What is NMDAR (N-methyl-D-aspartate) encephalitis?

NMDAR Encephalitis: Definition and Overview

NMDAR encephalitis is an autoimmune disorder of the central nervous system caused by antibodies targeting the N-methyl-D-aspartate receptor (NMDAR), resulting in receptor removal from synapses and leading to a characteristic multistage neuropsychiatric syndrome that is potentially reversible with immunotherapy. 1

Pathophysiology

• Antibodies bind to extracellular epitopes on NR1/NR2 heteromers of NMDAR, causing receptor internalization and decreased NMDAR density at synapses rather than direct receptor destruction 2, 3

• The antibodies are pathogenic, as evidenced by in vitro and in vivo reduction of NMDA receptors, and antibody titers correlate with clinical improvement 1

• The mechanism likely involves NMDAR hypofunction in GABAergic interneurons, leading to disinhibition of glutamatergic transmission and excessive glutamate release in prefrontal/subcortical structures 3

• Unlike classical paraneoplastic syndromes with intracellular antibodies, T cell infiltration is less conspicuous in NMDAR encephalitis, suggesting a predominantly antibody-mediated process 1

Clinical Presentation

Characteristic Multistage Evolution

• The syndrome evolves through 5 distinct stages: prodromal phase (fever, headache, viral-like illness), psychotic phase (schizophrenia-like symptoms), unresponsive/catatonic phase, hyperkinetic phase (most prolonged and crucial), and gradual recovery phase 3

Core Clinical Features

• Psychiatric symptoms including psychosis, behavioral changes, and memory deficits typically appear early and may be the presenting feature, particularly in young women 1, 4

• Dyskinetic movements (orofacial-limb dyskinesias, choreoathetosis) are highly characteristic and more frequent at onset in children 1

• Seizures and epilepsy, including refractory status epilepticus, occur frequently 1, 4

• Decreased level of consciousness progressing to catatonia and unresponsiveness 1, 4

• Autonomic instability and central hypoventilation frequently requiring mechanical ventilation 2, 3

• Cognitive dysfunction particularly affecting memory function 4, 2

Epidemiology

• NMDAR encephalitis is the single most common cause of encephalitis in patients under 30 years of age, exceeding the combined incidence of herpes simplex virus, West Nile virus, and varicella zoster virus 5, 4

• More than 500 cases have been reported, predominantly from the United States 1

• The disorder can occur in children, young women, adult men, and even in the absence of tumor (up to 35% of cases) 6, 3

Tumor Association

• Up to 50% of women over age 18 with NMDAR encephalitis have ovarian teratomas, while tumors are rare in children 1, 5

• The nervous tissues of teratomas exhibit strong expression of NR2B subunits and react with patients' antibodies, suggesting the tumor triggers the autoimmune response 3

• Tumor removal is a critical component of treatment, though recovery can occur without tumor resection in non-paraneoplastic cases 7, 3

Diagnostic Features

Laboratory Testing

• NMDAR antibodies are more sensitive and specific in CSF than serum, and CSF testing is crucial for diagnosis 7

• Cell-based indirect immunofluorescent antibody tests detect IgG antibodies to NMDAR and are the gold standard for diagnosis 2

• The target extracellular epitopes are conformational and not detectable by immunoblotting 3

Neuroimaging and Electrophysiology

• Brain MRI is usually unremarkable, though focal enhancement or medial temporal lobe abnormalities can be observed 3

• EEG often shows diffuse delta slowing without paroxysmal discharges despite frequent seizures, and may reveal extreme delta brush pattern (highly suggestive of NMDAR encephalitis) 4, 3

• CSF reveals nonspecific changes including pleocytosis and elevated protein 3

Prognosis and Reversibility

• This disorder is usually severe and can be fatal, but is potentially reversible with early immunotherapy 5, 2

• Once patients overcome the hyperkinetic phase, gradual improvement occurs over months with full recovery possible over 3 or more years 3

• Relapses occur in 10-30% of cases, mostly within the first two years from onset 7

• Early immunotherapy is crucial for better outcomes and prevention of long-term cognitive dysfunction 5

Special Considerations

• NMDAR antibodies have been detected in 30% of patients during herpes simplex encephalitis without clinical relapse, requiring careful clinical context interpretation 4

• Anti-NMDAR encephalitis can develop following viral infections (HSV, VZV, EBV, influenza A) 4

• The disorder provides important insights into the glutamatergic model of schizophrenia and neural circuit dysfunction in psychiatric disease 8