Andrew McKeon, M.B., B.Ch., M.D. , a neurologist with the clinical Neuroimmunology Laboratory at Mayo Clinic in Rochester, Minnesota, presents a summary of autoimmune central nervous system (CNS) disorders and Mayo Clinic's approach to the evaluation and management of patients affected by these disorders.
So my name is Andrew McKinnon. I'm a director off the Neuro Immunology Laboratory of Mayo Clinic and also a consultant in the Department of Neurology. In the Autumn of Neurology Clinic, I'm going to present a summary of ultimate and central nervous system disorders and the approach we take to the evaluation and management of patients affected by these disorders of mail. So automated central nervous system disorders, these air neurological disorders caused by an operated immune response. So you might think of multiple sclerosis in that situation when I mentioned that. But unlike M s, there is a specific antigenics that is affected is the target of the immune response in these patients. Thes disorders may be triggered in the setting off cancer, where there is a nervous system protein expressed in the concert that results in a new appropriate immune response against the concert. But you get some aberrant immune response against that same protein and the nervous system. There are also examples of power infectious autoimmune neurological disorders, how such as and get embrace syndrome, but also more recently with post HSV NMD, etcetera, encephalitis. But the majority of patients we see with these disorders the trigger is unknown. Many of these patients have auto immunity in their background, but the precise trigger and why it occurs at any particular moment a lot of the time is unclear that these disorders air unified by one one arm or antibody biomarkers in serum or spinal fluid. So how did the patients present? Typically, these patients present with have self acute onset symptoms of meaning that symptoms that evolved over days to weeks. So not over seconds, two minutes like and stroke and not like him, insidiously progressive over months, years like you might see in Alzheimer's disease. But something in between. Sometimes these patients are very rapid progression, though in other situations. Have a fluctuating course on these disorders can affect any neurological domain. And so, um, really, anywhere from cortex to see fibers. Andi Some of these disorders fall into a category of a classic Latina types, such as Olympic and satellite ISS. But then you may have a typical FINA types where cases don't quite fit into that classical textbook pattern. Such a Ziggy FP on from units, apple itis and then, in some circumstances, you kind of patients of multifocal disorders where this is not a classical presentation for any disorder. And with that sub acute aren't that. And with a combination of different levels of the nervous system involved, auto immunity or perennial plastic disorders may come to mind. So an example of that would be a patient with sudden onset Korea late life, no family history but also answered of neuropathy at that time. So in terms of the levels of the system and the associate, ID disorders were referring to encephalopathy at the cortical level, but also epilepsy and some patients with more of a rapidly progressive dementia. FINA type optic your itis written off with the basic idea of disorders such as moving disorders, a taxes and then in the A to brainstorm level. Then tu propia and a tax here, a spinal cord level in my lap of these are my like this. And then there could be some patients with my alone Europa. These sometimes party positive disorders can present with lumbar sacral ridiculous off of these Europa. These classic example is a sensory neuropathy that we see and, um in paranoia plastic disorders with small cell lung carcinomas, sometimes gynecologic cancers. We don't see patients with Ailes type presentation that tends to be exclusively into Jennifer disorder, though sometimes patients are referred because they have kind of been encephalomyelitis body of unknown cause and people are thinking onto your hearts out diseases on the list. Eso Sometimes it's a different they're they're It's a disorder that you have to differentiate from a l s on, then neuropathy these myopia these and then neuromuscular Junction Junction disorders such as my senior gravis and number even syndrome. So why do these disorders occur? Well through the examples were imagined and one of my previous slides. But just to delve into a little bit of detail here is faras um uh huh. Prototypical disorder of cancer related autoimmune neurological auto immunity weaken green a little bit about the path of physiology and also a little bit about how these antibodies service biomarkers and also have they may actually be disease causing themselves. So these IgG antibodies air generated in the setting of a T cell mediated disorder than you can have developed, decided toxic T cells would. You also may have development off B cells and then be cell maturation after stimulation by the T cell arm, and then you can have a variety of antibodies with different effects. But on the green side over here, this really emphasizes proteins that are the antigens that our interests editor. So there in the nucleus, cytoplasm, or sometimes the nuclear olis on the protein is degraded in the Proteas OEM. And then you get thes poly peptides that are expressed on MHC class one on the cell surface, and then these air recognized by side of toxic T cells rather than antibodies themselves. But in this whole milieu, if there's immune response, so you still get antibody generations. So these antibodies, they're still there. They're still robust biomarkers of whatever this particular responses. So this protein here could be a party peptide sequence from Hugh Protein and on a one on community, or say my to a zone example. But really, the kind of the main players here are the site of toxic T cells and we see that pathology eso antibodies. Why not disease causing in this scenario are still very good biomarkers in the lab. On the other hand, you have examples off here of auto antibodies and their potential pathogenic effects, where you have a cell surface receptors so not not in the side of positive in the nucleus or the nuclear noticed, but where you have these part of the protein expressed on the south surface and the the three dimensional structure off the protein as it is in the vote becomes important on DSO These antibodies air not directed against, um, linear rapid talks like we saw over here before these three dimensional laptops on examples of that include NMDA receptors, aka born four water channels on the's. Antibodies can have a swell has been called by market in. The lab can also have a role in disease. And there's more and more data coming out on that for various diseases, including NMDA receptor encephalitis, where down regulation of the receptor is important. Um, but in the other scenario, you could also have antibody activating complement and causing a lot of inflammation like a near my life is optical, where the water channel, aka form forest, targeted. So that's just to give you kind of a broad overview of the Papa physiology and the antibodies. Um, I was kind of broad groups, but the disease categories to consider are as follows in the these patients and staff a lot of the other typical limbic encephalitis or some other examples that would come to some patients with a kind of a more of a dementia FINA type that might mimic CJD epilepsy. Where it's It's a limbic encephalitis type presentation in some situations, but the person presents exclusively with seizures, and then you can have your My life is optical spectrum disorders, thes inflammatory disorders of the optic nerve and spinal cord dynamic multiple sclerosis. Ultimate movement disorders such as Korea's, for example, associated with crime. Five paranoia plastic mile up with these, such as associated with, um, again print five or Anna one anti you and then a variety of different Europe. These either paranoia plastic or idiopathic, some of which are responsive to immunotherapy, such as Casper to auto immunity and others that are a party responsive to immunotherapy, such as on a one or antique you. And then you have my senior gravis and number T syndrome, which are the Neuromuscular junction disorders, either post synoptic or pre synoptic on then myopathy, such as advertising autumn in my office. So the risk factors are sometimes they're non existing, but there can be clues. For example, in God 65 neurological community, such a stiff person syndrome or taxes or animo near my lighters. Optical patients very commonly have a history of autoimmune disease already established, and so asking about that asking about a lot of our community and the family could be can be helpful, a swell and then for a perennial plastic disorders, cancer history and smoking history could be important. Also, patients where the the person comes down with sub acute onset neurological problem on the cause is not immediately apparent. It's also important to focus on symptoms such as preceding flu like symptoms that might be a clue to a systemic infection. That, then is results in a post infectious inflammatory state. And some situations there are are antibody biomarkers. We find that scenario so evaluating further. So there's two parts to this. You know, it's really important to document the neurological examination, doing mental starters testing, for example, neuro psychometric testing, brain imaging electrophysiology has appropriate and all of these air really targeted towards the phenotype that's determined from the history in the exam. So it's so important then to think about okay, what are the kind of the basic kind of tests that we should be doing for that particular FINA type. So self acute onset neurological disorder copy resulting from things like that are very straightforward, like vitamin B 12 deficiency or fold a deficiency or or some other metabolic problem on. Then moving on to auto immune disease, we can think about close to auto immunity, such as tired antibodies, connective tissue disease antibodies and then mawr specific Reza Terry testing near a lot of antibodies in the serum or CSF, and then these other markers proteins, Alcantara, I. G. Index and synthesis right in Hollywood, clone bands could be very useful as well, so these are typically we think about these things in multiple sclerosis. But these can also be very helpful in for other inflammatory disorders of the nervous system such as autoimmune, apparently plastic disorders. So thinking about the auto antibodies themselves and these two kind of broad groups watery. What are we talking about? Well, these green ones where I was talking about earlier, where you have this side of toxic T cell predominant response, a lot of these fall into the kind of the groupings of antibodies that were originally described. These classical paranoid plastic antibodies. Small cell carcinomas. A big team here because small neo plasm essentially express a lot of neural antigens. And sometimes you can have a multitude of these antibodies positive in a patient with underlying small tell, you can see that there are some exceptions to this, including particularly for anti or PC, a one where it's many cancers of that affect women. On Ben, the I've highlights a kind of, ah, few other ones here, which were ones that have kind of a generally a pretty low level of cancer association. But they're still kind of fall into this bracket of a new antibody that's directed us a, uh, an interesting protein where decided decided toxic T cells and side of kinds and so forth they're likely have a big role in pathogenesis. So the but the other ones that I haven't highlighted in in in in that way typically have kind of a 70 to 80% positive predictive value for concert. In contrast, a lot of the synaptic auto antibodies have a lower, uh, cancer association such as our Jiwon Casper, too. We do encounter some occasional cases of time. MoMA under the concert ties but probably less than 10% overall. Andi. Similarly, for things like icing receptor antibody, DPP X, the ones that highlighted in blue here are kind of the opposite of what I just showed you. The other side. These actually have a stronger cancer association than the others. The NMDA receptors, amber receptors gotta be in particular. So how are the antibodies detected in the lab? So you've kind of determined your phenotype? You're kind of determined. Okay, The type of evaluation I might be thinking about here is faras on auto antibody profile for a particular disease states such as encephalitis. So when the when the serum or spinal fluid comes into the laboratory, then we have to determine what type of testing to dio. A lot of the the, um the different antibody Anna lights that we've that we've either discovered or brought in from labs elsewhere. Um, we've come really just evaluation a lot of different platforms to see which is the most often waited to test for a particular antibody. But in general terms, a lot of these plasma membrane protein expressed confirmation laptops. These three d appetites we talked about earlier Ah, lot of them are detected by cell based assays. Either observer based here or by flow Saitama Tree either is a screening test or by by or as a confirmation test on, then the real work horses, this tissue based on and off for us, since I say that you can see here the bottom. And so this is Matt's brain tissue. That's, uh, staying with the patient serum or spinal fluid. And then you have a a secondary anti human antibody. There's labor with the floor for, and you've got these different patterns of off staining of tissue. And so this is a very characteristic staining for PC, a one or anti yo that I mentioned earlier. And then there are other methods for detecting auto antibodies in the lab. Some have some pitfalls or Eliza radio community precipitation, essays. Um, so in particular context, these could be things can be helpful, but they sometimes can be problem, too. False positives, particularly kind of low, low antibody values. So examples if that will be saying, anti Cartoon Channel antibody, which we detect by a radio immuno precipitation. I'll say we can detect this and up to 2% of the general normal population, but at a very high value in a patient with Lambert Eaton syndrome, this is generally indicative of underlying small cell lung cancer. So so so so. My states require MAWR clinical interpretation than than others. And then an example of how we might detect an auto antibody by in a cell based are, say, in an automated format in the laboratories by flow Saitama Tree so typically flow. Saitama Tree is used, um, or has been used for detecting Auntie Jen so most people would be familiar with you. Give somebody rituximab, give a patient rituximab, and then you want to follow that C D 19 or C G 20 counts expressed on B lymphocytes. And so the way that's done is your. The theano light that you're interested in is actually the androgen. On the south surface of the B cells is C D 19 or C 20. Present on the detection antibody is a new anti commercial, anti C 19 or anti C 20 antibody. In this scenario, we're doing it the other way around. So where I think the is actually the antibody, that is what theano light of interest that we're trying to detect while the the, uh, the re agent that we're using to detect that is a cell that expresses either aka porn for or market protein and so that could be done by by doing the following. You have the cell population that's transacted with the protein of interest. And then this is labeled, um, with the patient serum or spinal fluid. And then you have a secondary antibody at that also gives off a signal on you can tell by looking at the different cell populations. Then watch your detecting here. And so in this example here, you're looking at at a negative spasm where you're not getting this anti human. I g signal at all. Where is in this one here you're seeing. Okay, I've got some population that don't express the GF pitak protein at all, and then I have this other population that do express it. But this population that does express it is also giving me this strong signal for the anti human secondary. And then you can express that has a as a as a fraction on give yourself in index. So reason I'm pointing this out is this kind of sort of a unique and novel way of using flow Saitama Tree for detecting auto antibodies on. That was kind of a high throughput, high throughput format on rapid turnaround time for clinical practice. So an example of how this kind of intersection between the clinical space and the laboratory space of male, um, has really worked for in a disease stage is normalizes obstacles. So these were kind of the the the the patients that the M S patients that, uh, people really had a lot of difficulty managing because it really they didn't respond to any classical Emma's drugs. These patients with animal would have attack after attack of inflammatory in your itis, object writers, or my life is. And when that would end up with very often with blindness and being wheelchair dependent, no matter what people did to treat them. But then, through some studies by Dr Wine Shankar and Dr Winger Chuck, it may Oh, these were clinically classified as distinct from from multiple sclerosis on. A lot of early clues were there, including the, um, the type of lesions that were seen on Emery Imaging and also the auto antibody associations in that these patients had a lot of pirate auto immunity and connective tissue diseases like Lupus. The doctor, Liu Canetti, observed that the pathology in these patients was different from multiple sclerosis and that there was evidence off, um compliment Cascade activation. Andi and political part of the compliment Cascade C nine deposit around blood vessels, which was unique as compared Toa multiple sclerosis. And then Dr Dr Lennon subsequently discovered in these original patients that have been described this particular auto antibody pattern that we news near my life is optical. I gig and then subsequently discovered that this was like a porn for G or an antibody against the ACA porn for water child on then. Dr Lennon also subsequently showed that the antibody had functional effects, including activation of the compliment cascade on DSO. Then there it was known that there were compliment inhibitors. Cascade inhibitors already out there for use in parks is a nocturnal hemoglobin area. So Dr P. Iraq and Dr Winger Chuck like this open level study in 2000 and 12, demonstrating a very promising effect from this. And then this was replicated in the Phase three Randomized control trial in 2019 was published in the New Wing Journal of Medicine. On subsequently, this drug became FDA approved. And so, like over the course of essentially 20 years, you went from orphan disease to a drug that could potentially cure patients. So that's what we really aiming to do in our in our clinical practice. A zit intersects from the from the face to face practice one side of Second Street in Rochester, on in the in the laboratory, setting across the street. So one of the other observations has bean over time as thes biomarkers that I showed you earlier. Aziz have begun to accumulate a number that's being increasing recognition of these disorders off autoimmune satellite is in particular on on when you take a population of patients in a new epidemiologic sense. Some decades ago, things would have broadly broken down into infectious, and satellite is accounting for the majority of cases automate, and satellite is accounting from minority on then. Also having this large group of patients with an undiagnosed or in satellite is of unknown cause. But this has changed over time. On essentially now infections and satellite is automated. Satellite is of a pretty similar incidence and prevalence. Andi, the number of unknown cases is dropping. And so, but this is really, we think, a reflection off case recognition on a lot of that probably has to do with increasing awareness because of a lot of publications around this, but also had diagnostic antibody markers in the laboratory. And so just to make a couple of points for for clinical practice about about thes auto antibodies under underutilization on DSO, there's an example of a patient with limbic encephalitis. This criminal flare Marie, and you can see that t to hyper intensities and the limbic regions, and you can see the types of symptoms of these patients have. But one principle that is important in the for these patients is a diagnosis that occurs quickly. So that's good clinical and radiological recognition, but also then serological confirmation. Onda. We find that a profile based approach is most helpful here, taking all of the auto antibodies that apartment to this particular presentation. Aunt testing for these At the same time, Why? Because time is brain in terms of getting patients on a UN attract for treatment as quickly as possible, being able to cancel patients as quickly as possible as to the likely outcome from this and also important they Can we diagnose a cancer in these patients, or do we need to be thinking seriously about cancer? And so a Z I mentioned earlier this this big differences between the cancer frequency and say, patients with van and one or algae. I want to Casper, too. So having this informational front, his is important. And so we don't advocate for testing for auto antibodies. Won't buy one for that reason. And then there are also we have to remember that there are some restricted form. So some patients who present with kind of more of an epilepsy or seizures predominant presentation, at least initially. So thinking about kind of the the other potential, um, presentations beyond living encephalitis thes air being increasingly recognized. And here's an example of GF Auto me and G F A P Astra site top of the that was described Mayo Clinic in 2016. So these patients have presentation arm or, like mimics, perhaps tuberculosis or sarcoidosis. Where you a lot of left, um, energia enhancement. But indeed, these patients have a nauta me in central nervous system disease that's very steroid. Responsive. Andi usually not accompanied by cancer, but can be in some in some circumstances. Other examples wouldn't that are outside of the kind of the realm of limbic encephalitis would include an empty A receptor encephalitis gather a receptor and satellite is where you have kind of more of a multifocal, um, cerebral hemisphere requite matter disorder with seizures and then also the neuronal intermediate filament antibodies. So an example of how auto antibody testing assistance in our clinical practice come is shown here. And so this is an example of auto means. Our battery taxi, where a patient presents with rapid onset desire three in coordination, gait, disturbance on the memory. They may have atrophy of the cerebellum, but on the face of it, if we didn't know anything else about this patient who might be quite difficult, even though we're suspecting all to me and to predict exactly what the outcome is likely to be from treatment and also about cancer to look for but in the laboratory way might see the PC a one antibody like I showed you earlier this anti euro anti body that I showed you on the kind of the laboratory techniques slide on that which is okay. This has got likely gynecological breast cancer. But also, unfortunately, the immunotherapy responses probably won't be very robust. And sometimes patients even progressed through those treatments to requiring wheelchair. But we might also see something different in the lab, even in a patient presents presents with like that. Initially, we might find this one or other of these antibodies like NWR one antibody and then stepped in five antibody we describe stepped in five antibody, and in 2018, you can see the standing pattern here in the lab. This is more of a synaptic type. Your appeal standing pattern that we see here, Um um in the in the cerebellum, particularly on this is distinct in the laboratory to what we want to show you earlier. That stains largely your own inside the plaza. And so the 75 patients generally don't have cancer. Andi also seemed to be immunotherapy responsive. And so the outcomes in these patients may be better than what we would see in the kind of the traditional perennial plastic A taxes. And so here's unexamined then, of how we might build out a profile of auto antibodies that are pertinent to a taxi? A in the lab. So patients serum or spinal fluid descent from the Ottoman Urology clinic across the street to the neuropathology lab Onda. We could see one or other of these different standing patterns that would lead us to suspect one or other of these particular auto antibodies. Onda, As you can see here, then we would, um, uh huh reflects that, then to a cell based assay in order to ensure that we get the right molecular targets to confirm of operas. Suspecting eso like what I showed for the limbic and satellite is earlier. We recommend, in this scenario, really taking a broad approach testing for auto antibodies in patients with suspected autoimmune attacks here. And here is the list off the various auto antibodies that air important here for free taxi. So for cancer screening, then that would largely be guided by either what's found in the lab by the type of antibody council for small cell lung cancer. Patient would probably be right that's suspected based on the antibody. Onda, somebody say that has had an award around. A huge detector would be pet ct on then, for a patient that has a gynecologic cancer suspected and a P C A. One or your patients would probably be, uh, ultrasound would transmit vaginal views are Marie. So then the treatment approach is largely around trying to establish. Is the person to Munich immunotherapy responsive what they're likely to respond to on? Then? What do we need to do, kind of going forward to maintain, Try to maintain that improvement or a mission so very often initially, were kind of thinking about. Okay, what is the objective measurements that we're going to bring to bear on the situation? And it might be an M r I scan or something in the neurologic exam. Then we're observing to see if there's any improvement in those patients and then considering an alternative treatment. If nothing, if that particular treatment does not work. If we do see improvement, then we might think about okay, is this sort of one where the person just completely roommates and we don't need to do anything further? Or is there a sense that this might be kind of relaxing course? Do we need to continue with kind of a fairly careful, uh, tapering off treatment? Do we need to consider adding in a steroid sparing medication for those patients who need longer term treatment. Aan den also thinking about some of the more novel drugs, such as activism mob that we mentioned earlier and in your my life is up to go. So the another thing that's very important in this situation is the time to treatment. So again, the importance of recognizing these autoimmune disorders, doing comprehensive evaluations quickly to try to establish the diagnosis and then also initiating treatment quickly on. So we have noted over time that really time is brain in the situation, not in the the hyper acute sense of stroke, but certainly kind of over the course of weeks. Um, it could really make quite a big difference how quickly a patient street and then we can kind of see some some things here. Some examples of objective measures by Marie on showing those improvements and how that can help so on the patients say, with a receptor encephalitis. You see improvement in the teacher signal abnormality in the temporal lobe, and then you, um, have similar things here, then for GF AP Astra side top of the where you have auto immunity and inflammation in the brain in a one and a two and the T to flare and the postcard Lindholm sequence. And then you see the resolution. But then when the steroids air tapered in this particular scenario, the patient relapsed, and you can see it here. Radiological e. But then they were treated with high dose steroids again on managed to have, ah remission and be maintained on the steroid sparing treatment. Only this Michael family. So the purpose of this side is to demonstrate that there are ways off predicting how come on thistle is an example of a scale devised by DR To Do Bay in our group whereby, uh, he devised this ape score based on a variety of different factors. That patient would have a presentation both clinical and on their testing, including the antibody test results. But the likelihood off, uh, the patient seizures improving with immunotherapy. And so this can be helpful because, as and when patients have intractable epilepsy on, there's a consideration of okay, should this person be a candidate for brain surgery to try and treat this or for some kind of neuromodulation or stimulation of the brain? Often patients are referred to us for consideration. Okay, Is this Could this possibly something autoimmune? Should we be thinking about immunotherapy? What's the likelihood of an immunotherapy response? So, in summary, these automatons, CNS disorders that they're important to consider because they do occurring clinical practice. So collectively they're more common than first believed has demonstrated by some of the epidemiologic studies that have been done. They're potentially treatable, but also may be indicative of a cult concert. The clues may emanate from history exam serum and CSF testing evaluations and response to treatment. Andi, I hope I've shown you how collaboration between a clinical diagnostic and development laboratory on a physical face to face clinical experience can really bring a lot to bear in terms of timely treatment time, the evaluation and treatment of these patients. Thank you.
