Autoimmune Epilepsy: From Testing to Treatment

I am honored to work with Practical Neurology to prepare this issue focusing on autoimmune epilepsy. Seizures are common manifestations of autoimmune encephalitis (AE); however, the relationship between central nervous system (CNS) autoimmunity, seizures, and long-term epilepsy is rarely straightforward. This issue focuses on the current evidence covering a broad spectrum of seizure disorders linked to the adaptive and innate arms of the immune system, including autoimmune encephalitis, GAD65 autoimmune-associated epilepsy (AAE), and new-onset refractory status epilepticus (NORSE).

For patients presenting with acute symptomatic seizures secondary to AE, early recognition is crucial as immunotherapy, rather than conventional antiseizure medications alone, is often central in controlling seizures, and early treatment is associated with more favorable long-term outcomes. Greater access to antibody testing, along with emerging evidence for strengths and limitations of antibody testing techniques are increasingly important aspects of diagnosing patients with antibody-mediated seizure disorders. Dr. Dubey and I cover this subject, including patient selection and antibody testing methods, circumstances that may produce false positives or negatives, and discuss the role of antibody testing beyond diagnosis.

Another form of autoimmune seizure disorder often not associated with an acute-subacute encephalitic presentation is GAD65 AAE, covered by Dr. Hébert. GAD65 AAE often presents as drug-resistant temporal lobe epilepsy in younger women and may lack features that suggest an autoimmune basis. Identification of these patients is important, as the immunotherapy response is most prominent early in the disease course. Newer evidence from cohorts with a shorter time to diagnosis suggests a minority may become seizure-free with antiseizure medications and immunotherapy, whereas drug-resistant epilepsy is otherwise the common trajectory in this condition.

As recognition of AE has improved, increasing attention has turned to treatment of these disorders over time. The treatment of autoimmune seizure disorders requires integration of immunotherapy and antiseizure medications, covered by Drs. Smith, McKeon, Britton, and Feyissa. As data from larger, multi-center cohorts are published, treatment of the more common forms of autoimmune encephalitis is increasingly informed by evidence, however many uncertainties remain, including the treatment of rarer forms of AE.

While seizure disorders associated with the adaptive branch of the immune system are relatively well described, recent attention has turned to the role of cytokines in autoimmune neurology, including use of anticytokine therapies in the treatment of various neuroinflammatory conditions. There is increasing evidence for the proconvulsant role of cytokines in animal models, and emerging evidence implicates cytokine-mediated pathophysiology in cryptogenic NORSE and febrile infection–related epilepsy syndrome (FIRES). Drs. Hanin, Demeret, Navarro, and Marois cover these disease entities, and review the rapid diagnostic workup and initiation of treatment, which includes both immunotherapy and antiseizure medication/anesthetics required to manage these often critically ill patients.

Taken together, these articles span the spectrum of autoimmune seizure disorders from critically ill NORSE patients to individuals with drug-resistant epilepsy in whom an autoimmune cause is considered. Despite increasingly sophisticated diagnostic and therapeutic tools, many questions remain unanswered in this field. Patients with antibodies against extracellular antigens often do not develop long-term epilepsy, and most seizures are responsive to immunotherapy. Conversely, those with antibodies against intracellular antigens, such as GAD65 AAE, have seizures increasingly driven by cytotoxic T cell–mediated structural pathology over time with a variable timeline of coexisting inflammation. We lack biomarkers that reliably establish whether persistent seizures over time reflect ongoing neuroinflammation or structural pathology. At extremes of the disease timeline, the relative contributions of inflammation and structural pathology are best estimated. However, uncertainty prevails throughout the mid-disease course, where immunotherapy and epilepsy-directed management decisions are often made. In refractory cases where immunotherapy response has been exhausted, epilepsy surgery and neuromodulatory techniques may benefit patients, although many uncertainties exist regarding management of these patients.

I am grateful to the authors who contributed their expertise to this issue, and to Practical Neurology for the opportunity to bring these perspectives together. I hope this collection provides neurologists with a practical framework to recognize and investigate autoimmune seizure disorders, and navigate them across the acute and chronic phases of these disease entities.