Heat Intolerance in Multiple Sclerosis

okay so I'm gonna talk about the issue of heat intolerance in patients with multiple sclerosis and related to myelinating diseases I'm sure those of you in the room who have one of these disorders is quite expert on what happens when people exercise or they're exposed to a high ambient temperature if you get angry with somebody we know that with anger blood pressure and heart rate goes up but when people are stressed out and angry what do they also do they sweat and you sweat primarily as a compensation mechanism to do what to bring down core body temperature and one of the things we've learned over the years is that patients with MS have some level of inadequate sweating they're a bit dysregulated and so other measures oftentimes have to be used you know a lot of patients if they get a bit overheated they may not walk as well they're thinking maybe slowed my movements can be affected the classic effect related to compromising neurological functioning with heat or exercise or even with Peri menstrual periods of the month is what we call uh tops phenomenon after Vilhelm boot off who was a German neurologist who was writing at the turn of the 19th into the 20th century and in 1889 he wrote a paper describing principally young women who had lost their vision during the period of visual loss they had pain and other changes that are very reminiscent of what most of us in the room would recognize as a story for optic neuritis and like optic neuritis the majority of these young women recovered their vision if not entirely pretty close to baseline which is also fortunately true in most optic neuritis not all certainly not in NMO neuro myelitis optical patients can have more sustained visual disability than patients with MS in general but these patients recovered and then they would come in subsequently for follow-up and would talk to doctor etaf and would describe the fact that their vision was better they were happy until they became overheated took a hot bath they were exercising or it was close to the time of their menstrual period what we call cata mania Lou toss now while I'll say that heat intolerance is very common in the disorders that we talk about it turns out some patients are peculiar you know there are always peculiar patients just like there are peculiar doctors yeah you know you know when you see them but there are people who are cold sensitive the so called inverse whoo coughs effect and then there are those people who have both sensitivities that with some elevation either an ambient or core body temperature like with a fever or there's a reduction in ambient temperature or people get cold they also can have a corresponding compromise and function so when I'm talking about heat intolerance what I'm really talking about is not just I don't like the heat it's uh makes me uncomfortable I'm talking about that this is a phenomenon where with a fever with exercise with stress there's some corresponding compromise in functional capability that's reversible and again it could be a change in gait mechanics it could be a change in bladder control it could be related to changes in thinking which is huge because if this occurs in your place of work then there can be some compromise in your function at work and lead to an inability to work so we clearly know that in many of our patients the most common reason why at least MS patients stop working is that it's usually related to cognitive and intellectual changes and fatigue and heat intolerance is as part of that we think that's the mechanism which is germane to these compromises so before I begin let me just show you my disclosures we all have disclosures and proud to have disclosures I think it's very important to underscore the role played by industry and those of us in the university settings and in the private practice settings who conduct investigations that most of the intellectual property that is discovered or developed in academic circles is ultimately translated into products not by your doctors or scientists or universities 99.999% it's done in industry so it's easy to demonize those folks who make profits on doing what they do but without the industry we wouldn't have these drugs the United States government is never going to make these drugs they're too expensive if abbott develops a drug that turns out to fail an abbot goes down the toilet another company will takes its place but obviously big institutions like the University of Texas can't take that risk and never will okay so what about this issue of pathophysiology what does this mean like when you have a disease like transverse myelitis or you have a disease like NMO Devex or neuro myelitis opteka you know we know physiology describes the normal function of the nervous system and when we say pathophysiology we're talking about what of the what are the characteristics that really describe what's different in people who have these diseases that's important it's important because you want to answer the question why do you care what does it matter and the reason why it matters is because people who have these signature changes in their physiology are compromised in their function whether it's thinking walking writing a check balancing your checkbook it's we think related to these changes in the structure and the function of the brain in the spinal cord and this is a variation of a picture you've probably seen in many different places and there are various iterations but what I want you to focus on is that this is a blood vessel inside an idealized plaque this could be in the spinal cord of a patient with myelitis it could be in the spinal cord of the optic nerve and a patient with nmo it could be anywhere in the brain or spinal cord in a patient with multiple sclerosis I think what you recognize is that we have an axon this is the transmission element or the wire of the neuron whose job it is to transmit electrical as well as chemical information from one part of the nervous system to the other that's easy to understand the harder part is that that information has to be transmitted very rapidly in order for it to be truly meaningful meaning to make adjustments when you step on a Rock or attack you got to move quickly or you may fall so this point to point or one point to many points of communication is contingent on rapid communication and part of what allows the nervous system to send information around the brain and spinal cord and then ultimately of course to the nerves and muscles and glandular tissue and everywhere else is this specialization here the ability of the oligodendrocytes which makes and maintains myelin internodes these little jelly rolls which are on the axon now you know and I know myelin is mostly fat right mostly fat a little bit of protein but you know and I know also that's not a conductor right so why am I saying that fat makes you fast people like it when I say that that makes you fast we should double double our two portions at lunch but that's not what I'm saying fat is an insulator and that's true not conducting but if you look what happens here the normal structural architecture of an axon is a myelin internode insulating not conducting but punctuated by areas where there is no myelin this is the so called node of ranvier and here I depicted as being naked but in reality most of these electrical nodes are covered by processes of a cell called astrocytes astrocytes do many things they're your friends and your foes in fact when you develop sclerosis in multiple sclerosis these astrocytes actually divide and proliferate and perform demonic sort of things that get your nerves in trouble and that is they form a glial scar which gets in the way of transmission or repair so Astro gliosis the division of these cells and their scars of sclerosis can be really a major obstacle to function and functional recovery in normal physiology they do many things they regulate the environment chemically they clearly play an important role at these nodes of ranvier because they partly are responsible for depositing the sodium channels on those nodes and what I mean by that is these sodium channels in a way act like little batteries they allow the of electrolytes in this particular case sodium to move from outside the environment of the axon to inside and by virtue of doing that that's what causes these electrical discharges so if fat is an insulator then what's happening at the nodes the electrical transmission moves from node to node to node literally the electricity can bypass this area because this is not conducting and this particular property of what we call nodal conduction in the context of healthy myelin is what we call saltatory or fast conduction and the reason why you care is because if you look at this axonal profile below this blood vessel below this blood vessel this is an axon cylinder where myelin has been removed can you see it nice orderly regular repetitive myelin internodes astrocytes at the nodes of ranvier nice and healthy here we have a normal internode of myelin but we have an oligodendrocyte which actually has a process on the axon but we've lost lots of myelin and in this particular case this is the signature structurally of what leads to what we think is slow conduction and when you have slow conduction and changes in these channels this is also the signature that we believe for lots of different reasons is predisposed to not only slow conduction but conduction that can get even slower and in some extremes can actually stop conducting and so there are examples of people who go out and Dallas on a very hot day in the middle of August it could be a hundred and ten hundred and fifteen heat index and by the time they get from a door to their car their leg is not working at all that's a block and conduction and then they cool off and even though the leg is still weak it's working so they have some restoration so heat and the topic of this talk of course in some ways is heat sensitivity but not only heat has an effect on the fidelity of electrical messaging across these axons for lots of different reasons some of which is related to the physiology of ion channels itself and it may be related to other machan that I'm not going to talk about what you can also see is in this blood vessel you see cells moving into the central nervous system B lymphocytes macrophages and T cells and of course these are the players that are involved in both pathology of multiple sclerosis because these cells come in and do things like make antibodies which may be injurious to some of the architecture of the brain and spinal cord or these cells may come in and make particular so-called cytokines like il-17 and others think of cytokines and chemokines as a currency system in a way of the immune system and there's a currency system that promotes inflammation which might be very adaptive if you have a virus or a bacterial infection and there are other currency systems where you turn off those responses you don't want to be in a state of chronic and perpetual inflammation you got to use it when you need it and you have to be able to turn it off and so there are these sort of yin and yang in a sense responses and you can see that a lot of that is occurring across blood vessels in the central nervous system tissue and then there are a whole bunch of other mediators that I have here such as free radicals nitric oxide really the take-home message there its oxidative stress it used to be just a hand waving thing you know oxidative stress take antioxidants it's not a joke anymore it's absolutely and totally real and supported by evidence that the downstream pathways of damage in this disease and stroke and Parkinson's disease Alzheimer's disease that the injury mechanisms used in these various disorders and not just in the brain also in the heart after a heart attack or in people who have chronic renal failure these mechanisms are actually common to many tissues they may not all be exact but there's a lot of overlap and the reason why that's important is if you know a lot about these final injury mechanisms in tissues like the heart and the kidney in skin with psoriasis people have a variety of these disorders one can sort of borrow information from Arius disciplines and seiji drugs we have for disease a or B may be applicable to n mo or MS from the standpoint of antioxidant agents that may lead to some preservation of tissue and there are real drugs under development today one of which is called BG 12 dimethyl fumarate acid which appears to have a very potent antioxidant effect quite removed from significant inflammatory or anti-inflammatory effects the new drug just approved by the FDA this last week right fty 720 Fingal amat or Julie Nia that drug while has a major effect on immune system circulation and functioning appears to also have some effect believe it or not we think at least in models on reducing this egg's uber n't division of astrocytes and scarring and it'll be interesting to see if that in fact has some impact on disability over time and maybe whether drugs like that among others may have some effect on potentially reversing Astro gliosis you know if you get disease activity out of the brain and spinal cord and out of the optic nerve and a lot of these disorders what are we oftentimes see we see evidence not only of exacted remission meaning you're not seeing attacks and lesions but in many patients certainly not enough but as time goes on I think we're going to be more successful at this we will see people exhibiting evidence of improvements partly because of intrinsic capability of tissue to repair itself and partly because we will be dealing with specific drugs that promote repair I was just talking next door about the use of the visual system as a potentially productive model to demonstrate the proof of principle that a blocker of a protein called lingo which keeps these baby oligodendrocytes in their state of Perpetual adolescence you know I have four kids so I can speak authoritative Lee about children who do not want to grow up and these cells oligodendrocyte progenitor or precursor cells are a bit beyond the stem-cell state but they're kind of in a state of developmental arrests they don't want to grow up and we now know that one among other proteins that keep it in that state is a protein called Lingam and so very smart people figured out if lingo keeps you as an adolescent and I've removed the effect of lingo what happens well what happens is that these cells differentiate they grow up and they become processed baring myelinating oligodendrocytes we know that the question is will we see in humans what has recently been seen in animals animals who have the animal model of inflammatory demyelination AE AE that you can see these animals dragging their legs behind them the so-called classic hind leg paralysis and then these animals get treated critical time period with these lingo one antagonists and then weeks later you see video tapes of these mice and rats dragging their hind legs and they're up and running around now I've seen this numerous times and I saw it again just a few weeks ago in Chicago every time I see it I can't help but be thinking this is some kind of trick but it's not a trick it's absolutely real and that drug for the first time this year has now been introduced into human research subjects so I think you will be hearing more about protocols by the way this has nothing to do with the topic in my talk but I couldn't help myself and you know here's my nurse practitioner right here Diana Diana Logan she knows me I just can't cuz I'm excited about this stuff I can't help it so if I were to go home I'd wake up in a cold sweat and I said hey I spoke to a lot of patients but I didn't bring this up shame on me absolutely you can clap that's right shame on me cuz it's about you right so my mother has gone a long time but she would say good boy you got to bring that up yeah I always have to know what this is all about my mother told me many years ago when she came to one of my talks and people clapped we got off she gave me a kiss she says oh you're so cute and she said to me but I never believe your own rhetoric you're usually little less than half as good as people tell you you are I think she's right about that and you know why cuz a lot of these hypotheses we have here some of them will be true and some of them will have to recant so we've got to be very careful but this looks very exciting and we think it we can preserve this axon if we can promote reconstitution of this normal myelinated pattern and spacing pattern then I think we do two things one is we have the ability to prevent the ultimate pathological change which is look at this trans section this axon is no longer in continuity you can't cut an electrical wire and pass current through it the circuit won't work the second issue is we now know that myelin is not only functioning to give rise to this electrical spacing for fast conduction but look at this myelin is always if healthy attached to the cell that makes it and maintains it and we now know that the axon that electrical cable has a protective and nutritional and trophic relationship with that oligodendrocyte that keeps them all happy and healthy so I would suggest that not only will function be preserved if we're successful in this limb and there will be other initiatives that will help protect this but this whole idea of changing function with exercise with heat with fever with stress that we will go a long way to either eliminating or at least mitigating that if we can move this signature to this normal signature and that's how this illustration I think is relevant to the topic of heat intolerance and in fact I would make the argument if you talk to most patients who are experts about recurrent myelitis or people with nmo have had multiple attacks or people with MS who know what it's like to have multiphasic attacks or multiple lesions ask those patients questions and they will tell you true attacks occur infrequently they have one or two a year and if you use treatment you have fewer and they're mitigated most people will tell you that their hour to hour week to week suffering and there's a lot of it occurs because of inadequate conduction this is what gets people in trouble when they get up and say well your battery may be a hundred percent they're talking about me because I'm like that ever-ready bunny just never stops never sleeps never breeze never eats right my patients say no no I get up and capacitance is 30% in a sense they're really smart they say I got to figure out where to spend my charge during the day if I work out in the morning I may not be able to work throughout the day but if I work and I titrate my charge throughout the day I may be good but then when it's time to work out at night cuz ok now I won't ruin the whole day by working out I'm exhausted and how do I do it so this gets to an issue of are there things that could change your 30% charge in the morning with either dressed or drugs could i reinvigorate another 30% somewhere halfway through the day or could I augment your 3250 and you know we've had a recently approved FDA drug and pura based on a drug called for amino pirating for AP which is a drug which blocks potassium channels on these axons and the reason why that's important is cuz when axons turn on they need the sodium channel but when they turn off potassium rushes from inside to outside so the mechanism and I'll go over this again a foramina pirating which we've used for 30 plus years and MS and related diseases and pura is a new formulation an important one but we've used the compounded for AP for many many years it blocks the potassium channel to extend the period of the on response in these axons and what does that mean to patients they can walk longer faster safer they can have sex they can balance their checkbook they can sit up they can feed themselves shame on the insurance companies I hope you're taping this anything I say is public domain I hope you're taping this shame on them for sending these little notes to us about you the patient's saying did the patient is this approved for MS for walking problems that's what the study looked at with AM pura and I understand that it's something you can measure did the patient walk between this range in terms of the number of seconds on the 25 foot time walk and if you're too fast if you're too good you don't get the drug and if you're too slow too bad you don't get the drug and then the patient's supposed to come back to the clinic and show the improvement so they were finding a way to extrapolate some of the criteria from the study to then apply to us in the clinic to make it so stringent that I can't figure a way to actually prescribe the drug for somebody sitting in a wheelchair who desperately needs it to sit up to brush their hair and teeth to feed themselves because you know and I know these potassium channels were blocking with this new drug isn't just blocking those channels in the pathways for walking that's what we could measure and show the FDA but these channels are being blockaded in multiple areas of the nervous system which can augment many domains of function so what we've had to learn how to do pretend this is the stopwatch that's in my hand I know they're recording this so the question is when do you hit the on in the off response and how do you get people up and walk them so I'm not saying we lie in clinic I'm not saying we do that because I know we're recording this but we work very hard we work very hard to coach our patients to make sure they're within the range and here's the blunder of this idea and insurance companies is the patient with post transverse myelitis deficits post ms deficits are they the same in my clinic at 8 o'clock compared to what they would have been at 4 o'clock on the same day no are they the same different seasons different things going on around the menstrual period you know the kids are acting badly function changes often in people with these diseases why because of this this is not my hypothesis I wish it was this has been known for a very long time since the time of you talk that there are stereotypic and often reversible changes in function and that stereotypic decline and walking could lead to a fall in a fracture or falling over in your chair and not able to take care of yourself which means you may end up being in an assisted care facility rather than at home taking care of yourself so we got a look at who is this really all about is this really about balancing the budget or the insurance companies finding a way to not pay for the drug yes that's what they're doing and we have our job which is to figure out how to get you the therapy as you desperately need particularly if you benefit from them so at least in my clinic I will not allow you to take away these tools I will find a way to treat the patients with these tools by the way we used to say you couldn't use interferons Copaxone these other drugs and people who didn't have two or more attacks because if you only had one you didn't really have that right cuz you have multiple attacks in space and time what a cardiologist look at a patient with one heart attack and say you know we really we really treat heart disease to make sure it's a probability issue to make sure you don't have another heart attack do you really have multiphasic coronary artery disease that's why we use aspirin and lipid lowering drugs and why we put in stents and we fix the nautic vessels nobody would say to a patient if you've had two heart attacks then we know you have multi phase of coronary artery disease you know we call that we call that malpractice but in our group of diseases one shoe has dropped and people sit around waiting for the other shoe so for years when we had the drugs the first one beta star on in 93 and then we had a band X Copaxone 96 and then Reba panics Davian then NAT ilysm Ave we have all these guys great so if I saw somebody with one event you know what I would do I would sit down and roll up real close look in their eyes and say we have to work really hard to get the right history I'm looking for that other attack and then usually the patient would look in their eyes would get wide and they'd say you know there was a time and they don't have to lie because if you go back how many people have had a first event of MS who when they look back in retrospect can tell you stories about neurogenic bladder chronic fatigue things that weren't explained but far and away and to date the development of their myelitis or their optic neuritis so we have a big challenge in front of us we've got new and exciting capabilities but we are faced with a formidable opponent and those are the bean counters and the abacus keepers of the insurance companies and I'm sorry they are our opponents and we better be good players if we're gonna get what we want for you but I got to tell you I almost always get what I want and then when I don't I just try it till I do I usually wear people out till I do so there you go so here's etaf and you know you didn't look very happy and neither did these guys so that's why I put myself in here with a hockey helmet and I look better but the hockey helmet serves a purpose and it underscores the whole issue of go for the ice because a lot of people with disorders of myelin have problems with conduction block because of the cartoon I just showed you so again I would make the argument whether it's myelitis or nmo or and as a lot of people suffer and compromise because of this reversible phenomenon that we now all over the world know by his name Lu tofs phenomenon so is there a way that we could take this phenomenology we've heard about it we clearly know that you could use cooling vests you could use fans you could bring the air conditioning up in the house and drop the temperature all kinds of things could be used ice-cold liquids the question is with the approval of an pura that's one and this is a very important drug in our tool chest it also happens to be a drug that most of us in this room know can potentially cause adverse events in some people the biggest of which is seizures right so if you get improved electrical fidelity in your track systems that are d myelinated could the drug produce an unwanted level of electrical excitation in parts of the brain that if left to their own device will get together assemblies of neurons and go into high gear and cause a seizure well fortunately seizures are rare but my point in bringing this up is that they can't occur they can't occur when people have a fever they're infected in fact when you have a fever you need a drug like for a pee but that's when I tell patients not to take it because fever plus for a pee could make your risk of seizures even higher but why I'm really bringing this up is that is there way to model this heat exercise stress very menstrual worsening of symptoms in people who have demyelinating disorders ms and mo transverse myelitis is there a way that we could test new drugs potentially more effective and even safer agents in a model that shows us this reversible change in conduction and you know if there wasn't one I wouldn't be sitting here telling you about it so the answer is yes there is a way there are a number of models but one of the best and this is not animal this is people this is human is that patients with multiple sclerosis commonly get optic neuritis so two patients with neuro myelitis optic ins back the two most common syndromes in ms are the same two most commons and drums and nmo optic neuritis and transverse myelitis partial myelitis but one of the things that's kind of unique to ms and to stroke we don't see it so much in n mo or in TM but we see this a lot in ms and in stroke those are the two diagnoses where we most commonly see I and O inter nuclear off Thal mo Paris vamonos in the eye this is a patient attempting to look to the left and the left eye has done a very good job but where is the right eye the right eye is still on the central target you can see this line moving right through the mid pupillary space by the way I'll tell you a second later both eyes were to the left so in some cases the eye doesn't move but in some cases it just moves more slowly it turns out this particular eye movement problem afflicts at some point in time during the disease of ms about 40% of the patients either know they have it and will come in and say my eyes aren't tracking together you know somebody who's got eyes like this is usually telling you what they see two images double vision if it's really fast and the slow eye gets over quickly enough they may say there's just a little blur or a little jiggle of vision and in some cases they don't even know they have this except they can't explain why they're crashing into people when they're looking to the left right or that they're falling when they turn real quickly because these are the circumstances where the eyes are actually separated by the way when these patients with MS are looking straight ahead the two eyes are straight ahead so they look fine until they look quickly to the left or to the right now the reason why I bring this up is that this is a common syndrome it occurs because the nerve cells that allowed the coordination of the two eyes to move together at the same velocity the same acceleration and at the same amplitude they're in the same place in space or what myelinated axons in the brainstem and they need myelin for what fidelity and speed and so in this particular case this is an example of where the pathway it's called the MLF the medial because it's in the midline longitudinal because it's long and it's a white matter track and we call those tracks fasciculus or fascicular so that's the name of the track the MLF and when it's d myelinated this is what you see now the reason why we might use this to model em s and the etaf and the temperature sensitivity effect is we know that at different core body temperatures the eye will move slower or faster depending upon whether your temperature is higher or lower let me prove it to you here's a here's an individual a character Chur who's this guy could be driving next to you by the way and look at the two eyes so hey is somebody on my left and this eyes now here this eyes over it could be there are two cars and the issue is there's a real one in a false image which one do you believe no I'm not sure I want to be there and guessing but it could happen here's a guy just turning his head and during the process of head turning specialized things happen to the eyes but suffice it to say many people with MS fall not necessarily during turning cuz they're weak where they have a cerebellar or a balance problem or they can't feel their limbs people fall because of that but there are other people who fall they don't have any of those features just because their eyes are not tracking we have a test where we can put cameras on the on the head and measure the speed and the position of where the eyes are and in general the eye should be together why the brain likes to focus on one image that's fused and if I can make one of you I see one of you but also with depth perception as soon as there's a break in fusion and there are two of you double vision not only do I have to figure out which is the real you and the false image I lose depth perception so the brain is making calculations about depth that is contingent on co-registration of the two eyes I'll prove it to you look anywhere in the room that you like and pick an edge pick the edge of the chandeliers pick the edge of the table and then look what's behind or in front of the edge of any edge in the room and then close an eye and look at how the images are right up on that edge you cannot tell death and then open your eyes and Death Comes back that's when you what you lose when you have a break in fusion and this can cause Falls accidents not seeing the edge of steps that's a really big deal particularly if you're walking is already compromised well it turns out if you take a ratio of the I'm moving away from the nose / the eye moving toward the nose for velocity acceleration or amplitude that should all be about what one if my eye moving away from the nose is moving at 400 degrees per second the eye moving toward the nose should be about 400 degrees per second and this is what we call the virginal this conjugacy ratio okay I'm sorry I had to tell you that but what dis conjugacy means you're not conjugate the eyes are not moving together a ratio of 1 would be moving together these are MS patients who have this eye movement problem and you can see there are various severity 'z there number of standard deviations away from a population average should be zero they should be right at where the average is in the population you know we do these calculations for bone densities as well we ask if you're 50 and female you look at your T score and your Z scores on a bone density and if you are right at where you should be for the average for your sex and your age the number of standard deviations above or below that average is zero you're right at the average now for bone density if you're above zero you're like rocking and rolling if you're significantly below zero that means you've had osteopenia and osteoporosis and you may be rock and rolling and falling and fracturing bones for this particular test you should be at zero but you can see here are people who are 5 or 10 or 20 standard deviations of slowing where the eyes are not moving together and here these waveforms represent this is the right eye moving 20 degrees to the right here's the left eye what do you see the two waveforms should be literally superimposed but they're separated and it's during this epoch in time where people see what two images either a blur or double vision until the two eyes come back together but they may have crashed right about here so this is position this is velocity look at the difference between the two eyes this one's way down and here's acceleration now the reason why I have to show you this kind of data is that if I have a way of testing a drug and showing you that this degree of slowing gets worse with heat or exercise it's going to be even worse but I have a drug that protects you against the slowing and the decay curve I ought to be able to use objective metrics we care about what patients tell us ultimately they're better they drive they're safer they're not falling yes but we also must show if we have protected the channels and the nerves are working or I got a better one for you if I've got a myelin recovery strategy and this eye is moving slower you can see it because of demyelination and now I've blocked lingo and the baby oligodendrocytes are growing up and now the MLF axons which help in the coordination of the two eyes are repaired this slowing and this velocity reduction this acceleration reduction ought to come up and the two eyes ought to be synchronized that's why you care we need a way of showing proof of principle to get our drugs approved so here is a normal subject in fact this is my wife so 25 years with me I'm not sure how much normal is left but there's some she doesn't have that mess that we know of these two colored lines represent the two eyes and we're spinning her around and you can see no matter what we do with head movement the two waveforms are nearly superimposed normal but here is an individual with MS undergoing the same turning that you might be doing when you turn your head to look at traffic next to you is it safe to change the lane or somebody who's turning they're walking walking and they're turning the eyes are separated and what does the brain see here two images well the question is if this gets worse and puts patients in greater damn a danger and compromises function and we know that heat katha menial or peri menstrual issues play a role stress plays a role exercise plays a role is there a way to model this decay or prevent it with drugs so by the way this is one of our patients she signed HIPAA so it's kosher she can be here here are the cameras and she has one of these eye movement problems just the same one I showed you here is a leotard it's a NASA suit which is impregnated with small tubes and we can therefore percolate water of any temperature we want through this suit she has swallowed an oral ingestible temperature probe the size of a citracal calcium supplement after she swallows it we can measure with a little telemetry box right across the stomach what her true core body temperature is and the reason why you care about this is the following here is another normal person remember this ratio is the eye moving away from the nose divided by the eye moving toward the nose and a normal person the ratio should be 1.0 which means the number of standard deviations away from an average population mean should be 0 there right at the average and sure enough when we take and record the eye movement position the velocity the acceleration during heating from 37 to 238 won by moving water through the suit and during the cooling phase you'll notice that this normal subject is all about being very close to 0 what does that mean the eyes are moving together even under these extremes of core body temperature change but now look at the patient with MS who has that eye movement problem at baseline temperature and by the way for this patient it's not 38 degrees it's 36 9 many patients with de myelinating disease live at a lower temperature need to remember that because if you show up in the ER and you're 38 you may have a temperature or I should say 98 degrees or if you're at 37.2 most people may be walking around fine look what happens to this patient at baseline their ratio is not one it's one and a half times faster in the eye moving away versus the eye moving toward the nose so this would be that patient with the slow high movement but look what happens the ratio bumps up to over two-to-one during the heating phase just like it might happen with a tremor with walking with thinking bladder mechanisms any track system that's affected by demyelination might show a curve of worsening is going up and then with cooling down eventually the patient comes down to baseline in fact a little bit better here are the curves I just showed you before the discrepancy between the two eyes worse during peak heating and actually look at this baseline versus cooling at the end active cooling actually improves the discrepancy the area between these two curves is a bit less than it was even at baseline hence the idea if it's a hundred and fifteen heat index and it's mid-august in Dallas maybe cooling down before you go outside maybe at some level protective versus just going outside again let me bring you back to the beginning who cares you care because if it's a valid test and I've got a panel of drugs that prevents this decay curve which could be again walking vision eye movements thinking having sex balancing a checkbook whatever it is this may be a model by which we can prove it and ultimately take our drugs to approval so real patients with real deficits can benefit this is the pathway I mentioned before remember it's in the brain stem the ml and it's the one that helps the eye move toward the nose so this is in a diagrammatic form what I showed you in that patient before my point is we're in a very specific system where myelin has been disrupted we also know that not only is this a beautiful system to look at the physiology in the normals and the pathophysiology in people who have demyelinating diseases but if I have a strategy where I'm going to repair myelin and normalize that healthy relationship between the axon and the oligodendrocyte and hopefully preserve the axon and the neuron we would like to look at discrete systems where we know where they are and we have a way of not just looking at function your eyes are now moving that matters and they're moving together but I can go back to the lesion here it is this is an MRI of the brain showing the lesion in the location that causes that problem in that medial longitudinal white matter fasciculus that causes that slow eye movement syndrome and so one could make the argument this is just conventional MRI we now have much more sophisticated techniques that not only show us the picture but actually ways that we can measure not just the picture but ways that we can measure the behavior of how water moves down a very ordered tract system if the axons are bundled beautifully like they are here and the myelin in your nodes are very healthy water which is depicted here in this kind of bubble moves in a very predictable fashion and we actually can assign a number to this one of which is what we call mean diffusivity of water another value is something we call FA or fractional anisotropy these are just fancy terms that mean how does water move inside central nervous system tissue architecture when it's normal see how that's beautifully bundled versus if there is demyelination if there's scarring if there's disruption or loss of axons these bubbles will now move in a non predictable way and we can get numbers from these techniques to tell us how abnormal and in which ways so if we're protecting tissue we may persist in the normal state if we've already had transverse myelitis or neural myelitis opteka or multiple sclerosis then the question is with restorative kinds of strategies can we move a very disrupted bubble of water behavior and its movement in the tissue back to a signature that looks more like normal and that's why these studies are so important and it's important not just to look in any piece of tissue we need to have tissue that's relevant to you it's in my optic nerve so you could tell me is vision better I can measure it with physiology to show that the physiologic signature of abnormal and normal is moving in a direction that I want to see it going ultimately it's about the patient's but for approval we have to show this relationship between structure and function very important these are the first images ever constructed in the world of tractography of this little small system here in blue the medial longitudinal fasciculus to give you an idea the difference the optic nerve contains each one in each eye about a million two hundred thousand individual little axons whereas this eye movement pathway the MLF on each side only 10,000 so that's what makes this particular image so striking is that we're able to cancel and subtract things around this longitudinal medial fasciculus of myelinated axons that works to coordinate the movement of the two eyes and I just wanted to show you just briefly that we've already done some studies these have been done in collaboration with our colleagues Bob Fox and Ken Sakai at Cleveland Clinic I think the thing that I've enjoyed most about my career in being completely focused on ms and related diseases is twofold one is collaborating with patients and my colleagues in our and secondly collaborating with really bright people anywhere in the world just because we have common interests we can but if you look here you can see that this represents a mathematical curve it's a particular signature from controls and a mathematical signature from people with MS who have this eye and know and you can tell these curves are far apart all I want that to mean to you is that there are market differences in these measures of tissue injury and again if we have lingo or other strategies that repair tissue or protect tissue we will either normalize this curve or prevent the curve from becoming abnormal it's a way of really showing proof of principle and there are these different maps I wanted to show you briefly this particular story a 25 year old medical student who developed sensory and motor myelitis at age 17 developed the eye movement problem I just showed you at age 20 also had some problems with bladder urgency he was a high school senior he was diagnosed as having a clinically isolated first syndrome at high risk for multiple sclerosis and nowadays we don't wait for a second event we ruled out other conditions and began treating this patient with an injectable disease-modifying therapy and then when he had this attack that affected the eyes he was treated with steroids and he took his medicine and he did quite well his MRI showed only three new small lesions in eight years so we would have considered this to be really quite effective however he had problems already with heaviness and the legs hip and knee pain which often can occur in people who have a change in walking mechanics there was fatigue with walking there was trips and some near Falls now this is a medical student so while on call working many hours he's fatiguing he's tired an increased use of a cane for safety after being up many hours of the day and evening and when turning the head while walking or during driving there was sense of a little jiggle of dizziness that's because of his I know the eye movement problem he would get bladder urgency and then have leakage and then because of symptoms became depressed had chronic fatigue and yes the topic of the talk here a lot of sensitivity not just to heat but as I told you walking around with a cane because fatigue ability along with heat sensitivity the exam showed there was weakness when trying to lift the legs there was stiffness what we call spasticity but also some jerks and spasms like in many of you these pay at this patient had brisk active reflexes and had some obliquity of the pelvis what does that mean the leg was weak that as the day went on he was circling his leg his pelvis was skewed he was oblique and then started to get gluteal you know pushy muscle pain it was uncomfortable because he was oblique in the way he was walking hyperextension of the knee which then developed into knee pain and he had of course on the exam these slow eye movements make a long story short what did we do with him the interventions stretching extraordinarily important heal cord stretching we used an anti spasticity agent baclofen for the tonic spasticity clonazepam the cousin of Valium for the jerks and spasms we immediately put this patient into resistance training weight training particularly for the hip and dorsi flexor so for the hip flexor and the lifter of the foot but this patient had a lot of bladder issues so we started on one of the medications for the bladder that was very helpful and we thought this was an ideal patient to use one of these electrical stimulators that helped lift the foot that go by the name of bio ness and also the walk aid had a lot of fatigue so we started him on an over-the-counter nutritional agent called acetyl l-carnitine so not an infant mean not per vigil we certainly recommend those but we started here but it turns out this was not enough and we ended up considering modafinil or provigil or vyvanse adderall or concerta there was a depression problem so he was treated with a particular agent why because most of the antidepressants caused a reduction in interest in sexual activity wellbutrin or bupropion same agent often times mitigates that effect on libido or has the opposite effect may actually increase libido so it's an agent that's commonly used in MS centres that are in the know because the other agents which are very effective for mood are also very effective in reducing libido and this is a problem in a disease where there's a lot of potential relationship discord already we did recommend that he consider particularly for stretching and breathing a yoga class those of you interested in yoga can go to my MS yoga com I made a yoga tape with Baron Baptiste one of the world's most famous yoga guys and that would not be me but it was patients with MS in the class if you just get on to my ms yoga comm you get it for free and believe me you will find out that if dr. Froman can do it as you'll see in the tape anybody can do it and it'll certainly be a source of great entertainment and laughter for you not that I was purposely trying to do it it's just that I am not that good so you can get it and we did recommend for amino pyridine for this guy now originally was on the compounded formulation and is now on AM pura the sustained-release formulation that was recently approved what does it do neural physiology 101 I just showed you this normal myelin internode node of ranvier sodium channels fast high fidelity conduction but oops a segment of demyelination and look what happens removal of these myelin Internode's uncovers an increased number of potassium channels which does what allows potassium to eat flux from in to out and what does that do to the nerve it turns it off so we have current leak which puts the action potential the firing of the nerve into the off response so the key here is to do something to potentially patch that if we don't this is what happens so before the segment of myelination we have a nice electrical response what we call the action potential nice and big but when the electrical current hits this portion of d myelinated axon boom it decays down we've lost conduction and if we get overheated or stressed out or too much exercise then this actually may lead to no conduction what we call conduction block when we put amp yura the potassium channel blocker foramina pirating and patched those potassium channels now look what happens we patch the channels you need to have some potassium efflux and you can't have the nerve on forever and now you see a normal response before the segment of demyelination and we preserve conduction across that segmental demyelination because we have reduced the current leak and not allowed the action potential to turn off why do you care well the reason why you care is because this is fatigue dragging the leg I can't think properly my eyes are slower when I exercise I'm overheated I have a fever I'm pissed off at my kids this is yeah I've got all that aggravation and I still have signs and symptoms but I have relative preservation of functional capability it's not a hundred percent and it doesn't work in everybody but when it works it's quite magical and very very very important this is just a little data from the trial showing when we looked at 25 foot walk time in people in the trial the significant benefit in those on the drug versus placebo two different trials you know we measured walking because that's something we could measure but be very careful the effect on walking in some people may be quite modest quite dramatic in others I've had other people walk much less now with their walker or cane not a cure there are other people whose effect on walking is modest but they have a market effect on trunk and postural control thinking bladder mechanics people on this drug will tell you many things I know because I've been giving it to patients for the last three decades we've used it for a long time but now we have it in sustained-release formulation so what happened to my patient I'm done we'll go through quickly improve rent you don't believe me right as the laughs is like what I said an hour ago right so improved range I never stopped ever even when they try to hook me I'd get away so improved range of mic you know if you see me in the bathroom you can ask me questions anywhere anytime just never stops ever I talk in my sleep my wife - I do used to solve calculus integrals in my sleep there are medicines for this but I would never take those medicines never I gotta be me so improve safety with the functional electrical stimulator on the leg so he clearly was better less trips less Falls and by the way what was he also with that electrical stimulator for walking he was more energy efficient while walking so not only safer but less fatiguing so reduced hip and knee pain why the genu recur bottom is improved by lifting the foot less pelvic obliquity he walks faster improved heat and exercise tolerance some of that is conditioning and exercise and some of that of course is the for amino Pyrrha Dean he had fewer incontinence episodes which means over time he stopped the bladder medicine just didn't need it less use of the cane and of course we were treating his depression and his fatigue and these were markedly improved more sustainability he has a doc improved heat and exercise tolerance less cane requirement reduction in fatigue and most importantly the quality of life was better so I'm gonna come to the end and just say that I think we have this is one but there are a number of models that we think would be effective in paneling and testing what's important to you which are therapeutics procedures techniques exercise initiatives that will augment function improve safety reduce energy consumption but most importantly improve your quality of life that's really what it's about are there risks of course there are always risks there are always the curmudgeons and say well what about seizures well it's very rare the new drugs we have what about PML what about this what about that you know ms train verse myelitis neuro myelitis optica the other disease is being covered at this meeting these diseases are dangerous and disability is much more expensive and dangerous in most cases than the expense and danger of these drugs yeah there's danger in we have to be honest about that but people are suffering and at a time when we've never had the the agents we currently have to reduce disease activity or to augment function it reminds me of this quote it's very important the cynic is the man or woman who knows the cost of everything but the value of nothing and I would say I'm probably the reciprocal opposite I want to treat I had the opportunity to do some things I want to get in there but we always must be honest and talk about the risks and the benefits and then we should decide what we're gonna do but you know who ultimately decides you do we work for you it's our job to make sure you're adequately informed never a problem with MS or nmo patients right you guys know more than anything you could teach the course and in fact you have been teaching us the course for many years that's how we're learning what we learn so I'm gonna stop there I saw Greenberg came in the room I want you guys to understand that you're in the midst of the future I mean you have no idea there are opinions but I value my opinion I think he is the future rockstar of MS and related diseases for the future long after I'm retired or dead because I won't retire until I'm dead I'll be watching him I know you're not getting rid of me that easy thanks very much

Channel: SRNA

Views: 27,667

Rating: 4.9512196 out of 5

Keywords: ADEM, optic neuritis, neuromyelitis optica, NMO, transverse myelitis, TM, medical, spinal cord, injury, disease

Id: Pv2x7ZVel5I

Length: 59min 22sec (3562 seconds)

Published: Tue Jun 28 2011

Reddit Comments

[u/adriandowe]

I've moved from nightmares and downward-facing dog crying toward hope when it comes to my wife's situation.