N-methyl-D-Aspartate (NMDA) type Glutamate Receptor Autoantibody Disorders - Anti-NMDA-Receptor Encephalitis

Anti-NMDA receptor encephalitis is a treatment-responsive inflammatory encephalopathic autoimmune disease associated with anti-NMDA receptor antibodies. The disease is mostly associated with teratomas of the ovaries and is thus considered a paraneoplastic neurologic syndrome (PNS). However, there are a significant number of cases with no detectable tumor.

  • Diagnosis
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

  • Evaluate encephalitis of unknown origin with memory deficit, bizarre behavioral changes, and/or seizures
  • Monitor treatment response (in individuals who are antibody positive)

Laboratory Testing

  • Nonspecific testing (Venkatesan 2013)
    • CBC – rule out meningitis
      • Leukocytosis may point to bacterial etiology
      • Relative lymphocytosis may suggest a viral etiology
    • Electrolyte panel, liver function studies – rule out metabolic encephalopathy
    • Serum testing
      • Routine blood cultures
      • HIV testing
      • Rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) testing for syphilis
      • Acute and convalescent specimens for specific testing based on clinical presentation (eg, mycoplasma for respiratory infection, serology for encephalitis)
      • Geographic viruses if clinical setting is appropriate
  • Cerebrospinal fluid (CSF) exam – necessary to rule out meningitis; collect at least 20 cc
    • Opening pressure – often normal
    • Cell count and differential – lymphocytosis predominates
    • Protein – often elevated
    • Glucose
    • Gram stain and bacterial culture
    • Viral studies – based on presentation; may include any of the following
    • CSF antigen antibody testing, when appropriate (eg, pneumococcal antigen)
    • Fungal and/or AFB testing (when clinically indicated)
      • Requires a HIGH VOLUME tap (at least 10 cc fluid)
      • Culture
      • Cryptococcal India ink or antigen testing
    • Oligoclonal bands with IgG  index – often elevated later in disease
  • Consider evaluation for other etiologies once infection has been ruled out
  • Testing based on symptoms
    • Psychotic symptoms
    • Limbic symptoms prominent
      • Autoimmune/limbic encephalitis evaluation (eg, AMPAR, GABABR, LGI1, mGluR5)
      • Human herpesvirus (HHV6/HHV7) PCR (serum, CSF)
      • Screen for malignancy
    • Parkinsonian syndrome symptoms

Imaging Studies

  • Head MRI/CT
    • Rule out anatomic abnormality or infection (eg, abscess)
    • MRI/CT typically normal or has nonspecific findings (eg, white matter lesions, cerebritis) without focal lesions
  • Abdominal ultrasound/MRI in females
  • Testicular ultrasound in males
    • Rule out testicular tumor
  • EEG – seizure activity, generalized slowing common

Differential Diagnosis

  • Serum anti-NMDA receptor antibodies – decreasing levels may be associated with therapeutic response
  • MRI and abdominal ultrasound in females for at least two years post diagnosis
    • Guidelines in males have not been established – consider MRI or PET with testicular ultrasound


  • Incidence – unknown
  • Age – affects all age groups with a low prevalence in individuals >50 years
  • Sex – M<F during reproductive age range


  • N-methyl-D-aspartate receptor (NMDAR) is a heteromeric tetramer protein made up of two subunits (NR1 and either NR2 or NR3) that contain extracellular epitopes
  • NMDAR is an ion channel located in both the pre- and post-synaptic membrane that plays a key role in synaptic transmission and plasticity
    • Highly expressed in the forebrain, limbic system, and hypothalamus
  • Anti-NMDAR IgG antibodies are directed against the extracellular epitope of the NR1 subunit (strongly associated with treatment-responsive limbic encephalitis)
    • Decreases their number on postsynaptic neuronal dendrites causing synaptic dysfunction
    • Presumed cause of psychotic symptoms characteristic of anti-NMDAR encephalitis
    • Binding is reversible and symptoms reverse
    • Significant portion is non paraneoplastic (particularly men and children)
      • Most common tumor – ovarian teratoma in females

Clinical Presentation

  • Prodromal phase 
    • Initial-low-grade fever, headache, and nonspecific viral-like illness
    • Lasts from 5 days to 2 weeks
  • Psychotic phase
    • Psychoses (eg, hallucinations, delusions, paranoia)
    • Memory issues, attention deficit, cognitive impairment
    • Paranoia
    • Seizures – more common in adult males
      • In males – partial seizures more common
      • In females – generalized seizures more common
    • Dyskinesia, movement disorders
  • Catatonic phase
    • Cardiac dysrhythmias
    • Autonomic dysfunction (hypoventilation, tachycardia, hypertension, hyperthermia)
    • Stereotypical automatisms (lip smacking, teeth clenching)
    • Speech and language dysfunction
    • May ultimately progress to catatonic state if not diagnosed
  • May have relapses; better clinical course if tumor is present and removed
    • Tumors found more frequently in females of childbearing age
      • Usually ovarian teratoma
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

N-methyl-D-Aspartate Receptor Antibody, IgG, Serum with Reflex to Titer 2004221
Method: Semi-Quantitative Indirect Fluorescent Antibody

N-methyl-D-Aspartate Receptor Antibody, IgG, CSF with Reflex to Titer 2005164
Method: Semi-Quantitative Indirect Fluorescent Antibody

Oligoclonal Band Profile 0080440
Method: Qualitative Isoelectric Focusing/Electrophoresis/Nephelometry

Voltage-Gated Potassium Channel (VGKC) Antibody with Reflex to LGI1 and CASPR2 Screen and Titer 2009463
Method: Quantitative Radioimmunoassay/Semi-Quantitative Indirect Fluorescent Antibody

Autoimmune Encephalitis Reflexive Panel 2013601
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Radioimmunoassay

Autoimmune Neurologic Disease Reflexive Panel 2013944
Method: Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot/Quantitative Radioimmunoassay/Semi-quantitative Enzyme-Linked Immunosorbent Assay


Venkatesan A, Tunkel AR, Bloch KC, Lauring AS, Sejvar J, Bitnun A, Stahl J, Mailles A, Drebot M, Rupprecht CE, Yoder J, Cope JR, Wilson MR, Whitley RJ, Sullivan J, Granerod J, Jones C, Eastwood K, Ward KN, Durrheim DN, Solbrig MV, Guo-Dong L, Glaser CA, International Encephalitis Consortium. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis. 2013; 57(8): 1114-28. PubMed

General References

Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, Dessain SK, Rosenfeld MR, Balice-Gordon R, Lynch DR. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008; 7(12): 1091-8. PubMed

Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Höftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Prüss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostásy K, Saiz A, Venkatesan A, Vincent A, Wandinger K, Waters P, Dalmau J. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016; 15(4): 391-404. PubMed

Hacohen Y, Wright S, Waters P, Agrawal S, Carr L, Cross H, De Sousa C, Devile C, Fallon P, Gupta R, Hedderly T, Hughes E, Kerr T, Lascelles K, Lin J, Philip S, Pohl K, Prabahkar P, Smith M, Williams R, Clarke A, Hemingway C, Wassmer E, Vincent A, Lim MJ. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens. J Neurol Neurosurg Psychiatry. 2013; 84(7): 748-55. PubMed

Lafond P, Varvat J, Tardy B. N-methyl-D-aspartate limbic encephalitis: diagnosis should respect well-recognized criteria. Crit Care Med. 2010; 38(7): 1615; author reply 1615-6. PubMed

Lazar-Molnar E, Tebo AE. Autoimmune NMDA receptor encephalitis. Clin Chim Acta. 2015; 438: 90-7. PubMed

Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies Ann N Y Acad Sci. 2015; 1338: 94-114. PubMed

Leypoldt F, Wandinger K. Paraneoplastic neurological syndromes. Clin Exp Immunol. 2014; 175(3): 336-48. PubMed

Lim M, Hacohen Y, Vincent A. Autoimmune encephalopathies Pediatr Clin North Am. 2015; 62(3): 667-85. PubMed

Miya K, Takahashi Y, Mori H. Anti-NMDAR autoimmune encephalitis. Brain Dev. 2014; 36(8): 645-52. PubMed

Peery HE, Day GS, Dunn S, Fritzler MJ, Prüss H, De Souza C, Doja A, Mossman K, Resch L, Xia C, Sakic B, Belbeck L, Foster WG. Anti-NMDA receptor encephalitis. The disorder, the diagnosis and the immunobiology. Autoimmun Rev. 2012; 11(12): 863-72. PubMed

Ramanathan S, Mohammad SS, Brilot F, Dale RC. Autoimmune encephalitis: recent updates and emerging challenges. J Clin Neurosci. 2014; 21(5): 722-30. PubMed

Vincent A, Bien CG. Anti-NMDA-receptor encephalitis: a cause of psychiatric, seizure, and movement disorders in young adults. Lancet Neurol. 2008; 7(12): 1074-5. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Lazar-Molnar E, Tebo AE. Autoimmune NMDA receptor encephalitis. Clin Chim Acta. 2015; 438: 90-7. PubMed

McMillin GA, Wood KE, Strathmann FG, Krasowski MD. Patterns of drugs and drug metabolites observed in meconium: What do they mean? Ther Drug Monit. 2015; 37(5): 568-80. PubMed

Medical Reviewers

Last Update: October 2017