00:01                           Good morning first. Sandy My sincere condolences. I didn’t know your wife personally.

00:08                           But I think everyone’s journey touches us all I’m going to start by also saying that although my title is Rare Neuro Immune Disorders and I agree with Ben anyone who has a creative title for the next set of symposia should share it with us. The word rare doesn’t really apply in this room because for you it’s not rare it’s real. And so for that I want to just emphasize that while there may not be thousands of people with your diagnosis or your condition there are plenty who are here. There are many others who are not here and there is an entire dedicated team of physicians and scientists, nurses, nurse practitioners, therapists and others who have dedicated their careers to trying to make your situation your life and your family situation better. And I hope we achieve that even more than we have to date.

00:57                           So what I’m going to do is walk you through a little bit about the disorders that we see. I won’t do justice to them all and I can’t spend nearly enough time on each of them but I wanted to give an overview of what this family of disorders includes I’m going to do this by telling you stories of children that I look after in order to of course always first and foremost emphasize that again while there’s a lot of science to share what matters most is the personal stories and the families and children we look after. And I will tell you their stories. I’m going to summarize them in a lot of fancy words that you see on there and then I’ll actually say it in English so that you understand what I’m saying. And then I have these slides at the end that talk about the approach.

01:43                           I’m not trying to teach all of you how to be neurologists although I suspect many of you could probably pass the boards at this point. But I am going to emphasize the approach to this which more to show that there is a strategy to trying to distinguish the different disorders that your clinicians and practitioners can use to better identify the way to make your treatment specific to what you need. So I’ll tell you about one of my patients this is a young man who I met when he was 16. He came in with lower limb weakness over the course of about two months which is unusual it took him a little time. It got worse over about a two-month period. He had some sensory deficits that had appeared over the 30 days before I met him.

02:24                           He denied any bladder impairment but he was pretty tired. He had been born in Africa. He had immigrated to a Canadian I’ll give that away at some point even though I’m now in Philadelphia I’m sure I’ll say “Eh” or some give away. And so I met him when I was still in Toronto. He was born in Africa and came to Canada at the age of two. So he grew up in a Canadian environment. And that might be important for some of the risk factors that drive these different neuro immune conditions. When we met he was a very alert articulate young man. He did have some vision loss in the right eye that he hadn’t realized. And I think many of you may have had that experience where if you have visual loss in one eye and the other eye is normal you rapidly adapt.

03:06                           And certainly in children particularly some of our youngest patients they may not appreciate unilateral visual loss and don’t tell their parents about it. You know deviating from this briefly one of my patients with Optic Neuritis was a young boy that was playing baseball and he got hit in the cheek from the baseball. And so, I got called to the emergency room to see him to find out why this injury to the lower part of his face that caused visual loss didn’t make any sense to the doctors and I pointed out that it wasn’t that the baseball caused any of his visual loss.

03:37                           He didn’t see the ball coming and he simply hadn’t realized that you had visual loss in one eye. And if any of you wear contacts and have ever dropped one particular in the morning before you have to go live a lecture not today but I’ve had this happen to me before. In about an hour you ignore the guy with the reduced vision you function pretty well. And so this young man has had the same experience. He did not realize he had visual loss in one eye. He did have weakness. He did have quite significant lower limb weakness when I met him. He was actually able to walk independently and his sensory level was in the spinal cord. So, we use a scale called the Expanded Disability Status Scale many of you may have heard that term. It’s basically a tool to help doctors communicate to each other with how severely affected someone is in the moment.

04:22                           And he was unable to walk independently without aid. We gave him high dose corticosteroids and again I suspect many of you are familiar with that treatment. And he did improve and he actually got back to being quite functional and used a cane very intermittently. So improve quickly over the next couple of years though he had multiple further events as you see listed there. He was diagnosed with Multiple Sclerosis and treated with standard at the time multiple sclerosis therapies. And at that point when we first met This is a number of years ago. Currently much more powerful therapies weren’t yet available and he did not really do as well as he would have liked. He was continuing to have relapses. And I won’t deviate into this CCSVI story.

05:07                           Chronic Cerebral Spinal Venous Insufficiency which was a theory that was put forth a number of years ago that the cause of some of these diseases was poor venous return. This of course has been proven to be false but because he was concerned he did go to Egypt to have a procedure to try to open up veins which unfortunately of course did not improve his situation since the disease is not caused by that. And then in 2014 Tysabri came on the market, Natalizumab. He was treated and has done much better. His MRI as shown here which illustrates that like many conditions where the immune system attacks in the brain or spine or optic nerve you see areas and I pointed to.

05:50                           A bright area in the spine. Anything bright white on those images in the brain are areas of inflammation.

05:57                           So he had a rather aggressive pediatric MS story and I shared his because one of the things that is becoming clear is that there are certain individuals or certain groups of individuals who do less well with certain conditions and particularly at least in pediatric multiple sclerosis. And in neuromyelitis optica, individuals that are African-American or in his case actually African itself really do less well than other groups and that suggests there may be a lack of some kind of protective factor or some kind of increased genetic risk for individuals who come from areas of the world where MS is rare but live in areas of the world as children were MS is common and we see this story over and over again suggesting at least some part of multiple sclerosis. Risk is defined by where you grow up. That does not mean we should all move.

06:51                           That’s not the strategy but it does bring to bear a lot of research on what is it about growing up in high risk regions that might propagate diseases like multiple sclerosis. Low Vitamin D and other factors have been implicated. So I have to ask I do this every time I give a talk to a lay audience and you some of you know where I’m going with this. A hand up or indication how many of you took vitamin D this morning supplement of some sort. This is great you guys are one of the best audiences I’ve asked that question too. How many of you in the audience have children or grandchildren? Almost everybody. How many of you know that they take vitamin D on a regular basis? Far fewer. This is an important point. While we do not suggest that vitamin D alone can prevent all of these conditions and I am not suggesting that I am though pointing out that living with low vitamin D levels is one of the risk factors that may be important to cross at the population level.

07:49                           So I do encourage you to contemplate the fact that it’s an easy strategy to make sure that everyone is taking their vitamin D including family members and others. That’s healthy for you. There’s no evidence that taking vitamin D is bad for you in any way but it might be helpful down the road. So this is what MS looks like in children. Unfortunately, one of the things that we do see in children with multiple sclerosis is on the bottom there where I’ve got a blue arrow. These are areas of tissue injury that aren’t repairing well they’re called black holes their focal areas where the area of inflammation has been present in the patient the child has not recovered well from that area.

08:27                           And I naively thought that children would heal faster than adults with multiple sclerosis. They do if you have a fracture in their arm they do have a sprained ankle where they don’t if they injure the brain. And so this points out a fundamental area that we as scientists need to address more than we have which is how can we how can we better promote repair how can we make the body use its resources to heal better what can we do to make this process better. And that is going to transcend every one of the disorders I’m going to talk about. All of us recognize that we can start to now control the immune response is much better.

09:01                           But we have another job to do which is to promote healthier and faster repair to prevent these areas of brain injury. So here’s another child. So this is a young lady completely healthy before she presented to the emergency room with back pain. Children should not have back pain it’s never growing pains. If a child has persistent significant back discomfort it is always something to take seriously. She had a lightning bolt feeling down her spine when she bent her neck which is called Lhermitte’s syndrome. She actually also had a facial nerve palsy. Which had come out the day or two before. She did have some deficits in her lower extremities her reflexes were increased. She had a what’s called a sensory level which many of you know what that means is under below a level in her spine everything felt numb and she did have some difficulty with the urinary hesitancy and going to the bathroom.

09:53                           She had an MRI that I hope shows on your screen that showed a bright signal all the way down. So everything that’s hazy white between those two arrows in the spinal cord is abnormal. So, this looks like Longitudinal Extensive Transverse Myelitis we then gave her gadolinium on her scan and I don’t know if this projects well enough. It does on my screen but I’m not sure it does on yours. But if you can see little white dots all the way around the outside covering of her spine that’s the look. What’s called the leptomeninges it’s the covering of the spinal cord. And it was enhanced. That’s not supposed to happen in Longitudinal Extensive Transverse Myelitis. So, we looked a little harder.

10:34                           Her spinal fluid had a lot more cells in it than you normally see and transverse myelitis. So there was a lot of immune cell activity going on. The protein was very high. So that’s again a clue that this is not you know this is a little bit atypical. She did have what are called oligoclonal bands.

10:51                           So these are proteins made by the immune system that are present in the spinal fluid and were not present in her serum suggesting that some of her immune cells that are behind that blood brain barrier were making an immune protein. We couldn’t find the typical infection but we did figure it out.

11:09                           So she had Lyme disease. Now we don’t normally see Longitudinal Extensive Transverse Myelitis and Lyme disease. But you can and the challenge with her was that initially we did one screening test which was positive and then we went to the next Western Blot test and it was negative which was puzzling. And then we did a little bit more history up until that point nobody had asked where she spent her summer vacation she told us that she had gone horseback riding in the summer and that’s where she had been just two months before we saw her but it didn’t occur to us initially to say where. Well she went to France.

11:43                           And the form of the infection in Europe is different than the Borrelia burgdorferi strain that we have in North America. So the test failed because we were using a kit that works in North America but doesn’t work if you’ve acquired the infection. The ticks are different. So, once we got the kit sent from Europe we made the correct diagnosis treated her with Ceftriaxone and steroids to reduce the inflammation and she’s now perfectly fine. So that is a rare situation but it highlights the fact that what looks like transverse myelitis is always something to look a little harder make sure you don’t miss another diagnosis. And the clue there was that enhancement that’s not typical of most people. So we’ll move on. This is another patient with an MRI that looks pretty much the same. Yes.

12:42                           It’s a good question. Are the ticks the same in Australia?

12:45                           Yeah.

12:51                           So there are different strains and that you do have to know what strain is endemic in the area in which you live in order to make sure the kit is sensitive to it. Now what I realized when I presented this case that a variety of you are now potentially going to say do I have Lyme disease and I presented this for two reasons. One because I get asked that question all the time and sometimes the answer is yes but the answer is No. Almost all the other time. So, the reason that I made this this example was to highlight we always do consider this and I get you know I think there’s a lot of need to make sure you keep everything on the table when you investigate someone with myelitis. But the vast majority of people of the Western blot is actually negative and this is not Lyme disease.

13:30                           But if you’re going to do the Western Blot you do need to make sure that you’re using the right kit. Absolutely. So, this is another patient with transverse myelitis. Again, the MRI looks pretty similar. She does not have enhancement of her cord and she meets the diagnostic criteria that you probably know and can recite for many of you who have been diagnosed with myelitis which is listed here which is that you have inflammation of the spinal cord with weakness and sensory deficits often with bladder difficulties and sometimes sexual dysfunction. We typically see some evidence that the immune system is active in the spinal fluid. Most people have their worst weakness within four to 21 days from when it starts in the vast majority. And of course, always we rule out a spinal cord tumor, spinal cord trauma, some kind of something pressing on the spinal cord that would need to be potentially surgically removed.

14:23                           When we looked at all of the children in our national Canadian study this is the distribution of where in the spine we see abnormalities and how those compare between patients with acute, one-time attack myelitis versus multiple sclerosis in this comparison. And just to remind you Longitudinal Extensive Transverse Myelitis, which is a mouthful, means an inflammation in the spinal cord that goes more than three of those vertebrae in length. So a long lesion involving a fair bit of the spinal cord. And that’s much more common in patients with what we call acute transverse myelitis are one time attack. It’s not as common in children with multiple sclerosis and I’m leaving neuromyelitis optica off this slide.

15:05                           I’m going to get to that in a minute. As you can see here so children with multiple sclerosis tend to have small lesions that are only little circles in the spine. Children with idiopathic transverse myelitis and children with neuromyelitis optica and children with myelitis in the context of acute disseminated encephalomyelitis or ADEM tend to have long lesions and this is just a slide from the French group which highlights a couple of important points and it might be a bit small to read so I’ll summarize. When you have acute myelitis all of us who look after children with my letters and Dr. Hopkins is here and she and I look after a lot of these children together in Philadelphia I think we all take a deep breath and you know get very worried when we see kids with myelitis because about a third of them no matter what we do at this point are left with some kind of residual deficit.

15:55                           Seventy percent get better and that’s a nice way of looking at that number. But for the 30 percent who don’t fully recover and they’re five you know it’s a really, I think humbling experience to try to do everything we can to make these children better. We give high dose corticosteroids we now use plasma exchange. And Dr. Greenberg and his team have been at the forefront of advocating for early plasma exchange for patients that have severe myelitis and certainly we’ve implemented that in children as young as eight or nine months of age who have myelitis to try to improve the outcome as quickly as we can. But not always unfortunately is that successful.

16:33                           So it remains a serious unmet need for us to address how to make that last 30 percent of patients recover more fully. And then we’ll skip that. So as I said 20 to 30 percent do not fully recover full ambulation after childhood onset. Myelitis this is a call to action for all of us that look after these children. So we’ll move onto someone else. This is a patient and I’m going to summarize her story briefly because Dr. Hopkins and Dr. Greenberg once to talk more about this condition but this is a little girl who had a cold and then developed arm weakness. She had a little bit of neck pain and no history of trauma. She was very weak in that arm. So two out of five means she couldn’t even lifted against gravity. Her reflexes were absent.

17:20                           So that’s atypical. Normally when we see patients with myelitis their reflexes go up. Hers were absent. Her sensory exam was completely normal. And she had again this hazy fuzziness in her spinal cord. But when you look at the red arrows at least on the far side the front part of her spinal cord was particularly target. This is the anterior component and she was one of the children that you’ll hear more about today and one of the workshops that present with Acute Flaccid Myelitis this entity is very likely to be infection and enterovirus D68 and other forms of enteroviral infection have been implicated. It’s actually very hard to prove that this is an infection first of all we don’t go around biopsying the spinal cord as you can well imagine that’s not a good idea. So, we don’t do that enteroviruses are the type of infections that go into a cell particularly in this case the anterior horn cells that are the cells that give that nerve message down to your muscles.

18:22                           So they’re hard viruses to detect and even though we saw this happen in the context of enteroviral infection in the community so we saw many many children with this enteroviral cough cold congestion. It isn’t easy to prove that that’s the virus that’s causing the spinal cord symptoms although a great deal of effort has gone into trying to prove that. But enteroviruses are in the family of polio or polio is, I should say that the other way around. Polio is in the family enteroviruses and this infection is a lot like polio. anterior horn cells involvement a lot of weakness in the cell distributions that are involved.

18:57                           And obviously very serious presentation and you’ll hear more about acute flaccid myelitis in one of the small group sessions and that’s what she had. In 2014 there were 115 cases in the United States. This was not unique to the United States. There were cases in Canada. There was a cluster in Europe and there were certainly clusters in Asia and I know I saw a cluster in Toronto in 2012. We just didn’t know that’s what it was at the time. So this is and there’s a syndrome called Hopkins syndrome not related to Dr. Hopkins here that occurred in Australia actually where patients presented very similarly in the context of a cough or a cold and then developed this polio like illness. And I suspect if we were able to get the samples that we could actually make the detection these kids would all have a very similar biology. The challenge with this is that while the recovery with rehab. Definitely is is positive the ability to fully recover seems to be even lower than in the typical more inflammatory transverse myelitis cases.

20:05                           So, I’ll move on. This is a 16-year-old girl who had been born in Jamaica but was growing up in Canada came in with headache and vomiting initially and had developed this incredible sleepiness. She would sleep 18 hours a day. She would actually fall asleep in clinic. At one point, I was. I mean I know I’m not necessarily riveting. But she fell asleep in mid-sentence. And so even my husband hasn’t done that.

20:32                           So she was really incredibly what we call hyper somnolent to the point we actually had to make sure that all of her food was caught up in very tiny pieces as we were so afraid she’d fall asleep while eating she had lost her normal menstrual cycles so she had developed this secondary irregularity with menstrual cycles she’d become very irritable, she’d be happy sad happy sad for no logical reason completely unlike her normal personality. She had developed an incredible appetite and had started to gain quite a bit of weight very quickly and then developed some balance impairment and the vomiting continued she had this ongoing vomiting syndrome. And when we look at her MRI here we see bright areas of signal abnormality in the sort of the lower part of the brain right near the vomiting Center. We do have a vomiting center in the brain and that was involved and then bright areas in what’s called the diencephalon which is the part of the brain that is closely tied with our wake.

21:32                           I was sorry. Let me rephrase that with our sort of hormonal hypothalamus endocrine system that drives in this case you know your normal cycles including women’s menstrual cycles and then the brainstem was also involved in the area that controls when we’re awake and when we’re asleep. And this is a pattern that is the brain manifestations of neuromyelitis optica. Now when neuromyelitis optica was originally described going back to the international criteria in the 1990s and early 2000s people focused on the title Neuromyelitis Optica, optic nerve and myelitis spinal cord and absolutely those are hallmark symptoms of neuromyelitis optica. But there are brain symptoms as well.

22:16                           And when we looked at why this is a slide taken from Dr. Wingerchuk’s work and he and the group at the Mayo Clinic were actually Dr. Lennon of specifically at the Mayo Clinic discovered that the vast majority of patients with neuromyelitis optica have antibodies which are immune proteins targeting something called Aquaporin 4. Aquaporin 4 is a protein that sits on part of the brain cell anatomy. And in this particular distribution. So the areas were Aquaporin 4 is present are the areas where the immune system is targeting and that is if you look on the different diagrams there are the spinal cord the optic nerves and very much the areas that were involved in her brain. So her symptoms make sense in terms of this particular biology of neuromyelitis optica. We see this disease and children certainly we see it in adults.

23:15                           It is a disorder that is overrepresented relative to other neuro immune conditions in Asia but no country, no race, no region of the world is immune from this neuro immune condition. It is occurring everywhere and we have definitely got better. I think at making the diagnosis because the blood tests certainly help us. Not everyone is positive. So, if there’s anyone in the room who has been diagnosed with neuromyelitis optica who’s Aquaporin 4 or NMO IgG is negative. That can happen. About 20 percent of people are negative. But the 70 to 80 percent depending on where you get the tests done are now positive or found to be positive for this antibody which does help us enormously in our diagnostics. And it’s still rare in close to 300 children in Canada that were presented with inflammation in the brain spine or optic nerve in the Canadian population.

24:08                           We had a very low likelihood of it being neuromyelitis optica and we check everyone now but it is still a condition that affects children and adults in the second paper there which is from the United Kingdom. About 5 percent of the children that come in with demyelination are found to have NMO antibodies. So it’s it is relatively infrequent within a group of already rare conditions. But I think all of us are seeing more and more patients. I’m not going to summarize all of this. The key point in this slide was only that in this detailed overview the number of children with brain abnormalities was very high and this highlights the fact that I think the brain symptoms were under recognized in the past and now we realize this is part of this condition.

24:52                           So not all people have antibodies to Aquaporin 4. There is an emerging story and this is a real time emerging story of people that have inflammation of the spine or ADEM or optic neuritis or an NMO like illness may have antibodies against a different protein. It’s called MOG. This is one of the proteins that has been identified and MOG is a protein that lives in the covering of the nerves so it lives in myelin I think probably you’ve heard that word before, myelin is the sort of fatty substance that coats the nerves that send messages and without myelin we would not be able to send electrical messages quickly. It’s very much sort of akin to the electrical cord that is wrapped in a covering in order to improve the ability of electricity to travel on an electric cord.

25:42                           This is nature’s version. And this protein is present in myelin. And what you can see on the top graph in children. The blue bars versus the yellow. About half the children with ADEM if you test them are positive for MOG antibodies. At least in this series. If you test them again though about three to six months later the vast majority of them no longer are positive and the vast majority of the children do not have any more attacks. So, the ability of your immune system to make proteins when you have an acute episode like ADEM is quite high. The key is that ongoing antibody driving new disease or was it a onetime acute illness. And that’s really an important thing that we’re all learning as we start doing these asses over time.

26:29                           I will tell you that we back in I think it was 2004 we did a study where we were looking at immune cell behavior in children with multiple sclerosis and we thought that we would be clever and compare that to children with Type 1 diabetes. And the reason for that study was at that precise moment there was an ongoing initiative to try to prevent Type 1 diabetes in siblings of children who were diagnosed under the age of 10. So, as you may know Type 1 diabetes starts often in childhood mostly in childhood and there is a familial risk.

27:02                           So the type 1 diabetes world had said well why is this going up. What’s changed in our world. And one of the things that has changed dramatically in our world is nutrition in the first year of life. Going back a couple of hundred years ago if you didn’t nurse successfully you didn’t survive because there was no pasteurization. So goat’s milk or cow’s milk that was unpasteurized almost always lead to dysentery and diarrhea and dehydration. So, pasteurization and the creation of formula has dramatically changed our infant nutrition. And so, in type 1 diabetes. The question was Is there something in cow’s milk protein that might drive some of the immune response that is part of the diabetes story. And there’s a reason I’m telling you all of this. And one of the reasons that they questioned that is that when you look at the proteins that are part of cow’s milk there’s a portion of that it was called bovine serum albumin that is very similar to proteins present in the pancreas.

28:02                           And so the question was Is this a mistake of the immune system. It was given a protein that wasn’t necessarily evolutionary ready to receive as an infant the immune system responded and then made a mistake and attacked a similar protein in this case in the pancreas. And so since that.

28:17                           Kind of fascinated me I thought it would be interesting to see whether there was any cow’s milk protein story in children with multiple sclerosis because if you look across bovine serum albumin there is a portion of that cow’s milk protein that is almost identical to myelin basic protein which is a protein that covers myelin and I thought that might be very interesting so turned out that in fact that was true there were children who had immune cells that vigorously responded to myelin basic protein whether they had MS or diabetes and they responded to this particular part of cow’s milk. So, we thought we were really clever we thought this was going to be something very very innovative. And then we thought well we better have another control population. So, we looked at the immune responses to children that had epilepsy surgery. They had no inflammation at all.

29:02                           They do not have M.S. they don’t have NMO they don’t have a diet certainly don’t have diabetes. And they had the same responses which was a humbling reminder that everybody in this room probably has some immune cells irrespective of your diagnosis that respond to proteins that you’ve been exposed to. Some of those in nutritional some of them may be in your brain. Some of them may be your pancreas. The key is whether those responses drive disease or whether they’re just a normal immune response to proteins that your immune system has identified. That’s the trickiest part of where we’re trying to go. What’s driving disease versus what’s just a normal experience of being human in a human environment. So, we’re still. Now that was 2004. We’re still trying to figure this out. Not for lack of effort.

29:46                           And I think progress is being made. But it remains an ongoing challenge and that’s what I think is happening here in the immune response to some children with ADEM, it is transient. It is not driving further disease and it probably didn’t cause the episode. If I could predict I think the children with ADEM the response was after the inflammation not what caused it but that needs to be proven. And again, depending on who you study these antibodies are definitely present in a number of people. And in fact, on Tuesday I will be sitting down with a group at a meeting in Europe. There’ll be about 100 of us from 40 countries in the entire day is going to be spent on MOG and what it means and what we should do about it. So, this time next year I may have a little bit more information from an international point of view.

30:32                           I’ll skip that for the interest of time. So, at this point most people with MOG antibodies do not have multiple sclerosis. Some have a neuromyelitis optica story and seem to be treated similarly to patients with neuromyelitis optica which is important. We don’t know what the antibody actually does in the brain at this stage. We don’t know what it binds to other than obviously the covering of myelin but does it really lead to loss of myelin and that’s not yet fully understood and how we should treat just based on that blood test is less clear than it is for patients with Aquaporin 4 antibodies and classic NMO where that Aquaporin 4 antibody very clearly indicates that you’re likely to have relapsing neuromyelitis optica.

31:12                           So there’s another story. And don’t worry about the slide but there is a disorder called NMDA Receptor encephalitis. These are proteins that are present in the brain. And this is if anybody read the book “Brain on Fire”. Nobody.

31:29                           OK. So, one or two people so “Brain on Fire” is a book written by a woman who has recovered from NMDA receptor encephalitis and this is an illness where. Previously healthy completely normal individual suddenly gets confused often becomes quite psychologically unstable seeing things hallucinations agitation abnormal movements and can progress into a state of being completely unresponsive to the normal environment. It is a horrible disease to see happen. When this was first being described nobody knew what it was and I don’t think anybody realized it was immune. However, in actual fact it is. It is an immune illness. Patients have antibodies to this particular brain receptor. We now treat these children on young adults with immune suppressant therapy and a lot of intensive care. Some of our patients are ill for two years. So, the most recent patient a wonderful young man that both Sarah and I know well spent two years in our hospital.

32:26                           Most of it. Completely unaware. I hope of his environment given that he was really incapacitated with these abnormal movements. Could not speak could not see could not respond last time I saw him after he. This is an illness that once you start with the recovery phase it then becomes very quick recovery it’s like they snap out of it. Last time I saw him was reading a book on civil history Civil War history and is now starting the first-year university is amazing journey to see it is a illness that if you didn’t know that two years down the road this child can be completely normal. You would wonder why you were doing all the things you’re doing it is so hard to watch. But he’s now perfectly fine and educating me on U.S. history.

33:10                           So I mentioned this disorder because it’s starting to overlap with some of the disorders that we see including MOG antibodies some patients that have NMDA receptor encephalitis then go on to have an episode of what looks like ADEM and have MOG antibodies and there is a group of children and maybe adults but particularly children who have herpes simplex infection.

33:32                           Clearly an infection. And then after they recover from the infection they get NMDA receptor encephalitis. And this is really bridging the whole story between immune directed brain inflammation infection and then an immune response following infection and ultimately the potential of having more than one antibody related disease. And so, we are learning real time about following these kids and making sure that we really look after this immune response because they do very well ultimately with quite intensive therapy. Moving on. I don’t know how much time I have. So, if I have one or two more stories to tell you if we have time. So, if not been can we but me. So, this is a 14-year-old girl who came in with optic neuritis. And as always, the case. Not everything that.

34:20                           We’re OK with Optic Neuritis to her she responded to corticosteroids as many patients do. Her vision returned to normal. She had an episode of seizures. Now most patients with Optic Neuritis do not have seizures. So that was a red flag we were dealing with something else. She kept having episodes of optic neuritis. So she would recover happened again. Recover happened again and this is what her brain MRI looked like. You can see these patchy areas of bright T-2 signal sitting mostly in what’s called the cortex or where our neurons live. Not so much in the white matter. So this was already a red flag. And then I don’t think it’s projects but she has areas of enhancement again in these in the covering of the brain and that lead to a brain biopsy to prove her diagnosis. And she has Small Vessel Vasculitis. So here the immune attack is actually on blood vessels. And this is a blood vessel. For those of you who have not taken anatomy This is a project. Oh good. OK. So these are blood vessel cells.

35:16                           The little purple circles are immune cells that are going right through the blood vessel wall. And then this bright pink stuff is what’s called hyalinization. And what that means is these cells are injured. So, this is an “itis” it’s an inflammation of the blood vessels. This is a treatable disease. This is another patient. Lots of inflammation. Everything purple should not be there. And she is now. This is all change on her MRI. She’s now doing really well clinically. You can see some brain volume loss and that is a consequence of this illness. But she is no longer having headaches she’s had no further optic neuritis episodes and she’s now more than two years after her last dose. At this time, we were using cyclophosphamide many people now are trying rituximab. But this is a vasculitis the only way to prove the diagnosis unfortunately is to actually get a piece of tissue with abnormal blood vessels so it’s a challenging diagnosis to make but very treatable if you actually have the correct biology.

36:11                           So I’ve mentioned it because it is on the differential and something that you have to look for.

36:18                           And then there are different vascular disorders that sometimes can mimic the story including these are this is a child with inflammation of bigger blood vessels so this is now called Angiitis. Bigger vessels. This is a child with sickle cell disease. Just to remind us that lots of things can get bright white spots in the brain and they’re not all neuro immune conditions. This is this is sickle cell disorder and this is a mitochondrial disease. So, a metabolic disorder and this is a disorder. Again, I won’t make you all become not only neurologist but neuro immunologists as well. But I put this slide up just because it is also a reminder that we can see very similar appearances with very different diagnoses and this is a disorder that’s called Hemophagocytic lymphohistiocytosis. And I have practice that many times.

37:05                           This is a genetic and in most cases, this is a genetic disorder that then drives abnormal immune attack in the brain. And what’s interesting is it’s triggered by Epstein-Barr virus in almost all patients and as many of you may know there’s a lot of interest in Epstein-Barr virus is one of the things that may trigger other neuro immune disorders particularly multiple sclerosis. So, this is a story that again is going to teach us a little bit about the interaction between the environment infection our genetic makeup and risks and our immune responses to that combination.

37:35                           And I’m going to skip this case in the interest of time because this is a little girl who does indeed have a metabolic disease. And I’m going to skip over that but this is one of the genetic disorders that we look for as pediatric neurologists when we see children with unusual patterns of brain inflammation. And so, I just won’t tell you what my last patient. This is a little boy who has inspired me every single time I’ve seen him. He was adopted at 18 months of age out of an environment of neglect. And so, his adoptive parents assumed that his lack of language low muscle tone and inability to walk was based on this horrific environment that he had been living in. And they worked with this little guy and by the time he started kindergarten he was almost caught up and he was doing really well and he has a wicked sense of humor.

38:21                           He then developed what looked like ADEM. He was off balance he became somnolence had lots of inflammation in the brain treated with steroids. This is before I met him at this point and did great to as many children. 97 percent of children with ADEM will recover very quickly with corticosteroids and he looked terrific. But then when I met him he came in with transverse myelitis and he this is not him this is a patient the same diagnosis but it illustrates Unfortunately his sort of appearance which is he has these bright changes. But he also has these areas of dark change within it which is very atypical for ADEM the spinal cord here is it. This isn’t my patient but it could absolutely be him. It’s the same story with this bright area in the middle. But these dark gray areas within that inflammation. And he actually has a mitochondrial disease.

39:08                           So he has transverse myelitis in the context of Metabolic Energy Failure Disorder. And you know he did not recover well from his myelitis although he is still improving. I have pictures of him. I wanted to ask parental permission to share with him I didn’t I couldn’t reach dad before I came of him at a camp that is held outside of Philadelphia where the kids go swimming he’s on a ventilator. He’s just he’s going to tracheostomy and the therapists and team get these kids in the pool they hand ventilate these kids while they swim. And you could not imagine a bigger grin on his face as he’s doing all these activities he went ziplining. I don’t quite know how but he in his.

39:46                           I’m never going ziplining but he went ziplining. And just last Friday he stood for the first time after being quadriplegic for more than a year. So, and he still has a wicked sense of humor and is an absolute flirt at all of nine.

40:03                           But just to remind you that not everything again that looks like transverse myelitis is purely immune. This is a very aggressive immune response to an underlying metabolic disorder. And I basically share that story because these kids keep me literally constantly vigilant to be sure that we look really hard at what might be going on because part of treatment for children with mitochondrial disorders is to try to improve their bio energetic health which is not something we normally would need to do in patients with myelitis and I’ll skip this. So.

40:35                           I have many more stories that I could tell but I think in the interest of time I’m going to move on to just comment on this.

40:42                           Do not try to memorize this is up here to tell you what your doctors need to do in that we share these algorithms as clinicians with each other just to say well how can we approach this problem how can we not miss a mitochondrial disease or a bio energetic failure disorder or a Lyme infection or an enteroviral infection and we have strategies that we share with each other. We have ways to group individuals and as Ben pointed out right at the beginning these groupings are to help us design therapy they are not absolute. There are so many shared features between the different disorders that one could make the case that really the grouping is rather arbitrary and we only do it if it guides better care. And again, this is busy on purpose. This is what our life is like when it comes to imaging.

41:33                           We have to look really closely and there are clues on the MRI to help guide us and these clues are shared and published so that even people working in centers that don’t have radiologists see a lot of normal conditions can recognize when they might be seeing one and seek advice from centers that do see a lot of patients with their immune conditions. And again, these are the type of things that we do and I’m not you know I put these on here even though knowing that this was a lay audience just to illustrate the point that we are careful and that the community of clinicians and investigators and scientists we know each other really well. I mean I think I owe Ben a beer from the last time that we all got together. We do sit and talk after these conferences we share what we’ve learned from our families and patients what we’ve seen in our clinics what we’ve done in our labs.

42:22                           This is a very open scientific and clinical care community. And these events for me I think are a wonderful opportunity to sit and listen to what is important to all of you care. And the sort of privilege not sort of the absolute privilege of being so involved in the lives of our patients is an imperative that the treatments that we bring forward the strategies that we use for rehabilitation have to meet the needs of the person that we’re working with and not always on the clinician side do we get that right. We don’t always know what it is that’s most important to each person we have to listen to that. And I think part of the day tomorrow as I understand it and certainly part of the afternoon today is to talk about some of the really important symptoms that I didn’t address at all but are extraordinarily relevant which are fatigue.

43:12                           You know quality of life cognition for some patients, pain for some patients, sexual health for some patients, every single one of which drives how you experience this illness and they’re just as important as everything I just said in terms of diagnosis and acute immune suppressant therapy. So on that I will thank you for your kind attention. I hope that I didn’t put any of you to sleep and I hope you enjoy the rest of the symposium.