anti-NMDA Receptor Encephalitis

Primer

anti-NMDA (N-methyl-D-aspartate) Receptor Encephalitis is an autoimmune encephalitis that is initially characterized by prominent psychiatric symptoms, then progressing to seizures, movement disorders, autonomic dysfunction, and hypoventilation. The prominent psychiatric symptoms often results in initial hospitalization in psychiatric units, and delays in diagnosis and treatment. It is associated with CSF IgG antibodies against the GluN1 subunit of the NMDA receptor.

Epidemiology
  • Anti-NMDA receptor encephalitis occurs across the life span. However, young women, often those with ovarian teratomas are most commonly affected.[1]
  • Increasingly, there is awareness that older adults can also be affected, most commonly presenting with cognitive decline and catatonic features.[2]
Comorbidity
  • Underlying ovarian teratoma and herpes simplex virus encephalitis are risk factors for anti-NMDA Receptor Encephalitis.
  • About 4% of patients with anti-NMDA receptor encephalitis develop two different syndromes that can occur separately or simultaneously (MOG-related or aquaporin 4 (AQP4)-related syndromes).

Diagnostic Criteria

Probable

Diagnosis can be made when all 3 of the following criteria have been met (Graus et al. 2016):[3]

  1. Rapid onset (less than 3 months) of at least 4 of the 6 following major groups of symptoms:
    • Abnormal (psychiatric) behaviour or cognitive dysfunction
    • Speech dysfunction (pressured speech, verbal reduction, mutism)
    • Seizures
    • Movement disorder, dyskinesias (orofacial, limb, or trunk), or rigidity/abnormal postures
    • Decreased level of consciousness
    • Autonomic dysfunction or central hypoventilation
  2. At least 1 of the following laboratory study results:
    • Abnormal EEG (focal or diffuse slow or disorganised activity, epileptic activity, or extreme delta brush)
    • CSF with pleocytosis or oligoclonal bands
  3. Reasonable exclusion of alternative causes (see Differential Diagnosis)

Systemic Teratomas

A probable diagnosis can also be made in the presence of 3 of the above groups of symptoms accompanied by a systemic teratoma.

Definite

A Definite diagnosis can be made in the presence of 1 or more of the 6 major groups of symptoms and IgG anti-GluN1 antibodies (including CSF testing), after reasonable exclusion of other disorders.

Common Symptoms

Young adults and adults typically present with abnormal behaviours, including psychosis, delusions, hallucinations, agitation, aggression, or catatonia. Irritability and insomnia are also common initial symptoms. Commonly, patients also have antipsychotic intolerance (fever, decreased alertness, or unusual extrapyramidal rigidity).[4][5] These psychiatric symptoms are then followed by dyskinesia, speech impairments, memory impairments, autonomic instability, and a decreased level of consciousness. Seizures also occur at any time during the disease state, but occurs earlier in males.[6] In the late stages of the illness, central hypoventilation and cerebellar ataxia or hemiparesis can occur, leading to potential mortality.

Pathophysiology

  • anti-NMDA Receptor Encephalitis is an autoantibody-mediated inflammation of the brain, and IgG autoantibodies are directed against the GluN1a subunit of the NMDA Receptor
  • Viral infections and ovarian teratomas are possible triggers for this autoantibody-mediated inflammation

Differential Diagnosis

anti-NMDA Receptor Encephalitis-specific Differential
Autoimmune Encephalitis Differential
  • Herpes simplex virus encephalitis
    • Characterized by fever and MRI hemorrhagic lesions. On MRI there are usually unilateral rather than bilateral temporal lobe changes, insular involvement, and absence of basal ganglia involvement.
  • HHV-6 encephalitis
    • Most commonly found in immunosuppressed patients
  • Glioma
  • Status epilepticus
    • More common in children and young adults. MRI abnormalities beyond temporal lobes.
  • Neurosyphilis
    • Symptoms and MRI findings beyond medial temporal lobe involvement.
  • Whipple
    • Systemic symptoms characterized by polyarthralgia and intermittent diarrhea), oculomasticatory myorhythmia.
  • Human Immunodeficiency Virus (HIV)
  • CNS infections (especially varicella zoster virus or tuberculosis)
  • Septic encephalopathy
  • Metabolic encephalopathy
  • Drug toxicity
  • Cerebrovascular disease
  • Neoplastic disorders
  • Creutzfeldt-Jakob disease
  • Epileptic disorders
  • Rheumatologic disorders (e.g. - lupus, sarcoidosis, other)
  • Paraneoplastic syndromes
  • Kleine-Levin
  • Reye syndrome (children)
  • Mitochondrial diseases
  • Inborn errors of metabolism (children)

Investigations

CSF

  • The most common finding in the CSF is mild leukocyte pleocytosis (typically < 100 leukocyte/μL)
    • Thus, a non-inflammatory CSF with a normal leukocyte count, normal protein and no CSF-specific oligoclonal bands reduces the likelihood of anti-NMDAR encephalitis.

EEG

  • EEG will most commonly reveal diffuse and generalized slowing in 90% of patients with anti-NMDAR encephalitis.[8]
  • Extreme delta brush is also specific for NMDA receptor encephalitis.[9]
  • More focal slowing (such as temporal slowing) can be seen but is non-specific for NMDAR encephalitis.
  • Thus, a normal EEG is atypical for anti-NMDAR encephalitis and reduces the likelihood of the disease.

Antibodies

  • Lumbar punctures to obtain CSF antibody studies to test for anti-NMDAR antibodies should be done if a patient meets the diagnostic criteria.
  • Do not do serum-only studies as the risk of a false-negative or false-positive diagnosis is high – up to 14% have antibodies in the CSF, but not in the serum.[10]
    • Additionally, only IgG antibodies against the GluN1 subunit of the NMDA receptor are specific for anti-NMDA receptor encephalitis. IgM or IgA antibodies have been reported in the serum of 10% of healthy patients, or those with other disorders.

Don't Forget About Herpes Simplex Virus Encephalitis

HSV encephalitis can be followed by anti-NMDA receptor encephalitis, with a seroconversion rate of up to 30 percent.[11][12] Thus, CSF analysis for NMDA receptor antibodies is mandatory in patients with a history of herpes simplex encephalitis presenting with a relapse.[13] A relapsing HSV encephalitis affects 20% of patients, and manifests as new-onset choreoathetosis in children, or psychiatric symptoms in teenagers, adults, and the elderly. The relapse can occur a few weeks or, rarely, months after the initial viral infection.

Treatment

  • First-line therapies used in anti-NMDAR encephalitis include steroids, intravenous immunoglobulin (IVIG) and plasma exchange.

Resources

For Providers

References

1) Dalmau, J., Lancaster, E., Martinez-Hernandez, E., Rosenfeld, M. R., & Balice-Gordon, R. (2011). Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. The Lancet Neurology, 10(1), 63-74.
2), 6), 11), 13) Giné-Servén, E., Serra-Mestres, J., Martinez-Ramirez, M., Boix-Quintana, E., Davi-Loscos, E., Guanyabens, N., ... & Labad, J. (2021). Anti-NMDA receptor encephalitis in older adults: A systematic review of case reports. General hospital psychiatry.
3) Graus, F., Titulaer, M. J., Balu, R., Benseler, S., Bien, C. G., Cellucci, T., ... & Glaser, C. A. (2016). A clinical approach to diagnosis of autoimmune encephalitis. The Lancet Neurology, 15(4), 391-404.
4) Giné Servén, E., Boix Quintana, E., Guanyabens Buscà, N., Casado Ruiz, V., Torres Rivas, C., Niubo Gurgui, M., ... & Palma, C. (2019). Considerations of psychotic symptomatology in anti‐NMDA encephalitis: Similarity to cycloid psychosis. Clinical Case Reports, 7(12), 2456-2461.
5) Lejuste, F., Thomas, L., Picard, G., Desestret, V., Ducray, F., Rogemond, V., ... & Leboyer, M. (2016). Neuroleptic intolerance in patients with anti-NMDAR encephalitis. Neurology-Neuroimmunology Neuroinflammation, 3(5), e280.
7) Al-Diwani, A., Handel, A., Townsend, L., Pollak, T., Leite, M. I., Harrison, P. J., ... & Irani, S. R. (2019). The psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient data. The Lancet Psychiatry, 6(3), 235-246.
8) Titulaer, M. J., McCracken, L., Gabilondo, I., Armangué, T., Glaser, C., Iizuka, T., ... & Dalmau, J. (2013). Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. The Lancet Neurology, 12(2), 157-165.
9) Schmitt, S. E., Pargeon, K., Frechette, E. S., Hirsch, L. J., Dalmau, J., & Friedman, D. (2012). Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology, 79(11), 1094-1100.
10) Gresa-Arribas, N., Titulaer, M. J., Torrents, A., Aguilar, E., McCracken, L., Leypoldt, F., ... & Graus, F. (2014). Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. The Lancet Neurology, 13(2), 167-177.
12) Ewida, A., Laxton, K., Lou, A., Suryadevara, N., & Sanders, A. (2019). An unusual late presentation of anti-NMDA Receptor (NMDA-R) Autoimmune Encephalitis following Herpes Simplex Virus (HSV) Encephalitis (P2. 2-014).