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 March 8, 2018; expires March 8, 2021

Overview

In this article, the author summarizes advances in the field of antibody-mediated epilepsies. This field is best defined by autoantibodies directed against neuronal cell-surface antigens including leucine-rich glioma inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the N-methyl, D-aspartate (NMDA), and gamma-aminobutyric acid (GABA) A and B receptors. Importantly, seizures in patients with these autoantibodies are often best treated with immunotherapies. Most strikingly, faciobrachial dystonic seizures have been recognized as a distinctive epilepsy semiology with frequent and brief dystonic episodes, typically involving the face and arm, and are consistently associated with LGI1-antibodies. Findings not only confirm a superior response of faciobrachial dystonic seizures to immunotherapies but also suggest that patients with the ensuring cognitive impairment, recognized in patients who present with faciobrachial dystonic seizures, may be prevented with immunotherapies. In addition, frequent temporal lobe seizures are also recognized in patients with autoantibodies against glutamic acid decarboxylase. Glutamic acid decarboxylase is an intracellular enzyme, and these patients often respond poorly to antiepileptic drugs or immunotherapies. These 2 paradigms imply that a proportion of patients with neuronal autoantibodies have frequent focal seizures with contrasting responses to immunotherapies. Clinical features allow recognition of these patients within unselected general epilepsy populations. This selection is critical for both etiologic and therapeutic implications, and to establish paradigms for recognition with the growing number of autoantibodies described in epileptic disorders.

Key points

 

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

 

• Faciobrachial dystonic seizures are very frequent brief dystonic events, typically affecting the ipsilateral arm and face, and are associated with LGI1-antibodies. Faciobrachial dystonic seizures often precede LGI1-antibody encephalitis, and early treatment may prevent the progression to “full-blown” encephalitis.

 

• Some patients with drug-resistant epilepsies, cryptogenic epilepsies, and new onset refractory status epilepticus have serum autoantibodies directed against neuronal surface proteins such as LGI1, CASPR2, the NMDA receptor, and the intracellular protein GAD.

 

• Testing for VGKC-complex antibodies should be halted, as this assay is less sensitive and far less specific for immunotherapy-responsive neurologic syndromes than directed testing for LGI1- and CASPR2-autoantibodies.

 

• 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. 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 1 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, and they showed a low incidence.

These early observations have been significantly extended in recent years with the discovery of a flurry of new autoantibodies. These discoveries have made it clear that limbic encephalitis is more commonly found in association with autoantibodies directed against the extracellular domains of neuronal proteins. These forms of limbic encephalitis can frequently be treated with immunotherapies, and are far less frequently associated with systemic tumors. In addition, some epilepsy patients without evident amnesia or disorientation have been reported to harbor these autoantibodies, supporting the hypothesis of autoimmune forms of epilepsy (Palace and Lang 2000). Indeed, several antigenic targets have now been described as forms of likely causative autoantibodies and have been shown to induce molecular effects consistent with epileptogenesis (Wright et al 2015; Seagar et al 2017; Thompson et al 2018).

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