Atypical NMDA Receptor Expression in a Diffuse Astrocytoma, MYB- or MYBL1-Altered as a Trigger for Autoimmune Encephalitis

Background/Purpose: Triggers for anti-NMDA receptor encephalitis (NMDARE) include viral infections and ovarian teratomas. In NMDARE patients, ovarian teratomas contain neuronal tissue that atypically expresses NMDARE and might cause abnormal antibody formation leading to encephalitis. Surprisingly, brain tumors have not yet been reported to trigger NMDARE. To investigate a possible link between NMDARE and glioneuronal brain tumors, we followed an atypical, refractory NMDARE in a child with diffuse astrocytoma, MYB- or MYBL1-altered, over 2 years.

Methods: Clinical data, cerebrospinal fluid (CSF), and tumor tissue were examined by immunostaining, confocal microscopy, and molecular pathology. We compared the NMDARE expression in the patient tumor with that in specimens from patients with various tumor entities, herpes simplex encephalitis (HSE), NMDARE without tumor as well as healthy controls.

Results: The index patient's brain tumor showed NMDARE expression. NMDARE signal was restricted atypically to the somata of dysmorphic neurons. Anti-NR1 antibodies in the patient's CSF targeted these cells and reproduced the staining pattern. The atypical NMDARE expression appeared to be specific to glioneuronal tissue. It was not found in tumor entities without dysmorphic neurons but was detected on neuronal somata in inflamed HSE tissue. A tumor resection in the index patient finally resulted in a decrease of the anti-NR1 titer and considerable clinical improvement.

Conclusion: We provide evidence of atypical NMDARE expression in certain tumors, in which NMDARE-positive dysmorphic neurons could provoke the formation of antibodies leading to autoimmune encephalitis. Following the findings on NMDARE in ovarian teratomas, we propose an etiologic concept in which immunogenic properties of neuroepithelial tumor tissue, whether outside or inside the brain, serve as triggers for NMDARE.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
13 November 2023