Pathophysiology
Clinical meaning
Autoimmune encephalitis (AE) encompasses a group of inflammatory brain disorders caused by antibodies directed against neuronal cell-surface or synaptic proteins, resulting in encephalopathy with cognitive impairment, psychiatric symptoms, seizures, and movement disorders. Unlike paraneoplastic encephalitides that involve T-cell-mediated neuronal destruction (targeting intracellular antigens), antibody-mediated AE targets extracellular epitopes on neuronal surface proteins, making the neuronal injury potentially reversible with immunotherapy and antibody removal. Anti-NMDA receptor encephalitis is the most common and best-characterized form of AE, affecting predominantly young women and children. The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-gated ion channel critical for synaptic plasticity, learning, memory, and excitatory neurotransmission. The NMDAR is a heterotetrameric receptor composed of two GluN1 (NR1) obligatory subunits and two GluN2 (NR2A-D) regulatory subunits that form a cation channel permeable to calcium, sodium, and potassium. In anti-NMDA receptor encephalitis, IgG antibodies target the GluN1 subunit, causing receptor internalization through cross-linking and antibody-mediated endocytosis. This dramatically reduces NMDAR density on the synaptic surface without destroying the neurons themselves. The reduction in NMDAR function produces a predictable clinical syndrome that mirrors the effects of NMDAR antagonists such as...