False Positive Cerebrospinal Fluid NMDA Receptor Antibodies: A Single Center Case Series

Objective To report the presence of CSF NMDA receptor antibodies in four patients without NMDA receptor encephalitis encountered at a single tertiary care center.

Background The diagnosis and confirmation of anti-NMDA encephalitis relies heavily on detection of IgG antibodies to the NR1 subunit of the NMDA receptor in cerebrospinal fluid. While this is generally considered a highly specific test for anti-NMDA encephalitis, there have been rare reports of false positive testing.

Design/Methods A retrospective chart review of medical records for patients with positive CSF NMDA receptor antibody testing at University of Texas Southwestern Medical Center between 2011 to 2021 was performed.

Results 40 patients were identified who had positive CSF NMDA receptor antibodies. Of these 40 patients, 4 (10%) were concluded to have false positive results. The false positive results consisted of 1 patient with refractory status epilepticus from suspected synthetic cannabinoid use, 1 patient with an anaplastic astrocytoma, 1 patient with fungal meningitis from Candida dubliniensis, and 1 patient with bifrontal cerebritis of suspected infectious etiology. Of the 4 patients with false positive antibody testing, 3 were immediately recognized as likely false positives while 1 patient was misdiagnosed and treated for an autoimmune encephalitis prior to a final diagnosis with tissue biopsy.

Conclusions Although uncommon, false positive CSF NMDA receptor antibodies pose significant diagnostic and therapeutic challenges for clinicians. In our case series, false positive tests occurred in patients with apparent central nervous system disorders, including seizure, infection, and neoplasm. While antibody testing is an essential tool for the diagnosis of NMDA receptor encephalitis, caution should be exercised in interpreting positive results when the clinical and paraclinical data are not consistent with the well characterized phenotype of NMDA receptor encephalitis.