By Hai H. Hoang, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: The neuropathological features of N-methyl-D-aspartate receptor (NMDAR)-encephalitis are described in an autopsy cohort of four patients — two diagnosed in life with comorbid brain disorders, and two diagnosed at autopsy and never treated. The two untreated patients had inflammatory infiltrates composed of perivascular and parenchymal T cells and B cells/plasma cells in the basal ganglia, amygdala, and hippocampus. The two treated patients had variable pathologies that reflected their underlying neurological disorders (lymphoproliferative disease and multiple sclerosis). Overall, the topographic distribution of inflammation in patients with NMDAR-encephalitis reflects the clinical symptoms of movement disorders, abnormal behavior, and memory dysfunction with inflammation predominantly observed in the basal ganglia, amygdala, and hippocampus. Loss of NMDAR-immunoreactivity correlated with disease severity.
SOURCE: Zrzavy T, Endmayr V, Bauer J, et. al. Neuropathological variability within a spectrum of NMDAR-encephalitis. Ann Neurol 2021;90:725-737.
N-methyl-D-aspartate receptor (NMDAR)-encephalitis is associated with a characteristic clinical syndrome presenting with acute psychiatric symptoms, cognitive deficits, epileptic seizures, movement disorders, and autonomic dysregulation. In vivo and in vitro experiments demonstrated that the antibodies bind to an extracellular region of the NMDAR, causing internalization of the receptor and neuronal dysfunction.
The reversibility of neuronal dysfunction is reflected by good response to immunotherapy. Neuropathologic assessments are rare, since most patients recover or reach a diagnosis with biopsy. This study characterized the spectrum of inflammatory changes in different brain areas in patients who have or have not been treated with immunotherapy.
Four patients who underwent autopsies were included in this study. Two patients died before NMDAR-encephalitis was systematically tested and did not receive immunotherapy. NMDAR antibodies were retrospectively tested in archival cerebrospinal fluid (CSF) samples. Two patients were diagnosed with NMDAR-encephalitis during their lifetime and treated with immunotherapy but developed a co-pathology and died. Both patients received immunosuppressants, including steroids and intravenous immunoglobulin (IVIG). One of the patients also received chemotherapy and plasma exchange.
Neuropathologic evaluation of one of the two patients with postmortem diagnosis of NMDAR-encephalitis demonstrated immunohistochemical staining of the hippocampus with a decrease in NMDAR-expression compared to an age-matched control. In one of the two patients with NMDAR-encephalitis and central nervous system (CNS) comorbidities, brain biopsy showed a monomorphic post-transplant lymphoproliferative disease (PTLD), Epstein-Barr virus (EBV)-associated diffuse large B cell lymphoma (DLBCL). EBV-negative plasma cells were abundant in the medial temporal lobe, including amygdala and hippocampus. In the other patient with NMDAR-encephalitis and CNS comorbidities, whole brain sections showed periventricular demyelinating plaques with perivenous finger-like extensions into the adjacent white matter consistent with multiple sclerosis. Immunohistochemistry for both patients with NMDAR and CNS comorbidities for NMDAR revealed a mild reduction of immunoreactivity in the hippocampus compared to a healthy control.
Significant negative findings in the autopsies of the patients included the absence of detection of complement deposits. Hematoxylin and eosin (H&E) and immunohistochemistry for neurofilament, glial fibrillary acidic protein (GFAP), and human leukocyte antigen-DR isotype (HLA-DR) showed no neuronal loss, reactive scar-forming astrocytes, or microglial nodules in the pyramidal cell layer of the hippocampus, cortical regions, brainstem, or cerebellum.
This is one of very few studies that evaluated the neuropathologic changes in patients with NMDAR-encephalitis. The investigators were able to compare two untreated NMDAR-encephalitis patients with two treated NMDAR-encephalitis patients, noting that the patients who were treated had other CNS comorbidities. As expected in the two untreated NMDAR-encephalitis patients, the authors found that the amygdala, hippocampus, and basal ganglia were the areas with greatest inflammation, which correlated with the clinical presentation of abnormal behavior, memory dysfunction, and movement disorders. Additionally, overlapping CNS pathologies in patients led to changes in the distribution and composition of inflammatory infiltrates, and the pro-inflammatory microenvironment may have enhanced the intensity of inflammation. Neurons were well preserved but had reduced NMDAR-immunoreactivity, and the extent of decreased immunoreactivity correlated with disease severity.
Clinical implications of this study include the identification of pharmacologic targets for future therapies. Given that no complement depositions were found in any of these autopsies, therapies, such as complement inhibitors used for the treatment of neuromyelitis optica and myasthenia gravis, would not be ideal therapies for patients with NMDAR-encephalitis.