Abstract
Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy
Toledano M, Britton JW, McKeon A, Shin C, Lennon VA, Quek AML, So E, Worrell GA, Cascino GD, Klein CJ, Lagerlund TD, Wirrell EC, Nickels KC, Pittock SJ. Neurology 2014;82:1578–1586.
OBJECTIVE: To evaluate a trial of immunotherapy as an aid to diagnosis in suspected autoimmune epilepsy. METHOD: We reviewed the charts of 110 patients seen at our autoimmune neurology clinic with seizures as a chief complaint. Twenty-nine patients met the following inclusion criteria: (1) auto-immune epilepsy suspected based on the presence of ≥1 neural autoantibody (n = 23), personal or family history or physical stigmata of autoimmunity, and frequent or medically intractable seizures; and (2) initiated a 6- to 12-week trial of IV methylprednisolone (IVMP), IV immune globulin (IVIg), or both. Patients were defined as responders if there was a 50% or greater reduction in seizure frequency. RESULTS: Eighteen patients (62%) responded, of whom 10 (34%) became seizure-free; 52% improved with the first agent. Of those receiving a second agent after not responding to the first, 43% improved. A favorable response correlated with shorter interval between symptom onset and treatment initiation (median 9.5 vs 22 months; p = 0.048). Responders included 14/16 (87.5%) patients with antibodies to plasma membrane antigens, 2/6 (33%) patients seropositive for glutamic acid decarboxylase 65 antibodies, and 2/6 (33%) patients without detectable antibodies. Of 13 responders followed for more than 6 months after initiating long-term oral immunosuppression, response was sustained in 11 (85%). CONCLUSIONS: These retrospective findings justify consideration of a trial of immunotherapy in patients with suspected autoimmune epilepsy. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with suspected autoimmune epilepsy, IVMP, IVIg, or both improve seizure control.
Population-Level Evidence for an Autoimmune Etiology of Epilepsy
Ong M-S, Kohane IS, Cai T, Gorman MP, Mandl KD. JAMA Neurol. 2014;71(5):569–574.
IMPORTANCE: Epilepsy is a debilitating condition, often with neither a known etiology nor an effective treatment. Auto-immune mechanisms have been increasingly identified. OBJECTIVE: To conduct a population-level study investigating the relationship between epilepsy and several common autoimmune diseases. DESIGN, SETTING, AND PARTICIPANTS: A retrospective population-based study using claims from a nationwide employer-provided health insurance plan in the United States. Participants were beneficiaries enrolled between 1999 and 2006 (N = 2 518 034). MAIN OUTCOMES AND MEASURES: We examined the relationship between epilepsy and 12 autoimmune diseases: type 1 diabetes mellitus, psoriasis, rheumatoid arthritis, Graves disease, Hashimoto thyroiditis, Crohn disease, ulcerative colitis, systemic lupus erythematosus, antiphospholipid syndrome, Sjögren syndrome, myasthenia gravis, and celiac disease. RESULTS: The risk of epilepsy was significantly heightened among patients with autoimmune diseases (odds ratio, 3.8; 95% CI, 3.6–4.0; P < .001) and was especially pronounced in children (5.2; 4.1–6.5; P < .001). Elevated risk was consistently observed across all 12 autoimmune diseases. CONCLUSIONS AND RELEVANCE: Epilepsy and autoimmune disease frequently co-occur; patients with either condition should undergo surveillance for the other. The potential role of autoimmunity must be given due consideration in epilepsy so that we are not overlooking a treatable cause.
Commentary
Despite all the recent interest in autoimmune epilepsy, it's still difficult to know when we've found it and what to do about it once it's been identified. Our knowledge of the phenomenon is in an evolving state at present, which can be seen best in the context of history. Seizures with an autoimmune basis were initially described about 25 years ago as part of the syndrome of acute limbic encephalitis, which includes cognitive and other deficits and was found in the setting of cancer (1). A tumor-induced immune cross reaction to brain components was confirmed with the finding of a number of causative antibodies such as anti-Hu (2).
The next step was the discovery of a number of additional antibodies, such as anti-GAD65 and anti–voltage-gated potassium channel, associated with epilepsy and other neurologic symptoms, without cancer (3). Sometimes these antibodies were associated with pure epilepsy, without a concomitant neurologic syndrome (4). As more and more epilepsy-associated antibodies were discovered (5), it led eventually to bigger questions: How do we know whom to treat? What sort of immune treatment should we use, and how well does it work? And, how many of these patients are out there?
Two recent papers provide intriguing data on this burgeoning area of inquiry. Many of us treat these patients with our standard acute neuroimmunologic therapies (i.e., steroids, IV immune globulin [IVIg], plasmapheresis) based upon clinical reasoning and experience, despite the lack of any evidence of their effectiveness. In the article by Toledano et al., the folks at Mayo Clinic, who have a large autoimmune neurology center, assess the outcome of treating presumed autoimmune epilepsy in this manner. They say “presumed” because, interestingly, not all of their patients had documented autoantibodies—6 of the 29 were given the diagnosis on clinical grounds, based upon MRI or CSF results, personal or family history of autoimmunity, or subacute onset of frequent, multiple-type, or drug-resistant seizures. Just over half of their population was drug resistant, and patients were treated (sequentially if needed) with steroids or IVIg. Their benchmark outcome, a 50% seizure reduction, was obtained in 62% of patients, with 34% becoming seizure-free. Better results were obtained with steroids than with gamma globulin, and much better results were obtained in the patients with documented plasma membrane antibodies (88% responders) than in those with anti-GAD65 or no antibody (33% response).
This is the first article to systematically document response to treatment for autoimmune epilepsy, which makes it quite noteworthy, especially in view of the generally favorable results. The article even comes with a nice algorithm for the practicing neurologist to identify and treat these patients (starting with steroids first). A number of caveats are in order, though. First, the outcome here is good, but not great; 50% responder rates are not really what we're looking for. And while a third of the patients became seizure-free, that leads us to the second caveat: this was a short-term study; in fact, the authors don't even tell us exactly how short term. They do tell us that 13 of the responders went on to long-term immune treatment, mostly with mycophenolate, and that 85% of them maintained their seizure response. Still, “response” is not really our goal, as mentioned. Furthermore, it leaves open the question of whether this is really a treatment effect, or merely the natural history of the disease; this is a question that cannot be answered well in an uncontrolled study, and there is evidence in “garden variety” epilepsy that changes in outcome are less often the result of treatment than we assume (6). Finally, the results among those without a plasma membrane antibody are disappointing, with only a third getting even a 50% reduction, pointing out gaps in both our case ascertainment and treatment.
Nonetheless, the improvement in some antibody-negative patients, along with the regular discovery of new antibodies, leads to the realization that there must be plenty of patients with autoimmune epilepsy due to antibodies that have yet to be identified. And that, in turn, leads to the question of just how many such patients there are. Is this a rare phenomenon? Or, is it possible that some sizable fraction of the one-third of patients with drug-resistant epilepsy have an autoimmune basis for their disease?
In the second article, Ong and colleagues utilize a novel, indirect method to examine this issue. Given that autoimmune diseases frequently coexist, they reasoned that if some significant fraction of epilepsy had an autoimmune basis, then epilepsy should be associated with other autoimmune diseases at a more-than-chance frequency. They tested this hypothesis in a large U.S. claims database (though it would have been nice if they'd told us which one!) by looking at the incidence of new epilepsy diagnoses in patients with a dozen different autoimmune conditions, using epilepsy incidence in those without autoimmune disease as the reference population. Sure enough, in both children and adults, the risk of epilepsy was markedly elevated for every autoimmune condition—at least double, and as high as 21 times! This was true for rheumatologic conditions (lupus, Sjogren syndrome), endocrine conditions (Hashimoto thyroiditis, type 1 diabetes mellitus), and inflammatory bowel diseases. Furthermore, of these comorbid patients, 30% developed epilepsy before the autoimmune condition was diagnosed, so it wasn't simply a question of the latter causing the former. The authors conclude that there is a true association that cannot be explained by direct brain effects of the diseases, as it occurs even in conditions without CNS involvement (e.g., myasthenia gravis), but that this does not necessarily imply that epilepsy is directly autoantibody mediated—it could instead be due to other autoimmune or inflammatory causes.
The fact that every single autoimmune disease showed an association with epilepsy raises the question of whether there is some bias that has infected the authors’ data. For example, is it possible that patients with one disease are simply more likely to come to medical attention for others, thereby resulting in an ascertainment bias for epilepsy? The appropriate control for this would have been to look for the association of other superficially similar nonimmune conditions (e.g., peptic ulcer disease, osteoarthritis) with epilepsy in the same dataset. Regrettably, they did not do this. Nonetheless, their data are highly intriguing and indicate, at a minimum, the need for other studies to confirm this phenomenon.
These two articles merely cruise around the crest of what may well be a giant, mostly submerged glacier of immune disease and epilepsy. The results indicate that further work is needed in the two areas noted at the beginning of this commentary: how to identify autoimmune epilepsy, and how to treat it once diagnosed. Is it possible that a considerable hunk of epilepsy cases are autoimmune in nature? Could that be why a third of patients resolutely fail to respond to any antiepileptic drug, regardless of its pharmacology? It is difficult to answer such questions without biomarkers for autoimmunity, so perhaps that is the direction in which our efforts should be turned while we grope for an understanding of the potential impact of this phenomenon on our population.