AUDREY HIXThe Relationship Between Critical Flicker Fusion Frequency and Arterial Resting Blood Pressure(Under the Direction of BILLY R. HAMMOND JR.)
The relationship between the cardiovascular and visual systems was examined via critical flicker
fusion frequency (CFF) and resting systolic blood pressure (SBP). Three different studies were
conducted. Study 1 assessed and found a significant positive correlation (p < .0002) between resting
SBP and CFF (N = 221). Study 2 assessed whether resting SBP and CFF covary across time for a
given individual (N = 12). The statistical results of this study were mixed. A multiple regression analysis
(using time as a factor) revealed that three participants showed highly significant covariation, six
participants showed marginally significant covariation, and three participants did not show a relationship
between CFF and SBP. Study 3 measured the effects of blood pressure (BP) medication on the
relationship between SBP and CFF (N = 1). This preliminary case study indicated the possibility that
BP medication could lower CFF thresholds as well as SBP.
Critical flicker fusion frequency, Systolic blood pressure, and
THE RELATIONSHIP BETWEEN CRITICAL FLICKER FUSION FREQUENCY AND
A Thesis Submitted to the Graduate Faculty of The University of Georgia in Partial Fulfillment of the
THE RELATIONSHIP BETWEEN CRITICAL FLICKER FUSION FREQUENCY AND
Gordhan L. PatelDean of the Graduate SchoolThe University of GeorgiaMay 2002
I would like to thank my major advisor and friend, Dr. Billy R. Hammond, Jr., for his extreme
patience and assistance on my thesis. I could not have accomplished such a feat without him. I would
also like to express my gratitude to Dr. Mary Ann Johnson and Dr. James M. Brown for their support
and advice on this project. Furthermore, I would like to thank my family and friends for always being so
wonderfully supportive and encouraging of me during the pursuit of my professional career.
CHAPTER 1: INTRODUCTION…………….……………………………………….…………………1
Critical Flicker Fusion Frequency………………….…………………………….……………6
Systolic Resting Blood Pressure…………………………….…………………….……………8
Purpose of Present Studies…………………………………………….………….…………….9
CHAPTER 2: STUDY 1…………………………….……………………….………….……….…….11
CHAPTER 3: STUDY 2……………………………….…………………….………….…………….18
CHAPTER 4: STUDY 3………………………………………………………………….…………….31
CHAPTER 5: GENERAL DISCUSSION………………………….………………….…………….35
When studying human anatomy, it is readily apparent that the functions of all the systems
of the body are interrelated. For example, the body’s immune system would be ineffective in
combating pathogens without the aid of the circulatory system in transporting antibodies to the
sites of infection. Similarly, the cardiovascular and visual systems are also interrelated. For
example, response to threat, initially apprehended by the visual system (e.g. seeing an angry
wolf), will cause sympathetic activation. This arousal will result in increased heart rate and
The visual system is also influenced by the cardiovascular system. The retina, the neural
tissue lining the back of the eye, has a very rich blood supply, being served by the anterior
vasculature and posterior choroid. Additionally, the cortical areas of the brain responsible for
vision (e.g. occipital lobe) have an extraordinarily rich blood supply. Evidence of the occipital
lobe’s ample supply of blood becomes strikingly apparent during conditions that affect central
circulation. For example, one of the first symptoms of carbon monoxide (CO) poisoning is blurry
vision. Since CO has a greater affinity for red blood cells than oxygen (O2), the fatal
characteristic of CO poisoning is suffocation.
Because the retina is such a metabolically active tissue, any small reduction in blood flow
will influence visual function. For example, when a vein in the eye becomes constricted or
occluded (as in retinal vein occlusive disease), the visual acuity of the eye is dramatically
reduced; vision becomes blurred or distorted (Cameron & Ryan, 1997). Furthermore, many
blinding retinal diseases, such as proliferative diabetic retinopathy or aged-related macular
degeneration (ARMD), cause circulation problems that may result in areas of the retina
becoming ischemic or oxygen-deprived. As a coping mechanism, the retina will form new blood
vessels (called neovascularization) in order to obtain an adequate blood supply. Unfortunately,
the growth of these blood vessels damages the retina. They hemorrhage easily, which can often
lead to retinal detachment, disciform scarring, and ultimately blindness. Systemic hypertension
(which is the most prominent risk factor for cardiovascular disease) is the condition most
commonly associated with visual diseases such as branch retinal vein occlusion, especially in
people over 50 years of age (for review see Cameron & Ryan, 1997).
Diseases that affect the visual system (e.g., cataracts and ARMD) and cardiovascular
system (e.g. coronary heart disease and stroke) often share similar risk factors. For example,
cigarette smoking and poor diet are primary risk factors for both cardiovascular and visual
diseases. Studies have indicated that cigarette smoking is strongly related to the development of
cataracts and ARMD (for review see West, 1999), which are the leading causes of blindness in
the world. Likewise, studies have indicated that cigarette smoking is a significant risk factor for
coronary heart disease (CHD) and stroke (The Eye Disease Case-Control Study Group, 1992;
Hahn, Heath, & Chang, 1998), which are two of the leading causes of death in the world. High
intake of dietary fat and cholesterol is an important risk factor for both ARMD (Mares-Perlman,
Brady, Klein, VandenLangenberg, Klein, & Palta, 1995) and cardiovascular disease (for reviews
see Hu, Manson, & Willett, 2001; Nicolosi, Wilson, Lawton, & Handelman, 2001). This risk is
largely due to intake of saturated fat rather than monounsaturated fats (Hu et al., 2001), which
again is true both for visual and coronary disease.
Untreated hypertension, which I have already mentioned is a primary risk factor for
cardiovascular disease (Hahn et al., 1998), is related to primary open angle glaucoma, POAG
(Wilson, Hertzmark, Walker, Childs-Shaw, & Epstein, 1987). Specifically, Wilson et al. (1987)
found a strong association between increased resting systolic blood pressure (SBP) and incident
POAG. This association was limited to untreated hypertensive patients. Tielsch, Katz, Sommer,
Quigley, and Javitt (1995) also found a positive correlation between hypertension and POAG.
However, unlike Wilson et al. (1987), these researchers expanded their analysis to include
resting diastolic blood pressure (DBP) and found similar results for both SBP and DBP,
particularly in older participants. Leighton and Phillips (1972) found that both SBP and DBP
were greater in patients with POAG than both normal controls and patients with low-tension
Studies have demonstrated links between arterial hypertension and intraocular pressure
(IOP) (e.g. Leske & Podgor, 1983), which is a well-established risk factor for glaucoma.
Specifically, Leske and Podgor (1983) found a significant positive correlation between
hypertension and IOP. Hypertension was defined as an average resting SBP of greater than or
equal to 160 millimeters (mm) of mercury (Hg), which is consistent with other studies (e.g.
Wilson et al., 1987), and an average resting DBP of greater than or equal to 95mmHg or a
history of using anti-hypertensive medication. Although IOP is an important risk factor of
glaucomatous damage to the optic nerve, it is not the defining characteristic of glaucoma. Many
patients with normal IOP develop glaucoma (Litwak, 2000). Langham (1994) suggested that the
diagnosis and treatment of glaucoma should be focused not only on IOP but also on the
microcirculation of blood flow to discrete areas of the optic nerve via ciliary choroidal blood
flow and how therapy modifies blood flow to the eyes. Langham’s recommendations emphasize
how even subtle variations in retinal hemodynamics can have significant influences on visual
The sensitivity of the eye to a flickering stimulus, or flicker sensitivity (FS), has also
been shown to be significantly associated with ocular hypertension (increased IOP) and
glaucoma (Tyler, 1981). Tyler (1981) found significant deficits in FS at higher frequencies of
modulation, 30 to 40 Hertz (Hz), in patients with glaucoma and elevated IOP. Lower frequencies
and critical flicker fusion frequency (CFF) were unaffected1. Tyler, Ryu, and Stamper (1984)
found a significant, negative correlation between IOP and FS. Similarly, Vo Van Toi, Grounauer,
and Burckhardt (1990) found that artificially increasing IOP decreases FS, the loss also being
most pronounced in the highest frequency range.
The fact that FS is related to IOP and glaucoma is interesting given that hypertension is
also related to IOP and glaucoma. Taken together, the results suggest that FS itself might be
related to blood pressure (BP) in normal individuals. This interpretation is consistent with data
from two past studies (i.e. Eisner & Samples, 2000; Hammond, Warner, & Fuld, 1995).
Hammond et al. (1995) found an inverse association between acute variations in SBP and FS in 6
out of 15 participants recruited (all healthy adults). Therefore, as the participants’ SBP increased,
their sensitivity to flicker significantly decreased. The BP increase in the Hammond et al. (1995)
study was induced by a psychological stressor. Thus, the inverse nature of the relationship may
reflect dynamic changes between FS and BP. However, when the baseline data (as opposed to
the change values induced by the stressor) from the “nonreactive” participants (as opposed to the
“reactive” participants) are replotted against the baseline FS values, a positive correlation is
observed (r = .40, N = 8). The correlation was not statistically significant, probably due to
insufficient statistical power. The participants who showed “less than a 10mmHg change in SBP
1 Both CFF and FS measure sensitivity to a flickering stimulus; however, CFF holds the
illuminance constant and varies the flickering rate of the stimulus, while FS holds the flickering
rate constant and varies the illuminance of the stimulus.
from their baseline” were labeled as “nonreactive” (p. 215). Eisner and Samples (2000) found a
negative correlation between mean arterial blood pressure to heart rate (MAP/HR) and
FS (N = 18). MAP is the average amount of pressure needed to drive blood through the
circulatory system throughout the cardiac cycle (MAP = diastolic BP + pulse pressure/ 3). Pulse
pressure is the difference between SBP and DBP.
In summary, there is a vast literature connecting systemic hypertension, which is a
prominent risk factor for cardiovascular disease (e.g. CHD), with visual disease such as
glaucoma (Leighton & Phillips, 1972; Tielsch, et al., 1995; Wilson et al., 1987), and there are
many studies connecting ocular hypertension (e.g. IOP), which is an important risk factor for
glaucoma, with systemic hypertension (e.g. Leske & Podgor, 1983). In addition, many studies
suggest an association between IOP and FS (e.g. Tyler, 1981; Tyler et al., 1984; Vo Van Toi et
al., 1990) and systemic hypertension and FS (Eisner & Samples, 2000; Hammond et. al., 1995).
With the exception of Eisner and Samples (2000) and Hammond et al. (1995), the
previously mentioned studies do not address a relationship between the normal functioning of the
cardiovascular and the normal functioning of the visual system under resting conditions. Little
data, beyond these two small studies, is available to adequately assess the relationship between
cardiovascular and visual functioning in the absence of disease and under resting conditions.
Although Eisner and Samples did assess resting blood pressure and FS in non-diseased
participants, their small sample did not allow for adequate control for the important confounding
influence of age. They studied individuals from 40-68 years of age. Moreover, both the
Hammond et al. study and the Eisner and Samples study measured FS. FS assesses both
luminance thresholds and flicker thresholds. Although under normal conditions, FS is highly
related to purely temporal measures such as critical flicker thresholds (Ferry-Porter law). Older
participants lose visual sensitivity (Hammond, Wooten, & Snodderly, 1998), as well as temporal
resolution (Curran, Wattis, Shillingford, & Hindmarch, 1990), which complicates the
interpretation of Eisner and Samples’ data. In our first study (Study 1), we had a goal similar to
Eisner and Samples, to quantify a relationship between visual and cardiovascular variables in
healthy individuals. However, we controlled for age by only selecting participants in a young,
narrow age range (~17-24). We also used a more narrowly defined visual function measure,
Critical flicker thresholds are determined using a descending method of limits. In a
typical paradigm, the flicker rate of a fused suprathreshold stimulus is reduced until a participant
just perceives flicker. Critical fusion thresholds are determined by increasing the flicker rate of a
flickering stimulus until the stimulus stops flickering and appears fused. CFF is taken as the
average of the descending flicker value and the ascending fused value.
The fact that past studies have found that glaucoma and IOP are more related to FS than
CFF (Tyler, 1981) is one indication that FS is more affected by factors influencing the eye
directly. In contrast, CFF is often used as a more holistic index of visual function that is probably
determined post-receptorally. For instance, Wells, Bernstein, Scott, Bennett, and Mendelson
(2001) conducted a recent study showing that, for rats, CFF thresholds were determined by the
simple, complex, and hypercomplex cells of areas 17 and 18 of the primary visual cortex.
Furthermore, studies have found that CFF is related to improved psychomotor performance and
reaction time (Grunberger, Saletu, Berner, & Stohr, 1982). Grunberger et al. (1982) also found
that CFF covaried with electroencephalogram (EEG) measurements, particularly with increasing
Due to data such as Wells et al. and Grunberger et al., CFF is commonly used as an
indicator of the overall state of arousal of the central nervous system (CNS), including variables
such as mental alertness and cognitive potential (Curran, et al., 1990; Volz & Strum, 1995). In
fact, CFF is widely used to study the effects of psychotropic drugs on the CNS of normal healthy
participants (Smith & Misiak, 1976). Drugs that stimulate the CNS increase CFF, and drugs that
depress the CNS decrease CFF (Simonson & Brozek, 1952; Smith & Misiak, 1976). Thus, if
CFF is associated with higher brain arousal and SBP is associated with CFF, then an association
between higher brain arousal and SBP seems highly probable.
There are many factors that affect CFF (e.g. illuminance, stimulus size, wavelength, age,
smoking, diet, and disease states), which should be accounted for when using CFF as an
experimental parameter. CFF increases approximately linearly with the log of illumination,
which is referred to as the Ferry-Porter law. This increase in CFF is most likely related to a
general speeding up of retinal processes, which occurs with increasing levels of light adaptation
(Schwartz, 1999). CFF also increases linearly with the log of stimulus area; thus, flicker is easier
to perceive with larger stimuli. This is referred to as the Granit-Harper law. To account for these
two effects, the illumination and size of the test stimulus used in the present study were held
Furthermore, age (Lachenmayr, Kojetinsky, Ostermaier, Angstwurm, Vivell, &
Schaumberger, 1994; Simonson & Brozek, 1952) and smoking (Simonson & Brozek, 1952) are
both negatively correlated with CFF thresholds. Age was controlled for in this study by the
recruiting of a relatively young sample. Smoking status was assessed by questionnaire, and the
results of the analysis are provided later in the methods section. Additionally, many
cardiovascular diseases and eye diseases will reduce CFF thresholds (Curran et al., 1990;
Simonson & Brozek, 1952), and there are many drugs that raise CFF (e.g. amphetamines) or
decrease CFF (e.g. barbiturates). Therefore, disease states and any drug use were also assessed
via questionnaire. Due to the younger age of the sample, disease influences and influences due to
prescription drug use were considered unlikely.
The most common parameter utilized when assessing cardiovascular functioning is
arterial resting blood pressure (RBP) because it provides a good index of cardiovascular response
that is relatively easy to obtain and quantify (Sherwood & Turner, 1992). Much like CFF
(Grunberger et al., 1982), SBP and DBP have been linked to ongoing electrocortical activity.
Walker and Walker (1983) found that “rhythmic oscillations of the EEG were time-locked to the
carotid pressure wave” (particularly those in the alpha range), and “EEG samples taken during
systolic and diastolic pressure were distinctly out of phase” (p. 70-71). These results seem to
suggest that cardiovascular functioning influences electro-cortical rhythms, which in turn
mediate the relationship between cardiac events and behavior (Walker & Walker, 1983). The fact
that the oscillations in electro-cortical activity were found primarily in the alpha range (Walker
& Walker, 1983) lends support to the idea that there is a possible relationship between
cardiovascular functioning and CFF, since Grunberger et al. (1982) found a positive relationship
2 However, while both SBP and DBP were measured in the present study, only the results for
SBP are reported. In general, we found similar results for DBP, only the effects were attenuated.
Furthermore, SBP has been more heavily linked to the risk of cardiovascular diseases (e.g. heart
disease & stroke) than DBP (review by He & Whelton, 1999), which lends more clinical interest
In addition, studies have found that SBP and DBP tend to vary with cardiac cycle during
social situations and solitude, but that heart rate (HR) only shows cyclic variations during
solitude (Warner & Stevens, 1991). The authors believe that their data are due to some type of
feedback mechanism. Likewise, Sandman, McCanne, Kaiser, and Diamond (1977) reported
enhanced visual performance during low HR suggesting that cardiac phase also influences visual
perception. However, another study investigating the average differences in visual sensitivity as
a function of cardiac cycles (Elliot & Graf, 1972) found small and unreliable differences.
A relatively recent study found that SBP, like CFF, might be a marker of subcortical
arousal (Davies, Bennet, Barbour, Tarassenko, & Stradling, 1999). This was a clinical study that
looked at a special type of sleep disorder called Cheyne-Stokes (which is a disorder of breathing
during sleep). Basically, they found that the participants’ SBP was in high concordance with the
progression of their cortical arousal as measured by an EEG.
The purpose of the present studies was to investigate the relationship between resting
systemic BP and visual functioning of normotensive, healthy participants. Specifically, the cross-
sectional relationship between resting SBP and CFF was assessed. Covariance between the two
variables for a given participant across a temporal dimension was also evaluated. For the reasons
previously outlined, we predicted that we would find a relationship between CFF and SBP. We
also predicted this relationship would be positive. Past studies have suggested that SBP may be a
marker of subcortical arousal (Davies et al., 1999). If higher resting SBP is arousing, and if it
leads to higher brain arousal, it should also lead to higher CFF values, which covaries with CNS
arousal (Wells et al., 2001). In summary, these studies attempted to address the following
questions: (1.) Are CFF and resting SBP related? (2.) Is higher resting SBP arousing? (3.) Does
higher resting SBP lead to higher brain arousal? (4.) Does CFF and resting SBP covary across
time? (5.) What are the affects of blood pressure medication on these relationships?
In order to address these questions, three different studies were conducted. As previously
alluded to, the design and motivation of the first study (Study 1) was to address the general
relationship between the cardiovascular system, via SBP, and the functioning of the visual
system, via CFF. Specifically, Study 1 was a between-subjects design in which participants’ CFF
and resting SBP were measured in one experimental session. Unlike the Eisner and Samples
study (which recruited 18 middle-aged adults), a much larger sample of young adults was
recruited for this study. This large sample size was necessary in order to control for the many
confounds that might be expected to influence CFF and SBP. Furthermore, by utilizing a
relatively younger population, variance due to the overall aging of the visual and cardiovascular
systems was decreased. As previously mentioned, the visual parameter that was used was CFF as
opposed to FS, and resting SBP was measured as opposed to MAP/HR, DBP, or dynamic
The second study (Study 2) was a within-subjects design in which participants’ CFF and
resting SBP were measured on ten separate occasions. This study was designed to assess
covariance in the two variables across time. The third study (Study 3) was a case study in which
the effects of BP medication on the relationship between CFF and resting SBP was examined.
This combination of study designs was selected in order to aid in the final interpretation of the
Participants. Two hundred and twenty-one undergraduates (126 women and 95 men)
were recruited from the University of Georgia (UGA). The mean age of participants was 19.59
years (SD = 2.45). Informed consent was obtained, and the Institutional Review Board (IRB)
approved all experimental procedures. Participant testing and data handling was conducted
according to the tenets outlined in the Declaration of Helsinki, which is a protocol accepted as a
standard when testing human participants in clinical research settings.
All participants were required to fill out a brief questionnaire including personal
information (e.g. age, sex, and iris color) and smoking history (e.g. current and past smoking
habits). Forty-five of the participants were smokers, 31 were past smokers, and 145 had never
smoked. Forty-nine had blue irises, 6 had bluish irises (e.g. blue/green, blue/hazel, and
blue/yellow), 85 had brown irises, 5 had brownish irises (e.g. brown/green and brown/hazel), 36
had green irises, 2 had greenish irises (e.g. greenish-brown and greenish-hazel), and 36 had hazel
The participants’ Snellen acuity was also assessed. Only the right eye of each participant
was measured. Ninety-one of the participants had 20/20 Snellen acuity, 5 participants had
20/17.5, and 85 had 20/15 or better visual acuity. Three participants had 20/25 Snellen acuity, 25
had 20/30, 8 had 20/40, 3 had 20/50, and one person had 20/70 visual acuity. For a summary of
the data collected on smoking status, iris color, and Snellen acuity see Table 1. Materials. An automatic, digital sphygmomanometer (Omron Healthcare, Inc., model
HEM-725C) was used to measure arterial RBP, in millimeters of mercury (mm Hg), via an arm
cuff on the left, brachial artery (upper arm). As previously mentioned, a Snellen eye chart was
Smoking Status, Iris Color, and Snellen Acuity of Participants in Study 1
utilized to measure visual acuity. CFF was measured psychophysically in Hertz (Hz) on a
Newtonian view optical system (using a 1-deg circular test stimulus). This optical system is
schematicized in Wooten, Hammond, Land, and Snodderly (1999).
To avoid absorption by preretinal media (e.g. lens and macular pigment), a 570-
nanometer (nm) light was used for the test stimulus. It was generated by a liquid energy display
(LED) with peak energy at 570-nm (half-width =20 nm), and was not presented on a background
(thus the background appeared black to the participants). Light from the LED source was
collimated with planoconvex lenses. The size of the test stimulus was defined by a circular
aperture placed after the collimating lenses of the system. The stimulus was delivered in square
wave alteration, and the rate at which it was presented could be varied over a 1-50 Hz range. The
illuminance of the 570-nm light was set at 30 candelas per square meter, and the radiance was
0.34 nanowatts. The system was calibrated periodically to assure that these settings remained
stable. The entire optical system was encased in a black, rectangular Plexiglas box. A 1-inch,
circular hole in the front of the box allowed participants to view the stimulus. A chin and
forehead rest was utilized in order to minimize head movements and maintain the visual angle of
Design and procedure. A between-subjects design was employed in Study 1, and each
session lasted approximately 30 minutes. Before any measurements were taken, the participants
filled out the consent form and questionnaire. Then, the participants’ Snellen acuity was assessed
by the experimenter and recorded on the questionnaire. Next, the participants’ RBP was
measured on their left brachial arteries (pulse was recorded along with RBP). After obtaining
RBP, the experimenter measured the participants’ CFF. At the end of the experimental session,
in order to obtain average measurements, the participants’ RBP and CFF were measured a
CFF was assessed using the ascending and descending Method of Limits. First, the
participants were placed in a darkened room (one at a time) and instructed to rest their heads on a
headrest in front of the Newtonian view optical system. Then, the flickering rate of the 1-deg,
570-nm circular stimulus was set at 12 Hz (consistent with past studies, Curran et al., 1990), and
participants’ were asked if they could see a black background with a green flickering circle.
Upon receiving an affirmation from the participants, the experimenter instructed them to state
when the flickering appeared to stop. Then, the experimenter gradually began increasing the
flicker rate of the stimulus until the participant perceived the stimulus as fused (the flickering
stopped); this rate (in Hz) was recorded. Finally, the experimenter adjusted the flickering rate
well above the previously obtained rate and instructed the participants to state when they first
perceived the stimulus to start flickering. This number was also recorded. The experimenter then
averaged the ascending and descending values to obtain one CFF measurement.
The overall average resting SBP was 115.73 (SD = 14.41), and the overall average CFF
threshold for the participants was 23.12 (SD = 2.73). To assess whether there were any sex
differences, we conducted two One-Sample T-Tests (in SPSS 10.1) comparing the male and
female SBP and CFF thresholds. The results of these tests indicated that there was a statistically
significant difference between the average resting SBP measurements for the males (M = 125.19,
SD = 12.40) and females (M = 108.59, SD = 11.42), t = 10.193 (p < 0.0001). Moreover, the
results indicated that there was a statistically significant difference between the average CFF
thresholds for the males (M= 23.87, SD = 2.87) and females (M = 22.54, SD = 2.48), t = 3.61 (p
We also did a correlational analysis (Pearson’s r) between SBP and CFF. This analysis
revealed a statistically significant, positive correlation (r = 0.23, p < 0.0002) between CFF and
resting systolic BP (see Figure 1). We did not find a sex difference in the SBP-CFF relationship.
The results of Study 1 support the hypothesis that resting SBP and CFF are positively
correlated. Additionally, the results reveal a statistically significant sex difference between both
SBP measurements and CFF thresholds. In particular, the males had higher resting SBP and
higher CFF thresholds. Note that the direction of this result is consistent with the hypothesis that
SBP and CFF are positively correlated. These sex differences may be clinically meaningful given
the fact that males have such higher incidence of cardiovascular disease. The average SBP of the
males was higher than the females despite the relatively young age of this sample. The results
would imply that even young males might have higher levels of brain arousal compared to
females. This higher state of arousal may be linked to increased SBP. If high levels of arousal is
rewarding, increased blood pressure in the males may actually be “learned” through operant
mechanisms (see Dworkin, Filewich, Miller, & Craigmyle, 1979).
Furthermore, the sex difference found in this study is consistent with past research. For
example, it has been noted that in nearly all developed countries (e.g. North American, Europe,
and Japan) young adult women consistently demonstrate lower systolic and diastolic pressures
than men (Whelton, He, & Klag, 1994). However, this association is variable over the entire
lifespan. The BP of children does not show any statistical effects of sex (for review see Laragh &
Brenner, 1995); however, in adolescence (e.g. starting around age 13) the mean SBP of boys is
significantly higher than that of teenage girls (Baron, Freyer, & Fixler, 1986). Furthermore,
between the ages of 35 - 44 years, SBP remains higher for men. However, by middle age (55-64
years) the difference becomes much smaller, and then by the sixth and seventh decades, women
have slightly higher SBP than men (OPCS, 1994).
Average Critical Flicker Fusion Frequency (Hz)
Average Resting Systolic Blood Pressure (mmHg)
Figure 1. The relationship between CFF and SBP (Y = 18 + 0.04x, r = 0.23, p < 0.0002) for the
entire sample tested (N = 221). Participants. A sample of 12 graduate and undergraduate students (3 men and 9 women,
mean age = 24.42, SD = 6.33) were recruited from the University of Georgia student body.
Informed consent was obtained, and the IRB approved all experimental procedures. Consistent
with Study 1, participants were required to fill out a questionnaire to assess their personal data
(e.g. age, sex, and iris color) and smoking history (e.g. current and past smoking habits).
Likewise, the visual acuity of their right eyes was measured by the experimenters using the
Because Study 2 recruited a much smaller sample size than Study 1, more visual,
medical, and dietary information was considered from the participants’ questionnaires.
Refractive errors, eye surgeries or treatments, history of eye disease, any medical conditions or
medications, and whether or not each participant was a vegetarian was assessed. All of this
information is listed in Tables 2.1 and 2.2. Materials. All materials used in Study 2 were identical to those used in Study 1. Average
resting BP was assessed with an automatic sphygmomanometer, visual acuity was measured with
a Snellen eye chart, and average CFF was measured on the Newtonian view optical system
(using a 1-deg circular test stimulus). Again, only the right eye of each participant was measured. Design and procedure. A within-subjects design was employed for Study 2. The
participants’ SBP and CFF were measured in the exact same manner as listed above; however,
measurements were taken on ten separate occasions. These separate days were not equally
spaced. Because of time constraints, three of the participants were unable to complete all ten
sessions. Participants MNK and KLM completed 9 sessions, and GLS completed 8 sessions. Qualitative Information on Study 2 Participants
Qualitative Information on Study 2 Participants continued…
DDW, GLS, JRD,KAM, KLM, MNK,MJP, SRP, &
Past Eye Diseases, Conditions, or Surgeries
Anti-depressants (Serzone & Zoloft) 2
Analysis one. To assess any covariance between the two variables (CFF and resting SBP),
the data of each participant was examined separately. Each person’s data was plotted on a
double-Y line graph. Time (specified in days) was placed on the abscissa, and average resting
SBP and average CFF was placed on the two ordinates. This allowed us to visually assess any
obvious covariance between the two variables. From this initial examination, we identified 5 out
of the 12 participants that illustrated potential significant covariance (see Figures 2 - 6). Analysis two. An unlagged cross-correlation function was employed (via the statistical
program SPSS 10.1) for each participant (averaging the two measures taken during a given
session). With critical values of r = 0.55 (df = 8, p < 0.05) and r = 0.62 (df = 6, p < 0.05) , this
analysis yielded marginally significant results for two participants, GLS and JRD (r = -0.52 and r
= -0.41 respectively). The analysis revealed null results for all subsequent participants. In
addition, we conducted an unlagged cross-correlation function on all the data points collected for
each individual. For instance, instead of just analyzing the 10 average CFF and SBP
measurements for participant JFC, we analyzed all 20 CFF and SBP measurements obtained
from this individual. This analysis yielded marginally significant results for three participants,
DLG, JRD, and MJP (r = 0.30, r = -0.37, and r = -0.35 respectively), and significant results for
one participant, JFC. JFC’s results revealed a statistically significant positive unlagged cross-
correlation (r = 0.40, p < 0.05). Analysis three. Our preliminary data analysis (see Figures 2 - 6) suggested that, while
there appeared to be significant covariation for many days during the study period, some days
were markedly divergent. Therefore, we conducted the analysis again but removed the data for
the one day that seemed most divergent. Participants DLG, GIC, JFC, JRD, and KAM all
showed statistically significant cross-correlations, which is for the most part consistent with our
initial beliefs that there was significant covariance between the CFF thresholds and SBP
measurements of these particular participants. For more detailed information see Table 3. This
analysis suggests that with additional measurements the results may have reached significance
without the necessity of windzoring the data. Results of the unlagged cross-correlation analysis on the windzored, Study 2 data.Analysis four. The pattern of covariance and non-covariance on the double-Y line graphs
constructed from the data, revealed that for some of the participants the two variables covaried
on days 1-5 but then fell out of sync on the last days of the study (see Figures 2 - 4, & 6). JRD’s
graph exhibited the exact opposite pattern (see Figure 5). Therefore, we conducted a multiple
regression analysis (in the statistical program Origin 6.0) in which we regressed CFF on SBP and
Trial (coded as early trials and late trials). For instance, the measurements taken in trials 1-10
(from days 1-5) were coded as 1’s and trials 11-20 (from days 6-10) were coded as 2’s. This
analysis yielded statistically significant F-values for 3 out of 12 participants (DDW, JRD, and
KLM), 7 participants showed marginally significant results (DLG, GLS, HST, JFC, KAM,
MNK, and SRP), and the remaining 2 participants (GIC and MJP) did not yield statistically
26.0 Average Critical Flicker Fusion Frequency (Hz)
Average Systolic Resting Blood Pressure (mmHg)
Figure 2. Data from participant DDW.
Average Critical Flicker Fusion Frequency (Hz)
Average Systolic Resting Blood Pressure (mmHg)
Figure 3. Data from participant GIC.
Average Critical Flicker Fusion Frequency (Hz)
Average Systolic Resting Blood Pressure (mmHg)
Figure 4. Data from participant JFC.
Average Critical Flicker Fusion Frequency (Hz)
Average Systolic Resting Blood Pressure (mmHg)
Figure 5. Data from participant JRD.
Average Critical Flicker Fusion Frequency (Hz)
Average Systolic Resting Blood Pressure (mmHg)
Figure 6. Data from participant KAM. Results from the Multiple Regression Analysis Study 2 Participants
The results of Study 2 are mixed. The cross-correlation analysis (analysis two) seemed to
support the null hypothesis that CFF and resting BP do not vary together across time. However,
Figures 2-6 suggest more than just random fluctuation. When we removed the data from one day
for each individual (analysis three), the results showed statistically significant results for 5 out of
the 12 participants. This suggests that we had insufficient statistical power to adequately
determine the magnitude of this effect. Indeed, two out of the three participants for whom we
obtained “marginally” significant results for in the analysis of the raw data were two of the
participants that did not complete the entire ten sessions of the study (MNK and GLS).
An examination of Figure 2- 6 (analysis one) suggest the possibility of a confounding
variable, which is sometimes present and sometimes absent. One possibility is based on the
results of Hammond et al. (1995). Their study suggested that, although resting BP may be
positively correlated with CFF, dynamic changes in BP are inversely correlated with CFF. It
should be noted here that this change is bi-directional. Increasing BP leads to decreasing CFF,
and decreasing BP leads to increasing CFF. It is possible that on days where BP and CFF
appeared divergent, the participants BP may not be reflecting true resting levels. Therefore, one
aim of future studies could be to analyze this possibility by carefully obtaining measures of SBP
Participants. Study 3 consisted of one, white male, 36 years of age. The participant
(BRH) had never smoked, had green/hazel irises, had a Snellen acuity of 20/20 in his right eye,
and had myopia (for which he wore corrective eye glasses). In addition, he had no history of eye
Materials. All materials used in Study 3 were identical to those used in Study 1 except
for one. Arterial resting BP was assessed with an automatic sphygmomanometer, visual acuity
was measured with a Snellen eye chart, and average CFF was assessed by the Newtonian view
optical system (using a 1-deg circular test stimulus). Consistent with Study 1 and 2, only the
right eye of the participant was measured. In addition to these materials, a generic brand of the
drug Ramipril, Altace, was prescribed by a doctor and taken by the participant for the second
half of the study (days 7-12). The participant took approximately 2 milligrams (mg) of the drug a
Design and procedure. The participant’s CFF and SBP were assessed in the above-
mentioned manner (see Study 1) on six different days prior to any medication. These data
provided a solid baseline measurement. Then, the participant began taking the Altace. Two days
later (allowing time for the drug to take affect), the participant’s CFF and SBP were measured
again and on five other subsequent days.
Data for this participant is presented in Figure 7. Note that the data are partitioned into
pre-medication and post-medication trials. His average SBP was 126.67 (SD = 10.71), and his
Average Critical Flicker Fusion Frequency (Hz)
Average Systolic Resting Blood Pressure (mmHg)
Figure 7. Data for participant BRH (pre-medication and post-medication measurements are
partitioned by the dotted line down the center of the graph).
average CFF threshold was 30.36 (SD = 0.94). Both of these levels are higher than average,
which is consistent with the results of Study 1. BRH’s average pre-medication SBP was 127.92
(SD = 11.90), and his average post-medication SBP was 125.42 (SD = 9.74). BRH’s mean pre-
medication CFF threshold was 30.83 (SD = 0.99), and his post-medication CFF threshold was
Since we were interested in whether or not BP medication decreases CFF thresholds as
well as resting SBP, we conducted two Paired Samples T-Tests (in SPSS 10.1) on the pre-
medication (trials 1-12, taken on days 1-6) and post-medication measurements (trials 13-24,
taken on days 7-12). One was conducted on the pre- and post-medication measurements of
resting SBP, and the other was conducted on the CFF assessments. The purpose of these analyses
was to determine if the pre-medication measurements were statistically significant from the post-
medication measurements. Interestingly, the findings of the one-tailed T-Test on SBP were not
significant (t = 0.52, p < 0.31), which indicated that the BP medication did not decrease the
participant’s BP as intended. However, the results of the one-tailed T-Test on CFF were
significant (t = 2.15, p < 0.03), which indicated that the BP medication did decrease BRH’s CFF
Furthermore, the data were analyzed using an unlagged cross-correlation function and a
multiple regression analysis in which CFF was regressed on resting SBP and trial (coded as
before and after intervention). Since BRH’s CFF and SBP was measured on 12 separate days,
both analyses consisted of 24 trials (instead of 20 trials as used in Study 2), which added
considerably more statistical power to the results.
The results of the cross-correlation analysis (using a one-tailed alpha level) revealed a
statistically significant correlation coefficient (r = 0.42, p < 0.025). Similarly, the findings of the
multiple regression analysis revealed a statistically significant F statistic (F = 6.61, p < 0.006)
and r-value (r = 0.39, p < 0.05). The regression equation for the best fitting line between CFF,
SBP, and trial (for BRH’s data) was Y = 27.63 + 0.03x (SBP)+ -0.85x (trial).
The findings of Study 3 support three of the initial hypotheses (1) that CFF and resting
SBP are positively correlated (2) that CFF and resting SBP vary together across time, and (3)
that CFF would decrease with resting SBP when taking blood pressure medication. Specifically,
the significant cross-correlation function strongly suggested a covariance of resting SBP and
CFF over time. In addition, the multiple regression analysis indicated that the participant’s CFF
threshold could be predicted by resting SBP and trial (coded as pre- and post-medication).
Finally, the results of the Paired Samples T-Test suggested that BP medication influenced this
In summary, the relationship between resting SBP and CFF for this participant were quite
robust. Preliminary results motivates the need to study more participants in order to clarify these
effects. Although not statistically significant, it is likely that BRH’s BP was also affected by the
medication. Unlike his CFF values, however, which only ranged over about 3 Hz (~10% of
total), his BP was quite variable (ranging from 114 to 137; ~18% of total). The greater variance
reduces the statistical discriminability of the test.
The combination of results from the present three studies strongly suggest that CFF and
resting SBP are related. This result is consistent with past studies that found a relationship
between cardiovascular and visual functioning in normal, healthy adults (e.g. Eisner & Samples,
2000). A statistically significant sex difference was also found in Study 1. The males had higher
resting SBP and higher CFF thresholds. Importantly, the results suggest that normal variations in
the BP of even young individuals can have measurable impacts on vision. This relationship may
reflect an important link in the development of long-term essential hypertension and
cardiovascular disease. This implication would be consistent with the biofeedback model
developed by B. R. Dworkin (for review see Dworkin, 1988).
Dworkin developed a model that attempts to explain the etiology of essential
hypertension. He outlined how physiological reactions to stressful events can lead to essential
hypertension through chronic baroreceptor activation. Based on his theory, the baroreceptor
reinforcement hypothesis, hypertension can be learned through operant mechanisms.
Baroreceptors are receptors that signal the stretching of major arteries such as the carotid and
aorta. Increased activity of the baroreceptors results in a signal being sent to the medulla, which
activates the vagal center causing reduction of BP. Thus, the baroreceptor-medulla-vagus reflex
arc forms a negative feedback loop which helps maintain homeostasis within the circulatory
system. Dworkin reviews evidence that showed that activation of the baroreceptors had the
secondary effect of dearousing the brain (through inhibition of the ascending reticular system).
This effect, he argued, was positively reinforcing since acute arousal is generally aversive. Since
the ultimate effect of having a BP response to a stressful situation is rewarding, the probability
that one would have such responses is increased. Having more BP reactions to stressful
situations over time would lead to chronic hypertension.
Many studies have examined how BP can be operantly conditioned (Elbert, Roberts,
Lutzenberger, & Birbaumer, 1992; Pickering, Brucker, Frankel, Mathias, Dworkin, & Miller,
1976; Plumlee, 1969). For instance, Plumlee (1969) conducted a study on four rhesus monkeys
in which he demonstrates the ease with which large BP rises can be conditioned. In addition, at
least one study has indicated that chronic high BP can be conditioned (Jonsson & Hansson,
1977). Consistent with Plumlee (1969), Elbert et al. (1992) found that participants were
successful (through the biofeedback mechanism mentioned previously) at learning to control
their BP, albeit for monetary reward. Furthermore, this study assessed whether instrumentally-
learned BP responses have any effects on electrocortical activity. Their study examined whether
baroreceptors regulate the cardiovascular system by the use of cortical inhibition as proposed by
Dworkin (Elbert et al., 1992). They found, through EEG and electrocardiogram (ECG)
measurements, a temporal relationship between cardiovascular and electrocortical changes which
supported their conclusion that “differentiation of slow potentials was secondary to activation of
the baroreceptors” (Elbert et al., 1992, p. 161). They also state that the positive-going slow
potentials they found signify cortical inhibition.
Hammond et al. (1995) looked at dynamic changes in BP rather than normal variations in
resting BP. Consistent with Dworkin (1988), they found that acute elevations in BP inhibit
sensory systems, specifically FS thresholds. Thus, as BP increases, FS decreases. This pattern of
results is consistent with research conducted on other sensory thresholds (e.g. pain). For
example, Angrilli, Mini, Mucha, and Rau (1997) conducted a study investigating the relationship
between pain thresholds and BP. Particularly, this study evaluated whether participants, who
were experiencing painful stimulations, preferred one of two conditions, baroreceptor activation
or baroreceptor inhibition. The authors recruited normotensives and hypotensives as participants,
and used the PRES (cardiac phase-related external suction) technique to induce pain. This
technique involved placing a cuff on the neck at the carotid artery. Electrical pulses were
delivered either during systolic suction (the largest baroreceptor activation) or diastolic pressure
(the largest baroreceptor deactivation). The results of the study indicated a negative correlation
between DBP (baroreceptor deactivation) and sensory thresholds (r = -0.44), and a positive
correlation between SBP (baroreceptor activation) and pain thresholds (r = 0.27). Painful stimuli
were perceived as less painful when presented during baroreceptor activation in the Normal BP
group. However, there was no significant difference in the Low BP group. Therefore, the data
indicate that participants with normal to high BP exhibit baroreceptor modulation of pain
responses; however, participants with low BP do not. The results of this study are consistent with
a past research (e.g. Rau, Brody, Larbig, Pauli, Voheringer, Harsh, Kroling, & Birbaumer, 1994).
One significant confound in this study (which is pretty common with research on pain
thresholds) was that all of the participants were men. In addition, studies have shown that
normotensive individuals with a parental history of hypertension (thus at high risk for developing
hypertension) had significantly higher pain thresholds than participants of normotensive parents
In contrast, the present studies indicate that normal variations in resting BP actually
increase sensory thresholds and cortical arousal rather than inhibit them (e.g. as BP increases,
CFF thresholds increases). Taken together, the results of the above mentioned studies suggest the
existence of two different mechanisms of reward, short-term de-arousal and long-term arousal.
Study 2 of this paper attempted to address any covariance between resting SBP and CFF
over time, which would have lent additional support to the previous postulation that the two
variables have a long-term association and impact on one another over time. However, the results
of this study are mixed. Statistically only a few of the results from this study support the
hypothesis that CFF and resting SBP vary together across time. Most of the data seemed to
indicate that the two variables are not correlated and randomly fluctuate. Overall the statistical
analyses of Study 2 indicated a weak and unreliable association. However, when we removed the
data from one particularly divergent day for each individual, the results convey statistically
significant results for 5 out of the 12 participants. Thus, these results suggest that with additional
measurements the results would have been statistically significant without the necessity of
windzoring the data. Furthermore, it was postulated that the days in which SBP and CFF seem to
vary together (as seen in Figures 2-6) are due to true resting SBP; however, the days in which
SBP and CFF fluctuate randomly are due to acute changes in SBP.
Study 3 was a case study that assessed the effects of BP medication on CFF thresholds.
Although, the actual statistical analyses of the data collected for Study 3 conveyed a strong
cross-correlation of resting SBP and CFF and a definite influence of BP medication on CFF
thresholds, there was only one participant. Thus, even though the data lend some support to all
three hypotheses (that resting SBP and CFF are positively correlated, that resting SBP and CFF
vary together across time, and the BP medication affects CFF thresholds), the data from one case
study is insufficient in order to generalize to the larger population.
In conclusion, the leading cause of death in the western world is cardiovascular disease.
Moreover, approximately 38 million people are blind, and a further 110 million have low vision
and are at risk for blindness in the world (Thylefors, Negrel, Pararajasegaram, & Dadzie, 1995).
Thus, empirical evidence for a quantifiable relationship between these two systems could
potentially have implications for the medical and scientific communities. One possible
application of the present studies could be the use of CFF as a possible biomarker for the future
development of hypertension. The finding that there is an association between SBP and CFF is
consistent with the idea that elevated resting BP is related to increased central arousal. If
increases in central arousal over time are rewarding, then efforts to block this arousal may reduce
the probability of developing chronic high BP. The fact that the CFF of the participant in Study 3
lowered significantly in response to BP medication is consistent with this possibility.
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Available online at www.sciencedirect.comProblem prescriptions in Sweden necessitating contactAnders Ekedahl, M.Sc.(Pharm.), Ph.D.(Med. aR&D department, National Corporation of Swedish Pharmacies (Apoteket AB), Apoteket Lejonet,bSchool of Pure and Applied Natural Sciences, University of Kalmar, Kalmar, SwedenBackground: Pharmacists have an important role in detecting, preventing, and
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Gene therapy for early-onset MLD patients has been approved in all 27 EU member states as well as the UK, Iceland, Liechtenstein, and Norway for early-onset (late infantile and early-juvenile) patients.
Following the receipt of a European Medicines Agency (EMA) positive opinion last November recommending full marketing authorization for Libmeldy™, the gene therapy becomes the first gene therapy for eligible patients with early-onset MLD, and MLD’s first commercial therapy.
LATE-INFANTILE & EARLY-JUVENILE FORMS
Presymptomatic late-infantile and early-juvenile forms of MLD are included in the approval. The approval also includes early-juveniles with early clinical manifestations (symptoms) who are still able to walk independently and have not started to declinecognitively.
OTHER FORMS of MLD … and ACCESS IN OTHER COUNTRIES, INCLUDING THE USA
Patients outside the EU and with later-onset forms of MLD are able to request Orchard for access to Libmeldy via Orchard’s Pre-Approval Access/Compassionate Use programs. Orchard reviews each request on a case by case basis. MLD Foundation will help you advocate for access for your loved loved ones.
THERE IS STILL MUCH LEFT TO DO
Access and reimbursement … EMA and EC approval is a huge milestone, but it is not the finish line. MLD Foundation will continue to work directly with Orchard, EU partners, and country officials as each EU member country undertakes its own Libmeldy price and reimbursement review to make the therapy formally made available to its citizens.
FDA (USA) … MLD Foundation has been in communication with the FDA and is in full support of Orchard’s IND activities that we expect will lead to a BLA request for review and eventual approval in the US.
Newborn screening … MLD Foundation is leading an MLDnewborn screening development, validation, and implementation effort to identify patients pre-symptomatically. We need your participation to make this effort successful. Click here to learn more and join us!
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* Libmeldy is the EU commercial name for the gene therapy and is a trademark of Orchard Therapeutics. * The image on this page is a screen capture of Orchard Therapeutic’s homepage featuring one of the first MLD gene therapy patients.
Along with your support, we’ve done a lot of heavy and consistent lifting these last 20 years.
If you read nothing else of this blog, please know that we gratefully THANK YOU and wish you and the MLD community a Happy New Year!!
Our Time is Now!
We look forward to reaping the benefits of these past two decades and our ongoing work during 2020 and the first couple of years in this new decade. During 2020, after many years of research, pilot studies, and clinical trials, families will start to benefit directly as this work becomes available to families to improve the quality of life for those with MLD.
NEWBORN SCREENING … Newborn screening is critical to identifying MLD at the earliest possible time – birth. These infants will have the greatest benefit from current and new disease-altering therapies.
We’ll see the launch of newborn screening in the first US public health system in parts of the state of New York as a precursor to a federal RUSP application, screening in more US states, and adding newborn screening to various international health systems too!
Teryn Suhr of MLD Foundation took the lead to develop the screening technique that is being used today. We’ve led in instituting powerful state NBS policy in California and Florida. We’ve hosted a Newborn Screening Summit for MLD experts and will host several more this year. We are continuing and expanding work as we are coordinate and manage a federal RUSP nomination as well as state-by-state & country-by-country MLD newborn screening implementation.
Early diagnosis through newborn screening and an expanding choice of therapies means each family can choose what is best for their child.
GENE THERAPY … gene therapy clinical trials have shown extraordinary results with pre-symptomatic children. Orchard Therapeutics filed with the EMA this past fall and should have their response – hopefully, an approval – around mid-year. We hope the US FDA review will start in early 2021 – maybe sooner!
MLD Foundation is and has been working with at least four other pharmaceutical companies and research spinouts but cannot share more about their pre-clinical work (yet) due to NDA requirements. We speak regularly with startup companies and venture capital companies about the opportunities and challenges surrounding MLD.
And there is more …
STEM CELL TRANSPLANT … we are seeing ongoing improvements in MLD stem cell transplant, MLD’s only widely available therapy. In addition to the studies underway at various hospitals and academic institutions to reduce mortality, reduce chemotherapy, and improve outcomes for current MLD transplants, Magenta Therapeutics has a clinical trial studying cell-expansion and is working in the lab to eliminate chemotherapy as part of the transplant process.
BETTER DISEASE UNDERSTANDING … There are over 300 mutations known to cause MLD – that’s 90,000 potential mutation combinations. We only know the progression of a handful of those mutation pairs with decent certainty. MLD Foundation is actively engaged in a genotype-phenotype study to better help families make optimal informed quality of life clinical and therapeutic decisions.
We’re also active in two academic Natural History studies and operate an MLD Patient Powered Registry where MLD families are sharing their MLD journies so we can improve not only the medical care, but also improve the social, emotional, financial, public services, and creative family-driven/inspired quality of life strategies and decisions.
We have been meeting with the FDA since 2007 to expand their understanding of MLD and the therapeutical needs of the community. As we get closer to a regulatory filing we will both focus and expand the communications with the agency.
But not everything about living with MLD is medical …
COMPASSION AND SUPPORT FOR FAMILIES … We do our best to address the needs of MLD families in hands-on practical ways … some recent examples of direct engagement: we’ve helped several families get wheelchair vans for their loved ones, We’ve re-purposed medical equipment, provided logistical and financial support to help a family get same-day passports to get to Italy for gene therapy evaluation, helped overturn MEDICAID out of state therapy rejections, visited Italy to help a family enroll in the gene therapy, helped families make numerous therapy and non-therapy decisions, appeared at a deposition to help a family get in-state MEDICAID support for their family.
But perhaps the most impactful work we do is when we meet with families in person, at conferences, and over the phone. As we all know, an MLD diagnosis is just the start of a journey filled with decisions impacting all facets of life all while grieving the impact of MLD on a loved one and our parental/spousal expectations for life.
We spend hours on the phone with many of the newly diagnosed families helping them to learn about the disease, what to expect, clinical and therapeutic decisions, life decisions, and just being there with them as they digest an overwhelming amount of information and make decisions no parent or spouse should ever have to make.
And of course, we have host an annual MLD Family Conference™. This is where you can meet with dozens of other MLD families face to face with extended time for conversation. There are always MLD clinical and research experts to engage as well. In 2019 we launched the MLD Newborn Screening Academy. In 2020 we will continue that education and empowerment. MLD cannot reach the finish line without your direct efforts in your home state.
How Do We Do It?
We do all of this with your support … financial, time, energies, introductions to your connections and resources, “tips” about new ideas, approaches, and activities, and with the support of your thoughts and prayers.
Our philosophy has always been to try to meet researchers, companies, regulators, policy-makers, investors, other advocacy organizations, and most importantly, families, in person whenever possible. We visit them in their offices, labs, hospital rooms, and homes. We have found that we can have more intimate, detailed and informative conversations in person than via email or phone. We make it a point to share whatever information we can to connect the knowledge, needs, and experiences of one person with another … and sometimes that includes finances too! We’ve seen dramatic results and huge leverage with this strategy.
As you can see below, it’s a lot of nights on the road on your behalf. Life with MLD never stops so there are no days off … we are always honored to be working for you as our mobile phones and laptops travel with us.
In addition to face-to-face meetings, we spend extensive time in Washington DC with the FDA, NIH, other advocacy groups, and policy-makers. There are a half dozen or so key conferences and events each year. However, we don’t just attend those conferences, we also actively participate by presenting, booth displays to educate, posters to educate, and participating in panels to inspire.
MLD PATIENT POWERED REGISTRY … This is how our experiences are being gathered to impact researchers, clinicians regulators like the FDA, and policymakers. Unlike most natural history studies that only ask a small number of families a limited and focused set of disease-specific medical questions, the MLD PPR covers all aspects of life with MLD … from diagnosis to extended family, finances, clinical care, social services, and much much more.
As we gather more data we gain breadth, understanding, and perspective. All of this allows us to have a greater impact as we use the data. Researchers can request access to the de-identified data so they can efficiently advance their work.
We want all families to participate … no matter how recent or long ago your MLD experience is, no matter if your loved one is living or has passed, no matter what your home country is – everyone has MLD journey experiences to share and for us to learn from.
Happy New Year! As we head out of the holiday season and into a new year, it is a time that we reflect on life, cherish family, and count our blessings for all that we hold close to our hearts. Holiday music has been playing everywhere you go for the past month; while I enjoy all of the holiday songs, one song in particular, “Grown-Up Christmas List”, profoundly speaks to me at this point in my life. The lyrics are:
“No more lives torn apart,
And wars would never start,
And time would heal all hearts.
And every one would have a friend,
And right would always win,
And love would never end
This is my grown-up Christmas list.
This is my only lifelong wish”
YES. With the commercialism of Christmas in today’s society, much of this gets lost in the shuffle. But for me, and for what my family has endured as a result of the devastating effects of MLD, my grown-up Christmas list goes far beyond gifts wrapped beautifully under a tree. For me, since MLD has been in our lives, the loss we and others have experienced glaringly exposes the lies of commercialized Christmas. Shiny presents under the tree do not address our hopes and dreams. What we want is life for our children, hope for future families receiving a diagnosis of MLD. My lifelong wish is to see a cure for MLD, so that no other child has to endure what my beautiful girl, Emily, has had to endure. So that the pain caused by MLD would be avoided, and so that families receiving an MLD diagnosis would not be faced with little to no options.
A few weeks ago, in mid-December, I had the privilege of attending a meeting organized by Dean & Teryn Suhr (MLD Foundation) with Dr. Alessandra Biffi and Dr. Florian Eichler at Mass General Hospital in Boston, MA. I came away from the meeting feeling like I had received a grown-up Christmas gift…two leading doctors/researchers investing and caring for OUR children and OUR rare disease. It was encouraging and refreshing. The goal of the meeting was to lay groundwork for future interaction; to discuss initiatives and action plans to make progress. [Dr. Biffi is on the MLD Foundation’s Medical and Scientific Advisory Board]
There is much to be done. Dean and Teryn are behind the scenes, pushing for good communication between those involved. Their involvement is a personal agenda that bears the weight of all of our hearts, collectively. They ultimately are fighting the MLD battle on the front lines for all of us. Dr. Eichler has been involved over the last 18 months creating a clinical & research community for ALD (adrenoleukodystrophy) called ALDConnect. The registry and community they created is a good prototype for what we can create for MLD patients to help advance research. Dr. Biffi and Dr. Eichler discussed what type of information would be helpful to obtain from MLD families. A similar patient-powered registry for MLD is in the final stages of debug by MLD Foundation (as a result of a federal grant like ALDConnect) and will be rolled out shortly. We, as the MLD Family, will become ultimately responsible in ensuring the success of information collected. A collection of information is vital for researchers to use in searching for a cure for MLD. We, as families, hold the KEY TO INFORMATION that is beyond valuable. It is my hope that we can harness our information and use it to its greatest potential.
In addition, we discussed the idea of Centers of Excellence, and what that could look like for MLD families. There is a tremendous need for knowledgeable and highly qualified centers for MLD patients and their families. Too often, our local doctors do not have the expertise or knowledge to adequately support MLD patients. With the help of a Center of Excellence, families would receive specialized care at a center, with support given to local medical teams.
Teryn’s work with developing a Newborn Screening Test for MLD was discussed. At this point a pilot study is being planned. The hope is that a 2016 pilot study will prove the test is reliable and credible. This would be HUGE!
It is very exciting to have Dr. Biffi now in the U.S. working on behalf of MLD. It is my hope that new interest will be sparked throughout the U.S. because of her presence here. As families who have been involved with Dr. Biffi’s gene therapy work in Italy have already experienced, I was greatly impressed by Dr. Biffi’s genuine concern for MLD and desire to make a difference. We, as MLD parents, obviously want to see research done on MLD because our children have been deeply affected by it. It is refreshing to see doctors with a heart for MLD born out of their own desire to make a difference.
At one point during our meeting we discussed the burden of responsiblity that many MLD families feel in paying it forward…helping others that will come after us even if our own children may not benefit. Dr. Biffi recognized that this has affected her very deeply in her own research and experience with MLD. She personally has experienced the selfless attitude of many families to do whatever it takes for the greater good, to make the world a better place in the future for MLD, even if we may not benefit immediately from it. I was touched by her emotion and recognition of the heart of MLD families as a whole.
Ultimately, I am encouraged. Things are happening for MLD, research is being done. Not as fast as I would like, but at least it is progress. Maybe, just maybe, our hope of a cure is coming….
Registration for our 2105 MLD Family Conference in Newark Delaware is underway and closes in just a couple of weeks. If you are a MLD Family we’re anxious to have you register.
Many of your MLD Family will be there to meet, share, and socialize with.
Please bring your MLD loved one with you – we not only want to meet them, we have a special professional photographer to take your family’s photo while capturing the spirit of our special loved ones and the MLD journey through photography.
You will again find familiar faces in the Respite room to care for your other children and your MLD loved ones.
Those with MLD angels are always lovingly encouraged to attend – you have so much to share with the rest of us and you will surely find folks that “just get it”.
* Dr. Biffi will be attending (in person) and sharing/discussing the Milano gene therapy clinical trial.
* Shire will be discussing their ERT clinical trial status and sharing some interim results.
* Newborn screening … updates on the assay development, federal/state policy & actions, and the RUSP Roundtable we are organizing … and how you can help!
* On Saturday, as usual, you will drive the Practical Care agenda, … including a discussion about medical marijuana & CBD oil .
* We’re working hard on a special fun Saturday evening event, a memorial butterfly release, the traditional MLD “bashing”, and MLD After Hours.
We have many of the global MLD experts attending so you can meet them and ask any questions you may have.
With travel support and scholarships available, all you need to do is register! You can defer paying the modest registration fees for a few weeks if you need to, but we want to know you are coming so we save the right number of sleeping rooms!
Earlier last month we had the opportunity to see several presentations about the Leukodystrophy Center of Excellence (CoE) at Children’s Hospital of Philadelphia(CHOP), which opened today, May 1st.
The mission of the [CHOP Leukodystrophy CoE] center is “to deliver cutting-edge, integrated, multidisciplinary clinical care, diagnostic evaluation, and therapeutics to infants, children and youth with inherited white matter disease.”
We are excited about the multi-disciplinary approach of collaborative and comprehensive care this center is now providing for leukodystrophy patients and families. Under the directorship of Dr. Amy Waldman, care plans are being developed by teams of specialists, with a designated CHOP care coordinator and extensive family/caregiver involvement. The CHOP team will include a standard suite of specialists and will include additional experts from other CHOP specialties who will come and go as situations arise. Appointments and treatments will be consolidated into one day’s visit, where possible, so families don’t have to make multiple trips to the CoE thereby improving the scope of care and reducing the burden on families and patients. We are planning to have representatives from CHOP come and present at our MLD Family Conference™ in Delaware this July. We also hope to hear 1st hand reports from Philly area families about the CHOP CoE.
MLD Foundation is an avid supporter of helping these existing centers work more closely together to improve patient care for all the leukodystrophies and to improve how network and clinical data is gathered, shared, and studied to improve care, advance understanding, and expedite therapies. This will require helping the centers to work more closely, establishing common methodologies, expanding their capabilities to serve all leukodystrophies, and putting more uniformity and structure into the clinical care and research strategies. As resources become available the program can be expanded to include CoE’s in other parts of the country so every leukodystrophy family has a CoE close to them.
We are actively working with GLIA (Global Leukodystrophy Initiative – a two-year old international collaboration of leukodystrophy clinical and research experts), industry pharma partners, advocacy groups, and other MLD experts to develop standards of care, registries for common data collection, resource directories, access to experts, training and awareness, and maybe even provide some seed funding to help new centers to launch. Imagine if these experts were able to implement CoE’s for leukodystrophies at all of their home medical centers – what a powerful and accessible clinical care and research force that network would be.
MLD Foundation’s OpenNHS Manifesto offers a peek into how we think pre-clinical Natural History Study collaborations should operate. We’re thinking the CoE picture should have similar overriding and undergirding principles. Maybe an OpenCoE Manifesto is in order?
A very interesting question came up today on the MLD Family Discussion List™ (a private list we run for MLD primary caregivers). I thought it might inspire some thinking so I am sharing my answer here as well:
I have a question and I don’t know if anyone has an answer but I am wondering if anyone knows what truly stops this disease? Is it a normal enzyme level? Will the kids stop declining if the enzyme level stays normal? Are there other things that contribute to the stabilization of MLD??
Your first guess is actually correct – we really don’t know. It will take lots of years of careful study looking at extended clinical trial/Phase III data, combined with more basic science bench work, natural history, and lots of patient & clinic reported progression/outcome data to really understand this disease. And on top of a basic understanding we have hundreds of mutations to study. We’re not planning on shutting down the MLD Foundation anytime soon!
From a practical perspective, the generally accepted consensus is that if the enzyme level in the blood is high enough (remember that “normal” levels vary all over the map and carriers with low blood enzyme levels appear to be metabolically “normal” people) then MLD’s progression will be dramatically slowed or halted. There is truth in this first order basic assumption – but it’s just the start of our understanding.
However (and not to scare you), there are three things to consider as we peel the MLD onion one layer (and there will be more subtleties as we further peel the MLD onion again in the future):
1) The first is that enzyme in the blood is of no value – it needs to be in the nerve cells that need it. Today’s therapies are primarily focused at crossing the CNS (central nervous system) into the brain. We measure enzyme levels in the blood and the CNS because it’s possible – brain biopsies on living people are not good! The state of our ability to get enzyme’s large molecules reliably across the blood brain barrier (BBB) is in its infancy and the results are inconsistent at best. The Milano gene therapy acknowledges this challenge by trying to make sure that whatever gets across the BBB produces 5-10x more enzyme than is typical hoping that the overproducing cells will share enzyme with their neighbors. Think of a gas tank in a car – a full tank shows “F” on the dial, but the engine won’t run if the fuel filter (BBB) is blocking the gas from getting to the engine (the brain).
2) The second thing to consider is once enzyme gets past the BBB will it get to all of the cells that need it? Are some/many of those cells already compromised or unreceptive, does the enzyme (actually it’s a protein) get distributed to all regions of the brain, are the cells fixed so they keep on producing the enzyme or are they waiting for anther infusion like Enzyme Replacement Therapy (ERT) is designed to provide? To continue the car analogy – the car may run if only 3 cylinders (brain regions) get fuel (enzyme) but you really need fuel to get to all of the cylinders (regions of the brain) to have the optimal/desired performance.
3) As mentioned, today’s therapies are primarily targeted at the brain/CNS, but our nervous system has a second component, the Peripheral Nervous System (PNS) that needs to be “fixed” as well. The PNS makes sure the messages from the brain/CNS get to the muscles and systems elsewhere in the body. We have historically seen a lot of transplants where the brain progression is slowed (stopped?) but the motor skills continue to decline (witness the many post-transplant children in wheelchairs). The PNS is slightly different in its makeup than the CNS. It also has a barrier, sometimes called the Blood Nerve Barrier (BNB), which is different from the BBB. The common response when we ask why current research is focused on the CNS and not the PNS is that it makes sense to prioritize the CNS. The challenge is that, to our knowledge, very little work has been done on the PNS barrier aspects of MLD. The car analogy is when the engine is running but the car is in neutral – lots of power under the hood but it is not getting to the wheels (limbs & organs) so the car is not going anywhere.
Also remember that some of these therapies require time to take hold. The transplants need to engraft and the “good” cells take over/replace the bad cells before they can be effective. With ERT the thinking is they need to maintain somewhat consistent levels in the CNS which drives dosages and frequency of infusion. Different issues, progressions and concerns will be at different priorities during the various early and long-term phases of each therapy.
And there are other therapies being developed as well … what if we reduced the amount of sulfatides produced so the little bit of enzyme that many MLD patients have doesn’t have to go as far? This is called substrate reduction therapy (SRT) and hopefully will require a small molecule which, like alcohol, can more easily cross the BBB. In the car analogy we still only get a little bit of gas through the clogged fuel filter – but what if the car was lighter and didn’t require as big an engine – their might be enough fuel getting by to be able to get from point A to point B?
We don’t have to completely understand all of this to make progress and see results in therapies. As I mentioned above, the studies will go on for many more years and hopefully, today’s therapies will be good, tomorrows will be better, and in 5 or 10 years they will be even better as we better understand MLD, the body systems and the therapies of today and the future. But for tomorrows therapies to be optimal, we do have to take the time to learn from every patient, every success, every valiant effort, every failure, and to explore every creative idea – many of which will lead us to increased knowledge even thought they are a practical dead-end.
At our upcoming Board meeting we are going to talk about investing in an independent formal MLD Registry to start to capture this scientific and medical history data in a more accessible scientifically managed database – we want the data to be there for future researchers to study when they have a creative idea. And by investing, I don’t just mean a few dollars, I mean that all of us, all of the MLD patients and their families, will be asked to contribute data as we begin to crowdsource MLD research in ways bigger than just one isolated project after another.