Guest guest Posted March 1, 2009 Report Share Posted March 1, 2009 NIDRR Rehabilitation Research and Training Center in Neuromuscular Diseases Roundtable Conference 2001: Role of Physical Activity and Exercise Training in Progressive Neuromuscular Diseases Sept. 30, Oct. 1-3, 2001 San Diego, CA http://www.nmdinfo.net/lectures/mcdonald/mcdonald1/mcdonald1.html CRAIG M. MCDONALD, MD Assoc. Professor Departments of PM & R and Pediatrics UC School of Medicine Director: RRTC in Neuromuscular Diseases; UCDMC Neuromuscular Disease Clinic; UCDMC Pediatric Rehabilitation Program Physical Activity in Neuromuscular Diseases First of all, I would like to acknowledge Bill Fowler who I think is the energy and driving force behind this whole state of the science round table, and I think Bill deserves a big round of applause. He has really put together a great program and I think you will all enjoy it over the next few days. This morning I am going to discuss issues pertaining to physical activity as opposed to formal exercise protocols in neuromuscular disease. As Bill mentioned earlier, neuromuscular diseases are peripheral disorders of the nervous system affecting anterior horn cells, peripheral nerves, neuromuscular junctions and muscle. Really one of the big challenges that we all have here in this room as we look at this body of literature, is that with these neuromuscular disease, we are dealing with well over 300 hundred diseases here, over 250 distinct genes have been identified which lead to the neuromuscular diseases. Many of these are a very rare phenomenon, so when we are talking about specific exercise guidelines, we have distinct challenges in that many of the guidelines really need to be disease specific, however, I think we owe it to our patients to come up with, in additional, generalizeable guidelines which may be applicable to the vast majority of patients. When we look at all these neuromuscular diseases as a whole, the prevalence is really quite substantial, 400,000, but when you look at acquiring additional hereditary neuromuscular diseases, the overall prevalence when looking at acquired peripheral neuropathy and so forth, over 4 million individuals are affected by neuromuscular diseases in the United States. So really, a substantial number of individuals in the United States are affected by these conditions. Our Rehabilitation Research and Training Center has now been in existence for 18 years, the current grant cycle or five year grant cycle, we are in our third year now and focusing on enhancing quality of life with persons with neuromuscular disease. Ted Abresch spearheaded this project working with quality of life according to consumers with neuromuscular diseases. Ted carried out a comprehensive quality of life survey of 1,200 individuals with neuromuscular diseases. These are the most frequent problems noted by them that negatively impact their quality of life: 1. Weakness 2. Difficulty getting exercise 3. Fatigue/poor endurance 4. Problems with weight I think all of these problems, the most important problems negatively impacting quality of life are directly related to issues pertaining to physical activity and exercise. So, this is really an important issue. Ted did administer the SF-36 in 1,200 individuals with neuromuscular disease. To the question, how much does your health limit you from the activities? Vigorous activities such as running, 93% were limited by a lot; walking more than a mile, 84% had a lot of limitation; walking several blocks 73% answered the question in this regard. So, again, you can see that physical activity and exercise is really a substantial issue for these consumers of neuromuscular diseases. This morning, I am going to focus on the impact of reduced physical activity on health and fitness, methodologic issues relating to the assessment of physical activity in the community and finally using a prototype neuromuscular disease, I am going to discuss some determinants of physical activity in a specific neuromuscular disease population, Duchenne's muscular dystrophy. The goals of physical activity and exercise in neuromuscular disease historically increase in cardiopulmonary endurance, increase lean mass, decrease fat mass, increase muscle strength and endurance, improves flexibility, improves health outcomes such as coronary artery disease, type II diabetes, and finally psychosocial benefits have been noted in exercise and physical activity. These are well- documented benefits in the able-bodies population, prevention and control of coronary artery disease, hypertension, non-insulin- dependent diabetes, osteoporosis, obesity, and a variety of psychosocial mental health benefits as well with exercise. Persons with neuromuscular disease represent a very sedentary deconditioned population. They have lower work capacity, lower peak VO2 capacity, reduced resting energy expenditure, probably on the basis of reduced metabolically active lean tissue. There are body composition changes, reduced lean muscle mass, increase in fat mass, particularly in dystrophic neuropathy where muscles are replaced by fat and connective tissue and then finally decreased muscle strength and endurance. Dr. mentioned a variety of age-related issues. In fact, in sedentary subjects, sedentary able-bodied subjects, there are definite specific age-related changes: Greater age-related decline in VO2 max is noted in sedentary subjects; greater decrease in age- related loss of muscle mass, called sarcopenia; greater loss in sedentary subjects; greater increase in body fat, again in sedentary subjects; greater decrease in strength and greater reduction in walking speed has been noted in elderly populations with weak knee extension. The reviewed neuromuscular disease population does not only have these disuse effects on the muscle, but there are also disease effects. The disease effects may be the primary culprit in reducing physical activity, reduced function of muscle mass as seen in the disease. The individual then experiences reduced physical activity, but then as a result of that reduced physical activity, there may in turn be additional disuse atrophy and from that reduction in functional muscle mass. So, as you can see, there may be a central problem going on here, both with disease effects as well as with disuse effects. Neufer stated, " To the extent that reduced exercise performance is due to the effects of detraining from a sedentary existence, endurance exercise may be helpful in reversing the negative effects of the deconditioned state. " Let me just briefly outline some of the current methods available to us to objectively assess physical activity in the community. Traditionally, many studies have used self-reported methods with physical activity diaries. These have been are problematic, particularly in younger populations, but our ability to recall our physical activity, even over relatively short periods of time is really fraught with a great deal of error. Doubly labeled water techniques assess total energy expenditure, but really do not give us information about the duration of physical activity, the intensity of physical activity and time spent in various intensities of physical activities. They really do not provide us with any profile of physical activity. Standard pedometry has been problematic with regard to accuracy but again usually gives us a total step count as opposed to a minute-to-minute physical activity value. Various accelerometers will be used, tri-axel accelerometers which assess physical activity. Part of the problem with these is that passive movement of the individuals, for instance, the individual gets into an automobile or rides a bicycle, the accelerometer can register three-dimensional acceleration with the individual exerting minimal energy. Long-term heart rate monitoring has been used by Dr. Kilmer, Sue Aitkens and other investigators at UC to assess quantitative physical activity in the community. I would like to outline a number of goals for any quantitative assessment of physical activity. First, we would like to know when during the day is the subject active versus sedentary. What is the magnitude of peak activity? What is the average total daily physical activity over an extended sampling time? Days to weeks rather than just hours. What is the mean proportion time spent at defined physical activity intensities? And finally, we would like a monitoring system to be objective and unobtrusive so that it can be utilized in the community setting and real world setting. Most of you are familiar with heart rate monitoring. Continuous heart rate monitoring is a form of activity assessment. The heart rate is calibrated to oxygen uptake in the laboratory and then an individual wears a heart rate monitor for a number of days. For this regression, a VO2 heart rate regression is formulated and minute-to- minute oxygen uptake is predicted from a minute-to-minute heart rate based on a regression equation. McCrory and Dr. Kilmer from our Research and Training Center at UC did one of the first studies that had quantitatively assessed physical activity in the neuromuscular disease populations. They looked 26 adults with slow, progressive neuromuscular diseases, myotonic dystrophy, hereditary motor sensory neuropathy, Limb-Girdle dystrophy, FSH, Becker muscular dystrophy and …………… disease, a motor neuron disease, spinal muscular atrophy type III, so you can see, very heterogeneous population of slowly progressive neuromuscular disease subjects that utilize community heart rate monitoring and they estimated the activity associated total energy expenditure as the difference between total energy expenditure and the resting energy expenditure. What they found really was quite striking in the male subjects, the male neuromuscular disease subjects spent a reduced percentage of their total energy expenditure engaged in physical activity minutes active the 126 minutes per day versus 248 minutes per day in the control subjects and again, the difference are even more dramatic in the female subjects. A total of 29% of energy expenditure in physical activity versus 44% and minutes active, 74 minutes active in the female NMD subjects versus 206 minutes in the control subjects. In this study, the NMD subjects reported spending less time exercising, formally exercising than controls and when they did exercise, the exercise was at a light level, controls exercised to the moderate level. Body fat in these NMD subjects was inversely related to minutes active and fat free mass. More recently, we utilized an accelerometer system referred to as the Step Activity Monitor, which gives us a minute-to-minute quantitative value of physical activity in the real work environment. This monitor is actually about the size of a digital pager. It is worn on the ankle. The information collected over periods of up to 3-4 weeks can then be downloaded into a laptop computer for analysis of minute- to-minute physical activity in a quantitative sense. The accuracy of the Step Activity Monitor has been established, this is observer counted steps versus Step Activity Monitor reported steps, a very close association there of greater than .99. Again, we get this type of data on each individual subject. This would be a daily printout of total steps per day, over 8,000; period spent jogging, walking to the bus, walking to work, period spent in office work. So, we get minute-to-minute step counts. Essentially, analogous to a Holter monitor of ambulatory function. Again, desk work, very sedentary, errands later in the day, walking home, doing some housework later in the day. Again, a quantitative profile of minute-to-minute physical activity. Not only that, but with the Step Activity Monitor, we can actually calculate the minutes per day spent at a low activity level, a moderate activity level and a high activity level. Again, we need quantitative data regarding minutes spent at various activity levels. We have done some normative studies in able-bodied children. There is a gender affect in physical activity, which is consistent with other physical activity assessment techniques done with water and so forth. Males are more physically active than females at a given age, and there is also, in addition to a gender affect, there is an age-related affect. Younger than age ten, decreasing activity with age to 16-20 years of age when children reach more of an adult physical activity level in the community. This is data on total daily steps per day. Again, even looking at children with obesity, we can pick up subtle differences in physical activity. This is data on children ages 6- 10. Minutes per day spent at a high activity level in obese children, 50 versus nearly 70 in the non-obese children; fewer number of steps taken at the high intensity activity and then we look at data on total steps per day; the obese children 5,100 total steps per day versus the control children who took 6,300 steps per day. I would like change focus now and discuss some determinants of physical activity and I think it is useful to utilize the model, which was put forth by the National Center of Medical Rehabilitation Research, which looked at specific domains of science relevant to medical rehabilitation. Pathophysiology, impairment, functional limitation, disability and societal limitation. To illustrate how this framework can be useful, I would like to focus now on Duchenne Muscular Dystrophy as a prototype of neuromuscular disease. There is a very stereotypic pattern of progression in Duchenne Muscular Dystrophy to a period of time when they lose ambulation between the ages of 7-13, a mean wheelchair reliance age of 10. Again the NCMRR model defined pathophysiology as interruption of or interference with normal physiologic and developmental processes or structures. The example here, pathophysiology: absence of dystrophin leads to progressive loss of functional muscle fibers in Duchenne Muscular Dystrophy. The gene, XP 21 locus, is the largest gene that has been identified in the human genome, 2.4 million base pairs. This codes for the protein dystrophin, which you are familiar with, a rod-shaped helical protein located on the intracellular side of the sarcolemmal membrane and the protein in turn bridges on to a number of transmembrane glycoproteins, the sacroglycan complex and dystroglycans, which in turn bind on to laminin in the extracellular matrix. So it appears that dystrophin plans an important role in maintaining structural integrity of the sarcolemmal membrane. This is an immunofluorescent stain of dystrophin located just underneath the sarcolemmal membrane and a muscle biopsy specimen. Again, with regard to the pathophysiology of Duchenne Muscular Dystrophy, we have a gene abnormality at the XP21 locus, usually a deletion which leads to absence of dystrophin, susceptibility of sarcolemmal membrane to mechanical injury, muscle fiber injury, degeneration and then the muscle fiber goes through cycles of degeneration and regeneration and eventually we have irreversible cell death and replacement of that muscle fiber by fat and connective tissue. Now, there is really a quite classic histology noted in Duchenne Muscular Dystrophy. We see normal fibers, hypertrophied fibers, degenerated fibers, atrophic fibers, regenerated fibers and the hallmark of a great deal of connective tissue and fatty infiltration. Here is a normal ………stain of a muscle biopsy specimen of a three-year old, nice orthogonal shape to the muscle fibers, peripherally located nuclei with very little connective tissue. This is a muscle biopsy specimen of a three-year old with Duchenne Muscular Dystrophy. Again, you can see some hypertrophied fibers, some atrophic or dystrophic fibers, some fibers with central nuclei, which are regenerating and then again some connective tissue infiltration as well as some fatty infiltration, already occurring in this three-year old child with Duchenne Muscular Dystrophy. This is an eight-year old child with Duchenne Muscular Dystrophy. Again, not much muscle fiber left actually some hypertrophied fibers, some fibers with central nuclei which are regenerating, some very dystrophic, atrophic fibers with a tremendous amount of connective tissue infiltration, some inflammatory cells and a great deal of fatty infiltration at age eight. This is a post-mortem specimen of a 19-year-old with Duchenne Muscular Dystrophy. There just is not much muscle fiber left. You have a few fibers, and the rest being really just fat. This is actually a post-mortem photograph demonstrating the elbow, biceps muscle, a great deal of subcutaneous tissue and the muscle just looks yellow and fatty replaced. This is a picture of that individual's gastrocnemius muscle. So again, there just isn't much muscle fiber left in this 19-year-old individual post-mortem. We can actually measure this fatty tissue replacement and degree of lean tissue mass now with better body composition measures which actually give us segmental body composition with DEXA (dual energy x- ray absorptiometry). This is validated by pig carcass analysis. Test-retest reliability is really quite high. More importantly, we are actually able to get segmental body composition. There is an end- stage DEXA scan in a 17-year-old male with Duchenne Muscular Dystrophy. You can see the tremendous contractures this individual has of scoliosis and again, this individual, you can't read it there, but actually the DEXA scan shows the body weight. This 17-year-old individual, has a body weight of 59 pounds. The percent of body fat in this individual is 30% body fat with a total body weight of only 59 pounds. Again, there is not much functional muscle fiber left. Greg : Can you get bone density off that? Craig Mc: Yes Greg : What's that bone density like? Craig Mc: The bone density is usually quite diminished, bone marrow content as well as bone density. Greg : Do you know how early that starts? Craig Mc: Actually, you can see that in the late school-aged child of actually diminished bone density in Duchenne Dystrophy. Body composition in Duchenne Dystrophy, again, in a series of patients we studied, between the ages of 6-12, they had elevated levels of total percent fat on DEXA and reduced total lean tissue on the DEXA scans. What is interesting about Duchenne Dystrophy is that we see a regional variation in body composition. Here is a DEXA scan looking at thigh lean tissue versus upper arm lean tissue. Again, there is really no substantial disability difference in upper arm lean tissue, but there is a substantial decrease in thigh lean tissue. Again, in the clinical findings of Duchenne Dystrophy in the lower extremity weakness tends to predate the upper extremity weakness, and perhaps the lower extremity fibers are experiencing mechanical load or mechanic stress early on in the course of the disease. There is a correlation again between body fat and physical activity in Duchenne Dystrophy. Percent body fat by DEXA and total steps per day was actually negative, correlating with a fairly high correlation of –0.61. Impairment- The NCMRR model defines impairment as the loss or abnormality of cognitive, emotional, physiological or anatomic structure or function, including all losses or abnormalities, not just those attributable to the initial pathophysiology. The example given in Duchenne Dystrophy, decreased strength in Duchenne Dystrophy due to loss of muscle fibers, impaired contractility of muscle fibers and/or disuse weakness of muscle groups would all be examples of impairment of Duchenne Muscular Dystrophy. We have done extensive quantitative testing in Duchenne Dystrophy with isokinetic testing paradigms as well as isometric testing paradigms. Here is actually some quantitative strength testing values with age in Duchenne Dystrophy. At age six, actually their quantitative strength on the dotted line as a percent of control value shown over here. Their strength is only 50% of control value by age six. So, relatively early in the disease process, their strength is already 50% reduced and then it goes down from there. This is manual muscle testing data, again showing the relative increase in sensitivity of quantitative strength testing versus manual muscle testing in individuals with weakness. Now, we are actually able to normalize our quantitative of strength measures to lean tissue measured by DEXA segmentally. We can actually calculate the strength of the knee extensors per gram of thigh tissue measured by DEXA. We can measure the strength of the elbow flexors per gram of upper arm lean tissue as measured by DEXA. We can see in a young population of six-year olds a dramatic difference between Duchenne strength per lean tissue and control strength per lean tissue. So, probably a better way to actually evaluate quantitative strength testing data. Again, impairment, on the NCMRR model is actually predictive of functional limitation. There is a correlation between knee extension strength and walking speed, which would be a functional limitation in Duchenne Dystrophy that would be high, about .7, and again, study that I published back in 1995, walking speed is actually very predictive of time to wheelchair. We actually used that information in the clinic to provide families with the anticipatory guidance as to when they might expect their child to transition to the wheelchair. Again, it goes both directions. Functional limitation can, in turn, lead to further impairment. Examples of this in Duchenne Dystrophy is transitioned to a more sedentary existence in a wheelchair actually leads to an increase in contractures in Duchenne Muscular Dystrophy. Also, short periods of bed rest, Dr. mentioned the cast immobilization that his sister experienced. Short periods of bed rest or immobilization results in significant loss of strength and function in Duchenne Muscular Dystrophy. Here is our natural history data on contractures in Duchenne Dystrophy. This shows the key percentage of patients who develop ankle plantar flexion contractures. Later in the course of the disease, maybe 100% may have ankle plantar flexion contractures. However, the contractures do not develop until after the child has transitioned to the wheelchair, for the most part. There is a rapid increase in the proportion of individuals developing contractures subsequent to transition to the wheelchair. Knee contractures- Again, no knee contractures occur when the individual transitions to the wheelchair, and the knee then becomes statically positioned in flexion and any rapid acceleration in the development of contractures is subsequent to transition to the wheelchair in Duchenne Dystrophy. Hip flexion contractures- Again, with transition to the wheelchair, on come hip flexion contractures. So the child takes on essentially the form of the wheelchair as their static position in flexion at the hip, flexion of the knee and they are no longer weight bearing to the ankle because of the tremendous replacement of the muscle by fat and scar tissue. Again, this point of static positioning of muscle fiber leads to contractures in Duchenne Muscular Dystrophy. Children who are ambulating, their arms are positioned down at their side in extension. Children who are sitting in wheelchairs rest their elbow on the elbow rest. So, sure enough, elbow flexion contractures. Again, with transition to the wheelchair, on come the elbow flexion contractures. Again, this is a direct result of static positioning in a sedentary situation. This is the classic picture we see clinically with hip flexion contractures, knee contractures and equinovarus contractures due to lack of weight bearing through the lower extremities. There are a number impairments in Duchenne Muscular Dystrophy which reduce physical activity. We have mentioned that weakness is probably the most important. This is due to the dystrophinopathy as well as disuse. Fatigue, and we will hear more about this by Dr. later in the session. Fatigue can actually lead to reduced physical activity in Duchenne Dystrophy. Cardiopulmonary involvement- If these individuals have a cardiomyopathy, we will hear more about cardiopulmonary involvement from Dr. Bernauer. I eluded to contractures which obviously have an impact on physical activity and then excessive weight gain. What about weight gain? In Duchenne Dystrophy, after these individuals transition to a wheelchair, they become more sedentary and we actually see an increase in obesity, but later on in the disease as they reach an end-stage period of time, their work of breathing increases and they actually become hypercatabolic and we actually see tremendous cacchexia in these young people, late in the stages of disease. Next we have our data on weight gain in Duchenne Dystrophy. At 9-13 years of age, in the transition to the wheelchair, Duchenne Dystrophy individuals actually gain excessive weight per year relative to controls. Then, later in the disease, 17-21, there is actually tremendous weight loss in this disorder relative to controls. Again, it really depends on the stage of the disease what the weight gain dynamics are. What about some examples of functional limitation? The NCMRR model defines functional limitation as a restriction or lack of ability to perform an action in a manner or within a range consistent with the purpose of an organ or organ system. So, examples of functional limitation would be decreased velocity of ambulation, decreased distance achieved per unit time or metabolically inefficient ambulation in Duchenne Dystrophy. Again, what about walking speeds in 6-10 year old children with Duchenne Dystrophy. There was a controlled speed of 79 meters per minute, Duchenne Dystrophy 48 meters per minute. Sprint velocity 233 meters per minute in the control, 75 meters per minute in the Duchenne population. Distance achieved in 10-minute walk, 770 meters in the control. What is interesting is that in ten minutes, these patients travel 339 meters. The average velocity over ten minutes would actually be 33 meters per minute. So actually they start out with comfortable ambulation and start out ambulating at 48 meters per minute. By the time they are approaching 10 minutes, they are down to 33.9, as an average velocity, so there may be some fatigue component here that we may be dealing with. In fact, if you look at the percent of Duchenne individuals who are able to walk a given distance in ten minutes, the blue line represents the controls. 100% of the controls get to 700 meters at ten minutes and you can see this, it almost looks like a survival curve here, of a reduced numbers of dystrophy patients able to achieve those greater distances over ten minutes. Recently, we have the advent of portable metabolic carts, which actually allow us to assess energy expenditure during real world locomotion in individuals with quite substantial mobility impairments. We have actually been able to test children down to age five with these portable metabolic carts, Cosmed, breath-to-breath cart, the K4b2 being one example. We are also able to assess energy expenditure during wheelchair propulsion. There is a young man with Duchenne Dystrophy who is pushing a wheelchair and we are actually able to collect data, energy expenditure during wheelchair propulsion; heart rate shown in the pink, oxygen uptake VO2, which is in the blue, and again, increased energy expenditure during wheelchair transfer from the gurney onto the wheelchair. There is the transfer and comfortable wheelchair propulsion over ten minutes, rest and return back to baseline and new data obtained during wheelchair sprint. I wanted to digress one moment to focus on the issue of metabolic penalty of obesity. We actually assessed this and issues of economy of movement in able-bodied obese children and able-bodied control children between the ages of 6-10. These were actually extremely obese children between the ages of 6-10. We have actual fat tissue content by DEXA of over 20 kg in these obese children versus 6 kg of fat tissue in control subjects. What we found was a striking difference in the meters traveled per liter of O2 consumed, essentially a measure of economy of movement, sort of like miles per gallon. We saw this across the age range between 6-10, so essentially the obese children here down below and were sort of like SUVs, whereas the able-bodied children were essentially economy vehicles. So, given there is a metabolic penalty of excessive adipose tissue to individuals who are able-bodied, and there may well be even greater metabolic penalty of excessive adipose tissue in individuals with weakness, such as neuromuscular diseases. We have measured oxygen cost during walking and sprinting in Duchenne Dystrophy. There are oxygen cost values which have significant differences in walking and 100 meter sprint. The Duchenne group has an increased oxygen cost, or greater oxygen consumed per meter traveled in this calculation and again, there is a direct relationship between velocity of information and oxygen cost. So, the blue indicators show high velocities, lower or more efficient oxygen costs and then as the velocity slows, the oxygen cost increases. So, as these individuals are more metabolically inefficient, they slow their speed at which they ambulate. Heart rate in Duchenne Dystrophy during the 100 meter sprint, we can collect heart rate and option uptake data during the 100 meter sprint. The Duchenne individual starts actually with a heart rate greater than their control counterparts and then they have this rather flat response here, as they sprint over a 100 meter distance, you can see this linear increase in heart rate in the control population. Again, the ability of the Duchenne to increase their heart rate appears to be diminished and similarly the ability for them to increase their VO2 a rather flat curve here as they sprint over the 100 meter distance and again a more linear increase in oxygen uptake in the control population. So, again, a baseline, relatively equivalent values, but substantial differences in VO2 with a 100 meter sprint. These are in fairly young children. In fact, we can normalize VO2 per grams of lean tissue by DEXA to see if this makes any difference in the Duchenne population versus control. And, again, we can look at the efficiency of locomotion during the sprint and can get similar data here with the controls here, and as we slow velocity we see more metabolically inefficient locomotion in the Duchenne population. Finally, to end, disability. The NCMRR model defines disability as the inability or limitation in performing tasks, activities and roles to levels expected within physical and social contexts. An example of disability would be the inability to exercise, decreased daily physical activity in the community in Duchenne muscular dystrophy. Again, with utilizing quantitative activity monitoring systems, we have been able to show quite marked reductions in physical activity measured quantitatively with the Duchenne population. There is Step Activity Monitoring data of 24 hours in the able-bodied child. Essentially, we can see these high intensity periods, total steps per day of 7,200 over a 24-hour period of time. We age-matched that Duchenne patient with 1,800 total steps per day, again a marked decrease in physical activity measured quantitatively. Indeed, when we look at step activity intensity, the control subjects take far more steps at the high activity level, more steps than the Duchenne at the moderate activity level and equivalent steps per day at the low activity level. Therefore, there seems to be dramatic differences in the Duchenne versus the control populations at the steps taken at the high activity levels. Again, total steps per day, control….. and then minutes per day at the high activity level 72 minutes per day in the controls versus only 43 minutes per day in the Duchenne population. The NCMRR model also discusses societal limitation and defines that as a restriction, attributable to social policy or barriers (structural or attitudinal) which limits fulfillment of roles or denies access to services and opportunities that are associated with full participation in society. An example being a teenager in a power wheelchair with Duchenne dystrophy is not able to participate in PE because adaptive PE is not available at the school or is poorly developed in the school system, as an example of societal limitation. To end, I think the number of needs here for scientifically based recommendations concerning optimal exercise guidelines, optimal guidelines for physical activity. Obviously, when it comes to issues of safety, we need disease specific recommendations relating to types of exercise, eccentric and so forth. With regard to safety, we really need disease specific recommendations. We also need recommendations regarding the minimum frequency, amount of exercise, amount of physical activity, duration of exercise required for beneficial health effects. Finally, in individuals with greater degrees of weakness, we need development of novel approaches to enhance levels of physical activity in persons with varied severities of impairment due to neuromuscular diseases. Thank you, Craig. Carlsen: When you talked about progression from leg muscle to four-limb muscle, what happens to the diaphragm? Craig Mc: The diaphragm, interestingly, is relatively spared earlier in the course of the disease. In fact, in younger patient population, there is actually a greater decline in maximal expiratory pressure, static airway pressures, which are more of a measurement of chest wall, accessory muscles of respiration. Whereas they had a relative preservation of maximal inspiratory pressures related to the maximum expiratory pressures. There is actually a greater decline in skeletal muscles, accessory muscles of respiration, relative preservation of the diaphragm. Of course, late in the disease, the diaphragm starts to become quite involved as well. Greg : In the X-model, the diaphragm has dystrophic changes way ahead of the skeletal muscles, and actually I have slides on that tomorrow. There are some interesting differences between human dystropinopathy and mouse, and that is one of them, I think. Ralph Nitkin: I was struck by the rapid progression to contractures, even in the elbows, where the kids presumably using their hands to move the wheelchair. I was wondering, how much of that is a unique case of muscular dystrophy where it could actually be due to the pathology itself as opposed to the disuse syndrome? Do you have any other parallel studies with kids with other disorders with a progression to a wheelchair with the onset of contractures? Craig Mc: I think that definitely the connective tissue character is different and, in fact, there is probably some heterogeneity among subjects as well. We see some subjects who have minimal or just moderate contractures and other subjects who have rather profound pseudohypertrophy connective tissue replacement and quite profound contractures. The other issue that is important here is that generally when we see contractures in individuals with less than antigravity muscle strength. So, we are unable to volitionally put their limbs through a full range of motion due to weakness. So, a combination of static positioning plus severe muscle weakness that precludes the individual from extending their muscle through its full available range of motion is generally set up for contractures. Usually, we don't see those contractures forming in more slowly progressive or mild neuromuscular disease conditions where the individual, just with functional activities, reaching overhead and so forth, can pull the muscle through full range of motion. So, it seems that this weakness places the muscle group in a static position really seems to be the problem in the Duchenne population. There are other populations where congenital muscular dystrophies where they have congenital contractures on the basis of interuterine positioning. Emery-Dreifuss, as Dr. eluded to earlier, made a quite profound elbow flexion contractures early on and there appears to be something different about the muscle fiber ultrastructurally as well as probably the connective tissue in those populations. Bob Fitts: On speculated data on the muscle force per lean tissue in patients, I wonder if you have any data that would explain it. Is it loss of contractile protein associated with that, or is there some other non-uniformity of sarcomeres or what is the explanation for that loss of force per lean tissue? Craig Mc: Again, I can't really explain it ultrastructurally, whether it is a contractile phenomenon. I clearly cannot explain it purely on the basis of loss of fiber or loss of lean tissue. There appears to be some contractile abnormalities as well. That is an excellent question and probably some animal work will probably be necessary to really get that issue. Bob Fitts: Didn't he work on diet in, for example, essential amino acid supplements seem to help in weightlessness conditions, and I am wondering if anything like that been tried with these disease states. Craig Mc: Dr. Kilmer, do you… Kilmer: I have not seen any work specifically with amino acid supplements. Almost every other kind of supplement has been tried… DR. MCDONALD: I think there has been some high branch chain amino acid diets that have been used, but not in any large series, though. Usually these are anecdotal reports that have been done for the most part. These individuals seem to be hypercatabolic late in the course of the disease and there appears to be a tremendous loss of protein that is occurring late in the course of the disease. In some people, we have actually advocated high protein diets for these young people later in the course of the disease, just because of the profound loss of protein. Bob Fitts: Is the loss of protein due to accelerated degradation, or is there a drop off in synthesis or do we know that? Craig Mc: Both. Fowler: The substance treatment of neuromuscular diseases follow exactly the same course as ergogenic age in athletes. It started out with amino acids and protein supplements back in the 40s, when they started feeding people this, and then moved its way up, and most recently it has been used in anabolic steroids. There have been a lot of studies now I think with creatin. Greg : A good example of that has been oxidative stress and to my knowledge, just pumping either animals or humans full of antioxidant cocktails does not seem to make a huge difference as far as cellular oxidative stress. Fowler: Vitamin E was a big treatment way back….. Tom Rando: People have tried a variety of antioxidants systemically in mice and humans, usually in very small anecdotal studies, open- ended a few months, so they are not very well studied. The other ongoing trial, in addition to creatine, there is a glutamine administration trial going on along with the creatin right now for boys with DMD but that is just getting going, nothing yet that I know of. Quote Link to comment Share on other sites More sharing options...
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