Anti-N-Methyl-D-aspartate Receptor Encephalitis: A Severe, Potentially Reversible Autoimmune Encephalitis

Abstract

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is potentially lethal, but it is also a treatable autoimmune disorder characterized by prominent psychiatric and neurologic symptoms. It is often accompanied with teratoma or other neoplasm, especially in female patients. Anti-NMDAR antibodies in cerebrospinal fluid (CSF) and serum are characteristic features of the disease, thereby suggesting a pathogenic role in the disease. Here, we summarize recent studies that have clearly documented that both clinical manifestations and the antibodies may contribute to early diagnosis and multidisciplinary care. The clinical course of the disorder is reversible and the relapse could occur in some patients. Anti-NMDAR encephalitis coexisting with demyelinating disorders makes the diagnosis more complex; thus, clinicians should be aware of the overlapping diseases.

Figure 1

Possible pathogenesis of anti-NMDAR encephalitis. Anti-NMDAR antibodies synthesized by peripheral plasma cells pass through the broken blood-brain barrier (BBB). Tumors, which express NMDA receptors, as well as viral infections, may play a role in triggering the synthesis of anti-NMDAR antibodies. IL-6 and IL-17A might play an important role in the intrathecal antibody synthesis. NMDA receptors are expressed in many regions of the brain, including the hippocampus, brain stem, and neocortex. Anti-NMDAR antibodies bind selectively to synaptic and extrasynaptic NMDA receptors. The specific bind leads to crosslinking and internalization of those receptors. The number of NMDA receptors on the postsynaptic membrane decreases. The effect is titer-dependent and reversible after antibody titers decrease. Thus, anti-NMDAR antibodies lead to a specific, titer-dependent, and reversible reduction of NMDA receptors on postsynaptic dendrites which results in neuronal hypoactivity.

Figure 2

Procedure of diagnosis and treatment of anti-NMDAR encephalitis. ∗ indicates that detection of antibodies should include CSF analysis. If only serum is available, in addition to cell-based assay (CBA), live neurons or tissue immunohistochemistry should be used as confirmatory test. ^&Supporting therapies include antiepileptic and antipsychotic treatments, respiratory and cardiac support, management of blood pressure and temperature, and prevention of deep venous thrombosis (DVT) and bedsore. ^※Cyclophosphamide, rituximab, or both.