Autoimmune movement disorders | Congress 2026

[00:00:25] Divyani Garg: let me begin by asking you, in terms of the autoimmune movement disorders, we are now recognizing a very large expanding spectrum of antibodies and also clinical phenotypes. So do you think that we are entering an era where the clinical phenotype is perhaps becoming less relevant compared to just recognizing the antibodies? Or do you think that careful clinical phenomenology is still the starting point of evaluation?

[00:00:50] Jerome Honnorat: It's a very difficult question because it's true that in the last years, we described a lot of new autoantibodies describing new disease that were totally unknown before. And at these times, it's one new autoantibody every six months, and we already described more than 100 autoantibodies, so it's a lot.

And all abnormal movements can be described in association with such autoimmune disease. But one very important point is that each clinical symptom is associated with a particular autoantibody. And so the clinical spectrum is reduced to particular subtypes that are associated with particular clinical presentation.

But for the clinician, it's not very helpful because you may have a large spectrum of abnormal movement that could be autoimmune. And the presence and the characterization of the autoantibodies are very important for two reasons. First, if it's positive, you can be sure of your diagnosis and propose immunomodulators to the patient to treat them.

On the opposite, if you have no biomarker, you cannot be sure of the disease and the role of the autoimmune system. And more and more, we are describing patients with normal CSF, without inflammation, that are clearly due to mechanisms of autoimmune disease. And so the lab and the characterization of the autoantibodies are very important, and it's important to have a reference lab able to characterize all the new autoantibodies.

[00:02:49] Divyani Garg: And just as another point related to that, you said that increasingly we are finding that there are patients who are antibody negative or who will have a normal CSF. So when we talk about movement disorders in relation to these antibodies, when you don't have an antibody, but you have a movement disorder which you strongly suspect is immune-mediated, we don't really have criteria or how to help the clinician to try to differentiate this. Because we have criteria for autoimmune encephalitis, but

for immune movement disorders—?

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[00:03:23] Jerome Honnorat: Even the criteria of autoimmune disorders that published with Frances Gross in 2016 now are not very accurate because a lot of patients have no CSF inflammation, have a very slow onset of the disease, suggesting neurodegenerative disease, and if you look at the clinical presentation of patients with CASPR2 or LGI1 autoantibodies, for example, in 40% of cases, these patients have not the criteria of Frances Gross published in Lancet Neurology. And so it's very useful for patients with acute autoimmune encephalitis or autoimmune encephalopathy to identify the patients, but these criteria are not efficient in patients with progressive onset of the disease.

And so I think that the most important is to understand very well the clinical presentation of the patients associated with such autoantibodies to think that it could be this diagnosis and to have a reference lab to be able to identify the autoantibodies. And for patients who are totally negative and tested in a reference lab, it's not so easy.

And we have to think and to define new criteria to be able to know if these patients could or could not be treated by immunomodulators. And the second thing is that it's a first step to say that if patients can be tested with a first line of immunomodulation to see if they can improve with that.

But the most difficult is after that. If we want to test a second or a third line, there are a lot of side effects, and so it's not so easy if there is no characterized autoantibody. So again, the lab is very important.

[00:05:26] Divyani Garg: And I think it's really challenging in these situations because you give the first-line immunotherapy, but after that the clinician is wondering whether to maintain the patient on long-standing immunotherapy considering the side effects. Do you think it would be helpful if there were some biomarkers that could tell us in these seronegative cases that there is a definite immune process happening just to guide the long-term treatment?

[00:05:49] Jerome Honnorat: At this time, there is no clear biomarker that can be used. But you can look at different markers of inflammation in the CSF, such as IL-10, IL-6, neopterin. You can look at the different biomarker of neurodegeneration suggesting a neuronal death that could explain what's happened, but to have the differential diagnosis with neurodegenerative disease is not so easy.

And so it's a number of arguments that could be used to qualify the patient. But again, it's very important to identify the autoantibodies, and we will speak about the very rare autoantibodies that have to be tested because you may have new syndromes in this subgroup of patients.

[00:06:41] Divyani Garg: Yeah. So could you elaborate more on that in terms of the newer antibodies or the rarer antibodies that have been identified?

[00:06:49] Jerome Honnorat: Yeah. So hundreds. So we cannot speak about all of them. And we have to be careful because one autoantibody can be described by one group but not tested on the right population to know the sensitivity and the specificity of the autoantibody. And so to admit that it's really a new disease and a new associated autoantibody, it must be described by different groups around the world.

And the methods to identify the autoantibodies are very important. And it must be also validated by different teams around the world. The second point that is very important is that, in fact, all the autoantibodies are associated with rare disease. One very important example is anti-Ri autoantibodies that have been described many years ago, initially in patient with opso-myoclonus and breast cancer.

It's a good biomarker of paraneoplastic syndromes. It's now defined as classical, but in fact, in France, among 66 million inhabitants, we identify only one or two patients per year. Compare with an NMDA receptor is 50 patients per year. The same level in patient with LGI1 or anti-Hu autoantibodies.

So, 50 patients among 66 million inhabitants, it's a rare disease. And one or two, it's a very rare disease. And so even the well-known autoantibodies that can be identified everywhere in the world are rare. So the new ones that have been described, we don't know exactly the incidence of these autoantibodies, but it's pretty much the same.

It's between 1 and 10 patients per year among 66 million inhabitants. So it's very low. And so the development of the methods and the methodology to identify these autoantibodies in one reference lab is very important because to measure the sensitivity and the specificity of one autoantibody, you must have positive and negative samples.

But negative sample is very easy. But to have positive samples to be able to validate your test is very important. And so I think that it is a world issue, to be able to exchange samples, to validate the test on different points around the world.

[00:09:34] Divyani Garg: I just wanted to ask you also regarding the testing, because we've been talking about the importance of having a reference laboratory to back up the findings, some of the antibodies... it's suggested that they may be false positives over-interpreted.

Can you just tell us a little bit about that?

[00:09:51] Jerome Honnorat: Yeah. It's a very important point because we have to be careful about the description of one autoantibody. There are many different methods to identify one autoantibody in a sample that could be CSF or serum. The initial description used specific methods. But some labs could use different methods and say that they are able to identify the same autoantibody.

It's not true. Because the sensitivity and the specificity have been evaluated with one method. If you change the methods, you have to specify the sensitivity and the specificity, and most of the time it's not the case. And so you may have, with some commercial test, a very high level of false-positive cases.

For example, we published few years ago that for YO2 antibodies, a commercial test produced more than 90 percent of false positive results because of the threshold and because also it was not the right antigen that was put in the test. So when you will say it for one patient a positive result, it's very important to compare the results with the clinical presentation.

If the clinical presentation is not that have been described in association with such autoantibodies, you must have some doubt about the true positivity of the autoantibodies and to ask about the methods that have been used to identify the panel of autoantibodies. It's also the case if it's negative to be sure that the test that has been used is enough sensitive.

You have to discuss with the lab and to compare with the clinical presentation of the patients. For example, if you have a patient with neuropathy and not ataxia, positive for YO2 antibodies, and furthermore, if it's a male, it's clearly a false positive and you do not have to take care of the positivity of the autoantibodies.

So again, the lab is very important. The lab must have a huge experience of the detection of autoantibodies. The lab must use different methods because it's not always easy. You may have one test positive and another test negative. To be able to propose different methods to identify the autoantibodies and at the end to say if it's a true positive or not.

[00:12:30] Divyani Garg: The antibodies give a clue towards possibly the underlying mechanism. So could you elaborate on these and is that relevant to how we treat patients eventually?

[00:12:39] Jerome Honnorat: I think that many years ago, we may have our idea that autoimmune disease was a huge group of patients with autoimmune reaction, and it was pretty similar, the mechanism. It's totally false. And now we are sure that according the associated autoantibodies, it's a specific mechanism of the immune reaction.

And the consequence is that the treatment must be different according to the patients. Clearly, we have at least two different mechanisms. One, according the target of the autoantibodies, if it's a membrane antigen or an intracellular antigen. In case of intracellular antigen, most of the times it's associated with cancer.

It's a paraneoplastic neurological syndrome. And the autoantibodies do not play a direct role in the mechanism of the disease. T-cells activated against brain antigens are involved, and the symptoms are related to neuronal death. And so the patients cannot improve completely with treatment, but we can stop the immune reaction and the spreading of the disease.

In case of membrane antigen, it's different. It's not always paraneoplastic. It will depend on the subtype of the autoantibodies. It will depend on the age and the sex of the patients. And the autoantibodies can play a direct role. The most powerful example is anti-NMDA receptor encephalitis.

In this case, the autoantibodies can block the interaction of the NMDA receptors with a protein called Ephrin B2 that maintain the receptor in the synapse, and after that, there is an internalization of the receptors, and so the inability to respond to the glutamate stimulation. In this case, we can treat the patients, and if the autoantibodies disappeared, you will have an improvement of the patient, and the patient can be cured from the symptoms.

So there is different mechanisms. We thought that LGI1 or CASPR2 could be the same mechanism. In fact, it's not exactly the same. And so we cannot have the same treatment and the same management of all the patients. It's the first rule. Another rule that is very interesting is that most of the time, except in patients with glutamate decarboxylase 65 autoantibodies, it's an acute immune activation.

And so the patient must be treated for a time, and not for a long time, because if it's acutely treated, you can cure the patient at the initial immune reaction to reorganize the immune reaction and to stabilize the patient. And so the treatment must be during a period of time and not along all the life of the patient.

[00:15:56] Divyani Garg: We have sometimes patients with a paraneoplastic antibody identified, but the cancer has not yet been identified. These patients would be initiated on immunotherapy, but they don't respond very well many times. What is your thought on escalating immunotherapy whilst we continue to do tumor surveillance in these patients?

[00:16:16] Jerome Honnorat: So you have to look for the presence of the cancer for a time of 5 years. Because we saw some patients that develop cancer 5 years after the onset of the neurological symptoms. Sometimes there is no associated cancer, and we have demonstrated that you may have, initially, regression of the cancer cells, and the patients can be cured only by the immune reaction.

And so you will never be able to identify the cancer. And so the patient must be treated, but again, you have to check that the immune reaction is still present. If there is no evolution of the patient, if the CSF has no inflammation, and you initially treated rightly the patient, it's not necessary to maintain the immunomodulation.

You have to discuss that.

[00:17:13] Divyani Garg: I just also wanted to ask you regarding immune checkpoint inhibitor-related autoimmunity, because these cases are now being identified worldwide more and more. Can you tell us a little bit about ICI-related autoimmune movement disorders?

[00:17:28] Jerome Honnorat: It's a very interesting point, and I think that we will describe a lot of things in the few future years because more and more patients are treated for cancer by immune checkpoint inhibitors. Everything can be observed, but two different groups. One, with acute reaction without associated autoantibodies regularly described in paraneoplastic syndromes.

Most of the times if you stop the ICI and if you treat the patient with corticosteroids, you will have an improvement of the neurological symptoms and a stabilization of the patient. And, very important point, you can reintroduce immune checkpoint inhibitors if necessary and propose a good treatment of the tumor evolution because most of the times the cancer is stage four in this patient and so it's very important to discuss.

Even in patients with paraneoplastic syndromes, if you treat them with immunomodulators, you will be able to propose immune checkpoint inhibitors to treat the cancer if necessary without evolution of the paraneoplastic syndrome.

The second case is patients treated for cancer without neurological syndromes that develop symptoms, but associated with regular autoantibodies such as anti-Hu or anti-MA2 autoantibodies.

In this case, it's more difficult. The disease is more aggressive and so it's very difficult to manage these patients and clearly the presence of autoantibodies is a bad prognostic factor in these patients. We don't know exactly all the panel of neurological symptoms that can be associated with immune checkpoint side effects.

Recently, we published an article in Neurology, Neuroimmunology & Neuroinflammation journal of five cases of Parkinson's disease that developed Parkinson's symptoms because it was bilateral and symmetric and subacute. But interestingly, we had dopaminergic differentiation in the patients that was reversible with corticosteroid treatment, and the patients improved with the treatment, suggesting clearly that the symptoms were due to the immune reaction.

And so probably we will be able to have some clues to understand the immune reaction and what is the role of the immune reaction to provoke the symptoms of the patient.

[00:20:16] Divyani Garg: Where do you think the field is headed over the next five years? What do you think will be the most important developments in the field?

[00:20:21] Jerome Honnorat: I think that the most important development will be the understanding of the fine mechanisms of the immune reaction to understand which kind of cytokines are implicated, which kind of cells, and the dialogue of lymphocytes between T-cells and B-cells that are at the origin of the disease.

And the second point is to understand what's happened in the tumor of patients with paraneoplastic syndromes. We already described some molecular abnormalities that could be the trigger of the immune breakdown observed in these patients. And so we will be able to understand exactly what's happened to provoke the immune breakdown, to provoke the immune activation, and to propose some specific treatment of the patients.

It's very important because, in fact, we have already in the market a large panel of immunological drugs that could be used to treat the patients. But the most important is to understand which one could be proposed in which subtype of autoimmune reaction. It is interesting to see that recently some new treatments have been described against autoantibodies and against complement in patient with myasthenia gravis.

We thought that this treatment could be efficient in autoimmune encephalitis. It's not the case, suggesting that the immune reaction is not the same. But we have other treatments that are available. And so if we identify the mechanisms, we'll be able to propose specific treatment. How we could do that with the new technology, analysis of single cell in the blood and in the CSF of the patient to look at exactly which kind of cells are present, which ones are activated, what is exactly the immune reaction.

We have also molecular analysis of the cancer cells to understand exactly what are the abnormalities that will provoke and trigger the immune reaction. And so I hope that in the next five years, we will be able to understand a lot of things and to describe a lot of different patients.

Just to conclude, I think that some patients with IgLON5 autoantibodies are very interesting to understand a huge panel of neurological disease because we have patients without clear immune reaction, but with one autoantibody called IgLON5 and a specific HLA that HLA subtype that is present in these patients, highly suggesting an immune reaction.

But when we look in the brain of these patients, there is no immune reaction, but tau phosphorylation, the deposit in neurons suggesting a neurodegenerative disease. So we have clearly an initiation of the disease with an immune reaction, and initially, the patients can be treated by immunomodulators, but after that, a process of neurodegeneration that is triggered by the immune reaction.

And so we have a model to understand what could happen in some patients with neurodegenerative disease and to propose initially some specific treatment to block the neurodegeneration. And so I think that, if you are young, there is plenty of work to understand what happened in these patients.

[00:24:17] Divyani Garg: Superb. Thank you so much for joining me today for the podcast.

[00:24:21] Jerome Honnorat: You're welcome. Thank you.