Autoimmune Antibodies in Patients with Epilepsy of Unknown Etiology
By Peter B. Forgacs, MD
Assistant Professor of Neuroscience and Neurology, Feil Family Brain and Mind Research Institute and Department of Neurology, Weill Cornell Medical College, New York; Adjunct Assistant Professor of Clinical Investigation, The Rockefeller University, New York
Dr. Forgacs reports no financial relationships relevant to this field of study.
SYNOPSIS: In this prospective study of patients with epilepsy of unknown origin (including new-onset and established epilepsy), more than 20% of patients were found to have neurological autoantibodies strongly suggesting autoimmune origin of their epilepsy.
SOURCE: Dubey D, Algallaf A, Hays R, et al. Neurological autoantibody prevalence in epilepsy of unknown etiology. JAMA Neurol 2017;74:397-402.
The etiology of more than 30% of all adult epilepsies remains elusive even after the most comprehensive evaluation, based on currently available diagnostic tests. As a result, targeted therapeutic interventions are highly limited and symptomatic treatment with anti-epileptic medications remains the only approach to prevent further seizures in these patients. Many ongoing studies aim to find specific causative processes in these cases, as understanding the underlying pathological mechanisms may open up new avenues in treatment of such epilepsies — or even a possible cure or prevention of progression of epilepsy in some patients. Over the last decades, autoimmunity has been recognized as an etiological factor in many neurological diseases previously thought to have uncertain origins. Specifically, seizures are a well-known symptom of some immune-mediated neurological diseases (such as autoimmune encephalitides). Therefore, it has been long thought that some epilepsies with unknown origin may have immune-mediated etiology. In addition, a number of autoantibodies have been identified that specifically target neuronal cells. The association between presence of these antibodies and seizures has been demonstrated in a number of retrospective studies or case series; however, this is the first major study to prospectively examine the prevalence of autoantibodies in new-onset or established epilepsies of unknown etiology.
A total of 112 patients were included in this study over a 12-month period from various inpatient and outpatient settings in a single center, including the epilepsy monitoring unit, neurology clinic, inpatient service, and intensive care units. Thirty-one percent of the patients had new-onset epilepsy; the remaining patients had previously established epilepsy with mean duration of more than 12 years.
The main result of the study is that serum antibodies suggesting a potential autoimmune etiology were detected in 34.8% of these patients. Even after excluding antibodies with unclear roles in the pathogenesis of autoimmune epilepsy (such as TPO-Ab) and antibodies of unknown significance that are prevalent in the general population (such as GAD65-Ab < 20 mmol/L), 20.5% of patients had evidence for at least one neurological antibody (or combination of antibodies) strongly suggestive of an autoimmune cause of epilepsy.
Additional important findings include prospective utilization of a clinical score that successfully predicted antibody prevalence in the observed cohort with sensitivity and specificity of ~80%). In fact, certain clinical characteristics were more commonly present in the group of patients with positive serological findings compared to patients with negative serology. These include a viral prodrome, autonomic dysfunction, neuropsychiatric changes, faciobrachial dystonias or dyskinesias, and, importantly, mesial temporal sclerosis on MRI. Additionally, patients with new-onset epilepsy had higher prevalence of antibodies compared to patients with established epilepsy (37% vs. 13%), and differences also were found in the specific antibody profile between these two groups.
Furthermore, a clinically highly relevant result of the study is that the presence of autoantibodies was associated with better seizure outcome at the time of their first follow-up (defined as 50% or more seizure reduction; P = 0.002), including higher proportion of seizure freedom (P = 0.02). Furthermore, in seropositive patients who received some form of immune-modulatory therapy (especially intravenous methylprednisolone or plasmapheresis), the treatment was associated with better seizure outcome.
COMMENTARY
This study is important as it sheds light on a possible mechanism of epileptogenesis in a potentially large number of patients with currently unknown etiology of their epilepsy. The high prevalence of autoantibodies found in this study population is striking and strongly warrants further follow-up studies.
This study raises many questions and some weaknesses that are worth mentioning. First, there may be additional, currently unidentified autoantibodies that also are associated with the development of epilepsy, raising the possibility that the number of patients with autoimmune epilepsy may be even higher than identified here. In addition, it is important to point out that the prospective design makes this study strong, but it remains a correlative study. The observed association between seropositivity and development of epilepsy does not necessarily prove causation, especially in an individual patient, which can explain why some patients did not respond to immunotherapy. Furthermore, some observed autoantibodies also may be present in the general population without causing any symptoms; therefore, it is also possible that the study overestimates the number of patients for whom immune-mediated mechanisms are responsible for the development of epilepsy.
Importantly, the proposed clinical score used in this study appears to have good sensitivity and specificity to predict immunological origin of epilepsy, but it will need further validation in independent studies before widespread clinical application should be considered. However, such clinical scoring could be very useful in determining which patients with unknown epilepsy should have antibody testing. Lastly, additional studies are needed to further clarify the natural history of autoimmune epilepsies and the best treatment strategies for patients with presence of neurological antibodies, such as selection criteria for patients who most likely will benefit from immunotherapy and the timing of introduction and optimal duration of immunotherapy. Sending a serum antibody panel in patients with unexplained epilepsy, especially if some clinical symptoms suggest possible immunological origin, should be strongly considered on an individual basis.
In this prospective study of patients with epilepsy of unknown origin (including new-onset and established epilepsy), more than 20% of patients were found to have neurological autoantibodies strongly suggesting autoimmune origin of their epilepsy.
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