reaction as these lesions predominantly contain T-helper cells and macrophages.In rheumatic fever, these lesions can be found in any layer of the heart causing different types of carditis. The inflammation may cause a serofibrinous pericardial exudate described as "bread-and-butter" pericarditis, which usually resolves without sequelae. Involvement of the endocardium typically results in fibrinoid necrosis and wart formation along the lines of closure of the left-sided heart valves. Warty projections arise from the deposition, while subendocardial lesions may induce irregular thickenings called MacCallum plaques.
Rheumatic heart disease
Chronic rheumatic heart disease (RHD) is characterized by repeated inflammation with fibrinous repair. The cardinal anatomic changes of the valve include leaflet thickening, commissural fusion, and shortening and thickening of the tendinous cords. It is caused by an autoimmune reaction to Group A β-hemolytic streptococci (GAS) that results in valvular damage. Fibrosis and scarring of valve leaflets, commissures and cusps leads to abnormalities that can result in valve stenosis or regurgitation. The inflammation caused by rheumatic fever, usually during childhood, is referred to as rheumatic valvulitis. About half of patients with rheumatic fever develop inflammation involving valvular endothelium. The majority of morbidity and mortality associated with rheumatic fever is caused by its destructive effects on cardiac valve tissue. The pathogenesis of RHD is complex and not fully understood, but it is known to involve molecular mimicry and genetic predisposition that lead to autoimmune reactions.Molecular mimicry occurs when epitopes are shared between host antigens and Streptococcus antigens. This causes an autoimmune reaction against native tissues in the heart that are incorrectly recognized as "foreign" due to the cross-reactivity of antibodies generated as a result of epitope sharing. The valvular endothelium is a prominent site of lymphocyte-induced damage. CD4+ T cells are the major effectors of heart tissue autoimmune reactions in RHD. Normally, T cell activation is triggered by the presentation of bacterial antigens. In RHD, molecular mimicry results in incorrect T cell activation, and these T lymphocytes can go on to activate B cells, which will begin to produce self-antigen-specific antibodies. This leads to an immune response attack mounted against tissues in the heart that have been misidentified as pathogens. Rheumatic valves display increased expression of VCAM-1, a protein that mediates the adhesion of lymphocytes. Self-antigen-specific antibodies generated via molecular mimicry between human proteins and streptococcal antigens up-regulate VCAM-1 after binding to the valvular endothelium. This leads to the inflammation and valve scarring observed in rheumatic valvulitis, mainly due to CD4+ T cell infiltration.While the mechanisms of genetic predisposition remain unclear, a few genetic factors have been found to increase susceptibility to autoimmune reactions in RHD. The dominant contributors are a component of MHC class II molecules, found on lymphocytes and antigen-presenting cells, specifically the DR and DQ alleles on human chromosome 6. Certain allele combinations appear to increase RHD autoimmune susceptibility. Human leukocyte antigen (HLA) class II allele DR7 (HLA-DR7) is most often associated with RHD, and its combination with certain DQ alleles is seemingly associated with the development of valvular lesions. The mechanism by which MHC class II molecules increase a hosts susceptibility to autoimmune reactions in RHD is unknown, but it is likely related to the role HLA molecules play in presenting antigens to T cell receptors, thus triggering an immune response. Also found on human chromosome 6 is the cytokine TNF-α which is also associated with RHD. High expression levels of TNF-α may exacerbate valvular tissue inflammation, contributing to RHD pathogenesis. Mannose-binding lectin (MBL) is an inflammatory protein involved in pathogen recognition. Different variants of MBL2 gene regions are associated in RHD. RHD-induced mitral valve stenosis has been associated with MBL2 alleles encoding for high production of MBL. Aortic valve regurgitation in RHD patients has been associated with different MBL2 alleles that encode for low production of MBL. Other genes are also being investigated to better understand the complexity of autoimmune reactions that occur in RHD.
Diagnosis
Modified Jones criteria were first published in 1944 by T. Duckett Jones, MD. They have been periodically revised by the American Heart Association in collaboration with other groups. According to revised Jones criteria, the diagnosis of rheumatic fever can be made when two of the major criteria, or one major criterion plus two minor criteria, are present along with evidence of streptococcal infection: elevated or rising antistreptolysin O titre or anti-DNase B. A recurrent episode is also diagnosed when three minor criteria are present. Exceptions are chorea and indolent carditis, each of which by itself can indicate rheumatic fever. An April 2013 review article in the Indian Journal of Medical Research stated that echocardiographic and Doppler (E & D) studies, despite some reservations about their utility, have identified a massive burden of rheumatic heart disease, which suggests the inadequacy of the 1992 Jones criteria. E & D studies have identified subclinical carditis in patients with rheumatic fever, as well as in follow-ups of rheumatic heart disease patients who initially presented as having isolated cases of Sydenhams chorea. Signs of a preceding streptococcal infection include: recent scarlet fever, raised antistreptolysin O or other streptococcal antibody titre, or positive throat culture. The last revision of 2015 suggested variable diagnostic criteria in low-risk and high-risk populations to avoid overdiagnosis in the first category and underdiagnosis in the last one. Low-risk populations were defined as those with acute rheumatic fever annual incidence ≤2 per 100 000 school-aged children or all-age rheumatic heart disease prevalence of ≤1 per 1000. All other populations were categorised as having a moderate or high risk.
Major criteria
Joint manifestations are the unique clinical signs that have different implications for different population-risk categories : Only polyarthritis (a temporary migrating inflammation of the large joints, usually starting in the legs and migrating upwards) is considered as a major criterion in low-risk populations, whereas monoarthritis, polyarthritis and polyarthralgia (joint pain without swelling) are all included as major criteria in high-risk populations.
Carditis: Carditis can involve the pericardium (pericarditis which resolves without sequelae), some regions of the myocardium (which might not provoke systolic dysfunction), and more consistently the endocardium in the form of valvulitis. Carditis is diagnosed clinically (palpitations, shortness of breath, heart failure, or a new heart murmur) or by echocardiography/Doppler studies revealing mitral or aortic valvulitis. Both of clinical and subclinical carditis are now considered a major criterion.
Subcutaneous nodules: Painless, firm collections of collagen fibers over bones or tendons. They commonly appear on the back of the wrist, the outside elbow, and the front of the knees.
Erythema marginatum: A long-lasting reddish rash that begins on the trunk or arms as macules, which spread outward and clear in the middle to form rings, which continue to spread and coalesce with other rings, ultimately taking on a snake-like appearance. This rash typically spares the face and is made worse with heat.
Sydenhams chorea (St. Vitus dance): A characteristic series of involuntary rapid movements of the face and arms. This can occur very late in the disease for at least three months from onset of infection.
Minor criteria
Arthralgia: Polyarthralgia in low-risk populations and monoarthralgia in others. However, joint manifestations cannot be considered in both major and minor categories in the same patient.
Fever: ≥ 38.5 °C (101.3 °F) in low-incidence populations and ≥ 38 °C (100.4 °F) in high-risk populations.
Raised erythrocyte sedimentation rate (≥60 mm in the first hour in lox-risk populations and ≥30 mm/h in others) or C reactive protein (>3.0 mg/dL).
ECG showing a prolonged PR interval after accounting for age variability (Cannot be included if carditis is present as a major symptom)
Prevention
Rheumatic fever can be prevented by effectively and promptly treating strep throat with antibiotics.In those who have previously had rheumatic fever, antibiotics in a preventative manner are occasionally recommended. As of 2017 the evidence to support long term antibiotics in those with underlying disease is poor.The American Heart Association suggests that dental health be maintained, and that people with a history of bacterial endocarditis, a heart transplant, artificial heart valves, or "some types of congenital heart defects" may wish to consider long-term antibiotic prophylaxis.
Treatment
The management of rheumatic fever is directed toward the reduction of inflammation with anti-inflammatory medications such as aspirin or corticosteroids. Individuals with positive cultures for strep throat should also be treated with antibiotics.Aspirin is the drug of choice and should be given at high doses.One should watch for side effects like gastritis and salicylate poisoning. In children and teenagers, the use of aspirin and aspirin-containing products can be associated with Reyes syndrome, a serious and potentially deadly condition. The risks, benefits, and alternative treatments must always be considered when administering aspirin and aspirin-containing products in children and teenagers. Ibuprofen for pain and discomfort and corticosteroids for moderate to severe inflammatory reactions manifested by rheumatic fever should be considered in children and teenagers.
Vaccine
No vaccines are currently available to protect against S. pyogenes infection, although research is underway to develop one. Difficulties in developing a vaccine include the wide variety of strains of S. pyogenes present in the environment and the large amount of time and people that will be needed for appropriate trials for safety and efficacy of the vaccine.
Infection
People with positive cultures for Streptococcus pyogenes should be treated with penicillin as long as allergy is not present. The use of antibiotics will not alter cardiac involvement in the development of rheumatic fever. Some suggest the use of benzathine benzylpenicillin.Monthly injections of long-acting penicillin must be given for a period of five years in patients having one attack of rheumatic fever. If there is evidence of carditis, the length of therapy may be up to 40 years. Another important cornerstone in treating rheumatic fever includes the continual use of low-dose antibiotics (such as penicillin, sulfadiazine, or erythromycin) to prevent recurrence.
Inflammation
While corticosteroids are often used, evidence to support this is poor. Salicylates are useful for pain.Steroids are reserved for cases where there is evidence of an involvement of the heart. The use of steroids may prevent further scarring of tissue and may prevent the development of sequelae such as mitral stenosis.
Heart failure
Some patients develop significant carditis which manifests as congestive heart failure. This requires the usual treatment for heart failure: ACE inhibitors, diuretics, beta blockers, and digoxin. Unlike typical heart failure, rheumatic heart failure responds well to corticosteroids.
Epidemiology
About 33 million people are affected by rheumatic heart disease with an additional 47 million having asymptomatic damage to their heart valves. As of 2010 globally it resulted in 345,000 deaths, down from 463,000 in 1990.In Western countries, rheumatic fever has become fairly rare since the 1960s, probably due to the widespread use of antibiotics to treat streptococcus infections. While it has been far less common in the United States since the beginning of the 20th century, there have been a few outbreaks since the 1980s. The disease is most common among Indigenous Australians (particularly in central and northern Australia), Māori, and Pacific Islanders, and is also common in Sub-Saharan Africa, Latin America, the Indian Subcontinent, and North Africa.Rheumatic fever primarily affects children between ages 5 and 17 years and occurs approximately 20 days after strep throat. In up to a third of cases, the underlying strep infection may not have caused any symptoms.The rate of development of rheumatic fever in individuals with untreated strep infection is estimated to be 3%. The incidence of recurrence with a subsequent untreated infection is substantially greater (about 50%). The rate of development is far lower in individuals who have received antibiotic treatment. Persons who have had a case of rheumatic fever have a tendency to develop flare-ups with repeated strep infections.The recurrence of rheumatic fever is relatively common in the absence of maintenance of low dose antibiotics, especially during the first three to five years after the first episode. Recurrent bouts of rheumatic fever can lead to valvular heart disease. Heart complications may be long-term and severe, particularly if valves are involved. In countries in Southeast-Asia, sub-Saharan Africa, and Oceania, the percentage of people with rheumatic heart disease detected by listening to the heart was 2.9 per 1000 children and by echocardiography it was 12.9 per 1000 children. Echocardiographic screening among children and timely initiation of secondary antibiotic prophylaxis in children with evidence of early stages of rheumatic heart disease may be effective to reduce the burden of rheumatic heart disease in endemic regions.
See also
Rapid strep test
References
External links
"Jones major criteria". Archived from the original on 4 August 2017. |
Riboflavin | Riboflavin, also known as vitamin B2, is a vitamin found in food and sold as a dietary supplement. It is essential to the formation of two major coenzymes, flavin mononucleotide and flavin adenine dinucleotide. These coenzymes are involved in energy metabolism, cellular respiration, and antibody production, as well as normal growth and development. The coenzymes are also required for the metabolism of niacin, vitamin B6, and folate. Riboflavin is prescribed to treat corneal thinning, and taken orally, may reduce the incidence of migraine headaches in adults.
Riboflavin deficiency is rare and is usually accompanied by deficiencies of other vitamins and nutrients. It may be prevented or treated by oral supplements or by injections. As a water-soluble vitamin, any riboflavin consumed in excess of nutritional requirements is not stored; it is either not absorbed or is absorbed and quickly excreted in urine, causing the urine to have a bright yellow tint. Natural sources of riboflavin include meat, fish and fowl, eggs, dairy products, green vegetables, mushrooms, and almonds. Some countries require its addition to grains.
Riboflavin was discovered in 1920, isolated in 1933, and first synthesized in 1935. In its purified, solid form, it is a water-soluble yellow-orange crystalline powder. In addition to its function as a vitamin, it is used as a food coloring agent. Biosynthesis takes place in bacteria, fungi and plants, but not animals. Industrial synthesis of riboflavin was initially achieved using a chemical process, but current commercial manufacturing relies on fermentation methods using strains of fungi and genetically modified bacteria.
Definition
Riboflavin, also known as vitamin B2, is a water-soluble vitamin and is one of the B vitamins. Unlike folate and vitamin B6, which occur in several chemically related forms known as vitamers, riboflavin is only one chemical compound. It is a starting compound in the synthesis of the coenzymes flavin mononucleotide (FMN, also known as riboflavin-5-phosphate) and flavin adenine dinucleotide (FAD). FAD is the more abundant form of flavin, reported to bind to 75% of the number of flavin-dependent protein encoded genes in the all-species genome (the flavoproteome) and serves as a co-enzyme for 84% of human-encoded flavoproteins.In its purified, solid form, riboflavin is a yellow-orange crystalline powder with a slight odor and bitter taste. It is soluble in polar solvents, such as water and aqueous sodium chloride solutions, and slightly soluble in alcohols. It is not soluble in non-polar or weakly polar organic solvents such as chloroform, benzene or acetone. In solution or during dry storage as a powder, riboflavin is heat stable if not exposed to light. When heated to decompose, it releases toxic fumes containing nitric oxide.
Functions
Riboflavin is essential to the formation of two major coenzymes, FMN and FAD. These coenzymes are involved in energy metabolism, cell respiration, antibody production, growth and development. Riboflavin is essential for the metabolism of carbohydrates, protein and fats. FAD contributes to conversion of tryptophan to niacin (vitamin B3) and the conversion of vitamin B6 to the coenzyme pyridoxal 5-phosphate requires FMN. Riboflavin is involved in maintaining normal circulating levels of homocysteine; in riboflavin deficiency, homocysteine levels increase, elevating the risk of cardiovascular diseases.
Redox reactions
Redox reactions are processes that involve the transfer of electrons. The flavin coenzymes support the function of roughly 70-80 flavoenzymes in humans (and hundreds more across all organisms, including those encoded by archeal, bacterial and fungal genomes) that are responsible for one- or two-electron redox reactions which capitalize on the ability of flavins to be converted between oxidized, half-reduced and fully reduced forms. FAD is also required for the activity of glutathione reductase, an essential enzyme in formation of the endogenous antioxidant, glutathione.
Micronutrient metabolism
Riboflavin, FMN, and FAD are involved in the metabolism of niacin, vitamin B6, and folate. The synthesis of the niacin-containing coenzymes, NAD and NADP, from tryptophan involves the FAD-dependent enzyme, kynurenine 3-monooxygenase. Dietary deficiency of riboflavin can decrease the production of NAD and NADP, thereby promoting niacin deficiency. Conversion of vitamin B6 to its coenzyme, pyridoxal 5-phosphate synthase, involves the enzyme, pyridoxine 5-phosphate oxidase, which requires FMN. An enzyme involved in folate metabolism, 5,10-methylenetetrahydrofolate reductase, requires FAD to form the amino acid, methionine, from homocysteine.Riboflavin deficiency appears to impair the metabolism of the dietary mineral, iron, which is essential to the production of hemoglobin and red blood cells. Alleviating riboflavin deficiency in people who are deficient in both riboflavin and iron improves the effectiveness of iron supplementation for treating iron-deficiency anemia.
Synthesis
Biosynthesis
Biosynthesis takes place in bacteria, fungi and plants, but not animals. The biosynthetic precursors to riboflavin are ribulose 5-phosphate and guanosine triphosphate. The former is converted to L-3,4-dihydroxy-2-butanone-4-phosphate while the latter is transformed in a series of reactions that lead to 5-amino-6-(D-ribitylamino)uracil. These two compounds are then the substrates for the penultimate step in the pathway, catalysed by the enzyme lumazine synthase in reaction EC 2.5.1.78.
In the final step of the biosynthesis, two molecules of 6,7-dimethyl-8-ribityllumazine are combined by the enzyme riboflavin synthase in a dismutation reaction. This generates one molecule of riboflavin and one of 5-amino-6-(D-ribitylamino) uracil. The latter is recycled to the previous reaction in the sequence.
Conversions of riboflavin to the cofactors FMN and FAD are carried out by the enzymes riboflavin kinase and FAD synthetase acting sequentially.
Industrial synthesis
The industrial-scale production of riboflavin uses various microorganisms, including filamentous fungi such as Ashbya gossypii, Candida famata and Candida flaveri, as well as the bacteria Corynebacterium ammoniagenes and Bacillus subtilis. B. subtilis that has been genetically modified to both increase the production of riboflavin and to introduce an antibiotic (ampicillin) resistance marker, is employed at a commercial scale to produce riboflavin for feed and food fortification. By 2012, over 4,000 tonnes per annum were produced by such fermentation processes.In the presence of high concentrations of hydrocarbons or aromatic compounds, some bacteria overproduce riboflavin, possibly as a protective mechanism. One such organism is Micrococcus luteus (American Type Culture Collection strain number ATCC 49442), which develops a yellow color due to production of riboflavin while growing on pyridine, but not when grown on other substrates, such as succinic acid.
Laboratory synthesis
The first total synthesis of riboflavin was carried out by Richard Kuhns group. A substituted aniline, produced by reductive amination using D-ribose, was condensed with alloxan in the final step:
Uses
Treatment of corneal thinning
Keratoconus is the most common form of corneal ectasia, a progressive thinning of the cornea. The condition is treated by corneal collagen cross-linking, which increases corneal stiffness. Cross-linking is achieved by applying a topical riboflavin solution to the cornea, which is then exposed to ultraviolet A light.
Migraine prevention
In its 2012 guidelines, the American Academy of Neurology stated that high-dose riboflavin (400 mg) is "probably effective and should be considered for migraine prevention," a recommendation also provided by the UK National Migraine Centre. A 2017 review reported that daily riboflavin taken at 400 mg per day for at least three months may reduce the frequency of migraine headaches in adults. Research on high-dose riboflavin for migraine prevention or treatment in children and adolescents is inconclusive, and so supplements are not recommended.
Food coloring
Riboflavin is used as a food coloring (yellow-orange crystalline powder), and is designated with the E number, E101, in Europe for use as a food additive.
Dietary recommendations
The National Academy of Medicine updated the Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for riboflavin in 1998. The EARs for riboflavin for women and men aged 14 and over are 0.9 mg/day and 1.1 mg/day, respectively; the RDAs are 1.1 and 1.3 mg/day, respectively. RDAs are higher than EARs to provide adequate intake levels for individuals with higher than average requirements. The RDA during pregnancy is 1.4 mg/day and the RDA for lactating females is 1.6 mg/day. For infants up to the age of 12 months, the Adequate Intake (AI) is 0.3–0.4 mg/day and for children aged 1–13 years the RDA increases with age from 0.5 to 0.9 mg/day. As for safety, the IOM sets tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of riboflavin there is no UL, as there is no human data for adverse effects from high doses. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in United States. For women and men aged 15 and older the PRI is set at 1.6 mg/day. The PRI during pregnancy is 1.9 mg/day and the PRI for lactating females is 2.0 mg/day. For children aged 1–14 years the PRIs increase with age from 0.6 to 1.4 mg/day. These PRIs are higher than the U.S. RDAs. The EFSA also considered the maximum safe intake and like the U.S. National Academy of Medicine, decided that there was not sufficient information to set an UL.
Safety
In humans, there is no evidence for riboflavin toxicity produced by excessive intakes and absorption becomes less efficient as doses increases. Any excess riboflavin is excreted via the kidneys into urine, resulting in a bright yellow color known as flavinuria. During a clinical trial on the effectiveness of riboflavin for treating the frequency and severity of migraines, subjects were given up to 400 mg of riboflavin orally per day for periods of 3–12 months. Abdominal pains and diarrhea were among the side effects reported.
Labeling
For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For riboflavin labeling purposes 100% of the Daily Value was 1.7 mg, but as of May 27, 2016, it was revised to 1.3 mg to bring it into agreement with the RDA. A table of the old and new adult daily values is provided at Reference Daily Intake.
Sources
The United States Department of Agriculture, Agricultural Research Service maintains a food composition database from which riboflavin content in hundreds of foods can be searched.
The milling of wheat results in an 85% loss of riboflavin, so white flour is enriched in some countries. Riboflavin is also added to baby foods, breakfast cereals, pastas and vitamin-enriched meal replacement products. It is difficult to incorporate riboflavin into liquid products because it has poor solubility in water, hence the requirement for riboflavin-5-phosphate (FMN, also called E101 when used as colorant), a more soluble form of riboflavin. The enrichment of bread and ready-to-eat breakfast cereals contributes significantly to the dietary supply of the vitamin. Free riboflavin is naturally present in animal-sourced foods along with protein-bound FMN and FAD. Cows milk contains mainly free riboflavin, but both FMN and FAD are present at low concentrations.
Fortification
Some countries require or recommend fortification of grain foods. As of 2021, 56 countries, mostly in North and South America and southeast Africa, require food fortification of wheat flour or maize (corn) flour with riboflavin or riboflavin-5-phosphate sodium. The amounts stipulated range from 1.3 to 5.75 mg/kg. An additional 16 countries have a voluntary fortification program. For example, the Indian government recommends 4.0 mg/kg for "maida" (white) and "atta" (whole wheat) flour.
Absorption, metabolism, excretion
More than 90% of riboflavin in the diet is in the form of protein-bound FMN and FAD. Exposure to gastric acid in the stomach releases the coenzymes, which are subsequently enzymatically hydrolyzed in the proximal small intestine to release free riboflavin.Absorption occurs via a rapid active transport system, with some additional passive diffusion occurring at high concentrations. Bile salts facilitate uptake, so absorption is improved when the vitamin is consumed with a meal. One small clinical trial in adults reported that the maximum amount of riboflavin that can be absorbed from a single dose is 27 mg. The majority of newly absorbed riboflavin is taken up by the liver on the first pass, indicating that postprandial appearance of riboflavin in blood plasma may underestimate absorption. Three riboflavin transporter proteins have been identified: RFVT1 is present in the small intestine and also in the placenta; RFVT2 is highly expressed in brain and salivary glands; and RFVT3 is most highly expressed in the small intestine, testes, and prostate. Infants with mutations in the genes encoding these transport proteins can be treated with riboflavin administered orally.Riboflavin is reversibly converted to FMN and then FAD. From riboflavin to FMN is the function of zinc-requiring riboflavin kinase; the reverse is accomplished by a phosphatase. From FMN to FAD is the function of magnesium-requiring FAD synthase; the reverse is accomplished by a pyrophosphatase. FAD appears to be an inhibitory end-product that down-regulates its own formation.When excess riboflavin is absorbed by the small intestine, it is quickly removed from the blood and excreted in urine. Urine color is used as a hydration status biomarker and, under normal conditions, correlates with urine specific gravity and urine osmolality. However, riboflavin supplementation in large excess of requirements causes urine to appear more yellow than normal. With normal dietary intake, about two-thirds of urinary output is riboflavin, the remainder having been partially metabolized to hydroxymethylriboflavin from oxidation within cells, and as other metabolites. When consumption exceeds the ability to absorb, riboflavin passes into the large intestine, where it is catabolized by bacteria to various metabolites that can be detected in feces. There is speculation that unabsorbed riboflavin could affect the large intestine microbiome.
Deficiency
Prevalence
Riboflavin deficiency is uncommon in the United States and in other countries with wheat flour or corn meal fortification programs. From data collected in biannual surveys of the U.S. population, for ages 20 and over, 22% of females and 19% of men reported consuming a supplement that contained riboflavin, typically a vitamin-mineral multi-supplement. For the non-supplement users, the dietary intake of adult women averaged 1.74 mg/day and men 2.44 mg/day. These amounts exceed the RDAs for riboflavin of 1.1 and 1.3 mg/day respectively. For all age groups, on average, consumption from food exceeded the RDAs. A 2001-02 U.S. survey reported that less than 3% of the population consumed less than the Estimated Average Requirement of riboflavin.
Signs and symptoms
Riboflavin deficiency (also called ariboflavinosis) results in stomatitis, symptoms of which include chapped and fissured lips, inflammation of the corners of the mouth (angular stomatitis), sore throat, painful red tongue, and hair loss. The eyes can become itchy, watery, bloodshot, and sensitive to light. Riboflavin deficiency is associated with anemia. Prolonged riboflavin insufficiency may cause degeneration of the liver and nervous system. Riboflavin deficiency may increase the risk of preeclampsia in pregnant women. Deficiency of riboflavin during pregnancy can result in fetal birth defects, including heart and limb deformities.
Risk factors
People at risk of having low riboflavin levels include alcoholics, vegetarian athletes, and practitioners of veganism. Pregnant or lactating women and their infants may also be at risk, if the mother avoids meat and dairy products. Anorexia and lactose intolerance increase the risk of riboflavin deficiency. People with physically demanding lives, such as athletes and laborers, may require higher riboflavin intake. The conversion of riboflavin into FAD and FMN is impaired in people with hypothyroidism, adrenal insufficiency, and riboflavin transporter deficiency.
Causes
Riboflavin deficiency is usually found together with other nutrient deficiencies, particularly of other water-soluble vitamins. A deficiency of riboflavin can be primary (i.e. caused by poor vitamin sources in the regular diet) or secondary, which may be a result of conditions that affect absorption in the intestine. Secondary deficiencies are typically caused by the body not being able to use the vitamin, or by an increased rate of excretion of the vitamin. Diet patterns that increase risk of deficiency include veganism and low-dairy vegetarianism. Diseases such as cancer, heart disease and diabetes may cause or exacerbate riboflavin deficiency.There are rare genetic defects that compromise riboflavin absorption, transport, metabolism or use by flavoproteins. One of these is riboflavin transporter deficiency, previously known as Brown-Vialetto-Van Laere syndrome. Variants of the genes SLC52A2 and SLC52A3 which code for transporter proteins RDVT2 and RDVT3, respectively, are defective. Infants and young children present with muscle weakness, cranial nerve deficits including hearing loss, sensory symptoms including sensory ataxia, feeding difficulties, and respiratory distress caused by a sensorimotor axonal neuropathy and cranial nerve pathology. When untreated, infants with riboflavin transporter deficiency have labored breathing and are at risk of dying in the first decade of life. Treatment with oral supplementation of high amounts of riboflavin is lifesaving.Other inborn errors of metabolism include riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency, also known as a subset of glutaric acidemia type 2, and the C677T variant of the methylenetetrahydrofolate reductase enzyme, which in adults has been associated with risk of high blood pressure.
Diagnosis and assessment
The assessment of riboflavin status is essential for confirming cases with non-specific symptoms whenever deficiency is suspected. Total riboflavin excretion in healthy adults with normal riboflavin intake is about 120 micrograms per day, while excretion of less than 40 micrograms per day indicates deficiency. Riboflavin excretion rates decrease as a person ages, but increase during periods of chronic stress and the use of some prescription drugs.Indicators used in humans are erythrocyte glutathione reductase (EGR), erythrocyte flavin concentration and urinary excretion. The erythrocyte glutathione reductase activity coefficient (EGRAC) provides a measure of tissue saturation and long-term riboflavin status. Results are expressed as an activity coefficient ratio, determined by enzyme activity with and without the addition of FAD to the culture medium. An EGRAC of 1.0 to 1.2 indicates that adequate amounts of riboflavin are present; 1.2 to 1.4 is considered low, greater than 1.4 indicates deficient. For the less sensitive "erythrocyte flavin method", values greater than 400 nmol/L are considered adequate and values below 270 nmol/L are considered deficient. Urinary excretion is expressed as nmol of riboflavin per gram of creatinine. Low is defined as in the range of 50 to 72 nmol/g. Deficient is below 50 nmol/g. Urinary excretion load tests have been used to determine dietary requirements. For adult men, as oral doses were increased from 0.5 mg to 1.1 mg, there was a modest linear increase in urinary riboflavin, reaching 100 micrograms for a subsequent 24-hour urine collection. Beyond a load dose of 1.1 mg, urinary excretion increased rapidly, so that with a dose of 2.5 mg, urinary output was 800 micrograms for a 24-hour urine collection.
History
The name "riboflavin" comes from "ribose" (the sugar whose reduced form, ribitol, forms part of its structure) and "flavin", the ring-moiety which imparts the yellow color to the oxidized molecule (from Latin flavus, "yellow"). The reduced form, which occurs in metabolism along with the oxidized form, appears as orange-yellow needles or crystals. The earliest reported identification, predating any concept of vitamins as essential nutrients, was by Alexander Wynter Blyth. In 1897, Blyth isolated a water-soluble component of cows milk whey, which he named "lactochrome", that fluoresced yellow-green when exposed to light.In the early 1900s, several research laboratories were investigating constituents of foods, essential to maintain growth in rats. These constituents were initially divided into fat-soluble "vitamine" A and water-soluble "vitamine" B. (The "e" was dropped in 1920.) Vitamin B was further thought to have two components, a heat-labile substance called B1 and a heat-stable substance called B2. Vitamin B2 was tentatively identified to be the factor necessary for preventing pellagra, but that was later confirmed to be due to niacin (vitamin B3) deficiency. The confusion was due to the fact that riboflavin (B2) deficiency causes stomatitis symptoms similar to those seen in pellagra, but without the widespread peripheral skin lesions. For this reason, early in the history of identifying riboflavin deficiency in humans the condition was sometimes called "pellagra sine pellagra" (pellagra without pellagra).In 1935, Paul Gyorgy, in collaboration with chemist Richard Kuhn and physician T. Wagner-Jauregg, reported that rats kept on a B2-free diet were unable to gain weight. Isolation of B2 from yeast revealed the presence of a bright yellow-green fluorescent product that restored normal growth when fed to rats. The growth restored was directly proportional to the intensity of the fluorescence. This observation enabled the researchers to develop a rapid chemical bioassay in 1933, and then isolate the factor from egg white, calling it ovoflavin. The same group then isolated the a similar preparation from whey and called it lactoflavin. In 1934, Kuhns group identified the chemical structure of these flavins as identical, settled on "riboflavin" as a name, and were also able to synthesize the vitamin.Circa 1937, riboflavin was also referred to as "Vitamin G". In 1938, Richard Kuhn was awarded the Nobel Prize in Chemistry for his work on vitamins, which had included B2 and B6. In 1939, it was confirmed that riboflavin is essential for human health through a clinical trial conducted by William H. Sebrell and Roy E. Butler. Women fed a diet low in riboflavin developed stomatitis and other signs of deficiency, which were reversed when treated with synthetic riboflavin. The symptoms returned when the supplements were stopped.
== References == |
Rickets | Rickets is a condition that results in weak or soft bones in children, and is caused by either dietary deficiency or genetic causes. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications may include bone deformities, bone pseudofractures and fractures, muscle spasms, or an abnormally curved spine.The most common cause of rickets is a vitamin D deficiency, although hereditary genetic forms also exist. This can result from eating a diet without enough vitamin D, dark skin, too little sun exposure, exclusive breastfeeding without vitamin D supplementation, celiac disease, and certain genetic conditions. Other factors may include not enough calcium or phosphorus. The underlying mechanism involves insufficient calcification of the growth plate. Diagnosis is generally based on blood tests finding a low calcium, low phosphorus, and a high alkaline phosphatase together with X-rays.Prevention for exclusively breastfed babies is vitamin D supplements. Otherwise, treatment depends on the underlying cause. If due to a lack of vitamin D, treatment is usually with vitamin D and calcium. This generally results in improvements within a few weeks. Bone deformities may also improve over time. Occasionally surgery may be performed to correct bone deformities. Genetic forms of the disease typically require specialized treatment.Rickets occurs relatively commonly in the Middle East, Africa, and Asia. It is generally uncommon in the United States and Europe, except among certain minority groups. It begins in childhood, typically between the ages of 3 and 18 months old. Rates of disease are equal in males and females. Cases of what is believed to have been rickets have been described since the 1st century, and the condition was widespread in the Roman Empire. The disease was common into the 20th century. Early treatments included the use of cod liver oil.
Signs and symptoms
Signs and symptoms of dietary deficiency rickets can include bone tenderness, and a susceptibility for bone fractures, particularly greenstick fractures. Early skeletal deformities can arise in infants such as soft, thinned skull bones – a condition known as craniotabes, which is the first sign of rickets; skull bossing may be present and a delayed closure of the fontanelles.
Young children may have bowed legs and thickened ankles and wrists; older children may have knock knees. Spinal curvatures of kyphoscoliosis or lumbar lordosis may be present. The pelvic bones may be deformed. A condition known as rachitic rosary can result as the thickening caused by nodules forming on the costochondral joints. This appears as a visible bump in the middle of each rib in a line on each side of the body. This somewhat resembles a rosary, giving rise to its name. The deformity of a pigeon chest may result in the presence of Harrisons groove.
Hypocalcemia, a low level of calcium in the blood can result in tetany – uncontrolled muscle spasms. Dental problems can also arise.An X-ray or radiograph of an advanced patient with rickets tends to present in a classic way: the bowed legs (outward curve of long bone of the legs) and a deformed chest. Changes in the skull also occur causing a distinctive "square headed" appearance known as "caput quadratum". These deformities persist into adult life if not treated. Long-term consequences include permanent curvatures or disfiguration of the long bones, and a curved back.
Cause
Maternal deficiencies may be the cause of overt bone disease from before birth and impairment of bone quality after birth. The primary cause of congenital rickets is vitamin D deficiency in the mothers blood, which the baby shares. Vitamin D ensures that serum phosphate and calcium levels are sufficient to facilitate the mineralization of bone. Congenital rickets may also be caused by other maternal diseases, including severe osteomalacia, untreated celiac disease, malabsorption, pre-eclampsia, and premature birth. Rickets in children is similar to osteoporosis in the elderly, with brittle bones. Pre-natal care includes checking vitamin levels and ensuring that any deficiencies are supplemented.Exclusively breast-fed infants may require rickets prevention by vitamin D supplementation or an increased exposure to sunlight.In sunny countries such as Nigeria, South Africa, and Bangladesh, there is sufficient endogenous vitamin D due to exposure to the sun. However, the disease occurs among older toddlers and children in these countries, which in these circumstances is attributed to low dietary calcium intakes due to a mainly cereal-based diet.Those at higher risk for developing rickets include:
Breast-fed infants whose mothers are not exposed to sunlight
Breast-fed infants who are not exposed to sunlight
Breast-fed babies who are exposed to little sunlight
Adolescents, in particular when undergoing the pubertal growth spurt
Any child whose diet does not contain enough vitamin D or calciumDiseases causing soft bones in infants, like hypophosphatasia or hypophosphatemia, can also lead to rickets.Strontium is allied with calcium uptake into bones; at excessive dietary levels strontium has a rachitogenic (rickets-producing) action.
Sunlight
Sunlight, especially ultraviolet light, lets human skin cells convert vitamin D from an inactive to active state. In the absence of vitamin D, dietary calcium is not properly absorbed, resulting in hypocalcaemia, leading to skeletal and dental deformities and neuromuscular symptoms, e.g. hyperexcitability. Foods that contain vitamin D include butter, eggs, fish liver oils, margarine, fortified milk and juice, portabella and shiitake mushrooms, and oily fishes such as tuna, herring, and salmon. A rare X-linked dominant form exists called vitamin D-resistant rickets or X-linked hypophosphatemia.Cases have been reported in Britain in recent years of rickets in children of many social backgrounds caused by insufficient production in the body of vitamin D because the suns ultraviolet light was not reaching the skin due to use of strong sunblock, too much "covering up" in sunlight, or not getting out into the sun. Other cases have been reported among the children of some ethnic groups in which mothers avoid exposure to the sun for religious or cultural reasons, leading to a maternal shortage of vitamin D, and people with darker skin need more sunlight to maintain vitamin D levels.
Rickets had historically been a problem in London, especially during the Industrial Revolution. Persistent thick fog and heavy industrial smog permeating the city blocked out significant amounts of sunlight to such an extent that up to 80 percent of children at one time had varying degrees of rickets in one form or the other. It is sometimes known "the English Disease" in some foreign languages (e.g. German: Die englische Krankheit, Dutch: Engelse ziekte, Hungarian: angolkór).
Skin color theory
Rickets is often a result of vitamin D3 deficiency. The correlation between human skin color and latitude is thought to be the result of positive selection to varying levels of solar ultraviolet radiation. Northern latitudes have selection for lighter skin that allows UV rays to produce vitamin D from 7-dehydrocholesterol. Conversely, latitudes near the equator have selection for darker skin that can block the majority of UV radiation to protect from toxic levels of vitamin D, as well as skin cancer.An anecdote often cited to support this hypothesis is that Arctic populations whose skin is relatively darker for their latitude, such as the Inuit, have a diet that is historically rich in vitamin D. Since these people acquire vitamin D through their diet, there is not a positive selective force to synthesize vitamin D from sunlight.Environment mismatch: vitamin D deficiency arises from a mismatch between an individuals previous and current environment. This risk of mismatch increases with advances in transportation methods and increases in urban population size at high latitudes.Similar to the environmental mismatch when dark-skinned people live at high latitudes, Rickets can also occur in religious communities that require long garments with hoods and veils. These hoods and veils act as sunlight barriers that prevent individuals from synthesizing vitamin D naturally from the sun.In a study by Mithal et al., vitamin D insufficiency of various countries was measured by lower 25-hydroxyvitamin D. 25(OH) D is an indicator of vitamin D insufficiency that can be easily measured. These percentages should be regarded as relative vitamin D levels, and not as predicting evidence for development of rickets.
Asian immigrants living in Europe have an increased risk for vitamin D deficiency. Vitamin D insufficiency was found in 40% of non-Western immigrants in the Netherlands, and in more than 80% of Turkish and Moroccan immigrants.
The Middle East, despite high rates of sun-exposure, has the highest rates of rickets worldwide. This can be explained by limited sun exposure due to cultural practices and lack of vitamin D supplementation for breast-feeding women. Up to 70% and 80% of adolescent girls in Iran and Saudi Arabia, respectively, have vitamin D insufficiency. Socioeconomic factors that limit a vitamin D rich diet also plays a role.
In the United States, vitamin D insufficiency varies dramatically by ethnicity. Among females aged 70 years and older, the prevalence of low serum 25(OH) D levels was 28.5% for non-Hispanic whites, 55% for Mexican Americans, and 68% for non-Hispanic blacks. Among males, the prevalence was 23%, 45%, and 58%, respectively.A systematic review published in the Cochrane Library looked at children up to three years old in Turkey and China and found there was a beneficial association between vitamin D and rickets. In Turkey children getting vitamin D had only a 4% chance of developing rickets compared to children who received no medical intervention. In China, a combination of vitamin D, calcium and nutritional counseling was linked to a decreased risk of rickets.Parents can supplement their nutritional intake with vitamin D enhanced beverages if they feel their child is at risk for vitamin D deficiency.A recent review links rickets disease to exclusive consumption of Neocate baby formula.
Diagnosis
Rickets may be diagnosed with the help of:
Blood tests:Serum calcium may show low levels of calcium, serum phosphorus may be low, and serum alkaline phosphatase may be high from bones or changes in the shape or structure of the bones. This can show enlarged limbs and joints.
A bone density scan may be undertaken.
Radiography typically show widening of the zones of provisional calcification of the metaphyses secondary to unmineralized osteoid. Cupping, fraying, and splaying of metaphyses typically appears with growth and continued weight bearing. These changes are seen predominantly at sites of rapid growth, including the proximal humerus, distal radius, distal femur and both the proximal and the distal tibia. Therefore, a skeletal survey for rickets can be accomplished with anteroposterior radiographs of the knees, wrists, and ankles.
Types
Vitamin D-related ricketsVitamin D deficiency
Vitamin D-dependent rickets (VDDR)Type 1: insufficiency in activation
VDDR1A: 25-Hydroxyvitamin D3 1-alpha-hydroxylase deficiency
VDDR1B: CYP2R1 deficiency
Type 2: resistance to calcitriol
VDDR2A: calcitriol receptor mutation
VDDR2B: unknown nuclear ribonucleoprotein interfering with signal transduction
Type 3: excessive inactivation (CYP3A4 mutation, dominant)
Hypocalcemia-related rickets
Hypocalcemia
Chronic kidney failure (CKD-BMD)
Hypophosphatemia-related rickets
Congenital
Vitamin D-resistant rickets
Autosomal dominant hypophosphatemic rickets (ADHR)
Autosomal recessive hypophosphatemic rickets (ARHR)
Hypophosphatemia (typically secondary to malabsorption)
Fanconis syndrome
Secondary to other diseases
Tumor-induced osteomalacia
McCune-Albright syndrome
Epidermal nevus syndrome
Dents disease
Differential diagnosis
Osteochondrodysplasias, also known as genetic bone diseases, may mimic the clinical picture of rickets in regard to the features of bone deformities. The radiologic picture and the laboratory findings of serum calcium, phosphate and alkaline phosphatase are important differentiating factors. Blounts disease is an important differential diagnosis because it causes knee deformities in a similar fashion to rickets namely bow legs or genu varum. Infants with rickets can have bone fractures. This sometimes leads to child abuse allegations. This issue appears to be more common for solely nursing infants of black mothers, in winter in temperate climates, suffering poor nutrition and no vitamin D supplementation. People with darker skin produce less vitamin D than those with lighter skin, for the same amount of sunlight.
Treatment
Diet and sunlight
Treatment involves increasing dietary intake of calcium, phosphates and vitamin D. Exposure to ultraviolet B light (most easily obtained when the sun is highest in the sky), cod liver oil, halibut-liver oil, and viosterol are all sources of vitamin D.A sufficient amount of ultraviolet B light in sunlight each day and adequate supplies of calcium and phosphorus in the diet can prevent rickets. Darker-skinned people need to be exposed longer to the ultraviolet rays. The replacement of vitamin D has been proven to correct rickets using these methods of ultraviolet light therapy and medicine.Recommendations are for 400 international units (IU) of vitamin D a day for infants and children. Children who do not get adequate amounts of vitamin D are at increased risk of rickets. Vitamin D is essential for allowing the body to uptake calcium for use in proper bone calcification and maintenance.
Supplementation
Sufficient vitamin D levels can also be achieved through dietary supplementation and/or exposure to sunlight. Vitamin D3 (cholecalciferol) is the preferred form since it is more readily absorbed than vitamin D2. Most dermatologists recommend vitamin D supplementation as an alternative to unprotected ultraviolet exposure due to the increased risk of skin cancer associated with sun exposure. Endogenous production with full body exposure to sunlight is approximately 250 µg (10,000 IU) per day.According to the American Academy of Pediatrics (AAP), all infants, including those who are exclusively breast-fed, may need vitamin D supplementation until they start drinking at least 17 US fluid ounces (500 ml) of vitamin D-fortified milk or formula a day.
Surgery
Occasionally surgery is needed to correct severe and persistent deformities of the lower limbs, especially around the knees namely genu varum and genu valgum. Surgical correction of rachitic deformities can be achieved through osteotomies or guided growth surgery. Guided growth surgery has almost replaced the use of corrective osteotomies. The functional results of guided growth surgery in children with rickets are satisfactory. While bone osteotomies work through acute/immediate correction of the limb deformity, guided growth works through gradual correction.
Epidemiology
In developed countries, rickets is a rare disease (incidence of less than 1 in 200,000). Recently, cases of rickets have been reported among children who are not fed enough vitamin D.In 2013/2014 there were fewer than 700 cases in England. In 2019 the number of cases hospitalised was said to be the highest in 50 years.Rickets occurs relatively commonly in the Middle East, Africa, and Asia.
History
Greek physician Soranus of Ephesus, one of the chief representatives of the Methodic school of medicine who practiced in Alexandria and subsequently in Rome, reported deformation of the bones in infants as early as the first and second centuries AD. Rickets was not defined as a specific medical condition until 1645, when an English physician Daniel Whistler gave the earliest known description of the disease. In 1650 a treatise on rickets was published by Francis Glisson, a physician at Caius College, Cambridge, who said it had first appeared about 30 years previously in the counties of Dorset and Somerset. In 1857, John Snow suggested rickets, then widespread in Britain, was being caused by the adulteration of bakers bread with alum. German pediatrician Kurt Huldschinsky successfully demonstrated in the winter of 1918–1919 how rickets could be treated with ultraviolet lamps. The role of diet in the development of rickets was determined by Edward Mellanby between 1918 and 1920. In 1923, American physician Harry Steenbock demonstrated that irradiation by ultraviolet light increased the vitamin D content of foods and other organic materials. Steenbocks irradiation technique was used for foodstuffs, but most memorably for milk. By 1945, rickets had all but been eliminated in the United States.
Etymology
The word rickets may be from the Old English word wrickken (to twist), although because this is conjectured, several major dictionaries simply say "origin unknown". The name rickets is plural in form but usually singular in construction. The Greek word rachitis (ῥαχίτης, meaning in or of the spine) was later adopted as the scientific term for rickets, due chiefly to the words similarity in sound.
See also
Hypervitaminosis D
References
External links
Media related to Rickets at Wikimedia Commons |
Rocky Mountain spotted fever | Rocky Mountain spotted fever (RMSF) is a bacterial disease spread by ticks. It typically begins with a fever and headache, which is followed a few days later with the development of a rash. The rash is generally made up of small spots of bleeding and starts on the wrists and ankles. Other symptoms may include muscle pains and vomiting. Long-term complications following recovery may include hearing loss or loss of part of an arm or leg.The disease is caused by Rickettsia rickettsii, a type of bacterium that is primarily spread to humans by American dog ticks, Rocky Mountain wood ticks, and brown dog ticks. Rarely the disease is spread by blood transfusions. Diagnosis in the early stages is difficult. A number of laboratory tests can confirm the diagnosis but treatment should be begun based on symptoms. It is within a group known as spotted fever rickettsiosis, together with Rickettsia parkeri rickettsiosis, Pacific Coast tick fever, and rickettsialpox.Treatment of RMSF is with the antibiotic doxycycline. It works best when started early and is recommended in all age groups, as well as during pregnancy. Antibiotics are not recommended for prevention. Approximately 0.5% of people who are infected die as a result. Before the discovery of tetracycline in the 1940s, more than 10% of those with RMSF died.Fewer than 5,000 cases are reported a year in the United States, most often in June and July. It has been diagnosed throughout the contiguous United States, Western Canada, and parts of Central and South America. Rocky Mountain spotted fever was first identified in the 1800s in the Rocky Mountains.
Signs and symptoms
Spotted fever can be very difficult to diagnose in its early stages, due to the similarity of symptoms with many different diseases.People infected with R. rickettsii usually notice symptoms following an incubation period of one to two weeks after a tick bite. The early clinical presentation of Rocky Mountain spotted fever is nonspecific and may resemble a variety of other infectious and noninfectious diseases.
Initial symptoms:
Fever
Nausea
Emesis (vomiting)
Severe headache
Muscle pain
MalaiseLater signs and symptoms:
Maculopapular rash
Petechial rash
Abdominal pain
Joint pain
Conjunctivitis
ForgetfulnessThe classic triad of findings for this disease are fever, rash, and history of tick bite. However, this combination is often not identified when patients initially present for care. The rash has a centripetal, or "inward" pattern of spread, meaning it begins at the extremities and courses towards the trunk.
Rash
The rash first appears two to five days after the onset of fever, and it is often quite subtle. Younger patients usually develop the rash earlier than older patients. Most often the rash begins as small, flat, pink, nonitchy spots (macules) on the wrists, forearms, and ankles. These spots turn pale when pressure is applied and eventually become raised on the skin. The characteristic red, spotted (petechial) rash of Rocky Mountain spotted fever is usually not seen until the sixth day or later after onset of symptoms, but this type of rash occurs in only 35 to 60% of patients with Rocky Mountain spotted fever. The rash involves the palms or soles in as many as 80% of people. However, this distribution may not occur until later on in the course of the disease. As many as 15% of patients may never develop a rash.
Complications
People can develop permanent disabilities including "cognitive deficits, ataxia, hemiparesis, blindness, deafness, or amputation following gangrene".
Cause
Ticks are the natural hosts of the disease, serving as both reservoirs and vectors of R. rickettsii. Ticks transmit the bacteria primarily by their bites. Less commonly, infections may occur following exposure to crushed tick tissues, fluids, or tick feces.
A female tick can transmit R. rickettsii to her eggs in a process called transovarial transmission. Ticks can also become infected with R. rickettsii while feeding on blood from the host in either the larval or nymphal stage. After the tick develops into the next stage, the R. rickettsii may be transmitted to the second host during the feeding process. Furthermore, male ticks may transfer R. rickettsii to female ticks through body fluids or spermatozoa during the mating process. These types of transmission represent how generations or life stages of infected ticks are maintained. Once infected, the tick can carry the pathogen for life.Rickettsiae are transmitted through saliva injected while a tick is feeding. Unlike Lyme disease and other tick-borne pathogens that require a prolonged attachment period to establish infection, a person can become infected with R. rickettsii in a feeding time as short as 2 hours. In general, about 1-3% of the tick population carries R. rickettsii, even in areas where the majority of human cases are reported. Therefore, the risk of exposure to a tick carrying R. rickettsii is low.The disease is spread by the American dog tick (Dermacentor variabilis), Rocky Mountain wood tick (D. andersoni), brown dog tick (Rhipicephalus sanguineus), and Amblyomma sculptum. Not all of these are of equal importance, and most are restricted to certain geographic areas.
The two major vectors of R. rickettsii in the United States are the American dog tick and the Rocky Mountain wood tick. American dog ticks are widely distributed east of the Rocky Mountains and they also occur in limited areas along the Pacific Coast. Dogs and medium-sized mammals are the preferred hosts of an adult American dog tick, although it feeds readily on other large mammals, including human beings. This tick is the most commonly identified species responsible for transmitting R. rickettsii to humans. Rocky Mountain wood ticks (D. andersoni) are found in the Rocky Mountain states and in southwestern Canada. The lifecycle of this tick may require up to three years for its completion. The adult ticks feed primarily on large mammals. The larvae and nymphs feed on small rodents.Other tick species have been shown to be naturally infected with R. rickettsii or serve as experimental vectors in the laboratory. These species are likely to play only a minor role in the ecology of R. rickettsii.
Pathophysiology
Entry into host
Rickettsia rickettsii can be transmitted to human hosts through the bite of an infected tick. As with other bacterium transmitted via ticks, the process generally requires a period of attachment of 4 to 6 hours. However, in some cases a Rickettsia rickettsii infection has been contracted by contact with tick tissues or fluids. Then, the bacteria induce their internalization into host cells via a receptor-mediated invasion mechanism.Researchers believe that this mechanism is similar to that of Rickettsia conorii. This species of Rickettsia uses an abundant cell surface protein called OmpB to attach to a host cell membrane protein called Ku70. It has previously been reported that Ku70 migrates to the host cell surface in the presence of "Rickettsia". Then, Ku70 is ubiquitinated by c-Cbl, an E3 ubiquitin ligase. This triggers a cascade of signal transduction events resulting in the recruitment of Arp2/3 complex. CDC42, protein tyrosine kinase, phosphoinositide 3-kinase, and Src-family kinases then activate Arp2/3. This causes the alteration of local host cytoskeletal actin at the entry site as part of a zipper mechanism. Then, the bacteria is phagocytosized by the host cell and enveloped by a phagosome.Studies have suggested that rOmpB is involved in this process of adhesion and invasion. Both rOmpA and rOmpB are members of a family of surface cell antigens (Sca) which are autotransporter proteins; they act as ligands for the Omp proteins and are found throughout the rickettsiae.
Exit from host cell
The cytosol of the host cell contains nutrients, adenosine triphosphate, amino acids, and nucleotides which are used by the bacteria for growth. For this reason, as well as to avoid phagolysosomal fusion and death, rickettsiae must escape from the phagosome. To escape from the phagosome, the bacteria secrete phospholipase D and hemolysin C. This causes disruption of the phagosomal membrane and allows the bacteria to escape. Following generation time in the cytoplasm of the host cells, the bacteria utilizes actin based motility to move through the cytosol.RickA, expressed on the rickettsial surface, activates Arp2/3 and causes actin polymerization. The rickettsiae use the actin to propel themselves throughout the cytosol to the surface of the host cell. This causes the host cell membrane to protrude outward and invaginate the membrane of an adjacent cell. The bacteria are then taken up by the neighboring cell in a double membrane vacuole that the bacteria can subsequently lyse, enabling spread from cell to cell without exposure to the extracellular environment.
Consequences of infection
Rickettsia rickettsii initially infect blood vessel endothelial cells, but eventually migrate to vital organs such as the brain, skin, and the heart via the blood stream. Bacterial replication in host cells causes endothelial cell proliferation and inflammation, resulting in mononuclear cell infiltration into blood vessels and subsequent red blood cell leakage into surrounding tissues. The characteristic rash observed in Rocky Mountain spotted fever is the direct result of this localized replication of rickettsia in blood vessel endothelial cells.
Diagnosis
This disease can be diagnosed by a doctor with and without the use of lab testing. Lab tests are not always relied upon because treatment may be necessary before the results are returned.Abnormal laboratory findings seen in patients with Rocky Mountain spotted fever may include a low platelet count, low blood sodium concentration, or elevated liver enzyme levels. Serology testing and skin biopsy are considered to be the best methods of diagnosis. Although immunofluorescent antibody assays are considered some of the best serology tests available, most antibodies that fight against R. rickettsii are undetectable on serology tests during the first seven days after infection.Differential diagnosis includes dengue, leptospirosis, chikungunya, and Zika fever.
Treatment
Appropriate antibiotic treatment should be started immediately when there is a suspicion of Rocky Mountain spotted fever. Treatment should not be delayed for laboratory confirmation of disease as early initiation of treatment of Rocky Mountain spotted fever is associated with lower mortality. Failure to respond to a tetracycline argues against a diagnosis of Rocky Mountain spotted fever. Severely ill people may require longer periods before their fever resolves, especially if they have experienced damage to multiple organ systems. Preventive therapy in healthy people who have had recent tick bites is not recommended and may only delay the onset of disease.Doxycycline (a tetracycline) is the drug of choice for patients with Rocky Mountain spotted fever. According to the CDC, "Doctors often avoid prescribing doxycycline to young children because of a warning that tooth staining may occur when used in children less than 8 years old. ..Misperceptions about the use of doxycycline for children prevent kids from getting lifesaving treatment" of rickettsial diseases. "Delay in treatment of rickettsial diseases may lead to severe illness or death. Children are five times more likely than adults to die from RMSF." A 2013 study shows that "short courses of…doxycycline can be used in children without causing tooth staining or weakening of tooth enamel." The CDC observed that "clearer language on the drug label may help avoid hesitation in prescribing life-saving doxycycline to children."Treatment typically consists of 100 milligrams every 12 hours, or for children under 45 kg (99 lb) at 4 mg/kg of body weight per day in two divided doses. Treatment should be continued for at least three days after the fever subsides, and until there is unequivocal evidence of clinical improvement. This will be generally for a minimum time of five to ten days. Severe or complicated outbreaks may require longer treatment courses. Chloramphenicol is an alternative drug that can be used to treat Rocky Mountain spotted fever, specifically in pregnancy. However, this drug may be associated with a wide range of side effects, and careful monitoring of blood levels is required.
Prognosis
Rocky Mountain spotted fever can be a very severe illness and patients often require hospitalization. Because R. rickettsii infects the cells lining blood vessels throughout the body, severe manifestations of this disease may involve the respiratory system, central nervous system, gastrointestinal system, or kidneys. Long-term health problems following acute Rocky Mountain spotted fever infection include partial paralysis of the lower extremities, gangrene requiring amputation of fingers, toes, or arms or legs, hearing loss, loss of bowel or bladder control, movement disorders, and language disorders. These complications are most frequent in persons recovering from severe, life-threatening disease, often following lengthy hospitalizations.
Epidemiology
There are between 500 and 2500 cases of Rocky Mountain spotted fever reported in the United States per year, and in only about 20% can the tick be found.Host factors associated with severe or fatal Rocky Mountain spotted fever include advanced age, male sex, African or Caribbean background, long-term excessive alcohol use and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Deficiency of G6PD is a genetic condition affecting about 12 percent of the Afro-American male population. Deficiency in this enzyme is associated with a high proportion of severe cases of Rocky Mountain spotted fever. This is a rare clinical complication that is often fatal within five days of the onset of the disease.
In the early 1940s, outbreaks were described in the Mexican states of Sinaloa, Sonora, Durango, and Coahuila driven by dogs and Rhipicephalus sanguineus sensu lato, the brown dog tick. Over the ensuing 100 years case fatality rates were 30%–80%. In 2015, there was an abrupt rise in Sonora cases with 80 fatal cases. From 2003 to 2016, cases increased to 1394 with 247 deaths.
History
Rocky Mountain spotted fever (or "black measles" because of its characteristic rash) was recognized in the early 1800s, and in the last 10 years of the 1800s (1890–1900) it became very common, especially in the Bitterroot Valley of Montana. The disease was originally noted to be concentrated on the west-side of the Bitterroot river. Though it would be decades before scientists discovered the tick as the carrier of the disease, in as early as 1866, Doctor John B. Buker (establishing a practice in Missoula, MT) noticed a tick embedded in the skin of one of his patients. His notes were later studied as part of later research.In 1901, Dr. A. F. Longeway was appointed to solve "the black measles problem" in Montana. He in turn enlisted his friend, Dr. Earl Strain to help him. Strain suspected that the illness was from ticks. In 1906, Howard T. Ricketts, a pathologist recruited from the University of Chicago, was the first to establish the identity of the infectious organism (the organism smaller than a bacterium and larger than a virus) that causes this disease. He and others characterized the basic epidemiological features of the disease, including the role of tick vectors. Their studies found that Rocky Mountain spotted fever is caused by Rickettsia rickettsii, named in Rickettss honor. Ricketts died of typhus (another rickettsial disease) in Mexico in 1910, shortly after completing his studies on Rocky Mountain spotted fever.
Prior to 1922, Doctors McCray and McClintic both died while doing research on Rocky Mountain spotted fever, as did an aide of Noguchi Hideyo at the Rockefeller Institute.
Research began in 1922 in western Montana, in the Bitterroot Valley around Hamilton, Montana, after the Governors daughter and his son-in-law died of the fever. However, prior to that, in 1917, Dr. Lumford Fricks introduced herds of sheep into the Bitterroot Valley. His hypothesis was that the sheep would eat the tall grasses where ticks lived and bred. Past Assistant Surgeon R.R. Spencer of the Hygienic Laboratory of the U.S. Public Health Service was ordered to the region, and he led a research team at an abandoned schoolhouse through about 1924. Spencer was assisted by R. R. Parker, Bill Gettinger, Henry Cowan, Henry Greenup, Elmer Greenup, Gene Hughes, Salsbury, Kerlee, and others, of whom Gettinger, Cowan and Kerlee died of Rocky Mountain spotted fever. Through a series of discoveries, the team found that a previous blood meal was necessary to make the tick deadly to its hosts, as well as other facets of the disease. On May 19, 1924, Spencer put a large dose of mashed wood ticks, from lot 2351B, and some weak carbolic acid into his arm by injection. This vaccine worked, and for some years after it was used by people in that region to convert the illness from one with high fatality rate (albeit low incidence) to one that could be either prevented entirely (for many of them) or modified to a non-deadly form (for the rest). Today there is no commercially available vaccine for RMSF because, unlike in the 1920s when Spencer and colleagues developed one, antibiotics are now available to treat the disease, so prevention by vaccination is no longer the sole defense against likely death.
Much of the early research was conducted at Rocky Mountain Laboratories a part of the National Institute of Allergy and Infectious Diseases. The schoolhouse laboratory of 1922–1924, filled with ticks in various phases of the life cycle, is identifiable in retrospect as a biohazard, although the team did not fully appreciate it at first. The deaths of Gettinger and Cowan, and the near death of the janitors son, were the results of inadequate biocontainment, but in the 1920s, the elaborate biocontainment systems of today had not been invented.
Society
Research into this disease in Montana is a sub-plot of the 1937 film Green Light, starring Errol Flynn. Some of the researchers who perished are mentioned by name and their photographs are shown.
Rocky Mountain spotted fever is a big part of the 1947 Republic Pictures movie Driftwood, starring Walter Brennan, James Bell, Dean Jagger, Natalie Wood, and Hobart Cavanaugh.
In December 2013, hockey player Shane Doan was diagnosed with Rocky Mountain spotted fever, and returned to play in January 2014.
Other names
Some synonyms for Rocky Mountain spotted fever in other countries include "tick typhus," "Tobia fever" (Colombia), "São Paulo fever" or "febre maculosa" (Brazil), and "fiebre manchada" (Mexico).
References
External links
"Rocky Mountain spotted fever". Centers for Disease Control. 2018-10-26. |
Rosacea | Rosacea is a long-term skin condition that typically affects the face. It results in redness, pimples, swelling, and small and superficial dilated blood vessels. Often, the nose, cheeks, forehead, and chin are most involved. A red, enlarged nose may occur in severe disease, a condition known as rhinophyma.The cause of rosacea is unknown. Risk factors are believed to include a family history of the condition. Factors that may potentially worsen the condition include heat, exercise, sunlight, cold, spicy food, alcohol, menopause, psychological stress, or steroid cream on the face. Diagnosis is based on symptoms.While not curable, treatment usually improves symptoms. Treatment is typically with metronidazole, doxycycline, minocycline, or tetracycline. When the eyes are affected, azithromycin eye drops may help. Other treatments with tentative benefit include brimonidine cream, ivermectin cream, and isotretinoin. Dermabrasion or laser surgery may also be used. The use of sunscreen is typically recommended.Rosacea affects between 1% and 10% of people. Those affected are most often 30 to 50 years old and female. People with paler skin or European ancestry are more frequently affected. The condition was described in The Canterbury Tales in the 1300s, and possibly as early as the 200s BC by Theocritus.
Signs and symptoms
Rosacea typically begins with reddening of the skin in symmetrical patches near the center of the face. Common signs can depend on age and sex: flushing and red swollen patches are common in the young, small and visible dilated blood vessels in older individuals, and swelling of the nose is common in men. Other signs include lumps on the skin (papules or pustules) and swelling of the face. Many people experience stinging or burning pain and rarely itching.Skin problems tend to be aggravated by particular trigger factors, that differ for different people. Common triggers are ultraviolet light, heat, cold, or certain foods or beverages.
Erythematotelangiectatic rosacea
Erythematotelangiectatic rosacea rosacea (also known as "vascular rosacea") is characterized by prominent history of prolonged (over 10 minutes) flushing reaction to various stimuli, such as emotional stress, hot drinks, alcohol, spicy foods, exercise, cold or hot weather, or hot baths and showers.
Glandular rosacea
In glandular rosacea, men with thick sebaceous skin predominate, a disease in which the papules are edematous, and the pustules are often 0.5 to 1.0 cm in size, with nodulocystic lesions often present.
Cause
The exact cause of rosacea is unknown. Triggers that cause episodes of flushing and blushing play a part in its development. Exposure to temperature extremes, strenuous exercise, heat from sunlight, severe sunburn, stress, anxiety, cold wind, and moving to a warm or hot environment from a cold one, such as heated shops and offices during the winter, can each cause the face to become flushed. Certain foods and drinks can also trigger flushing, such as alcohol, foods and beverages containing caffeine (especially hot tea and coffee), foods high in histamines, and spicy foods.Medications and topical irritants have also been known to trigger rosacea flares. Some acne and wrinkle treatments reported to cause rosacea include microdermabrasion and chemical peels, as well as high dosages of isotretinoin, benzoyl peroxide, and tretinoin.
Steroid-induced rosacea is caused by the use of topical steroids. These steroids are often prescribed for seborrheic dermatitis. Dosage should be slowly decreased and not immediately stopped to avoid a flare-up.
Cathelicidins
In 2007, Richard Gallo and colleagues noticed that patients with rosacea had high levels of the antimicrobial peptide cathelicidin and elevated levels of stratum corneum tryptic enzymes (SCTEs). Antibiotics have been used in the past to treat rosacea, but they may only work because they inhibit some SCTEs.
Demodex folliculitis and Demodex mites
Studies of rosacea and Demodex mites have revealed that some people with rosacea have increased numbers of the mite, especially those with steroid-induced rosacea. Demodex folliculitis (demodicidosis, also known as "mange" in animals) is a condition that may have a "rosacea-like" appearance.A 2007, National Rosacea Society-funded study demonstrated that Demodex folliculorum mites may be a cause or exacerbating factor in rosacea. The researchers identified Bacillus oleronius as distinct bacterium associated with Demodex mites. When analyzing blood samples using a peripheral blood mononuclear cell proliferation assay, they discovered that B. oleronius stimulated an immune system response in 79 percent of 22 patients with subtype 2 (papulopustular) rosacea, compared with only 29% of 17 subjects without the disorder. They concluded, "The immune response results in inflammation, as evident in the papules (bumps) and pustules (pimples) of subtype 2 rosacea. This suggests that the B. oleronius bacteria found in the mites could be responsible for the inflammation associated with the condition."
Intestinal bacteria
Small intestinal bacterial overgrowth (SIBO) was demonstrated to have greater prevalence in rosacea patients and treating it with locally acting antibiotics led to rosacea lesion improvement in two studies. Conversely in rosacea patients who were SIBO negative, antibiotic therapy had no effect. The effectiveness of treating SIBO in rosacea patients may suggest that gut bacteria play a role in the pathogenesis of rosacea lesions.
Diagnosis
Most people with rosacea have only mild redness and are never formally diagnosed or treated. No test for rosacea is known. In many cases, simple visual inspection by a trained health-care professional is sufficient for diagnosis. In other cases, particularly when pimples or redness on less-common parts of the face is present, a trial of common treatments is useful for confirming a suspected diagnosis. The disorder can be confused or co-exist with acne vulgaris or seborrheic dermatitis. The presence of a rash on the scalp or ears suggests a different or co-existing diagnosis because rosacea is primarily a facial diagnosis, although it may occasionally appear in these other areas.
Classification
Four rosacea subtypes exist, and a patient may have more than one subtype:: 176
Erythematotelangiectatic rosacea exhibits permanent redness (erythema) with a tendency to flush and blush easily. Also small, widened blood vessels visible near the surface of the skin (telangiectasias) and possibly intense burning, stinging, and itching are common. People with this type often have sensitive skin. Skin can also become very dry and flaky. In addition to the face, signs can also appear on the ears, neck, chest, upper back, and scalp.
Papulopustular rosacea presents with some permanent redness with red bumps (papules); some pus-filled pustules can last 1–4 days or longer. This subtype is often confused with acne.
Phymatous rosacea is most commonly associated with rhinophyma, an enlargement of the nose. Signs include thickening skin, irregular surface nodularities, and enlargement. Phymatous rosacea can also affect the chin (gnathophyma), forehead (metophyma), cheeks, eyelids (blepharophyma), and ears (otophyma). Telangiectasias may be present.
In ocular rosacea, affected eyes and eyelids may appear red due to telangiectasias and inflammation, and may feel dry, irritated, or gritty. Other symptoms include foreign-body sensations, itching, burning, stinging, and sensitivity to light. Eyes can become more susceptible to infection. About half of the people with subtypes 1–3 also have eye symptoms. Blurry vision and vision loss can occur if the cornea is affected.
Variants
Variants of rosacea include:: 689
Pyoderma faciale, also known as rosacea fulminans, is a conglobate, nodular disease that arises abruptly on the face.
Rosacea conglobata is a severe rosacea that can mimic acne conglobata, with hemorrhagic nodular abscesses and indurated plaques.
Phymatous rosacea is a cutaneous condition characterized by overgrowth of sebaceous glands. Phyma is Greek for swelling, mass, or bulb, and these can occur on the face and ears.: 693
Treatment
The type of rosacea a person has informs the choice of treatment. Mild cases are often not treated at all, or are simply covered up with normal cosmetics.
Therapy for the treatment of rosacea is not curative, and is best measured in terms of reduction in the amount of facial redness and inflammatory lesions, a decrease in the number, duration, and intensity of flares, and concomitant symptoms of itching, burning, and tenderness. The two primary modalities of rosacea treatment are topical and oral antibiotic agents. Laser therapy has also been classified as a form of treatment. While medications often produce a temporary remission of redness within a few weeks, the redness typically returns shortly after treatment is suspended. Long-term treatment, usually 1–2 years, may result in permanent control of the condition for some patients. Lifelong treatment is often necessary, although some cases resolve after a while and go into a permanent remission. Other cases, if left untreated, worsen over time. Some people has also reported better results after changing diet. This is not confirmed by medical studies, even though some studies relate the histamine production to outbreak of rosacea.
Behavior
Avoiding triggers that worsen the condition can help reduce the onset of rosacea, but alone will not normally lead to remission except in mild cases. Keeping a journal is sometimes recommended to help identify and reduce food and beverage triggers.
Because sunlight is a common trigger, avoiding excessive exposure to the sun is widely recommended. Some people with rosacea benefit from daily use of a sunscreen; others opt for wearing hats with broad brims. Like sunlight, emotional stress can also trigger rosacea. People who develop infections of the eyelids must practice frequent eyelid hygiene.
Managing pretrigger events such as prolonged exposure to cool environments can directly influence warm-room flushing.
Medications
Medications with good evidence include topical ivermectin and azelaic acid creams and brimonidine, and doxycycline and isotretinoin by mouth. Lesser evidence supports topical metronidazole cream and tetracycline by mouth.Metronidazole is thought to act through anti-inflammatory mechanisms, while azelaic acid is thought to decrease cathelicidin production. Oral antibiotics of the tetracycline class such as doxycycline, minocycline, and oxytetracycline are also commonly used and thought to reduce papulopustular lesions through anti-inflammatory actions rather than through their antibacterial capabilities.Using alpha-hydroxy acid peels may help relieve redness caused by irritation, and reduce papules and pustules associated with rosacea. Oral antibiotics may help to relieve symptoms of ocular rosacea. If papules and pustules persist, then sometimes isotretinoin can be prescribed. The flushing and blushing that typically accompany rosacea are typically treated with the topical application of alpha agonists such as brimonidine and less commonly oxymetazoline or xylometazoline.A review found that ivermectin was more effective than alternatives for treatment of papulopustular acne rosacea. An ivermectin cream has been approved by the FDA, as well as in Europe, for the treatment of inflammatory lesions of rosacea. The treatment is based upon the hypothesis that parasitic mites of the genus Demodex play a role in rosacea. In a clinical study, ivermectin reduced lesions by 83% over 4 months, as compared to 74% under a metronidazole standard therapy. Quassia amara extract at 4% demonstrated to have clinical efficacy for rosacea. When compared to metronidazole 0.75% as usual care in a randomized, double-blinded clinical trial, Quassia amara extract at 4% demonstrated earlier onset of action, including improvement in telangiectasia, flushing, and papules. Quassia amara showed a sustained reduction of global assessment score at day 42 (reduced to 4.68 from baseline 7.65) compared to metronidazole at day 42 (reduced to 6.32 from baseline 7.2), p<0.001.
Laser
Evidence for the use of laser and intense pulsed-light therapy in rosacea is poor.
Outcomes
The highly visible nature of rosacea symptoms are often psychologically challenging for those affected. People with rosacea can experience issues with self-esteem, socializing, and changes to their thoughts, feelings, and coping mechanisms.
Epidemiology
Rosaceae affects around 5% of people worldwide. Incidence varies by ethnicity, and is particularly prevalent in those with Celtic heritage. Men and women are equally like to develop rosacea.
See also
Seborrheic dermatitis
Keratosis pilaris
References
External links
Rosacea at Curlie
Rosacea photo library at Dermnet
Questions and Answers about Rosacea, from the US National Institute of Arthritis and Musculoskeletal and Skin Diseases |
Roughness | Roughness may refer to:
Surface roughness, the roughness of a surface
Roughness length, roughness as applied in meteorology
International Roughness Index, the roughness of a road
Hydraulic roughness, the roughness of land and waterway features
Roughness (psychophysics) in psychoacoustics refers to the level of dissonance
The roughness of a line or surface, measured numerically by the Hausdorff dimension
Roughness/resel, the resel/roughness of an image/volume
Unnecessary roughness, a type of foul in gridiron football
See also
Surface finish |
Nematode infection | A nematode infection is a type of helminthiasis caused by organisms in the nematode phylum.An example is enterobiasis. Several antinematodal agents are available.
References
== External links == |
Salmonellosis | Salmonellosis is a symptomatic infection caused by bacteria of the Salmonella type. It is also a food-borne disease and are defined as diseases, usually either infectious or toxic in nature, caused
by agents that enter the body through the ingestion of food. In humans, the most common symptoms are diarrhea, fever, abdominal cramps, and vomiting. Symptoms typically occur between 12 hours and 36 hours after exposure, and last from two to seven days. Occasionally more significant disease can result in dehydration. The old, young, and others with a weakened immune system are more likely to develop severe disease. Specific types of Salmonella can result in typhoid fever or paratyphoid fever.There are two species of Salmonella: Salmonella bongori and Salmonella enterica with many subspecies. However, subgroups and serovars within a species may be substantially different in their ability to cause disease. This suggests that epidemiologic classification of organisms at the subspecies level may improve management of Salmonella and similar pathogens.Both vegetarian and non-vegetarian populations are susceptible to Salmonella infections due to the consumption of contaminated meat and milk.
Infection is usually spread by eating contaminated meat, eggs, water or milk. Other foods may spread the disease if they have come into contact with manure. A number of pets including cats, dogs, and reptiles can also carry and spread the infection. Diagnosis is by a stool test or blood tests.Efforts to prevent the disease include the proper washing, preparation, and cooking of food to appropriate temperature. Mild disease typically does not require specific treatment. More significant cases may require treatment of electrolyte problems and intravenous fluid replacement. In those at high risk or in whom the disease has spread outside the intestines, antibiotics are recommended.Salmonellosis is one of the most common causes of diarrhea globally. In 2015, 90,300 deaths occurred from nontyphoidal salmonellosis, and 178,000 deaths from typhoidal salmonellosis. In the United States, about 1.35 million cases and 450 deaths occur from non-typhoidal salmonellosis a year. In Europe, it is the second most common foodborne disease after campylobacteriosis.
Signs and symptoms
Enteritis
After a short incubation period of a few hours to one day, the bacteria multiply in the small intestine, causing an intestinal inflammation (enteritis). Most people with salmonellosis develop diarrhea, fever, vomiting, and abdominal cramps 12 to 72 hours after infection. Diarrhea is often watery and non-bloody but may be mucoid and bloody. In most cases, the illness lasts four to seven days, and does not require treatment. In some cases, though, the diarrhea may be so severe that the patient becomes dangerously dehydrated and must be hospitalized. At the hospital, the patient may receive fluids intravenously to treat the dehydration, and may be given medications to provide symptomatic relief, such as fever reduction. In severe cases, the Salmonella infection may spread from the intestines to the blood stream, and then to other body sites, and can cause death, unless the person is treated promptly with antibiotics.In otherwise healthy adults, the symptoms can be mild. Normally, no sepsis occurs, but it can occur exceptionally as a complication in the immunocompromised. However, in people at risk such as infants, small children, and the elderly, Salmonella infections can become very serious, leading to complications. In infants, dehydration can cause a state of severe toxicity. Extraintestinal localizations are possible, especially Salmonella meningitis in children, osteitis, etc. Children with sickle-cell anemia who are infected with Salmonella may develop osteomyelitis. Treatment of osteomyelitis, in this case, will be to use fluoroquinolones (ciprofloxacin, levofloxacin, etc., and nalidixic acid).Those whose only symptom is diarrhea usually completely recover, but their bowel habits may not return to normal for several months.
Typhoid fever
Typhoid fever occurs when Salmonella bacteria enter the lymphatic system and cause a systemic form of salmonellosis. Endotoxins first act on the vascular and nervous apparatus, resulting in increased permeability and decreased tone of the vessels, upset thermal regulation, vomiting, and diarrhea. In severe forms of the disease, enough liquid and electrolytes are lost to upset the fluid balance, cause an electrolyte imbalance, decrease the circulating blood volume and arterial pressure, and cause hypovolemic shock. Septic shock may also develop. Shock of mixed character (with signs of both hypovolemic and septic shock) are more common in severe salmonellosis. Oliguria and azotemia develop in severe cases as a result of renal involvement due to hypoxia and toxemia.
Long-term
Salmonellosis is associated with later irritable bowel syndrome and inflammatory bowel disease. Evidence however does not support it being a direct cause of the latter.A small number of people afflicted with salmonellosis experience reactive arthritis, which can last months or years and can lead to chronic arthritis. In sickle-cell anemia, osteomyelitis due to Salmonella infection is much more common than in the general population. Though Salmonella infection is frequently the cause of osteomyelitis in people with sickle-cell, it is not the most common cause, which is Staphylococcus infection.Those infected may become asymptomatic carriers, but this is relatively uncommon, with shedding observed in only 0.2 to 0.6% of cases after a year.
Causes
Contaminated food, often having no unusual look or smell
Poor kitchen hygiene, especially problematic in institutional kitchens and restaurants because this can lead to a significant outbreak
Excretions from either sick or infected but apparently clinically healthy people and animals (especially dangerous are caregivers and animals)
Polluted surface water and standing water (such as in shower hoses or unused water dispensers)
Unhygienically thawed poultry (the meltwater contains many bacteria)
An association with reptiles (pet tortoises, snakes, iguanas, and aquatic turtles) is well described.
Amphibians such as frogsSalmonella bacteria can survive for some time without a host; they are frequently found in polluted water, with contamination from the excrement of carrier animals being particularly important.The European Food Safety Authority highly recommends that when handling raw turkey meat, consumers and people involved in the food supply chain should pay attention to personal and food hygiene.An estimated 142,000 Americans are infected each year with Salmonella Enteritidis from chicken eggs, and about 30 die. The shell of the egg may be contaminated with Salmonella by feces or environment, or its interior (yolk) may be contaminated by penetration of the bacteria through the porous shell or from a hen whose infected ovaries contaminate the egg during egg formation.Nevertheless, such interior egg yolk contamination is theoretically unlikely. Even under natural conditions, the rate of infection was very small (0.6% in a study of naturally contaminated eggs and 3.0% among artificially and heavily infected hens).
Prevention
The US Food and Drug Administration (FDA) has published guidelines to help reduce the chance of food-borne salmonellosis. Food must be cooked to 145–165 °F (63–74 °C), and liquids such as soups or gravies should be boiled when reheating. Freezing kills some Salmonella, but it is not sufficient to reliably reduce them below infectious levels. While Salmonella is usually heat-sensitive, it acquires heat-resistance in high-fat environments such as peanut butter.
Vaccine
Antibodies against nontyphoidal Salmonella were first found in Malawi children in research published in 2008. The Malawian researchers identified an antibody that protects children against bacterial infections of the blood caused by nontyphoidal Salmonella. A study at Queen Elizabeth Hospital in Blantyre found that children up to two years old develop antibodies that aid in killing the bacteria. This could lead to a possible Salmonella vaccine for humans.A 2014 study tested a vaccine on chickens which offered efficient protection against salmonellosis.Vaccination of chickens against Salmonella essentially wiped out the disease in the United Kingdom. A similar approach was considered in the United States, but the Food and Drug Administration decided not to mandate vaccination of hens.
Industrial hygiene
Since 2011, Denmark has had three cases of human salmonella poisoning. The country eradicated salmonella without vaccines and antibiotics by focusing on eliminating the infection from "breeder stocks", implementing various measures to prevent infection, and taking a zero-tolerance policy towards salmonella in chickens.
Treatment
Electrolytes may be replenished with oral rehydration supplements (typically containing salts sodium chloride and potassium chloride).Appropriate antibiotics, such as ceftriaxone, may be given to kill the bacteria, but are not necessary in most cases. Azithromycin has been suggested to be better at treating typhoid in resistant populations than both fluoroquinolone drugs and ceftriaxone. There are recommendations on choice of antibiotic to avoid promoting antibiotic resistance.There is no evidence of benefit of treating healthy people with diarrhea due to non-typhoidal salmonellosis. However, the evidence for the very young, very old or people with severe diseases are uncertain.
Epidemiology
United States
Salmonellosis annually causes, per CDC estimation, about 1.2 million illnesses, 23,000 hospitalizations, and 450 deaths in the United States every year. About 142,000 people in the United States are infected each year with Salmonella Enteritidis specifically from chicken eggs, and about 30 die.In 2010, an analysis of death certificates in the United States identified a total of 1,316 Salmonella-related deaths from 1990 to 2006. These were predominantly among older adults and those who were immunocompromised. The U.S. government reported as many as 20% of all chickens were contaminated with Salmonella in the late 1990s, and 16.3% were contaminated in 2005.The United States has struggled to control salmonella infections, with the rate of infection rising from 2001 to 2011. In 1998, the USDA moved to close plants if salmonella was found in excess of 20 percent, which was the industrys average at the time, for three consecutive tests. Texas-based Supreme Beef Processors, Inc. sued on the argument that Salmonella is naturally occurring and ultimately prevailed when a federal appeals court affirmed a lower court. These issues were highlighted in a proposed Kevins Law (formally proposed as the Meat and Poultry Pathogen Reduction and Enforcement Act of 2003), of which components were included the Food Safety Modernization Act passed in 2011, but that law applies only to the FDA and not the USDA. The USDA proposed a regulatory initiative in 2011 to Office of Management and Budget.Salmonella is found in 8% of the chicken parts tested by the USDA and 25% of ground chicken.
Europe
An outbreak of salmonellosis started in Northern Europe in July 2012, caused by Salmonella thompson. The infections were linked to smoked salmon from the manufacturer Foppen, where the contamination had occurred. Most infections were reported in the Netherlands; over 1060 infections with this subspecies and four fatalities were confirmed.A case of widespread infection was detected mid-2012 in seven EU countries. Over 400 people had been infected with Salmonella enterica serovar Stanley (S. Stanley) that usually appears in the regions of Southeast Asia. After several DNA analyses seemed to point to a specific Belgian strain, the "Joint ECDC/E FSA Rapid Risk Assessment" report detected turkey production as the source of infection.In Germany, food poisoning infections must be reported. Between 1990 and 2005, the number of officially recorded cases decreased from about 200,000 to about 50,000.
Elsewhere
In March 2007, around 150 people were diagnosed with salmonellosis after eating tainted food at a governors reception in Krasnoyarsk, Russia. Over 1,500 people attended the ball on March 1 and fell ill as a consequence of ingesting Salmonella-tainted sandwiches.About 150 people were sickened by Salmonella-tainted chocolate cake produced by a major bakery chain in Singapore in December 2007.South Africa reported contamination of its poultry carcasses by Salmonella. Egypt showed that Salmonella was predominant in poultry along with other non-typhoid strains. In Indonesia, the isolation of Salmonella Typhi was the main focus, while other serovars were also included from poultry. In India, Salmonella was predominant in poultry. Romania reported Salmonella serovars in poultry that affect humans.
History
Both salmonellosis and the microorganism genus Salmonella derive their names from a modern Latin coining after Daniel E. Salmon (1850–1914), an American veterinary surgeon. He had help from Theobald Smith, and together they found the bacterium in pigs.Salmonella enterica was possibly the cause of the 1576 cocliztli epidemic in New Spain.
Four-inch regulation
The "Four-inch regulation" or "Four-inch law" is a colloquial name for a regulation issued by the U.S. FDA in 1975, restricting the sale of turtles with a carapace length less than four inches (10 cm).The regulation was introduced, according to the FDA, "because of the public health impact of turtle-associated salmonellosis". Cases had been reported of young children placing small turtles in their mouths, which led to the size-based restriction.
Regulation elsewhere
FSSAI regulation
The FSSAI has been established under the Food Safety and Standards Act, 2006, which is a consolidating statute related to food safety and regulation in India. FSSAI is responsible for protecting and promoting public health through the regulation and supervision of food safety.
The major importance of the FSSAI License is that it ensures that the food is verified chemically and hence is safe to consume. Health before wealth is a common quote as well as fact. Therefore, anything related directly to health is a matter of great sensitivity.
See also
1984 Rajneeshee bioterror attack
2012 salmonella outbreak
2018 outbreak of Salmonella
List of foodborne illness outbreaks
References
External links
CDC website, Division of Bacterial and Mycotic Diseases, Disease Listing: Salmonellosis |
Scabies | Scabies (also known as the seven-year itch) is a contagious skin infestation by the mite Sarcoptes scabiei. The most common symptoms are severe itchiness and a pimple-like rash. Occasionally, tiny burrows may appear on the skin. In a first-ever infection, the infected person will usually develop symptoms within two to six weeks. During a second infection, symptoms may begin within 24 hours. These symptoms can be present across most of the body or just certain areas such as the wrists, between fingers, or along the waistline. The head may be affected, but this is typically only in young children. The itch is often worse at night. Scratching may cause skin breakdown and an additional bacterial infection in the skin.Scabies is caused by infection with the female mite Sarcoptes scabiei var. hominis, an ectoparasite. The mites burrow into the skin to live and deposit eggs. The symptoms of scabies are due to an allergic reaction to the mites. Often, only between 10 and 15 mites are involved in an infection. Scabies is most often spread during a relatively long period of direct skin contact with an infected person (at least 10 minutes) such as that which may occur during sex or living together. Spread of the disease may occur even if the person has not developed symptoms yet. Crowded living conditions, such as those found in child-care facilities, group homes, and prisons, increase the risk of spread. Areas with a lack of access to water also have higher rates of disease. Crusted scabies is a more severe form of the disease. It typically only occurs in those with a poor immune system and people may have millions of mites, making them much more contagious. In these cases, spread of infection may occur during brief contact or by contaminated objects. The mite is very small and usually not directly visible. Diagnosis is based on the signs and symptoms.A number of medications are available to treat those infected, such as ivermectin or permethrin, crotamiton, and lindane creams. Sexual contacts within the last month and people who live in the same house should also be treated at the same time. Bedding and clothing used in the last three days should be washed in hot water and dried in a hot dryer. As the mite does not live for more than three days away from human skin, more washing is not needed. Symptoms may continue for two to four weeks following treatment. If after this time symptoms continue, retreatment may be needed.Scabies is one of the three most common skin disorders in children, along with ringworm and bacterial skin infections. As of 2015, it affects about 204 million people (2.8% of the world population). It is equally common in both sexes. The young and the old are more commonly affected. It also occurs more commonly in the developing world and tropical climates. The word scabies is from Latin: scabere, to scratch. Other animals do not spread human scabies. Infection in other animals is typically caused by slightly different but related mites and is known as sarcoptic mange.
Signs and symptoms
The characteristic symptoms of a scabies infection include intense itching and superficial burrows. Because the host develops the symptoms as a reaction to the mites presence over time, typically a delay of four to six weeks occurs between the onset of infestation and the onset of itching. Similarly, symptoms often persist for one to several weeks after successful eradication of the mites. As noted, those re-exposed to scabies after successful treatment may exhibit symptoms of the new infestation in a much shorter period—as little as one to four days.
Itching
In the classic scenario, the itch is made worse by warmth, and is usually experienced as being worse at night, possibly because distractions are fewer. As a symptom, it is less common in the elderly.
Rash
The superficial burrows of scabies usually occur in the area of the finger webs, feet, ventral wrists, elbows, back, buttocks, and external genitals. Except in infants and the immunosuppressed, infection generally does not occur in the skin of the face or scalp. The burrows are created by excavation of the adult mite in the epidermis. Acropustulosis, or blisters and pustules on the palms and soles of the feet, are characteristic symptoms of scabies in infants.
In most people, the trails of the burrowing mites are linear or S-shaped tracks in the skin often accompanied by rows of small, pimple-like mosquito or insect bites. These signs are often found in crevices of the body, such as on the webs of fingers and toes, around the genital area, in stomach folds of the skin, and under the breasts.Symptoms typically appear two to six weeks after infestation for individuals never before exposed to scabies. For those having been previously exposed, the symptoms can appear within several days after infestation. However, symptoms may appear after several months or years.
Crusted scabies
The elderly, disabled, and people with impaired immune systems, such as those with HIV/AIDS, cancer, or those on immunosuppressive medications, are susceptible to crusted scabies (also called Norwegian scabies). On those with weaker immune systems, the host becomes a more fertile breeding ground for the mites, which spread over the hosts body, except the face. The mites in crusted scabies are not more virulent than in noncrusted scabies; however, they are much more numerous (up to two million). People with crusted scabies exhibit scaly rashes, slight itching, and thick crusts of skin that contain large numbers of scabies mites. For this reason, persons with crusted scabies are more contagious to others than those with typical scabies. Such areas make eradication of mites particularly difficult, as the crusts protect the mites from topical miticides/scabicides, necessitating prolonged treatment of these areas.
Cause
Scabies mite
In the 18th century, Italian biologists Giovanni Cosimo Bonomo and Diacinto Cestoni (1637–1718) described the mite now called Sarcoptes scabiei, variety hominis, as the cause of scabies. Sarcoptes is a genus of skin parasites and part of the larger family of mites collectively known as scab mites. These organisms have eight legs as adults, and are placed in the same phylogenetic class (Arachnida) as spiders and ticks.S. scabiei mites are under 0.5 mm in size, but are sometimes visible as pinpoints of white. Gravid females tunnel into the dead, outermost layer (stratum corneum) of a hosts skin and deposit eggs in the shallow burrows. The eggs hatch into larvae in three to ten days. These young mites move about on the skin and molt into a "nymphal" stage, before maturing as adults, which live three to four weeks in the hosts skin. Males roam on top of the skin, occasionally burrowing into the skin. In general, the total number of adult mites infesting a healthy hygienic person with noncrusted scabies is small, about 11 females in burrows, on average.The movement of mites within and on the skin produces an intense itch, which has the characteristics of a delayed cell-mediated inflammatory response to allergens. IgE antibodies are present in the serum and the site of infection, which react to multiple protein allergens in the body of the mite. Some of these cross-react to allergens from house dust mites. Immediate antibody-mediated allergic reactions (wheals) have been elicited in infected persons, but not in healthy persons; immediate hypersensitivity of this type is thought to explain the observed far more rapid allergic skin response to reinfection seen in persons having been previously infected (especially having been infected within the previous year or two).
Transmission
Scabies is contagious and can be contracted through prolonged physical contact with an infested person. This includes sexual intercourse, although a majority of cases are acquired through other forms of skin-to-skin contact. Less commonly, scabies infestation can happen through the sharing of clothes, towels, and bedding, but this is not a major mode of transmission; individual mites can survive for only two to three days, at most, away from human skin at room temperature. As with lice, a latex condom is ineffective against scabies transmission during intercourse, because mites typically migrate from one individual to the next at sites other than the sex organs.Healthcare workers are at risk of contracting scabies from patients, because they may be in extended contact with them.
Pathophysiology
The symptoms are caused by an allergic reaction of the hosts body to mite proteins, though exactly which proteins remains a topic of study. The mite proteins are also present from the gut, in mite feces, which are deposited under the skin. The allergic reaction is both of the delayed (cell-mediated) and immediate (antibody-mediated) type, and involves IgE (antibodies are presumed to mediate the very rapid symptoms on reinfection). The allergy-type symptoms (itching) continue for some days, and even several weeks, after all mites are killed. New lesions may appear for a few days after mites are eradicated. Nodular lesions from scabies may continue to be symptomatic for weeks after the mites have been killed.Rates of scabies are negatively related to temperature and positively related to humidity.
Diagnosis
Scabies may be diagnosed clinically in geographical areas where it is common when diffuse itching presents along with either lesions in two typical spots or itchiness is present in another household member. The classical sign of scabies is the burrow made by a mite within the skin. To detect the burrow, the suspected area is rubbed with ink from a fountain pen or a topical tetracycline solution, which glows under a special light. The skin is then wiped with an alcohol pad. If the person is infected with scabies, the characteristic zigzag or S pattern of the burrow will appear across the skin; however, interpreting this test may be difficult, as the burrows are scarce and may be obscured by scratch marks. A definitive diagnosis is made by finding either the scabies mites or their eggs and fecal pellets. Searches for these signs involve either scraping a suspected area, mounting the sample in potassium hydroxide and examining it under a microscope, or using dermoscopy to examine the skin directly.
Differential diagnosis
Symptoms of early scabies infestation mirror other skin diseases, including dermatitis, syphilis, erythema multiforme, various urticaria-related syndromes, allergic reactions, ringworm-related diseases, and other ectoparasites such as lice and fleas.
Prevention of passing on scabies to other people
Mass-treatment programs that use topical permethrin or oral ivermectin have been effective in reducing the prevalence of scabies in a number of populations. No vaccine is available for scabies. The simultaneous treatment of all close contacts is recommended, even if they show no symptoms of infection (asymptomatic), to reduce rates of recurrence. Since mites can survive for only two to three days without a host, other objects in the environment pose little risk of transmission except in the case of crusted scabies. Therefore, cleaning is of little importance. Rooms used by those with crusted scabies require thorough cleaning.
Management
Treatment
A number of medications are effective in treating scabies. Treatment should involve the entire household, and any others who have had recent, prolonged contact with the infested individual. Options to control itchiness include antihistamines and prescription anti-inflammatory agents. Bedding, clothing and towels used during the previous three days should be washed in hot water and dried in a hot dryer.Treatment protocols for crusted scabies are significantly more intense than for common scabies.
Permethrin
Permethrin, a pyrethroid insecticide, is the most effective treatment for scabies, and remains the treatment of choice. It is applied from the neck down, usually before sleep, and left on for about eight to 14 hours, then washed off in the morning. Care should be taken to coat the entire skin surface, not just symptomatic areas; any patch of skin left untreated can provide a "safe haven" for one or more mites to survive. One application is normally sufficient, as permethrin kills eggs and hatchlings, as well as adult mites, though many physicians recommend a second application three to seven days later as a precaution. Crusted scabies may require multiple applications, or supplemental treatment with oral ivermectin (below). Permethrin may cause slight irritation of the skin that is usually tolerable.
Ivermectin
Oral ivermectin is effective in eradicating scabies, often in a single dose. It is the treatment of choice for crusted scabies, and is sometimes prescribed in combination with a topical agent. It has not been tested on infants, and is not recommended for children under six years of age.Topical ivermectin preparations have been shown to be effective for scabies in adults, though only one such formulation is available in the United States at present, and it is not FDA-approved as a scabies treatment. It has also been useful for sarcoptic mange (the veterinary analog of human scabies).One review found that the efficacy of permethrin is similar to that of systemic or topical ivermectin. A separate review found that although oral ivermectin is usually effective for treatment of scabies, it does have a higher treatment failure rate than topical permethrin. Another review found that oral ivermectin provided a reasonable balance between efficacy and safety. A study has demonstrated that scabies is markedly reduced in populations taking ivermectin regularly; the drug is widely used for treating scabies and other parasitic diseases particularly among the poor and disadvantaged in the tropics, beginning with the developer Merck providing the drug at no cost to treat onchocerciasis from 1987.
Others
Other treatments include lindane, benzyl benzoate, crotamiton, malathion, and sulfur preparations. Lindane is effective, but concerns over potential neurotoxicity have limited its availability in many countries. It is banned in California, but may be used in other states as a second-line treatment. Sulfur ointments or benzyl benzoate are often used in the developing world due to their low cost; Some 10% sulfur solutions have been shown to be effective, and sulfur ointments are typically used for at least a week, though many people find the odor of sulfur products unpleasant. Crotamiton has been found to be less effective than permethrin in limited studies. Crotamiton or sulfur preparations are sometimes recommended instead of permethrin for children, due to concerns over dermal absorption of permethrin.
Communities
Scabies is endemic in many developing countries, where it tends to be particularly problematic in rural and remote areas. In such settings, community-wide control strategies are required to reduce the rate of disease, as treatment of only individuals is ineffective due to the high rate of reinfection. Large-scale mass drug administration strategies may be required where coordinated interventions aim to treat whole communities in one concerted effort. Although such strategies have shown to be able to reduce the burden of scabies in these kinds of communities, debate remains about the best strategy to adopt, including the choice of drug.The resources required to implement such large-scale interventions in a cost-effective and sustainable way are significant. Furthermore, since endemic scabies is largely restricted to poor and remote areas, it is a public health issue that has not attracted much attention from policy makers and international donors.
Epidemiology
Scabies is one of the three most common skin disorders in children, along with tinea and pyoderma. As of 2010, it affects about 100 million people (1.5% of the population) and its frequency is not related to gender. The mites are distributed around the world and equally infect all ages, races, and socioeconomic classes in different climates. Scabies is more often seen in crowded areas with unhygienic living conditions. Globally as of 2009, an estimated 300 million cases of scabies occur each year, although various parties claim the figure is either over- or underestimated. About 1–10% of the global population is estimated to be infected with scabies, but in certain populations, the infection rate may be as high as 50–80%.
History
Scabies has been observed in humans since ancient times. Archeological evidence from Egypt and the Middle East suggests scabies was present as early as 494 BC. In the fourth century BC, Aristotle reported on "lice" that "escape from little pimples if they are pricked" – a description consistent with scabies. Arab physician, Ibn Zuhr is believed to have been the first to provide a clinical description of the scabies mites.The Roman encyclopedist and medical writer Aulus Cornelius Celsus (c. 25 BC – 50 AD) is credited with naming the disease "scabies" and describing its characteristic features. The parasitic etiology of scabies was documented by the Italian physician Giovanni Cosimo Bonomo (1663–1696) in his 1687 letter, "Observations concerning the fleshworms of the human body". Bonomos description established scabies as one of the first human diseases with a well-understood cause.In Europe in the late 19th through mid-20th centuries, a sulfur-bearing ointment called by the medical eponym of Wilkinsons ointment was widely used for topical treatment of scabies. The contents and origins of several versions of the ointment were detailed in correspondence published in the British Medical Journal in 1945.
Society and culture
The International Alliance for the Control of Scabies was started in 2012, and brings together over 150 researchers, clinicians, and public-health experts from more than 15 countries. It has managed to bring the global health implications of scabies to the attention of the World Health Organization. Consequently, the WHO has included scabies on its official list of neglected tropical diseases and other neglected conditions.
Scabies in animals
Scabies may occur in a number of domestic and wild animals; the mites that cause these infestations are of different subspecies from the one typically causing the human form. These subspecies can infest animals that are not their usual hosts, but such infections do not last long. Scabies-infected animals experience severe itching and secondary skin infections. They often lose weight and become frail.The most frequently diagnosed form of scabies in domestic animals is sarcoptic mange, caused by the subspecies Sarcoptes scabiei canis, most commonly in dogs and cats. Sarcoptic mange is transmissible to humans who come into prolonged contact with infested animals, and is distinguished from human scabies by its distribution on skin surfaces covered by clothing. Scabies-infected domestic fowl develop what is known as "scaly leg". Domestic animals that have gone feral and have no veterinary care are frequently affected by scabies and a host of other ailments. Nondomestic animals have also been observed to develop scabies. Gorillas, for instance, are known to be susceptible to infection by contact with items used by humans.Scabies is also a concern for cattle.
Research
Moxidectin is being evaluated as a treatment for scabies. It is established in veterinary medicine to treat a range of parasites, including sarcoptic mange. Its advantage over ivermectin is its longer half life in humans and, thus, potential duration of action.Tea tree oil appears to be effective in the laboratory setting.
References
External links
American Academy of Dermatology pamphlet on Scabies
Scabies FAQ from the National Pediculosis Association |
Schilling test | The Schilling test was a medical investigation used for patients with vitamin B12 (cobalamin) deficiency. The purpose of the test was to determine how well a patient is able to absorb B12 from their intestinal tract. The test is now considered obsolete and is rarely performed, and is no longer available at many medical centers. It is named for Robert F. Schilling.
Process
The Schilling test has multiple stages. As noted below, it can be done at any time after vitamin B12 supplementation and body store replacement, and some clinicians recommend that in severe deficiency cases, at least several weeks of vitamin repletion be done before the test (more than one B12 shot, and also oral folic acid), in order to ensure that impaired absorption of B12 (with or without intrinsic factor) is not occurring due to damage to the intestinal mucosa from the B12 and folate deficiency themselves.
Stage 1: oral vitamin B12 plus intramuscular vitamin B12 (without IF)
In the first part of the test, the patient is given radiolabeled vitamin B12 to drink or eat. The most commonly used radiolabels are 57Co and 58Co. An intramuscular injection of unlabeled vitamin B12 is given an hour later. This is not enough to replete or saturate body stores of B12. The purpose of the single injection is to temporarily saturate B12 receptors in the liver with enough normal vitamin B12 to prevent radioactive vitamin B12 binding in body tissues (especially in the liver), so that if absorbed from the G.I. tract, it will pass into the urine. The patients urine is then collected over the next 24 hours to assess the absorption.
Normally, the ingested radiolabeled vitamin B12 will be absorbed into the body. Since the body already has liver receptors for transcobalamin/vitamin B12 saturated by the injection, much of the ingested vitamin B12 will be excreted in the urine.
A normal result shows at least 10% of the radiolabeled vitamin B12 in the urine over the first 24 hours.
In patients with pernicious anemia or with deficiency due to impaired absorption, less than 10% of the radiolabeled vitamin B12 is detected.The normal test will result in a higher amount of the radiolabeled cobalamin in the urine because it would have been absorbed by the intestinal epithelium, but passed into the urine because all hepatic B12 receptors were occupied. An abnormal result is caused by less of the labeled cobalamin to appear in the urine because it will remain in the intestine and be passed into the feces.
Stage 2: vitamin B12 and intrinsic factor
If an abnormality is found, i.e. the B12 in the urine is only present in low levels, the test is repeated, this time with additional oral intrinsic factor.
If this second urine collection is normal, this shows a lack of intrinsic factor production. This is by definition pernicious anemia.
A low result on the second test implies abnormal intestinal absorption (malabsorption), which could be caused by coeliac disease, biliary disease, Whipples disease, small bowel bacterial overgrowth syndrome, fish tapeworm infestation (Diphyllobothrium latum), or liver disease. Malabsorption of B12 can be caused by intestinal dysfunction from a low vitamin level in-and-of-itself (see below), causing test result confusion if repletion has not been done for some days previously.
Stage 3: vitamin B12 and antibiotics
This stage is useful for identifying patients with bacterial overgrowth syndrome. The physician will provide you a course of 2 weeks of antibiotics to eliminate any possible bacterial overgrowth and repeat the test to check whether radio-labeled Vitamin B12 would be found in urine or not.
Stage 4: vitamin B12 and pancreatic enzymes
This stage, in which pancreatic enzymes are administered, can be useful in identifying patients with pancreatic insufficiency. The physician will give you 3 days of pancreatic enzymes followed by repeating the test to check if radio-labeled Vitamin B12 would be detected in urine.
Combined stage 1 and stage 2
In some versions of the Schilling test, B12 can be given both with and without intrinsic factor at the same time, using different cobalt radioisotopes 57Co and 58Co, which have different radiation signatures, in order to differentiate the two forms of B12. This is performed with the Dicopac kitset. This allows for only a single radioactive urine collection.
Complications
Note that the B12 shot which begins the Schilling test is enough to go a considerable way toward treating B12 deficiency, so the test is also a partial treatment for B12 deficiency. Also, the classic Schilling test can be performed at any time, even after full B12 repletion and correction of the anemia, and it will still show if the cause of the B12 deficiency was intrinsic-factor related. In fact, some clinicians have suggested that folate and B12 replacement for several weeks be normally performed before a Schilling test is done, since folate and B12 deficiencies are both known to interfere with intestinal cell function, and thus cause malabsorption of B12 on their own, even if intrinsic factor is being made. This state would then tend to cause a false-positive test for both simple B12 and intrinsic factor-related B12 malabsorption. Several weeks of vitamin replacement are necessary, before epithelial damage to the G.I. tract from B12 deficiency is corrected.
Many labs have stopped performing the Schilling test, due to lack of production of the cobalt radioisotopes and labeled-B12 test substances. Also, injection replacement of B12 has become relatively inexpensive, and can be self-administered by patients, as well as megadose oral B12. Since these are the same treatments which would be administered for most causes of B12 malabsorption even if the exact cause were identified, the diagnostic test may be omitted without damage to the patient (so long as follow-up treatment and occasional serum B12 testing is not allowed to lapse).
It is possible for use of other radiopharmaceuticals to interfere with interpretation of the test.
Diagnoses
References
External links
MedlinePlus Encyclopedia: 003572 |
Schistosomiasis | Schistosomiasis, also known as snail fever, bilharzia, and Katayama fever, is a disease caused by parasitic flatworms called schistosomes. The urinary tract or the intestines may be infected. Symptoms include abdominal pain, diarrhea, bloody stool, or blood in the urine. Those who have been infected for a long time may experience liver damage, kidney failure, infertility, or bladder cancer. In children, it may cause poor growth and learning difficulty.The disease is spread by contact with fresh water contaminated with the parasites. These parasites are released from infected freshwater snails. The disease is especially common among children in developing countries, as they are more likely to play in contaminated water. Other high-risk groups include farmers, fishermen, and people using unclean water during daily living. It belongs to the group of helminth infections. Diagnosis is by finding eggs of the parasite in a persons urine or stool. It can also be confirmed by finding antibodies against the disease in the blood.Methods of preventing the disease include improving access to clean water and reducing the number of snails. In areas where the disease is common, the medication praziquantel may be given once a year to the entire group. This is done to decrease the number of people infected, and consequently, the spread of the disease. Praziquantel is also the treatment recommended by the World Health Organization for those who are known to be infected.Schistosomiasis affected about 236.6 million people worldwide in 2019. An estimated 4,400 to 200,000 people die from it each year. The disease is most commonly found in Africa, Asia, and South America. Around 700 million people, in more than 70 countries, live in areas where the disease is common. In tropical countries, schistosomiasis is second only to malaria among parasitic diseases with the greatest economic impact. Schistosomiasis is listed as a neglected tropical disease.
Signs and symptoms
Many individuals do not experience symptoms. If symptoms do appear, they usually take 4–6 weeks from the time of infection. The first symptom of the disease may be a general feeling of illness. Within 12 hours of infection, an individual may complain of a tingling sensation or light rash, commonly referred to as "swimmers itch", due to irritation at the point of entrance. The rash that may develop can mimic scabies and other types of rashes. Other symptoms can occur 2–10 weeks later and can include fever, aching, a cough, diarrhea, chills, or gland enlargement. These symptoms can also be related to avian schistosomiasis, which does not cause any further symptoms in humans.The manifestations of schistosomal infection vary over time as the cercariae, and later adult worms and their eggs, migrate through the body. If eggs migrate to the brain or spinal cord, seizures, paralysis, or spinal-cord inflammation are possible.
Acute Infection
Manifestation of acute infection from schistosoma include cercarial dermatitis (hours to days) and acute schistosomiasis (2–8 weeks).
Cercarial dermatitis
The first potential reaction is an itchy, maculopapular rash that results from cercariae penetrating the skin within the first 12 hours to days of cercarial skin penetration. The first time a non-sensitized person is exposed, the rashes are usually mild with an associated prickling sensation that quickly disappear on its own since this is a type of hypersensitivity reaction. In sensitized people who have previously been infected, the rash can develop into itchy, red, raised lesions (papules) with some turning into fluid-filled lesions (vesicles). Previous infections with cercariae causes a faster developing and worse presentation of dermatitis due to the stronger immune response. The round bumps are usually one to three centimeters across. Because people living in affected areas have often been repeatedly exposed, acute reactions are more common in tourists and migrants. The rash can occur between the first few hours and a week after exposure, and they normally resolve on their own in around 7–10 days. For human schistosomiasis, A similar type of dermatitis called "swimmers itch" can also be caused by cercariae from animal trematodes that often infect birds. Cercarial dermatitis is not contagious and can not be transmitted from person-to-person.Symptoms may include:
Flat, red rash
Small red, raised pimples
Small red blisters
Prickling or tingling sensation, burning, itching of the skinScratching the rash can lead to secondary bacterial infection of the skin, thus it is important to refrain from scratching. Some common treatments for itching include corticosteroid cream, anti-itch lotion, application of cool compresses to rash, bathing in Epsom salts or baking soda, and in severe itching cases, prescription strength cream and lotions. Oral antihistamines can also help relieve the itching.
Acute Schistosomiasis (Katayama fever)
Acute schistosomiasis (Katayama fever) may occur weeks or months (around 2–8 weeks) after the initial infection as a systemic reaction against migrating schistosomulae as they pass through the bloodstream through the lungs to the liver and also against the antigens of eggs. Similarly to swimmers itch, Katayama fever is more commonly seen in people with their first infection such as migrants and tourists, and it is associated with heavy infection. It is seen, however, in native residents of China infected with S. japonicum. S. japonicum can cause acute schistosomiasis in chronically infected population, and it can lead to a more severe form of acute schistosomiasis.Symptoms may include:
Dry cough with changes on chest X-ray
Fever
Fatigue
Muscle aches
Headache
Malaise
Abdominal pain
Diarrhea
Enlargement of both the liver and the spleen
HivesAcute schistosomiasis usually self-resolves in 2–8 weeks in most cases., but a small proportion of people have persistent weight loss, diarrhea, diffuse abdominal pain, and rash.Complications may include:
Spinal cord inflammation (transverse myelitis) may occur if worms or eggs travel to the spinal cord during this acute phase of infection.Treatment may include:
Corticosteroid such as prednisone is used to alleviate the hypersensitivity reaction and reduce inflammation
Praziquantel can be administered to kill the adult schistosomes to prevent chronic infection in addition to corticosteroid therapy. Praziquantel is not effective to recent infection as it only targets the adult worms, but not the premature schistosomulae. Therefore, a repeat treatment of Praziquantel several weeks after initial infection may be warranted. It is recommended to treat with Praziquantel 4–6 weeks after initial exposure since it targets adult worms.
Chronic Infection
In long-established disease, adult worms lay eggs that can cause inflammatory reactions. The eggs secrete proteolytic enzymes that help them migrate to the bladder and intestines to be shed. The enzymes also cause an eosinophilic inflammatory reaction when eggs get trapped in tissues or embolize to the liver, spleen, lungs, or brain. The long-term manifestations are dependent on the species of schistosome, as the adult worms of different species migrate to different areas. Many infections are mildly symptomatic, with anemia and malnutrition being common in endemic areas.
Intestinal schistosomiasis
The worms of S. mansoni and S. japonicum migrate to the veins of the gastrointestinal tract and liver. Eggs in the gut wall can lead to pain, blood in the stool, and diarrhea (especially in children). Severe disease can lead to narrowing of the colon or rectum.In intestinal schistosomiasis, eggs become lodged in the intestinal wall during their migration from the mesenteric venules to the intestinal lumen, and the trapped eggs cause an immune system reaction called a granulomatous reaction. They mostly affect the large bowel and rectum, and involvement of the small bowel is more rare. This immune response can lead to obstruction of the colon and blood loss. The infected individual may have what appears to be a potbelly. There is a strong correlation between morbidity of intestinal schistosomiasis and the intensities of infection. In cases of light infections, symptoms may be mild and can go unrecognized. The most common species to cause intestinal schistosomiasis are S. mansoni and S. japonicum, however, S. mekongi and S. intercalatum can also cause this disease.Symptoms may include:
Abdominal pain and discomfort
Loss of appetite
Mucous diarrhea with or without gross blood
Blood in feces that is not visibly present (fecal occult blood)
Abdominal distentionComplications may include:
Intestinal polyps
Intestinal ulcers
Iron deficient anemia
Fistula
Bowel strictures (narrowing of colon or rectum)
Protein-losing enteropathy
Partial or complete bowel obstruction
Appendicitis (rare)Approximately 10-50% of people living in endemic regions of S. mansoni and S. japonicum develop intestinal schistosomiasis. S. mansoni infection epidemiologically overlaps with high HIV prevalence in Sub-Saharan Africa, where gastrointestinal schistosomiasis has been linked to increased HIV transmission.
Hepatosplenic Schistosomiasis
Eggs also migrate to the liver leading to fibrosis in 4 to 8% of people with chronic infection, mainly those with long-term heavy infection.Eggs can become lodged in the liver, leading to portal hypertension, splenomegaly, the buildup of fluid in the abdomen, and potentially life-threatening dilations or swollen areas in the esophagus or gastrointestinal tract that can tear and bleed profusely (esophageal varices). This condition can be separated into two distinct phases: inflammatory hepatic schistosomiasis (early inflammatory reaction) and chronic hepatic schistosomiasis. Most common species to cause this condition are S. mansoni, S. japonicum, and S. mekongi.
Inflammatory hepatic schistosomiasis
This condition occurs mainly in children and adolescents due to early immune reaction to eggs trapped within the periportal and presinusoidal spaces of the liver creating numerous granulomas. Liver function is not affected, and the severity of liver and spleen enlargement is correlated to the intensity of the infection. It is characterized by an enlarged left lobe of the liver with a sharp edge and enlarged spleen with nodules. The enlargement of liver and spleen is usually mild, but in severe cases, they can enlarge to the level of the belly button and even into the pelvis.
Chronic (fibrotic) hepatic schistosomiasis
This is a late stage liver disease that occurs mainly in young and middle-aged adults who have been chronically infected with a heavy infection and whose immune regulation of fibrosis is not functioning properly. It affects only a small proportion of people who are infected. Liver function and liver architecture are not affected unlike cirrhosis. The pathogenesis of this disease is caused by deposition of collagen and extracellular matrix proteins within the periportal space, which leads to liver portal fibrosis and enlarged fibrotic portal tracts (Symmers pipe stem fibrosis). The periportal fibrosis physically compress the portal vein leading to portal hypertension (increased portal venous pressure), increased pressure of the splenic vein, and subsequent enlargement of the spleen. Portal hypertension can also increase the pressure in portosystemic anastomoses (vessel connections between the portal circulation and systemic circulation) leading to esophageal varices and caput medusae. These portosystemic anastomoses also allows a pathway for the eggs to travel to locations such as the lungs, spinal cord, or brain. Co-infection with hepatitis is common in regions endemic to schistosomiasis with Hepatitis B or Hepatitis C, and co-infection with Hepatitis C is associated with more rapid liver deterioration and worse outcome. Fibrotic hepatic schistosomiasis caused by S. mansoni usually develops in around 5–15 years, while it can take less time for S. japonicum.
Symptoms may include:
Esophageal varices (can cause life-threatening esophageal variceal bleed)
Ascites (end-stage)
Caput medusae
Enlarged spleen and liver
Complications may include:
Neuroschistosomiasis due to portosystemic anastomoses from portal hypertension
Pulmonary Schistosomiasis due to portosystemic anastomoses from portal hypertension
Pulmonary schistosomiasis
Portal hypertension secondary to hepatosplenic schistosomiasis can cause vessel connections between the portal (liver and gut) circulation and systemic circulation to develop, which creates a pathway for the eggs and worms to travel to the lungs. The eggs can be deposited around the alveolar capillary beds and causes granulomatous inflammation of the pulmonary arterioles followed by fibrosis. This leads to high blood pressure in the pulmonary circulation system (pulmonary hypertension), increased pressure in the right heart, enlargement of the pulmonary artery and right atria, and thickening of the right ventricular wall.Symptoms of pulmonary hypertension may include:
Shortness of breath
Chest pain
Feeling tired
Fainting during physical exertion
Urogenital schistosomiasis
The worms of S. haematobium migrate to the veins around the bladder and ureters where they reproduce. S. haematobium can produce up to 3000 eggs per day, these eggs migrate from the veins to the bladder and ureter lumens, but up to 50 percent of them can become trapped in the surrounding tissues causing granulomatous inflammation, polyps formation, and ulceration of bladder, ureter, and genital tract tissues. This can lead to blood in the urine 10 to 12 weeks after infection. Over time, fibrosis can lead to obstruction of the urinary tract, hydronephrosis, and kidney failure. Bladder cancer diagnosis and mortality are generally elevated in affected areas; efforts to control schistosomiasis in Egypt have led to decreases in the bladder cancer rate. The risk of bladder cancer appears to be especially high in male smokers, perhaps due to chronic irritation of the bladder lining allowing it to be exposed to carcinogens from smoking.In women, genitourinary disease can also include genital lesions that may lead to increased rates of HIV transmission. If lesions involve the fallopian tubes or ovaries, it may lead to infertility. If the reproductive organs in male are affected, there could be blood in the sperm.Urinary symptoms may include:
Blood in the urine - blood is usually seen at the end of an urine stream (most common symptom)
Painful urination
Increase frequency of urination
Protein in the urine
Secondary urinary tract infection
Secondary kidney infectionGenital symptoms may include:
Inflammation and ulceration of uterine cervix, vagina, or vulva
Blood in the sperm
Infertility in femaleKidney function is unaffected in many cases, and the lesions are reversible with proper treatment to eliminate the worms.
Neuroschistosomiasis
Central nervous system lesions occur occasionally due to inflammation and granuloma development around eggs or worms that find their way to the brain or spinal cord through the circulatory system, and they can potentially develop irreversible scarring without proper treatment. Cerebral granulomatous disease may be caused by S. japonicum eggs in the brain during both the acute and chronic phase of the disease. Communities in China affected by S. japonicum have rates of seizures eight times higher than baseline. Cerebral granulomatous infection may also be caused by S. mansoni. In situ egg deposition following the anomalous migration of the adult worm, which appears to be the only mechanism by which Schistosoma can reach the central nervous system in people with schistosomiasis. The destructive action on the nervous tissue and the mass effect produced by a large number of eggs surrounded by multiple, large granulomas in circumscribed areas of the brain characterize the pseudotumoral form of neuroschistosomiasis and are responsible for the appearance of clinical manifestations: headache, hemiparesis, altered mental status, vertigo, visual abnormalities, seizures, and ataxia. Similarly, granulomatous lesions from S. mansoni and S. haematobium eggs in the spinal cord can lead to transverse myelitis (inflammation of the spinal cord) with flaccid paraplegia. In cases with advanced hepatosplenic and urinary schistosomiasis, the continuous embolization of eggs from the portal mesenteric system (S. mansoni) or portal mesenteric-pelvic system (S. haematobium) to the brain, results in a sparse distribution of eggs associated with scant periovular inflammatory reaction, usually with little or no clinical significance.Spinal cord inflammation (transverse myelitis) symptoms may include:
Paralysis of the lower extremities
Loss of bowel or urinary control
Loss of sensation below the level of the lesion
Pain below the level of the lesionCerebral granulomatous infection symptoms may include:
Seizures
Headaches
Motor impairment
Sensory impairment
Cerebellar symptomsUnsteady gait
Inability to stand or sit without support
Uncoordinated movements
Scanning speech
Irregular eye movementsCorticosteroids is used to prevent permanent neurological damage from the inflammatory response to the eggs, and sometimes anticonvulsant is needed to stop the seizures. Corticosteroid is given prior to administration of Praziquantel.
Transmission and life cycle
Infected individuals release Schistosoma eggs into water via their fecal material or urine. After larvae hatch from these eggs, the larvae infect a very specific type of freshwater snail. For example, in S. haematobium and S. intercalatum it is snails of the genus Bulinus, in S. mansoni it is Biomphalaria, and in S. japonicum it is Oncomelania. The Schistosoma larvae undergo the next phase of their lifecycles in these snails, spending their time reproducing and developing. Once this step has been completed, the parasite leaves the snail and enters the water column. The parasite can live in the water for only 48 hours without a mammalian host. Once a host has been found, the worm enters its blood vessels. For several weeks, the worm remains in the vessels, continuing its development into its adult phase. When maturity is reached, mating occurs and eggs are produced. Eggs enter the bladder/intestine and are excreted through urine and feces and the process repeats. If the eggs do not get excreted, they can become engrained in the body tissues and cause a variety of problems such as immune reactions and organ damage. While transmission typically occurs only in countries where the freshwater snails are endemic, a case in Germany was reported where a man got Schistosoma by an infected snail in his aquarium.Humans encounter larvae of the Schistosoma parasite when they enter contaminated water while bathing, playing, swimming, washing, fishing, or walking through the water.
Life Cycle
The excretion Schistosome eggs in urine or feces depending on species
The hatching of the eggs leading to release of the free-swimming, ciliated larvae called miracidia
Miracidia find and penetrate the snails, which are the intermediate hosts (specific species of snails is dependent on the species of schistosoma)
Within the snails, two successive generations of sporocysts occur
Sporocyts gives rise to the infective free-swimming larvae with forked tails called cercariae, and they leave the snails to enter the water
Cercariae finds the human hosts and penetrate their skin
Upon entrance into the human hosts, cercariae lose their tails and become schistosomulae
The schistosomulae travels to the lungs and heart via the venous circulation
They migrate to the portal venous system of the liver where they mature into the adult form with two separate sexes
The adult male and female are paired together, exits the liver via portal venous system, and travel to the venous systems of the intestines or bladder (species dependent) and produce eggs
S. japonicum - superior mesenteric veins (but can also inhabit inferior mesenteric veins)
S. mansoni - inferior mesenteric veins (but can also inhabit superior mesenteric veins)
S. haematobium - vesicular and pelvic venous plexus of the bladder (occasionally rectal venules)
S. intercalatum and S. guineensis - inferior mesenteric plexus (lower portion of the bowels compared to S. mansoni)Schistosomes can live an average of 3–5 years, and the eggs can survive for more than 30 years after infection.
Other hosts
Schistosomiasis is also a concern of cattle husbandry and mice. O-methyl-threonine is weakly effective in mouse schistosomiasis but is not in use.
Pathogenesis
The infectious stage starts when the free-swimming larval form of the schistosome, cercariae, penetrates the human skin using their suckers, proteolytic enzymes, and tail movements; the cercariae transformed into schistosomulae by losing its tail and subsequently travels to the heart and lungs through venous system until it eventually reach the liver where it will mature into the adult form. The diseases caused by the schistomes are characterized into acute schistosomiasis and chronic schistosomiasis, and they can vary dependent on the species of schistosome.Acute Infection
Minutes to days after initial infection:
Cercerial dermatitis (Swimmers itch) - swimmers itch is caused by a localized allergic reaction at the sites of skin penetration by the cercariae causing an inflammatory reaction that is characterized by itchy red pimples and blisters.
Few weeks to months after initial infection:
Acute Schistosomiasis (Katayamas Fever) - the exact pathophysiology of this disease remains unknown. It has been hypothesized to be caused by a systemic immune response due to immune complex formation (Type III hypersensivity) with the foreign antigens on the migratory schistosomula and the eggs, and the subsequent deposition of these complexes on various tissues leading to activation of an autoimmune response. Acute schistosomiasis caused by S. mansoni and S. haematobium generally affect people who have been infected for the first time such as tourists visiting endemic regions. In contrast, cases of acute schistosomiasis caused by S. japonicum can occur in reinfection to population who reside in endemic regions, and they occur in higher incidences and can have worse prognosis. It was proposed that the large amount of egg antigens released by S. japonicum interact with antibodies leading to the formation of high volume of immune complexes, which cause enlargement of the lymph tissues. This sequence of events can lead to clinical manifestation of fever, enlargement of spleen and liver due to fibrosis, portal hypertension, and death.Chronic Infection
The clinical manifestations of chronic infection is mainly caused by immune reaction to the eggs entrapment within tissues resulting in granuloma formation and chronic inflammation. Adult worms live together in pairs (one male and female), sexually reproduce, and lay eggs in the veins around the intestines and bladder depending on the species, and these eggs can rupture the wall of the veins to escape to the surrounding tissues. The eggs make their way through the tissues to the intestinal or bladder lumen with help of proteolytic enzymes, however, a large amount of eggs are unable to finish their journey and remained stuck within the tissues where they can elicit an immune response. The miracidia in these eggs can then release antigens that stimulate an inflammatory immune response. The miracidia within the eggs live for around 6–8 weeks before they die and stop releasing the antigens. The granulomatous response is a cellular immune response mediated by CD4+ T cells, neutrophils, eosinophils, lymphocytes, macrophages, and monocytes, and this chronic inflammatory response elicited by the eggs can cause fibrosis, tissue destruction, and granuloma nodules that disrupt the functions of the organs involved. Th1 helper cell response is prominent releasing cytokines such as IFN-γ during the early phases of infection, and it transitions to Th2 response leading to increase in level of IgE, IL-4, and eosinophils as egg production progresses. In chronic infections, the Th2 response shifts to increasing the level of IL-10, IL-13, and IgG4, which reverses the progression of the granulomas and lead to collagen deposition at the sites of the granulomas. The specific clinical symptoms and severity of the disease this causes depends on the type of schistosome infection, duration of infection, number of eggs, and the organ at which the eggs are deposited. The amount of eggs entrapped in the tissues will continue to increase if the schistosoma are not eliminated.
Diagnosis
Identification of eggs in stools
Diagnosis of infection is confirmed by the identification of eggs in stools. Eggs of S. mansoni are about 140 by 60 µm in size and have a lateral spine. The diagnosis is improved through the use of the Kato-Katz technique, a semiquantitative stool examination technique. Other methods that can be used are enzyme-linked immunosorbent assay, circumoval precipitation test, and alkaline phosphatase immunoassay.Microscopic identification of eggs in stool or urine is the most practical method for diagnosis. Stool examination should be performed when infection with S. mansoni or S. japonicum is suspected, and urine examination should be performed if S. haematobium is suspected. Eggs can be present in the stool in infections with all Schistosoma species. The examination can be performed on a simple smear (1 to 2 mg of fecal material). Because eggs may be passed intermittently or in small numbers, their detection is enhanced by repeated examinations or concentration procedures, or both. In addition, for field surveys and investigational purposes, the egg output can be quantified by using the Kato-Katz technique (20 to 50 mg of fecal material) or the Ritchie technique. Eggs can be found in the urine in infections with S. haematobium (recommended time for collection: between noon and 3 PM) and with S. japonicum. Quantification is possible by using filtration through a nucleopore filter membrane of a standard volume of urine followed by egg counts on the membrane. Tissue biopsy (rectal biopsy for all species and biopsy of the bladder for S. haematobium) may demonstrate eggs when stool or urine examinations are negative.Identification of microhematuria in urine using urine reagent strips is more accurate than circulating antigen tests in the identification of active schistosomiasis in endemic areas.
Antibody detection
Antibody detection can be useful to indicate schistosome infection in people who have traveled to areas where schistosomiasis is common and in whom eggs cannot be demonstrated in fecal or urine specimens. Test sensitivity and specificity vary widely among the many tests reported for the serologic diagnosis of schistosomiasis and are dependent on both the type of antigen preparations used (crude, purified, adult worm, egg, cercarial) and the test procedure.At the U.S. Centers for Disease Control and Prevention, a combination of tests with purified adult worm antigens is used for antibody detection. All serum specimens are tested by FAST-ELISA using S. mansoni adult microsomal antigen. A positive reaction (greater than 9 units/µl serum) indicates infection with Schistosoma species. Sensitivity for S. mansoni infection is 99%, 95% for S. haematobium infection, and less than 50% for S. japonicum infection. Specificity of this assay for detecting schistosome infection is 99%. Because test sensitivity with the FAST-ELISA is reduced |
Schistosomiasis | for species other than S. mansoni, immunoblots of the species appropriate to the persons travel history are also tested to ensure detection of S. haematobium and S. japonicum infections. Immunoblots with adult worm microsomal antigens are species-specific, so a positive reaction indicates the infecting species. The presence of antibody is indicative only of schistosome infection at some time and cannot be correlated with clinical status, worm burden, egg production, or prognosis. Where a person has traveled can help determine which Schistosoma species to test for by immunoblot.In 2005, a field evaluation of a novel handheld microscope was undertaken in Uganda for the diagnosis of intestinal schistosomiasis by a team led by Russell Stothard from the Natural History Museum of London, working with the Schistosomiasis Control Initiative, London.
Molecular diagnostics
Polymerase chain reaction (PCR) based testing is accurate and rapid. However, it is not frequently used in countries where the disease is common due to the cost of the equipment and the technical expertise required to run the tests. Using a microscope to detect eggs costs about US$0.40 per test whereas PCR is about $US 7 per test as of 2019. Loop-mediated isothermal amplification are being studied as they are lower cost. LAMP testing is not commercially available as of 2019.
Laboratory testing
S. haematobium screening in the community can be done by using urine dip-stick to check for hematuria, and the stool guaiac test can be used to test for blood in the stool for potential S. mansoni and S. japonicum infection. For travelers or migrants in endemic regions, complete blood count with differential can be used to identify a high level of eosinophil in the blood, which could be indicative of an acute infection. Liver function test can be ordered if hepatosplenic schistosomiasis is suspected, and a subsequent hepatitis test panel can be ordered if liver function test is abnormal.
Tissue biopsy
If other diagnostic methods of schistosomiasis have failed to detect the infection, but there is still a high suspicion for schistosomiasis, tissue biopsy from the rectum, bladder, and liver can be obtained to look for schistosome eggs within the tissue samples.
Imaging
Imaging modalities such as x-rays, ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) can be utilized to evaluate for severity of schistosomiasis and damages of the infected organs. For example, x-ray and CT scans of the chest can be used to detect lesions in the lungs from pulmonary schistosomiasis, and pelvic x-ray can reveal calcification of the bladder in chronic urinary schistosomiasis. Ultrasound may be used to look for abnormalities in the liver and spleen in hepatosplenic schistosomiasis, and CT scan of the liver is a good tool to look for calcification in the liver associated with S. japonicum infection. CT scan can also be used to assess damages from the schistosomiasis infection in the intestinal, urogenital, and central nervous system. MRI is used to evaluate schistosomiasis of the central nervous system, liver, and genital.PET/CT scan that identifies tissues with higher metabolic activity have been used to help diagnose schistosomiasis in rare cases. This is due to the high level of inflammation caused by the schistosomal eggs, which increases the metabolic rate of the surrounding tissues.
Prevention
Many countries are working towards eradicating the disease. The World Health Organization is promoting these efforts. In some cases, urbanization, pollution, and the consequent destruction of snail habitat have reduced exposure, with a subsequent decrease in new infections. The elimination of snail populations using molluscicides had been attempted to prevent schistosomiasis in the past, but it was an expensive process that often only reduce but not eliminate the snail population. The drug praziquantel is used for prevention in high-risk populations living in areas where the disease is common. The Centers for Disease Control and Prevention advises avoiding drinking or coming into contact with contaminated water in areas where schistosomiasis is common.A 2014 review found tentative evidence that increasing access to clean water and sanitation reduces schistosome infection.Other important preventive measures include hygiene education leading to behavioral change and sanitary engineering to ensure safe water supply.
Preventive chemotherapy
For schistosomiasis control, World Health Organization recommends preventive chemotherapy, which is treatment of entire affected population and periodic treatment of all groups at high-risk at acquiring schistosomiasis with use of Praziquantel. In 2019, 44.5% of people with schistosomiasis was treated globally, and 67.2% of school-aged children needed preventive chemotherapy received treatment.
Snails, dams, and prawns
For many years from the 1950s onwards, vast dams and irrigation schemes were constructed, causing a massive rise in water-borne infections from schistosomiasis. The detailed specifications laid out in various United Nations documents since the 1950s could have minimized this problem. Irrigation schemes can be designed to make it hard for the snails to colonize the water and to reduce the contact with the local population. Even though guidelines on how to design these schemes to minimise the spread of the disease had been published years before, the designers were unaware of them. The dams appear to have reduced the population of the large migratory prawn Macrobrachium, which eats the snails. After the construction of fourteen large dams, greater increases in schistosomiasis occurred in the historical habitats of native prawns than in other areas. Further, at the 1986 Diama Dam on the Senegal River, restoring prawns upstream of the dam reduced both snail density and the human schistosomiasis reinfection rate.
Integrated strategy in China
In China, the national strategy for schistosomiasis control has shifted three times since it was first initiated: transmission control strategy (from mid-1950s to early 1980s), morbidity control strategy (from mid-1980s to 2003), and the "new integrated strategy" (2004 to present). The morbidity control strategy focused on synchronous chemotherapy for humans and bovines and the new strategy developed in 2004 intervenes in the transmission pathway of schistosomiasis, mainly including replacement of bovines with machines, prohibition of grazing cattle in the grasslands, improving sanitation, installation of fecal-matter containers on boats, praziquantel drug therapy, snail control, and health education. A 2018 review found that the "new integrated strategy" was highly effective to reduce the rate of S. japonicum infection in both humans and the intermediate host snails and reduced the infection risk by 3–4 times relative to the conventional strategy.
Treatment
Two drugs, praziquantel and oxamniquine, are available for the treatment of schistosomiasis. They are considered equivalent in relation to efficacy against S. mansoni and safety. Because of praziquantels lower cost per treatment, and oxaminiquines lack of efficacy against the urogenital form of the disease caused by S. haematobium, in general praziquantel is considered the first option for treatment. Praziquantel can be safely used in pregnant women and young children. The treatment objective is to cure the disease and to prevent the evolution of the acute to the chronic form of the disease. All cases of suspected schistosomiasis should be treated regardless of presentation because the adult parasite can live in the host for years.Schistosomiasis is treatable by taking by mouth a single dose of the drug praziquantel annually.Praziquantel only eliminates the adult schistosomes, but it is not effective in killing the eggs and immature worms. Live eggs can be excreted by the infected individuals for weeks after treatment with Praziquantel. The immature worms can survive and grow up to be adult schistosomes after Praziquantel therapy. Thus, it is important to have repeated schistosomiasis testing of the stool and/or urine around 4–6 weeks after Praziquantel therapy. Treatment of Praziquantel may be repeated to ensure complete elimination of the parasite.The WHO has developed guidelines for community treatment based on the impact the disease has on children in villages in which it is common:
When a village reports more than 50 per cent of children have blood in their urine, everyone in the village receives treatment.
When 20 to 50 percent of children have bloody urine, only school-age children are treated.
When fewer than 20 percent of children have symptoms, mass treatment is not implemented.Other possible treatments include a combination of praziquantel with metrifonate, artesunate, or mefloquine. A Cochrane review found tentative evidence that when used alone, metrifonate was as effective as praziquantel. Mefloquine, which has previously been used to treat and prevent malaria, was recognised in 2008–2009 to be effective against Schistosoma.Historically, antimony potassium tartrate remained the treatment of choice for schistosomiasis until the development of praziquantel in the 1980s.Post-treatment monitoring
Osteopontin (OPN) is a promising tool for monitoring Praziquantel efficacy and post-treatment fibrosis regression as (OPN) expression is modulated by Schistosoma mansoni egg antigens and its levels correlate with severity of schistosomiasis fibrosis and portal hypertension in mice and humans. Praziquantel (PZQ) pharmacotherapy reduces systemic OPN levels and liver collagen content in mice.
Epidemiology
The disease is found in tropical countries in Africa, the Caribbean, eastern South America, Southeast Asia, and the Middle East. S. mansoni is found in parts of South America and the Caribbean, Africa, and the Middle East; S. haematobium in Africa and the Middle East; and S. japonicum in the Far East. S. mekongi and S. intercalatum are found locally in Southeast Asia and central West Africa, respectively.The disease is endemic in about 75 developing countries and mainly affects people living in rural agricultural and peri-urban areas.
Infection estimates
In 2010, approximately 238 million people were infected with schistosomiasis, 85 percent of whom live in Africa. An earlier estimate from 2006 had put the figure at 200 million people infected. As of the latest WHO record, 236.6 million people were infected in 2019. In many of the affected areas, schistosomiasis infects a large proportion of children under 14 years of age. An estimated 600 to 700 million people worldwide are at risk from the disease because they live in countries where the organism is common. In 2012, 249 million people were in need of treatment to prevent the disease. This likely makes it the most common parasitic infection with malaria second and causing about 207 million cases in 2013.S. haematobium, the infectious agent responsible for urogenital schistosomiasis, infects over 112 million people annually in Sub-Saharan Africa alone. It is responsible for 32 million cases of dysuria, 10 million cases of hydronephrosis, and 150,000 deaths from kidney failure annually, making S. haematobium the worlds deadliest schistosome.
Deaths
Estimates regarding the number of deaths vary. Worldwide, the Global Burden of Disease Study issued in 2010 estimated 12,000 direct deaths while the WHO in 2014 estimated more than 200,000 annual deaths related to schistosomiasis. Another 20 million have severe consequences from the disease. It is the most deadly of the neglected tropical diseases.
History
The most ancient evidence of schistosomiasis dates back to more than 6000 years ago. Studies conducted on human skeletal remains found in northern Syria (5800–4000 BC), demonstrated the evidence of a terminal spined schistosome from the pelvic sediment of skeletal remains. Even if these evidence comes from Syria, it has been suggested that the cradle of schistosomes lies in the region of African great lakes, an area in which both the parasites and their intermediate hosts are in an active state of evolution. Subsequently, it is believed that schistosomiasis have spread to Egypt as a result of the importation of monkeys and slaves during reign of the fifth dynasty of pharaohs (~ 2494–2345 BC).Schistosomiasis is known as bilharzia or bilharziosis in many countries, after German physician Theodor Bilharz, who first described the cause of urinary schistosomiasis in 1851.The first physician who described the entire disease cycle was the Brazilian parasitologist Pirajá da Silva in 1908. The earliest known case of infection was discovered in 2014, belonging to a child who lived 6,200 years ago.It was a common cause of death for Egyptians in the Greco-Roman Period.In 2016 more than 200 million people needed treatment but only 88 million people were actually treated for schistosomiasis.
Etymology
Schistosomiasis is named for the genus of parasitic flatworm Schistosoma, whose name means split body. The name Bilharzia comes from Theodor Bilharz, a German pathologist working in Egypt in 1851 who first discovered these worms.
Society and culture
Schistosomiasis is endemic in Egypt, exacerbated by the countrys dam and irrigation projects along the Nile. From the late 1950s through the early 1980s, infected villagers were treated with repeated injections of tartar emetic. Epidemiological evidence suggests that this campaign unintentionally contributed to the spread of hepatitis C via unclean needles. Egypt has the worlds highest hepatitis C infection rate, and the infection rates in various regions of the country closely track the timing and intensity of the anti-schistosomiasis campaign. From ancient times to the early 20th century, schistosomiasis symptom of blood in the urine was seen as a male version of menstruation in Egypt and was thus viewed as a rite of passage for boys.Among human parasitic diseases, schistosomiasis ranks second behind malaria in terms of socio-economic and public health importance in tropical and subtropical areas.
Research
A proposed vaccine against S. haematobium infection called "Bilhvax" underwent a phase 3 clinical trial among children in Senegal: the results, reported in 2018, showed that it was not effective despite provoking some immune response. Using CRISPR gene editing technology, researchers decreased the symptoms due to schistosomiasis in an animal model.
See also
Angiostrongyliasis, another disease transmitted by snails
References
External links
Schistosomiasis at Curlie
River of Hope — documentary about the rise of schistosomiasis along the Senegal river (video, 47 mins)
Schistosomiasis information for travellers from IAMAT (International Association for Medical Assistance to Travellers) |
Scorpion sting | A scorpion sting is an injury caused by the stinger of a scorpion resulting in the medical condition known as scorpionism, which may vary in severity. The anatomical part of the scorpion that delivers the sting is called a "telson". In typical cases, scorpion stings usually result in pain, paresthesia, and variable swelling. In serious cases, scorpion stings may involve the envenomation of humans by toxic scorpions, which may result in extreme pain, serious illness, or even death depending on the toxicity of the venom.Most scorpion stings range in severity from minor swelling to medically significant lesions, with only a few able to cause severe allergic, neurotic or necrotic reactions. However, scorpion stings account for approximately 3,000 deaths a year worldwide. The Brazilian yellow scorpion (Tityus serrulatus) is one species known for being especially dangerous, being responsible for most scorpion sting fatalities in South America.Scorpion stings are seen all over the world but are predominantly seen in the tropical and subtropical areas. In the Western hemisphere, these areas include Mexico, northern South America and southeast Brazil. In the Eastern hemisphere, these regions include Sub-Saharan Africa, the Middle East, and the Indian subcontinent.
Characteristics and side effects
The byproducts of some arthropods may be used as an aphrodisiac. Some of these arthropods whose byproduct may be used as medicines can be found in North America. Across North America, the Arizona bark scorpion (Centruroides sculpturatus) has proven to be the most venomous scorpion. While stings from this species will rarely result in death, side effects can include numbness, tingling, convulsions, difficult breathing, and occasionally, paralysis. These side effects may last up to 72 hours after injection of the venom. It is also observed that penile erection may occur after being stung. The pain of a sting from the Arizona Bark Scorpion has been compared to being struck by a bolt of lightning or electrical current. These symptoms may become visible 4 to 7 minutes after envenomation.
Envenomation of a human by a scorpion may affect the sympathetic or parasympathetic systems depending on the species of scorpion. Some of the more severe side effects include respiratory distress syndrome, pulmonary edema, cardiac dysfunction, impaired hemostasis, pancreatitis, and multiple organ failure. Additionally, treatment of the sting depends on the severity of the incident, which is classified as mild, moderate, or severe. This treatment is composed of three different aspects of the sting: symptomatic measures, vital functions support, and injection antivenom. Not all envenomations result in systemic complications; only a small proportion of stings have this effect on the victim.
Mechanism
The composition of scorpion venom consists of different compounds of varying concentrations. The compounds consist of neurotoxins, cardiotoxin, nephrotoxin, hemolytic toxic, phosphodiesterases, phospholipase, histamine, serotonin, etc. Of these different toxins, the most important and most potent one is the neurotoxin concentration. This compound has neuromuscular and neuroautonomic effects, as well as damages the surrounding local tissue. Neurotoxins work to change voltage-dependent sodium channels, resulting in prolonged neuronal and neuromuscular activity. This prolonged activity of sodium channels results in an erection. There may be nerve damage due to the stabilization of voltage-dependent sodium channels in the open conformation. This position leads to the prolonged and continuous firing of neurons in the somatic, sympathetic, and parasympathetic nervous systems. Continuous firing of neurons causes over excitation and prevents the transmission of normal nerve impulses down the axon.The venom composition of the deathstalker scorpion contains neurotoxins which are almost completely responsible for this symptom. The poison from this scorpion contain 4 components: chlorotoxin, charybdotoxin, scyllatoxin, and agitoxins. Upon injection with the venom, sacral parasympathetic nerve are stimulated causing a change in the neuronal transmission in vascular and nonvascular smooth muscles. The compound known as the vasoactive intestinal polypeptide (VIP) is the main transmitter. This polypeptide is realized from nerves found long the erectile tissue of the corpus calosum. VIP is the strongest relaxant of penile smooth muscle structure, resulting in an erection upon envenomation. This is the proposed mechanics for all scorpion of the family Buthidae, whose venom composition contains these compounds.
Epidemiology
Overview
Scorpions are nocturnal animals that typically live in deserts, mountains, caves, and under rocks. It is when they are disturbed that they attack. Scorpions that possess the ability to inject toxic venom with their sting belong to the family Buthidae. The Middle East and North Africa are home to the deadliest scorpions, belonging to the genus Buthus, Leiurus, Androctonus, and Hottentotta. In South America, the deadliest scorpion belongs to genus Tityus. In India and Mexico, the deadliest scorpions involved in scorpionism are Mesobuthus and Centruroides, respectively.
Weather, seasons, and climate
Scorpions are nocturnal arachnids that have shown a seasonal pattern that is also related to climate. Specifically in Central America, scorpion attacks are mostly seen during the hot months of the year, noting that in Argentina this occurs in the months of October to April. Additionally, a rainy climate may also change the frequency of scorpion incidents. Lower levels of rainfall, specifically precipitation below 30 mm/month, can be associated with fewer scorpion stings, whereas rainfall greater than 30 mm/month shows no relationship to incident rate. This could be due to potentially disruptive effects of rainfall on scorpion habitat.
Central America
In Central America, most scorpion stings are mildly toxic to humans. However, Panama has reported an incidence of 52 cases per 100,000 people in 2007. Between 1998 and 2006, 28 people have died as result of scorpion stings. In Panama, the taxa of scorpions responsible for these deaths belong to the genus Tityus. This scorpion species is also found in parts of northern South America. Historically, the presence of these scorpions in Panama could be due to the closure of the Panamanian isthmus, thus allowing for the migration of the scorpions from Panama into the northern part of South America. Tityus pachyurus is among the most important scorpionist species. Envenomation by this scorpion is characterized by intense local pain, that usually does not result in tissue injury. Scorpions possess venom glands located at the distal extremity of their abdomen. There are currently 1,400 known species of scorpions and each possesses venom glands. However, of these 1,400 species, only 25 are known to be dangerous enough to humans to potentially cause death upon envenomation. Other countries in Central America are habitat to the scorpion genus Centruroides. Species in this genus are only mildly toxic to humans even though they have ion channel-active toxins in their venom.
== References == |
Scurvy | Scurvy is a disease resulting from a lack of vitamin C (ascorbic acid). Early symptoms of deficiency include weakness, feeling tired and sore arms and legs. Without treatment, decreased red blood cells, gum disease, changes to hair, and bleeding from the skin may occur. As scurvy worsens there can be poor wound healing, personality changes, and finally death from infection or bleeding.It takes at least a month of little to no vitamin C in the diet before symptoms occur. In modern times, scurvy occurs most commonly in people with mental disorders, unusual eating habits, alcoholism, and older people who live alone. Other risk factors include intestinal malabsorption and dialysis. While many animals produce their own vitamin C, humans and a few others do not. Vitamin C is required to make the building blocks for collagen. Diagnosis is typically based on physical signs, X-rays, and improvement after treatment.Treatment is with vitamin C supplements taken by mouth. Improvement often begins in a few days with complete recovery in a few weeks. Sources of vitamin C in the diet include citrus fruit and a number of vegetables, including red peppers, broccoli, and tomatoes. Cooking often decreases the residual amount of vitamin C in foods.Scurvy is rare compared to other nutritional deficiencies. It occurs more often in the developing world in association with malnutrition. Rates among refugees are reported at 5 to 45 percent. Scurvy was described as early as the time of ancient Egypt. It was a limiting factor in long-distance sea travel, often killing large numbers of people. During the Age of Sail, it was assumed that 50 percent of the sailors would die of scurvy on a major trip. A Scottish surgeon in the Royal Navy, James Lind, is generally credited with proving that scurvy can be successfully treated with citrus fruit in 1753. Nevertheless, it was not until 1795 that health reformers such as Gilbert Blane persuaded the Royal Navy to routinely give lemon juice to its sailors.
Signs and symptoms
Early symptoms are malaise and lethargy. After one to three months, patients develop shortness of breath and bone pain. Myalgias may occur because of reduced carnitine production. Other symptoms include skin changes with roughness, easy bruising and petechiae, gum disease, loosening of teeth, poor wound healing, and emotional changes (which may appear before any physical changes). Dry mouth and dry eyes similar to Sjögrens syndrome may occur. In the late stages, jaundice, generalised edema, oliguria, neuropathy, fever, convulsions, and eventual death are frequently seen.
Cause
Scurvy, including subclinical scurvy, is caused by a deficiency of dietary vitamin C since humans are unable to metabolically synthesize vitamin C. Provided the diet contains sufficient vitamin C, the lack of working L-gulonolactone oxidase (GULO) enzyme has no significance, and in modern Western societies, scurvy is rarely present in adults, although infants and elderly people are affected. Virtually all commercially available baby formulas contain added vitamin C, preventing infantile scurvy. Human breast milk contains sufficient vitamin C, if the mother has an adequate intake. Commercial milk is pasteurized, a heating process that destroys the natural vitamin C content of the milk.Scurvy is one of the accompanying diseases of malnutrition (other such micronutrient deficiencies are beriberi and pellagra) and thus is still widespread in areas of the world depending on external food aid.
Although rare, there are also documented cases of scurvy due to poor dietary choices by people living in industrialized nations.
Pathogenesis
Vitamins are essential to the production and use of enzymes that are involved in ongoing processes throughout the human body. Ascorbic acid is needed for a variety of biosynthetic pathways, by accelerating hydroxylation and amidation reactions. In the synthesis of collagen, ascorbic acid is required as a cofactor for prolyl hydroxylase and lysyl hydroxylase. These two enzymes are responsible for the hydroxylation of the proline and lysine amino acids in collagen. Hydroxyproline and hydroxylysine are important for stabilizing collagen by cross-linking the propeptides in collagen.
Collagen is a primary structural protein in the human body, necessary for healthy blood vessels, muscle, skin, bone, cartilage, and other connective tissues.
Defective connective tissue leads to fragile capillaries, resulting in abnormal bleeding, bruising, and internal hemorrhaging.
Collagen is an important part of bone, so bone formation is also affected. Teeth loosen, bones break more easily, and once-healed breaks may recur.
Defective collagen fibrillogenesis impairs wound healing.
Untreated scurvy is invariably fatal.
Diagnosis
Diagnosis is typically based on physical signs, X-rays, and improvement after treatment.
Differential diagnosis
Various childhood onset disorders can mimic the clinical and X-ray picture of scurvy such as:
Rickets
Osteochondrodysplasias especially osteogenesis imperfecta
Blounts disease
Osteomyelitis
Prevention
Scurvy can be prevented by a diet that includes uncooked vitamin C-rich foods such as amla, bell peppers (sweet peppers), blackcurrants, broccoli, chili peppers, guava, kiwifruit, and parsley. Other sources rich in vitamin C are fruits such as lemons, limes, oranges, papaya, and strawberries. It is also found in vegetables, such as brussels sprouts, cabbage, potatoes, and spinach. Some fruits and vegetables not high in vitamin C may be pickled in lemon juice, which is high in vitamin C. Nutritional supplements which provide ascorbic acid well in excess of what is required to prevent scurvy may cause adverse health effects.Some animal products, including liver, muktuk (whale skin), oysters, and parts of the central nervous system, including the adrenal medulla, brain, and spinal cord, contain large amounts of vitamin C, and can even be used to treat scurvy. Fresh meat from animals, notable internal organs, contains enough vitamin C to prevent scurvy, and even partly treat it..Scotts 1902 Antarctic expedition used lightly fried seal meat and liver, whereby complete recovery from incipient scurvy was reported to have taken less than two weeks.
Treatment
Scurvy will improve with doses of vitamin C as low as 10 mg per day though doses of around 100 mg per day are typically recommended. Most people make a full recovery within 2 weeks.
History
Symptoms of scurvy have been recorded in Ancient Egypt as early as 1550 BCE. In Ancient Greece, the physician Hippocrates (460-370 BCE) described symptoms of scurvy, specifically a "swelling and obstruction of the spleen."
In 406 CE, the Chinese monk Faxian wrote that ginger was carried on Chinese ships to prevent scurvy.The knowledge that consuming foods containing vitamin C is a cure for scurvy has been repeatedly forgotten and rediscovered into the early 20th century.
Early modern era
In the 13th century, the Crusaders frequently developed scurvy. In the 1497 expedition of Vasco da Gama, the curative effects of citrus fruit were already known and confirmed by Pedro Álvares Cabral and his crew in 1507.The Portuguese planted fruit trees and vegetables in Saint Helena, a stopping point for homebound voyages from Asia, and left their sick, who had scurvy and other ailments, to be taken home by the next ship if they recovered.In 1500, one of the pilots of Cabrals fleet bound for India noted that in Malindi, its king offered the expedition fresh supplies such as lambs, chickens, and ducks, along with lemons and oranges, due to which "some of our ill were cured of scurvy".Unfortunately, these travel accounts did not stop further maritime tragedies caused by scurvy, first because of the lack of communication between travelers and those responsible for their health, and because fruits and vegetables could not be kept for long on ships.In 1536, the French explorer Jacques Cartier, exploring the St. Lawrence River, used the local natives knowledge to save his men who were dying of scurvy. He boiled the needles of the arbor vitae tree (eastern white cedar) to make a tea that was later shown to contain 50 mg of vitamin C per 100 grams. Such treatments were not available aboard ship, where the disease was most common.
In February 1601, Captain James Lancaster, while sailing to Sumatra, landed on the northern coast of Madagascar specifically to obtain lemons and oranges for his crew to stop scurvy. Captain Lancaster conducted an experiment using four ships under his command. One ships crew received routine doses of lemon juice while the other three ships did not receive any such treatment. As a result, members of the non-treated ships started to contract scurvy, with many dying as a result.During the Age of Exploration (between 1500 and 1800), it has been estimated that scurvy killed at least two million sailors. Jonathan Lamb wrote: "In 1499, Vasco da Gama lost 116 of his crew of 170; In 1520, Magellan lost 208 out of 230;...all mainly to scurvy."In 1579, the Spanish friar and physician Agustin Farfán published a book in which he recommended oranges and lemons for scurvy, a remedy that was already known in the Spanish Navy.In 1593, Admiral Sir Richard Hawkins advocated drinking orange and lemon juice as a means of preventing scurvy.In 1614, John Woodall, Surgeon General of the East India Company, published The Surgions Mate as a handbook for apprentice surgeons aboard the companys ships. He repeated the experience of mariners that the cure for scurvy was fresh food or, if not available, oranges, lemons, limes, and tamarinds. He was, however, unable to explain the reason why, and his assertion had no impact on the prevailing opinion of the influential physicians of the age, that scurvy was a digestive complaint.
Apart from ocean travel, even in Europe, until the late Middle Ages, scurvy was common in late winter, when few green vegetables, fruits and root vegetables were available. This gradually improved with the introduction from the Americas of potatoes; by 1800, scurvy was virtually unheard of in Scotland, where it had previously been endemic.: 11
18th century
In 2009, a handwritten household book authored by a Cornishwoman in 1707 was discovered in a house in Hasfield, Gloucestershire, containing a "Recp.t for the Scurvy" amongst other largely medicinal and herbal recipes. The recipe consisted of extracts from various plants mixed with a plentiful supply of orange juice, white wine or beer.In 1734, Leiden-based physician Johann Bachstrom published a book on scurvy in which he stated, "scurvy is solely owing to a total abstinence from fresh vegetable food, and greens; which is alone the primary cause of the disease", and urged the use of fresh fruit and vegetables as a cure.It was not until 1747 that James Lind formally demonstrated that scurvy could be treated by supplementing the diet with citrus fruit, in one of the first controlled clinical experiments reported in the history of medicine. As a naval surgeon on HMS Salisbury, Lind had compared several suggested scurvy cures: hard cider, vitriol, vinegar, seawater, oranges, lemons, and a mixture of balsam of Peru, garlic, myrrh, mustard seed and radish root. In A Treatise on the Scurvy (1753)
Lind explained the details of his clinical trial and concluded "the results of all my experiments was, that oranges and lemons were the most effectual remedies for this distemper at sea." However, the experiment and its results occupied only a few paragraphs in a work that was long and complex and had little impact. Lind himself never actively promoted lemon juice as a single cure. He shared medical opinion at the time that scurvy had multiple causes – notably hard work, bad water, and the consumption of salt meat in a damp atmosphere which inhibited healthful perspiration and normal excretion – and therefore required multiple solutions. Lind was also sidetracked by the possibilities of producing a concentrated rob of lemon juice by boiling it. This process destroyed the vitamin C and was therefore unsuccessful.During the 18th century, scurvy killed more British sailors than wartime enemy action. It was mainly by scurvy that George Anson, in his celebrated voyage of 1740–1744, lost nearly two-thirds of his crew (1,300 out of 2,000) within the first 10 months of the voyage. The Royal Navy enlisted 184,899 sailors during the Seven Years War; 133,708 of these were "missing" or died from disease, and scurvy was the leading cause.Although throughout this period sailors and naval surgeons were increasingly convinced that citrus fruits could cure scurvy, the classically trained physicians who determined medical policy dismissed this evidence as merely anecdotal, as it did not conform to their theories of disease. Literature championing the cause of citrus juice, therefore, had no practical impact. The medical theory was based on the assumption that scurvy was a disease of internal putrefaction brought on by faulty digestion caused by the hardships of life at sea and the naval diet. Although this basic idea was given different emphases by successive theorists, the remedies they advocated (and which the navy accepted) amounted to little more than the consumption of fizzy drinks to activate the digestive system, the most extreme of which was the regular consumption of elixir of vitriol – sulphuric acid taken with spirits and barley water, and laced with spices.
In 1764, a new and similarly inaccurate theory on scurvy appeared. Advocated by Dr David MacBride and Sir John Pringle, Surgeon General of the Army and later President of the Royal Society, this idea was that scurvy was the result of a lack of fixed air in the tissues which could be prevented by drinking infusions of malt and wort whose fermentation within the body would stimulate digestion and restore the missing gases. These ideas received wide and influential backing, when James Cook set off to circumnavigate the world (1768–1771) in HM Bark Endeavour, malt and wort were top of the list of the remedies he was ordered to investigate. The others were beer, Sauerkraut (a good source of vitamin C) and Linds rob. The list did not include lemons.Cook did not lose a single man to scurvy, and his report came down in favour of malt and wort, although it is now clear that the reason for the health of his crews on this and other voyages was Cooks regime of shipboard cleanliness, enforced by strict discipline, as well as frequent replenishment of fresh food and greenstuffs. Another beneficial rule implemented by Cook was his prohibition of the consumption of salt fat skimmed from the ships copper boiling pans, then a common practice elsewhere in the Navy. In contact with air, the copper formed compounds that prevented the absorption of vitamins by the intestines.The first major long distance expedition that experienced virtually no scurvy was that of the Spanish naval officer Alessandro Malaspina, 1789–1794. Malaspinas medical officer, Pedro González, was convinced that fresh oranges and lemons were essential for preventing scurvy. Only one outbreak occurred, during a 56-day trip across the open sea. Five sailors came down with symptoms, one seriously. After three days at Guam all five were healthy again. Spains large empire and many ports of call made it easier to acquire fresh fruit.Although towards the end of the century MacBrides theories were being challenged, the medical authorities in Britain remained committed to the notion that scurvy was a disease of internal putrefaction and the Sick and Hurt Board, run by administrators, felt obliged to follow its advice. Within the Royal Navy, however, opinion – strengthened by first-hand experience of the use of lemon juice at the siege of Gibraltar and during Admiral Rodneys expedition to the Caribbean – had become increasingly convinced of its efficacy. This was reinforced by the writings of experts like Gilbert Blane and Thomas Trotter and by the reports of up-and-coming naval commanders.
With the coming of war in 1793, the need to eliminate scurvy acquired a new urgency. But the first initiative came not from the medical establishment but from the admirals. Ordered to lead an expedition against Mauritius, Rear Admiral Gardner was uninterested in the wort, malt and elixir of vitriol which were still being issued to ships of the Royal Navy, and demanded that he be supplied with lemons, to counteract scurvy on the voyage. Members of the Sick and Hurt Board, recently augmented by two practical naval surgeons, supported the request, and the Admiralty ordered that it be done. There was, however, a last minute change of plan, and the expedition against Mauritius was cancelled. On 2 May 1794, only HMS Suffolk and two sloops under Commodore Peter Rainier sailed for the east with an outward bound convoy, but the warships were fully supplied with lemon juice and the sugar with which it had to be mixed.
In March 1795, it was reported that the Suffolk had arrived in India after a four-month voyage without a trace of scurvy and with a crew that was healthier than when it set out. The effect was immediate. Fleet commanders clamoured also to be supplied with lemon juice, and by June the Admiralty acknowledged the groundswell of demand in the navy and agreed to a proposal from the Sick and Hurt Board that lemon juice and sugar should in future be issued as a daily ration to the crews of all warships.It took a few years before the method of distribution to all ships in the fleet had been perfected and the supply of the huge quantities of lemon juice required to be secured, but by 1800, the system was in place and functioning. This led to a remarkable health improvement among the sailors and consequently played a critical role in gaining the advantage in naval battles against enemies who had yet to introduce the measures.
Scurvy was not only a disease of seafarers. The only colonists of Australia suffered greatly because of the lack of fresh fruit and vegetables in the winter. There the disease was called Spring fever or Spring disease and described an often fatal condition associated with skin lesions, bleeding gums and lethargy. It was eventually identified as scurvy and the remedies already in use at sea implemented.
19th century
The surgeon-in-chief of Napoleons army at the Siege of Alexandria (1801), Baron Dominique-Jean Larrey, wrote in his memoirs that the consumption of horse meat helped the French to curb an epidemic of scurvy. The meat was cooked but was freshly obtained from young horses bought from Arabs, and was nevertheless effective. This helped to start the 19th-century tradition of horse meat consumption in France.Lauchlin Rose patented a method used to preserve citrus juice without alcohol in 1867, creating a concentrated drink known as Roses lime juice. The Merchant Shipping Act of 1867 required all ships of the Royal Navy and Merchant Navy to provide a daily lime ration of one pound to sailors to prevent scurvy. The product became nearly ubiquitous, hence the term "limey", first for British sailors, then for English immigrants within the former British colonies (particularly America, New Zealand and South Africa), and finally, in old American slang, all British people.The plant Cochlearia officinalis, also known as "common scurvygrass", acquired its common name from the observation that it cured scurvy, and it was taken on board ships in dried bundles or distilled extracts. Its very bitter taste was usually disguised with herbs and spices; however, this did not prevent scurvygrass drinks and sandwiches from becoming a popular fad in the UK until the middle of the nineteenth century, when citrus fruits became more readily available.West Indian limes began to supplement lemons, when Spains alliance with France against Britain in the Napoleonic Wars made the supply of Mediterranean lemons problematic, and because they were more easily obtained from Britains Caribbean colonies and were believed to be more effective because they were more acidic. It was the acid, not the (then-unknown) Vitamin C that was believed to cure scurvy. In fact, the West Indian limes were significantly lower in Vitamin C than the previous lemons and further were not served fresh but rather as lime juice, which had been exposed to light and air, and piped through copper tubing, all of which significantly reduced the Vitamin C. Indeed, a 1918 animal experiment using representative samples of the Navy and Merchant Marines lime juice showed that it had virtually no antiscorbutic power at all.The belief that scurvy was fundamentally a nutritional deficiency, best treated by consumption of fresh food, particularly fresh citrus or fresh meat, was not universal in the 19th and early 20th centuries, and thus sailors and explorers continued to have scurvy into the 20th century. For example, the Belgian Antarctic Expedition of 1897–1899 became seriously affected by scurvy when its leader, Adrien de Gerlache, initially discouraged his men from eating penguin and seal meat.
In the Royal Navys Arctic expeditions in the 19th century it was widely believed that scurvy was prevented by good hygiene on board ship, regular exercise, and maintaining the morale of the crew, rather than by a diet of fresh food. Navy expeditions continued to be plagued by scurvy even while fresh (not jerked or tinned) meat was well known as a practical antiscorbutic among civilian whalers and explorers in the Arctic. Even cooking fresh meat did not entirely destroy its antiscorbutic properties, especially as many cooking methods failed to bring all the meat to high temperature.
The confusion is attributed to a number of factors:
while fresh citrus (particularly lemons) cured scurvy, lime juice that had been exposed to light, air and copper tubing did not – thus undermining the theory that citrus cured scurvy;
fresh meat (especially organ meat and raw meat, consumed in arctic exploration) also cured scurvy, undermining the theory that fresh vegetable matter was essential to preventing and curing scurvy;
increased marine speed via steam shipping, and improved nutrition on land, reduced the incidence of scurvy – and thus the ineffectiveness of copper-piped lime juice compared to fresh lemons was not immediately revealed.In the resulting confusion, a new hypothesis was proposed, following the new germ theory of disease – that scurvy was caused by ptomaine, a waste product of bacteria, particularly in tainted tinned meat.
Infantile scurvy emerged in the late 19th century because children were being fed pasteurized cows milk, particularly in the urban upper class. While pasteurization killed bacteria, it also destroyed vitamin C. This was eventually resolved by supplementing with onion juice or cooked potatoes. Native Americans helped save some newcomers from scurvy by directing them to eat wild onions.
20th century
By the early 20th century, when Robert Falcon Scott made his first expedition to the Antarctic (1901–1904), the prevailing theory was that scurvy was caused by "ptomaine poisoning", particularly in tinned meat. However, Scott discovered that a diet of fresh meat from Antarctic seals cured scurvy before any fatalities occurred.In 1907, an animal model which would eventually help to isolate and identify the "antiscorbutic factor" was discovered. Axel Holst and Theodor Frølich, two Norwegian physicians studying shipboard beriberi contracted by ships crews in the Norwegian Fishing Fleet, wanted a small test mammal to substitute for the pigeons then used in beriberi research. They fed guinea pigs their test diet of grains and flour, which had earlier produced beriberi in their pigeons, and were surprised when classic scurvy resulted instead. This was a serendipitous choice of animal. Until that time, scurvy had not been observed in any organism apart from humans and had been considered an exclusively human disease. Certain birds, mammals, and fish are susceptible to scurvy, but pigeons are unaffected, since they can synthesize ascorbic acid internally. Holst and Frølich found they could cure scurvy in guinea pigs with the addition of various fresh foods and extracts. This discovery of an animal experimental model for scurvy, which was made even before the essential idea of "vitamins" in foods had been put forward, has been called the single most important piece of vitamin C research.In 1915, New Zealand troops in the Gallipoli Campaign had a lack of vitamin C in their diet which caused many of the soldiers to contract scurvy. It is thought that scurvy is one of many reasons that the Allied attack on Gallipoli failed.Vilhjalmur Stefansson, an arctic explorer who had lived among the Inuit, proved that the all-meat diet they consumed did not lead to vitamin deficiencies. He participated in a study in New Yorks Bellevue Hospital in February 1928, where he and a companion ate only meat for a year while under close medical observation, yet remained in good health.In 1927, Hungarian biochemist Albert Szent-Györgyi isolated a compound he called "hexuronic acid". Szent-Györgyi suspected hexuronic acid, which he had isolated from adrenal glands, to be the antiscorbutic agent, but he could not prove it without an animal-deficiency model. In 1932, the connection between hexuronic acid and scurvy was finally proven by American researcher Charles Glen King of the University of Pittsburgh. Kings laboratory was given some hexuronic acid by Szent-Györgyi and soon established that it was the sought-after anti-scorbutic agent. Because of this, hexuronic acid was subsequently renamed ascorbic acid.
21st century
Rates of scurvy in most of the world are low. Those most commonly affected are malnourished people in the developing world and the homeless. There have been outbreaks of the condition in refugee camps. Case reports in the developing world of those with poorly healing wounds have occurred.
Human trials
Notable human dietary studies of experimentally induced scurvy were conducted on conscientious objectors during World War II in Britain and in the United States on Iowa state prisoner volunteers in the late 1960s. These studies both found that all obvious symptoms of scurvy previously induced by an experimental scorbutic diet with extremely low vitamin C content could be completely reversed by additional vitamin C supplementation of only 10 mg per day. In these experiments, no clinical difference was noted between men given 70 mg vitamin C per day (which produced blood levels of vitamin C of about 0.55 mg/dl, about 1⁄3 of tissue saturation levels), and those given 10 mg per day (which produced lower blood levels). Men in the prison study developed the first signs of scurvy about 4 weeks after starting the vitamin C-free diet, whereas in the British study, six to eight months were required, possibly because the subjects were pre-loaded with a 70 mg/day supplement for six weeks before the scorbutic diet was fed.Men in both studies, on a diet devoid or nearly devoid of vitamin C, had blood levels of vitamin C too low to be accurately measured when they developed signs of scurvy, and in the Iowa study, at this time were estimated (by labeled vitamin C dilution) to have a body pool of less than 300 mg, with daily turnover of only 2.5 mg/day.
In other animals
Most animals and plants are able to synthesize vitamin C through a sequence of enzyme-driven steps, which convert monosaccharides to vitamin C. However, some mammals have lost the ability to synthesize vitamin C, notably simians and tarsiers. These make up one of two major primate suborders, haplorrhini, and this group includes humans. The strepsirrhini (non-tarsier prosimians) can make their own vitamin C, and these include lemurs, lorises, pottos, and galagos. Ascorbic acid is also not synthesized by at least two species of caviidae, the capybara and the guinea pig. There are known species of birds and fish that do not synthesize their own vitamin C. All species that |
Scurvy | do not synthesize ascorbate require it in the diet. Deficiency causes scurvy in humans, and somewhat similar symptoms in other animals.Animals that can contract scurvy all lack the L-gulonolactone oxidase (GULO) enzyme, which is required in the last step of vitamin C synthesis. The genomes of these species contain GULO as pseudogenes, which serve as insight into the evolutionary past of the species.
Name
In babies, scurvy is sometimes referred to as Barlows disease, named after Thomas Barlow, a British physician who described it in 1883. However, Barlows disease may also refer to mitral valve prolapse (Barlows syndrome), first described by John Brereton Barlow in 1966.
References
Further reading
== External links == |
Seasonal affective disorder | Seasonal affective disorder (SAD) is a mood disorder subset, in which people who have normal mental health throughout most of the year exhibit depressive symptoms at the same time each year, most commonly in winter. Common symptoms include sleeping too much, having little to no energy, and overeating. The condition in the summer can include heightened anxiety.In the Diagnostic and Statistical Manual of Mental Disorders DSM-IV and DSM-5, its status was changed. It is no longer classified as a unique mood disorder, but is now a specifier, called "with seasonal pattern", for recurrent major depressive disorder that occurs at a specific time of the year, and fully remits otherwise. Although experts were initially skeptical, this condition is now recognized as a common disorder. However, the validity of SAD has been questioned by a 2016 analysis by the Center for Disease Control, in which no links were detected between depression and seasonality or sunlight exposure.
In the United States, the percentage of the population affected by SAD ranges from 1.4% of the population in Florida, to 9.9% in Alaska. SAD was formally described and named in 1984, by Norman E. Rosenthal and colleagues at the National Institute of Mental Health.
History
SAD was first systematically reported and named in the early 1980s, by Norman E. Rosenthal, M.D., and his associates at the National Institute of Mental Health (NIMH). Rosenthal was initially motivated by his desire to discover the cause of his own experience of depression during the dark days of the northern US winter, called polar night. He theorized that the reduction in available natural light during winter was the cause. Rosenthal and his colleagues then documented the phenomenon of SAD in a placebo-controlled study utilizing light therapy. A paper based on this research was published in 1984. Although Rosenthals ideas were initially greeted with skepticism, SAD has become well recognized, and his 1993 book, Winter Blues has become the standard introduction to the subject.Research on SAD in the United States began in 1979, when Herb Kern, a research engineer, had also noticed that he felt depressed during the winter months. Kern suspected that scarcer light in winter was the cause, and discussed the idea with scientists at the NIMH who were working on bodily rhythms. They were intrigued, and responded by devising a lightbox to treat Kerns depression. Kern felt much better within a few days of treatments, as did other patients treated in the same way.
Signs and symptoms
SAD is a type of major depressive disorder, and those with the condition may exhibit any of the associated symptoms, such as feelings of hopelessness and worthlessness, thoughts of suicide, loss of interest in activities, withdrawal from social interaction, sleep and appetite problems, difficulty with concentrating and making decisions, decreased libido, a lack of energy, or agitation. Symptoms of winter SAD often include falling asleep earlier or in less than 5 minutes in the evening, oversleeping or difficulty waking up in the morning, nausea, and a tendency to overeat, often with a craving for carbohydrates, which leads to weight gain. SAD is typically associated with winter depression, but springtime lethargy or other seasonal mood patterns are not uncommon. Although each individual case is different, in contrast to winter SAD, people who experience spring and summer depression may be more likely to show symptoms such as insomnia, decreased appetite and weight loss, and agitation or anxiety.
Bipolar disorder
With seasonal pattern is a specifier for bipolar and related disorders, including bipolar I disorder and bipolar II disorder.
Most people with SAD experience major depressive disorder, but as many as 20% may have a bipolar disorder. It is important to distinguish between diagnoses because there are important treatment differences. In these cases, people who have the With seasonal pattern specifier may experience a depressive episode either due to major depressive disorder or as part of bipolar disorder during the winter and remit in the summer. Around 25% of patients with bipolar disorder may present with a depressive seasonal pattern, which is associated with bipolar II disorder, rapid cycling, eating disorders, and more depressive episodes. Differences in biological sex display distinct clinical characteristics associated to seasonal pattern: males present with more Bipolar II disorder and a higher number of depressive episodes, and females with rapid cycling and eating disorders.
Cause
In many species, activity is diminished during the winter months, in response to the reduction in available food, the reduction of sunlight (especially for diurnal animals), and the difficulties of surviving in cold weather. Hibernation is an extreme example, but even species that do not hibernate often exhibit changes in behavior during the winter. The preponderance of women with SAD suggests that the response may also somehow regulate reproduction.Various proximate causes have been proposed. One possibility is that SAD is related to a lack of serotonin, and serotonin polymorphisms could play a role in SAD, although this has been disputed. Mice incapable of turning serotonin into N-acetylserotonin (by serotonin N-acetyltransferase) appear to express "depression-like" behavior, and antidepressants such as fluoxetine increase the amount of the enzyme serotonin N-acetyltransferase, resulting in an antidepressant-like effect. Another theory is that the cause may be related to melatonin, which is produced in dim light and darkness by the pineal gland, since there are direct connections, via the retinohypothalamic tract and the suprachiasmatic nucleus, between the retina and the pineal gland. Melatonin secretion is controlled by the endogenous circadian clock, but can also be suppressed by bright light.One study looked at whether some people could be predisposed to SAD based on personality traits. Correlations between certain personality traits, higher levels of neuroticism, agreeableness, openness, and an avoidance-oriented coping style, appeared to be common in those with SAD.
Pathophysiology
Seasonal mood variations are believed to be related to light. An argument for this view is the effectiveness of bright-light therapy. SAD is measurably present at latitudes in the Arctic region, such as northern Finland (64°00′N), where the rate of SAD is 9.5%. Cloud cover may contribute to the negative effects of SAD. There is evidence that many patients with SAD have a delay in their circadian rhythm, and that bright light treatment corrects these delays which may be responsible for the improvement in patients.The symptoms of it mimic those of dysthymia or even major depressive disorder. There is also potential risk of suicide in some patients experiencing SAD. One study reports 6–35% of people with the condition required hospitalization during one period of illness. At times, patients may not feel depressed, but rather lack energy to perform everyday activities.Subsyndromal Seasonal Affective Disorder is a milder form of SAD experienced by an estimated 14.3% (vs. 6.1% SAD) of the U.S. population. The blue feeling experienced by both those with SAD and with SSAD can usually be dampened or extinguished by exercise and increased outdoor activity, particularly on sunny days, resulting in increased solar exposure. Connections between human mood, as well as energy levels, and the seasons are well documented, even in healthy individuals.
Diagnosis
According to the American Psychiatric Association DSM-IV criteria, Seasonal Affective Disorder is not regarded as a separate disorder. It is called a "course specifier" and may be applied as an added description to the pattern of major depressive episodes in patients with major depressive disorder or patients with bipolar disorder.
The "Seasonal Pattern Specifier" must meet four criteria: depressive episodes at a particular time of the year; remissions or mania/hypomania at a characteristic time of year; these patterns must have lasted two years with no nonseasonal major depressive episodes during that same period; and these seasonal depressive episodes outnumber other depressive episodes throughout the patients lifetime. The Mayo Clinic describes three types of SAD, each with its own set of symptoms.
Management
Treatments for classic (winter-based) seasonal affective disorder include light therapy, medication, ionized-air administration, cognitive-behavioral therapy, and carefully timed supplementation of the hormone melatonin.
Light therapy
Photoperiod-related alterations of the duration of melatonin secretion may affect the seasonal mood cycles of SAD. This suggests that light therapy may be an effective treatment for SAD. Light therapy uses a lightbox, which emits far more lumens than a customary incandescent lamp. Bright white "full spectrum" light at 10,000 lux, blue light at a wavelength of 480 nm at 2,500 lux or green (actually cyan or blue-green) light at a wavelength of 500 nm at 350 lux are used, with the first-mentioned historically preferred.Bright light therapy is effective with the patient sitting a prescribed distance, commonly 30–60 cm, in front of the box with her/his eyes open, but not staring at the light source, for 30–60 minutes. A study published in May 2010 suggests that the blue light often used for SAD treatment should perhaps be replaced by green or white illumination. Discovering the best schedule is essential. One study has shown that up to 69% of patients find lightbox treatment inconvenient, and as many as 19% stop use because of this.Dawn simulation has also proven to be effective; in some studies, there is an 83% better response when compared to other bright light therapy. When compared in a study to negative air ionization, bright light was shown to be 57% effective vs. dawn simulation 50%. Patients using light therapy can experience improvement during the first week, but increased results are evident when continued throughout several weeks. Certain symptoms like hypersomnia, early insomnia, social withdrawal, and anxiety resolve more rapidly with light therapy than with cognitive behavioral therapy. Most studies have found it effective without use year round, but rather as a seasonal treatment lasting for several weeks, until frequent light exposure is naturally obtained.Light therapy can also consist of exposure to sunlight, either by spending more time outside or using a computer-controlled heliostat to reflect sunlight into the windows of a home or office. Although light therapy is the leading treatment for seasonal affective disorder, prolonged direct sunlight or artificial lights that dont block the ultraviolet range should be avoided, due to the threat of skin cancer.The evidence base for light therapy as a preventive treatment for seasonal affective disorder is limited. The decision to use light therapy to treat people with a history of winter depression before depressive symptoms begin should be based on a persons preference of treatment.
Medication
SSRI (selective serotonin reuptake inhibitor) antidepressants have proven effective in treating SAD. Effective antidepressants are fluoxetine, sertraline, or paroxetine. Both fluoxetine and light therapy are 67% effective in treating SAD, according to direct head-to-head trials conducted during the 2006 Can-SAD study. Subjects using the light therapy protocol showed earlier clinical improvement, generally within one week of beginning the clinical treatment. Bupropion extended-release has been shown to prevent SAD for one in four people, but has not been compared directly to other preventive options in trials. In a 2021 updated Cochrane review of second-generation antidepressant medications for the treatment of SAD, a definitive conclusion could not be drawn, due to lack of evidence, and the need for larger randomized controlled trials.Modafinil may be an effective and well-tolerated treatment in patients with seasonal affective disorder/winter depression.Another explanation is that vitamin D levels are too low when people do not get enough Ultraviolet-B on their skin. An alternative to using bright lights is to take vitamin D supplements. However, studies did not show a link between vitamin D levels and depressive symptoms in elderly Chinese, nor among elderly British women given only 800IU when 6,000IU is needed. 5-HTP (an amino acid that helps to produce serotonin, and is often used to help those with depression) has also been suggested as a supplement that may help treat the symptoms of SAD, by lifting mood, and regulating sleep schedule for those with the condition. However, those who take antidepressants are not advised to take 5-HTP, as antidepressant medications may combine with the supplement to create dangerously high levels of serotonin – potentially resulting in serotonin syndrome.
Other treatments
Depending upon the patient, one treatment (e.g., lightbox) may be used in conjunction with another (e.g., medication).Negative air ionization, which involves releasing charged particles into the sleep environment, has been found effective, with a 47.9% improvement if the negative ions are in sufficient density (quantity).Physical exercise has shown to be an effective form of depression therapy, particularly when in addition to another form of treatment for SAD. One particular study noted marked effectiveness for treatment of depressive symptoms, when combining regular exercise with bright light therapy. Patients exposed to exercise which had been added to their treatments in 20 minutes intervals on the aerobic bike during the day, along with the same amount of time underneath the UV light were seen to make a quick recovery.Of all the psychological therapies aimed at the prevention of SAD, cognitive-behaviour therapy, typically involving thought records, activity schedules and a positive data log, has been the subject of the most empirical work. However, evidence for CBT or any of the psychological therapies aimed at preventing SAD remains inconclusive.
Epidemiology
Nordic countries
Winter depression is a common slump in the mood of some inhabitants of most of the Nordic countries. Iceland, however, seems to be an exception. A study of more than 2000 people there found the prevalence of seasonal affective disorder and seasonal changes in anxiety and depression to be unexpectedly low in both sexes. The studys authors suggested that propensity for SAD may differ due to some genetic factor within the Icelandic population. A study of Canadians of wholly Icelandic descent also showed low levels of SAD. It has more recently been suggested that this may be attributed to the large amount of fish traditionally eaten by Icelandic people. In 2007, about 90 kilograms of fish per person was consumed per year in Iceland, as opposed to about 24 kilograms in the US and Canada, rather than to genetic predisposition; a similar anomaly is noted in Japan, where annual fish consumption in recent years averages about 60 kilograms per capita. Fish are high in vitamin D. Fish also contain docosahexaenoic acid (DHA), which help with a variety of neurological dysfunctions.
Other countries
In the United States, a diagnosis of seasonal affective disorder was first proposed by Norman E. Rosenthal, M.D. in 1984. Rosenthal wondered why he became sluggish during the winter after moving from sunny South Africa to (cloudy in winter) New York. He started experimenting increasing exposure to artificial light, and found this made a difference. In Alaska it has been established that there is a SAD rate of 8.9%, and an even greater rate of 24.9% for subsyndromal SAD.
Around 20% of Irish people are affected by SAD, according to a survey conducted in 2007. The survey also shows women are more likely to be affected by SAD than men. An estimated 3% of the population in the Netherlands experience winter SAD.
See also
Diurnal Cycle
Seasonal effects on suicide rates
Seasonal Pattern Assessment Questionnaire
Vitamin D deficiency
References
External links
Seasonal Affective Disorder at Curlie
USA National Institute of Mental Health webpages https://www.nimh.nih.gov/health/topics/seasonal-affective-disorder/index.shtml |
Seborrhoeic dermatitis | Seborrhoeic dermatitis, sometimes inaccurately referred to as seborrhoea, is a long-term skin disorder. Symptoms include red, scaly, greasy, itchy, and inflamed skin. Areas of the skin rich in oil-producing glands are often affected including the scalp, face, and chest. It can result in social or self-esteem problems. In babies, when the scalp is primarily involved, it is called cradle cap. Dandruff is a milder form of the condition without inflammation.The cause is unclear but believed to involve a number of genetic and environmental factors. Risk factors include poor immune function, Parkinsons disease, and alcoholic pancreatitis. The condition may worsen with stress or during the winter. The Malassezia yeast is believed to play a role. It is not a result of poor hygiene. Diagnosis is typically based on the symptoms. The condition is not contagious.The typical treatment is antifungal cream and anti-inflammatory agents. Specifically, ketoconazole or ciclopirox are effective. It is unclear if other antifungals, such as miconazole, are equally effective as they have been poorly studied. Other options may include salicylic acid, coal tar, benzoyl peroxide, and phototherapy.The condition is most common in infants within the first 3 months or in adults aged 30 to 70 years. In adults between 1% and 10% of people are affected. Males are more often affected than females. Up to 70% of babies may be affected at some point in time.
Signs and symptoms
Seborrhoeic dermatitis symptoms appear gradually, and usually the first signs are flaky skin and scalp. Symptoms occur most commonly anywhere on the skin of the scalp, behind the ears, on the face, and in areas where the skin folds. Flakes may be yellow, white or grayish. Redness and flaking may also occur on the skin near the eyelashes, on the forehead, around the sides of the nose, on the chest, and on the upper back.
In more severe cases, yellowish to reddish scaly pimples appear along the hairline, behind the ears, in the ear canal, on the eyebrows, on the bridge of the nose, around the nose, on the chest, and on the upper back.Commonly, patients experience mild redness, scaly skin lesions and in some cases hair loss. Other symptoms include patchy scaling or thick crusts on the scalp, red, greasy skin covered with flaky white or yellow scales, itching, soreness and yellow or white scales that may attach to the hair shaft.Seborrhoeic dermatitis can occur in infants younger than three months and it causes a thick, oily, yellowish crust around the hairline and on the scalp. Itching is not common among infants. Frequently, a stubborn diaper rash accompanies the scalp rash.
Causes
The cause of seborrhoeic dermatitis has not been fully clarified.In addition to the presence of Malassezia, genetic, environmental, hormonal, and immune-system factors are necessary for and/or modulate the expression of seborrhoeic dermatitis. The condition may be aggravated by illness, psychological stress, fatigue, sleep deprivation, change of season, and reduced general health. In children and babies, excessive vitamin A intake or issues with Δ6-desaturase enzymes have been correlated with increased risk. Seborrhoeic dermatitis-like eruptions are also associated with vitamin B6 deficiency. Those with immunodeficiency (especially infection with HIV) and with neurological disorders such as Parkinsons disease (for which the condition is an autonomic sign) and stroke are particularly prone to it.
Climate
Low humidity and low temperature are responsible for high frequency of seborrheic dermatitis.
Fungi
The condition is thought to be due to a local inflammatory response to over-colonization by Malassezia fungi species in sebum-producing skin areas including the scalp, face, chest, back, underarms, and groin. This is based on observations of high counts of Malassezia species in skin affected by seborrhoeic dermatitis and on the effectiveness of antifungals in treating the condition. Such species of Malassezia include M. furfur (formerly Pityrosporum ovale), M. globosa, M. restricta, M. sympodialis, and M. slooffiae. Although Malassezia appears to be the central predisposing factor in seborrhoeic dermatitis, it is thought that other factors are necessary for the presence of Malassezia to result in the pathology characteristic of the condition. This is based on the fact that summer growth of Malassezia in the skin alone does not result in seborrhoeic dermatitis. Besides antifungals, the effectiveness of anti-inflammatory drugs, which reduce inflammation, and antiandrogens, which reduce sebum production, provide further insights into the pathophysiology of seborrhoeic dermatitis. Eunuchs, owing to their low androgen levels and small sebaceous glands, do not develop seborrheic dermatitis.
Management
Humidity
A humidifier can be used to prevent low indoor humidity during winter (especially with indoor heating), and dry season. And a dehumidifier can be used during seasons with excessive humidity.
Medications
A variety of different types of medications are able to reduce symptoms of seborrhoeic dermatitis. These include certain antifungals, anti-inflammatory agents like corticosteroids and nonsteroidal anti-inflammatory drugs, antiandrogens, and antihistamines, among others.
Antifungals
Regular use of an over-the-counter or prescription antifungal shampoo or cream may help those with recurrent episodes. The topical antifungal medications ketoconazole and ciclopirox have the best evidence. It is unclear if other antifungals are equally effective as this has not been sufficiently studied. Antifungals that have been studied and found to be effective in the treatment of seborrhoeic dermatitis include ketoconazole, fluconazole, miconazole, bifonazole, sertaconazole, clotrimazole, flutrimazole, ciclopirox, terbinafine, butenafine, selenium sulfide, and lithium salts such as lithium gluconate and lithium succinate. Topical climbazole appears to have little effectiveness in the treatment of seborrhoeic dermatitis. Systemic therapy with oral antifungals including itraconazole, fluconazole, ketoconazole, and terbinafine is effective.
Anti-inflammatory treatments
Topical corticosteroids have been shown to be effective in short-term treatment of seborrhoeic dermatitis and are as effective or more effective than antifungal treatment with azoles. There is also evidence for the effectiveness of calcineurin inhibitors like tacrolimus and pimecrolimus as well as lithium salt therapy.Oral immunosuppressive treatment, such as with prednisone, has been used in short courses as a last resort in seborrhoeic dermatitis due to its potential side effects.
Antiandrogens
Seborrhoea, which is sometimes associated with seborrhoeic dermatitis, is recognized as an androgen-sensitive condition – that is, it is caused or aggravated by androgen sex hormones such as testosterone and dihydrotestosterone – and is a common symptom of hyperandrogenism (e.g., that seen in polycystic ovary syndrome). In addition, seborrhoea, as well as acne, are commonly associated with puberty due to the steep increase of androgen levels at that time.In accordance with the involvement of androgens in seborrhoea, antiandrogens, such as cyproterone acetate, spironolactone, flutamide, and nilutamide, are highly effective in alleviating the condition. As such, they are used in the treatment of seborrhoea, particularly severe cases. While beneficial in seborrhoea, effectiveness may vary with different antiandrogens; for instance, spironolactone (which is regarded as a relatively weak antiandrogen) has been found to produce a 50% improvement after three months of treatment, whereas flutamide has been found to result in an 80% improvement within three months. Cyproterone acetate, similarly more potent and effective than spironolactone, results in considerable improvement or disappearance of acne and seborrhoea in 90% of patients within three months.Systemic antiandrogen therapy is generally used to treat seborrhoea only in women, not in men, as these medications can result in feminization (e.g., gynecomastia), sexual dysfunction, and infertility in males. In addition, antiandrogens theoretically have the potential to feminize male fetuses in pregnant women and, for this reason, are usually combined with effective birth control in sexually active women who can or may become pregnant.
Antihistamines
Antihistamines are used primarily to reduce itching, if present. However, research studies suggest that some antihistamines have anti-inflammatory properties.
Other treatments
Coal tar can be effective. Although no significant increased risk of cancer in human treatment with coal tar shampoos has been found, caution is advised since coal tar is carcinogenic in animals, and heavy human occupational exposures do increase cancer risks.
Isotretinoin, a sebosuppressive agent, may be used to reduce sebaceous gland activity as a last resort in refractory disease. However, isotretinoin has potentially serious side effects, and few patients with seborrhoeic dermatitis are appropriate candidates for therapy.
Keratolytics like topical urea
Metronidazole
Topical 4% nicotinamide
Phototherapy
Another potential option is natural and artificial UV radiation since it can curb the growth of Malassezia yeast. Some recommend photodynamic therapy using UV-A and UV-B laser or red and blue LED light to inhibit the growth of Malassezia fungus and reduce seborrhoeic inflammation.
Epidemiology
Seborrhoeic dermatitis affects 1 to 5% of the general population. It is slightly more common in men, but affected women tend to have more severe symptoms. The condition usually recurs throughout a persons lifetime. Seborrhoeic dermatitis can occur in any age group but usually starts at puberty and peaks in incidence at around 40 years of age. It can reportedly affect as many as 31% of older people. Severity is worse in dry climates. Seborrhoeic dermatitis is common in this with alcoholism, between 7 and 11 percent, which is twice the normal expected occurrence.
See also
Seborrheic keratosis
Eczema herpeticum, condition that primarily manifests in childhood
References
External links
American Academy of Dermatology: Seborrheic dermatitis |
Seborrheic keratosis | A seborrheic keratosis is a non-cancerous (benign) skin tumour that originates from cells in the outer layer of the skin. Like liver spots, seborrheic keratoses are seen more often as people age.The tumours (also called lesions) appear in various colours, from light tan to black. They are round or oval, feel flat or slightly elevated, like the scab from a healing wound, and range in size from very small to more than 2.5 centimetres (1 in) across. They can often come in association with other skin conditions, including basal cell carcinoma. Rarely seborrheic keratosis and basal cell carcinoma occur at the same location. At clinical examination the differential diagnosis includes warts and melanoma. Because only the top layers of the epidermis are involved, seborrheic keratoses are often described as having a "pasted on" appearance. Some dermatologists refer to seborrheic keratoses as "seborrheic warts", because they resemble warts, but strictly speaking the term "warts" refers to lesions that are caused by human papillomavirus.
Cause
The cause of seborrheic keratosis is not known. The only definitive association is that its prevalence increases with age.
Diagnosis
Visual diagnosis is made by the "stuck on" appearance, horny pearls or cysts embedded in the structure. Darkly pigmented lesions can be challenging to distinguish from nodular melanomas. Furthermore, thin seborrheic keratoses on facial skin can be very difficult to differentiate from lentigo maligna even with dermatoscopy. Clinically, epidermal nevi are similar to seborrheic keratoses in appearance. Epidermal nevi are usually present at or near birth. Condylomas and warts can clinically resemble seborrheic keratoses, and dermatoscopy can be helpful. On the penis and genital skin, condylomas and seborrheic keratoses can be difficult to differentiate, even on biopsy.A study examining over 4,000 biopsied skin lesions identified as seborrheic keratoses showed 3.1% were malignancies. Two thirds of those were squamous cell carcinoma. To date, the gold standard in the diagnosis of seborrheic keratosis is represented by the histolopathologic analysis of a skin biopsy.
Subtypes
Seborrheic keratoses may be divided into the following types:
Main differential diagnoses
Dermatosis papulosa nigra (DPN) is a condition of many small, benign skin lesions on the face, a condition generally presenting on dark-skinned individuals.: 638–9 DPN is extremely common, affecting up to 30% of Black people in the US.
Treatment
No treatment of seborrheic keratoses is necessary, except for aesthetic reasons. Generally, lesions can be treated with electrodesiccation and curettage, or cryosurgery. When correctly performed, removal of seborrheic keratoses will not cause much visible scarring.
Epidemiology
Seborrheic keratosis is the most common benign skin tumor. Incidence increases with age. There is less prevalence in people with darker skin. In large-cohort studies, 100% of the patients over age 50 had at least one seborrheic keratosis. Onset is usually in middle age, although they are common in younger patients too—found in 12% of 15-year-olds to 25-year-olds—making the term "senile keratosis" a misnomer.
See also
The sign of Leser-Trélat
Notes
References
External links
DermAtlas 185 |
Sézary disease | Sézary disease, or Sézary syndrome, is a type of cutaneous T-cell lymphoma that was first described by Albert Sézary. The affected T cells, known as Sézarys cells or Lutzner cells, have pathological quantities of mucopolysaccharides. Sézary disease is sometimes considered a late stage of mycosis fungoides with lymphadenopathy.
Signs and symptoms
Sézary disease and mycosis fungoides are cutaneous T-cell lymphomas having a primary manifestation in the skin. The diseases origin is a peripheral CD4+ T-lymphocyte, although rarer CD8+/CD4- cases have been observed. Epidermotropism (lymphocytes residing in the epidermis) by neoplastic CD4+ lymphocytes with the formation of Pautriers microabscesses is the hallmark sign of the disease. Although the condition can affect people of all ages, it is commonly diagnosed in adults over age 60. The dominant signs and symptoms of the disease are:
Generalized erythroderma– redness of the skin
Lymphadenopathy – swollen, enlarged lymph nodes
Atypical T cells – malignant lymphocytes known as "Sézary cells" seen in the peripheral blood with typical cerebriform nuclei (brain-shaped, convoluted nuclei)
Hepatosplenomegaly– enlarged liver and spleen
Palmoplantar keratoderma – thickening of the palms of the hands, and soles of the feet
Diagnosis
Those who have Sézary disease often present with skin lesions that do not heal with normal medication. A blood test generally reveals any change in the levels of lymphocytes in the blood, which is often associated with a cutaneous T-cell lymphoma. Finally, a biopsy of a skin lesion can be performed to rule out any other causes.The immunohistochemical features are very similar to those presented in mycosis fungoides except for the following differences:
More monotonous cellular infiltrates (large, clustered atypical pagetoid cells) in Sézary syndrome
Sometimes absent epidermotropism
Increased lymph node involvement with infiltrates of Sézary syndrome.
Treatment
Treatment typically includes some combination of photodynamic therapy, radiation therapy, chemotherapy, and biologic therapy.Treatments are often used in combination with phototherapy and chemotherapy, though pure chemotherapy is rarely used today. No single treatment type has revealed clear-cut benefits in comparison to others, treatment for all cases remains problematic.
Radiation therapy
A number of types of radiation therapy may be used including total skin electron therapy. While this therapy does not generally result in systemic toxic effects it can produce side effects involving the skin. It is only available at a few institutions.
Chemotherapy
Romidepsin, vorinostat and a few others are a second-line drug for cutaneous T-cell lymphoma. Mogamulizumab has been approved in Japan and the United States.
Epidemiology
In the Western population, there are around 3 cases of Sézary syndrome per 1,000,000 people. Sézary disease is more common in males with a ratio of 2:1, and the mean age of diagnosis is between 55 and 60 years of age.
See also
List of cutaneous conditions
References
External links
Sezary Syndrome lymphoma information |
Shigellosis | Shigellosis is an infection of the intestines caused by Shigella bacteria. Symptoms generally start one to two days after exposure and include diarrhea, fever, abdominal pain, and feeling the need to pass stools even when the bowels are empty. The diarrhea may be bloody. Symptoms typically last five to seven days and it may take several months before bowel habits return entirely to normal. Complications can include reactive arthritis, sepsis, seizures, and hemolytic uremic syndrome.Shigellosis is caused by four specific types of Shigella. These are typically spread by exposure to infected feces. This can occur via contaminated food, water, or hands or sexual contact. Contamination may be spread by flies or when changing diapers (nappies). Diagnosis is by stool culture.The risk of infection can be reduced by properly washing the hands. There is no vaccine. Shigellosis usually resolves without specific treatment. Rest, and sufficient fluids by mouth, are recommended. Bismuth subsalicylate may help with the symptoms; however, medications that slow the bowels such as loperamide are not recommended. In severe cases antibiotics may be used but resistance is common. Commonly used antibiotics include ciprofloxacin and azithromycin.A 2005 report by the World Health Organization estimated that shigellosis occurs in at least 80 million people and results in about 700,000 deaths a year globally. Most cases occur in the developing world. Young children are most commonly affected. Outbreaks of disease may occur in childcare settings and schools. It is also relatively common among travelers. In the United States about half a million cases occur a year.
Signs and symptoms
Signs and symptoms may range from mild abdominal discomfort to full-blown dysentery characterized by cramps, diarrhea, with slimy-consistent stools, fever, blood, pus, or mucus in stools or tenesmus. Onset time is 12 to 96 hours, and recovery takes 5 to 7 days.
Infections are associated with mucosal ulceration, rectal bleeding, and drastic dehydration. Reactive arthritis and hemolytic uremic syndrome are possible sequelae that have been reported in the aftermath of shigellosis.The most common neurological symptom includes seizures.
Cause
Bacteria
Shigellosis is caused by a bacterial infection with Shigella, a bacterium that is genetically similar to and was once classified as E. coli. There are three serogroups and one serotype of Shigella:
Shigella flexneri
Shigella boydii
Shigella dysenteriae and
Shigella sonnei (serotype)The probability of being infected by any given strain of Shigella varies around the world. For instance, S. sonnei is the most common in the United States, while S. dysenteriae and S. boydii are rare in the U.S.
Transmission
Shigella is transmitted through the fecal-oral route of individuals infected with the disease, whether or not they are exhibiting symptoms. Long-term carriers of the bacteria are rare. The bacteria can infect not just humans but other primates as well.
Mechanism
Upon ingestion, the bacteria pass through the gastrointestinal tract until they reach the small intestine. There they begin to multiply until they reach the large intestine. In the large intestine, the bacteria cause cell injury and the beginning stages of Shigellosis via two main mechanisms: direct invasion of epithelial cells in the large intestine and production of enterotoxin 1 and enterotoxin 2.Unlike other bacteria, Shigella is not destroyed by the gastric acid in the stomach. As a result, it takes only 10 to 200 cells to cause an infection. This infectious dose is several order of magnitudes smaller than that of other species of bacteria (e.g. cholera, caused by the bacterium Vibrio cholerae, has an infectious dose between 108 and 1011 cells).
Diagnosis
The diagnosis of shigellosis is made by isolating the organism from diarrheal fecal sample cultures. Shigella species are negative for motility and are generally not lactose fermenters, but S. sonnei can ferment lactose. They typically do not produce gas from carbohydrates (with the exception of certain strains of S. flexneri) and tend to be overall biochemically inert. Shigella should also be urea hydrolysis negative. When inoculated to a triple sugar iron slant, they react as follows: K/A, gas -, and H2S -. Indole reactions are mixed, positive and negative, with the exception of S. sonnei, which is always indole negative. Growth on Hektoen enteric agar produces bluish-green colonies for Shigella and bluish-green colonies with black centers for Salmonella.
Prevention
Simple precautions can be taken to prevent getting shigellosis: wash hands before handling food and thoroughly cook all food before eating. The primary prevention methods are improved sanitation and personal and food hygiene, but a low-cost and efficacious vaccine would complement these methods.Since shigellosis is spread very quickly among children, keeping infected children out of daycare for 24 hours after their symptoms have disappeared, will decrease the occurrence of shigellosis in daycares.
Vaccine
Currently, no licensed vaccine targeting Shigella exists. Several vaccine candidates for Shigella are in various stages of development including live attenuated, conjugate, ribosomal, and proteosome vaccines. Shigella has been a longstanding World Health Organization target for vaccine development, and sharp declines in age-specific diarrhea/dysentery attack rates for this pathogen indicate that natural immunity does develop following exposure; thus, vaccination to prevent the disease should be feasible. Shigellosis is resistant to many antibiotics used to treat the disease, so vaccination is an important part of the strategy to reduce morbidity and mortality.
Treatment
Treatment consists mainly of replacing fluids and salts lost because of diarrhea. Replacement by mouth is satisfactory for most people, but some may need to receive fluids intravenously. Antidiarrheal drugs (such as diphenoxylate or loperamide) may prolong the infection and should not be used.
Antibiotics
Antibiotics should only be used in severe cases or for certain populations with mild symptoms (elderly, immunocompromised, food service industry workers, child care workers). For Shigella-associated diarrhea, antibiotics shorten the length of infection, but they are usually avoided in mild cases because many Shigella strains are becoming resistant to common antibiotics. Furthermore, effective medications are often in short supply in developing countries, which carry the majority of the disease burden from Shigella. Antidiarrheal agents may worsen the sickness, and should be avoided.In most cases, the disease resolves within four to eight days without antibiotics. Severe infections may last three to six weeks. Antibiotics, such as trimethoprim-sulfamethoxazole, ciprofloxacin may be given when the person is very young or very old, when the disease is severe, or when the risk of the infection spreading to other people is high. Additionally, ampicillin (but not amoxicillin) was effective in treating this disease previously, but now the first choice of drug is pivmecillinam.
Epidemiology
Insufficient data exist, but it is estimated to have caused the death of 34,000 children under the age of five in 2013, and 40,000 deaths in people over five years of age. Shigella also causes about 580,000 cases annually among travelers and military personnel from industrialized countries.An estimated 500,000 cases of shigellosis occur annually in the United States. Infants, the elderly, and the critically ill are susceptible to the most severe symptoms of disease, but all humans are susceptible to some degree. Individuals with acquired immune deficiency syndrome (AIDS) are more frequently infected with Shigella. Shigellosis is a more common and serious condition in the developing world; fatality rates of shigellosis epidemics in developing countries can be 5–15%.Orthodox Jewish communities (OJCs) are a known risk group for shigellosis; Shigella sonnei is cyclically epidemic in these communities in Israel, with sporadic outbreaks occurring elsewhere in among these communities. "Through phylogenetic and genomic analysis, we showed that strains from outbreaks in OJCs outside of Israel are distinct from strains in the general population and relate to a single multidrug-resistant sublineage of S. sonnei that prevails in Israel. Further Bayesian phylogenetic analysis showed that this strain emerged approximately 30 years ago, demonstrating the speed at which antimicrobial drug–resistant pathogens can spread widely through geographically dispersed, but internationally connected, communities."
See also
Gastroenteritis
Shiga-like toxin
Shiga toxin
Travelers diarrhea
References
External links
CDCs Shigellosis Page
Vaccine Resource Library: Shigellosis and enterotoxigenic Escherichia coli (ETEC) |
Short bowel syndrome | Short bowel syndrome (SBS, or simply short gut) is a rare malabsorption disorder caused by a lack of functional small intestine. The primary symptom is diarrhea, which can result in dehydration, malnutrition, and weight loss. Other symptoms may include bloating, heartburn, feeling tired, lactose intolerance, and foul-smelling stool. Complications can include anemia and kidney stones.Most cases are due to the surgical removal of a large portion of the small intestine. This is most often required due to Crohns disease in adults and necrotising enterocolitis in young children. Other causes include damage to the small intestine from other means and being born with an abnormally short intestine. It usually does not develop until less than 2 m (6.6 ft) of the normally 6.1 m (20 ft) small intestine remains.Treatment may include a specific diet, medications, or surgery. The diet may include slightly salty and slightly sweet liquids, vitamin and mineral supplements, small frequent meals, and the avoidance of high fat food. Occasionally nutrients need to be given through an intravenous line, known as parenteral nutrition. Medications used may include antibiotics, antacids, loperamide, teduglutide, and growth hormone. Different types of surgery, including an intestinal transplant, may help some people.Short bowel syndrome newly occurs in about three per million people each year. There are estimated to be about 15,000 people with the condition in the United States. The prevalence in the United States is approximately 30 cases per million and in Europe it is approximately 1.4 cases per million (but the rate varies widely between countries). The prevalence of short bowel syndrome has increased by more than 2 fold in the last 40 years. It is classified as a rare disease by the European Medicines Agency. Outcomes depend on the amount of bowel remaining and whether or not the small bowel remains connected with the large bowel.
Signs and symptoms
The symptoms of short bowel syndrome can include:
Abdominal pain
Diarrhea and steatorrhea (oily, bulky stool, which can be malodorous)
Fluid depletion
Weight loss and malnutrition
FatiguePersons with short bowel syndrome may have complications caused by malabsorption of vitamins and minerals, such as deficiencies in vitamins A, D, E, K, B9 (folic acid), and B12, calcium, magnesium, iron, and zinc. These may appear as anemia, hyperkeratosis (scaling of the skin), easy bruising, muscle spasms, poor blood clotting, and bone pain.
Causes
Short bowel syndrome in adults and children is most commonly caused by surgery (intestinal resection). In those who undergo intestinal resection, approximately 15% eventually develop small bowel syndrome (75% of those due to 1 large resection and 25% due to multiple separate intestinal resections). This surgery may be done for:
Crohns disease, an inflammatory disorder of the digestive tract
Mesenteric ischemia, embolic or thrombotic events that may occur in the arteries or veins that supply or drain the intestines respectively, leading to disruption of blood supply to the intestines and ischemia.
Volvulus, a twisting of the small intestine often caused by intestinal malrotation that quickly cuts off blood supply and leads to tissue death
Tumors of the small intestine
Radiation enteropathy, radiation injury to the small intestine, due to radiation therapy for cancer
Injury or trauma to the small intestine
Necrotizing enterocolitis (premature newborn)
Bypass surgery to treat obesity
Surgery to remove diseases or damaged portion of the small intestineSome children are also born with an abnormally short small intestine, known as congenital short bowel.Surgical complications, requiring re-surgery, are a common cause of small bowel syndrome, contributing up to 50% of cases based on some estimates. These surgical complications include internal hernias, volvuli, ischemia or profound hypotension.
Pathophysiology
The length of the small intestine can vary greatly, from as short as 2.75 m (9.0 ft) to as long as 10.49 m (34.4 ft). On average it is about 6.1 m (20 ft). Due to this variation it is recommended that following surgery the amount of bowel remaining be specified rather than the amount removed.Short bowel syndrome usually develops when there is less than 2 meters (6.6 feet) of the small intestine left to absorb sufficient nutrients.The resection of specific areas of the small bowel can lead to distinct symptoms in short bowel syndrome. The resection of the ileum leads to a malabsorption of vitamin B12, bile acids and the fat soluble vitamins A, D, E and K. Loss of the distal ileum also leads to loss of inhibitory hormones; leading to gastric hypersecretion, intestinal hypermotility (decreases in the intestinal transit time) leading to secretory diarrhea and macronutrient, micronutrient, vitamin and mineral deficiencies. Loss of the ileocecal valve leads to small intestinal bacterial overgrowth(SIBO) as bacterial flora normally found in the large intestines migrate proximally and colonize the small intestines leading to further malabsorption. SIBO leads to malabsorption as the bacteria colonizing the small intestine metabolize nutrients, directly competing with the intestinal absorption of nutrients. The bacteria colonizing the small intestines in SIBO may also cause bile acid deconjugation leading to malabsorption of lipids.In a process called intestinal adaptation, physiological changes to the remaining portion of the small intestine occur to increase its absorptive capacity. These changes usually take place over 1-2 years. These changes include:
Enlargement (increased diameter) and lengthening of the villi found in the lining
Increase in the diameter of the small intestine
Slow down in peristalsis or movement of food through the small intestine (an increase in the transit time) to increase the time available for nutrient absorptionOsteoporosis is a very common comorbidity in people with short bowel syndrome who are on parenteral nutrition, with an estimated prevalence of 57-67%. The contributing factors to the osteoporosis include malnutrition, vitamin D deficiency due to malabsorption and vitamin D deficiency due to scarce sunlight exposure due to chronic disability.
Diagnosis
Definition
Intestinal failure is decreased intestinal function such that nutrients, water, and electrolytes are not sufficiently absorbed. Short bowel syndrome is when there is less than 2 m (6.6 ft) of working bowel and is the most common cause of intestinal failure.
Treatments
Symptoms of short bowel syndrome are usually addressed with medication. These include:
Anti-diarrheal medicine (e.g. loperamide, codeine)
Vitamin, mineral supplements and L-glutamine powder mixed with water
H2 blocker and proton pump inhibitors to reduce stomach acid
Lactase supplement (to improve the bloating and diarrhea associated with lactose intolerance)In 2004, the USFDA approved a therapy that reduces the frequency and volume of total parenteral nutrition (TPN), comprising: NutreStore (oral solution of glutamine) and Zorbtive (growth hormone, of recombinant DNA origin, for injection) together with a specialized oral diet. After 24 weeks of successful Phase III patient treatment trials, Teduglutide was shown to be relatively safe and effective with varying degrees of benefits and adverse effects per patient. Adequate safety evaluations prove to be difficult due to a limited sample size available for study, however. In 2012, an advisory panel to the USFDA voted unanimously to approve for treatment of SBS the agent teduglutide, a glucagon-like peptide-2 analog developed by NPS Pharmaceuticals, who intend to market the agent in the United States under the brandname Gattex. Teduglutide had been previously approved for use in Europe and is marketed under the brand Revestive by Nycomed.Surgical procedures to lengthen dilated bowel include the Bianchi procedure, where the bowel is cut in half and one end is sewn to the other, and a newer procedure called serial transverse enteroplasty (STEP), where the bowel is cut and stapled in a zigzag pattern. Heung Bae Kim, MD, and Tom Jaksic, MD, both of Childrens Hospital Boston, devised the STEP procedure in the early 2000s. The procedure lengthens the bowel of children with SBS and may allow children to avoid the need for intestinal transplantation. As of June 2009, Kim and Jaksic have performed 18 STEP procedures. The Bianchi and STEP procedures are usually performed by pediatric surgeons at quaternary hospitals who specialize in small bowel surgery.
Prognosis
After resection; having a remnant small bowel length of less than 75 cm and a remaining large bowel length of less than 57% of the original length are both associated with subsequent dependence on parenteral nutrition.There is no cure for short bowel syndrome except transplant. In newborn infants, the 4-year survival rate on parenteral nutrition is approximately 70%. In newborn infants with less than 10% of expected intestinal length, 5 year survival is approximately 20%. Some studies suggest that much of the mortality is due to a complication of the total parenteral nutrition (TPN), especially chronic liver disease. Much hope is, as of 2006, vested in Omegaven, a type of lipid TPN feed, in which recent case reports suggest the risk of liver disease is much lower.Although promising, small intestine transplant has a mixed success rate, with postoperative mortality rate of up to 30%. One-year and 4-year survival rate are 90% and 60%, respectively.
See also
Bowel-associated dermatosis–arthritis syndrome, another syndrome that can result from small-bowel bypass (or other causes)
References
External links
Short bowel syndrome at Curlie
National Digestive Diseases Information Clearinghouse - Short Bowel Syndrome Archived 2014-03-21 at the Wayback Machine |
Hypersalivation | Hypersalivation, or ptyalism, also known as sialorrhea or hypersialosis is the excessive production of saliva. It has also been defined as increased amount of saliva in the mouth, which may also be caused by decreased clearance of saliva.Hypersalivation can contribute to drooling if there is an inability to keep the mouth closed or difficulty in swallowing (dysphagia) the excess saliva, which can lead to excessive spitting.
Hypersalivation also often precedes emesis (vomiting), where it accompanies nausea (a feeling of needing to vomit).
Causes
Excessive production
Conditions that can cause saliva overproduction include:
Rabies
Pellagra (niacin or Vitamin B3 deficiency)
Gastroesophageal reflux disease, in such cases specifically called a water brash (a loosely defined lay term), and is characterized by a sour fluid or almost tasteless saliva in the mouth
Gastroparesis (main symptoms are nausea, vomiting, and reflux)
Pregnancy
Fluoride therapy
Excessive starch intake
Anxiety (common sign of separation anxiety in dogs)
Pancreatitis
Liver disease
Serotonin syndrome
Mouth ulcers
Oral infections
Sjögren syndrome (an early symptom in some patients)Medications that can cause overproduction of saliva include:
aripiprazole
clozapine
pilocarpine
ketamine
potassium chlorate
risperidone
pyridostigmineSubstances that can cause hypersalivation include:
mercury
copper
organophosphates (insecticide)
arsenic
nicotine
thallium
Decreased clearance
Causes of decreased clearance of saliva include:
Infections such as tonsillitis, retropharyngeal and peritonsillar abscesses, epiglottitis and mumps.
Problems with the jaw, e.g., fracture or dislocation
Radiation therapy
Neurologic disorders such as Amyotrophic lateral sclerosis, myasthenia gravis, Parkinsons disease, multiple system atrophy, rabies, bulbar paralysis, bilateral facial nerve palsy, and hypoglossal nerve palsy
Treatment
Hypersalivation is optimally treated by treating or avoiding the underlying cause. Mouthwash and tooth brushing may have drying effects.In the palliative care setting, anticholinergics and similar drugs that would normally reduce the production of saliva causing a dry mouth could be considered for symptom management: scopolamine, atropine, propantheline, hyoscine, amitriptyline, glycopyrrolate.As of 2008, it is unclear if medication for people who have too much saliva due to clozapine treatment is useful.
References
== External links == |
Night terror | Night terror, also called sleep terror, is a sleep disorder causing feelings of panic or dread and typically occurring during the first hours of stage 3–4 non-rapid eye movement (NREM) sleep and lasting for 1 to 10 minutes. It can last longer, especially in children. Sleep terror is classified in the category of NREM-related parasomnias in the International Classification of Sleep Disorders. There are two other categories: REM-related parasomnias and other parasomnias. Parasomnias are qualified as undesirable physical events or experiences that occur during entry into sleep, during sleep, or during arousal from sleep.Sleep terrors usually begin in childhood and usually decrease as age increases. Factors that may lead to sleep terrors are young age, sleep deprivation, medications, stress, fever, and intrinsic sleep disorders. The frequency and severity differ among individuals; the interval between episodes can be as long as weeks and as short as minutes or hours. This has created a situation in which any type of nocturnal attack or nightmare may be confused with and reported as a night terror.Night terrors tend to happen during periods of arousal from delta sleep, or slow-wave sleep. Delta sleep occurs most often during the first half of a sleep cycle, which indicates that people with more delta-sleep activity are more prone to night terrors. However, they can also occur during daytime naps. Night terrors can often be mistaken for confusional arousal.While nightmares (bad dreams during REM sleep that cause feelings of horror or fear) are relatively common during childhood, night terrors occur less frequently. The prevalence of sleep terrors in general is unknown. The number of small children who experience sleep terror episodes (distinct from sleep terror disorder, which is recurrent and causes distress or impairment) are estimated at 36.9% at 18 months of age and at 19.7% at 30 months. In adults, the prevalence is lower, at only 2.2%. Night terrors have been known since ancient times, although it was impossible to differentiate them from nightmares until rapid eye movement was studied.
Signs and symptoms
The universal feature of night terrors is inconsolability, very similar to that of a panic attack. During night terror bouts, people are usually described as "bolting upright" with their eyes wide open and a look of fear and panic on their faces. They will often yell, scream, or attempt to speak, though such speech is often incomprehensible. Furthermore, they will usually sweat, exhibit rapid breathing, and have a rapid heart rate (autonomic signs). In some cases, individuals are likely to have even more elaborate motor activity, such as a thrashing of limbs—which may include punching, swinging, or fleeing motions. There is a sense that the individuals are trying to protect themselves and/or escape from a possible threat of bodily injury. Although people may seem to be awake during a night terror, they will appear confused, be inconsolable and/or unresponsive to attempts to communicate with them, and may not recognize others familiar to them. Occasionally, when a person with a night terror is awakened, they will lash out at the one awakening them, which can be dangerous to that individual. Most people who experience this do not remember the incident the next day, although brief dream images or hallucinations may occur and be recalled. Sleepwalking is also common during night-terror bouts, as sleepwalking and night terrors are different manifestations of the same parasomnia. Both children and adults may display behaviour indicative of attempting to escape; some may thrash about or get out of bed and begin walking or running around aimlessly while inconsolable, increasing the risk of accidental injury. The risk of injury to others may be exacerbated by inadvertent provocation by nearby people, whose efforts to calm the individual may result in a physically violent response from the individual as they attempt to escape.During lab tests, subjects are known to have very high voltages of electroencephalography (EEG) delta activity, an increase in muscle tone, and a doubled or faster heart rate. Brain activities during a typical episode show theta and alpha activity when monitored with an EEG. Episodes can include tachycardia. Night terrors are also associated with intense autonomic discharge of tachypnea, flushing, diaphoresis, and mydriasis—that is, unconscious or involuntary rapid breathing, reddening of the skin, profuse sweating, and dilation of the pupils. Abrupt but calmer arousal from NREM sleep, short of a full night-terror episode, is also common.
In children with night terrors, there is no increased occurrence of psychiatric diagnoses. However, in adults with night terrors there is a close association with psychopathology and mental disorders. There may be an increased occurrence of night terrors—particularly among those with post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD). It is also likely that some personality disorders may occur in individuals with night terrors, such as dependent, schizoid, and borderline personality disorders. There have been some symptoms of depression and anxiety that have increased in individuals that have frequent night terrors. Low blood sugar is associated with both pediatric and adult night terrors. A study of adults with thalamic lesions of the brain and brainstem have been occasionally associated with night terrors. Night terrors are closely linked to sleepwalking and frontal lobe epilepsy.
Children
Night terrors typically occur in children between the ages of three and twelve years, with a peak onset in children aged three and a half years old.
An estimated 1–6% of children experience night terrors. Children of both sexes and all ethnic backgrounds are affected equally. In children younger than three and a half years old, peak frequency of night terrors is at least one episode per week. Among older children, peak frequency of night terrors is one or two episodes per month. The children will most likely have no recollection of the episode the next day. Pediatric evaluation may be sought to exclude the possibility that the night terrors are caused by seizure disorders or breathing problems. Most children will outgrow sleep terrors.
Adults
Night terrors in adults have been reported in all age ranges. Though the symptoms of night terrors in adolescents and adults are similar, the cause, prognosis and treatment are qualitatively different. These night terrors can occur each night if the individual does not eat a proper diet, get the appropriate amount or quality of sleep (e.g. sleep apnea), is enduring stressful events, or if he or she remains untreated. Adult night terrors are much less common, and often respond to treatments to rectify causes of poor quality or quantity of sleep. Night terrors are classified as a mental and behavioral disorder in the ICD. A study done about night terrors in adults showed that other psychiatric symptoms were prevalent in most patients experiencing night terrors hinting at the comorbidity of the two. There is some evidence of a link between night terrors and hypoglycemia.When a night terror happens, it is typical for a person to wake up yelling and kicking and to be able to recognize what he or she is saying. The person may even run out of the house (more common among adults) which can then lead to violent actions. It has been found that some adults who have been on a long-term intrathecal clonidine therapy show side effects of night terrors, such as feelings of terror early in the sleep cycle. This is due to the possible alteration of cervical/brain clonidine concentration. In adults, night terrors can be symptomatic of neurological disease and can be further investigated through an MRI procedure.
Causes
There is some evidence that a predisposition to night terrors and other parasomnias may be congenital. Individuals frequently report that past family members have had either episodes of sleep terrors or sleepwalking. In some studies, a ten-fold increase in the prevalence of night terrors in first-degree biological relatives has been observed—however, the exact link to inheritance is not known. Familial aggregation has been found suggesting that there is an autosomal mode of inheritance. In addition, some laboratory findings suggest that sleep deprivation and having a fever can increase the likelihood of a night terror episode occurring. Other contributing factors include nocturnal asthma, gastroesophageal reflux, central nervous system medications, and a constricted nasal passage. Special consideration must be used when the subject with narcolepsy, as there may be a link. There have been no findings that show a cultural difference between manifestations of night terrors, though it is thought that the significance and cause of night terrors differ within cultures.
Also, older children and adults provide highly detailed and descriptive images associated with their sleep terrors compared to younger children, who either cannot recall or only vaguely remember. Sleep terrors in children are also more likely to occur in males than females; in adults, the ratio between sexes is equal. A longitudinal study examined twins, both identical and fraternal, and found that a significantly higher concordance rate of night terror was found in identical twins than in fraternal.Though the symptoms of night terrors in adolescents and adults are similar, their causes, prognoses, and treatments are qualitatively different. There is some evidence that suggests that night terrors can occur if the individual does not eat a proper diet, does not get the appropriate amount or quality of sleep (e.g., because of sleep apnea), or is enduring stressful events. Adults who have experienced sexual abuse are more likely to receive a diagnosis of sleep disorders, including night terrors. Overall, though, adult night terrors are much less common and often respond best to treatments that rectify causes of poor quality or quantity of sleep.
Diagnosis
The DSM-5 diagnostic criteria for sleep terror disorder requires:
Recurrent periods where the individual abruptly but not completely wakes from sleep, usually occurring during the first third major period of sleep.
The individual experiences intense fear with a panicky scream at the beginning and symptoms of autonomic arousal, such as increased heart rate, heavy breathing, and increased perspiration. The individual cannot be soothed or comforted during the episode.
The individual is unable or almost unable to remember images of the dream (only a single visual scene for example).
The episode is completely forgotten.
The occurrence of the sleep terror episode causes clinically significant distress or impairment in the individuals functioning.
The disturbance is not due to the effects of a substance, general medical condition or medication.
Coexisting mental or medical disorders do not explain the episodes of sleep terrors.
Differential diagnosis
Night terrors are distinct from nightmares. In fact, in nightmares there are almost never vocalization or agitation, and if there are any, they are less strong in comparison to night terrors. In addition, nightmares appear ordinarily during REM sleep in contrast to night terrors, which occur in NREM sleep. Finally, individuals with nightmares can wake up completely and easily and have clear and detailed memories of their dreams.A distinction between night terrors and epileptic seizure is required. Indeed, an epileptic seizure could happen during the night but also during the day. To make the difference between both of them, an EEG can be done and if there are some anomalies on it, it would rather be an epileptic seizure.
Assessment
The assessment of sleep terrors is similar to the assessment of other parasomnias and must include:
When the episode occurs during the sleep period
Age of onset
How often these episodes occur (frequency) and how long they last for (duration)
Description of the episode, including behavior, emotions, and thoughts during and after the event
How responsive the patient is to external stimuli during the episode
How conscious or aware the patient is, when awakened from an episode
If the episode is remembered afterwards
The triggers or precipitating factors
Sleep–wake pattern and sleep environment
Daytime sleepiness
Other sleep disorders that might be present
Family history for NREM parasomnias and other sleep disorders
Medical, psychiatric, and neurological history
Medication and substance use historyAdditionally, a home video might be helpful for a proper diagnosis. A polysomnography in the sleep laboratory is recommended for ruling out other disorders, however, sleep terrors occur less frequently in the sleep laboratory than at home and a polysomnography can therefore be unsuccessful at recording the sleep terror episode.
Treatment
In most children, night terrors eventually subside and do not need to be treated. It may be helpful to reassure the child and their family that they will outgrow this disorder.The duration of one episode is mostly brief but it may last longer if parents try to wake up the child. Awakening the child may make their agitation stronger. For all these reasons, it is important to let the sleep terror episode fade away and to just be vigilant in order for them not to fall to the ground.Considering an episode could be violent, it may be advisable to secure the environment in which the child sleeps. Windows should be closed and potentially dangerous items should be removed from the bedroom, and additionally, alarms can be installed and the child placed in a downstairs bedroom.There is some evidence to suggest that night terrors can result from lack of sleep or poor sleeping habits. In these cases, it can be helpful to improve the amount and quality of sleep which the child is getting. It is also important to have a good sleep hygiene, if a child has night terrors parents could try to change their sleep hygiene. Another option could be to adapt childs naps so that they are not too long or too short. Then, excessive stress or conflicts in a childs life could also have an impact on their sleep too, so to have some strategies to cope with stress combined with psychotherapy could decrease the frequency of the episodes. A polysomnography can be recommended if the child continues to have a lot of night terror episodes.Hypnosis could be efficient. Sleepers could become less sensitive to their sleep terrors.One technique is to wake up just before the sleep terrors begin. When they appear regularly, this method can prevent their appearance.Psychotherapy or counseling might be helpful in some cases.
If all these methods are not enough, benzodiazepines (such as diazepam) or tricyclic antidepressants may be used; however, medication is only recommended in extreme cases. Widening the nasal airway by surgical removal of the adenoid was previously considered and demonstrated to be effective; nowadays, however, invasive treatments are generally avoided.
Research
A small study of paroxetine found some benefit.Another small trial found benefit with L-5-hydroxytryptophan (L-5-HTP).
See also
Ephialtes (illness)
Horror and terror
Sleep paralysis
References
External links
Night Terror Resource Center
National Library of Medicine - Medical Subject Headings: Night Terrors |
Smallpox | Smallpox was an infectious disease caused by one of two virus variants, Variola major and Variola minor. The agent of variola virus (VARV) belongs to the genus Orthopoxvirus. The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) certified the global eradication of the disease in 1980, making it the only human disease to be eradicated.The initial symptoms of the disease included fever and vomiting. This was followed by formation of ulcers in the mouth and a skin rash. Over a number of days, the skin rash turned into the characteristic fluid-filled blisters with a dent in the center. The bumps then scabbed over and fell off, leaving scars. The disease was spread between people or via contaminated objects. Prevention was achieved mainly through the smallpox vaccine. Once the disease had developed, certain antiviral medication may have helped. The risk of death was about 30%, with higher rates among babies. Often, those who survived had extensive scarring of their skin, and some were left blind.The earliest evidence of the disease dates to around 1500 BCE in Egyptian mummies. The disease historically occurred in outbreaks. In 18th-century Europe, it is estimated that 400,000 people died from the disease per year, and that one-third of all cases of blindness were due to smallpox. Smallpox is estimated to have killed up to 300 million people in the 20th century and around 500 million people in the last 100 years of its existence. Earlier deaths included six European monarchs. As recently as 1967, 15 million cases occurred a year.Inoculation for smallpox appears to have started in China around the 1500s. Europe adopted this practice from Asia in the first half of the 18th century. In 1796, Edward Jenner introduced the modern smallpox vaccine. In 1967, the WHO intensified efforts to eliminate the disease. Smallpox is one of two infectious diseases to have been eradicated, the other being rinderpest in 2011. The term "smallpox" was first used in Britain in the early 16th century to distinguish the disease from syphilis, which was then known as the "great pox". Other historical names for the disease include pox, speckled monster, and red plague.
Classification
There are two forms of the smallpox virus. Variola major is the severe and most common form, with a more extensive rash and higher fever. Variola minor is a less common presentation, causing less severe disease, typically discrete smallpox, with historical death rates of 1% or less. Subclinical (asymptomatic) infections with Variola virus were noted but were not common. In addition, a form called variola sine eruptione (smallpox without rash) was seen generally in vaccinated persons. This form was marked by a fever that occurred after the usual incubation period and could be confirmed only by antibody studies or, rarely, by viral culture. In addition, there were two very rare and fulminating types of smallpox, the malignant (flat) and hemorrhagic forms, which were usually fatal.
Signs and symptoms
The initial symptoms were similar to other viral diseases that are still extant, such as influenza and the common cold: fever of at least 38.3 °C (101 °F), muscle pain, malaise, headache and fatigue. As the digestive tract was commonly involved, nausea, vomiting, and backache often occurred. The early prodromal stage usually lasted 2–4 days. By days 12–15, the first visible lesions – small reddish spots called enanthem – appeared on mucous membranes of the mouth, tongue, palate, and throat, and the temperature fell to near-normal. These lesions rapidly enlarged and ruptured, releasing large amounts of virus into the saliva.Smallpox virus tended to attack skin cells, causing the characteristic pimples, or macules, associated with the disease. A rash developed on the skin 24 to 48 hours after lesions on the mucous membranes appeared. Typically the macules first appeared on the forehead, then rapidly spread to the whole face, proximal portions of extremities, the trunk, and lastly to distal portions of extremities. The process took no more than 24 to 36 hours, after which no new lesions appeared. At this point, variola major infection could take several very different courses, which resulted in four types of smallpox disease based on the Rao classification: ordinary, modified, malignant (or flat), and hemorrhagic smallpox. Historically, ordinary smallpox had an overall fatality rate of about 30%, and the malignant and hemorrhagic forms were usually fatal. The modified form was almost never fatal. In early hemorrhagic cases, hemorrhages occurred before any skin lesions developed. The incubation period between contraction and the first obvious symptoms of the disease was around 12 days.
Ordinary
Ninety percent or more of smallpox cases among unvaccinated persons were of the ordinary type. In this form of the disease, by the second day of the rash the macules had become raised papules. By the third or fourth day, the papules had filled with an opalescent fluid to become vesicles. This fluid became opaque and turbid within 24–48 hours, resulting in pustules.
By the sixth or seventh day, all the skin lesions had become pustules. Between seven and ten days the pustules had matured and reached their maximum size. The pustules were sharply raised, typically round, tense, and firm to the touch. The pustules were deeply embedded in the dermis, giving them the feel of a small bead in the skin. Fluid slowly leaked from the pustules, and by the end of the second week, the pustules had deflated and began to dry up, forming crusts or scabs. By day 16–20 scabs had formed over all of the lesions, which had started to flake off, leaving depigmented scars.Ordinary smallpox generally produced a discrete rash, in which the pustules stood out on the skin separately. The distribution of the rash was most dense on the face, denser on the extremities than on the trunk, and denser on the distal parts of the extremities than on the proximal. The palms of the hands and soles of the feet were involved in most cases. Sometimes, the blisters merged into sheets, forming a confluent rash, which began to detach the outer layers of skin from the underlying flesh. Patients with confluent smallpox often remained ill even after scabs had formed over all the lesions. In one case series, the case-fatality rate in confluent smallpox was 62 percent.
Modified
Referring to the character of the eruption and the rapidity of its development, modified smallpox occurred mostly in previously vaccinated people. It was rare in unvaccinated people, with one case study showing 1–2% of modified cases compared to around 25% in vaccinated people. In this form, the prodromal illness still occurred but may have been less severe than in the ordinary type. There was usually no fever during the evolution of the rash. The skin lesions tended to be fewer and evolved more quickly, were more superficial, and may not have shown the uniform characteristic of more typical smallpox. Modified smallpox was rarely, if ever, fatal. This form of variola major was more easily confused with chickenpox.
Malignant
In malignant-type smallpox (also called flat smallpox) the lesions remained almost flush with the skin at the time when raised vesicles would have formed in the ordinary type. It is unknown why some people developed this type. Historically, it accounted for 5–10 percent of cases, and most (72 percent) were children. Malignant smallpox was accompanied by a severe prodromal phase that lasted 3–4 days, prolonged high fever, and severe symptoms of viremia. The prodromal symptoms continued even after the onset of the rash. The rash on the mucous membranes (enanthem) was extensive. Skin lesions matured slowly, were typically confluent or semi-confluent, and by the seventh or eighth day, they were flat and appeared to be buried in the skin. Unlike ordinary-type smallpox, the vesicles contained little fluid, were soft and velvety to the touch, and may have contained hemorrhages. Malignant smallpox was nearly always fatal and death usually occurred between the 8th and 12th day of illness. Often, a day or two before death, the lesions turned ashen gray, which, along with abdominal distension, was a bad prognostic sign. This form is thought to be caused by deficient cell-mediated immunity to smallpox. If the person recovered, the lesions gradually faded and did not form scars or scabs.
Hemorrhagic
Hemorrhagic smallpox is a severe form accompanied by extensive bleeding into the skin, mucous membranes, gastrointestinal tract, and viscera. This form develops in approximately two percent of infections and occurs mostly in adults. Pustules do not typically form in hemorrhagic smallpox. Instead, bleeding occurs under the skin, making it look charred and black, hence this form of the disease is also referred to as variola nigra or "black pox". Hemorrhagic smallpox has very rarely been caused by Variola minor. While bleeding may occur in mild cases and not affect outcomes, hemorrhagic smallpox is typically fatal. Vaccination does not appear to provide any immunity to either form of hemorrhagic smallpox and some cases even occurred among people that were revaccinated shortly before. It has two forms.
Early
The early or fulminant form of hemorrhagic smallpox (referred to as purpura variolosa) begins with a prodromal phase characterized by a high fever, severe headache, and abdominal pain. The skin becomes dusky and erythematous, and this is rapidly followed by the development of petechiae and bleeding in the skin, conjunctiva and mucous membranes. Death often occurs suddenly between the fifth and seventh days of illness, when only a few insignificant skin lesions are present. Some people survive a few days longer, during which time the skin detaches and fluid accumulates under it, rupturing at the slightest injury. People are usually conscious until death or shortly before. Autopsy reveals petechiae and bleeding in the spleen, kidney, serous membranes, skeletal muscles, pericardium, liver, gonads and bladder. Historically, this condition was frequently misdiagnosed, with the correct diagnosis made only at autopsy. This form is more likely to occur in pregnant women than in the general population (approximately 16% of cases in unvaccinated pregnant women were early hemorrhagic smallpox, versus roughly 1% in nonpregnant women and adult males). The case fatality rate of early hemorrhagic smallpox approaches 100%.
Late
There is also a later form of hemorrhagic smallpox (referred to late hemorrhagic smallpox, or variolosa pustula hemorrhagica). The prodrome is severe and similar to that observed in early hemorrhagic smallpox, and the fever persists throughout the course of the disease. Bleeding appears in the early eruptive period (but later than that seen in purpura variolosa), and the rash is often flat and does not progress beyond the vesicular stage. Hemorrhages in the mucous membranes appear to occur less often than in the early hemorrhagic form. Sometimes the rash forms pustules which bleed at the base and then undergo the same process as in ordinary smallpox. This form of the disease is characterized by a decrease in all of the elements of the coagulation cascade and an increase in circulating antithrombin. This form of smallpox occurs anywhere from three to 25 percent of fatal cases, depending on the virulence of the smallpox strain. Most people with the late-stage form die within eight to 10 days of illness. Among the few who recover, the hemorrhagic lesions gradually disappear after a long period of convalescence. The case fatality rate for late hemorrhagic smallpox is around 90-95%. Pregnant women are slightly more likely to experience this form of the disease, though not as much as early hemorrhagic smallpox.
Cause
Smallpox was caused by infection with Variola virus, which belongs to the family Poxviridae, subfamily Chordopoxvirinae, and genus Orthopoxvirus.
Evolution
The date of the appearance of smallpox is not settled. It most probably evolved from a terrestrial African rodent virus between 68,000 and 16,000 years ago. The wide range of dates is due to the different records used to calibrate the molecular clock. One clade was the Variola major strains (the more clinically severe form of smallpox) which spread from Asia between 400 and 1,600 years ago. A second clade included both Alastrim minor (a phenotypically mild smallpox) described from the American continents and isolates from West Africa which diverged from an ancestral strain between 1,400 and 6,300 years before present. This clade further diverged into two subclades at least 800 years ago.A second estimate has placed the separation of variola from Taterapox (an Orthopoxvirus of some African rodents including gerbils) at 3,000 to 4,000 years ago. This is consistent with archaeological and historical evidence regarding the appearance of smallpox as a human disease which suggests a relatively recent origin. If the mutation rate is assumed to be similar to that of the herpesviruses, the divergence date of variola from Taterapox has been estimated to be 50,000 years ago. While this is consistent with the other published estimates, it suggests that the archaeological and historical evidence is very incomplete. Better estimates of mutation rates in these viruses are needed.
Examination of a strain that dates from c. 1650 found that this strain was basal to the other presently sequenced strains. The mutation rate of this virus is well modeled by a molecular clock. Diversification of strains only occurred in the 18th and 19th centuries.
Virology
Variola is a large brick-shaped virus measuring approximately 302 to 350 nanometers by 244 to 270 nm, with a single linear double stranded DNA genome 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end. The two classic varieties of smallpox are variola major and variola minor.
Four orthopoxviruses cause infection in humans: variola, vaccinia, cowpox, and monkeypox. Variola infects only humans in nature, although primates and other animals have been infected in an experimental setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature.The life cycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. Poxviruses are unique among human DNA viruses in that they replicate in the cytoplasm of the cell rather than in the nucleus. To replicate, poxviruses produce a variety of specialized proteins not produced by other DNA viruses, the most important of which is a viral-associated DNA-dependent RNA polymerase.
Both enveloped and unenveloped virions are infectious. The viral envelope is made of modified Golgi membranes containing viral-specific polypeptides, including hemagglutinin. Infection with either variola major or variola minor confers immunity against the other.
Variola Major
The more common, infectious form of the virus comes from the Variola major strain.
Variola minor
Variola minor, also called alastrim, was a less common form of the virus, and much less deadly. Although Variola minor had the same incubation period and pathogenetic stages as smallpox, it is believed to have had a mortality rate of less than 1%, as compared to smallpoxs 30%. Like Variola major, Variola minor was spread through inhalation of the virus in the air, which could occur through face-to-face contact or through fomites. Infection with Variola minor conferred immunity against the more dangerous variola major.
Because variola minor was a less debilitating disease than smallpox, patients were more frequently ambulant and thus able to infect others more rapidly. As such, Variola minor swept through the United States, Great Britain, and South Africa in the early 20th century, becoming the dominant form of the disease in those areas and thus rapidly decreasing mortality rates. Along with Variola major, the minor form has now been totally eradicated from the globe. The last case of indigenous Variola minor was reported in a Somali cook, Ali Maow Maalin, in October 1977, and smallpox was officially declared eradicated worldwide in May 1980. Variola minor was also called white pox, kaffir pox, Cuban itch, West Indian pox, milk pox, and pseudovariola.
Genome composition
The genome of Variola major is about 186,000 base pairs in length. It is made from linear double stranded DNA and contains the coding sequence for about 200 genes. The genes are usually not overlapping and typically occur in blocks that point towards the closer terminal region of the genome. The coding sequence of the central region of the genome is highly consistent across orthopoxviruses, and the arrangement of genes is consistent across chordopoxvirusesThe center of the variola genome contains the majority of the essential viral genes, including the genes for structural proteins, DNA replication, transcription, and mRNA synthesis. The ends of the genome vary more across strains and species of orthopoxviruses. These regions contain proteins that modulate the hosts immune systems, and are primarily responsible for the variability in virulence across the orthopoxvirus family. These terminal regions in poxviruses are inverted terminal repetitions (ITR) sequences. These sequences are identical but oppositely oriented on either end of the genome, leading to the genome being a continuous loop of DNA Components of the ITR sequences include an incompletely base paired A/T rich hairpin loop, a region of roughly 100 base pairs necessary for resolving concatomeric DNA (a stretch of DNA containing multiple copies of the same sequence), a few open reading frames, and short tandemly repeating sequences of varying number and length. The ITRs of poxviridae vary in length across strains and species. The coding sequence for most of the viral proteins in Variola major have at least 90% similarity with the genome of Vaccinia, a related virus used for vaccination against smallpox.
Gene expression
Gene expression of variola occurs entirely within the cytoplasm of the host cell, and follows a distinct progression during infection. After entry of an infectious virion into a host cell, synthesis of viral mRNA can be detected within 20 minutes. About half of the viral genome is transcribed prior to the replication of viral DNA. The first set of expressed genes are transcribed by pre-existing viral machinery packaged within the infecting virion. These genes encode the factors necessary for viral DNA synthesis and for transcription of the next set of expressed genes. Unlike most DNA viruses, DNA replication in variola and other poxviruses takes place within the cytoplasm of the infected cell. The exact timing of DNA replication after infection of a host cell varies across the poxviridae. Recombination of the genome occurs within actively infected cells. Following the onset of viral DNA replication, an intermediate set of genes codes for transcription factors of late gene expression. The products of the later genes include transcription factors necessary for transcribing the early genes for new virions, as well as viral RNA polymerase and other essential enzymes for new viral particles. These proteins are then packaged into new infectious virions capable of infecting other cells.
Research
Two live samples of Variola major remain, one in the United States at the CDC in Atlanta, and one at the Vector Institute in Koltsovo, Russia. Research with the remaining virus samples is tightly controlled, and each research proposal must be approved by the WHO and the World Health Assembly (WHA). Most research on poxviruses is performed using the closely related Vaccinia virus as a model organism. Vaccinia virus, which is used to vaccinate for smallpox, is also under research as a viral vector for vaccines for unrelated diseases.The genome of Variola major was first sequenced in its entirety in the 1990s. The complete coding sequence is publicly available online.The current reference sequence for Variola major was sequenced from a strain that circulated in India in 1967. In addition, there are sequences for samples of other strains that were collected during the WHO eradication campaign. A genome browser for a complete database of annotated sequences of Variola and other poxviruses is publicly available through the Viral Bioinformatics Resource Center.
Genetic engineering
The WHO currently bans genetic engineering of the smallpox virus. However, in 2004, a committee advisory to the WHO voted in favor of allowing editing of the genome of the two remaining samples of Variola major to add a marker gene. This gene, called GFP, or green fluorescent protein, would cause live samples of the virus to glow green under fluorescent light. The insertion of this gene, which would not influence the virulence of the virus, would be the only allowed modification of the genome. The committee stated the proposed modification would aid in research of treatments by making it easier to assess whether a potential treatment was effective in killing viral samples. The recommendation could only take effect if approved by the WHA. When the WHA discussed the proposal in 2005, it refrained from taking a formal vote on the proposal, stating that it would review individual research proposals one at a time. Addition of the GFP gene to the Vaccinia genome is routinely performed during research on the closely related Vaccinia virus.
Controversies
The public availability of variolas complete sequence has raised concerns about the possibility of illicit synthesis of infectious virus. Vaccinia, a cousin of the smallpox virus, was artificially synthesized in 2002 by NIH scientists. They used a previously established method that involved using a recombinant viral genome to create a self-replicating bacterial plasmid that produced viral particles.In 2016, another group synthesized the horsepox virus using publicly available sequence data for horsepox. The researchers argued that their work would be beneficial to creating a safer and more effective vaccine for smallpox, although an effective vaccine is already available. The horsepox virus had previously seemed to have gone extinct, raising concern about potential revival of Variola major and causing other scientists to question their motives. Critics found it especially concerning that the group was able to recreate viable virus in a short time frame with relatively little cost or effort. Although the WHO bans individual laboratories from synthesizing more than 20% of the genome at a time, and purchases of smallpox genome fragments are monitored and regulated, a group with malicious intentions could compile, from multiple sources, the full synthetic genome necessary to produce viable virus.
Transmission
Transmission occurred through inhalation of airborne Variola virus, usually droplets expressed from the oral, nasal, or pharyngeal mucosa of an infected person. It was transmitted from one person to another primarily through prolonged face-to-face contact with an infected person, usually, within a distance of 1.8 m (6 feet), but could also be spread through direct contact with infected bodily fluids or contaminated objects (fomites) such as bedding or clothing. Rarely, smallpox was spread by virus carried in the air in enclosed settings such as buildings, buses, and trains. The virus can cross the placenta, but the incidence of congenital smallpox was relatively low. Smallpox was not notably infectious in the prodromal period and viral shedding was usually delayed until the appearance of the rash, which was often accompanied by lesions in the mouth and pharynx. The virus can be transmitted throughout the course of the illness, but this happened most frequently during the first week of the rash when most of the skin lesions were intact. Infectivity waned in 7 to 10 days when scabs formed over the lesions, but the infected person was contagious until the last smallpox scab fell off.Smallpox was highly contagious, but generally spread more slowly and less widely than some other viral diseases, perhaps because transmission required close contact and occurred after the onset of the rash. The overall rate of infection was also affected by the short duration of the infectious stage. In temperate areas, the number of smallpox infections was highest during the winter and spring. In tropical areas, seasonal variation was less evident and the disease was present throughout the year. Age distribution of smallpox infections depended on acquired immunity. Vaccination immunity declined over time and was probably lost within thirty years. Smallpox was not known to be transmitted by insects or animals and there was no asymptomatic carrier state.
Mechanism
Once inhaled, the variola virus invaded the mucus membranes of the mouth, throat, and respiratory tract. From there, it migrated to regional lymph nodes and began to multiply. In the initial growth phase, the virus seemed to move from cell to cell, but by around the 12th day, widespread lysis of infected cells occurred and the virus could be found in the bloodstream in large numbers, a condition known as viremia. This resulted in the second wave of multiplication in the spleen, bone marrow, and lymph nodes.
Diagnosis
The clinical definition of ordinary smallpox is an illness with acute onset of fever equal to or greater than 38.3 °C (101 °F) followed by a rash characterized by firm, deep-seated vesicles or pustules in the same stage of development without other apparent cause. When a clinical case was observed, smallpox was confirmed using laboratory tests.
Microscopically, poxviruses produce characteristic cytoplasmic inclusion bodies, the most important of which are known as Guarnieri bodies, and are the sites of viral replication. Guarnieri bodies are readily identified in skin biopsies stained with hematoxylin and eosin, and appear as pink blobs. They are found in virtually all poxvirus infections but the absence of Guarnieri bodies could not be used to rule out smallpox. The diagnosis of an orthopoxvirus infection can also be made rapidly by electron microscopic examination of pustular fluid or scabs. All orthopoxviruses exhibit identical brick-shaped virions by electron microscopy. If particles with the characteristic morphology of herpesviruses are seen this will eliminate smallpox and other orthopoxvirus infections.
Definitive laboratory identification of Variola virus involved growing the virus on chorioallantoic membrane (part of a chicken embryo) and examining the resulting pock lesions under defined temperature conditions. Strains were characterized by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Serologic tests and enzyme linked immunosorbent assays (ELISA), which measured Variola virus-specific immunoglobulin and antigen were also developed to assist in the diagnosis of infection.Chickenpox was commonly confused with smallpox in the immediate post-eradication era. Chickenpox and smallpox could be distinguished by several methods. Unlike smallpox, chickenpox does not usually affect the palms and soles. Additionally, chickenpox pustules are of varying size due to variations in the timing of pustule eruption: smallpox pustules are all very nearly the same size since the viral effect progresses more uniformly. A variety of laboratory methods were available for detecting chickenpox in the evaluation of suspected smallpox cases.
Prevention
The earliest procedure used to prevent smallpox was inoculation with variola minor (known as variolation after the introduction of smallpox vaccine to avoid possible confusion), which likely occurred in India, Africa, and China well before the practice arrived in Europe. The idea that inoculation originated in India has been challenged, as few of the ancient Sanskrit medical texts described the process of inoculation. Accounts of inoculation against smallpox in China can be found as early as the late 10th century, and the procedure was widely practiced by the 16th century, during the Ming dynasty. If successful, inoculation produced lasting immunity to smallpox. Because the person was infected with Variola virus |
Smallpox | , a severe infection could result, and the person could transmit smallpox to others. Variolation had a 0.5–2 percent mortality rate, considerably less than the 20–30 percent mortality rate of the disease. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers.Lady Mary Wortley Montagu observed smallpox inoculation during her stay in the Ottoman Empire, writing detailed accounts of the practice in her letters, and enthusiastically promoted the procedure in England upon her return in 1718. According to Voltaire (1742), the Turks derived their use of inoculation from neighbouring Circassia. Voltaire does not speculate on where the Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years". In 1721, Cotton Mather and colleagues provoked controversy in Boston by inoculating hundreds. After publishing The present method of inoculating for the small-pox in 1767, Dr Thomas Dimsdale was invited to Russia to variolate the Empress Catherine the Great of Russia and her son, Grand Duke Paul, which he successfully did in 1768. In 1796, Edward Jenner, a doctor in Berkeley, Gloucestershire, rural England, discovered that immunity to smallpox could be produced by inoculating a person with material from a cowpox lesion. Cowpox is a poxvirus in the same family as variola. Jenner called the material used for inoculation vaccine from the root word vacca, which is Latin for cow. The procedure was much safer than variolation and did not involve a risk of smallpox transmission. Vaccination to prevent smallpox was soon practiced all over the world. During the 19th century, the cowpox virus used for smallpox vaccination was replaced by the vaccinia virus. Vaccinia is in the same family as cowpox and variola but is genetically distinct from both. The origin of the vaccinia virus and how it came to be in the vaccine are not known.
The current formulation of the smallpox vaccine is a live virus preparation of the infectious vaccinia virus. The vaccine is given using a bifurcated (two-pronged) needle that is dipped into the vaccine solution. The needle is used to prick the skin (usually the upper arm) several times in a few seconds. If successful, a red and itchy bump develops at the vaccine site in three or four days. In the first week, the bump becomes a large blister (called a "Jennerian vesicle") which fills with pus and begins to drain. During the second week, the blister begins to dry up, and a scab forms. The scab falls off in the third week, leaving a small scar.The antibodies induced by the vaccinia vaccine are cross-protective for other orthopoxviruses, such as monkeypox, cowpox, and variola (smallpox) viruses. Neutralizing antibodies are detectable 10 days after first-time vaccination and seven days after revaccination. Historically, the vaccine has been effective in preventing smallpox infection in 95 percent of those vaccinated. Smallpox vaccination provides a high level of immunity for three to five years and decreasing immunity thereafter. If a person is vaccinated again later, the immunity lasts even longer. Studies of smallpox cases in Europe in the 1950s and 1960s demonstrated that the fatality rate among persons vaccinated less than 10 years before exposure was 1.3 percent; it was 7 percent among those vaccinated 11 to 20 years prior, and 11 percent among those vaccinated 20 or more years before infection. By contrast, 52 percent of unvaccinated persons died.
There are side effects and risks associated with the smallpox vaccine. In the past, about 1 out of 1,000 people vaccinated for the first time experienced serious, but non-life-threatening, reactions, including toxic or allergic reaction at the site of the vaccination (erythema multiforme), spread of the vaccinia virus to other parts of the body, and spread to other individuals. Potentially life-threatening reactions occurred in 14 to 500 people out of every 1 million people vaccinated for the first time. Based on past experience, it is estimated that 1 or 2 people in 1 million (0.000198 percent) who receive the vaccine may die as a result, most often the result of postvaccinial encephalitis or severe necrosis in the area of vaccination (called progressive vaccinia).Given these risks, as smallpox became effectively eradicated and the number of naturally occurring cases fell below the number of vaccine-induced illnesses and deaths, routine childhood vaccination was discontinued in the United States in 1972 and was abandoned in most European countries in the early 1970s. Routine vaccination of health care workers was discontinued in the U.S. in 1976, and among military recruits in 1990 (although military personnel deploying to the Middle East and Korea still receive the vaccination). By 1986, routine vaccination had ceased in all countries. It is now primarily recommended for laboratory workers at risk for occupational exposure. However, the possibility of smallpox virus being used as a biological weapon has rekindled interest in the development of newer vaccines. The smallpox vaccine is also used to protect against monkeypox, of which the smallpox vaccine also protects against.
Treatment
Smallpox vaccination within three days of exposure will prevent or significantly lessen the severity of smallpox symptoms in the vast majority of people. Vaccination four to seven days after exposure can offer some protection from disease or may modify the severity of the disease. Other than vaccination, treatment of smallpox is primarily supportive, such as wound care and infection control, fluid therapy, and possible ventilator assistance. Flat and hemorrhagic types of smallpox are treated with the same therapies used to treat shock, such as fluid resuscitation. People with semi-confluent and confluent types of smallpox may have therapeutic issues similar to patients with extensive skin burns.In July 2018, the Food and Drug Administration approved tecovirimat, the first drug approved for treatment of smallpox. Antiviral treatments have improved since the last large smallpox epidemics, and studies suggest that the antiviral drug cidofovir might be useful as a therapeutic agent. The drug must be administered intravenously, and may cause serious kidney toxicity.ACAM2000 is a smallpox vaccine developed by Acambis. It was approved for use in the United States by the U.S. FDA on August 31, 2007. It contains live vaccinia virus, cloned from the same strain used in an earlier vaccine, Dryvax. While the Dryvax virus was cultured in the skin of calves and freeze-dried, ACAM2000s virus is cultured in kidney epithelial cells (Vero cells) from an African green monkey. Efficacy and adverse reaction incidence are similar to Dryvax. The vaccine is not routinely available to the US public; it is, however, used in the military and maintained in the Strategic National Stockpile.In June 2021, brincidofovir was approved for medical use in the United States for the treatment of human smallpox disease caused by variola virus.
Prognosis
The mortality rate from variola minor is approximately 1%, while the mortality rate from variola major is approximately 30%.Ordinary type-confluent is fatal about 50–75% of the time, ordinary-type semi-confluent about 25–50% of the time, in cases where the rash is discrete the case-fatality rate is less than 10%. The overall fatality rate for children younger than 1 year of age is 40–50%. Hemorrhagic and flat types have the highest fatality rates. The fatality rate for flat or late hemorrhagic type smallpox is 90% or greater and nearly 100% is observed in cases of early hemorrhagic smallpox. The case-fatality rate for variola minor is 1% or less. There is no evidence of chronic or recurrent infection with Variola virus. In cases of flat smallpox in vaccinated people, the condition was extremely rare but less lethal, with one case series showing a 66.7% death rate.In fatal cases of ordinary smallpox, death usually occurs between days 10-16 of the illness. The cause of death from smallpox is not clear, but the infection is now known to involve multiple organs. Circulating immune complexes, overwhelming viremia, or an uncontrolled immune response may be contributing factors. In early hemorrhagic smallpox, death occurs suddenly about six days after the fever develops. The cause of death in early hemorrhagic cases is commonly due to heart failure and pulmonary edema. In late hemorrhagic cases, high and sustained viremia, severe platelet loss and poor immune response were often cited as causes of death. In flat smallpox modes of death are similar to those in burns, with loss of fluid, protein and electrolytes, and fulminating sepsis.
Complications
Complications of smallpox arise most commonly in the respiratory system and range from simple bronchitis to fatal pneumonia. Respiratory complications tend to develop on about the eighth day of the illness and can be either viral or bacterial in origin. Secondary bacterial infection of the skin is a relatively uncommon complication of smallpox. When this occurs, the fever usually remains elevated.Other complications include encephalitis (1 in 500 patients), which is more common in adults and may cause temporary disability; permanent pitted scars, most notably on the face; and complications involving the eyes (2% of all cases). Pustules can form on the eyelid, conjunctiva, and cornea, leading to complications such as conjunctivitis, keratitis, corneal ulcer, iritis, iridocyclitis, and atrophy of the optic nerve. Blindness results in approximately 35-40% of eyes affected with keratitis and corneal ulcer. Hemorrhagic smallpox can cause subconjunctival and retinal hemorrhages. In 2-5% of young children with smallpox, virions reach the joints and bone, causing osteomyelitis variolosa. Bony lesions are symmetrical, most common in the elbows, legs, and characteristically cause separation of the epiphysis and marked periosteal reactions. Swollen joints limit movement, and arthritis may lead to limb deformities, ankylosis, malformed bones, flail joints, and stubby fingers.Between 65 and 80% of survivors are marked with deep pitted scars (pockmarks), most prominent on the face.
History
Disease emergence
The earliest credible clinical evidence of smallpox is found in the descriptions of smallpox-like disease in medical writings from ancient India (as early as 1500 BCE), and China (1122 BCE), as well as a study of the Egyptian mummy of Ramses V, who died more than 3000 years ago (1145 BCE). It has been speculated that Egyptian traders brought smallpox to India during the 1st millennium BCE, where it remained as an endemic human disease for at least 2000 years. Smallpox was probably introduced into China during the 1st century CE from the southwest, and in the 6th century was carried from China to Japan. In Japan, the epidemic of 735–737 is believed to have killed as much as one-third of the population. At least seven religious deities have been specifically dedicated to smallpox, such as the god Sopona in the Yoruba religion in West Africa. In India, the Hindu goddess of smallpox, Shitala, was worshipped in temples throughout the country.A different viewpoint is that smallpox emerged 1588 CE and the earlier reported cases were incorrectly identified as smallpox.The timing of the arrival of smallpox in Europe and south-western Asia is less clear. Smallpox is not clearly described in either the Old or New Testaments of the Bible or in the literature of the Greeks or Romans. While some have identified the Plague of Athens – which was said to have originated in "Ethiopia" and Egypt – or the plague that lifted Carthages 396 BCE siege of Syracuse – with smallpox, many scholars agree it is very unlikely such a serious disease as variola major would have escaped being described by Hippocrates if it had existed in the Mediterranean region during his lifetime.While the Antonine Plague that swept through the Roman Empire in 165–180 CE may have been caused by smallpox, Saint Nicasius of Rheims became the patron saint of smallpox victims for having supposedly survived a bout in 450, and Saint Gregory of Tours recorded a similar outbreak in France and Italy in 580, the first use of the term variola. Other historians speculate that Arab armies first carried smallpox from Africa into Southwestern Europe during the 7th and 8th centuries. In the 9th century the Persian physician, Rhazes, provided one of the most definitive descriptions of smallpox and was the first to differentiate smallpox from measles and chickenpox in his Kitab fi al-jadari wa-al-hasbah (The Book of Smallpox and Measles). During the Middle Ages several smallpox outbreaks occurred in Europe. However, smallpox had not become established there until the population growth and mobility marked by the Crusades allowed it to do so. By the 16th century, smallpox had become entrenched across most of Europe, where it had a mortality rate as high as 30 percent. This endemic occurrence of smallpox in Europe is of particular historical importance, as successive exploration and colonization by Europeans tended to spread the disease to other nations. By the 16th century, smallpox had become a predominant cause of morbidity and mortality throughout much of the world.
There were no credible descriptions of smallpox-like disease in the Americas before the westward exploration by Europeans in the 15th century CE. Smallpox was introduced into the Caribbean island of Hispaniola in 1507, and into the mainland in 1520, when Spanish settlers from Hispaniola arrived in Mexico, inadvertently carrying smallpox with them. Because the native Amerindian population had no acquired immunity to this new disease, their peoples were decimated by epidemics. Such disruption and population losses were an important factor in the Spanish achieving conquest of the Aztecs and the Incas. Similarly, English settlement of the east coast of North America in 1633 in Plymouth, Massachusetts was accompanied by devastating outbreaks of smallpox among Native American populations, and subsequently among the native-born colonists. Case fatality rates during outbreaks in Native American populations were as high as 90%. Smallpox was introduced into Australia in 1789 and again in 1829, though colonial surgeons, who by 1829 were attempting to distinguish between smallpox and chickenpox (which could be almost equally fatal to Aborigines), were divided as to whether the 1829–1830 epidemic was chickenpox or smallpox. Although smallpox was never endemic on the continent, it has been described as the principal cause of death in Aboriginal populations between 1780 and 1870.
By the mid-18th century, smallpox was a major endemic disease everywhere in the world except in Australia and small islands untouched by outside exploration. In 18th century Europe, smallpox was a leading cause of death, killing an estimated 400,000 Europeans each year. Up to 10 percent of Swedish infants died of smallpox each year, and the death rate of infants in Russia might have been even higher. The widespread use of variolation in a few countries, notably Great Britain, its North American colonies, and China, somewhat reduced the impact of smallpox among the wealthy classes during the latter part of the 18th century, but a real reduction in its incidence did not occur until vaccination became a common practice toward the end of the 19th century. Improved vaccines and the practice of re-vaccination led to a substantial reduction in cases in Europe and North America, but smallpox remained almost unchecked everywhere else in the world. By the mid-20th century, variola minor occurred along with variola major, in varying proportions, in many parts of Africa. Patients with variola minor experience only a mild systemic illness, are often ambulant throughout the course of the disease, and are therefore able to more easily spread disease. Infection with v. minor induces immunity against the more deadly variola major form. Thus, as v. minor spread all over the US, into Canada, the South American countries, and Great Britain, it became the dominant form of smallpox, further reducing mortality rates.
Eradication
The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his Dòuzhěn xīnfǎ (痘疹心法) published in 1549, with earliest hints of the practice in China during the 10th century. In China, powdered smallpox scabs were blown up the noses of the healthy. People would then develop a mild case of the disease and from then on were immune to it. The technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers. Voltaire (1742) reports that the Chinese had practiced smallpox inoculation "these hundred years". Variolation had also been witnessed in Turkey by Lady Mary Wortley Montagu, who later introduced it in the UK.An early mention of the possibility of smallpoxs eradication was made in reference to the work of Johnnie Notions, a self-taught inoculator from Shetland, Scotland. Notions found success in treating people from at least the late 1780s through a method devised by himself despite having no formal medical background. His method involved exposing smallpox pus to peat smoke, burying it in the ground with camphor for up to 8 years, and then inserting the matter into a persons skin using a knife, and covering the incision with a cabbage leaf. He was reputed not to have lost a single patient. Arthur Edmondston, in writings on Notions technique that were published in 1809, stated, "Had every practitioner been as uniformly successful in the disease as he was, the small-pox might have been banished from the face of the earth, without injuring the system, or leaving any doubt as to the fact."
The English physician Edward Jenner demonstrated the effectiveness of cowpox to protect humans from smallpox in 1796, after which various attempts were made to eliminate smallpox on a regional scale. In Russia in 1796, the first child to receive this treatment was bestowed the name "Vaccinov" by Catherine the Great, and was educated at the expense of the nation.The introduction of the vaccine to the New World took place in Trinity, Newfoundland in 1800 by Dr. John Clinch, boyhood friend and medical colleague of Jenner. As early as 1803, the Spanish Crown organized the Balmis expedition to transport the vaccine to the Spanish colonies in the Americas and the Philippines, and establish mass vaccination programs there. The U.S. Congress passed the Vaccine Act of 1813 to ensure that safe smallpox vaccine would be available to the American public. By about 1817, a robust state vaccination program existed in the Dutch East Indies.On August 26, 1807, Bavaria became the first country in the world to introduce compulsory vaccinations. Baden followed in 1809, Prussia in 1815, Württemberg in 1818, Sweden in 1816 and the German Empire in 1874 through the Reichs Vaccination Act. In Lutheran Sweden, the Protestant clergy played a pioneering role in voluntary smallpox vaccination as early as 1800. The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate.In British India a program was launched to propagate smallpox vaccination, through Indian vaccinators, under the supervision of European officials. Nevertheless, British vaccination efforts in India, and in Burma in particular, were hampered by indigenous preference for inoculation and distrust of vaccination, despite tough legislation, improvements in the local efficacy of the vaccine and vaccine preservative, and education efforts. By 1832, the federal government of the United States established a smallpox vaccination program for Native Americans. In 1842, the United Kingdom banned inoculation, later progressing to mandatory vaccination. The British government introduced compulsory smallpox vaccination by an Act of Parliament in 1853.In the United States, from 1843 to 1855, first Massachusetts and then other states required smallpox vaccination. Although some disliked these measures, coordinated efforts against smallpox went on, and the disease continued to diminish in the wealthy countries. In Northern Europe a number of countries had eliminated smallpox by 1900, and by 1914, the incidence in most industrialized countries had decreased to comparatively low levels.
Vaccination continued in industrialized countries as protection against reintroduction until the mid to late 1970s. Australia and New Zealand are two notable exceptions; neither experienced endemic smallpox and never vaccinated widely, relying instead on protection by distance and strict quarantines.
The first hemisphere-wide effort to eradicate smallpox was made in 1950 by the Pan American Health Organization. The campaign was successful in eliminating smallpox from all countries of the Americas except Argentina, Brazil, Colombia, and Ecuador. In 1958 Professor Viktor Zhdanov, Deputy Minister of Health for the USSR, called on the World Health Assembly to undertake a global initiative to eradicate smallpox. The proposal (Resolution WHA11.54) was accepted in 1959. At this point, 2 million people were dying from smallpox every year. Overall, the progress towards eradication was disappointing, especially in Africa and in the Indian subcontinent. In 1966 an international team, the Smallpox Eradication Unit, was formed under the leadership of an American, Donald Henderson. In 1967, the World Health Organization intensified the global smallpox eradication by contributing $2.4 million annually to the effort, and adopted the new disease surveillance method promoted by Czech epidemiologist Karel Raška.
In the early 1950s, an estimated 50 million cases of smallpox occurred in the world each year. To eradicate smallpox, each outbreak had to be stopped from spreading, by isolation of cases and vaccination of everyone who lived close by. This process is known as "ring vaccination". The key to this strategy was the monitoring of cases in a community (known as surveillance) and containment.
The initial problem the WHO team faced was inadequate reporting of smallpox cases, as many cases did not come to the attention of the authorities. The fact that humans are the only reservoir for smallpox infection and that carriers did not exist played a significant role in the eradication of smallpox. The WHO established a network of consultants who assisted countries in setting up surveillance and containment activities. Early on, donations of vaccine were provided primarily by the Soviet Union and the United States, but by 1973, more than 80 percent of all vaccine was produced in developing countries. The Soviet Union provided one and a half billion doses between 1958 and 1979, as well as the medical staff.The last major European outbreak of smallpox was in 1972 in Yugoslavia, after a pilgrim from Kosovo returned from the Middle East, where he had contracted the virus. The epidemic infected 175 people, causing 35 deaths. Authorities declared martial law, enforced quarantine, and undertook widespread re-vaccination of the population, enlisting the help of the WHO. In two months, the outbreak was over. Prior to this, there had been a smallpox outbreak in May–July 1963 in Stockholm, Sweden, brought from the Far East by a Swedish sailor; this had been dealt with by quarantine measures and vaccination of the local population.By the end of 1975, smallpox persisted only in the Horn of Africa. Conditions were very difficult in Ethiopia and Somalia, where there were few roads. Civil war, famine, and refugees made the task even more difficult. An intensive surveillance and containment and vaccination program was undertaken in these countries in early and mid-1977, under the direction of Australian microbiologist Frank Fenner. As the campaign neared its goal, Fenner and his team played an important role in verifying eradication. The last naturally occurring case of indigenous smallpox (Variola minor) was diagnosed in Ali Maow Maalin, a hospital cook in Merca, Somalia, on 26 October 1977. The last naturally occurring case of the more deadly Variola major had been detected in October 1975 in a three-year-old Bangladeshi girl, Rahima Banu.The global eradication of smallpox was certified, based on intense verification activities, by a commission of eminent scientists on 9 December 1979 and subsequently endorsed by the World Health Assembly on 8 May 1980. The first two sentences of the resolution read:
Having considered the development and results of the global program on smallpox eradication initiated by WHO in 1958 and intensified since 1967 … Declares solemnly that the world and its peoples have won freedom from smallpox, which was a most devastating disease sweeping in epidemic form through many countries since earliest time, leaving death, blindness and disfigurement in its wake and which only a decade ago was rampant in Africa, Asia and South America.
Costs and benefits
The cost of the eradication effort, from 1967 to 1979, was roughly US$300 million. Roughly a third came from the developed world, which had largely eradicated smallpox decades earlier. The United States, the largest contributor to the program, has reportedly recouped that investment every 26 days since in money not spent on vaccinations and the costs of incidence.
Post-eradication
The last case of smallpox in the world occurred in an outbreak in the United Kingdom in 1978. A medical photographer, Janet Parker, contracted the disease at the University of Birmingham Medical School and died on 11 September 1978. Although it has remained unclear how Parker became infected, the source of the infection was established to be the smallpox virus grown for research purposes at the Medical School laboratory. All known stocks of smallpox worldwide were subsequently destroyed or transferred to two WHO-designated reference laboratories with BSL-4 facilities – the United States Centers for Disease Control and Prevention (CDC) and the Soviet Unions (now Russias) State Research Center of Virology and Biotechnology VECTOR.WHO first recommended destruction of the virus in 1986 and later set the date of destruction to be 30 December 1993. This was postponed to 30 June 1999. Due to resistance from the U.S. and Russia, in 2002 the World Health Assembly agreed to permit the temporary retention of the virus stocks for specific research purposes. Destroying existing stocks would reduce the risk involved with ongoing smallpox research; the stocks are not needed to respond to a smallpox outbreak. Some scientists have argued that the stocks may be useful in developing new vaccines, antiviral drugs, and diagnostic tests; a 2010 review by a team of public health experts appointed by WHO concluded that no essential public health purpose is served by the U.S. and Russia continuing to retain virus stocks. The latter view is frequently supported in the scientific community, particularly among veterans of the WHO Smallpox Eradication Program.On March 31, 2003, smallpox scabs were found inside an envelope in an 1888 book on Civil War medicine in Santa Fe, New Mexico. The envelope was labeled as containing scabs from a vaccination and gave scientists at the CDC an opportunity to study the history of smallpox vaccination in the United States.
On July 1, 2014, six sealed glass vials of smallpox dated |
Smallpox | 1954, along with sample vials of other pathogens, were discovered in a cold storage room in an FDA laboratory at the National Institutes of Health location in Bethesda, Maryland. The smallpox vials were subsequently transferred to the custody of the CDC in Atlanta, where virus taken from at least two vials proved viable in culture. After studies were conducted, the CDC destroyed the virus under WHO observation on February 24, 2015.In 2017, Canadian scientists recreated an extinct horse pox virus to demonstrate that the smallpox virus can be recreated in a small lab at a cost of about $100,000, by a team of scientists without specialist knowledge. This makes the retention controversy irrelevant since the virus can be easily recreated even if all samples are destroyed. Although the scientists performed the research to help development of new vaccines as well as trace smallpoxs history, the possibility of the techniques being used for nefarious purposes was immediately recognized, raising questions on dual use research and regulations.In September 2019, the Russian lab housing smallpox samples experienced a gas explosion that injured one worker. It did not occur near the virus storage area, and no samples were compromised, but the incident prompted a review of risks to containment.
Society and culture
Biological warfare
In 1763, Pontiacs War broke out as a Native American confederacy led by Pontiac attempted to counter British control over the Great Lakes region. A group of Native American warriors laid siege to British-held Fort Pitt on June 22. In response, Henry Bouquet, the commander of the fort, ordered his subordinate Simeon Ecuyer to give smallpox-infested blankets from the infirmary to a Delaware delegation outside the fort. Bouquet had discussed this with his superior, Sir Jeffrey Amherst, who wrote to Bouquet stating: "Could it not be contrived to send the small pox among the disaffected tribes of Indians? We must on this occasion use every stratagem in our power to reduce them." Bouquet agreed with the proposal, writing back that "I will try to inocculate [sic] the Indians by means of Blankets that may fall in their hands". On 24 June 1763, William Trent, a local trader and commander of the Fort Pitt militia, wrote, "Out of our regard for them, we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect." The effectiveness of this effort to broadcast the disease is unknown. There are also accounts that smallpox was used as a weapon during the American Revolutionary War (1775–1783).According to a theory put forward in Journal of Australian Studies (JAS) by independent researcher Christopher Warren, Royal Marines used smallpox in 1789 against indigenous tribes in New South Wales. This theory was also considered earlier in Bulletin of the History of Medicine and by David Day. However it is disputed by some medical academics, including Professor Jack Carmody, who in 2010 claimed that the rapid spread of the outbreak in question was more likely indicative of chickenpox—a more infectious disease which, at the time, was often confused, even by surgeons, with smallpox, and may have been comparably deadly to Aborigines and other peoples without natural immunity to it. Carmody noted that in the 8-month voyage of the First Fleet and the following 14 months there were no reports of smallpox amongst the colonists and that, since smallpox has an incubation period of 10–12 days, it is unlikely it was present in the First Fleet; however, Warren argued in the JAS article that the likely source was bottles of smallpox virus possessed by First Fleet surgeons. Ian and Jennifer Glynn, in The life and death of smallpox, confirm that bottles of "variolous matter" were carried to Australia for use as a vaccine, but think it unlikely the virus could have survived till 1789. In 2007, Christopher Warren offered evidence that the British smallpox may have been still viable. However, the only non-Aborigine reported to have died in this outbreak was a seaman called Joseph Jeffries, who was recorded as being of "American Indian" origin.W. S. Carus, an expert in biological weapons, has written that there is circumstantial evidence that smallpox was deliberately introduced to the Aboriginal population. However Carmody and the Australian National Universitys Boyd Hunter continue to support the chickenpox hypothesis. In a 2013 lecture at the Australian National University, Carmody pointed out that chickenpox, unlike smallpox, was known to be present in the Sydney Cove colony. He also suggested that all c. 18th century (and earlier) identifications of smallpox outbreaks were dubious because: "surgeons … would have been unaware of the distinction between smallpox and chickenpox – the latter having traditionally been considered a milder form of smallpox."
During World War II, scientists from the United Kingdom, United States, and Japan (Unit 731 of the Imperial Japanese Army) were involved in research into producing a biological weapon from smallpox. Plans of large scale production were never carried through as they considered that the weapon would not be very effective due to the wide-scale availability of a vaccine.In 1947, the Soviet Union established a smallpox weapons factory in the city of Zagorsk, 75 km to the northeast of Moscow. An outbreak of weaponized smallpox occurred during testing at a facility on an island in the Aral Sea in 1971. General Prof. Peter Burgasov, former Chief Sanitary Physician of the Soviet Army and a senior researcher within the Soviet program of biological weapons, described the incident:
On Vozrozhdeniya Island in the Aral Sea, the strongest recipes of smallpox were tested. Suddenly I was informed that there were mysterious cases of mortalities in Aralsk. A research ship of the Aral fleet came to within 15 km of the island (it was forbidden to come any closer than 40 km). The lab technician of this ship took samples of plankton twice a day from the top deck. The smallpox formulation – 400 gr. of which was exploded on the island – "got her" and she became infected. After returning home to Aralsk, she infected several people including children. All of them died. I suspected the reason for this and called the Chief of General Staff of the Ministry of Defense and requested to forbid the stop of the Alma-Ata–Moscow train in Aralsk. As a result, the epidemic around the country was prevented. I called Andropov, who at that time was Chief of KGB, and informed him of the exclusive recipe of smallpox obtained on Vozrazhdenie Island.
Others contend that the first patient may have contracted the disease while visiting Uyaly or Komsomolsk-on-Ustyurt, two cities where the boat docked.Responding to international pressures, in 1991 the Soviet government allowed a joint U.S.–British inspection team to tour four of its main weapons facilities at Biopreparat. The inspectors were met with evasion and denials from the Soviet scientists and were eventually ordered out of the facility. In 1992, Soviet defector Ken Alibek alleged that the Soviet bioweapons program at Zagorsk had produced a large stockpile – as much as twenty tons – of weaponized smallpox (possibly engineered to resist vaccines, Alibek further alleged), along with refrigerated warheads to deliver it. Alibeks stories about the former Soviet programs smallpox activities have never been independently verified.
In 1997, the Russian government announced that all of its remaining smallpox samples would be moved to the Vector Institute in Koltsovo. With the breakup of the Soviet Union and unemployment of many of the weapons programs scientists, U.S. government officials have expressed concern that smallpox and the expertise to weaponize it may have become available to other governments or terrorist groups who might wish to use virus as means of biological warfare. Specific allegations made against Iraq in this respect proved to be false.Concern has been expressed by some that artificial gene synthesis could be used to recreate the virus from existing digital genomes, for use in biological warfare. Insertion of the synthesized smallpox DNA into existing related pox viruses could theoretically be used to recreate the virus. The first step to mitigating this risk, it has been suggested, should be to destroy the remaining virus stocks to enable unequivocal criminalization of any possession of the virus.
Notable cases
Famous historical figures who contracted smallpox include Lakota Chief Sitting Bull, Ramses V, the Kangxi Emperor (survived), Shunzhi Emperor and Tongzhi Emperor of China, Emperor Komei of Japan (died of smallpox in 1867), and Date Masamune of Japan (who lost an eye to the disease). Cuitláhuac, the 10th tlatoani (ruler) of the Aztec city of Tenochtitlan, died of smallpox in 1520, shortly after its introduction to the Americas, and the Incan emperor Huayna Capac died of it in 1527 (causing a civil war of succession in the Inca empire and the eventual conquest by the Spaniards). More recent public figures include Guru Har Krishan, 8th Guru of the Sikhs, in 1664, Louis I of Spain in 1724 (died), Peter II of Russia in 1730 (died), George Washington (survived), Louis XV of France in 1774 (died) and Maximilian III Joseph of Bavaria in 1777 (died).
Prominent families throughout the world often had several people infected by and/or perish from the disease. For example, several relatives of Henry VIII of England survived the disease but were scarred by it. These include his sister Margaret, his wife Anne of Cleves, and his two daughters: Mary I in 1527 and Elizabeth I in 1562. Elizabeth tried to disguise the pockmarks with heavy makeup. Mary, Queen of Scots, contracted the disease as a child but had no visible scarring.
In Europe, deaths from smallpox often changed dynastic succession. Louis XV of France succeeded his great-grandfather Louis XIV through a series of deaths of smallpox or measles among those higher in the succession line. He himself died of the disease in 1774. Peter II of Russia died of the disease at 14 years of age. Also, before becoming emperor, Peter III of Russia caught the virus and suffered greatly from it. He was left scarred and disfigured. His wife, Catherine the Great, was spared but fear of the virus clearly had its effects on her. She feared for the safety of her son, Paul, so much that she made sure that large crowds were kept at bay and sought to isolate him. Eventually, she decided to have herself inoculated by a British doctor, Thomas Dimsdale. While this was considered a controversial method at the time, she succeeded. Paul was later inoculated as well. Catherine then sought to have inoculations throughout her empire stating: "My objective was, through my example, to save from death the multitude of my subjects who, not knowing the value of this technique, and frightened of it, were left in danger." By 1800, approximately 2 million inoculations were administered in the Russian Empire.In China, the Qing dynasty had extensive protocols to protect Manchus from Pekings endemic smallpox.
U.S. Presidents George Washington, Andrew Jackson, and Abraham Lincoln all contracted and recovered from the disease. Washington became infected with smallpox on a visit to Barbados in 1751. Jackson developed the illness after being taken prisoner by the British during the American Revolution, and though he recovered, his brother Robert did not. Lincoln contracted the disease during his presidency, possibly from his son Tad, and was quarantined shortly after giving the Gettysburg address in 1863.Famous theologian Jonathan Edwards died of smallpox in 1758 following an inoculation.Soviet leader Joseph Stalin fell ill with smallpox at the age of seven. His face was badly scarred by the disease. He later had photographs retouched to make his pockmarks less apparent.Hungarian poet Ferenc Kölcsey, who wrote the Hungarian national anthem, lost his right eye to smallpox.
Tradition and religion
In the face of the devastation of smallpox, various smallpox gods and goddesses have been worshipped throughout parts of the Old World, for example in China and India. In China, the smallpox goddess was referred to as Tou-Shen Niang-Niang (Chinese: 痘疹娘娘). Chinese believers actively worked to appease the goddess and pray for her mercy, by such measures as referring to smallpox pustules as "beautiful flowers" as a euphemism intended to avert offending the goddess, for example (the Chinese word for smallpox is 天花, literally "heaven flower"). In a related New Years Eve custom it was prescribed that the children of the house wear ugly masks while sleeping, so as to conceal any beauty and thereby avoid attracting the goddess, who would be passing through sometime that night. If a case of smallpox did occur, shrines would be set up in the homes of the victims, to be worshipped and offered to as the disease ran its course. If the victim recovered, the shrines were removed and carried away in a special paper chair or boat for burning. If the patient did not recover, the shrine was destroyed and cursed, to expel the goddess from the house.In the Yoruba language smallpox is known as ṣọpọná, but it was also written as shakpanna, shopona, ṣhapana, and ṣọpọnọ. The word is a combination of 3 words, the verb ṣán, meaning to cover or plaster (referring to the pustules characteristic of smallpox), kpa or pa, meaning to kill, and enia, meaning human. Roughly translated, it means One who kills a person by covering them with pustules. Among the Yorùbá people of West Africa, and also in Dahomean religion, Trinidad, and in Brazil, The deity Sopona, also known as Obaluaye, is the deity of smallpox and other deadly diseases (like leprosy, HIV/AIDS, and fevers). One of the most feared deities of the orisha pantheon, smallpox was seen as a form of punishment from Shopona. Worship of Shopona was highly controlled by his priests, and it was believed that priests could also spread smallpox when angered. However, Shopona was also seen as a healer who could cure the diseases he inflicted, and he was often called upon his victims to heal them. The British government banned the worship of the god because it was believed his priests were purposely spreading smallpox to their opponents.Indias first records of smallpox can be found in a medical book that dates back to 400 CE. This book describes a disease that sounds exceptionally like smallpox. India, like China and the Yorùbá, created a goddess in response to its exposure to smallpox. The Hindu goddess Shitala was both worshipped and feared during her reign. It was believed that this goddess was both evil and kind and had the ability to inflict victims when angered, as well as calm the fevers of the already affected. Portraits of the goddess show her holding a broom in her right hand to continue to move the disease and a pot of cool water in the other hand in an attempt to soothe patients. Shrines were created where many Indian natives, both healthy and not, went to worship and attempt to protect themselves from this disease. Some Indian women, in an attempt to ward off Shitala, placed plates of cooling foods and pots of water on the roofs of their homes.In cultures that did not recognize a smallpox deity, there was often nonetheless a belief in smallpox demons, who were accordingly blamed for the disease. Such beliefs were prominent in Japan, Europe, Africa, and other parts of the world. Nearly all cultures who believed in the demon also believed that it was afraid of the color red. This led to the invention of the so-called red treatment, where patients and their rooms would be decorated in red. The practice spread to Europe in the 12th century and was practiced by (among others) Charles V of France and Elizabeth I of England. Afforded scientific credibility through the studies by Niels Ryberg Finsen showing that red light reduced scarring, this belief persisted even until the 1930s.
See also
List of epidemics
Population history of indigenous peoples of the Americas#Depopulation from disease
References
Further reading
External links
Smallpox Biosafety: A Website About Destruction of Smallpox Virus Stocks
Detailed CIDRAP Smallpox overview
Agent Fact Sheet: Smallpox, Center for Biosecurity
Smallpox Images and Diagnosis Synopsis Archived 29 July 2008 at the Wayback Machine
Virus Pathogen Database and Analysis Resource (ViPR): Poxviridae
Episode 1 (of 4): Vaccines of the BBC Four and PBS show: Extra Life: A Short History of Living Longer (2021) |
Snakebite | A snakebite is an injury caused by the bite of a snake, especially a venomous snake. A common sign of a bite from a venomous snake is the presence of two puncture wounds from the animals fangs. Sometimes venom injection from the bite may occur. This may result in redness, swelling, and severe pain at the area, which may take up to an hour to appear. Vomiting, blurred vision, tingling of the limbs, and sweating may result. Most bites are on the hands, arms, or legs. Fear following a bite is common with symptoms of a racing heart and feeling faint. The venom may cause bleeding, kidney failure, a severe allergic reaction, tissue death around the bite, or breathing problems. Bites may result in the loss of a limb or other chronic problems or even death.The outcome depends on the type of snake, the area of the body bitten, the amount of snake venom injected, the general health of the person bitten and whether or not anti-venom serum has been administered by a doctor in a timely manner. Problems are often more severe in children than adults, due to their smaller size. Allergic reactions to snake venom can further complicate outcomes and can include anaphylaxis, requiring additional treatment and in some cases resulting in death.Snakes bite, both as a method of hunting, and as a means of protection. Risk factors for bites include working outside with ones hands such as in farming, forestry, and construction. Snakes commonly involved in envenomations include elapids (such as kraits, cobras and mambas), vipers, and sea snakes. The majority of snake species do not have venom and kill their prey by squeezing them. Venomous snakes can be found on every continent except Antarctica. Determining the type of snake that caused a bite is often not possible. The World Health Organization says snakebites are a "neglected public health issue in many tropical and subtropical countries", and in 2017, the WHO categorized snakebite envenomation as a Neglected Tropical Disease (Category A). The WHO also estimates that between 4.5 and 5.4 million people are bitten each year, and of those figures 40-50% develop some kind of clinical illness as a result. Furthermore, the death toll of such an injury could range between 80,000 and 130,000 people per year. The purpose was to encourage research, expand accessibility of antivenoms, and improve snakebite management in "developing countries".Prevention of snake bites can involve wearing protective footwear, avoiding areas where snakes live, and not handling snakes. Treatment partly depends on the type of snake. Washing the wound with soap and water and holding the limb still is recommended. Trying to suck out the venom, cutting the wound with a knife, or using a tourniquet is not recommended. Antivenom is effective at preventing death from bites; however, antivenoms frequently have side effects. The type of antivenom needed depends on the type of snake involved. When the type of snake is unknown, antivenom is often given based on the types known to be in the area. In some areas of the world, getting the right type of antivenom is difficult and this partly contributes to why they sometimes do not work. An additional issue is the cost of these medications. Antivenom has little effect on the area around the bite itself. Supporting the persons breathing is sometimes also required.The number of venomous snakebites that occur each year may be as high as five million. They result in about 2.5 million envenomations and 20,000 to 125,000 deaths. The frequency and severity of bites vary greatly among different parts of the world. They occur most commonly in Africa, Asia, and Latin America, with rural areas more greatly affected. Deaths are relatively rare in Australia, Europe and North America. For example, in the United States, about seven to eight thousand people per year are bitten by venomous snakes (about one in 40 thousand people) and about five people die (about one death per 65 million people).
Signs and symptoms
The most common first symptom of all snakebites is an overwhelming fear, which may contribute to other symptoms, and may include nausea and vomiting, diarrhea, vertigo, fainting, tachycardia, and cold, clammy skin. Snake bites can have a variety of different signs and symptoms depending on their species.Dry snakebites and those inflicted by a non-venomous species may still cause severe injury. The bite may become infected from the snakes saliva. The fangs sometimes harbor pathogenic microbial organisms, including Clostridium tetani, and may require an updated tetanus immunization.Most snakebites, from either a venomous or a non-venomous snake, will have some type of local effect. Minor pain and redness occur in over 90 percent of cases, although this varies depending on the site. Bites by vipers and some cobras may be extremely painful, with the local tissue sometimes becoming tender and severely swollen within five minutes. This area may also bleed and blister, and may lead to tissue necrosis. Other common initial symptoms of pit viper and viper bites include lethargy, bleeding, weakness, nausea, and vomiting. Symptoms may become more life-threatening over time, developing into hypotension, tachypnea, severe tachycardia, severe internal bleeding, altered sensorium, kidney failure, and respiratory failure.Bites by some snakes, such as the kraits, coral snake, Mojave rattlesnake, and the speckled rattlesnake, may cause little or no pain, despite their serious and potentially life-threatening venom. Some people report experiencing a "rubbery", "minty", or "metallic" taste after being bitten by certain species of rattlesnake. Spitting cobras and rinkhalses can spit venom in a persons eyes. This results in immediate pain, ophthalmoparesis, and sometimes blindness.
Some Australian elapids and most viper envenomations will cause coagulopathy, sometimes so severe that a person may bleed spontaneously from the mouth, nose, and even old, seemingly healed wounds. Internal organs may bleed, including the brain and intestines, and ecchymosis (bruising) of the skin is often seen.The venom of elapids, including sea snakes, kraits, cobras, king cobra, mambas, and many Australian species, contains toxins which attack the nervous system, causing neurotoxicity. The person may present with strange disturbances to their vision, including blurriness. Paresthesia throughout the body, as well as difficulty in speaking and breathing, may be reported. Nervous system problems will cause a huge array of symptoms, and those provided here are not exhaustive. If not treated immediately they may die from respiratory failure.Venom emitted from some types of cobras, almost all vipers and some sea snakes causes necrosis of muscle tissue. Muscle tissue will begin to die throughout the body, a condition known as rhabdomyolysis. Rhabdomyolysis can result in damage to the kidneys as a result of myoglobin accumulation in the renal tubules. This, coupled with hypotension, can lead to acute kidney injury, and, if left untreated, eventually death.Snakebite is also known to cause depression and post-traumatic stress disorder in a high proportion of people who survive.
Cause
In the developing world most snakebites occur in those who work outside such as farmers, hunters, and fishermen. They often happen when a person steps on the snake or approaches it too closely. In the United States and Europe snakebites most commonly occur in those who keep them as pets.The type of snake that most often delivers serious bites depends on the region of the world. In Africa, it is mambas, Egyptian cobras, puff adders, and carpet vipers. In the Middle East, it is carpet vipers and elapids. In Latin America, it is snakes of the Bothrops and Crotalus types, the latter including rattlesnakes. In North America, rattlesnakes are the primary concern, and up to 95% of all snakebite-related deaths in the United States are attributed to the western and eastern diamondback rattlesnakes. In South Asia, it was previously believed that Indian cobras, common kraits, Russells viper, and carpet vipers were the most dangerous; other snakes, however, may also cause significant problems in this area of the world.
Pathophysiology
Since envenomation is completely voluntary, all venomous snakes are capable of biting without injecting venom into a person. Snakes may deliver such a "dry bite" rather than waste their venom on a creature too large for them to eat, a behaviour called venom metering. However, the percentage of dry bites varies among species: 80 percent of bites inflicted by sea snakes, which are normally timid, do not result in envenomation, whereas only 25 percent of pit viper bites are dry. Furthermore, some snake genera, such as rattlesnakes, significantly increase the amount of venom injected in defensive bites compared to predatory strikes.Some dry bites may also be the result of imprecise timing on the snakes part, as venom may be prematurely released before the fangs have penetrated the person. Even without venom, some snakes, particularly large constrictors such as those belonging to the Boidae and Pythonidae families, can deliver damaging bites; large specimens often cause severe lacerations, or the snake itself pulls away, causing the flesh to be torn by the needle-sharp recurved teeth embedded in the person. While not as life-threatening as a bite from a venomous species, the bite can be at least temporarily debilitating and could lead to dangerous infections if improperly dealt with.While most snakes must open their mouths before biting, African and Middle Eastern snakes belonging to the family Atractaspididae are able to fold their fangs to the side of their head without opening their mouth and jab a person.
Snake venom
It has been suggested that snakes evolved the mechanisms necessary for venom formation and delivery sometime during the Miocene epoch. During the mid-Tertiary, most snakes were large ambush predators belonging to the superfamily Henophidia, which use constriction to kill their prey. As open grasslands replaced forested areas in parts of the world, some snake families evolved to become smaller and thus more agile. However, subduing and killing prey became more difficult for the smaller snakes, leading to the evolution of snake venom. Other research on Toxicofera, a hypothetical clade thought to be ancestral to most living reptiles, suggests an earlier time frame for the evolution of snake venom, possibly to the order of tens of millions of years, during the Late Cretaceous.Snake venom is produced in modified parotid glands normally responsible for secreting saliva. It is stored in structures called alveoli behind the animals eyes, and ejected voluntarily through its hollow tubular fangs.
Venom in many snakes, such as pit vipers, affects virtually every organ system in the human body and can be a combination of many toxins, including cytotoxins, hemotoxins, neurotoxins, and myotoxins, allowing for an enormous variety of symptoms. Snake venom may cause cytotoxicity as various enzymes including hyaluronidases, collagenases, proteinases and phospholipases lead to breakdown (dermonecrosis) and injury of local tissue and inflammation which leads to pain, edema and blister formation. Metalloproteinases further lead to breakdown of the extracellular matrix (releasing inflammatory mediators) and cause microvascular damage, leading to hemorrhage, skeletal muscle damage (necrosis), blistering and further dermonecrosis. The metalloproteinase release of the inflammatory mediators leads to pain, swelling and white blood cell (leukocyte) infiltration. The lymphatic system may be damaged by the various enzymes contained in the venom leading to edema; or the lymphatic system may also allow the venom to be carried systemically. Snake venom may cause muscle damage or myotoxicity via the enzyme phospholipase A2 which disrupts the plasma membrane of muscle cells. This damage to muscle cells may cause rhabdomyolysis, respiratory muscle compromise, or both. Other enzymes such as bradykinin potentiating peptides, natriuretic peptides, vascular endothelial growth factors, proteases can also cause hypotension or low blood pressure. Toxins in snake venom can also cause kidney damage (nephrotoxicity) via the same inflammatory cytokines. The toxins cause direct damage to the glomeruli in the kidneys as well as causing protein deposits in Bowmans capsule. Or the kidneys may be indirectly damaged by envenomation due to shock, clearance of toxic substances such as immune complexes, blood degradation products or products of muscle breakdown (rhabdomyolysis).In venom-induced consumption coagulopathy, toxins in snake venom promote hemorrhage via activation, consumption and subsequent depletion of clotting factors in the blood. These clotting factors normally work as part of the coagulation cascade in the blood to form blood clots and prevent hemorrhage. Toxins in snake venom (especially the venom of new world pit vipers (the family crotalina)) may also cause low platelets (thrombocytopenia) or altered platelet function also leading to bleeding.Snake venom is known to cause neuromuscular paralysis, usually as a flaccid paralysis that is descending; starting at the facial muscles, causing ptosis or drooping eyelids and dysarthria or poor articulation of speech, and descending to the respiratory muscles causing respiratory compromise. The neurotoxins can either bind to and block membrane receptors at the post-synaptic neurons or they can be taken up into the pre-synaptic neuron cells and impair neurotransmitter release. Venom toxins that are taken up intra-cellularly, into the cells of the pre-synaptic neurons are much more difficult to reverse using anti-venom as they are inaccessible to the anti-venom when they are intracellular.The strength of venom differs markedly between species and even more so between families, as measured by median lethal dose (LD50) in mice. Subcutaneous LD50 varies by over 140-fold within elapids and by more than 100-fold in vipers. The amount of venom produced also differs among species, with the Gaboon viper able to potentially deliver from 450 to 600 milligrams of venom in a single bite, the most of any snake. Opisthoglyphous colubrids have venom ranging from life-threatening (in the case of the boomslang) to barely noticeable (as in Tantilla).
Prevention
Snakes are most likely to bite when they feel threatened, are startled, are provoked, or when they have been cornered. Snakes are likely to approach residential areas when attracted by prey, such as rodents. Regular pest control can reduce the threat of snakes considerably. It is beneficial to know the species of snake that are common in local areas, or while travelling or hiking. Africa, Australia, the Neotropics, and South Asia in particular are populated by many dangerous species of snake. Being aware of—and ultimately avoiding—areas known to be heavily populated by dangerous snakes is strongly recommended.When in the wilderness, treading heavily creates ground vibrations and noise, which will often cause snakes to flee from the area. However, this generally only applies to vipers, as some larger and more aggressive snakes in other parts of the world, such as mambas and cobras, will respond more aggressively. If presented with a direct encounter, it is best to remain silent and motionless. If the snake has not yet fled, it is important to step away slowly and cautiously.The use of a flashlight when engaged in camping activities, such as gathering firewood at night, can be helpful. Snakes may also be unusually active during especially warm nights when ambient temperatures exceed 21 °C (70 °F). It is advised not to reach blindly into hollow logs, flip over large rocks, and enter old cabins or other potential snake hiding-places. When rock climbing, it is not safe to grab ledges or crevices without examining them first, as snakes are cold-blooded and often sunbathe atop rock ledges.In the United States, more than 40 percent of people bitten by snake intentionally put themselves in harms way by attempting to capture wild snakes or by carelessly handling their dangerous pets—40 percent of that number had a blood alcohol level of 0.1 percent or more.It is also important to avoid snakes that appear to be dead, as some species will actually roll over on their backs and stick out their tongue to fool potential threats. A snakes detached head can immediately act by reflex and potentially bite. The induced bite can be just as severe as that of a live snake.
As a dead snake is incapable of regulating the venom injected, a bite from a dead snake can often contain large amounts of venom.
Treatment
It may be difficult to determine if a bite by any species of snake is life-threatening. A bite by a North American copperhead on the ankle is usually a moderate injury to a healthy adult, but a bite to a childs abdomen or face by the same snake may be fatal. The outcome of all snakebites depends on a multitude of factors: the type of snake, the size, physical condition, and temperature of the snake, the age and physical condition of the person, the area and tissue bitten (e.g., foot, torso, vein or muscle), the amount of venom injected, the time it takes for the person to find treatment, and finally the quality of that treatment. An overview of systematic reviews on different aspects of snakebite management found that the evidence base from majority of treatment modalities is low quality. An analysis of World Health Organization guidelines found that they are of low quality, with inadequate stakeholder involvement and poor methodological rigour.
Snake identification
Identification of the snake is important in planning treatment in certain areas of the world, but is not always possible. Ideally the dead snake would be brought in with the person, but in areas where snake bite is more common, local knowledge may be sufficient to recognize the snake. However, in regions where polyvalent antivenoms are available, such as North America, identification of snake is not a high priority item. Attempting to catch or kill the offending snake also puts one at risk for re-envenomation or creating a second person bitten, and generally is not recommended.The three types of venomous snakes that cause the majority of major clinical problems are vipers, kraits, and cobras. Knowledge of what species are present locally can be crucial, as is knowledge of typical signs and symptoms of envenomation by each type of snake. A scoring system can be used to try to determine the biting snake based on clinical features, but these scoring systems are extremely specific to particular geographical areas and might be compromised by the presence of escaped or released non-native species.
First aid
Snakebite first aid recommendations vary, in part because different snakes have different types of venom. Some have little local effect, but life-threatening systemic effects, in which case containing the venom in the region of the bite by pressure immobilization is desirable. Other venoms instigate localized tissue damage around the bitten area, and immobilization may increase the severity of the damage in this area, but also reduce the total area affected; whether this trade-off is desirable remains a point of controversy. Because snakes vary from one country to another, first aid methods also vary.
Many organizations, including the American Medical Association and American Red Cross, recommend washing the bite with soap and water. Australian recommendations for snake bite treatment recommend against cleaning the wound. Traces of venom left on the skin/bandages from the strike can be used in combination with a snake bite identification kit to identify the species of snake. This speeds determination of which antivenom to administer in the emergency room.
Pressure immobilization
As of 2008, clinical evidence for pressure immobilization via the use of an elastic bandage is limited. It is recommended for snakebites that have occurred in Australia (due to elapids which are neurotoxic). It is not recommended for bites from non-neurotoxic snakes such as those found in North America and other regions of the world. The British military recommends pressure immobilization in all cases where the type of snake is unknown.The object of pressure immobilization is to contain venom within a bitten limb and prevent it from moving through the lymphatic system to the vital organs. This therapy has two components: pressure to prevent lymphatic drainage, and immobilization of the bitten limb to prevent the pumping action of the skeletal muscles.
Antivenom
Until the advent of antivenom, bites from some species of snake were almost universally fatal. Despite huge advances in emergency therapy, antivenom is often still the only effective treatment for envenomation. The first antivenom was developed in 1895 by French physician Albert Calmette for the treatment of Indian cobra bites. Antivenom is made by injecting a small amount of venom into an animal (usually a horse or sheep) to initiate an immune system response. The resulting antibodies are then harvested from the animals blood.
Antivenom is injected into the person intravenously, and works by binding to and neutralizing venom enzymes. It cannot undo damage already caused by venom, so antivenom treatment should be sought as soon as possible. Modern antivenoms are usually polyvalent, making them effective against the venom of numerous snake species. Pharmaceutical companies which produce antivenom target their products against the species native to a particular area. Although some people may develop serious adverse reactions to antivenom, such as anaphylaxis, in emergency situations this is usually treatable and hence the benefit outweighs the potential consequences of not using antivenom. Giving adrenaline (epinephrine) to prevent adverse reactions to antivenom before they occur might be reasonable in cases where they occur commonly. Antihistamines do not appear to provide any benefit in preventing adverse reactions.
Chronic Complications
Chronic health effects of snakebite include but is not limited to non-healing and chronic ulcers, musculoskeletal disorders, amputations, chronic kidney disease, and other neurological and endocrine complications. The treatment of chronic complications of snakebite has not been well researched and there a systems approach consisting of a multi-component intervention.
Outmoded
The following treatments, while once recommended, are considered of no use or harmful, including tourniquets, incisions, suction, application of cold, and application of electricity. Cases in which these treatments appear to work may be the result of dry bites.
Application of a tourniquet to the bitten limb is generally not recommended. There is no convincing evidence that it is an effective first-aid tool as ordinarily applied. Tourniquets have been found to be completely ineffective in the treatment of Crotalus durissus bites, but some positive results have been seen with properly applied tourniquets for cobra venom in the Philippines. Uninformed tourniquet use is dangerous, since reducing or cutting off circulation can lead to gangrene, which can be fatal. The use of a compression bandage is generally as effective, and much safer.
Cutting open the bitten area, an action often taken prior to suction, is not recommended since it causes further damage and increases the risk of infection; the subsequent cauterization of the area with fire or silver nitrate (also known as infernal stone) is also potentially threatening.
Sucking out venom, either by mouth or with a pump, does not work and may harm the affected area directly. Suction started after three minutes removes a clinically insignificant quantity—less than one-thousandth of the venom injected—as shown in a human study. In a study with pigs, suction not only caused no improvement but led to necrosis in the suctioned area. Suctioning by mouth presents a risk of further poisoning through the mouths mucous tissues. The helper may also release bacteria into the persons wound, leading to infection.
Immersion in warm water or sour milk, followed by the application of snake-stones (also known as la Pierre Noire), which are believed to draw off the poison in much the way a sponge soaks up water.
Application of a one-percent solution of potassium permanganate or chromic acid to the cut, exposed area. The latter substance is notably toxic and carcinogenic.
Drinking abundant quantities of alcohol following the cauterization or disinfection of the wound area.
Use of electroshock therapy in animal tests has shown this treatment to be useless and potentially dangerous.In extreme cases, in remote areas, all of these misguided attempts at treatment have resulted in injuries far worse than an otherwise mild to moderate snakebite. In worst-case scenarios, thoroughly constricting tourniquets have been applied to bitten limbs, completely shutting off blood flow to the area. By the time the person finally reached appropriate medical facilities their limbs had to be amputated.
In development
Several new drugs and treatments are under development for snakebite. For instance, the metal chelator dimercaprol has recently been shown to potently antagonize the activity of Zn2+-dependent snake venom metalloproteinases in vitro. New monoclonal antibodies, polymer gels and a small molecule inhibitor called Varespladib are in development.
Epidemiology
Estimates vary from 1.2 to 5.5 million snakebites, 421,000 to 2.5 million envenomings, and 20,000 to 125,000 deaths. Since reporting is not mandatory in much of the world, the data on the frequency of snakebites is not precise. Many people who survive bites have permanent tissue damage caused by venom, leading to disability. Most snake envenomings and fatalities occur in South Asia, Southeast Asia, and sub-Saharan Africa, with India reporting the most snakebite deaths of any country.Most snakebites are caused by non-venomous snakes. Of the roughly 3,000 known species of snake found worldwide, only 15% are considered dangerous to humans. Snakes are found on every continent except Antarctica. The most diverse and widely distributed snake family, the colubrids, has approximately 700 venomous species, but only five genera—boomslangs, twig snakes, keelback snakes, green snakes, and slender snakes—have caused human fatalities.Worldwide, snakebites occur most frequently in the summer season when snakes are active and humans are outdoors. Agricultural and tropical regions report more snakebites than anywhere else. In the United States, those bitten are typically male and between 17 and 27 years of age. Children and the elderly are the most likely to die.
Mechanics
When venomous snakes bite a target, they secrete venom through their venom delivery system. The venom delivery system generally consists of two venom glands, a compressor muscle, venom ducts, a fang sheath, and fangs. The primary and accessory venom glands store the venom quantities required during envenomation. The compressor muscle contracts during bites to increase the pressure throughout the venom delivery system. The pressurized venom travels through the primary venom duct to the secondary venom duct that leads down through the fang sheath and fang. The venom is then expelled through the exit orifice of the fang. The total volume and flow rate of venom administered into a target varies widely, sometimes as much as an order of magnitude. One of the largest factors is snake species and size, larger snakes have been shown to administer larger quantities of venom.
Predatory vs. defensive bites
Snake bites are classified as either predatory or defensive in nature. During defensive strikes, the rate of venom expulsion and total volume of venom expelled is much greater than during predatory strikes. Defensive strikes can have 10 times as much venom volume expelled at 8.5 times the flow rate. This can be explained by the snakes need to quickly subdue a threat. While employing similar venom expulsion mechanics, predatory strikes are quite different from defensive strikes. Snakes usually release the prey shortly after the envenomation allowing the prey to run away and die. Releasing prey prevents retaliatory damage to the snake. The venom scent allows the snake to relocate the prey once it is deceased. The amount of venom injected has been shown to increase with the mass of the prey animal. Larger venom volumes allow snakes to effectively euthanize larger prey while remaining economical during strikes against smaller prey. This is an important skill as venom is a metabolically expensive resource.
Venom Metering
Venom metering is the ability of a snake to have neurological control over the amount of venom released into a target during a strike based on situational cues. This ability would prove useful as venom is a limited resource, larger animals are |
Snakebite | less susceptible to the effects of venom, and various situations require different levels of force. There is a lot of evidence to support the venom metering hypothesis. For example, snakes frequently use more venom during defensive strikes, administer more venom to larger prey, and are capable of dry biting. A dry bite is a bite from a venomous snake that results in very little or no venom expulsion, leaving the target asymptomatic. However, there is debate among many academics about venom metering in snakes. The alternative to venom metering is the pressure balance hypothesis.
The pressure balance hypothesis cites the retraction of the fang sheath as the many mechanism for producing outward venom flow from the venom delivery system. When isolated, fang sheath retraction has experimentally been shown to induce very high pressures in the venom delivery system. A similar method was used to stimulate the compressor musculature, the main muscle responsible for the contraction and squeezing of the venom glad, and then measuring the induced pressures. It was determined that the pressure created from the fang sheath retraction was at times an order of magnitude greater than those created by the compressor musculature. Snakes do not have direct neurological control of the fang sheath, it can only be retracted as the fangs enter a target and the targets skin and body provide substantial resistance to retract the sheath. For these reasons, the pressure balance hypothesis concludes that external factors, mainly the bite and physical mechanics, are responsible for the quantity of venom expelled.
Venom Spitting
Venom spitting is another venom delivery method that is unique to some Asiatic and African cobras. In venom spitting, a stream of venom is propelled at very high pressures outwards up to 3 meters. The venom stream is usually aimed at the eyes and face of the target as a deterrent for predators. There are non-spitting cobras that provide useful information on the unique mechanics behind venom spitting. Unlike the elongated oval shaped exit orifices of non-spitting cobras, spitting cobras have circular exit orifice at their fang tips. This combined with the ability to partially retract their fang sheath by displacing the palato-maxillary arch and contracting the adductor mandibulae, allows the spitting cobras to create large pressures within the venom delivery system. While venom spitting is a less common venom delivery system, the venom can still cause the effects if ingested.
Society and culture
Snakes were both revered and worshipped and feared by early civilizations. The ancient Egyptians recorded prescribed treatments for snakebites as early as the Thirteenth Dynasty in the Brooklyn Papyrus, which includes at least seven venomous species common to the region today, such as the horned vipers. In Judaism, the Nehushtan was a pole with a snake made of copper fixed upon it. The object was regarded as a divinely empowered instrument of God that could bring healing to Jews bitten by venomous snakes while they were wandering in the desert after their exodus from Egypt. Healing was said to occur by merely looking at the object as it was held up by Moses.
Historically, snakebites were seen as a means of execution in some cultures. Reportedly, in Southern Han during Chinas Five Dynasties and Ten Kingdoms period and in India a form of capital punishment was to throw people into snake pits, leaving people to die from multiple venomous bites. According to popular belief, the Egyptian queen Cleopatra VII committed suicide by let herself be bitten by an asp—likely an Egyptian cobra—after hearing of Mark Antonys death, while contemporary ancient authors rather assume a direct application of poison.
Snakebite as a surreptitious form of murder has been featured in stories such as Sir Arthur Conan Doyles The Adventure of the Speckled Band, but actual occurrences are virtually unheard of, with only a few documented cases. It has been suggested that Boris III of Bulgaria, who was allied to Nazi Germany during World War II, may have been killed with snake venom, although there is no definitive evidence. At least one attempted suicide by snakebite has been documented in medical literature involving a puff adder bite to the hand.
Research
In 2018, the World Health Organization listed snakebite envenoming as a neglected tropical disease. In 2019, they launched a strategy to prevent and control snakebite envenoming, which involved a program targeting affected communities and their health systems.
Other animals
Several animals acquired immunity against venom of snakes that occur in the same habitat. This has been documented in some humans as well.
References
Bibliography
Further reading
External links
WHO Snake Antivenoms Database
Organization (2016). Guidelines for the management of snakebites. Regional Office for South-East Asia, World Health Organization. hdl:10665/249547. ISBN 9789290225300. |
Spasmodic dysphonia | Spasmodic dysphonia, also known as laryngeal dystonia, is a disorder in which the muscles that generate a persons voice go into periods of spasm. This results in breaks or interruptions in the voice, often every few sentences, which can make a person difficult to understand. The persons voice may also sound strained or they may be nearly unable to speak. Onset is often gradual and the condition is lifelong.The cause is unknown. Risk factors may include family history. Triggers may include an upper respiratory infection, injury to the larynx, overuse of the voice, and psychological stress. The underlying mechanism is believed to typically involve the central nervous system, specifically the basal ganglia. Diagnosis is typically made following examination by a team of healthcare providers. It is a type of focal dystonia.While there is no cure, treatment may improve symptoms. Most commonly this involves injecting botulinum toxin into the affected muscles of the larynx. This generally results in improvement for a few months. Other measures include voice therapy, counselling, and amplification devices. If this is not effective, surgery may be considered; however, evidence to support surgery is limited.The disorder affects an estimated 2 per 100,000 people. Women are more commonly affected. Onset is typically between the ages of 30 and 50. Severity is variable between people. In some, work and social life are affected. Life expectancy is, however, normal.
Signs and symptoms
Symptoms of spasmodic dysphonia can come on suddenly or gradually appear over the span of years. They can come and go for hours or even weeks at a time, or remain consistent. Gradual onset can begin with the manifestation of a hoarse voice quality, which may later transform into a voice quality described as strained with breaks in phonation. These phonation breaks have been compared to stuttering in the past, but there is a lack of research in support of spasmodic dysphonia being classified as a fluency disorder. It is commonly reported by people with spasmodic dysphonia that symptoms almost only occur on vocal sounds that require phonation. Symptoms are less likely to occur at rest, while whispering, or on speech sounds that do not require phonation. It is hypothesized this occurs because of an increase in sporadic, sudden, and prolonged tension found in the muscles around the larynx during phonation. This tension affects the abduction and adduction (opening and closing) of the vocal folds. Consequently, the vocal folds are unable to retain subglottal air pressure (required for phonation) and breaks in phonation can be heard throughout the speech of people with spasmodic dysphonia.Regarding types of spasmodic dysphonia, the main characteristic of spasmodic dysphonia, breaks in phonation, is found along with other varying symptoms. The voice quality of adductor spasmodic dysphonia can be described as “strained-strangled” from tension in the glottal region. Voice quality for abductor spasmodic dysphonia can be described as breathy from variable widening of the glottal region. Vocal tremor may also be seen in spasmodic dysphonia. A mix and variance of these symptoms are found in mixed spasmodic dysphonia.Symptoms of spasmodic dysphonia typically appear in middle aged people, but have also been seen in people in their twenties, with symptoms emerging as young as teenage years.
Cause
Although the exact cause of spasmodic dysphonia is still unknown, epidemiological, genetic, and neurological pathogenic factors have been proposed in recent research.Risk factors include:
Being female
Being middle aged
Having a family history of neurological diseases (e.g., tremor, dystonia, meningitis, and other neurological diseases)
Stressful events
Upper respiratory tract infections
Sinus and throat illnesses
Heavy voice use
Cervical dystonia
Childhood measles or mumps
Pregnancy and parturitionIt has not been established whether these factors directly affect the development of spasmodic dysphonia (SD), however these factors could be used to identify possible and/or at-risk patients.Researchers have also explored the possibility of a genetic component to SD. Three genes have been identified that may be related to the development of focal or segmental dystonia: TUBB4A, THAP1 and TOR1A genes. However, a recent study that examined the mutation of these three genes in 86 SD patients found that only 2.3% of the patients had novel/rare variants in THAP1 but none in TUBB4A and TOR1A. Evidence of a genetic contribution for dystonia involving the larynx is still weak and more research is needed in order to establish a causal relationship between SD and specific genes.SD is a neurological disorder rather than a disorder of the larynx, and as in other forms of dystonia, interventions at the end organ (i.e., larynx) have not offered a definitive cure, only symptomatic relief. The pathophysiology underlying dystonia is becoming better understood as a result of discoveries about genetically based forms of the disorder, and this approach is the most promising avenue to a long-term solution.SD is classified as a neurological disorder. However, because the voice can sound normal or near normal at times, some practitioners believe it to be psychogenic; that is, originating in the affected persons mind rather than from a physical cause. This was especially true in the 19th and 20th centuries. No medical organizations or groups take this position. A comparison of SD patients compared with vocal fold paralysis (VFP) patients found that 41.7% of the SD patients met the DSM-IV criteria for psychiatric comorbidity compared with 19.5% of the VFP group. However, another study found the opposite, with SD patients having significantly less psychiatric comorbidity compared to VFP patients: "The prevalence of major psychiatric cases varied considerably among the groups, from a low of seven percent (1/14) for spasmodic dysphonia, to 29.4 percent (5/17) for functional dysphonia, to a high of 63.6 percent (7/11) for vocal cord paralysis." A review in the journal Swiss Medicine Weekly states that "Psychogenic causes, a psychological disequilibrium, and an increased tension of the laryngeal muscles are presumed to be one end of the spectrum of possible factors leading to the development of the disorder". Alternatively, many investigations into the condition feel that the psychiatric comorbidity associated with voice disorders is a result of the social isolation and anxiety that patients with these conditions feel as a consequence of their difficulty with speech, as opposed to the cause of their dysphonia. The opinion that SD is psychogenic is not upheld by experts in the scientific community.SD is formally classified as a movement disorder; it is a type of focal dystonia known as laryngeal dystonia.
Diagnosis
Diagnosis of spasmodic dysphonia requires a multidisciplinary team and consideration of both perceptual and physiological factors. There is currently no universally accepted diagnostic test for spasmodic dysphonia, which presents a challenge for diagnosis. Additionally, diagnostic criteria have not been agreed upon as the distinguishing features of this disorder have not been well-characterized.A team of professionals including a speech-language pathologist, an otolaryngologist, and a neurologist, are typically involved in spasmodic dysphonia assessment and diagnosis. The speech-language pathologist conducts a speech assessment including case history questions to gather information about voice use and symptoms. This is followed by clinical observation and perceptual rating of voice characteristics such as voice breaks or strain, which are selectively present in normal speech over other voice activities such as whispering or laughing. Symptoms also vary across types of spasmodic dysphonia. For example, voiced sounds are more affected in adductor spasmodic dysphonia, while unvoiced sounds are more affected in abductor spasmodic dysphonia. Following speech assessment, the otolaryngologist conducts a flexible transnasal laryngoscopy to view the vocal folds and activity of the muscles controlling them in order to eliminate other possible causes of the voice disorder. In spasmodic dysphonia, producing long vowels or speaking sentences results in muscle spasms which are not observed during other vocal activities such as coughing, breathing, or whispering. To evaluate the individual for any other neurological problems, this examination is followed up with an assessment by the neurologist.
Voice quality symbol
The voice quality symbol for spasmodic dysphonia is ꟿ.
Differential diagnosis
Because spasmodic dysphonia shares many characteristics with other voice disorders, misdiagnosis frequently occurs. A common misdiagnosis is muscle tension dysphonia, a functional voice disorder which results from use of the voice, rather than a structural abnormality. Some parameters can help guide the clinician towards a decision. In muscle tension dysphonia, the vocal folds are typically hyperadducted in constant way, not in a spasmodic way. Additionally, the voice difficulties found in spasmodic dysphonia can be task specific, as opposed to those found in muscle tension dysphonia. Being able to differentiate between muscle tension dysphonia and spasmodic dysphonia is important because muscle tension dysphonia typically responds well to behavioural voice treatment but spasmodic dysphonia does not. This is crucial to avoid providing inappropriate treatment, but in some cases a trial of behavioural voice treatment can also be helpful to establish a differential diagnosis.Spasmodic dysphonia can also be misdiagnosed as voice tremor. The movements that are found in this disorder are typically rhythmic in nature, as opposed to the muscle spasms of spasmodic dysphonia. It is important to note that voice tremor and spasmodic dysphonia can co-occur in some patients.Differential diagnosis is particularly important for determining appropriate interventions, as the type and cause of the disorder determine the most effective treatment. Differences in treatment effectiveness are present even between the types of spasmodic dysphonia. Diagnosis of spasmodic dysphonia is often delayed due to these challenges, which in turn presents difficulties in choosing the proper interventions.
Types
The three types of spasmodic dysphonia (SD) are adductor spasmodic dysphonia, abductor spasmodic dysphonia, and mixed spasmodic dysphonia. A fourth type called whispering dysphonia has also been proposed. Adductor spasmodic dysphonia is the most common type.
Adductor spasmodic dysphonia
Adductor spasmodic dysphonia (ADSD) is the most common type, affecting around 87% of individuals with SD. In ADSD, sudden involuntary muscle movements or spasms cause the vocal folds (or vocal cords) to squeeze together and stiffen. As the name suggests, these spasms occur in the adductor muscles of the vocal folds, specifically the thyroarytenoid and the lateral cricoarytenoid. These spasms make it difficult for the vocal folds to vibrate and produce voice. Words are often cut off or are difficult to start because of the muscle spasms. Therefore, speech may be choppy but differs from stuttering. The voice of an individual with adductor spasmodic dysphonia is commonly described as strained or strangled and full of effort. Surprisingly, the spasms are usually absent while laughing, speaking at a high pitch, or speaking while singing, but singers can experience a loss of range or the inability to produce certain notes of a scale or with projection. Stress, however, often makes the muscle spasms more severe.
Abductor spasmodic dysphonia
Abductor spasmodic dysphonia (ABSD) is the second most common type, affecting around 13% of individuals with SD. In ABSD, sudden involuntary muscle movements or spasms cause the vocal folds to open. As the name suggests, these spasms occur in the single abductor muscle of the vocal folds, called the posterior cricoarytenoid. The vocal folds cannot vibrate when they are open. The open position of the vocal folds also allows air to escape from the lungs during speech. As a result, the voices of these individuals often sound weak, quiet, and breathy or whispery. As with adductor spasmodic dysphonia, the spasms are often absent during activities such as laughing or singing, but singers can experience a loss of range or the inability to produce certain notes of a scale or with projection.
Mixed spasmodic dysphonia
Mixed spasmodic dysphonia is the most rare type. Mixed spasmodic dysphonia involves both muscles that open the vocal folds and those that close them and therefore has features of both adductor and abductor spasmodic dysphonia. Some researchers believe that a subset of cases classified as mixed spasmodic dysphonia may actually be ADSD or ABSD subtype with the addition of compensatory voice behaviours that make it appear mixed. This further adds to the difficulty in achieving accurate diagnosis.
Whispering dysphonia
A fourth type has also been described. This appears to be caused by mutations in the TUBB4 gene on the short arm of chromosome 19 (19p13.2-p13.3). This gene encodes a tubulin gene. The pathophysiology of this condition has yet to be determined.
Treatment
There are a number of potential treatments for spasmodic dysphonia, including Botox, voice therapy, and surgery. A number of medications have also been tried including anticholinergics (such as benztropine) which have been found to be effective in 40-50% of people, but which are associated with a number of side effects.
Botulinum toxin
Botulinum toxin (Botox) is often used to improve some symptoms of spasmodic dysphonia through weakening or paralyzing the vocal folds, thus preventing muscle spasms. The level of evidence for its use is currently limited; little is known about optimal dosage, frequency of injections, or exact location of injection. However, it remains a choice for many people due to the predictability and low chance of long term side effects. It results in periods of some improvement, with the duration of benefit lasting for 10–12 weeks on average before symptoms return to baseline. Repeat injection is required to sustain good vocal production, as results are only temporary. Some transient side effects observed in adductor spasmodic dysphonia include reduced speaking volume, difficulty swallowing, and a breathy and hoarse voice quality. While treatment outcomes are generally positive, it is presently unclear whether this treatment approach is more or less effective than others.
Voice therapy
Voice therapy appears to be ineffective in cases of true spasmodic dysphonia. However, as it is difficult to distinguish between spasmodic dysphonia and functional dysphonias, and misdiagnosis is relatively common, trial of voice therapy is often recommended before more invasive procedures are tried. Some also state that it is useful for mild symptoms and as an add-on to botox therapy and others report success in more severe cases. Laryngeal manual therapy, which is massaging of the neck and cervical structures, also shows positive results for intervention of functional dysphonia.
Surgery
If other measures are not effective, surgery may be considered; however, evidence to support surgery as a treatment for SD is limited. Treatment outcomes are generally positive, though more research is required to determine its effectiveness. Post-surgery voices can be imperfect and about 15% of people have significant difficulties. If symptoms do recur, this typically happens in the first 12 months. As of 2011, surgery was rarely used as a treatment approach for SD. Surgical approaches include recurrent laryngeal nerve resection, selective laryngeal adductor denervation-reinnervation (SLAD-R), thyroplasty, thyroarytenoid myectomy, and laryngeal nerve crush. Recurrent laryngeal nerve resection involves removing a section of the recurrent laryngeal nerve. Recurrent laryngeal nerve avulsion is a more drastic removal of sections of the nerve, and has positive outcomes of 80% at three years. SLAD-R is effective specifically for adductor spasmodic dysphonia, for which it has shown good outcomes in about 80% of people at 8 years. Thyroplasty changes the position or length of the vocal folds.
History
Initial surgical efforts to treat the condition were published in 1976 by Herbert Dedo and involved cutting of the recurrent laryngeal nerve.
Notable cases
Scott Adams, creator of the comic strip Dilbert
Johnny Bush, country and western musician and songwriter
Susan Collins, U.S. Senator from Maine
Keath Fraser, Canadian author who has documented the challenges and treatment of his condition in the book The Voice Gallery: Travels With a Glass Throat (2002)
Chip Hanauer, American hydroplane racing driver
Robert F. Kennedy Jr., political and environmental activist, son of Robert F. Kennedy
Mary Lou Lord, indie folk musician
Benny Martin (1928–2001), American bluegrass fiddler, affected from 1980 to 1997
Darryl McDaniels of the rap group Run DMC
Jenny Morris (OAM), New Zealand-born Australian pop, rock singer-songwriter
Diane Rehm, American public radio talk show host
Mark Stuart, American Christian rock musician, of Audio Adrenaline
Linda Thompson, British folk-rock musician
Aleesha Rome, causing her to quit her singing career.
References
== External links == |
Spider bite | A spider bite, also known as arachnidism, is an injury resulting from the bite of a spider. The effects of most bites are not serious. Most bites result in mild symptoms around the area of the bite. Rarely they may produce a necrotic skin wound or severe pain.: 455 Most spiders do not cause bites that are of importance. For a bite to be significant, substantial envenomation is required. Bites from the widow spiders involve a neurotoxic venom which produces a condition known as latrodectism. Symptoms may include pain which may be at the bite or involve the chest and abdomen, sweating, muscle cramps and vomiting among others. Bites from the recluse spiders cause the condition loxoscelism, in which local necrosis of the surrounding skin and widespread breakdown of red blood cells may occur. Headaches, vomiting and a mild fever may also occur. Other spiders that can cause significant bites include the Australian funnel-web spider and South American wandering spider.Efforts to prevent bites include clearing clutter and the use of pesticides. Most spider bites are managed with supportive care such as nonsteroidal anti-inflammatory drugs (including ibuprofen) for pain and antihistamines for itchiness. Opioids may be used if the pain is severe. While an antivenom exists for black widow spider venom, it is associated with anaphylaxis and therefore not commonly used in the United States. Antivenom against funnel web spider venom improves outcomes. Surgery may be required to repair the area of injured skin from some recluse bites.Spider bites may be overdiagnosed or misdiagnosed. In many reports of spider bites it is unclear if a spider bite actually occurred. Historically a number of conditions were attributed to spider bites. In the Middle Ages a condition claimed to arise from spider bites was tarantism, where people danced wildly. While necrosis has been attributed to the bites of a number of spiders, good evidence only supports this for recluse spiders.
Signs and symptoms
Almost all spiders are venomous, but not all spider bites result in the injection of venom. Pain from non-venomous bites, so-called "dry bites", typically lasts for 5 to 60 minutes while pain from envenomating spider bites may last for longer than 24 hours. Bleeding also may occur with a bite. Signs of a bacterial infection due to a spider bite occur infrequently (0.9%).A study of 750 definite spider bites in Australia indicated that 6% of spider bites cause significant effects, the vast majority of these being redback spider bites causing significant pain lasting more than 24 hours. Activation of the sympathetic nervous system can lead to sweating, high blood pressure and gooseflesh.Most recluse spider bites are minor with little or no necrosis. However, a small number of bites produce necrotic skin lesions. First pain and tenderness at the site begin. The redness changes over two to three days to a bluish sinking patch of dead skin—the hallmark of necrosis. The wound heals slowly over months but usually completely. Rarely, bites may cause widespread symptoms, with occasional fatalities.There are a few spiders that can bite human skin and cause a skin reaction, but spiders are blamed for many more reactions. In particular the misdiagnosis of infections and other skin ailments are commonly attributed to brown recluses.
Cause
Spiders do not feed on humans and typically bites occur as a defense mechanism. This can occur from unintentional contact or trapping of the spider. Most spiders have fangs too small to penetrate human skin. Most bites by species large enough for their bites to be noticeable will have no serious medical consequences.Medically significant spider venoms include various combinations and concentrations of necrotic agents, neurotoxins, and pharmacologically active compounds such as serotonin. Worldwide only two spider venoms have impact on humans—those of the widow and recluse spiders. Unlike snake and scorpion envenomation, widow and recluse species bites rarely have fatal consequences. In addition to the widespread widow and recluse spiders, some spider families found exclusively in remote tropical regions have a lethal neurotoxic venom: the wandering spider in Brazil and the funnel web in Australia. However, due to limited contact between these spiders and humans, deaths have always been rare, and since the introduction of anti-venom in Australia, there have been no funnel web related deaths.
Pathophysiology
A primary concern of the bite of a spider is the effect of its venom. A spider envenomation occurs whenever a spider injects venom into the skin. Not all spider bites involve injection of venom, and the amount of venom injected can vary based on the type of spider and the circumstances of the encounter. The mechanical injury from a spider bite is not a serious concern for humans. However, it is generally the toxicity of spider venom that poses the most risk to human beings; several spiders are known to have venom that can cause injury to humans in the amounts that a spider could inject when biting.
While venoms are by definition toxic substances, most spiders do not have venom that is directly toxic (in the quantities delivered) to require medical attention and, of those that do, severity is typically mild.
Spider venoms work on one of two fundamental principles; they are either neurotoxic (attacking the nervous system) or necrotic (attacking tissues surrounding the bite). In some cases, the venom affects vital organs and systems. The venoms of the widow spiders, Brazilian wandering spider and Australian funnel-web are neurotoxic. Heart muscle damage is an unusual complication of widow venom that may lead to death. Pulmonary edema, which is fluid accumulation in the lungs, is a feared and potentially serious but uncommon complication of funnel-web venom. Recluse and South African sand spider venoms are necrotic. Recluse venom may also cause severe hemolysis (destruction of red blood cells), though this is typically uncommon.
Diagnosis
Reliable diagnoses of spider bites require three conditions: first, there should be clinical effects of the bite at the time or soon afterwards, although there are no symptoms universally diagnostic of a spider bite, and bites by some spiders, e.g. Loxosceles species, may initially be painless; second, the spider should be collected, either at the time of the bite or immediately afterwards; and third, the spider should be identified by an expert arachnologist.Spider bites are commonly misdiagnosed. A review published in 2016 showed that 78% of 134 published medical case studies of supposed spider bites did not meet the necessary criteria for a spider bite to be verified. In the case of the two genera with the highest reported number of bites, Loxosceles and Latrodectus, spider bites were not verified in over 90% of the reports. Even when verification had occurred, details of the treatment and its effects were often lacking. Unverified bite reports likely represent many other conditions, both infectious and non-infectious, which can be confused with spider bites. Many of these conditions are far more common and more likely to be the source of necrotic wounds. An affected person may think that a wound is a spider bite when it is actually an infection with methicillin-resistant Staphylococcus aureus (MRSA). False reports of spider bites in some cases have led to misdiagnosis and mistreatment, with potentially life-threatening consequences.
Prevention
Efforts to prevent bites include clearing clutter and the use of pesticides.OSHA recommends that workers take following measures to prevent spider bite:
Wear a long-sleeved shirt, hat, gloves, and boots when handling boxes, firewood, lumber, rocks, etc.
Inspect and shake out clothing and shoes before getting dressed.
Use insect repellents, such as DEET or Picaridin, on clothing and footwear.
Management
Most spider bites are harmless, and require no specific treatment. Treatment of bites may depend on the type of spider; thus, capture of the spider—either alive, or in a well-preserved condition, is useful.Treatment of spider bites includes washing the wound with soap and water and ice to reduce inflammation. Analgesics and antihistamines may be used; however, antibiotics are not recommended unless there is also a bacterial infection present. Black widow post-envenomation treatment seeks to control resulting pain and nausea.
In the case of bites by widow spiders, Australian funnel-web spiders, or Brazilian wandering spiders, medical attention should be sought immediately as in some cases the bites of these spiders develop into a medical emergency. Antivenom is available for severe widow and funnel-web envenomation.
Necrosis
In almost all cases, recluse bites are self-limited and typically heal without any medical intervention. Recommendations to limit the extent of damage include elevation and immobilization of the affected limb, application of ice. Both local wound care, and tetanus prophylaxis, are simple standards. There is no established treatment for more extensive necrosis. Many therapies have been used including hyperbaric oxygen, dapsone, antihistamines (e.g., cyproheptadine), antibiotics, dextran, glucocorticoids, vasodilators, heparin, nitroglycerin, electric shock, curettage, surgical excision, and antivenom. None of these treatments conclusively show benefit. Studies have shown surgical intervention is ineffective and may worsen outcome. Excision may delay wound healing, cause abscesses, and lead to objectionable scarring.Dapsone, an antibiotic, is commonly used in the United States and Brazil for the treatment of necrosis. There have been conflicting reports with some supporting its efficacy and others have suggested it should no longer be used routinely, if at all.
Antivenom
Use of antivenom for severe spider bites may be indicated, especially in the case of neurotoxic venoms. Effective antivenoms exist for Latrodectus, Atrax, and Phoneutria venom. Antivenom in the United States is in intravenous form but is rarely used, as anaphylactic reaction to the antivenom has resulted in deaths. In Australia, antivenom in intramuscular form was once commonly used, but use has declined. In 2014 some doubt as to antivenom effectiveness has been raised. In South America an antivenom is available for Loxosceles bites, and it appears antivenom may be the most promising therapy for recluse bites. However, in experimental trials recluse antivenom is more effective when given early, and patients often do not present for 24 or more hours after envenomation, possibly limiting the effect of such intervention.
Epidemiology
Estimating the number of spider bites that occur is difficult as the spider involvement may not be confirmed or identified. Several researchers recommend only evaluating verified bites: those that have an eyewitness to the bite, the spider is brought in, and identified by expert. With "suspected arachnidism" the diagnosis came without a spider positively identified.
Africa
Several Latrodectus species (button spiders) live in Africa. South Africa also has six-eyed sand spiders (Hexophthalma species), whose bite may potentially cause skin necrosis. Physicians are advised that the diagnosis may be difficult without a spider.
Australia
Bites by the redbacks (Latrodectus hasselti) number a few thousand yearly throughout the country. Antivenom use is frequent but declining. Children may have fewer complications from bites. Funnel web spider bites are few 30–40 per year and 10% requiring intervention. The Sydney funnel web and related species are only on the east coast of Australia.
Europe
In Switzerland about ten to one hundred spider bites occur per one million people per year. During epidemics of latrodectism from the European black widow upwards of 150 bites a year were documented.
North America
The American Association of Poison Control Centers reported that they received calls regarding nearly 10,000 spider bites in 1994. The spiders of most concern in North America are brown recluse spiders, with nearly 1,500 bites in 2013 and black widow spiders with 1,800 bites. The native habitat of brown recluse spiders is in the southern and central United States, as far north as Iowa. Encounters with brown recluse outside this native region are very rare and bites are thought to be suspect. A dozen major complications were reported in 2013.
South America
Numerous spider bites are recorded in Brazil with 5000+ annually. Loxosceles species are responsible for the majority of reports. Accidents are concentrated in the southern state of Parana with rates as high as 1 per 1,000 people. Bite from Phoneutria (Brazilian wandering spider) number in the thousands with most being mild. Severe effects are noted in 0.5% of cases, mostly in children.
History
Recorded treatment from the 1890s for spider bites in general was rubbing in tobacco juice to the bitten skin, similar to some of the traditional uses of the tobacco plant for various bites and stings from Central and South America. Wild dancing and music was the cure for tarantism—the frenzy was believed to arise from the bite of a spider. An antivenom was developed against wolf spiders in Brazil and used for decades. Wolf spiders have since been exonerated—they never caused illness.
See also
ArachnoServer database
Raventoxin
Vanillotoxin
References
External links
Medical Journal of Australia article gives statistics on the most frequent biters and the most serious bites.
CDC – Venomous Spiders – NIOSH Workplace Safety and Health Topic |
Spontaneous bacterial peritonitis | Spontaneous bacterial peritonitis (SBP) is the development of a bacterial infection in the peritoneum, despite the absence of an obvious source for the infection. It is specifically an infection of the ascitic fluid – an increased volume of peritoneal fluid. Ascites is most commonly a complication of cirrhosis of the liver. It can also occur in patients with nephrotic syndrome. SBP has a high mortality rate.The diagnosis of SBP requires paracentesis, a sampling of the peritoneal fluid taken from the peritoneal cavity. If the fluid contains large numbers of white blood cells known as neutrophils (>250 cells/µL), infection is confirmed and antibiotics will be given, without waiting for culture results. In addition to antibiotics, infusions of albumin are usually administered.Other life-threatening complications such as kidney malfunction and increased liver insufficiency can be triggered by spontaneous bacterial peritonitis. 30% of SBP patients develop kidney malfunction, one of the strongest predictors for mortality. Where there are signs of this development albumin infusion will also be given.Spontaneous fungal peritonitis (SFP) can also occur and this can sometimes accompany a bacterial infection.
Signs and symptoms
Signs and symptoms of spontaneous bacterial peritonitis (SBP) include fevers, chills, nausea, vomiting, abdominal pain and tenderness, general malaise, altered mental status, and worsening ascites. Thirteen percent of patients have no signs or symptoms. In cases of acute or chronic liver failure SBP is one of the main triggers for hepatic encephalopathy, and where there is no other clear causal indication for this, SBP may be suspected.These symptoms can also be the same for a spontaneous fungal peritonitis (SFP) and therefore make a differentiation difficult. Delay of diagnosis can delay antifungal treatment and lead to a higher mortality rate.
Causes
SBP is most commonly caused by gram-negative E. coli, followed by Klebsiella. Common gram-positive bacteria identified include species of Streptococcus, Staphylococcus, and Enterococcus. The percentage of gram-positive bacteria responsible has been increasing.A spontaneous fungal infection can often follow a spontaneous bacterial infection that has been treated with antibiotics. The use of antibiotics can result in an excessive growth of fungi in the gut flora which can then translocate into the peritoneal cavity. Although fungi are much larger than bacteria, the increased intestinal permeability resulting from advanced cirrhosis makes their translocation easier. SFP is mostly caused by species of Candida and most commonly by Candida albicans.
Pathophysiology
H2 antagonists and proton-pump inhibitors are medications that decrease or suppress the secretion of acid by the stomach. Their use in treating cirrhosis is associated with the development of SBP. Bacterial translocation is thought to be the key mechanism for the development of SBP. Small intestinal bacterial overgrowth which may be implicated in this translocation, is found in a large percentage of those with cirrhosis.
With respect to compromised host defenses, patients with severe acute or chronic liver disease are often deficient in complement and may also have malfunctioning of the neutrophilic and reticuloendothelial systems.As for the significance of ascitic fluid proteins, it was demonstrated that cirrhotic patients with ascitic protein concentrations below 1 g/dL were 10 times more likely to develop SBP than individuals with higher concentrations. It is thought that the antibacterial, or opsonic, activity of ascitic fluid is closely correlated with the protein concentration. Additional studies have confirmed the validity of the ascitic fluid protein concentration as the best predictor of the first episode of SBP.In nephrotic syndrome, SBP can frequently affect children but only very rarely can it affect adults.
Diagnosis
Infection of the peritoneum causes an inflammatory reaction with a subsequent increase in the number of neutrophils in the fluid. Diagnosis is made by paracentesis (needle aspiration of the ascitic fluid); SBP is diagnosed if the fluid contains neutrophils at greater than 250 cells per mm3 (equals a cell count of 250 x106/L) fluid in the absence of another reason for this (such as inflammation of one of the internal organs or a perforation).The fluid is also cultured to identify bacteria. If the sample is sent in a plain sterile container, 40% of samples will identify an organism, while if the sample is sent in a bottle with culture medium, the sensitivity increases to 72–90%.
Prevention
All people with cirrhosis might benefit from antibiotics (oral fluoroquinolone norfloxacin) if:
Ascitic fluid protein <1.0 g/dL. Patients with fluid protein <15 g/L and either Child-Pugh score of at least 9 or impaired renal function may also benefit.
Previous SBPPeople with cirrhosis admitted to the hospital should receive prophylactic antibiotics if:
They have bleeding esophageal varicesStudies on the use of rifaximin in cirrhotic patients, have suggested that its use may be effective in preventing spontaneous bacterial peritonitis.
Treatment
Antibiotics
Although there is no high-quality evidence, the third-generation cephalosporins are considered the standard empirical treatment for spontaneous bacterial peritonitis in people with cirrhosis.In practice, cefotaxime is the agent of choice for treatment of SBP. After confirmation of SBP, hospital admission is usually advised for observation and intravenous antibiotic therapy.Where there is a risk of kidney malfunction developing in a syndrome called hepatorenal syndrome, intravenous albumin is usually administered too. Paracentesis may be repeated after 48 hours to ensure control of infection. After recovery from a single episode of SBP, indefinite prophylactic antibiotics are recommended.
Prokinetics
The addition of a prokinetic drug to an antibiotic regimen reduces the incidence of spontaneous bacterial peritonitis possibly via decreasing small intestinal bacterial overgrowth.
Intravenous albumin
A randomized controlled trial found that intravenous albumin on the day of admission and on hospital day 3 can reduce kidney impairment.
Epidemiology
Patients with ascites underwent routine paracentesis, the incidence of active SBP ranged from 10% to 27% at the time of hospital admission.
History
SBP was first described in 1964 by Harold O. Conn.
References
== External links == |
Sporotrichosis | Sporotrichosis, also known as rose handlers disease, is a fungal infection that affects skin, lungs, bone and joint, and can be widespread. It presents with firm painless nodules that later ulcerate. It can be localized or widespread. The disease progresses over a week to several months after the initial exposure to the fungus. Serious complications can also develop in people who have a weakened immune system.Sporotrichosis is caused by fungi of the Sporothrix schenckii species complex. Because S. schenckii is naturally found in soil, hay, sphagnum moss, and plants, it usually affects farmers, gardeners, and agricultural workers. It enters through small cuts in the skin to cause the infection. In case of sporotrichosis affecting the lungs, the fungal spores enter by breathing in. Sporotrichosis can also be acquired from handling cats with the disease; it is an occupational hazard for veterinarians.Treatment depends on the site and extent of infection. Topical antifungals can be applied to skin lesions. Deep infection in lungs may require surgery. Medications used include Itraconazole, posaconazole and amphotericin B. With treatment most people recover. The outcome may not be so good if there is a weak immune system or widespread disease.The causal fungus is found worldwide. The species was named for Benjamin Schenck, a medical student who in 1896 was the first to isolate it from a human specimen.It has been reported in cats, mules, dogs, mice and rats.
Signs and symptoms
Cutaneous or skin sporotrichosisThis is the most common form of this disease. Symptoms of this form include nodular lesions or bumps in the skin, at the point of entry and also along lymph nodes and vessels. The lesion starts off small and painless, and ranges in color from pink to purple. Left untreated, the lesion becomes larger and look similar to a boil and more lesions will appear, until a chronic ulcer develops.Usually, cutaneous sporotrichosis lesions occur in the finger, hand, and arm.Pulmonary sporotrichosisThis rare form of the disease occur when S. schenckii spores are inhaled. Symptoms of pulmonary sporotrichosis include productive coughing, nodules and cavitations of the lungs, fibrosis, and swollen hilar lymph nodes. Patients with this form of sporotrichosis are susceptible to developing tuberculosis and pneumoniaDisseminated sporotrichosisWhen the infection spreads from the primary site to secondary sites in the body, the disease develops into a rare and critical form called disseminated sporotrichosis. The infection can spread to joints and bones (called osteoarticular sporotrichosis) as well as the central nervous system and the brain (called sporotrichosis meningitis).The symptoms of disseminated sporotrichosis include weight loss, anorexia, and appearance of bony lesions.
Complications
Sporotrichosis lesions on the skin can become infected with bacteria. Cellulitis may also occur.
Diagnosis
Sporotrichosis is a chronic disease with slow progression and often subtle symptoms. It is difficult to diagnose, as many other diseases share similar symptoms and therefore must be ruled out.
Patients with sporotrichosis will have antibody against the fungus S. schenckii, however, due to variability in sensitivity and specificity, it may not be a reliable diagnosis for this disease. The confirming diagnosis remains culturing the fungus from the skin, sputum, synovial fluid, and cerebrospinal fluid. Smears should be taken from the draining tracts and ulcers.
Cats with sporotrichosis are unique in that the exudate from their lesions may contain numerous organisms. This makes cytological evaluation of exudate a valuable diagnostic tool in this species. Exudate is pyogranulomatous and phagocytic cells may be packed with yeast forms. These are variable in size, but many are cigar-shaped.
Differential diagnosis
Differential diagnosis includes: leishmaniasis, nocardiosis, mycobacterium marinum, cat-scratch disease, leprosy, syphilis, sarcoidosis and tuberculosis.
Prevention
The majority of sporotrichosis cases occur when the fungus is introduced through a cut or puncture in the skin while handling vegetation containing the fungal spores. Prevention of this disease includes wearing long sleeves and gloves while working with soil, hay bales, rose bushes, pine seedlings, and sphagnum moss.
The risk of sporotrichosis in cats is increased in male cats that roam outdoors. Accordingly, the risk may be reduced by keeping cats indoors or neutering them. Isolating infected animals can also be a preventive measure. The risk of spread from infected cats to humans can be reduced by appropriate biosafety measures, including wearing protective equipment when handling a cat with suspected sporotrichosis and by washing hands, arms and clothing after handling the cat.
Treatment
Treatment of sporotrichosis depends on the severity and location of the disease. The following are treatment options for this condition:
Oral potassium iodidePotassium iodide is an anti-fungal drug that is widely used as a treatment for cutaneous sporotrichosis. Despite its wide use, there is no high-quality evidence for or against this practice. Further studies are needed to assess the efficacy and safety of oral potassium iodide in the treatment of sporotrichosis.Itraconazole (Sporanox) and fluconazoleThese are antifungal drugs. Itraconazole is currently the drug of choice and is significantly more effective than fluconazole. Fluconazole should be reserved for patients who cannot tolerate itraconazole.Amphotericin BThis antifungal medication is delivered intravenously. Many patients, however, cannot tolerate Amphotericin B due to its potential side effects of fever, nausea, and vomiting.
Lipid formulations of amphotericin B are usually recommended instead of amphotericin B deoxycholate because of a better adverse-effect profile. Amphotericin B can be used for severe infection during pregnancy. For children with disseminated or severe disease, amphotericin B deoxycholate can be used initially, followed by itraconazole.In case of sporotrichosis meningitis, the patient may be given a combination of Amphotericin B and 5-fluorocytosine/Flucytosine.Terbinafine500mg and 1000mg daily dosages of terbinafine for twelve to 24 weeks has been used to treat cutaneous sporotrichosis.Newer triazolesSeveral studies have shown that posaconazole has in vitro activity similar to that of amphotericin B and itraconazole; therefore, it shows promise as an alternative therapy. However, voriconazole susceptibility varies. Because the correlation between in vitro data and clinical response has not been demonstrated, there is insufficient evidence to recommend either posaconazole or voriconazole for treatment of sporotrichosis at this time.SurgeryIn cases of bone infection and cavitary nodules in the lungs, surgery may be necessary.Heat therapyHeat creates higher tissue temperatures, which may inhibit fungus growth while the immune system counteracts the infection. The "pocket warmer" used for this purpose has the advantage of being able to maintain a constant temperature of 44 degrees-45 degrees C on the skin surface for several hours, while permitting unrestricted freedom of movement. The duration of treatment depends on the type of lesion, location, depth, and size. Generally, local application for 1-2 h per day, or in sleep time, for 5-6 weeks seems to be sufficient.
Other animals
Sporotrichosis can be diagnosed in domestic and wild mammals. In veterinary medicine it is most frequently seen in cats and horses. Cats have a particularly severe form of cutaneous sporotrichosis. Infected cats may exhibit abscesses, cellulitis, or draining wounds that fail to respond to antibiotic treatment.Sporotrichosis can spread from nonhuman animals to humans (zoonosis). Infected cats in particular exude large quantities of Sporothrix organisms from their skin leasions and can spread the infection to people who handle them. Although cats are the most common animal source, the infection has also been known to spread to humans from dogs, rats, squirrels, and armadillos.
See also
Mucormycosis
List of cutaneous conditions
References
External links
Sporotrichosis by Health in Plain English (with pictures)
Sporotrichosis by Centers for Disease Control and Prevention (CDC) |
Strabismus | Strabismus is a vision disorder in which the eyes do not properly align with each other when looking at an object. The eye that is focused on an object can alternate. The condition may be present occasionally or constantly. If present during a large part of childhood, it may result in amblyopia, or lazy eyes, and loss of depth perception. If onset is during adulthood, it is more likely to result in double vision.Strabismus can occur due to muscle dysfunction, farsightedness, problems in the brain, trauma or infections. Risk factors include premature birth, cerebral palsy and a family history of the condition. Types include esotropia, where the eyes are crossed ("cross eyed"); exotropia, where the eyes diverge ("lazy eyed" or "wall eyed"); and hypertropia or hypotropia where they are vertically misaligned. They can also be classified by whether the problem is present in all directions a person looks (comitant) or varies by direction (incomitant). Diagnosis may be made by observing the light reflecting from the persons eyes and finding that it is not centered on the pupil. This is known as the Hirschberg reflex. Another condition that produces similar symptoms is a cranial nerve disease.Treatment depends on the type of strabismus and the underlying cause. This may include the use of glasses and possibly surgery. Some types benefit from early surgery. Strabismus occurs in about 2% of children. The term comes from the Ancient Greek word στραβισμός (strabismós), meaning a squinting. Other terms for the condition include "squint" and "cast of the eye". "Wall-eye" has been used when the eyes turn away from each other.
Signs and symptoms
When observing a person with strabismus, the misalignment of the eyes may be quite apparent. A person with a constant eye turn of significant magnitude is very easy to notice. However, a small magnitude or intermittent strabismus can easily be missed upon casual observation. In any case, an eye care professional can conduct various tests, such as cover testing, to determine the full extent of the strabismus.Symptoms of strabismus include double vision and eye strain. To avoid double vision, the brain may adapt by ignoring one eye. In this case, often no noticeable symptoms are seen other than a minor loss of depth perception. This deficit may not be noticeable in someone who has had strabismus since birth or early childhood, as they have likely learned to judge depth and distances using monocular cues. However, a constant unilateral strabismus causing constant suppression is a risk for amblyopia in children. Small-angle and intermittent strabismus are more likely to cause disruptive visual symptoms. In addition to headaches and eye strain, symptoms may include an inability to read comfortably, fatigue when reading, and unstable or "jittery" vision.
Psychosocial effects
People of all ages who have noticeable strabismus may experience psychosocial difficulties. Attention has also been drawn to potential socioeconomic impact resulting from cases of detectable strabismus. A socioeconomic consideration exists as well in the context of decisions regarding strabismus treatment, including efforts to re-establish binocular vision and the possibility of stereopsis recovery.One study has shown that strabismic children commonly exhibit behaviors marked by higher degrees of inhibition, anxiety, and emotional distress, often leading to outright emotional disorders. These disorders are often related to a negative perception of the child by peers. This is due not only to an altered aesthetic appearance, but also because of the inherent symbolic nature of the eye and gaze, and the vitally important role they play in an individuals life as social components. For some, these issues improved dramatically following strabismus surgery. Notably, strabismus interferes with normal eye contact, often causing embarrassment, anger, and feelings of awkwardness, thereby affecting social communication in a fundamental way, with a possible negative effect on self esteem.Children with strabismus, particularly those with exotropia, an outward turn, may be more likely to develop a mental health disorder than normal-sighted children. Researchers have theorized that esotropia (an inward turn) was not found to be linked to a higher propensity for mental illness due to the age range of the participants, as well as the shorter follow-up time period; esotropic children were monitored to a mean age of 15.8 years, compared with 20.3 years for the exotropic group.A subsequent study with participants from the same area monitored people with congenital esotropia for a longer time period; results indicated that people who are esotropic were also more likely to develop mental illness of some sort upon reaching early adulthood, similar to those with constant exotropia, intermittent exotropia, or convergence insufficiency. The likelihood was 2.6 times that of controls. No apparent association with premature birth was observed, and no evidence was found linking later onset of mental illness to psychosocial stressors frequently encountered by those with strabismus.Investigations have highlighted the impact that strabismus may typically have on quality of life. Studies in which subjects were shown images of strabismic and non-strabismic persons showed a strong negative bias towards those visibly displaying the condition, clearly demonstrating the potential for future socioeconomic implications with regard to employability, as well as other psychosocial effects related to an individuals overall happiness.Adult and child observers perceived a right heterotropia as more disturbing than a left heterotropia, and child observers perceived an esotropia as "worse" than an exotropia. Successful surgical correction of strabismus, for adult as well as children, has been shown to have a significantly positive effect on psychological well-being.Very little research exists regarding coping strategies employed by adult strabismics. One study categorized coping methods into three subcategories: avoidance (refraining from participation in an activity), distraction (deflecting attention from the condition), and adjustment (approaching an activity differently). The authors of the study suggested that individuals with strabismus may benefit from psychosocial support such as interpersonal skills training. No studies have evaluated whether psychosocial interventions have had any benefits on individuals undergoing strabismus surgery.
Pathophysiology
The extraocular muscles control the position of the eyes. Thus, a problem with the muscles or the nerves controlling them can cause paralytic strabismus. The extraocular muscles are controlled by cranial nerves III, IV, and VI. An impairment of cranial nerve III causes the associated eye to deviate down and out and may or may not affect the size of the pupil. Impairment of cranial nerve IV, which can be congenital, causes the eye to drift up and perhaps slightly inward. Sixth nerve palsy causes the eyes to deviate inward and has many causes due to the relatively long path of the nerve. Increased cranial pressure can compress the nerve as it runs between the clivus and brain stem. Also, if the doctor is not careful, twisting of the babys neck during forceps delivery can damage cranial nerve VI.Evidence indicates a cause for strabismus may lie with the input provided to the visual cortex. This allows for strabismus to occur without the direct impairment of any cranial nerves or extraocular muscles.Strabismus may cause amblyopia due to the brain ignoring one eye. Amblyopia is the failure of one or both eyes to achieve normal visual acuity despite normal structural health. During the first seven to eight years of life, the brain learns how to interpret the signals that come from an eye through a process called visual development. Development may be interrupted by strabismus if the child always fixates with one eye and rarely or never fixates with the other. To avoid double vision, the signal from the deviated eye is suppressed, and the constant suppression of one eye causes a failure of the visual development in that eye.Also, amblyopia may cause strabismus. If a great difference in clarity occurs between the images from the right and left eyes, input may be insufficient to correctly reposition the eyes. Other causes of a visual difference between right and left eyes, such as asymmetrical cataracts, refractive error, or other eye disease, can also cause or worsen strabismus.Accommodative esotropia is a form of strabismus caused by refractive error in one or both eyes. Due to the near triad, when a person engages accommodation to focus on a near object, an increase in the signal sent by cranial nerve III to the medial rectus muscles results, drawing the eyes inward; this is called the accommodation reflex. If the accommodation needed is more than the usual amount, such as with people with significant hyperopia, the extra convergence can cause the eyes to cross.
Diagnosis
During an eye examination, a test such as cover testing or the Hirschberg test is used in the diagnosis and measurement of strabismus and its impact on vision. Retinal birefringence scanning can be used for screening of young children for eye misalignment. A Cochrane review to examine different types of diagnosis test found only one study. This study used a photoscreener which was found to have high specificity (accurate in identifying those without the condition) but low sensitivity (inaccurate in identifying those with the condition).Several classifications are made when diagnosing strabismus.
Latency
Strabismus can be manifest (-tropia) or latent (-phoria). A manifest deviation, or heterotropia (which may be eso-, exo-, hyper-, hypo-, cyclotropia or a combination of these), is present while the person views a target binocularly, with no occlusion of either eye. The person is unable to align the gaze of each eye to achieve fusion. A latent deviation, or heterophoria (eso-, exo-, hyper-, hypo-, cyclophoria or a combination of these), is only present after binocular vision has been interrupted, typically by covering one eye. This type of person can typically maintain fusion despite the misalignment that occurs when the positioning system is relaxed. Intermittent strabismus is a combination of both of these types, where the person can achieve fusion, but occasionally or frequently falters to the point of a manifest deviation.
Onset
Strabismus may also be classified based on time of onset, either congenital, acquired, or secondary to another pathological process. Many infants are born with their eyes slightly misaligned, and this is typically outgrown by six to 12 months of age. Acquired and secondary strabismus develop later. The onset of accommodative esotropia, an overconvergence of the eyes due to the effort of accommodation, is mostly in early childhood. Acquired non-accommodative strabismus and secondary strabismus are developed after normal binocular vision has developed. In adults with previously normal alignment, the onset of strabismus usually results in double vision.
Any disease that causes vision loss may also cause strabismus, but it can also result from any severe and/or traumatic injury to the affected eye. Sensory strabismus is strabismus due to vision loss or impairment, leading to horizontal, vertical or torsional misalignment or to a combination thereof, with the eye with poorer vision drifting slightly over time. Most often, the outcome is horizontal misalignment. Its direction depends on the persons age at which the damage occurs: people whose vision is lost or impaired at birth are more likely to develop esotropia, whereas people with acquired vision loss or impairment mostly develop exotropia. In the extreme, complete blindness in one eye generally leads to the blind eye reverting to an anatomical position of rest.Although many possible causes of strabismus are known, among them severe and/or traumatic injuries to the affected eye, in many cases no specific cause can be identified. This last is typically the case when strabismus is present since early childhood.Results of a U.S. cohort study indicate that the incidence of adult-onset strabismus increases with age, especially after the sixth decade of life, and peaks in the eighth decade of life, and that the lifetime risk of being diagnosed with adult-onset strabismus is approximately 4%.
Laterality
Strabismus may be classified as unilateral if the one eye consistently deviates, or alternating if either of the eyes can be seen to deviate. Alternation of the strabismus may occur spontaneously, with or without subjective awareness of the alternation. Alternation may also be triggered by various tests during an eye exam. Unilateral strabismus has been observed to result from a severe or traumatic injury to the affected eye.
Direction and latency
Horizontal deviations are classified into two varieties, using prefixes: eso- describes inward or convergent deviations towards the midline, while exo- describes outward or divergent misalignment. Vertical deviations are also classified into two varieties, using prefixes: hyper- is the term for an eye whose gaze is directed higher than the fellow eye, while hypo- refers to an eye whose gaze is directed lower. Finally, the prefix cyclo- refers to torsional strabismus, which occurs when the eyes rotate around the anterior-posterior axis to become misaligned and is quite rare.
These five directional prefixes are combined with -tropia (if manifest) or -phoria (if latent) to describe various types of strabismus. For example, a constant left hypertropia exists when a persons left eye is always aimed higher than the right. A person with an intermittent right esotropia has a right eye that occasionally drifts toward the persons nose, but at other times is able to align with the gaze of the left eye. A person with a mild exophoria can maintain fusion during normal circumstances, but when the system is disrupted, the relaxed posture of the eyes is slightly divergent.
Other considerations
Strabismus can be further classified as follows:
Paretic strabismus is due to paralysis of one or several extraocular muscles.
Nonparetic strabismus is not due to paralysis of extraocular muscles.
Comitant (or concomitant) strabismus is a deviation that is the same magnitude regardless of gaze position.
Noncomitant (or incomitant) strabismus has a magnitude that varies as the person shifts his or her gaze up, down, or to the sides.Nonparetic strabismus is generally concomitant. Most types of infant and childhood strabismus are comitant. Paretic strabismus can be either comitant or noncomitant. Incomitant strabismus is almost always caused by a limitation of ocular rotations that is due to a restriction of extraocular eye movement (ocular restriction) or due to extraocular muscle paresis. Incomitant strabismus cannot be fully corrected by prism glasses, because the eyes would require different degrees of prismatic correction dependent on the direction of the gaze. Incomitant strabismus of the eso- or exo-type are classified as "alphabet patterns": they are denoted as A- or V- or more rarely λ-, Y- or X-pattern depending on the extent of convergence or divergence when the gaze moves upward or downward. These letters of the alphabet denote ocular motility pattern that have a similarity to the respective letter: in the A-pattern there is (relatively speaking) more convergence when the gaze is directed upwards and more divergence when it is directed downwards, in the V-pattern it is the contrary, in the λ-, Y- and X-patterns there is little or no strabismus in the middle position but relatively more divergence in one or both of the upward and downward positions, depending on the "shape" of the letter.Types of incomitant strabismus include: Duane syndrome, horizontal gaze palsy, and congenital fibrosis of the extraocular muscles.When the misalignment of the eyes is large and obvious, the strabismus is called large-angle, referring to the angle of deviation between the lines of sight of the eyes. Less severe eye turns are called small-angle strabismus. The degree of strabismus can vary based on whether the person is viewing a distant or near target.
Strabismus that sets in after eye alignment had been surgically corrected is called consecutive strabismus.
Differential diagnosis
Pseudostrabismus is the false appearance of strabismus. It generally occurs in infants and toddlers whose bridge of the nose is wide and flat, causing the appearance of esotropia due to less sclera being visible nasally. With age, the bridge of the childs nose narrows and the folds in the corner of the eyes become less prominent.
Management
Retinoblastoma may also result in abnormal light reflection from the eye.
Strabismus is usually treated with a combination of eyeglasses, vision therapy, and surgery, depending on the underlying reason for the misalignment. As with other binocular vision disorders, the primary goal is comfortable, single, clear, normal binocular vision at all distances and directions of gaze.Whereas amblyopia (lazy eye), if minor and detected early, can often be corrected with use of an eye patch on the dominant eye or vision therapy, the use of eye patches is unlikely to change the angle of strabismus.
Glasses
In cases of accommodative esotropia, the eyes turn inward due to the effort of focusing far-sighted eyes, and the treatment of this type of strabismus necessarily involves refractive correction, which is usually done via corrective glasses or contact lenses, and in these cases surgical alignment is considered only if such correction does not resolve the eye turn.
In case of strong anisometropia, contact lenses may be preferable to spectacles because they avoid the problem of visual disparities due to size differences (aniseikonia) which is otherwise caused by spectacles in which the refractive power is very different for the two eyes. In a few cases of strabismic children with anisometropic amblyopia, a balancing of the refractive error eyes via refractive surgery has been performed before strabismus surgery was undertaken.Early treatment of strabismus when the person is a baby may reduce the chance of developing amblyopia and depth perception problems. However, a review of randomized controlled trials concluded that the use of corrective glasses to prevent strabismus is not supported by existing research. Most children eventually recover from amblyopia if they have had the benefit of patches and corrective glasses. Amblyopia has long been considered to remain permanent if not treated within a critical period, namely before the age of about seven years; however, recent discoveries give reason to challenge this view and to adapt the earlier notion of a critical period to account for stereopsis recovery in adults.
Eyes that remain misaligned can still develop visual problems. Although not a cure for strabismus, prism lenses can also be used to provide some temporary comfort and to prevent double vision from occurring.
Glasses affect the position by changing the persons reaction to focusing. Prisms change the way light, and therefore images, strike the eye, simulating a change in the eye position.
Surgery
Strabismus surgery does not remove the need for a child to wear glasses. Currently it is unknown whether there are any differences for completing strabismus surgery before or after amblyopia therapy in children.Strabismus surgery attempts to align the eyes by shortening, lengthening, or changing the position of one or more of the extraocular eye muscles. The procedure can typically be performed in about an hour, and requires about six to eight weeks for recovery. Adjustable sutures may be used to permit refinement of the eye alignment in the early postoperative period. It is unclear if there are differences between adjustable versus non-adjustable sutures as it has not been sufficiently studied. An alternative to the classical procedure is minimally invasive strabismus surgery (MISS) that uses smaller incisions than usual.
Medication
Medication is used for strabismus in certain circumstances. In 1989, the US FDA approved botulinum toxin therapy for strabismus in people over 12 years old. Most commonly used in adults, the technique is also used for treating children, in particular children affected by infantile esotropia. The toxin is injected in the stronger muscle, causing temporary and partial paralysis. The treatment may need to be repeated three to four months later once the paralysis wears off. Common side effects are double vision, droopy eyelid, overcorrection, and no effect. The side effects typically resolve also within three to four months. Botulinum toxin therapy has been reported to be similarly successful as strabismus surgery for people with binocular vision and less successful than surgery for those who have no binocular vision.
Prognosis
When strabismus is congenital or develops in infancy, it can cause amblyopia, in which the brain ignores input from the deviated eye. Even with therapy for amblyopia, stereoblindness may occur. The appearance of strabismus may also be a cosmetic problem. One study reported 85% of adult with strabismus "reported that they had problems with work, school, and sports because of their strabismus." The same study also reported 70% said strabismus "had a negative effect on their self-image." A second operation is sometimes required to straighten the eyes.
Other animals
Siamese cats and related breeds are prone to having crossed eyes. Research suggests this is a behavioral compensation for developmental abnormalities in the routing of nerves in the optic chiasm.Strabismus may also occur in dogs, most often due to imbalanced muscle tone of the muscles surrounding the eye. Some breeds such as the Shar Pei are genetically predisposed to the condition. Treatment may involve surgery or therapy to strengthen the muscles.
References
Further reading
Donahue SP, Buckley EG, Christiansen SP, Cruz OA, Dagi LR (August 2014). "Difficult problems: strabismus". Journal of American Association for Pediatric Ophthalmology and Strabismus. 18 (4): e41. doi:10.1016/j.jaapos.2014.07.132.
External links
AAO Complex strabismus simulator
UC Davis strabismus simulator |
Strongyloidiasis | Strongyloidiasis is a human parasitic disease caused by the nematode called Strongyloides stercoralis, or sometimes the closely related S. fülleborni. These helminths belong to a group of nematodes called roundworms. These intestinal worms can cause a number of symptoms in people, principally skin symptoms, abdominal pain, diarrhea and weight loss, but also many other specific and vague symptoms in disseminated disease, and severe life-threatening conditions through hyperinfection. In some people, particularly those who require corticosteroids or other immunosuppressive medication, Strongyloides can cause a hyperinfection syndrome that can lead to death if untreated. The diagnosis is made by blood and stool tests. The medication ivermectin is widely used to treat strongyloidiasis.
Strongyloidiasis is a type of soil-transmitted helminthiasis. Low estimates postulate it to affect 30–100 million people worldwide, mainly in tropical and subtropical countries, while higher estimates conservatively extrapolate that infection is upwards to or above 370 million people. It belongs to the group of neglected tropical diseases, and worldwide efforts are aimed at eradicating the infection.
Signs and symptoms
Strongyloides infection occurs in five forms. As the infection continues and the larvae matures, there may be respiratory symptoms (Löfflers syndrome). The infection may then become chronic with mainly digestive symptoms. On reinfection (when larvae migrate through the body) from the skin to the lungs and finally to the small intestine, there may be respiratory, skin and digestive symptoms. Finally, the hyperinfection syndrome causes symptoms in many organ systems, including the central nervous system.
Uncomplicated disease
Frequently asymptomatic. Gastrointestinal system symptoms include abdominal pain and diarrhea and/or conversely constipation. Pulmonary symptoms (including Löfflers syndrome) can occur during pulmonary migration of the filariform larvae. Pulmonary infiltrate may be present through radiological investigation. Dermatologic manifestations include urticarial rashes in the buttocks and waist areas as well as larva currens. Eosinophilia is generally present. Strongyloidiasis can become chronic and then become completely asymptomatic.
Disseminated disease
Disseminated strongyloidiasis occurs when patients with chronic strongyloidiasis become immunosuppressed. There is a distinction to be made between dissemination and hyperinfection. It is mainly a semantic distinction. There can be mild dissemination where the worm burden is relatively lower yet causes insidious symptoms, or extreme dissemination that the term hyperinfection is used to describe. Thus hyperinfection of varying levels of severe dissemination may present with abdominal pain, distension, shock, pulmonary and neurologic complications, sepsis, haemorrhage, malabsorption, and depending on the combination, degree, number, and severity of symptoms, is potentially fatal. The worms enter the bloodstream from the bowel wall, simultaneously allowing entry of bowel bacteria such as Escherichia coli. This may cause symptoms such as sepsis (bloodstream infection), and the bacteria may spread to other organs where they may cause localized infection such as meningitis. Dissemination without hyperinfection may present to a lesser degree the above and many other symptoms.Dissemination can occur many decades after the initial infection and has been associated with high dose corticosteroids, organ transplant, any other instances and causes of immunosuppression, HIV, lepromatous leprosy, tertiary syphilis, aplastic anemia, malnutrition, advanced tuberculosis and radiation poisoning. It is often recommended that patients being started on immunosuppression be screened for chronic strongyloidiasis; however, this is often impractical (screen tests are often unavailable) and in developed countries, the prevalence of chronic strongyloidiasis is very small, so screening is usually not cost-effective, except in endemic areas. The reality of global travel and need for modern advanced healthcare, even in the so-called "developed world", necessitates that in non-endemic areas there is easily accessible testing and screening for neglected tropical diseases such as strongyloidiasis.It is important to note that there is not necessarily any eosinophilia in the disseminated disease. Absence of eosinophilia in an infection limited to the gastrointestinal tract may indicate poor prognosis. Eosinophilia is often absent in disseminated infection. Steroids will also suppress eosinophilia, while leading to dissemination and potential hyperinfection.Escalated disseminated infections caused by immunosuppression can result in a wide variety and variable degree of disparate symptoms depending on the condition and other biological aspects of the individual, that may emulate other diseases or diagnoses. In addition to the many palpable gastrointestinal and varied other symptoms drastic cachexia amidst lassitude is often present, although severe disseminated infections can occur in individuals without weight loss regardless of body mass index.
Diagnosis
Diagnosis rests on the microscopic identification of larvae (rhabditiform and occasionally filariform) in the stool or duodenal fluid. Examination of many samples may be necessary, and not always sufficient, because direct stool examination is relatively insensitive, with a single sample only able to detect larvae in about 25% of cases. It can take 4 weeks from initial infection to the passage of larvae in the stool.
The stool can be examined in wet mounts:
directly
after concentration (formalin-ethyl acetate)
after recovery of the larvae by the Baermann funnel technique
after culture by the Harada-Mori filter paper technique
after culture in agar platesCulture techniques are the most sensitive, but are not routinely available in the West. In the UK, culture is available at either of the Schools of Tropical Medicine in Liverpool or London. Direct examination must be done on stool that is freshly collected and not allowed to cool down, because hookworm eggs hatch on cooling and the larvae are very difficult to distinguish from Strongyloides.Finding Strongyloides in the stool is negative in up to 70% of tests. It is important to undergo frequent stool sampling as well as duodenal biopsy if a bad infection is suspected. The duodenal fluid can be examined using techniques such as the Enterotest string or duodenal aspiration. Larvae may be detected in sputum from patients with disseminated strongyloidiasis.
Given the poor ability of stool examination to diagnose Strongyloides, detecting antibodies by ELISA can be useful. Serology can cross-react with other parasites, remain positive for years after successful treatment or be falsely negative in immunocompromised patients. Infected patients will also often have an elevated eosinophil count, with an average of absolute eosinophil count of 1000 in one series. Eosinophilia of a gastrointestinal infection may fluctuate in response to larval output, or may be permanently lacking in some disseminated infections. Hence lack of eosinophilia is not evidence of absence of infection. The combination of clinical suspicion, a positive antibody and a peripheral eosinophilia can be strongly suggestive of infection.It would be greatly useful to have significant advances in the sensitivity of the means of diagnosis, as it would also solve the challenging problem of proof of cure. If definitive diagnosis is solved then it stands to reason that proof of cure becomes easily realizable.
Treatment
The consensus drug of choice for the treatment of uncomplicated strongyloidiasis is ivermectin. However, even if it is considered the main drug of choice, recent studies have illustrated the challenges in ivermectin curing strongyloidiasis. Ivermectin does not kill the Strongyloides larvae, only the adult worms, therefore repeat dosing may be necessary to properly eradicate the infection. There is an auto-infective cycle of roughly two weeks in which ivermectin should be re-administered; however, additional dosing may still be necessary as it will not kill Strongyloides in the blood or larvae deep within the bowels or diverticula. Other drugs that can be effective are albendazole and thiabendazole (25 mg/kg twice daily for 5 days—400 mg maximum (generally)). All patients who are at risk of disseminated strongyloidiasis should be treated. The optimal duration of treatment for patients with disseminated infections is not clear.Treatment of strongyloidiasis can be difficult and if ceasing treatment before being entirely cleared Strongyloides via the autoinfective cycle has been known to live in individuals for decades; even after initial or inadequate sustained treatment. Continued treatment, blood and stool monitoring thus may be necessary even if symptoms temporarily resolve. As cited earlier, due to the fact that some infections are insidiously asymptomatic, and relatively expensive bloodwork is often inconclusive via false-positives or false-negatives, just as stool samples can be unreliable in diagnoses, there is yet unfortunately no real gold standard for proof of cure, mirroring the lack of an efficient and reliable methodology of diagnosis. An objective eradication standard for strongyloidiasis is elusive given the high degree of suspicion needed to even begin treatment, the sometimes difficulty of the only definitive diagnostic criteria of detecting and isolating larvae or adult Strongyloides, the importance of early diagnosis, particularly before steroid treatments, and the very wide variability and exclusion/inclusion of differing collections of diffuse symptoms. Disregarding mis-ascribing bonafide delusional parasitosis disorders, strongyloidiasis should be more well known among medical professionals and have serious consideration for broad educational campaigns in effected geographic locales both within the semi-tropical developed world and otherwise, as well as in the tropical developing world where, among many other neglected tropical diseases, it is endemic.Government programs are needed to help decontaminate endemic areas and to help effected populations from infection. Furthermore, progress is required in establishing financial support to facilitate and cover affordable medications for individuals in effected at-risk regions and communities to help continuing treatments.There are conflicting reports on effective drug treatments. Ivermectin ineffectiveness and rising drug resistance has been documented. Albendazole is noted by the WHO as being the least effective. Thiabendazole can have severe side effects and is unavailable in many countries. Major inroads are required to advance the development of successful medications and drug protocols for strongyloidiasis and other neglected tropical diseases.Contagiousness via textiles, unlike Enterobius vermicularis, is unfounded. As is, generally speaking, person to person contagiousness of asymptomatic and disseminated infection. It has rarely been transmitted through organ transplantation. Married Vietnam War veterans who were infected, yet never developed significant hyperinfection, lived for multiple decades with non-debilitating disseminated infection, without treatment, with wives who failed to ever contract infection. Contraction occurs overwhelmingly from skin exposure to any contaminated soil, contaminated potting soil, contaminated waters, lack of sanitation, or environmental factors as potential vectors. Nearly never to extraordinarily very rarely documented is transmission from person to person (besides from infected male homosexual sex), other than closeness of contact to the productive coughing of a very ill hyperinfected individual. It has been shown possible to occur in that situation, or potentially other similar scenarios, it is speculated via pulmonary secretions of a direly hyperinfected individual. In which case treatment for others may be indicated, if deemed necessary by proximity, symptoms, precautions, probable exposures to the same vectors, or through screening of serology and stool samples, until infection is eradicated.Before administering steroids at least somewhat screening for infection in even remotely potentially susceptible individuals in order to prevent escalating the infection is advised. As not doing so in certain cohorts can have extremely high mortality rates from inadvertently caused hyperinfection via immunosuppression of application of certain steroids. Thus extreme caution with respect to iatrogenic risks is crucial to avoiding deaths or other adverse consequences in treatment, that of course prefigures a correct diagnosis. People with high exposure to Strongyloides stercoralis may mitigate the risk of strongyloidiasis hyperinfection associated with corticosteroid treatment, with the presumptive use of ivermectin. Such hyperinfection has been a particular concern during the COVID-19 pandemic because of the use of corticosteroids for treatment of COVID-19 symptoms. The CDC and other international bodies recommend the use of ivermectin for refugees from areas which have a risk of strongyloidiasis.During the 1940s, the treatment of choice was enteric coated tablets of 60 mg gentian violet, three times daily, for 16 days. The cure rate was reported to be only about 50 to 70 percent, requiring repeat courses. It is possible the cure rate was even less than that published in the literature, due to the difficulty in positively diagnosing infection.
Epidemiology
Low estimates postulate it to affect 30–100 million people worldwide, mainly in tropical and subtropical countries, while higher estimates conservatively extrapolate that infection is upwards to or above 370 million people. It belongs to the group of neglected tropical diseases, and worldwide efforts are aimed at eradicating the infection.
History
The disease was first recognized in 1876 by the French physician Louis Alexis Normand, working in the naval hospital in Toulon; he identified the adult worms, and sent them to Arthur Réné Jean Baptiste Bavay, chief inspector for health, who observed that these were the adult forms of the larvae found in the stool. In 1883 the German parasitologist Rudolf Leuckart made initial observations on the life cycle of the parasite, and Belgian physician Paul Van Durme (building on observations by the German parasitologist Arthur Looss) described the mode of infection through the skin. The German parasitologist Friedrich Fülleborn described autoinfection and the way by which strongyloidiasis involves the intestine. Interest in the condition increased in the 1940s when it was discovered that those who had acquired the infection abroad and then received immunosuppression developed hyperinfestation syndrome.
References
External links
Strongyloidiasis. U.S. Centers for Disease Control and Prevention (CDC) |
Sympathetic ophthalmia | Sympathetic ophthalmia (SO), also called spared eye injury, is a diffuse granulomatous inflammation of the uveal layer of both eyes following trauma to one eye. It can leave the affected person completely blind. Symptoms may develop from days to several years after a penetrating eye injury. It typically results from a delayed hypersensitivity reaction.
Signs and symptoms
Eye floaters and loss of accommodation are among the earliest symptoms. The disease may progress to severe inflammation of the uveal layer of the eye (uveitis) with pain and sensitivity of the eyes to light. The affected eye often remains relatively painless while the inflammatory disease spreads through the uvea, where characteristic focal infiltrates in the choroid named Dalén–Fuchs nodules can be seen. The retina, however, usually remains uninvolved, although perivascular cuffing of the retinal vessels with inflammatory cells may occur. Swelling of the optic disc (papilledema), secondary glaucoma, vitiligo, and poliosis of the eyelashes may accompany SO.
Pathophysiology
Sympathetic ophthalmia is currently thought to be an autoimmune inflammatory response toward ocular antigens, specifically a delayed hypersensitivity to melanin-containing structures from the outer segments of the photoreceptor layer of the retina. The immune system, which normally is not exposed to ocular proteins, is introduced to the contents of the eye following traumatic injury. Once exposed, it senses these antigens as foreign, and begins attacking them. The onset of this process can be from days to years after the inciting traumatic event.
Diagnosis
Diagnosis is clinical, seeking a history of eye injury. An important differential diagnosis is Vogt–Koyanagi–Harada syndrome (VKH), which is thought to have the same pathogenesis, without a history of surgery or penetrating eye injury.
Still experimental, skin tests with soluble extracts of human or bovine uveal tissue are said to elicit delayed hypersensitivity responses in these patients. Additionally, circulating antibodies to uveal antigens have been found in patients with SO and VKH, as well as those with long-standing uveitis, making this a less than specific assay for SO and VKH.
Treatment
Because SO is so rarely encountered following eye injury, even when the injured eye is retained, the first choice of treatment may not be enucleation or evisceration, especially if there is a chance that the injured eye may regain some function. Additionally, with current advanced surgical techniques, many eyes once considered nonviable now have a fair prognosis.
However, only if the injured eye has completely lost its vision and has no potential for any visual recovery, prevention of SO is done by enucleation of the injured eye preferably within the first 2 weeks of injury. Evisceration—the removal of the contents of the globe while leaving the sclera and extraocular muscles intact—is easier to perform, offers long-term orbital stability, and is more aesthetically pleasing, i.e., a greater measure of movement of the prosthesis and thus a more natural appearance. There is concern, however, that evisceration may lead to a higher incidence of SO compared to enucleation. Several retrospective studies involving over 3,000 eviscerations, however, have failed to identify a single case of SO.
Once SO is developed, immunosuppressive therapy is the mainstay of treatment. When initiated promptly following injury, it is effective in controlling the inflammation and improving the prognosis. Mild cases may be treated with local application of corticosteroids and pupillary dilators. More severe or progressive cases require high-dose systemic corticosteroids for months to years. Patients who become resistant to corticosteroids or develop side effects of long-term corticosteroid therapy (osteoporosis and pathologic fractures, mental status changes, etc.), may be candidates for therapy with chlorambucil, cyclophosphamide, or ciclosporin.
Epidemiology
Sympathetic ophthalmia is rare, affecting 0.2% to 0.5% of non-surgical eye wounds, and less than 0.01% of surgical penetrating eye wounds. There are no gender or racial differences in incidence of SO.
History
Although descriptions of sympathetic ophthalmia can be found in ancient Greek texts, modern understanding of SO derives from the works of Scotlands William MacKenzie who characterized and named the disease sympathetic ophthalmitis. At MacKenzies time, oral mercury and leeches applied to the conjunctiva were the treatments of choice for SO.It is thought that Louis Braille, who injured one of his eyes as a child, lost vision in his other eye owing to SO. James Thurbers adult blindness was also diagnosed as sympathetic ophthalmia deriving from the loss of an eye when he was six years old.
See also
Vogt–Koyanagi–Harada disease
References
== External links == |
Eucestoda | Eucestoda, commonly referred to as tapeworms, is the larger of the two subclasses of flatworms in the class Cestoda (the other subclass is Cestodaria). Larvae have six posterior hooks on the scolex (head), in contrast to the ten-hooked Cestodaria. All tapeworms are endoparasites of vertebrates, living in the digestive tract or related ducts. Examples are the pork tapeworm (Taenia solium) with a human definitive host, and pigs as the secondary host, and Moniezia expansa, the definitive hosts of which are ruminants.
Body structure
Adult Eucestoda have a white-opaque dorso-ventrally flattened appearance, and are elongated, ranging in length from a few millimeters to 25 meters. Almost all members, except members of the orders Caryophyllidea and Spathebothriidea, are polyzoic with repeated sets of reproductive organs down the body length, and almost all members, except members of the order Dioecocestidae, are protandral hermaphrodites. Most except caryophyllideans consist of a few to 4000 proglottids (segments) that show a characteristic body differentiation pattern into scolex (head), neck, and strobila.The scolex, located at the anterior end, is a small (usually less than 1 mm) holdfast organ with specific systems for fastening itself to materials: rostrum, acetabula, suckers, bothria, grooves, and hooks. The small neck region, directly behind the scolex, consists of an undifferentiated tissue region of proglottid proliferation, leading into a zone of increasing and continuous proglottid differentiation. As such, the main and largest section of the body, the strobila, consists of a chain of increasingly mature proglottids. These cytological processes are not well understood at present.
Members of the Eucestoda have no mouth or digestive tract, and instead absorb nutrients through a layer of microtriches over the tegument at the shared body wall surface. In addition to the body wall, several other systems are common to the whole length of the tapeworm, including excretory canals, nerve fibers, and longitudinal muscles. The excretory system is responsible for osmoregulation and consists of blind-ending flame bulbs communicating through a duct system. The nervous system, often referred to as a "ladder system," is a system of longitudinal connectives and transverse ring commissures.
Reproduction
The reproductive systems develop progressively along the differentiated proglottids of the strobila region, with each proglottid developing one or two sets of sexual organs that differentiate at different times in a species-specific pattern, usually male-first. Thus, moving in the posterior direction of the continuously maturing proglottid chain, there are proglottids with mature male reproductive organs, then proglottids with mature female reproductive organs, and then proglottids with fertilized eggs in the uterus, a condition commonly referred to as "gravid."
Proglottids
An atrium on the lateral margin of each proglottid contains the openings to both the male and female genital ducts. Follicular testes produce sperm, which are carried by a system of ducts to the cirrus, an eversible copulatory organ that usually has a hypodermic system of spines and a holdfast system of hooks. The main specialized female reproductive organs are an ovary that produces eggs and a vitellarium that produces yolk cells. Yolk cells travel in a duct system to the oviduct, where, in a modified region, the ovum is enclosed in a shell with yolk cells. After the gonads and their ducts have finished maturing, the female reproductive organs begin to mature. The oviduct develops a vagina and enlarges into the uterus, where fertilization and embryonic development occur.Egg formation is a result of copulation. A proglottid can copulate with itself, with other proglottids in the same worm, or with proglottids in other worms, and hypodermic fertilization sometimes occurs. When a gravid proglottid that is distended with an embryo reaches the end of the strobila, it detaches and passes out of the host intact with feces, with or without some tissue degeneration. In the order Pseudophyllidea, the uterus has a pore and the proglottid sheds the shelled embryo, only becoming detached when exhausted.Some members of the Eucestoda (such as Echinococcus, Sparganum, Taenia multiceps sp., and Mesocestoides sp.) can reproduce asexually through budding, which initiates a metagenesis of alternating sexually and asexually reproducing generations.
Life stages
A tapeworm can live from a few days to over 20 years. Eucestoda ontogenesis continues through metamorphosing in different larval stages inside different hosts. The initial six-hooked embryo, known as an
oncosphere or hexacanth, forms through cleavage. In the order Pseudophyllidea, it remains enclosed in a ciliated embryophore. The embryo continues to develop in other host species, with two intermediate hosts generally needed. It gains entry to its first intermediate host by being eaten.
Except for members of the order Taeniidae, the first intermediate host is an arthropod, and except for in the case of Archigetes spp. (which can attain sexual maturity in freshwater oligochaeta), the second host is usually a fish, but can be another invertebrate or vertebrate. After the scolex has differentiated and matured in the larval stage, growth will stop until a vertebrate eats the intermediate host, and then the strobila develops. Adult tapeworms often have a high final host specificity, with some species only found in one host vertebrate.
Common infective species
Medical importance
Taeniasis
Taeniasis is an infection within the intestines by adult tapeworms belonging to the genus Taenia. It is due to eating contaminated undercooked beef or pork. There are generally no or only mild symptoms. Symptoms may occasionally include weight loss or abdominal pain. Segments of tapeworm may be seen in the stool.
Cysticercosis
Cysticercosis is a tissue infection caused by the young form of the pork tapeworm. Infection occurs through swallowing or antiperistaltic contractions during regurgitation carrying eggs or gravid proglottids to the stomach. At this point, larvae hatch when exposed to enzymes and penetrate the intestinal wall, travelling through the body through blood vessels to tissues like the brain, the eye, muscles, and the nervous system (called neurocysticercosis).At these sites, the parasites lodge and form cysts, a condition called cysticercosis, producing inflammatory reactions and clinical issues when they die, sometimes causing serious or fatal damage. In the eye, the parasites can cause visual loss, and infection of the spine and adjacent leptomeninges can cause paresthesias, pain, or paralysis.
Echinococcosis (hydatid disease)
Humans become accidental hosts to worms of the genus Echinococcus, playing no role in the worms biological cycle. This can result in echinococcosis, also called hydatid disease. Humans (usually children) become infected by direct contact with dogs and eating food contaminated with dog feces. Common sites of infection are the liver, the lungs, muscles, bones, kidneys, and the spleen.Eggs hatch in the gastrointestinal tract after the consumption of contaminated food, after which the larvae travel to the liver through portal circulation. Here, the larvae are trapped and usually develop into hydatid cysts. While the liver is the first filter for trapping them, the lungs act as the second filter site, trapping most of the larvae that are not trapped by the liver. Some larvae escape from the lungs to cause cysts in other tissues.When a larva becomes established in tissue, it develops into a "bladderworm" or "hydatid" and can cause various cancer-like cysts that may rupture and interact with nearby organs. Most cases are asymptomatic, and the mortality rate is low, but various complications from these interactions may lead to debilitating illness.
Hymenolepiasis
Arthropods are intermediate hosts of Hymenolepis nana, otherwise known as the "dwarf tapeworm," while humans are used as final hosts. Humans become infected and develop hymenolepiasis through eating infected arthropods, ingesting eggs in water inhabited by arthropods, or from dirty hands. This is a common and widespread intestinal worm.While light infections are usually asymptomatic, autoinfection through eating the eggs of worms in the intestines is possible, and it can lead to hyperinfection. Humans can also become hyperinfected through ingesting grain products contaminated by infected insects. Infections involving more than two thousand worms can cause many different gastrointestinal symptoms and allergic responses. Common symptoms include chronic urticaria, skin eruption, and phlyctenular keratoconjunctivitis.
Diphyllobothriasis
Diphyllobothriasis is caused by infection with Diphyllobothrium latum (also known as the "broad tapeworm" or "fish tapeworm") and related species. Humans become infected by eating raw, undercooked, or marinated fish acting as a second intermediate or paratenic host harboring metacestodes or plerocercoid larvae.Clinical symptoms are due to the large size of the tapeworm, which often reaches a length exceeding 15 m (49 ft). The most common symptom is pernicious anemia, caused by the absorption of vitamin B12 by the worm. Other symptoms include various intestinal issues, slight leukocytosis, and eosinophilia.
Sparganosis
Sparganosis is caused by the plerocercoid larvae of the tapeworm Spirometra. Humans become infected by drinking contaminated water, eating raw or poorly cooked infected flesh, or from using poultices of raw infected flesh (usually raw pork or snake) on skin or mucous membranes.The most common symptom is a painful, slowly growing nodule in the subcutaneous tissues, which may migrate. Infection in the eye area can cause pain, irritation, edema, and excess watering. When the orbital tissues become infected, the swelling can cause blindness. An infected bowel may become perforated. Brain infection can cause granulomas, hematomas, and abscesses.
Subdivisions
The evolutionary history of the Eucestoda has been studied using ribosomal RNA, mitochondrial and other DNA, and morphological analysis and continues to be revised. "Tetraphyllidea" is seen to be paraphyletic; "Pseudophyllidea" has been broken up into two orders, Bothriocephalidea and Diphyllobothriidea. Hosts, whose phylogeny often mirrors that of the parasites (Fahrenholzs rule), are indicated in italics and parentheses, the life-cycle sequence (where known) shown by arrows as (intermediate host1 [→ intermediate host2 ] → definitive host). Alternatives, generally for different species within an order, are shown in square brackets.
References
Bale, James F. "Cysticercosis." Current Treatment Options in Neurology. 2000. pp. 355–360.
Dunn, J., and Philip E. S. Palmer. "Sparganosis." Seminars in Roentgenology. 1998. pp. 86–88.
Esteban, J. G., Munoz-Antoli, C., and R. Toledo. "Human Infection by a "Fish Tapeworm," Diphyllobothrium latum, in a Non-Endemic Country." Infection. 2014. pp. 191–194.
Kim, Bong Jin, et al. "Heavy Hymenoleptis nana Infection Possibly Through Organic Food: Report of a Case." The Korean Journal of Parasitology. 2014. pp. 85–87.
Mehlhorn, Heinz. "Eucestoda Classification." Encyclopedia of Parasitology. 2008. pp. 495–497.
Rohde, Klaus. "Eucestoda." AccessScience. McGraw-Hill Ryerson.
Usharani, A., et al. "Case Reports of Hydatid Disease." Journal of Epidemiology and Global Health. 2013. p. 63–66. |
Tendinopathy | Tendinopathy, a type of tendon disorder that results in pain, swelling, and impaired function. The pain is typically worse with movement. It most commonly occurs around the shoulder (rotator cuff tendinitis, biceps tendinitis), elbow (tennis elbow, golfers elbow), wrist, hip, knee (jumpers knee, popliteus tendinopathy), or ankle (Achilles tendinitis).Causes may include an injury or repetitive activities. Less common causes include infection, arthritis, gout, thyroid disease, diabetes and the use of Quinolone_antibiotic medicines. Groups at risk include people who do manual labor, musicians, and athletes. Diagnosis is typically based on symptoms, examination, and occasionally medical imaging. A few weeks following an injury little inflammation remains, with the underlying problem related to weak or disrupted tendon fibrils.Treatment may include rest, NSAIDs, splinting, and physiotherapy. Less commonly steroid injections or surgery may be done. About 80% of patients recover completely within six months. Tendinopathy is relatively common. Older people are more commonly affected. It results in a large amount of missed work.
Signs and symptoms
Symptoms include tenderness on palpation, swelling, and pain, often when exercising or with a specific movement.
Cause
Causes may include an injury or repetitive activities. Groups at risk include people who do manual labor, musicians, and athletes. Less common causes include infection, arthritis, gout, thyroid disease, and diabetes. Despite the injury of the tendon, there are roads to healing which includes rehabilitation therapy and/or surgery. Obesity, or more specifically, adiposity or fatness, has also been linked to an increasing incidence of tendinopathy.Quinolone antibiotics are associated with increased risk of tendinitis and tendon rupture. A 2013 review found the incidence of tendon injury among those taking fluoroquinolones to be between 0.08 and 0.2%. Fluoroquinolones most frequently affect large load-bearing tendons in the lower limb, especially the Achilles tendon which ruptures in approximately 30 to 40% of cases.
Types
Achilles tendinitis
Calcific tendinitis
Patellar tendinitis (jumpers knee)
Pathophysiology
As of 2016 the pathophysiology of tendinopathy is poorly understood. While inflammation appears to play a role, the relationships among changes to the structure of tissue, the function of tendons, and pain are not understood and there are several competing models, none of which have been fully validated or falsified. Molecular mechanisms involved in inflammation includes release of inflammatory cytokines like IL-1β which reduces the expression of type I collagen mRNA in human tenocytes and causes extracellular matrix degradation in the tendon.There are multifactorial theories that could include: tensile overload, tenocyte related collagen synthesis disruption, load-induced ischemia, neural sprouting, thermal damage, and adaptive compressive responses. The intratendinous sliding motion of fascicles and shear force at interfaces of fascicles could be an important mechanical factor for the development of tendinopathy and predispose tendons to rupture.The most commonly accepted cause for this condition is seen to be an overuse syndrome in combination with intrinsic and extrinsic factors leading to what may be seen as a progressive interference or the failing of the innate healing response. Tendinopathy involves cellular apoptosis, matrix disorganization and neovascularization.Classic characteristics of "tendinosis" include degenerative changes in the collagenous matrix, hypercellularity, hypervascularity, and a lack of inflammatory cells which has challenged the original misnomer "tendinitis".Histological findings include granulation tissue, microrupture, degenerative changes, and there is no traditional inflammation. As a consequence, "lateral elbow tendinopathy or tendinosis" is used instead of "lateral epicondylitis".Examination of tennis elbow tissue reveals noninflammatory tissue, so the term "angiofibroblastic tendinosis" is used.Cultures from tendinopathic tendons contain an increased production of type III collagen.Longitudinal sonogram of the lateral elbow displays thickening and heterogeneity of the common extensor tendon that is consistent with tendinosis, as the ultrasound reveals calcifications, intrasubstance tears, and marked irregularity of the lateral epicondyle. Although the term "epicondylitis" is frequently used to describe this disorder, most histopathologic findings of studies have displayed no evidence of an acute, or a chronic inflammatory process. Histologic studies have demonstrated that this condition is the result of tendon degeneration, which causes normal tissue to be replaced by a disorganized arrangement of collagen. Therefore, the disorder is more appropriately referred to as "tendinosis" or "tendinopathy" rather than "tendinitis".Colour Doppler ultrasound reveals structural tendon changes, with vascularity and hypo-echoic areas that correspond to the areas of pain in the extensor origin.Load-induced non-rupture tendinopathy in humans is associated with an increase in the ratio of collagen III:I proteins, a shift from large to small diameter collagen fibrils, buckling of the collagen fascicles in the tendon extracellular matrix, and buckling of the tenocyte cells and their nuclei.
Diagnosis
Symptoms can vary from aches or pains and local joint stiffness, to a burning that surrounds the whole joint around the inflamed tendon. In some cases, swelling occurs along with heat and redness, and there may be visible knots surrounding the joint. With this condition, the pain is usually worse during and after activity, and the tendon and joint area can become stiff the following day as muscles tighten from the movement of the tendon. Many patients report stressful situations in their life in correlation with the beginnings of pain which may contribute to the symptoms.
Medical imaging
Ultrasound imaging can be used to evaluate tissue strain, as well as other mechanical properties. Ultrasound-based techniques are becoming more popular because of its affordability, safety, and speed. Ultrasound can be used for imaging tissues, and the sound waves can also provide information about the mechanical state of the tissue.
Treatment
Treatment of tendon injuries is largely conservative. Use of non-steroidal anti-inflammatory drugs (NSAIDs), rest, and gradual return to exercise is a common therapy. Resting assists in the prevention of further damage to the tendon. Ice, compression and elevation are also frequently recommended. Physical therapy, occupational therapy, orthotics or braces may also be useful. Initial recovery is typically within 2 to 3 days and full recovery is within 3 to 6 months. Tendinosis occurs as the acute phase of healing has ended (6–8 weeks) but has left the area insufficiently healed. Treatment of tendinitis helps reduce some of the risks of developing tendinosis, which takes longer to heal.There is tentative evidence that low-level laser therapy may also be beneficial in treating tendinopathy. The effects of deep transverse friction massage for treating tennis elbow and lateral knee tendinitis is unclear.
NSAIDs
NSAIDs may be used to help with pain. They however do not alter long term outcomes. Other types of pain medication, like paracetamol, may be just as useful.
Steroids
Steroid injections have not been shown to have long term benefits but have been shown to be more effective than NSAIDs in the short term. They appear to have little benefit in tendinitis of the rotator cuff. There are some concerns that they may have negative effects.
Other injections
There is insufficient evidence on the routine use of injection therapies (autologous blood, platelet-rich plasma, deproteinised haemodialysate, aprotinin, polysulphated glycosaminoglycan, skin derived fibroblasts etc.) for treating Achilles tendinopathy. As of 2014 there was insufficient evidence to support the use of platelet-rich therapies for treating musculoskeletal soft tissue injuries such as ligament, muscle and tendon tears and tendinopathies.
Prognosis
Initial recovery is usually within 2 to 3 months, and full recovery usually within 3 to 6 months. About 80% of people will fully recover within 12 months.
Epidemiology
Tendon injury and resulting tendinopathy are responsible for up to 30% of consultations to sports doctors and other musculoskeletal health providers. Tendinopathy is most often seen in tendons of athletes either before or after an injury but is becoming more common in non-athletes and sedentary populations. For example, the majority of patients with Achilles tendinopathy in a general population-based study did not associate their condition with a sporting activity. In another study the population incidence of Achilles tendinopathy increased sixfold from 1979–1986 to 1987–1994. The incidence of rotator cuff tendinopathy ranges from 0.3% to 5.5% and annual prevalence from 0.5% to 7.4%.
Terminology
Tendinitis is a very common, but misleading term. By definition, the suffix "-itis" means "inflammation of". Inflammation is the bodys local response to tissue damage which involves red blood cells, white blood cells, blood proteins with dilation of blood vessels around the site of injury. Tendons are relatively avascular.
Corticosteroids are drugs that reduce inflammation. Corticosteroids can be useful to relieve chronic tendinopathy pain, improve function, and reduce swelling in the short term. However, there is a greater risk of long-term recurrence. They are typically injected along with a small amount of a numbing drug called lidocaine. Research shows that tendons are weaker following corticosteroid injections.
Tendinitis is still a very common diagnosis, though research increasingly documents that what is thought to be tendinitis is usually tendinosis.Anatomically close but separate conditions are:
Enthesitis, wherein there is inflammation of the entheses, the sites where tendons or ligaments insert into the bone. It is associated with HLA B27 arthropathies such as ankylosing spondylitis, psoriatic arthritis, and reactive arthritis.
Apophysitis, inflammation of the bony attachment, generally associated with overuse among growing children.
Research
The use of a nitric oxide delivery system (glyceryl trinitrate patches) applied over the area of maximal tenderness was found to reduce pain and increase range of motion and strength.A promising therapy involves eccentric loading exercises involving lengthening muscular contractions.
Other animals
Bowed tendon is a horsemans term for tendinitis (inflammation) and tendinosis (degeneration), most commonly seen in the superficial digital flexor tendon in the front leg of horses.
Mesenchymal stem cells, derived from a horses bone marrow or fat, are currently being used for tendon repair in horses.
References
External links
Questions and Answers about Bursitis and Tendinitis - US National Institute of Arthritis and Musculoskeletal and Skin Diseases |
Tenosynovial giant cell tumor | Tenosynovial giant cell tumor (TGCT) is a group of rare, typically non-malignant tumors of the joints. TGCT tumors often develop from the lining of joints (also known as synovial tissue).: 100 : 245 Common symptoms of TGCT include swelling, pain, stiffness and reduced mobility in the affected joint or limb.: 102 This group of tumors can be divided into different subsets according to their site, growth pattern, and prognosis.: 361 Localized TGCT is sometimes referred to as giant cell tumor of the tendon sheath;: 100 diffuse TGCT is also called pigmented villonodular synovitis (PVNS).: 102
Classification
Classification for TGCT encompasses two subtypes that can be divided according to site – within a joint (intra-articular) or outside of the joint (extra-articular) – and growth pattern (localized or diffuse) of the tumor(s).: 100 : 361 Localized and diffuse subsets of TGCT differ in their prognosis, clinical presentation, and biological behavior, but share a similar manner of disease development.: 100
Localized TGCT
Localized TGCT is sometimes referred to as localized pigmented villonodular synovitis (L-PVNS), giant cell tumor of the tendon sheath (GCT-TS), nodular tenosynovitis, localized nodular tenosynovitis, and L-TGCT.: 1 : 100 The localized form of TGCT is more common.: 100 : 245 Localized TGCT tumors are typically 0.5 cm-4 cm),: 101 develop over years,: 100 are benign and non-destructive to the surrounding tissue, and may reoccur in the affected area.: 101 The most common symptom is painless swelling.: 101 Localized TGCT most often occurs in fingers, but can also occur in other joints.
Diffuse TGCT
Diffuse TGCT is sometimes referred to as pigmented villonodular synovitis (PVNS), conventional PVNS, and D-TGCT.: 1 : 361 : 1 : 102 Diffuse TGCT occurs less frequently and is locally aggressive (in some cases, tumors may infiltrate surrounding soft tissue).: 245 : 1 : 102 : 1 It most commonly affects people under 40 years old, though the age of occurrence varies.: 102 Diffuse TGCT may occur inside a joint (intra-articular) or outside of a joint (extra-articular). Intra-articular tumors typically occur in the knee (approximately 75% of cases) and hip (approximately 15% of cases).: 102 Extra-articular tumors are usually found in the knee, thigh, and foot.: 101 Symptoms include swelling, pain, sensitivity, and/or limited range of motion.: 102 The rate of reoccurrence is estimated to be 18-46% for intra-articular tumors and 33-50% for extra-articular tumors.: 103 : 1
Complications
Diffuse TGCT is locally aggressive and can spread to surrounding tissues, causing bone erosion and tissue damage. If not treated early, it can spread to areas outside the joint, extra-articular, and potentially cause permanent loss of range as well as intense pain.
Mechanism
TGCT tumors grow due to genetic overexpression of colony stimulating factor 1. This causes colony-stimulating factor-1 receptor (CSF1R) cells to accumulate in the joint tissue.
Diagnosis
TGCT can be diagnosed by magnetic resonance imaging (MRI), by biopsy, or during surgery. The disorder is difficult to identify and is often not diagnosed for years due to nonspecific symptoms or a general paucity of symptoms. TGCT cases are often misdiagnosed as osteoarthritis, localized trauma, sports injuries, xanthomas, or other conditions. One study of 122 diffuse TGCT patients found that the average delay in diagnosis was 2.9 years.
Treatment
Surgery has been the most common form of treatment for both localized: 101 : 361 and diffuse TGCT.: 103 : 361 : 1 After surgery, patients may receive physical therapy in order to help rehabilitate affected joints. However, recurrence of TGCT after surgery is common, with a higher rate of recurrence for diffuse TGCT than for localized TGCT.: 361 In cases of recurrent or resistant disease, multiple surgeries, total joint arthroplasties, or amputation may be required.: 1 A multidisciplinary approach, supplementing surgery with radiotherapy or other treatments, can also improve outcomes in cases of recurrent TGCT. In the late 2010s, treatment with CSF1R inhibitors emerged as an option that may help improve functionality for patients with recurrent TGCT or TGCT that is not easily managed by surgery.: 361
Epidemiology
A study conducted in the Netherlands estimated that the worldwide incidence of TGCT is 43 cases per million person-years. The majority – 39 cases per million person-years – were estimated to be localized TGCT; the remaining 4 cases per million person-years were estimated to be diffuse TGCT. TGCT can occur in patients of any age, but people with localized TGCT are typically between 30 and 50 years old,: 100–101 while diffuse TGCT tends to affect people under the age of 40.: 102–103
See also
Fibroma of tendon sheath
List of cutaneous conditions
References
== External links == |
Tetanus | Tetanus, also known as lockjaw, is a bacterial infection caused by Clostridium tetani, and is characterized by muscle spasms. In the most common type, the spasms begin in the jaw and then progress to the rest of the body. Each spasm usually lasts a few minutes. Spasms occur frequently for three to four weeks. Some spasms may be severe enough to fracture bones. Other symptoms of tetanus may include fever, sweating, headache, trouble swallowing, high blood pressure, and a fast heart rate. Onset of symptoms is typically three to twenty-one days following infection. Recovery may take months. About ten percent of cases prove to be fatal.C. tetani is commonly found in soil, saliva, dust, and manure. The bacteria generally enter through a break in the skin such as a cut or puncture wound by a contaminated object. They produce toxins that interfere with normal muscle contractions. Diagnosis is based on the presenting signs and symptoms. The disease does not spread between people.Tetanus can be prevented by immunization with the tetanus vaccine. In those who have a significant wound and have had fewer than three doses of the vaccine, both vaccination and tetanus immune globulin are recommended. The wound should be cleaned and any dead tissue should be removed. In those who are infected, tetanus immune globulin or, if unavailable, intravenous immunoglobulin (IVIG) is used. Muscle relaxants may be used to control spasms. Mechanical ventilation may be required if a persons breathing is affected.Tetanus occurs in all parts of the world but is most frequent in hot and wet climates where the soil has a high organic content. In 2015 there were about 209,000 infections and about 59,000 deaths globally. This is down from 356,000 deaths in 1990. In the US there are about 30 cases per year, almost all of which have not been vaccinated. An early description of the disease was made by Hippocrates in the 5th century BC. The cause of the disease was determined in 1884 by Antonio Carle and Giorgio Rattone at the University of Turin, and a vaccine was developed in 1924.
Signs and symptoms
Tetanus often begins with mild spasms in the jaw muscles—also known as lockjaw. Similar spasms can also be a feature of trismus. The spasms can also affect the facial muscles resulting in an appearance called risus sardonicus. Chest, neck, back, abdominal muscles and buttocks may be affected. Back muscle spasms often cause arching, called opisthotonus. Sometimes the spasms affect muscles that help with breathing, which can lead to breathing problems.Prolonged muscular action causes sudden, powerful, and painful contractions of muscle groups, called tetany. These episodes can cause fractures and muscle tears. Other symptoms include fever, headache, restlessness, irritability, feeding difficulties, breathing problems, burning sensation during urination, urinary retention and loss of stool control.Even with treatment, about 10% of people who contract tetanus die. The mortality rate is higher in unvaccinated people and people over 60 years of age.
Incubation period
The incubation period of tetanus may be up to several months, but is usually about ten days. In general, the farther the injury site is from the central nervous system, the longer the incubation period. The shorter the incubation period, the more severe the symptoms. In trismus nascentium (i.e. neonatal tetanus), symptoms usually appear from 4 to 14 days after birth, averaging about 7 days. On the basis of clinical findings, four different forms of tetanus have been described.
Generalized tetanus
Generalized tetanus is the most common type of tetanus, representing about 80% of cases. The generalized form usually presents with a descending pattern. The first sign is trismus or lockjaw, and the facial spasms are called risus sardonicus, followed by stiffness of the neck, difficulty in swallowing, and rigidity of pectoral and calf muscles. Other symptoms include elevated temperature, sweating, elevated blood pressure, and episodic rapid heart rate. Spasms may occur frequently and last for several minutes with the body shaped into a characteristic form called opisthotonos. Spasms continue for up to four weeks, and complete recovery may take months.
Neonatal tetanus
Neonatal tetanus (trismus nascentium) is a form of generalized tetanus that occurs in newborns, usually those born to mothers who themselves have not been vaccinated. If the mother has been vaccinated against tetanus, the infants acquire passive immunity and are thus protected. It usually occurs through infection of the unhealed umbilical stump, particularly when the stump is cut with a non-sterile instrument. As of 1998 neonatal tetanus was common in many developing countries and was responsible for about 14% (215,000) of all neonatal deaths. In 2010 the worldwide death toll was 58,000 newborns. As the result of a public health campaign, the death toll from neonatal tetanus was reduced by 90% between 1990 and 2010, and by 2013 the disease had been largely eliminated from all but 25 countries. Neonatal tetanus is rare in developed countries.
Local tetanus
Local tetanus is an uncommon form of the disease, in which people have persistent contraction of muscles in the same anatomic area as the injury. The contractions may persist for many weeks before gradually subsiding. Local tetanus is generally milder; only about 1% of cases are fatal, but it may precede the onset of generalized tetanus.
Cephalic tetanus
Cephalic tetanus is the rarest form of the disease (0.9–3% of cases) and is limited to muscles and nerves in the head. It usually occurs after trauma to the head area, including skull fracture, laceration, eye injury, dental extraction, and otitis media, but it has been observed from injuries to other parts of the body. Paralysis of the facial nerve is most frequently implicated, which may cause lockjaw, facial palsy, or ptosis, but other cranial nerves can also be affected. Cephalic tetanus may progress to a more generalized form of the disease. Due to its rarity, clinicians may be unfamiliar with the clinical presentation and may not suspect tetanus as the illness. Treatment can be complicated as symptoms may be concurrent with the initial injury that caused the infection. Cephalic tetanus is more likely than other forms of tetanus to be fatal, with the progression to generalized tetanus carrying a 15–30% case fatality rate.
Cause
Tetanus is caused by the tetanus bacterium Clostridium tetani. Tetanus is an international health problem, as C. tetani endospores are ubiquitous. Endospores can be introduced into the body through a puncture wound (penetrating trauma). Due to C. tetani being an anaerobic bacterium, it and its endospores thrive in environments that lack oxygen, such as a puncture wound. With the changes in oxygen levels, the drumstick-shaped endospore can result in quick spread.The disease occurs almost exclusively in persons inadequately immunized. It is more common in hot, damp climates with soil rich in organic matter. Manure-treated soils may contain spores, as they are widely distributed in the intestines and feces of many animals such as horses, sheep, cattle, dogs, cats, rats, guinea pigs, and chickens. In agricultural areas, a significant number of human adults may harbor the organism.The spores can also be found on skin surfaces and in contaminated heroin. Heroin users, particularly those who inject the drug subcutaneously, appear to be at high risk of contracting tetanus. Rarely, tetanus can be contracted through surgical procedures, intramuscular injections, compound fractures, and dental infections. Animal bites can transmit tetanus.Tetanus is often associated with rust, especially rusty nails. Although rust itself does not cause tetanus, objects that accumulate rust are often found outdoors or in places that harbor anaerobic bacteria. Additionally, the rough surface of rusty metal provides crevices for dirt containing C. tetani, while a nail affords a means to puncture skin and deliver endospores deep within the body at the site of the wound. An endospore is a non-metabolizing survival structure that begins to metabolize and cause infection once in an adequate environment. Hence, stepping on a nail (rusty or not) may result in a tetanus infection, as the low-oxygen (anaerobic) environment may exist under the skin, and the puncturing object can deliver endospores to a suitable environment for growth. It is a common misconception that rust itself is the cause and that a puncture from a rust-free nail is not a risk.
Pathophysiology
Tetanus neurotoxin (TeNT) binds to the presynaptic membrane of the neuromuscular junction, is internalized and is transported back through the axon until it reaches the central nervous system. Here, it selectively binds to and is transported into inhibitory neurons via endocytosis. It then leaves the vesicle for the neuron cytosol where it cleaves vesicle associated membrane protein (VAMP) synaptobrevin, which is necessary for membrane fusion of small synaptic vesicles (SSVs). SSVs carry neurotransmitter to the membrane for release, so inhibition of this process blocks neurotransmitter release.Tetanus toxin specifically blocks the release of the neurotransmitters GABA and glycine from inhibitory neurons. These neurotransmitters keep overactive motor neurons from firing and also play a role in the relaxation of muscles after contraction. When inhibitory neurons are unable to release their neurotransmitters, motor neurons fire out of control and muscles have difficulty relaxing. This causes the muscle spasms and spastic paralysis seen in tetanus infection.The tetanus toxin, tetanospasmin, is made up of a heavy chain and a light chain. There are three domains, each of which contributes to the pathophysiology of the toxin. The heavy chain has two of the domains. The N-terminal side of the heavy chain helps with membrane translocation, and the C-terminal side helps the toxin locate the specific receptor site on the correct neuron. The light chain domain cleaves the VAMP protein once it arrives in the inhibitory neuron cytosol.There are four main steps in tetanuss mechanism of action: binding to the neuron, internalization of the toxin, membrane translocation, and cleavage of the target VAMP.
Neurospecific binding
The toxin travels from the wound site to the neuromuscular junction through the bloodstream where it binds to the presynaptic membrane of a motor neuron. The heavy chain C-terminal domain aids in the binding to the correct site, recognizing and binding to the correct glycoproteins and glycolipids in the presynaptic membrane. The toxin binds to a site that will be taken into the neuron as an endocytic vesicle that will travel down the axon, past the cell body, and down the dendrites to the dendritic terminal at the spine and central nervous system. Here it will be released into the synaptic cleft and allowed to bind with the presynaptic membrane of inhibitory neurons in a similar manner seen with the binding to the motor neuron.
Internalization
Tetanus toxin is then internalized again via endocytosis, this time in an acidic vesicle. In a mechanism not well understood, depolarization caused by the firing of the inhibitory neuron causes the toxin to be pulled into the neuron inside vesicles.
Membrane translocation
The toxin then needs a way to get out of the vesicle and into the neuron cytosol for it to act on its target. The low pH of the vesicle lumen causes a conformational change in the toxin, shifting it from a water-soluble form to a hydrophobic form. With the hydrophobic patches exposed, the toxin can slide into the vesicle membrane. The toxin forms an ion channel in the membrane that is nonspecific for Na+, K+, Ca2+, and Cl− ions. There is a consensus among experts that this new channel is involved in the translocation of the toxins light chain from the inside of the vesicle to the neuron cytosol, but the mechanism is not well understood or agreed upon. It has been proposed that the channel could allow the light chain (unfolded from the low pH environment) to leave through the toxin pore, or that the pore could alter the electrochemical gradient enough, by letting in or out ions, to cause osmotic lysis of the vesicle, spilling the vesicles contents.
Enzymatic target cleavage
The light chain of the tetanus toxin is zinc-dependent protease. It shares a common zinc protease motif (His-Glu-Xaa-Xaa-His) that researchers hypothesized was essential for target cleavage until this was more recently confirmed by experiment: when all zinc was removed from the neuron with heavy metal chelators, the toxin was inhibited, only to be reactivated when the zinc was added back in. The light chain binds to VAMP and cleaves it between Gln76 and Phe77. Without VAMP, vesicles holding the neurotransmitters needed for motor neuron regulation (GABA and glycine) cannot be released, causing the above-mentioned deregulation of motor neurons and muscle tension.
Diagnosis
There are currently no blood tests for diagnosing tetanus. The diagnosis is based on the presentation of tetanus symptoms and does not depend upon isolation of the bacterium, which is recovered from the wound in only 30% of cases and can be isolated from people without tetanus. Laboratory identification of C. tetani can be demonstrated only by production of tetanospasmin in mice. Having recently experienced head trauma may indicate cephalic tetanus if no other diagnosis has been made.The "spatula test" is a clinical test for tetanus that involves touching the posterior pharyngeal wall with a soft-tipped instrument and observing the effect. A positive test result is the involuntary contraction of the jaw (biting down on the "spatula") and a negative test result would normally be a gag reflex attempting to expel the foreign object. A short report in The American Journal of Tropical Medicine and Hygiene states that, in an affected subject research study, the spatula test had a high specificity (zero false-positive test results) and a high sensitivity (94% of infected people produced a positive test).
Prevention
Unlike many infectious diseases, recovery from naturally acquired tetanus does not usually result in immunity. This is due to the extreme potency of the tetanospasmin toxin. Tetanospasmin will likely be lethal before it will provoke an immune response.Tetanus can be prevented by vaccination with tetanus toxoid. The CDC recommends that adults receive a booster vaccine every ten years, and standard care practice in many places is to give the booster to any person with a puncture wound who is uncertain of when he or she was last vaccinated, or if he or she has had fewer than three lifetime doses of the vaccine. The booster may not prevent a potentially fatal case of tetanus from the current wound, however, as it can take up to two weeks for tetanus antibodies to form.In children under the age of seven, the tetanus vaccine is often administered as a combined vaccine, DPT/DTaP vaccine, which also includes vaccines against diphtheria and pertussis. For adults and children over seven, the Td vaccine (tetanus and diphtheria) or Tdap (tetanus, diphtheria, and acellular pertussis) is commonly used.The World Health Organization certifies countries as having eliminated maternal or neonatal tetanus. Certification requires at least two years of rates of less than 1 case per 1,000 live births. In 1998 in Uganda, 3,433 tetanus cases were recorded in newborn babies; of these, 2,403 died. After a major public health effort, Uganda in 2011 was certified as having eliminated maternal and neonatal tetanus.
Post-exposure prophylaxis
Tetanus toxoid can be given in case of suspected exposure to tetanus. In such cases, it can be given with or without tetanus immunoglobulin (also called tetanus antibodies or tetanus antitoxin). It can be given as intravenous therapy or by intramuscular injection.The guidelines for such events in the United States for non-pregnant people 11 years and older are as follows:
Treatment
Mild tetanus
Mild cases of tetanus can be treated with:
Tetanus immunoglobulin (TIG), also called tetanus antibodies or tetanus antitoxin. It can be given as intravenous therapy or by intramuscular injection.
Antibiotic therapy to reduce toxin production. Metronidazole intravenous (IV) is a preferred treatment.
Benzodiazepines can be used to control muscle spasms. Options include diazepam and lorazepam, oral or IV.
Severe tetanus
Severe cases will require admission to intensive care. In addition to the measures listed above for mild tetanus:
Human tetanus immunoglobulin injected intrathecally (which increases clinical improvement from 4% to 35%)
Tracheotomy and mechanical ventilation for 3 to 4 weeks. Tracheotomy is recommended for securing the airway because the presence of an endotracheal tube is a stimulus for spasm
Magnesium sulfate, as an intravenous infusion, to control spasm and autonomic dysfunction
Diazepam as a continuous IV infusion
The autonomic effects of tetanus can be difficult to manage (alternating hyper- and hypotension hyperpyrexia/hypothermia) and may require IV labetalol, magnesium, clonidine, or nifedipineDrugs such as diazepam or other muscle relaxants can be given to control the muscle spasms. In extreme cases it may be necessary to paralyze the person with curare-like drugs and use a mechanical ventilator.To survive a tetanus infection, the maintenance of an airway and proper nutrition are required. An intake of 3,500 to 4,000 calories and at least 150 g of protein per day is often given in liquid form through a tube directly into the stomach (percutaneous endoscopic gastrostomy), or through a drip into a vein (parenteral nutrition). This high-caloric diet maintenance is required because of the increased metabolic strain brought on by the increased muscle activity. Full recovery takes 4 to 6 weeks because the body must regenerate destroyed nerve axon terminals.The antibiotic of choice is metronidazole. It can be given as intravenously, by mouth, or by rectum. Of likewise efficiency is penicillin, but some raise the concern of provoking spasms because it inhibits GABA receptor, which is already affected by tetanospasmin.
Epidemiology
In 2013 it caused about 59,000 deaths – down from 356,000 in 1990. Tetanus – in particular, the neonatal form – remains a significant public health problem in non-industrialized countries with 59,000 newborns worldwide dying in 2008 as a result of neonatal tetanus. In the United States, from 2000 through 2007 an average of 31 cases were reported per year. Nearly all of the cases in the United States occur in unimmunized individuals or individuals who have allowed their inoculations to lapse.
History
Tetanus was well known to ancient civilizations who recognized the relationship between wounds and fatal muscle spasms. In 1884, Arthur Nicolaier isolated the strychnine-like toxin of tetanus from free-living, anaerobic soil bacteria. The etiology of the disease was further elucidated in 1884 by Antonio Carle and Giorgio Rattone, two pathologists of the University of Turin, who demonstrated the transmissibility of tetanus for the first time. They produced tetanus in rabbits by injecting pus from a person with fatal tetanus into their sciatic nerves and testing their reactions while tetanus was spreading.In 1891, C. tetani was isolated from a human victim by Kitasato Shibasaburō, who later showed that the organism could produce disease when injected into animals and that the toxin could be neutralized by specific antibodies. In 1897, Edmond Nocard showed that tetanus antitoxin induced passive immunity in humans, and could be used for prophylaxis and treatment. Tetanus toxoid vaccine was developed by P. Descombey in 1924, and was widely used to prevent tetanus induced by battle wounds during World War II.
Etymology
The word tetanus comes from the Ancient Greek: τέτανος, romanized: tetanos, lit. taut, which is further from the Ancient Greek: τείνειν, romanized: teinein, lit. to stretch.
Research
There is insufficient evidence that tetanus can be treated or prevented by vitamin C. This is at least partially due to the fact that historically trials conducted trying to look for a possible connection between vitamin C and helping tetanus patients were of poor quality.
See also
Renshaw cell
Tetanized state
Tetanospasmin
References
External links
Tetanus Information from Medline Plus
Tetanus Surveillance -- United States, 1998-2000 (Data and Analysis)
"Tetanus". MedlinePlus. U.S. National Library of Medicine. |
Thrombocythemia | Thrombocythemia is a condition of high platelet (thrombocyte) count in the blood. Normal count is in the range of 150x109 to 450x109 platelets per liter of blood, but investigation is typically only considered if the upper limit exceeds 750x109/L.
When the cause is unknown, the term thrombocythemia is used, as either primary thrombocythemia or essential thrombocythemia. The condition arises from a fault in the bone marrow cells leading to over-production of platelets but the cause of the fault is unknown, and this type is not common.When the cause is known such as another disorder or disease, the term thrombocytosis is preferred, as either secondary or reactive thrombocytosis. Reactive thrombocytosis is the most common type and though it can often have no symptoms it can sometimes predispose to thrombosis. In contrast, thrombocytopenia refers to abnormally low blood platelet numbers in the blood.
Signs and symptoms
High platelet counts do not necessarily signal any clinical problems, and can be picked up on a routine full blood count. However, it is important that a full medical history be elicited to ensure that the increased platelet count is not due to a secondary process. Often, it occurs in tandem with an inflammatory disease as the principal stimulants of platelet production (e.g. thrombopoietin) are elevated in these clinical states as part of the acute phase reaction. High platelet counts can occur in patients with polycythemia vera (high red blood cell counts), and is an additional risk factor for complications.A very small number of people report symptoms of erythromelalgia, a burning sensation and redness of the extremities that resolves with cooling, or aspirin or both.Scientific literature sometimes excludes thrombocytosis from the scope of thrombophilia by definition, but practically, by the definition of thrombophilia as an increased predisposition to thrombosis, thrombocytosis (especially primary thrombocytosis) is a potential cause of thrombophilia. Conversely, secondary thrombocytosis very rarely causes thrombotic complications.
Causes
Reactive thrombocythemia is the most common cause of a high platelet count. It accounts for 88% to 97% of thrombocythemia cases in adults, and near 100% in children. In adults, acute infection, tissue damage, chronic inflammation and malignancy are the common causes of reactive thrombocythemia. Usually, one or more of these conditions is present in more than 75% of the cases with reactive thrombocythemia. Causes for reactive thrombocythemia in children are similar to adults. In addition, hemolytic anemia and thalassemia are often present in children living in the Middle East. Other causes of reactive thrombocythemia include: post surgery, iron deficiency, drugs, and rebound effect after bone marrow suppression.The SARS disease caused thrombocytosis.Once the reactive causes of thrombocythemia are ruled out, clonal thrombocythemia should be considered. The most common cause of clonal thrombocythemia is a myeloproliferative neoplasm. These include: essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, and primary myelofibrosis.Extremely rare causes of thrombocythemia are spurious causes. This is due to the presence of structures resembling platelets in the blood such as needle-like cryoglobulin crystals, cytoplasmic fragments of circulating leukemic cells, bacteria, and red blood cell microvesicles. These structures are counted as platelets by the automated machine counter; therefore, causing the platelet number to be falsely elevated. However, such error can be avoided by doing a peripheral blood smear.
Diagnosis
Laboratory tests might include: full blood count, liver enzymes, renal function and erythrocyte sedimentation rate.If the cause for the high platelet count remains unclear, bone marrow biopsy is often undertaken, to differentiate whether the high platelet count is reactive or essential.
Treatment
Often, no treatment is required or necessary for reactive thrombocytosis. In cases of reactive thrombocytosis of more than 1,000x109/L, it may be considered to administer daily low dose aspirin (such as 65 mg) to minimize the risk of stroke or thrombosis.However, in essential thrombocythemia where platelet counts are over 750x109/L or 1,000x109/L, especially if there are other risk factors for thrombosis, treatment may be needed. Selective use of aspirin at low doses is thought to be protective. Extremely high platelet counts can be treated with hydroxyurea (a cytoreducing agent) or anagrelide (Agrylin).In Janus kinase 2 positive disorders, ruxolitinib (Jakafi) can be effective.
References
Schafer AI (March 2004). "Thrombocytosis". N. Engl. J. Med. 350 (12): 1211–9. doi:10.1056/NEJMra035363. PMID 15028825.
== External links == |
Tinea barbae | Tinea barbae is a fungal infection of the hair. Tinea barbae is due to a dermatophytic infection around the bearded area of men. Generally, the infection occurs as a follicular inflammation, or as a cutaneous granulomatous lesion, i.e. a chronic inflammatory reaction. It is one of the causes of folliculitis. It is most common among agricultural workers, as the transmission is more common from animal-to-human than human-to-human. The most common causes are Trichophyton mentagrophytes and T. verrucosum.
Signs and symptoms
Main symptoms that occur when affected with tinea barbae is pimple or blister amongst affected area, swelling and redness around infected area, red and lumpy skin on infected area. Crusting around hairs in infected area will occur, hairs on infected area will also be effortless to pull out. Tinea barbae can be itchy or painful to touch but these symptoms do not always occur.
Transmission
The transmission of tinea barbae to humans occurs through contact of an infected animal to the skin of a human. Infection can occasionally be transmitted through contact of infected animal hair on human skin. Tinea barbae is very rarely transmitted through human to human contact but is not completely impossible.
Diagnosis
Diagnosis of tinea barbae will firstly include questions being asked from doctors about interactions with farm animals and lifestyle experiences. Doctor will then gain knowledge on possible disease by microscopy, this is viewing the skin under a microscope to get an enlarge view of infected area. Skin scraping and removal of hairs on infected area will occur for medical examination. To acquire causation of tinea barbae putting infected area under ultraviolet light can achieve this, as infection caused by animal and human contact will not show up as fluorescent under the ultraviolet light, compared to other causes of this disease.
Treatment
Treatment can vary with severity of the infection. Moderate cases of tinea barbae can be treated with topical antifungal medications. Topical antifungal medications will come in the form of cream, which can normally be obtained over the counter. More serious cases of tinea barbae warrant an oral antifungal medication.
References
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Tinea capitis | Tinea capitis (also known as "herpes tonsurans", "ringworm of the hair", "ringworm of the scalp", "scalp ringworm", and "tinea tonsurans") is a cutaneous fungal infection (dermatophytosis) of the scalp. The disease is primarily caused by dermatophytes in the genera Trichophyton and Microsporum that invade the hair shaft. The clinical presentation is typically single or multiple patches of hair loss, sometimes with a black dot pattern (often with broken-off hairs), that may be accompanied by inflammation, scaling, pustules, and itching. Uncommon in adults, tinea capitis is predominantly seen in pre-pubertal children, more often boys than girls.
At least eight species of dermatophytes are associated with tinea capitis. Cases of Trichophyton infection predominate from Central America to the United States and in parts of Western Europe. Infections from Microsporum species are mainly in South America, Southern and Central Europe, Africa and the Middle East. The disease is infectious and can be transmitted by humans, animals, or objects that harbor the fungus. The fungus can also exist in a carrier state on the scalp, without clinical symptomatology. Treatment of tinea capitis requires an oral antifungal agent; griseofulvin is the most commonly used drug, but other newer antimycotic drugs, such as terbinafine, itraconazole, and fluconazole have started to gain acceptance.
Symptoms
It may appear as thickened, scaly, and sometimes boggy swellings, or as expanding raised red rings (ringworm). Common symptoms are severe itching of the scalp, dandruff, and bald patches where the fungus has rooted itself in the skin. It often presents identically to dandruff or seborrheic dermatitis. The highest incidence in the United States of America is in American boys of school age.There are three type of tinea capitis, microsporosis, trichophytosis, and favus; these are based on the causative microorganism, and the nature of the symptoms. In microsporosis, the lesion is a small red papule around a hair shaft that later becomes scaly; eventually the hairs break off 1–3 mm above the scalp. This disease used to be caused primarily by Microsporum audouinii, but in Europe, M. canis is more frequently the causative fungus. The source of this fungus is typically sick cats and kittens; it may be spread through person to person contact, or by sharing contaminated brushes and combs. In the United States, Trichophytosis is usually caused by Trichophyton tonsurans, while T. violaceum is more common in Eastern Europe, Africa, and India. This fungus causes dry, non-inflammatory patches that tend to be angular in shape. When the hairs break off at the opening of the follicle, black dots remain. Favus is caused by T. schoenleinii, and is endemic in South Africa and the Middle East. It is characterized by a number of yellowish, circular, cup-shaped crusts (scutula) grouped in patches like a piece of honeycomb, each about the size of a split pea, with a hair projecting in the center. These increase in size and become crusted over, so that the characteristic lesion can only be seen around the edge of the scab.
Pathophysiology
From the site of inoculation, the fungus grows down into the stratum corneum, where it invades keratin. Dermatophytes are unique in that they produce keratinase, which enables them to use keratin as a nutrient source. Infected hairs become brittle, and after three weeks, the clinical presentation of broken hairs is evident.There are three types of infection:
Ectothrix: Characterized by the growth of fungal spores (arthroconidia) on the exterior of the hair shaft. Infected hairs usually fluoresce greenish-yellow under a Wood lamp (blacklight). Associated with Microsporum canis, Microsporum gypseum, Trichophyton equinum, and Trichophyton verrucosum.
Endothrix: Similar to ectothrix, but characterized by arthroconidia restricted to the hair shaft, and restricted to anthropophilic bacteria. The cuticle of the hair remains intact and clinically this type does not have fluorescence. Associated with Trichophyton tonsurans and Trichophyton violaceum, which are anthropophilic.
Favus: Causes crusting on the surface of the skin, combined with hair loss. Associated with Trichophyton schoenleini.
Diagnosis
Tinea capitis may be difficult to distinguish from other skin diseases that cause scaling, such as psoriasis and seborrhoeic dermatitis; the basis for the diagnosis is positive microscopic examination and microbial culture of epilated hairs. Woods lamp examination will reveal bright green to yellow-green fluorescence of hairs infected by M. canis, M. audouinii, M. rivalieri, and M. ferrugineum and a dull green or blue-white color of hairs infected by T. schoenleinii. Individuals with M. canis infection trichoscopy will show characteristic small comma hairs. Histopathology of scalp biopsy shows fungi sparsely distributed in the stratum corneum and hyphae extending down the hair follicle, placed on the surface of the hair shaft. These findings are occasionally associated with inflammatory tissue reaction in the local tissue.
Treatment
The treatment of choice by dermatologists is a safe and inexpensive oral medication, griseofulvin, a secondary metabolite of the fungus Penicillium griseofulvin. This compound is fungistatic (inhibiting the growth or reproduction of fungi) and works by affecting the microtubular system of fungi, interfering with the mitotic spindle and cytoplasmic microtubules. The recommended pediatric dosage is 10 mg/kg/day for 6–8 weeks, although this may be increased to 20 mg/kg/d for those infected by T. tonsurans, or those who fail to respond to the initial 6 weeks of treatment. Unlike other fungal skin infections that may be treated with topical therapies like creams applied directly to the affected area, griseofulvin must be taken orally to be effective; this allows the drug to penetrate the hair shaft where the fungus lives. The effective therapy rate of this treatment is generally high, in the range of 88–100%.
Other oral antifungal treatments for tinea capitis also frequently reported in the literature include terbinafine, itraconazole, and fluconazole; these drugs have the advantage of shorter treatment durations than griseofulvin. A 2016 meta-analysis of randomized controlled trials found that terbinafine, itraconazole and fluconazole were at least equally effective as griseofulvin for children infected with Trichophyton, and terbinafine is more effective than griseofulvin for children with T. tonsurans infection. However, concerns have been raised about the possibility of rare side effects like liver toxicity or interactions with other drugs; furthermore, the newer drug treatments tend to be more expensive than griseofulvin.On September 28, 2007, the U.S. Food and Drug Administration stated that Lamisil (Terbinafine hydrochloride, by Novartis AG) is a new treatment approved for use by children aged 4 years and older. The antifungal granules can be sprinkled on a childs food to treat the infection. Lamisil carries hepatotoxic risk, and can cause a metallic taste in the mouth.
Epidemiology
Tinea capitis caused by species of Microsporum and Trichophyton is a contagious disease that is endemic in many countries. Affecting primarily pre-pubertal children between 6 and 10 years, it is more common in males than females; rarely does the disease persist past age sixteen. Because spread is thought to occur through direct contact with affected individuals, large outbreaks have been known to occur in schools and other places where children are in close quarters; however, indirect spread through contamination with infected objects (fomites) may also be a factor in the spread of infection. In the US, tinea capitis is thought to occur in 3-8% of the pediatric population; up to one-third of households with contact with an infected person may harbor the disease without showing any symptoms.The fungal species responsible for causing tinea capitis vary according to the geographical region, and may also change over time. For example, Microsporum audouinii was the predominant etiological agent in North America and Europe until the 1950s, but now Trichophyton tonsurans is more common in the US, and becoming more common in Europe and the United Kingdom. This shift is thought to be due to the widespread use of griseofulvin, which is more effective against M. audounii than T. tonsurans; also, changes in immigration patterns and increases in international travel have likely spread T. tonsurans to new areas. Another fungal species that has increased in prevalence is Trichophyton violaceum, especially in urban populations of the United Kingdom and Europe.
See also
List of cutaneous conditions
Ringworm affair
Footnotes
References
Richardson M. (2003). Fungal Infection: Diagnosis and Management. Cambridge, MA: Blackwell Publishers. ISBN 1-4051-1578-5.
== External links == |
Tinea corporis | Tinea corporis is a fungal infection of the body, similar to other forms of tinea. Specifically, it is a type of dermatophytosis (or ringworm) that appears on the arms and legs, especially on glabrous skin; however, it may occur on any superficial part of the body.
Signs and symptoms
It may have a variety of appearances; most easily identifiable are the enlarging raised red rings with a central area of clearing (ringworm). The same appearances of ringworm may also occur on the scalp (tinea capitis), beard area (tinea barbae) or the groin (tinea cruris, known as jock itch or dhobi itch).
Other classic features of tinea corporis include:
Itching occurs on infected area.
The edge of the rash appears elevated and is scaly to touch.
Sometimes the skin surrounding the rash may be dry and flaky.
Almost invariably, there will be hair loss in areas of the infection.
Causes
Tinea corporis is caused by a tiny fungus known as dermatophyte. These tiny organisms normally live on the superficial skin surface, and when the opportunity is right, they can induce a rash or infection.The disease can also be acquired by person-to-person transfer usually via direct skin contact with an infected individual. Animal-to-human transmission is also common. Ringworm commonly occurs on pets (dogs, cats) and the fungus can be acquired while petting or grooming an animal. Ringworm can also be acquired from other animals such as horses, pigs, ferrets and cows. The fungus can also be spread by touching inanimate objects like personal care products, bed linen, combs, athletic gear, or hair brushes contaminated by an affected person.Individuals at high risk of acquiring ringworm include those who:
Live in crowded, humid conditions.
Sweat excessively, as sweat can produce a humid wet environment where the pathogenic fungi can thrive. This is most common in the armpits, groin creases and skin folds of the abdomen.
Participate in close contact sports like soccer, rugby, or wrestling.
Wear tight, constrictive clothing with poor aeration.
Have a weakened immune system (e.g., those infected with HIV or taking immunosuppressive drugs).
Diagnosis
Superficial scrapes of skin examined underneath a microscope may reveal the presence of a fungus. This is done by utilizing a diagnostic method called KOH test, wherein the skin scrapings are placed on a slide and immersed on a dropful of potassium hydroxide solution to dissolve the keratin on the skin scrappings thus leaving fungal elements such as hyphae, septate or yeast cells viewable. If the skin scrapings are negative and a fungus is still suspected, the scrapings are sent for culture. Because the fungus grows slowly, the culture results do take several days to become positive.
Prevention
Because fungi prefer warm, moist environments, preventing ringworm involves keeping skin dry and avoiding contact with infectious material. Basic prevention measures include:
Washing hands after handling animals, soil, and plants.
Avoiding touching characteristic lesions on other people.
Wearing loose-fitting clothing.
Practicing good hygiene when participating in sports that involve physical contact with other people.
Treatment
Most cases are treated by application of topical antifungal creams to the skin, but in extensive or difficult to treat cases, systemic treatment with oral medication may be required. The over-the-counter options include tolnaftate, as well as ketoconazole (available as Nizoral shampoo that can be applied topically).
Among the available prescription drugs, the evidence is best for terbinafine and naftifine, but other agents may also work.Topical antifungals are applied to the lesion twice a day for at least 3 weeks. The lesion usually resolves within 2 weeks, but therapy should be continued for another week to ensure the fungus is completely eradicated. If there are several ringworm lesions, the lesions are extensive, complications such as secondary infection exist, or the patient is immunocompromised, oral antifungal medications can be used. Oral medications are taken once a day for 7 days and result in higher clinical cure rates. The antifungal medications most commonly used are itraconazole, terbinafine, and ketoconazole.The benefits of the use of topical steroids in addition to an antifungal is unclear. There might be a greater cure rate but no guidelines currently recommend its addition. The effect of Whitfields ointment is also unclear.
Prognosis
Tinea corporis is moderately contagious and can affect both humans and pets. If a person acquires it, the proper measures must be taken to prevent it from spreading. Young children in particular should be educated about the infection and preventive measures: avoid skin to skin contact with infected persons and animals, wear clothing that allows the skin to breathe, and dont share towels, clothing or combs with others. If pets are kept in the household or premises, the animal should be checked for tinea, especially if hair loss in patches is noticed or the pet is scratching excessively. The majority of people who have acquired tinea know how uncomfortable the infection can be. However, the fungus can easily be treated and prevented in individuals with a healthy immune system.
Society and culture
When the dermatophytic infection presents in wrestlers, with skin lesions typically found on the head, neck, and arms it is sometimes called tinea corporis gladiatorum.
See also
Fungal folliculitis
References
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