T cells and Acute Neuronal Damage Play a Relevant Role in the Immunopathology of Anti-GABA-B Receptor Encephalitis, Shaping Long-term Outcome
Robin van Steenhoven1, Jeroen Kerstens1, Nina Fransen2, Valerie A. Quinot4, Verena Endmayr4, Romana Höftberger4, Annemieke Rozemuller3, Maarten Titulaer1
1Neurology, Erasmus University Medical Center, 2Pathology, 3Neuropathology, Amsterdam University Medical Center, 4Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna
Objective:
To characterize the outcome and clinicopathological correlation of anti-GABA-B receptor encephalitis (anti-GABA-BR-E).
Background:
Anti-GABA-BR-E is characterized by neuropsychiatric symptoms, seizures and rapidly progressive dementia. In anti-NMDA receptor encephalitis, B cells and antibody-mediated mechanisms play a critical role, largely explaining the effectiveness of immunotherapy. However, in anti-GABA-BR-E, a limited treatment response has been recognized, suggesting additional pathogenic mechanisms.
Design/Methods:
Anti-GABA-BR-E patients were retrospectively and prospectively included from January 2011 to September 2024 at the Erasmus University Medical Center (The Netherlands). Demographics, tumor status, immunotherapy, and 1-year outcome (modified ranking scale [mRS]) were collected. Post mortem brain tissue, obtained at autopsy, of anti-GABA-BR-E cases and age- and sex-matched controls were analyzed by immunohistochemistry, quantifying B and plasma cells, T cells, IgG and neuronal damage.
Results:
Sixty-five patients were enrolled (36/65 female;55%, median age 68 years), of whom 45 (69%) had an underlying tumor and 48/65 (74%) received immunotherapy. Twenty-six of 36 treated patients (72%) with sufficient follow-up had an unfavorable (mRS≥3) 1-year outcome, including 5/6 (83%) non-paraneoplastic cases. Autopsy was performed in four patients, of whom three were untreated and one had a tumor. Immunopathology was characterized by perivascular lymphocytic cuffing, predominantly in the hippocampus and amygdala. A prominent CD8+ T cell response was observed infiltrating the brain parenchyma and perivascular area, with significantly higher positive cells/mm² in anti-GABA-BR-E compared to controls in the hippocampus (16.1 vs. 7.5, p=0.048) and amygdala (17.4 vs. 6.2, p=0.046). Deposition of granzyme B and amyloid precursor protein was observed in corresponding regions, compatible with acute T cell mediated neuronal and axonal damage. IgG producing B cells and plasma cells, were primarily located in perivascular regions.
Conclusions:
A limited treatment response is observed in the majority of anti-GABA-BR-E patients, probably explained by a strong cytotoxic T cell response with acute neuronal damage, in addition to the anticipated B cell–mediated antibody effects.
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