Autoimmune Neurologic Disorders: Treatable Conditions That Should Not Be Missed

Podcast Transcript

Intro: Neuro Pathways, a Cleveland Clinic podcast, exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD: Autoimmune encephalitis and other auto-immune neurologic disorders are increasingly identified causes of unexplained dementia and other neurologic symptoms. Their prompt recognition is important, as these disorders can often be successfully treated with steroids or more specific immunotherapies before permanent neurologic damage develops.

In today's episode of Neuro Pathways, we're discussing treatable auto-immune neurologic disorders that should not be missed. I'm your host, Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to have Dr. Amy Kunchok joined me for today's conversation. Dr. Kunchok is a neurologist in the Mellen Center for Multiple Sclerosis Treatment and Research in Cleveland Clinic's Neurological Institute. Amy, welcome to Neuro Pathways.

Amy Kunchok, MD: Thank you very much, Dr. Stevens.

Glen Stevens, DO, PhD: So, Amy, let's start off today's conversation and discuss the current state of auto-immune neurological disorders within the field of neurology and how it is developed over time?

Amy Kunchok, MD: Thank you. I mean, autoimmune encephalitis had many great advances in the field of autoimmune neurology and particularly for autoimmune encephalitis in the last 20 years, firstly, in recognizing the clinical phenotype of autoimmune encephalitis and then further delineating the associated auto antibody biomarkers.

We've now developed a greater understanding also of the pathogenesis of many of these disorders. For example, antiNMDA-R encephalitis we understand has an association with ovarian teratoma, but more recently, we've understood that there is an association with herpes simplex virus infections, suggesting post-viral-induced autoimmunity. Studies of HLA associations have identified that there may be distinct immunogenetic pathways for LGI1-IgG and CASPR2-IgG encephalitis and, further, by studying more recent developments of biological therapies, such as immune checkpoint inhibitors, we are gaining important insights into the development of central nervous system auto-immunity.

There are other disorders as well under the umbrella of auto-immune neurology, which include the more atypical demyelinating disorders such as neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein associated disorders (MOG-lgG1).

For NMOSD, which was first recognized approximately 20 years ago now, more recently we've seen great advances in the management of this disorder. There's recently been three randomized clinical trials of new immunotherapies, which have shown very good efficacy. And these will hopefully lead to improved management of NMOSD with fewer relapses.

I mentioned also MOG antibody associated disorders. These are increasingly recognized and understood and are often associated with ADEM optic neuritis, myelitis and encephalitis as a clinical phenotype. And there's been a huge amount of research in the recent years looking at characterizing the clinical, radiological and serological phenotypes of these disorders, as well as looking at clinical outcomes and response to immune therapies.

Glen Stevens, DO, PhD: So, Amy, what the folks that aren't at the Cleveland Clinic don't realize is that monthly you've been running a very interesting neuro immunology encephalitis conference where we've discussed cases on service. You mentioned the LGI1. There was an interesting case of the faciobrachial seizures recently. Can you talk about that disorder a little bit?

Amy Kunchok, MD: Sure. Yeah, that's right. We did recently discuss this in a case conference and we talked a lot about the faciobrachial dystonic seizures and the clinical presentation, how these seizures may involve even just subtle movements of the hand or arm. These can be dystonic-like movements. They can also involve facial movements. These movements are often so subtle at the beginning and can also have normal EEG, so there can be no epileptic correlate in some of these cases, which can make it difficult to initially recognize them. But this is a very pathognomonic finding for the LGI1 encephalitis.

We also reviewed in that case conference a lesser common phenotype of these patients was recently seen in some of our patients with pilomotor seizures, so where they have goosebumps. The patient we discussed had had some patients with bradycardiac episodes as well, which is an interesting phenotype, which is seen less commonly, but is described in LGI1 encephalitis.

Glen Stevens, DO, PhD: So some patients have a very classic presentation, but you know how it is when you're on service and the residents come up to you, and they say, "Hey, I think this patient may have some type of auto-immune neurologic disorder." What's the workup that we should do for these patients? Do we just order a big panel of tests? What's the sequence? How can you help our listeners?

Amy Kunchok, MD: Okay. Well, I think that the first test that we often do is an MRI and typically a common finding for limbic encephalitis would be the T2 FLAIR abnormalities in the mesial temporal lobe. So that would be a first step test, and EEG to look for either epileptic activity or sort of asymmetrical slow wave activities and other routine tests that we would do to start with. Spinal fluid evaluation is key, and we can look for things like a pleocytosis protein, elevated IgG index and oligoclonal bands. And, of course, the very specific neural auto antibodies can be tested both in CSF and in serum. The panel that we typically use here is the panel that is sent to Mayo Clinic, the autoimmune encephalopathy panel, which has a comprehensive test panel for the most common neural auto antibody biomarkers. So that would be the standard workup to start with for a patient that's considered to possibly have encephalitis.

Glen Stevens, DO, PhD: So if I look at the CSF and there are no oligoclonal bands and the Tourtellotte’s are not showing IgG synthesis, is it then not an autoimmune encephalitis? Or we can't say that?

Amy Kunchok, MD: I think that's a really good question. Although IgG index in bands typically tells us that there is intrathecal synthesis of IgG and indicates CNS autoimmunity, there are cases that are negative. We just talked about LGI1 encephalitis, and we did have some patients last week that we discussed that didn't have IgG index or bands present. So I think that if you have a strong clinical suspicion, it's still worth looking further, even if the initial spinal fluid is negative, to look further with the neural auto antibodies and some of the other workup I mentioned with an MRI and EEG.

Glen Stevens, DO, PhD: Let's move to treatment. So I see a patient, I have a strong clinical suspicion based on the disorder that they're presenting with. How soon should I start treatment, and what should I use?

Amy Kunchok, MD: Typically, the first treatment would be intravenous methylprednisolone. Typically, we'd give 1 gram for five days and we would give that early on essentially once you have a phenotype that is strongly suspicious for encephalitis, as early [immunotherapy] such as steroids is associated with better outcomes.

After the steroids, additional acute immunotherapies can be considered, and these would include IVIG and also plasma exchange. These would all be considered within the first week or two of a patient presenting as acute immunotherapies.

Glen Stevens, DO, PhD: So if you're sending off the Mayo panel, how long does it take to come back?

Amy Kunchok, MD: Roughly takes between one and two weeks to return.

Glen Stevens, DO, PhD: Okay. You know, I think we always teach the residents if you have a high index of suspicion, a couple of weeks' brain tissue, so always interested in considering treating earlier rather than delaying, for sure.

Amy Kunchok, MD: Yes, completely agree.

Glen Stevens, DO, PhD: So since we're in the time of COVID, I was on a hospital service about a week and a half ago and saw a young lady who presented with an acute syndrome that really on imaging showed enhancing lesion that looked like a demyelinating lesion and she had received the COVID vaccine the day before. There are a couple of other spots there and the question was, was this an ADEM or was this an unmasking of MS that was not yet presenting? Have you seen any of this? Have you read anything on this? Thoughts?

Amy Kunchok, MD: [9:24] I haven't seen personally any of these cases [of COVID with ADEM], but there are descriptions in the literature of [COVID associated] with demyelination, MOG-associated disorders, which I mentioned earlier, and of encephalitis in the literature, however these are small numbers. So I think it's something to consider.

Glen Stevens, DO, PhD: You know, I like the fact that I used to just think it was NMO, but I'm willing to learn new things. I'm glad it's now a spectrum disorder that's there and that we're moving forward and looking for the great things that you're doing as time goes on. So let's switch gears. Congratulations on your lead authorship on a recent JAMA Neurology article that had to do with rheumatologic therapies. Can you tell us a little bit about that?

Amy Kunchok, MD: Yes. This was a study I did at Mayo Clinic. We had seen in the autoimmune and multiple sclerosis clinics several patients who have autoimmune disorders that presented with either demyelination or other inflammatory events. And the question was raised often in our clinical meetings, was this associated or not with their TNF-alpha inhibitor use?

So we designed a study to try and examine this question, and we took a large cohort of patients that had both rheumatological and also inflammatory bowel disorders. Within that cohort, we identified patients that had seen as inflammatory events and then matched them [by] age and sex to a cohort from the same population and then look to see what proportion of patients had been treated with TNF-alpha inhibitors.

Interestingly, we did find that there was an association with TNF-alpha inhibitor use and the development of these inflammatory events, and the majority of patients that were treated with TNF-alpha inhibitors were treated within one year. 90% of those that had been treated were treated within one year of developing their inflammatory disorder so it wasn't necessarily a remote event.

However, it’s complicated because these patients also have a clear predisposition to auto-immunity. They already have an underlying autoimmune disorder, so it is a difficult area to study. But we concluded that it should be considered when you're evaluating a patient, particularly one of these autoimmune patients that is on these [TNF alpha inhibitor] therapies. The medication history is vital to be reviewed and to consider whether there is in that patient a history of TNF-alpha inhibitor use and an association.

But I think it's also important to remember that these are highly effective therapies. So we're not necessarily recommending that people stop these highly effective therapies in any way. Because these are very effective therapies for those disorders, and these events are probably extremely rare outcomes.

Glen Stevens, DO, PhD: Let's go back to treatment and I'm going to try and get off the auto-immune nihilism train and talk about outcome. Tell us some success stories, patients that are treated early and did well. Not everybody does poorly with these disorders, right?

Amy Kunchok, MD: For sure. In fact, amongst my current cohort of patients, we have several patients, quite a few, that either have LGI1 encephalitis, for example, that have done very well with steroids. Some of them have had to also additional immunotherapy, for example, rituximab, but they've done very well and have improved in their cognition. The faciobrachial dystonic seizures have settled down with immunotherapy and some of them have even returned to work. I have one patient that has returned to work within three months of receiving immunotherapy.

Additionally, also with anti-NMDA-R encephalitis, which is considered to be in some cases often a severe encephalitis, I have quite a few patients that have been treated very promptly within the hospital service, seizures have settled down and within a year several of our young patients have returned to study or work. Actually, I've got a patient that's completing a degree at present only one year after having antiNMDA-R encephalitis. So some very good outcomes as a result of prompt immunotherapy in the acute setting probably and as well as some longer-term immunotherapy.

Glen Stevens, DO, PhD: Excellent. I think it's just puts the onus on us to be excellent clinicians, identify the disorders and initiate the treatment early enough, so really appreciate that. What do you see on the next frontier in auto-immune neurology research and maybe even things that we're doing here at the Cleveland Clinic's Mellen Center?

Amy Kunchok, MD: Well, I think there's so much to be done for autoimmune neurology. It's a new field. There's so many different areas from the bench right to the bedside, research questions that need to be addressed. At the Mellen Center, the focus of the Mellen Center is very much on a comprehensive clinical care and providing patients with the opportunity to be part of observational clinical research as part of that routine clinical care. So what that means is when patients come to see us, they get comprehensive clinical evaluations and that data is used as part of clinical studies.

I think for some of the questions that really need to be looked at now, now that we've have very good diagnostic markers and there is greater recognition of these disorders, I think the next questions are about how to identify what is the best treatment? How long should patients be treated for? How can we predict outcomes or define a clinical outcome? How should we monitor patients? Are there good biomarkers of disease activity? For example, in multiple sclerosis and NMOSD, now we've seen that there are several good biomarkers to demonstrate clinical relapse, can we objectively define a clinical relapse using some of these biomarkers? This would help us a lot in the longitudinal follow-up of our patients. These are the kind of clinical questions that I'm very interested in and I think that the Mellen Center will be offering participation in research in these areas to our patients into the future.

Glen Stevens, DO, PhD: Well, Amy, thank you very much for joining us today. I really appreciate your time and insights and wish you the best. Thank you.

Amy Kunchok, MD: Thank you very much, Dr. Stevens.

Outro: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, ClevelandClinic.org/neuropodcast or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our consult QD website. That's consultqd.clevelandclinic.org/neuro or follow us on Twitter @CleClinicMD, all one word and thank you for listening.