Neuropathological Variability within a Spectrum of NMDAR‐Encephalitis

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