What is Anti NMDA (N-methyl-D-aspartate) receptor encephalitis?

What is Anti-NMDA Receptor Encephalitis?

Anti-NMDA receptor encephalitis is an autoimmune disorder caused by antibodies against the N-methyl-D-aspartate (NMDA) receptor that presents with a characteristic multi-stage progression of psychiatric symptoms, seizures, movement disorders, autonomic instability, and decreased consciousness, predominantly affecting young women and children. 1, 2

Epidemiology and Clinical Significance

• Anti-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 2, 3

• The median age at presentation is 25 years with a male-to-female ratio of 1:2 4

• Up to 50% of young adult female patients have an associated ovarian teratoma, though these tumors are much less common in children 1, 4

Clinical Presentation and Disease Progression

The disease follows a recognizable multi-stage pattern that distinguishes it from typical limbic encephalitis:

Initial Psychiatric Phase

• Patients, particularly children and young women, initially present with acute anxiety, behavioral changes, or psychosis and are often first admitted to psychiatric wards 1, 5

• Memory deficits, confusion, and disorientation develop early in the course 1, 6

Neurological Progression (Days to Weeks)

• Seizures or neuropsychological deficits emerge within days, defining the condition as organic rather than purely psychiatric 1, 5

• Movement disorders including dyskinesias and choreoathetosis become prominent 1, 3

• Reduced consciousness progresses over days to weeks 1, 3

Severe Phase (Requiring Intensive Care)

• Hypoventilation and autonomic instability often necessitate ICU admission 1, 3

• Autonomic imbalance with cardiovascular and temperature dysregulation occurs 1

• In children, the disease can present with behavioral disturbance and dyskinesias, historically misclassified as encephalitis lethargica 1

Pathophysiology

• The disease is mediated by IgG autoantibodies against the NR1 subunit of the NMDA receptor, a protein critical for memory function and synaptic plasticity 7, 8

• The autoimmune response is often triggered by an underlying tumor, particularly ovarian teratoma in young women 2, 4

• Anti-NMDAR encephalitis can develop following viral infections including HSV, VZV, EBV, and influenza A 3

Diagnostic Features

Neuroimaging

• MRI is frequently not informative in anti-NMDAR encephalitis, distinguishing it from typical limbic encephalitis where 60% show medial temporal lobe inflammation 1

• When abnormal, MRI may show temporal lobe signal alterations 5

Cerebrospinal Fluid Analysis

• Pleocytosis at onset is very common, unlike VGKC-complex associated limbic encephalitis where CSF changes are uncommon 1

• Oligoclonal bands are rare 1

Electroencephalography

• EEG may show widespread activity slowing 5

• The extreme delta brush pattern is suggestive of NMDAR encephalitis when present 3

Antibody Testing

• Anti-NMDA receptor antibodies must be detected in both serum and CSF for diagnostic confirmation 5, 8

• A cell-based indirect immunofluorescent antibody test is the reliable diagnostic method 8

Tumor Association and Screening

• In female patients, 20-50% harbor an ovarian teratoma that requires surgical removal 2, 4

• All patients should undergo appropriate imaging to identify associated tumors, particularly ovarian teratoma in young women 1, 2

• Tumor screening should be performed annually for several years, particularly if treatment response is poor or relapses occur 1, 4

Prognosis and Relapse Risk

• With prompt immunotherapy or tumor removal, 74% of patients achieve full or substantial recovery at 1 year 1

• Relapses occur in 20-25% of non-paraneoplastic patients and can be separated by months or years 1

• Treatment started within 4 weeks of symptom onset confers the best recovery 1

• Delayed diagnosis and treatment may be associated with worse outcomes including death 6

Key Clinical Pitfalls

• The initial psychiatric presentation often leads to misdiagnosis as a primary psychiatric disorder, delaying appropriate immunotherapy 1, 5, 6

• The absence of frank psychosis combined with neurologic features related to memory and cognition should prompt consideration of anti-NMDAR encephalitis rather than primary psychiatric illness 6

• NMDAR antibodies have been detected in 30% of patients during herpes simplex encephalitis without clinical relapse, so positive antibody results must be interpreted in proper clinical context 3