Neuropathological Variability within a Spectrum of NMDAR-Encephalitis

Ann Neurol. 2021 Nov;90(5):725-737. doi: 10.1002/ana.26223. Epub 2021 Oct 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-N-Methyl-D-Aspartate Receptor Encephalitis / diagnosis*
  • Anti-N-Methyl-D-Aspartate Receptor Encephalitis / pathology*
  • Brain / pathology
  • Complement System Proteins / metabolism
  • Humans
  • Male
  • Neoplasm Recurrence, Local / pathology*
  • Nervous System Diseases / pathology
  • Receptors, N-Methyl-D-Aspartate / metabolism*


  • Receptors, N-Methyl-D-Aspartate
  • Complement System Proteins