Tobias Zrzavy1, Verena Endmayr2, Jan Bauer3, Stefan Macher1, Nilufar Mossaheb4, Carmen Schwaiger2, Gerda Ricken2, Michael Winklehner2, Sarah Glatter5, Markus Breu5, Isabella Wimmer1, Gabor G Kovacs6, Daniele U Risser7, Nikolaus Klupp7, Ingrid Simonitsch-Klupp8, Thomas Roetzer2, Paulus Rommer1, Thomas Berger1, Ellen Gelpi2,9, Hans Lassmann3, Francesc Graus10, Josep Dalmau10,11,12, Romana Höftberger2. 1. Department of Neurology, Medical University of Vienna, Vienna, Austria. 2. Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria. 3. Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria. 4. Department of Psychiatry and Psychotherapy, Clinical Division of Social Psychiatry, Medical University of Vienna, Vienna, Austria. 5. Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. 6. Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada. 7. Center for Forensic Medicine, Medical University of Vienna, Vienna, Austria. 8. Department of Pathology, Medical University of Vienna, Vienna, Austria. 9. Neurological Tissue Bank of the Biobank-Hospital Clinic-IDIBAPS, Barcelona, Spain. 10. Neuroimmunology Programme, Institut d'Investigacions Biomèdiques August Pi i Sunyer Hospital Clínic, University of Barcelona, Barcelona, Spain. 11. Department of Neurology, University of Pennsylvania, Philadelphia, PA. 12. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
Abstract
OBJECTIVE: To describe the neuropathological features of N-methyl-D-aspartate receptor (NMDAR)-encephalitis in an archival autopsy cohort. METHODS: We examined four autopsies from patients with NMDAR-encephalitis; two patients were untreated, three had comorbidities: small cell lung cancer, brain post-transplant lymphoproliferative disease (PTLD), and overlapping demyelination. RESULTS: The two untreated patients had inflammatory infiltrates predominantly composed of perivascular and parenchymal CD3+ /CD8- T cells and CD79a+ B cells/plasma cells in basal ganglia, amygdala, and hippocampus with surrounding white matter. The hippocampi showed a significant decrease of NMDAR-immunoreactivity that correlated with disease severity. The patient with NMDAR-encephalitis and immunosuppression for kidney transplantation developed a brain monomorphic PTLD. Inflammatory changes were compatible with NMDAR-encephalitis. Additionally, plasma cells accumulated in the vicinity of the necrotic tumor along with macrophages and activated microglia that strongly expressed pro-inflammatory activation markers HLA-DR, CD68, and IL18. The fourth patient developed demyelinating lesions in the setting of a relapse 4 years after NMDAR-encephalitis. These lesions exhibited the hallmarks of classic multiple sclerosis with radially expanding lesions and remyelinated shadow plaques without complement or immunoglobulin deposition, compatible with a pattern I demyelination. INTERPRETATION: The topographic distribution of inflammation in patients with NMDAR-encephalitis reflects the clinical symptoms of movement disorders, abnormal behavior, and memory dysfunction with inflammation dominantly observed in basal ganglia, amygdala, and hippocampus, and loss of NMDAR-immunoreactivity correlates with disease severity. Co-occurring pathologies influence the spatial distribution, composition, and intensity of inflammation, which may modify patients' clinical presentation and outcome. ANN NEUROL 2021;90:725-737.
OBJECTIVE: To describe the neuropathological features of N-methyl-D-aspartate receptor (NMDAR)-encephalitis in an archival autopsy cohort. METHODS: We examined four autopsies from patients with NMDAR-encephalitis; two patients were untreated, three had comorbidities: small cell lung cancer, brain post-transplant lymphoproliferative disease (PTLD), and overlapping demyelination. RESULTS: The two untreated patients had inflammatory infiltrates predominantly composed of perivascular and parenchymal CD3+ /CD8- T cells and CD79a+ B cells/plasma cells in basal ganglia, amygdala, and hippocampus with surrounding white matter. The hippocampi showed a significant decrease of NMDAR-immunoreactivity that correlated with disease severity. The patient with NMDAR-encephalitis and immunosuppression for kidney transplantation developed a brain monomorphic PTLD. Inflammatory changes were compatible with NMDAR-encephalitis. Additionally, plasma cells accumulated in the vicinity of the necrotic tumor along with macrophages and activated microglia that strongly expressed pro-inflammatory activation markers HLA-DR, CD68, and IL18. The fourth patient developed demyelinating lesions in the setting of a relapse 4 years after NMDAR-encephalitis. These lesions exhibited the hallmarks of classic multiple sclerosis with radially expanding lesions and remyelinated shadow plaques without complement or immunoglobulin deposition, compatible with a pattern I demyelination. INTERPRETATION: The topographic distribution of inflammation in patients with NMDAR-encephalitis reflects the clinical symptoms of movement disorders, abnormal behavior, and memory dysfunction with inflammation dominantly observed in basal ganglia, amygdala, and hippocampus, and loss of NMDAR-immunoreactivity correlates with disease severity. Co-occurring pathologies influence the spatial distribution, composition, and intensity of inflammation, which may modify patients' clinical presentation and outcome. ANN NEUROL 2021;90:725-737.