Symptomatologic pathomechanism of N-methyl D-aspartate receptor encephalitis.

Abstract

N-methyl D-aspartate receptor (NMDAR) encephalitis is a well-characterized clinical syndrome. The main molecular mechanism of NMDAR encephalitis is autoantibody-mediated NMDAR hypofunction in the neuronal synapse. Several pathomechanistic hypotheses might explain how NMDAR hypofunction causes the typical symptoms and prognosis of NMDAR encephalitis. Suppression of NMDAR-dependent gamma-aminobutyric acid interneurons provokes an accelerated activation of the positive feedback loops of the dorsolateral prefrontal cortex/subiculum-nucleus accumbens circuit in the striatum, the ventral tegmental area (VTA), and the nucleus reuniens in the thalamus-hippocampus-VTA loop. Dysregulated activation of the VTA and cortex via those positive feedback loops may explain the rapid clinical deterioration at acute stages of the disease and the well-characterized syndrome that includes limbic system dysfunction, intractable seizures, dyskinesia, coma, and the characteristic extreme delta brush. Progressive cerebellar atrophy is correlated with cumulative disease burden and is associated with worse long-term outcomes, which might be explained by the NMDAR-dependent pathways required to maintain neuronal survival. Those pathomechanistic hypotheses for NMDAR encephalitis support the rationale for the early introduction of combination immunotherapy and the use of adjuvant immunotherapy in patients with persisting symptoms in chronic disease phases.