Figure 6. Clinical correlates of antibody-mediated decrease of NMDAR.

The figure is based on data from animal models of pharmacological or genetic decrease of NMDAR (N-methyl-D-aspartate receptor). Each step has been shown in these models or in individuals treated with antagonists of NMDAR. The pronounced resemblance with the clinical features of anti-NMDAR encephalitis leads us to postulate that an antibody-mediated decrease of NMDAR predominantly inactivates GABAergic neurons (which are rich in NMDAR), leading to disinhibition of excitatory pathways and increase of extracellular glutamate. As a result patients develop a frontostriatal syndrome, which is characteristic of anti-NMDAR encephalitis. The complexity of orofacial and limb movements in patients with this disorder is probably explained by disinhibition of a brainstem central pattern generator that under normal conditions is tonically inhibited by the GABAergic system.⁸⁵ Because genetic disruption of NR1 causes hypoventilation,⁸⁰ a direct effect of the antibodies on the medullary-pontine respiratory network (nuclei of Kölliker-Fuse) might result in breathing dysfunction.⁸³ The presence of NMDAR in dopaminergic, cholinergic, and noradrenergic systems probably explains the autonomic manifestations (hypersalivation, hypertension, hyperthermia, cardiac dysrhythmia) that are also typical of NMDAR antagonists.²⁶ Figure adapted from Florance-Ryan and Dalmau⁸⁶ with permission from Wolters Kluwer Health. GABA= γ-amino-butyric acid.