Pathological Findings in Male Patients With Anti-N-methyl-d-Aspartate Receptor Encephalitis

Abstract

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is the most common type of autoimmune encephalitis. The disease predominantly affects women (1:5–1:10), with only 3 reports of autopsy findings in women being published to date. The present study reports findings from the first autopsy performed on a man with anti-NMDAR encephalitis. The patient had some scattered lesions in the limbic system with neuronal loss, gliosis, and microglial activation. The temporal and frontal cortices showed additional patchy demyelination. T-lymphocyte infiltration was detectable in the fusiform gyrus lesion. These findings were partly similar to those reported in female patients. Although clinical differences based on the sex of the patient are reported for this disease, the observed pathological similarities potentially help to establish common therapeutic strategies for all patients. Severe testicular damage was additionally observed in the male patient in this study. Biopsy-proven severe testicular damage was also confirmed in another, previously fertile man who became azoospermic. Moreover, serum follicle-stimulating hormone levels, which often increased in response to disturbed spermatogenesis, were elevated, and testosterone/luteinizing hormone ratio reflecting Leydig cell function was low in all 5 male patients in this study. Overall, these findings suggest similar brain pathology in patients of both sexes and severe testicular damage in male patients.

Genome-wide association study identifies two new loci associated with anti-NMDAR encephalitis

“…While it is well known that the hippocampus is a prime target of anti-NMDAR encephalitis, the ubiquitous expression of NMDA receptors containing the GluN1 subunit in the brain, the manifold symptoms of anti-NMDAR encephalitis and pathologic studies suggest an involvement of most if not all brain regions. 29 Therefore, we think that cerebellum and hypothalamus are valid target regions. In immune cells, we detected colocalization of the genes NR1H3, ACP2, DDB2 , and C11orf49 with eQTL in various immune cells including T-lymphocytes.…”

Paraneoplastic and Other Autoimmune Encephalitides: Antineuronal Antibodies, T Lymphocytes, and Questions of Pathogenesis

“…In all, these findings confirm a direct role for antibodies in the pathogenesis of anti-NMDAR encephalitis and, importantly, suggest that neuronal receptor function can recover and result in clinical improvement. Very few autopsy studies of anti-NMDAR encephalitis have been reported, and most of these have involved patients with a short duration of illness ( 63 , 64 ). An as-yet unanswered question is thus whether prolonged neuronal exposure to anti-NMDAR antibodies in affected patients might eventually produce significant neuronal death or irreversible neuronal dysfunction.…”

Neuropathological Variability within a Spectrum of NMDAR‐Encephalitis

“…1,5 Due to the frequent recovery of patients, neuropathological studies on NMDAR-encephalitis are rare and mainly based on isolated cases with overlapping pathologies or small biopsy specimens, lacking systematic assessment of immune cell infiltration and anatomic correlations. [6][7][8][9][10][11][12][13][14] This study aims to characterize the spectrum of inflammatory changes in different brain areas in patients who have or have not been treated with immunotherapy. Moreover, we describe the overlapping neuropathology of NMDAR-encephalitis with multiple sclerosis (MS)-type demyelination and post-transplant lymphoproliferative disease (PTLD).…”

“…NMDAR‐encephalitis is characterized by prominent intrathecal production of pathogenic autoantibodies and the reversibility of neuronal dysfunction is reflected by good response to immunotherapy 1,5 . Due to the frequent recovery of patients, neuropathological studies on NMDAR‐encephalitis are rare and mainly based on isolated cases with overlapping pathologies or small biopsy specimens, lacking systematic assessment of immune cell infiltration and anatomic correlations 6–14 . This study aims to characterize the spectrum of inflammatory changes in different brain areas in patients who have or have not been treated with immunotherapy.…”