Anti-NMDA Receptor Encephalitis
Anti-NMDA receptor encephalitis is one of the most common and clinically distinctive forms of autoimmune encephalitis, first described by Dalmau and colleagues in 2007. Antibodies target the GluN1 subunit of the NMDA receptor, causing receptor internalization and a characteristic polysymptomatic neuropsychiatric syndrome. It predominantly affects young women and children, frequently in association with ovarian teratoma. Despite the severity of the acute illness — which can include coma and need for ICU admission — the majority of patients achieve good outcomes with early and aggressive immunotherapy, making it a critical “not to miss” diagnosis.
Bottom Line
- Demographics: Median age 21 years; F:M ratio 4:1; affects ages 2 months to 85 years
- Clinical stages: Prodromal (viral-like) → psychiatric/cognitive → movement disorder/seizures → dysautonomia/hypoventilation → gradual recovery (months)
- MRI is often normal: 70–80% of patients have normal or nonspecific brain MRI despite severe clinical presentation
- CSF: 80% abnormal with lymphocytic pleocytosis and unpaired OCBs; CSF antibody testing is essential
- Tumor: Ovarian teratoma in ~60% of females aged 15–35; tumor removal is a critical part of treatment
- EEG: 90% abnormal; extreme delta brush pattern is relatively specific
- Prognosis: 80% achieve mRS 0–2 by 24 months; ~5% mortality; recovery can take months to years
Pathophysiology
NMDA receptor antibodies are of the IgG1 subclass and are directly pathogenic through receptor cross-linking and internalization:
- Antibodies bind the extracellular N-terminal domain of the GluN1 subunit
- IgG-mediated cross-linking triggers receptor endocytosis, reducing cell-surface NMDA receptor density
- This leads to NMDA receptor hypofunction, disrupting glutamatergic neurotransmission
- The process is potentially reversible with antibody removal, explaining the capacity for recovery
- Complement activation plays a minimal role (unlike AQP4-NMOSD)
Triggers
- Ovarian teratoma: Mature cystic teratoma containing neural tissue that expresses NMDA receptors, triggering autoimmunity through tumor antigen exposure
- Post-HSV-1 encephalitis: Neuronal death releases NMDA receptors, triggering secondary autoimmunity; especially recognized in children
- Idiopathic: Many cases, particularly in males and children, have no identifiable trigger
Clinical Features
Typical Staged Progression
| Stage | Features | Timing |
|---|---|---|
| 1. Prodrome | Headache, fever, fatigue, upper respiratory symptoms (viral-like illness) | Days before onset |
| 2. Psychiatric/Cognitive | Behavioral changes, agitation, hallucinations, delusions, paranoia, psychosis, short-term memory loss, language dysfunction (speech reduction to mutism) | First 1–2 weeks |
| 3. Movement Disorder/Seizures | Polymorphic movement disorder (orofacial dyskinesia, choreoathetosis, dystonic posturing, stereotypies), seizures (generalized or focal) | Weeks 2–4 |
| 4. Autonomic/Hypoventilation | Autonomic instability (tachycardia, blood pressure fluctuations, hyperthermia), central hypoventilation requiring intubation, decreased consciousness progressing to coma | Weeks to months |
| 5. Recovery | Gradual improvement in reverse order of symptom onset; cognitive and behavioral deficits may persist longest | Months to years |
Diagnostic Red Flags
- Young women with new-onset psychosis should be evaluated for anti-NMDA receptor encephalitis before attributing symptoms to a primary psychiatric disorder
- Movement disorders (especially orofacial dyskinesias) emerging after psychiatric symptoms are highly suggestive
- Autonomic instability and central hypoventilation distinguish this from primary psychiatric illness
- Language deterioration progressing to mutism is characteristic
- Seizures in the context of psychiatric symptoms should prompt antibody testing
Age-Related Differences
| Feature | Adults (>12 years) | Children (≤12 years) |
|---|---|---|
| Initial presentation | Psychiatric symptoms predominate | Seizures and movement disorders often first |
| Movement disorder | Orofacial dyskinesia, choreoathetosis | More varied; dystonia, choreoathetosis |
| Teratoma risk | ~60% in females 15–35y | Rare (<10%) |
| Post-HSV trigger | Uncommon | Well-recognized |
| Outcome | Good with treatment; cognitive deficits may persist | Generally good; behavioral and developmental concerns during recovery |
Investigations
Brain MRI
Brain MRI is normal or nonspecific in 70–80% of patients, which is remarkably discordant with the severity of the clinical presentation. When abnormal, findings may include:
- Nonspecific white matter changes
- Mesial temporal T2/FLAIR hyperintensity in a minority
- Rarely, cortical or cerebellar abnormalities
- Functional imaging shows substantial deficits despite normal structural MRI
CSF Analysis
- 80% abnormal: Lymphocytic pleocytosis is common
- Unpaired oligoclonal bands (OCBs) — intrathecal antibody synthesis
- NMDA receptor antibodies in CSF are essential for diagnosis; CSF is more sensitive and specific than serum for this antibody
- Serum alone may miss cases or yield false positives
EEG
- 90% abnormal: Diffuse slowing is most common
- 20% show epileptiform abnormalities
- Extreme delta brush pattern: Rhythmic delta activity with superimposed beta bursts; relatively specific for NMDA receptor encephalitis, though not pathognomonic
Tumor Screening
Cancer Screening Protocol
- All females aged 12–50: Pelvic ultrasound and/or MRI for ovarian teratoma
- If initial screen negative: Repeat imaging at 6-month intervals for at least 2 years
- Males and older females: CT chest/abdomen/pelvis; PET-CT if clinical suspicion
- Children post-HSV: Teratoma rare; focus on clinical monitoring
- Tumor removal accelerates recovery and reduces relapse risk
Diagnostic Criteria
Probable anti-NMDA receptor encephalitis can be diagnosed with:
- Rapid onset (<3 months) of ≥4 of the following: psychiatric symptoms, memory deficit, speech disorder, seizures, movement disorder, decreased consciousness, autonomic dysfunction, central hypoventilation
- At least one of: abnormal EEG, CSF pleocytosis, or oligoclonal bands
- Reasonable exclusion of other disorders
Definite diagnosis requires detection of IgG antibodies against GluN1 subunit in CSF (with or without serum positivity) in the presence of ≥1 of the six major symptom groups, after reasonable exclusion of other disorders.
Treatment
First-Line Immunotherapy
- IV methylprednisolone: 1 g/day for 3–5 days
- IVIg: 0.4 g/kg/day for 5 days
- Plasma exchange: 5–7 sessions on alternate days
- These may be used in combination; approximately 50% improve within 4 weeks of first-line therapy
Tumor Removal
- Surgical resection of ovarian teratoma should occur as early as possible
- Tumor removal improves outcomes and reduces relapse risk from ~35% to ~10–15%
Second-Line Immunotherapy
- Rituximab: 375 mg/m² weekly × 4 or 1 g × 2 (2 weeks apart)
- Cyclophosphamide: IV pulse dosing
- Approximately 60% of first-line non-responders improve with second-line therapy
- Second-line therapy should not be delayed — early escalation improves outcomes
Maintenance Therapy
- Rituximab or mycophenolate mofetil for relapse prevention (the 2025 LEARN RCT showed adjunctive MMF reduced 2-year relapse from 26.5% to 5.9%)
- Duration individualized; typically 1–2 years minimum
- Serial antibody titers are not reliable for guiding treatment decisions — clinical status is the preferred metric
Prognosis
| Outcome | Detail |
|---|---|
| Good outcome (mRS 0–2) | ~80% by 24 months |
| Improvement timeline | Weeks to months; can continue improving for up to 24 months |
| Relapse rate | 10–15% overall; reduced by immunotherapy and tumor removal |
| Mortality | ~5% |
| Residual deficits | Almost all patients have some residual neuropsychiatric deficits, particularly in executive function and memory |
| Favorable prognostic factors | Early treatment, tumor removal when applicable, less severe initial presentation |
Differential Diagnosis
- Primary psychiatric disorders: First-episode psychosis, catatonia — key distinction: movement disorder, autonomic instability, hypoventilation
- Infectious encephalitis: HSV, enterovirus — CSF viral studies, MRI pattern differs
- Drug intoxication: Ketamine, phencyclidine (NMDA receptor antagonists produce similar phenomenology)
- Metabolic encephalopathy: Hepatic, uremic, thyroid
- Other autoimmune encephalitis: LGI1, GABAB — clinical features and demographics differ
- Neuroleptic malignant syndrome: Can be triggered by antipsychotics given for presumed psychiatric illness
References
- Irani SR. Autoimmune encephalitis. Continuum (Minneap Minn). 2024;30(4):995-1020.
- Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091-1098.
- Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis. Lancet Neurol. 2013;12(2):157-165.
- Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.