Autoimmune Encephalitis: A Practical Guide to Diagnosis and Management

Podcast Transcript

Introduction: 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:

Over the past few years, our understanding of autoimmune encephalitis, an umbrella term for a group of non-infectious inflammatory central nervous system diseases, has dramatically expanded. Prompt diagnosis and treatment hinges on clinicians' familiarity with the conditions.

In today's episode of Neuro Pathways, we're discussing a practical approach to the diagnosis and management of autoimmune encephalitis. I'm your host, Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to have Dr. Amy Kunchok join me for today's conversation. Dr. Kunchok is a neurologist in the Mellen Center for Multiple Sclerosis Treatment and Research within Cleveland Clinic's Neurological Institute. Amy, welcome to Neuro Pathways.

Amy Kunchok, MD, PhD:

Thanks, Glen. It's great to be here.

Glen Stevens, DO, PhD:

So just as a start, just so our audience can understand you a little bit for just a little background, tell me a little bit about yourself. Tell me how you got to the Cleveland Clinic, how you got interested in the area.

Amy Kunchok, MD, PhD:

I've been interested in autoimmune neurology for several years, during my training in Australia. And then after my neurology training I went to the Mayo Clinic for fellowships in autoimmune neurology and also in MS and neuroimmunology. After completing those fellowships, I joined here as staff at the Mellen Center and my clinical practice involves a mix of autoimmune neurology as well as multiple sclerosis.

Glen Stevens, DO, PhD:

Great. It's great having somebody interested in autoimmune encephalitis so we're glad that you're here and have a specific interest in it. The differential diagnosis of encephalitis is very broad. What should prompt clinicians to further examine a patient for autoimmune encephalitis?

Amy Kunchok, MD, PhD:

I think it's really important to think about the clinical presentation and whether you have supportive data. So clinical presentation would typically be a subacute onset of neurological symptoms such as cognitive impairment, seizures in particular, and sometimes psychiatric symptoms. Those are sort of key common features clinically. And then supportive clinical data could be things like spinal fluid that shows a pleocytosis, or elevated protein, or an MRI that shows features of classical limbic encephalitis with T2 flare, hyper-intensity of the temporal lobes.

Glen Stevens, DO, PhD:

You mentioned it just a little bit, but what does a comprehensive evaluation for suspected autoimmune encephalitis include? What would you work up?

Amy Kunchok, MD, PhD:

We would typically do a spinal fluid. And in addition to doing routine analyses, we would send it for neural antibody testing. So looking for antibody biomarkers for autoimmune encephalitis. We would often send the spinal fluid for differential diagnoses such as infective encephalitides, so setting it for routine infective PCRs. Other markers in the spinal fluid that are helpful are things like oligoclonal bands or IgG index, which can also point to intrathecal immune activation.

In the serum, we also send neural antibodies and we also look in the serum for other differentials. We make sure that patients have a complete blood count, metabolic panel, any other screening that may be relevant for an alternative diagnosis of encephalopathies. In some cases, that may mean toxicology testing, B12, folate, thyroid function tests, et cetera. Other tests that we routinely do include a EEG if a patient has new onset seizures. This can also be helpful also to identify encephalopathy and an MRI of the brain can be useful to look for the classical features of limbic encephalitis as well as other inflammatory changes.

Glen Stevens, DO, PhD:

If I had a patient and I was thinking about doing antibodies, would I check both serum and CSF, or just one of those?

Amy Kunchok, MD, PhD:

Great question. Yes, we generally recommend that patients have testing in both serum and CSF, and this is because it increases the sensitivity and specificity of your testing. There's some neural antibodies that are more sensitive in the serum but lack specificity and the spinal fluid can be much more specific for some antibodies, in particular, NMDAR IgG, and GFAP IgG are much more specific in the spinal fluid, GAD65 as well.

Glen Stevens, DO, PhD:

What about checking patients routinely for CT of the chest, abdomen, pelvis or a PET scan? Is that an overkill or only if strongly suspecting cancer or do you routinely check that?

Amy Kunchok, MD, PhD:

I think that the neural antibodies can guide you somewhat. There are neural antibodies that are highly associative paraneoplastic neurological syndromes. Some of these might be ANNA1, or anti-Hu, Ma1, Ma2, PCA-1, or anti-Yo, some of the classical onconeuronal antibodies. These ones are almost always seen in the setting of cancer. So in those patients, yes, I would recommend malignancy screening. There are some neural antibodies that have lower frequencies of malignancy. An example might be LGI1. We still typically often do screen at the first evaluation because often when we are first evaluating capitis, we don't have all the neural antibodies back, but you may triage further screening after you get those initial neural antibodies and decide whether you need to continue surveillance depending on the risk.

Glen Stevens, DO, PhD:

Yeah, so I think that's a very important point that you just raised. How long does it take for the antibodies to come back? Are these done in-house or they're all sent out?

Amy Kunchok, MD, PhD:

Yeah, the antibodies that we test for at Cleveland Clinic, the samples get sent to Mayo Clinic, and the turnaround time is between one and two weeks. So often, we do have to make clinical decisions before we get those results back.

Glen Stevens, DO, PhD:

Yeah, this is probably the point that I always discuss with the residents that we need to have a high index of suspicion because by the time we get the antibodies back, maybe we've lost a window of opportunity. So what would we do as initial treatment if we have a high suspicion for autoimmune encephalitis?

Amy Kunchok, MD, PhD:

But typically the first line treatment that we start in patients is intravenous methylprednisolone, and we would typically start at a gram. And give this over five days, a gram a day for five days. That would be our first line treatment while we're waiting for results to come back. Depending on the severity and the clinical suspicion, you may also add adjunct therapies. So sometimes we have a case that we're confident about the diagnosis and the patient is also in a severe clinical state. We may consider things like plasma exchange. And additionally, other therapies that we sometimes use as an adjunct to steroids include intravenous immunoglobulin.

Glen Stevens, DO, PhD:

So sometimes residents will ask me, "Can I use oral steroids versus intravenous methylprednisolone?" Any difference? Do we have any data on that?

Amy Kunchok, MD, PhD:

Not certain we have any specific data on that question, but generally, it's much more easier to give patients intravenous steroids, to give the equivalent dose. Oral is a huge pill burden, approximately 25 tablets a day. And so there can be also challenges of absorption. And further, some of our patients are severely encephalopathic and we can't reliably give them oral therapies. So more often than not, we would elect to treat with intravenous steroids.

Glen Stevens, DO, PhD:

So someone that's listening to this talk that is at a center and they're thinking about sending out for antibodies, should they just pick and choose the antibody they like or should they have confidence in the panels that are there a la carte, off the menu, or how do you feel about the panels?

Amy Kunchok, MD, PhD:

I think in the United States, most of the laboratories offer panel testing as opposed to individual antibody testing. It's probably different in different countries what's available. So I can speak mainly to what's available to us in the United States. I think the advantage of panel testing is that you do get to all of your results immediately and there's not sort of a second round of testing that needs to be done if you get initial negative results with just a few select testing. So we typically use the autoimmune encephalopathy panel that gets sent to Mayo Clinic. There are similar panels that go to laboratories and also other laboratories, such as Quest.

Glen Stevens, DO, PhD:

So we have a patient, have a high suspicion, treat the patient. How do we assess the effectiveness of the treatment that we gave?

Amy Kunchok, MD, PhD:

So we use our clinical assessment to judge clinical response, and this is because we don't have all that great tests that we can use to longitudinally follow patients. So we usually judge based on their clinical symptomatology and whether that's improved. So someone who presents with seizures have their seizures improved. Cognitive impairment, we often assess these patients with, if they're able to, participate in cognitive screening and look at the results of these tests. So looking at clinical response is the main feature. Sometimes patients do have abnormalities on the MRI that can be tracked. You can follow up with an MRI at an interval, but MRI is less sensitive in encephalitis and there are patients that have grossly normal MRIs.

Glen Stevens, DO, PhD:

What about following antibody titers? Helpful, not helpful?

Amy Kunchok, MD, PhD:

Often, the titer doesn't necessarily correlate with the clinical activity. And so we don't tend to make our decisions based on the titers. We use our clinical judgment instead.

Glen Stevens, DO, PhD:

And I've heard some individuals will say that if a patient was doing okay and then sort of had a relapse of symptoms, you could repeat the CSF and if the IgG synthesis is increased, maybe that suggests some new ongoing neuronal abnormality. Any truth to that, helpful, not helpful to monitor?

Amy Kunchok, MD, PhD:

I think if a patient has a clinical relapse, it probably is useful to repeat a spinal fluid and look for evidence of inflammation. And that can be multimodal. So you could look at cell count protein and also IgG index or oligoclonal bands. But again, I'd put it together, these markers together, with a clinical assessment in addition to perhaps other tests such as an MRI altogether. So I would use my clinical assessment in conjunction with these other paraclinical markers.

Glen Stevens, DO, PhD:

So historically, one of the things that people have asked me about over time is voltage gated potassium channels. And I always cringe when I hear that. How often is that responsible for an autoimmune encephalitis or is it one of these true, true and unrelated?

Amy Kunchok, MD, PhD:

The very early testing for VGKC did identify that some patients do have limbic encephalitis and that's why it became a biomarker. But more refinement of this testing, mainly driven by the Oxford Autoimmune Group, identified that there are more specific extracellular antigens, which is LGI1 and CASPR2. And testing for these has much greater specificity for limbic encephalitis or central nervous system autoimmunity. So we generally recommend that if a patient comes to our clinic or the hospital with VGKC positivity, and there's a question of encephalitis that we proceed with this further more specialized testing for LGI1 and CASPR2. And the reason is that VGKC has been shown to be not very specific and we can see it in other neurological disorders such as neurodegenerative diseases, but also in non-neurological conditions.

Glen Stevens, DO, PhD:

Now, when a patient first presents, the assumption is if they have a autoimmune encephalitis, it's going to be a cell surface process of which steroids and IVIG may be more helpful. But if it's an interneuronal process, then maybe these are less helpful. But I guess you don't know upfront, right? You just treat everybody the same until the markers come back.

Amy Kunchok, MD, PhD:

Yeah, that's true. It's often difficult to distinguish initially, clinically between patients. Patients with intercellular antibodies, we still do tend to try treatment, but it is true that they may be less responsive to these types of immunosuppressive therapies.

Glen Stevens, DO, PhD:

So where's the research in the field going? Anything hot going on? Anything new, exciting?

Amy Kunchok, MD, PhD:

Yes, I think there is some new developments in autoimmune encephalitis, mainly in the field of therapeutics. And we have now three randomized control trials planned for autoimmune encephalitis, which I think will generate a lot more understanding both of the conditions but also of therapeutic responses in these patients. So there are three therapies that are currently going to be opening or have just recently opened for randomized control trials. The first one is a study, the ExTINGUISH trial led by Dr. Stacey Clardy in Utah. And this is a trial for anti-NMDAR encephalitis. And in this population, the trial drug is Inebilizumab, so that's an anti-CD19 therapy. And the theory behind this therapy and its potential efficacy is that it targets anti-CD19, which has a broader expression throughout B-cell development than just anti-CD20.

So that's one interesting study. The other two studies that are opening at the moment are, there's firstly the CLO trial, which is using certolizumab, and that's an anti-IL6 receptor blocker. And this trial is going to be in patients with anti-NMDAR and encephalitis and anti-LGI1 encephalitis. Then the third therapy, which is of interest is rozanolixizumab. And that's a little bit of a mouthful. And this therapy is going to be trialed in anti-LGI1 patients. And this is a interesting therapy that's been shown to have some efficacy in myasthenia gravis. It's an anti-FCR receptor blocker, so it prevents IgG recycling and leads to unbound IgG being eliminated. And the advantage of this therapy is that it doesn't cause widespread immunosuppression. And this therapy is also planned for a trial in MOG antibody disease as well. So some interesting therapies. I think that these may change somewhat of our understanding of these diseases, but also perhaps our therapeutic approach.

Glen Stevens, DO, PhD:

And how many of these trials are we going to look at opening at the Cleveland Clinic?

Amy Kunchok, MD, PhD:

We're going to be a site for the CLO, or certolizumab trial, as well as the … which is the rozanolixizumab trial. And we won't be a site unfortunately for the ExTINGUISH trial because we're not part of the NeuroNEXT network.

Glen Stevens, DO, PhD:

And maybe I should have asked you this question at the start, but what percentage of the population or neurologic patients do we see that have autoimmune encephalitis? How common is it?

Amy Kunchok, MD, PhD:

Still quite rare. I think the population based studies have estimated about one per 100,000 in population based studies in the United States. So still a fairly rare disease. But similar to the incidents and prevalence of infective encephalitis, of course, over time studying rare diseases is hard and to determine the exact prevalence and incidence. But we do think that over time we're having greater recognition of these disorders and they are important therefore to target and treat these patients.

Glen Stevens, DO, PhD:

Yes, it seems that whenever I'm on hospital service, it seems very prevalent in terms of the thought process. But of course the reality is much, much less. But if you don't think about it, you'll never diagnose it, of course.

Amy Kunchok, MD, PhD:

Yeah, that's true that probably we also need to temper our enthusiasm for looking for these disorders and make sure that we always consider that common things are common. And particularly in the hospital service, there are many other causes for altered mental status other than autoimmune encephalitis.

Glen Stevens, DO, PhD:

So any last practical tips you'd like to share with our audience?

Amy Kunchok, MD, PhD:

I think the main thing, just thinking along that point of common things are common, is just to think when we're evaluating patients acutely, particularly in the hospital service, to make sure that we are very careful and judicious in looking at differential diagnoses and not overcalling the diagnoses. So a patient with alter mental status, it's important to think through if there are any metabolic causes, toxic causes for the encephalopathy, as well as other differentials. So sometimes, there can be mimics on MRI imaging, so tumors or mitochondrial disorders that can also mimic these types of inflammatory changes on MRI. And then finally, I think neurodegenerative disorders and primary psychiatric disorders can also sometimes mimic clinical presentations of encephalitis. So just keeping an open mind and making sure that we're very judicious about diagnosing these patients.

Glen Stevens, DO, PhD:

Yeah. I'd like to just give a shout out to a article that you published in the Cleveland Clinic Journal of Medicine in 2021, volume 88, where you did a review of autoimmune encephalitis. For those that are just chomping at the bit to get a little bit more information, they can look that up and provide some additional details. So Amy, thank you very much for joining us today. I always learn some additional things when I talk with you. I'm excited about the fact we've got some research trials going on here and also nationally for this. And look forward to continued collaboration with you. Thank you very much.

Amy Kunchok, MD, PhD:

Thanks very much, Glen.

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