Antibody-mediated epilepsies

Sarosh R Irani MD (Dr. Irani of Oxiford University Hospitals received royalties from Nil as a patent co-applicant.)
Jerome Engel Jr MD PhD, editor. (Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, has no relevant financial relationships to disclose.)
Originally released November 10, 2011; last updated November 21, 2016; expires November 21, 2019

Overview

In this article, the authors summarize advances in the field of antibody-mediated epilepsies. This entity began to be defined with the frequent observation of seizures in encephalitides associated with autoantibodies directed against neuronal cell-surface antigens. The antibodies are often directed against LGI1, CASPR2, and the N-methyl, D-aspartate (NMDAR), GABAA-, and GABAB-receptors. Surprisingly, the seizures in the antibody-positive cases are typically best controlled with immunotherapies. Several studies have examined the presence of these potentially pathogenic autoantibodies in a proportion of patients with cryptogenic and drug-refractory epilepsies, with limited or no cognitive impairment. The results are varied but have not yet translated to routine epilepsy practice. However, a new distinctive epilepsy semiology with frequent and brief dystonic episodes, typically involving the face and arm, has been recognized and has been found to be associated with LGI1-antibodies. Patients with these “faciobrachial dystonic seizures” have a relatively poor response to antiepileptic drugs, but their seizures often respond better to immunotherapies. Emerging data suggest that patients who present with faciobrachial dystonic seizures progress to develop cognitive impairment, which may be prevented by treatment of the faciobrachial dystonic seizures. In addition, glutamic acid decarboxylase (GAD) is an intracellular enzyme, and antibodies directed against GAD are found in patients with frequent temporal lobe seizures. However, these patients often respond poorly to antiepileptic drugs or immunotherapies. These 2 paradigms imply that a proportion of patients with neuronal autoantibodies may have frequent focal seizures. Furthermore, in cases with neuronal surface autoantibodies, the seizures may respond well to immunotherapies. The antibody-mediated epilepsies are a growing field with important etiologic and therapeutic implications for both children and adults.

Key points

 

• The antibody-mediated epilepsies often show an abrupt onset of frequent focal seizures.

 

• Faciobrachial dystonic seizures are very frequent brief dystonic events, typically affecting the ipsilateral arm and face, and they are found in association with LGI1-antibodies. Patients show other epileptic features ictally, and 10% have EEG changes. Faciobrachial dystonic seizures often precede LGI1-antibody encephalitis, and it is hypothesized that early treatment may prevent the progression to “full-blown” encephalitis in some patients.

 

• A few patients with drug-resistant and cryptogenic epilepsies have serum autoantibodies directed against neuronal surface proteins such as LGI1, CASPR2, and the NMDA receptor. The intracellular protein glutamic acid decarboxylase (GAD) is also an established target. In some patients with VGKC-complex antibodies, without a proven extracellular neuronal target, the antibodies may not be pathogenic and may simply be a biomarker of an underlying inflammatory process.

 

• The spectrum of autoantibody-mediated epilepsies is likely to expand in the near future with the ongoing discovery of new autoantibodies.

Historical note and terminology

In the 1960s, Brierley, Corsellis, and colleagues showed that patients with a subacute onset of amnesia, disorientation, and seizures had histological evidence of limbic system inflammation, predominantly affecting the hippocampi (Brierley et al 1960; Corsellis et al 1968). They termed this syndrome “limbic encephalitis.” However, the relevance of observed concurrent systemic malignancy was not fully appreciated at that time. Since this observation, a number of patients with limbic encephalitis and systemic tumors of lung, testicular, breast, and gynecological origin have been reported (Gultekin et al 2000). The term “paraneoplastic neurologic syndrome” has been used to describe cancer-related conditions that are pathologically remote to the cancer (Graus et al 2004), and one such paraneoplastic condition is often limbic encephalitis. However, these syndromes appeared to be associated with antibodies directed against intracellular antigens such as Hu, Ma2, and CV2/CRMP5, which are unlikely to be pathogenic.

These earlier observations have been significantly extended and revised in recent years. Indeed, it has become clear that limbic encephalitis is more commonly found in association with antibodies against the extracellular domains of neuronal proteins. These forms of limbic encephalitis are more common, can be treated with immunotherapies, and are not typically associated with systemic tumors are. In addition, some epilepsy patients without evident amnesia or disorientation have been reported to harbor these autoantibodies, supporting the existing evidence for an autoimmune etiology in some forms of epilepsy (Palace and Lang 2000; Granata et al 2011). This was reviewed in great detail in 2016 (Bakpa et al 2016). More generally, there are mounting pieces of evidence supporting a role for inflammation in humans and animal models of epilepsy (Ong et al 2014; Vezzani 2014).

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