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

Anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis is a treatment-responsive inflammatory encephalopathic autoimmune neurologic 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.


Indications for Testing

Evaluate encephalitis of unknown origin with memory deficit, bizarre behavioral changes, and/or seizures

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 acid-fast bacillus (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 immunoglobulin G (IgG) index: often elevated later in disease
  • Consider evaluation for other etiologies once infection has been ruled out
  • Testing based on symptoms
    • Psychotic symptoms
      • Anti-NMDA receptor antibodies (serum, CSF)
      • Rabies virus
      • Creutzfeldt-Jakob disease
      • Paraneoplastic neurological syndrome
        • Screen for malignancy if syndrome established
    • Limbic symptoms prominent
      • Autoimmune/limbic encephalitis evaluation (eg, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor [AMPAR], gamma [γ]-aminobutyric acid-B receptor [GABABR], leucine-rich glioma-inactivated protein 1 [LGI1], metabotropic glutamate receptor 5 [mGluR5])
      • Human herpesvirus 6 (HHV-6) and 7 (HHV-7) PCR (serum, CSF)
      • Screen for malignancy
    • Parkinsonian syndrome symptoms

Imaging Studies

  • Head magnetic resonance imaging (MRI)/computed tomography (CT) scan
    • 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: rule out ovarian pathology
  • Testicular ultrasound in males: rule out testicular tumor
  • Electroencephalography (EEG): seizure activity, generalized slowing common

Differential Diagnosis


  • Monitor treatment response (in individuals who are antibody positive)
    • Serum anti-NMDA receptor antibodies: decreasing levels may be associated with therapeutic response
  • Females: MRI and abdominal ultrasound ≥2 years after diagnosis
  • Males: guidelines have not been established; consider MRI or positron emission tomography (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 2 subunits (NR1 and either NR2 or NR3) that contain extracellular epitopes
  • NMDAR is an ion channel located in both the pre- and postsynaptic 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 the number of receptors 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 of patients are nonparaneoplastic (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

ARUP Laboratory Tests

Select individual antibody tests are available. Refer to the ARUP Laboratory Test Directory at www.aruplab.com.

Confirm diagnosis of anti-NMDA receptor encephalitis

May be used in monitoring treatment response in individuals who are antibody positive

Refer to the Anti-NMDA Receptor (NR1) IgG Antibodies Test Fact Sheet for additional information

May be useful to differentiate anti-NMDA disease from multiple sclerosis

Screening test for voltage-gated potassium channel (VGKC) antibody receptor complex-associated autoantibodies which reflexes to contactin associated protein 2 (CASPR2) and leucine-rich glioma inactivated 1 protein (LGI1) antibodies individually

Differential evaluation of encephalitis of unknown origin with subacute onset of seizures, confusion, memory loss, and/or behavioral change

Comprehensive panel for the evaluation of paraneoplastic and neuromuscular junction disorders, and/or encephalitis, in the presence or absence of malignancy

Comprehensive panel for the evaluation of paraneoplastic disorders and/or encephalitis in the presence or absence of malignancy

Use to aid in diagnosis of limbic encephalitis

May be used in monitoring treatment response in individuals who are antibody positive


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