all right well what I’m gonna do is I’m gonna run you through the diagnostic approach this tree that I was telling you about this morning how to start to sort out what somebody has and it’s a decision tree that looks like this that looks very complicated but I think going through it almost step-by-step is very illustrative about how we think these diseases are related and how they’re unique so I want to go through that with you and a lot of this is really designed for a physician making the initial call but I want you to work through it and make sure your physicians have done this and have thought about these various cousins of transverse myelitis and different forms of transverse myelitis okay so what happens how do you start off well what we’re talking about is defining the presence of a mile off of the Amaya lapa the– you all know by now is an acute spinal cord dysfunction so the spinal cord is just not working and so what the first thing is to define by a history and a physical examination where is the spinal cord not working what are some of the features about this how is the bladder and bowel function preserved and etc so that’s the first step that should have been done and for an acute treating physician you want to make sure that this is for example spinal cord dysfunction not dysfunction of peripheral nerves that would be a related disorders anybody know what I’m talking about there’s an acute problem with peripheral nerves called guillain-barre syndrome you’ve heard about that a lot of you people have been told initially that you did have Keon Beret so what is it then that defines a myelopathy well there’s really four symptom groups motor sensory autonomic and pain so let’s go through those four quickly the motor can be anywhere from just a touch of weakness maybe just a touch of clumsiness all the way to complete paraplegia which means no movement of the legs or in some cases quadriplegia which is no movement of the arms and legs usually in the spinal cord the legs are involved more so than the arms and the arms maybe only just a touch involved while the legs may be completely not moving at all although there’s an exception to that so some of the lesions that we’ve talked about and you’ve seen some MRIs today are right in the middle part of the spinal cord and if you remember your neuro Anatomy lessons from dr. Greenberg and Pardo this morning parts of the fibers from the arms come in more in the middle of the spinal cord whereas those from the legs are right at the very surface of the spinal cord so if there is a lesion smack in the middle of the spinal cord the arms may be more likely to be involved than the legs tongue so the physician taking care of you should really start to play with the legs play with the arms ask you to go real dead and loose and floppy and see how the tone is the tone is basically the resting innervation to the muscles the resting firing of these nerves and when we are relaxed those muscles should be relaxed but all of you who’ve had a myelopathy transverse myelitis Devex disease will know that those legs are stiff they fire all the time sometimes they have these spontaneous spasms those are all manifestations of the motor involvement of the spinal cord consistent with a myelopathy sensory paresthesias is really a pins and needles sensation it could be numbness now in many cases numbness people will describe this differently is really the absence of sensation so if you try to touch a patient and they feel nothing they will often say well numb I can’t feel a single thing pins and needles is a little bit different right because that’s a weird sensation to be honest with you I actually like that better some of you come say boy I’ve got all kinds of pins and needles and it’s really uncomfortable and I say good right because that means that those sensory nerves are firing not firing normally but at least they’re awake and firing okay sometimes people will describe it as a warmth or a burning sensation and pee and the physician should really be doing a pinprick down the front and the back to define what level of the spinal cord is involved because the sensory nerves go

into the spinal cord at a specific level and so to define a myelopathy you really need to define a sensory level if at all possible and you’ll hear us say stuff like oh this is a t6 lesion or a t4 lesion or a c5 lesion it’s all really dependent upon that sensory examination that’s done so what about autonomic that’s the second of the four cardinal groups urinary urgency is most common and in fact the most sensitive sign for an involvement of the spinal cord and that really is defined as a decreased interval from bladder fullness to evacuation put simply somebody says oh my bladders full I gotta go now or I’m gonna have an accident and that can happen during the day it can happen during the night and some of my patients will say oh it’s about 30 seconds that means I’ve got 30 seconds from the sense of bladder fullness to when I’ve got to get there and sometimes the medicines we use try to get them five minutes or seven minutes or eight minutes of time from sense of bladder fullness until they’ve got to go more ominous or more worrisome is a urinary retention where people sometimes say they can feel bladder fullness but they can’t go and they need to be catheterized bowel urgency and retention typically go together although most people report more notably in the acute phase urinary urgency or urinary retention pain is a big feature of transverse myelitis or indeed of any myelopathy and for those of you who have it you know it can be the most debilitating Specht of this the worst aspect of this it can be burning or the radicular means it’s shooting to one side or down one arm or down one side it can be a tight squeeze in or a banding sensation and it can be very difficult to treat we’ll talk about this later there are lots of treatments there’s a pyramid approach where you start with the simple things and you move up until you get better control of this so I’m not going to go over this table but we’ve published this and this is part of our approach to educating physicians who don’t see as much of this as we do that there are clinical features that suggests particular types of myelopathy whether it is neuro myelitis opteka or it’s associated with a vascular problem or it’s associated with a rheumatologic problem there are clinical and radiologic things which can be very helpful in distinguished but distinguishing between those possibilities there are radiologic features as well so most of you in the acute phase if if a myelopathy is being considered we’ll get an MRI and again this is more for the physician than to go over each of these here but there are certain things about the MRI that can say look this is more like ms or neuro myelitis opteka or sarcoid or a stroke of the spinal cord those are variations on the theme and what we know by now is this patient has a myelopathy but we haven’t yet figured out what type it is now getting back to this Gyan beret Gyan beret is the GBS up here it is an acute autoimmune inflammatory attack of the peripheral nerves not the spinal cord it – like transverse myelitis usually follows on the heels of an infection and is really an example of the immune system gone amok so that the immune system has become activated in response to the infection but then it gets it wrong and it attacks the spinal cord in trance myelitis the peripheral nerves in Gion beret now there are very simple things that can be used to distinguish between these two but they often get mistaken for example I talked to you about a spinal cord sensory level so that’s where the physician has to figure out if there is an area on the trunk below which sensation is impaired because if that occurs the patient says I feel this normally normally normally normally not at all that’s a sensory level that’s a smile appa thei period not AG e on beret very clear way to distinguish between those two second thing to distinguish between those two the autonomic findings I already told you this bowel and bladder are very commonly abnormal in myelitis but almost never involved in guillain-barre a by contrast in Gion beret the heart beats too quickly or too

slowly so another very clear-cut way to distinguish between these two there are some physical exam findings that are able to distinguish between Keon beret and transverse myelitis and the spinal fluid also distinguishes between the two in transverse myelitis what you see are lots of white blood cells that’s the inflammation in Gion beret you don’t see white blood cells all you see is an elevated protein so those are the ways that you can usually distinguish between these two okay so the first step now we’ve defined this is an acute my lap ethey the first step is is it compressive in other words is something pushing the spinal cord from the outside or is this an intrinsic within the spinal cord inflammatory or vascular process so how do you do that how do you figure that out well ideally we’ll get this MRI that we’ve been talking about because it’ll help us get towards transverse myelitis but it also defines if it’s compressive here is an example of an MRI and you’ve seen several today but this is really a compressive myelopathy it’s called spondylosis spondylosis is a word which just means arthritis as we age the bones kind of squeeze in a little bit about the spinal cord the spinal cord is the gray column here and you see the white on either side of it what is that white on either side of the grey spinal cord spinal fluid not inflammation spinal fluid and the spinal fluid is around the spinal cord bathing it and nourishing it but look what happens here there’s none of that right and that’s your sign that the bones have crunched in a little bit and so you can imagine that this person might be doing pretty well but gets a little bit of a motor vehicle accident has a little bit of a hyperextension and all of a sudden gets a myelopathy that’s not transverse myelitis right that’s a compressive myelopathy the bones have actually squeezed the spinal cord that’s cervical spondylitis myelopathy this is the most common cause of myelopathy in the elderly may have a minimum and antecedent injury falling down the stairs or even a car accident that kind of brought this on the arthritis had been there but was okay until this accident occurred mostly a hyperextension type injury brought this on and from a clinical management immobilised the neck and we can get flexion or extension x-rays and an MRI to define how bad this is and what the treatments would be very important to get this out of the way right up front there are other ways right that can help you distinguish whether it’s compressive or not and we’re going to get to that because we want to know if there’s any inflammation right because in a compressive myelopathy there won’t be any true inflammation it’s not inflammatory at all its compressive so how are you going to define if this is an itis as in transverse myelitis itís being inflammation well you’re going to get a lumbar puncture and we’re gonna go back and reevaluate now this MRI the MRI was given with gadolinium gadolinium as a stuff given into the vein that stuff should stay in the vein if it doesn’t stay in the vein but gets into the spinal cord it says that the barrier between the blood and the spinal cord has been broken down this dye gets out and lights up like a light bulb that’s inflammatory so you got two ways to define whether it’s an itis the dye gets from the vein into the spinal cord and the spinal fluid is hot and I say hot I mean lots of white blood cells okay so here is a case of a 61 year old man with a history of a subarachnoid hemorrhage 30 years ago who developed an a sending left leg numbness over a year and then bilateral lower extremity weakness and ultimately progressed into a wheelchair does that sound like transverse myelitis no a couple things worry you that it’s not actually an itis but maybe some other cause of a myelopathy one might have been that there was a subarachnoid hemorrhage which is a bleed before and the other might be that it progressed over a year so what do you think it is what’s that it could be compressive that’s the first thing that you should think about or it could be vascular those are the two things at this point that you would

worry about now CSF was normal so there you have it it’s not inflammatory it’s going to be compressive or vascular also the MRI shows a non enhancing lesion so there’s a lesion a plaque something but it’s non inflammatory here I don’t know how well you can see this but you can see a little area of bright signal in the spinal cord and then a dark area above and below it so this actually happens to be just an abnormal collection of a blood vessel called a cavernous angioma so it’s just an abnormal blood vessel it’s not inflammatory and it’s not compressive but this is really critical to make this diagnosis because it’s not that uncommon and of course the treatment will be different what was done for this this vascular abnormality was removed once it was removed the pressure within the spinal cord got better and the patient improved there’s another type of a vascular malformation that you need to know about this isn’t called an AVM arterial vascular malformation it really occurs only in people over the age of 40 usually only in males and it presents with pain progressive weakness numbness in the buttocks and perineal area claudication which means pain on walking and urinary urgency it is a slowly progressive or stuttering course over years the etiology of this is this increased venous pressure by virtue of this a vm and I’m not going to get into this except to say that what happens is the arterial venous malformation causes the spinal cord to be too congested because the spinal cord cannot drain blood away and people progress into a wheelchair and they may be there for a year or two or a three and the beautiful thing about this is if you altima lead ooh make the diagnosis and you treat this arteriovenous malformation people may get better they may have a return of function as you resolve this congestion within the spinal cord this is what it looks like this is an example of this arteriovenous fistula on the surface of the spinal cord and this is what it looks like when we define it by a spinal angiogram okay now I’m going to go through the rest of this because now I’m we’re gonna say look there is inflammation here unlike those that I previously taught you there is in lemay ssin as defined by what order the two ways hot spinal fluid and gadolinium enhancement on the MRI now we’ve got to sort out what type of itis it is so the first thing is to see if it’s an infection is there is the inflammation there because it’s a direct infection of the spinal cord and this will be on the quiz at the end but these are the things you think about and there’s a whole series of tests that we often will run in this context there is one thing that we see fairly regularly which is Epstein Barr virus Epstein Barr is a herpes virus and it is important to look for that in the acute phase of a transverse myelitis because you can define the presence of the virus in the spinal fluid and can initiate antiviral therapy if you catch this early so you think about this because there are appropriate antibiotics or antiviral therapies in the case of certain infectious myelitis okay the second step then to define the type of itis it is is could this be part of a systemic rheumatologic disorder is this really part of Sjogren’s or lupus or sarcoidosis and Julius Birnbaum is going to tell you about that in a bit in some more detail but again there are a series of things that need to be asked because if they are present a rash swollen glands fevers chills night sweats blood in the urine those types of things make you think that yes this is transverse myelitis but it’s really part of a systemic rheumatologic disorder it’s important for a couple reasons one you’ve got to treat the systemic rheumatologic disorder to the risk of recurrence is much higher than if it were transverse myelitis in and of

itself not associated with a systemic room it’s a logic disorder Sjogren’s syndrome you will hear from dr. Birnbaum so I’m going to skip this for now but we have also found that transverse myelitis is associated with antibodies that you often see in patients with Sjogren’s syndrome and so there is an overlap here and in this case we check at first onset of transverse myelitis for particular antibodies in this case called s SI or anti-ro antibodies because if it is present it like nmo IgG in the appropriate context context predicts recurrence and so here we are in the first phase of an acute attack trying to define what the risk is of recurrence and the ssa and the nmo IgG antibody both help with that who’s heard of star coy ptosis it is a relapsing autoimmune disease that often involves the lung but can affect the spinal cord it can affect the brain and the optic nerves as well something important to consider there are certain tests which we will ask for to rule this in or rule this out it is important to know because it too can be recurring over time okay so now what if it’s inflammatory but it’s not associated with a systemic rheumatologic disorder or an infection the question is where is it within the nervous system is it just one spot or is it multiple spots up and down the brain and the spinal cord so we’re interested in defining if it is multifocal CNS inflammation so you need an MRI of the brain you need an MRI of the entire spinal cord and you need some other tests such as evoked potentials or Oct to test that because this is what we’re down to it’s a very bottom of that chart you can have a tea Pathak transverse myelitis you can have longitudinally extensive transverse myelitis and Shawn already told you that that fits most appropriately in the context of the neuro myelitis optical spectrum and so that’s why we put this over here because it’s really important to know that that’s more likely to involve the optic nerve ultimately it’s also more likely to recur and we think of those treatments such as Rituxan that are effective for neuro myelitis optica and the nmo IgG helps here what if it’s an acute partial transverse myelitis meaning it wasn’t that severe it was fairly mild asymmetric people were not catheter dependent it was mainly sensory symptoms that’s good right dr. Greenberg told you this but that actually is more likely to go on to become something like multiple sclerosis and so that raises our warning flags that this is the beginning of what is ultimately to be defined as multiple sclerosis and the reason we have to get to all of these and the reason why these criteria are important is because we think the therapies differ the risk of recurrence differs and the most appropriate therapies differ and that’s why going through this exercise I think is important for the physicians because it stratifies into different categories okay I’ve already told you this there are certain MRI and clinical factors which tell us oh this is really ultimately going to be multiple sclerosis the image looks different that presentation looks different the spinal fluid looks different so now let me just spend a few seconds with you telling you about idiopathic transverse myelitis I’ve already gone through the various shades of this the various cousins of transverse myelitis but idiopathic transverse myelitis in and of itself is typically mono phasic and mono focal less than 10% of people in this group ricoeur we still don’t know although i told you this morning about auto super antigens and post-infectious autoimmunity so i’ve told you that in many cases it is the infection which triggers the immune system to lose tolerance for self and we know that to be the case in many cases of transverse myelitis in large part because of some of the work that i told you about this morning that philippe your ends had

published what we don’t know is why a specific region of the spinal cord but this is what it looks like this is the itis right so this is the spinal cord which was from a biopsy and what you’re seeing is a massive infiltrative inflammatory process each of the blue dots here is an immune cell well those immune cells should be in the blood surveying for infections what the heck are they doing all amassing within the spinal cord and the reason is they’ve been called there and they have been recruited in large numbers and are actually injuring the spinal cord here’s a view around a blood vessel and you see even within this small area several thousand immune cells that are recruited into the spinal cord and so this is our task in the acute phases is to recognize that the immune system has gone amok and to call it off as quickly as you can because the results of that inflammation can be either demyelination here seen in one example the blue color here is for myelin and what you’re seeing are multiple areas of demyelination but the alternative is a more severe type of transverse myelitis which the result of that inflammation is necrosis or axonal injury and that tends to occur in the people who had a more severe presentation and are left largely or complete with an injury no bowel no bladder no sense so why did in some cases the inflammation result in demyelination which is milder and may get better but in other cases we’ll leave you with a complete necrotizing injury well we’ve started to look at that and we’ve got some answers to that so we started the transverse myelitis in 1999 we’ve now seen around fourteen hundred and thirty-two patients with an acute non compressive myelopathy and we’ve sorted them out into these various categories now we did this at one point and we haven’t kept up with but we’ve sorted them into all of these different bushel baskets right what kind was it compressive was it non compressive but also non inflammatory and if it was inflammatory what type infectious associated with a rheumatologic disorder or etc and so this has allowed us to really understand each of these subgroups of transverse myelitis and we focused on for the sake of this understanding the pathogenesis the idiopathic group why do people get idiopathic transverse myelitis and adam kaplan said about doing this looking at the cytokines or inflammatory factors I told you it’s inflammatory we didn’t know much more than that it was inflammatory so what have you stood look I want to see what type of inflammatory factors are there well it turns out that there’s only a few inflammatory factors that are elevated one of them is interleukin 6 you can see here by this very bright these two very bright white dots that are present in the transverse myelitis patient but not in the control so we did that one time when we said hmm cool but maybe unique to that one patient we did it 10 15 20 30 times and said look this is something which we see an awful lot in transverse myelitis patients and so we graph that and what you find if you do this now over 20 patients is that they all look the same they’ve got really i interleukin 6 and they’ve got not much else of anything going on so really quite interesting as a biomarker for transverse myelitis but also maybe it to like song with the n mo IgG maybe it too is involved in the pathogenesis so that’s the way we think about it is it a biomarker only or is it involved in the disease itself I won’t go about what we know of interleukin 6 but we know that it can injure tissues we know that it can injure the heart for example and when we looked at the CSF aisle six levels of a bunch of patients we found that it was a little bit elevated in multiple sclerosis but man was it elevated in transverse myelitis normal people had to picograms per mil transverse myelitis

patients on average have about 435 picograms per mil of interleukin 6 so that was very informative from a diagnostic perspective and what Adam showed in his work is that the higher the il 6 is in the acute phase the worse you do long term so this is just a graph of that this just shows you the the EDS S which is disability those who are attend were are very bad and there’s a direct correlation between these two so again the worst the higher your il-6 levels in the acute phase the worse you do long term so much so that you can divide patients in the acute phase of TM into two groups they come in with low il-6 virtually all of them walk independently again they come in in a high il-6 group they never walk independently again everybody here that that that’s my daughter put that on my ring for Raiders of the Lost Ark and Indiana Jones so that I think is very important as a diagnostic tool and we are now using this on a regular basis yes sure how long does the aisle six-level last just in the acute phase within the first two weeks yeah so if we look well we certainly know that by six weeks the interleukin 6 levels have gone back to normal and in fact interestingly although we we’ve only done this in several patients not more than that in those in whom the il-6 has not gone back to normal those are the people who will recur so at six weeks most people there on sixth level has gone back down the topeka grants per mil if it hasn’t it bodes poorly for a chance of another recurrence but it’s only helpful in the acute phase okay so ah yeah question if if there is a recurrence does the interleukin 6 level change the answer is yes it goes back up hey no it would be into one of those different boxes the question is would it change the diagnosis no it goes into one of those different boxes but it does tell you that chronic immunosuppressive therapy is going to be required that indeed this process has not corrected itself because in the majority of TN patients the auto immune dysregulation if the immune system has gone amuck but it quickly corrects itself but in some patients that doesn’t occur so this is where we are now I haven’t gone through the data at the animal data are showing you that interleukin 6 is actually very clearly involved in the pathogenesis here but that is the case and it now raises once you’ve got these participants in mind now it gives you targets now it says we can think about rational approaches to drug therapy to block this pathway and see if patients will do better because remember I told you this morning the tools we’ve got currently are pretty blunt and pretty crude and were predicated on the fact that we had no clue what this inflammation was about but if we did and we now do you can think about more specific therapies and each of these green boxes is really one of the things that we’re hoping to look at and to test so I will stop there and show you a few pictures this is Paula obviously with my daughter and Adam Kaplan’s daughter and this is at the Victory Junction Gang Camp and one more this is sandy with his hair colored pink and purple his nails are done but so are mine I’ll stop there only in the spinal fluid is il-6 not in the serum unfortunately we had hoped that it might be a serum marker wouldn’t that be cool not the case so for a serum marker you’re gonna need Ben’s stuff that he was talking about and he’s developing its final fluid from a lumbar puncture interleukin 6 is found in the spinal

fluid yep not in the blood it’s made by the central nervous system cells as part of the initial inflammatory response we think it then recruits all these immune cells in so it’s only in spinal fluid sir would the il-6 be a standard part of a result of a lumbar puncture absolutely not not tested not tested and it’s hard because the spinal fluid has to be obtained these cellular eyes in other words you get rid of the cell debris take the supernate and freeze it and then send it to somebody including us but a lot of clinical labs will do it but if if you just take the spinal fluid it’s got a lot of cells in there and things like that the results are weird so you have to get rid of the cells first and then quickly freeze the spinal fluid ma’am what percentage of the neurologists throughout the country know to look for interleukin 6 very few very few and so we’re how do we get that out to them we’re trying we’re trying and it’s being used more in fact we’re starting to see people who come into the transverse myelitis center now and they’ve had their il-6 level tested it’s getting there but it’s slower than we would like look so the question is how yeah the question is how would the identification of nmo for example as an aquaporin channel Appa the– how would that allow you to design a very specific therapy to that it’s hard there’s no immediate answer to that but I think what it points to from my mind is that if you can understand how the aquaporin for channel function is altered there are things that modulate water channel function and so and there are drugs that enhance water transit and those types of things so it is possible that the therapy would directed more at reestablishing normal water channel conduction but we don’t know yet what we’re interested in actually is very much in how did that start in the first place how did you develop an autoimmune response to the water channel because we think something happened to make the immune system think it was foreign would you always have an elevated white-blood-cell counting your spinal fluid if you had transverse myelitis no if it usually goes away completely again by six weeks so normal white blood cells in the spinal fluid zero to five it should it should return to normal if it doesn’t again it worries us that you may be at a risk for a recurrent disease among one of the other boxes that I told you about it would be elevated in the acute phase of transverse myelitis meaning the white blood cells out to around six weeks yep do most of those results hold true in pediatric cases you no less so the two things that are less reliable in pediatric cases is gadolinium enhancement is less common especially in infantile cases and a robust cellular inflammatory response and it’s very interesting because those are the two things that I told you define and itis and yet in kids especially in infants they’re not as reliable so in kids what we found on many occasions is by all the other criteria this is non inflammatory there’s no gadolinium enhancement and there’s no cells and yet the il-6 level is sky-high so that’s quite interesting that that may be the most reliable marker of inflammation more so than the classic ones that we use to diagnose great question is in the infantile cases which

often are the worst the worst outcomes in some cases come from kids who had transverse myelitis before the age of one year and all is their il-6 level higher and in many cases it is the highest we’ve actually seen is in nmo patients but we’ve seen four and five thousand picograms per mil in infantile TM cases who were left quadriplegic and ventilator dependent unfortunately we haven’t felt justified in doing that at this point we may get to that point so we have to prospectively assess I’m sorry I sorry the question is would you go back and get a follow-up spinal fluid to assess a return to normal I’ll six levels and it makes sense and we often will do that but we don’t feel like we’re fully justified at this point in using that to guide treatment decisions it’s a bit too early we hope to get there now yeah so that’s a good question is and the question is in that’s exactly the point is and now that we know that aisle six is not only a biomarker but is participatory in the disease it’s causing the injury are there better ways to down regulate this il-6 quite quickly and we think there are and we think that that will be a useful way to call off the disease progression because we give steroids now and many of you have received steroids and recognize that it’s not that good it helped to some degree but could we do better and so there are certain things for example one of them that we’re we’re very interested in testing is the lid amide the lid amide is a every good drug in certain circumstances and it’s very good at decreasing aisle six and the responsiveness to aisle six sounds perfect right so we’d love to do this but that’s a tough study to get done right because you need patience to get into a hospital to get aisle six level tested quickly and then to get put on the lid amide or placebo in addition to steroids I think it’s a really good study I think it would be very important to do but you know even at Hopkins we don’t see enough in the first several days you know you really need a patient within the first four days of onset to do that study and so that bi’ness by definition has to be a multicenter study oh wow all right that’s good yeah so there are two two cytokines il-6 and tgf-beta that that pushed the immune system into a particularly nasty cell called a TI all set il-17 cells so you heard about th1 cells well there’s one that is a really bad cell that is just a t-cell out of control and that’s a T il-17 cell and il-6 is one of the things that makes your body make T il-17 cells and and so yes we’ve been very interested in that and in fact we’ve looked in our transverse myelitis patients and they have much higher levels of T il-17 cells than controls well duh but they’ve also gotten much higher level of T il-17 cells than MS patients than sarcoid patients and then nmo patient so there’s something very unique about transverse myelitis and elevation of io6 that drives the production of these cells you couldn’t yank me off before you know I just keep going

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