Drebrin autoantibodies in patients with seizures and suspected encephalitis.

OBJECTIVE: Assess occurrence of the dendritic spine scaffolding protein Drebrin as pathophysiologically relevant autoantibody target in patients with recurrent seizures and suspected encephalitis as leading symptoms. METHODS: Sera of four patients with adult onset epilepsy and suspected encephalitis of unresolved etiology and equivalent results in autoantibody screening were subjected to epitope identification. We combined a wide array of approaches ranging from immunoblotting, immunoprecipitation and mass-spectrometry, subcellular binding pattern analyses in primary neuronal cultures, immunohistochemistry in brains of wildtype and Drebrin knockout mice to in vitro analyses on impaired synapse formation, morphology and aberrant neuronal excitability by antibody exposure. RESULTS: In the serum of a patient with adult onset epilepsy and suspected encephalitis, a strong signal at ~70 kDa was detected by immunoblotting, for which mass-spectrometry revealed Drebrin as putative antigen. Three other patients whose sera also showed strong immunoreactivity around 70 kDa in western blotting were also anti-Drebrin positive. Seizures, memory impairment and increased protein content in cerebrospinal fluid occurred in anti-Drebrin seropositive patients. Alterations in cerebral MRI comprised amygdalo-hippocampal T2-signal increase and hippocampal sclerosis. Diagnostic biopsy revealed T-lymphocytic encephalitis in an anti-Drebrin seropositive patient. Exposure of primary hippocampal neurons to anti-Drebrin autoantibodies resulted in aberrant synapse composition and Drebrin distribution as well as increased spike rates and the emergence of burst discharges reflecting network hyperexcitability. INTERPRETATION: Anti-Drebrin autoantibodies define a chronic syndrome of recurrent seizures, neuropsychiatric impairment as well as inflammation of limbic and occasionally cortical structures. Immunosuppressant therapies should be considered in this disorder. This article is protected by copyright. All rights reserved.