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

Diagnosis

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 – to rule out meningitis
      • Leukocytosis may point to bacterial etiology
      • Relative lymphocytosis may suggest a viral etiology
    • Electrolyte panel, liver function studies – to 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 for ruling 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
    • Viral culture from CSF – not indicated (perform nucleic-acid amplification testing)
    • 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

Imaging Studies

  • Head MRI/CT
    • To 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
    • To rule out testicular tumor
  • EEG – seizure activity, generalized slowing common

Differential Diagnosis

Monitoring

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

Clinical Background

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.

Epidemiology

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

Pathophysiology

  • 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
    • 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

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
N-methyl-D-Aspartate Receptor Antibody, IgG, Serum with Reflex to Titer 2004221
Method: Semi-Quantitative Indirect Fluorescent Antibody

Confirm diagnosis of anti-NMDAR encephalitis

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

   
Cerebrospinal Fluid (CSF) Culture and Gram Stain 0060106
Method: Stain/Culture/Identification

May be helpful in diagnosing infectious etiology

   
Cell Count, CSF 0095018
Method: Cell Count/Differential

May be helpful in diagnosing infectious etiology

   
Glucose, CSF 0020515
Method: Enzymatic

May be helpful in diagnosing infectious etiology

   
Protein, Total, CSF 0020514
Method: Reflectance Spectrophotometry

May be helpful in diagnosing infectious etiology

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

May be useful to differentiate antiNMDA disease from multiple sclerosis

Profile includes:

  • IgG, Serum
  • IgG, CSF
  • IgG Index
  • Albumin, CSF
  • Albumin, Serum by Nephelometry
  • Albumin Index
  • CSF IgG/Albumin ratio
  • CSF IgG Synthesis Rate
  • CSF Oligoclonal Bands
   
Voltage-Gated Potassium Channel (VGKC) Antibody with Reflex to LGI1 and CASPR2 Screen and Titer 2009463
Method: Quantitative Radioimmunoassay/Semi-Quantitative Indirect Fluorescent Antibody

Screening test for Voltage-Gated Potassium Channel (VGKC) antibody receptor complex-associated autoantibodies which reflexes to CASPR2 and LGI1 antibodies individually

Antibodies are associated with acquired neuromyotonia, limbic encephalitis, painful neuropathy, Morvan syndrome, and rare tumors (eg, thymoma, small-cell lung cancer)

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

Confirm diagnosis of anti-NMDAR encephalitis in CSF

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

May be helpful in diagnosing infectious etiology

Electrolyte Panel 0020410
Method: Quantitative Ion-Selective Electrode/Enzymatic
Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Aid in ruling out metabolic encephalopathy

Fungal Culture 0060149
Method: Culture/Identification

May be helpful in evaluation of encephalitis if fungal etiology suspected

Blood Culture, Fungal 0060070
Method: Continuous Monitoring Blood Culture/Identification

May be helpful in evaluation of encephalitis if fungal etiology suspected

AMPA-Receptor (GluR1/2) Antibody IgG, Serum (Temporary Delay as of 10/21/14 - no referral available) 2011050
Method: Qualitative Immunofluorescence 

May be useful in evaluation of certain types of new-onset cryptogenic epilepsy (eg, associated with movement disorders, psychiatric manifestations, history of autoimmune diseases)

AMPA-Receptor (GluR1/2) Antibody IgG, CSF (Temporary Delay as of 10/21/14 - no referral available) 2011048
Method: Qualitative Immunofluorescence 

May be useful in evaluation of certain types of new-onset cryptogenic epilepsy (eg, associated with movement disorders, psychiatric manifestations, history of autoimmune diseases)

Gamma-Aminobutyric Acid-B (GABA-B) Receptor Antibody, Serum (Temporary Delay as of 10/21/14 - no referral available) 2011023
Method: Qualitative Immunofluorescence

May be useful in evaluation of certain types of new-onset cryptogenic epilepsy (eg, associated with movement disorders, psychiatric manifestations, history of autoimmune diseases)

Gamma-Aminobutyric Acid-B (GABA-B) Receptor Antibody, CSF (Temporary Delay as of 10/21/14 - no referral available) 2011021
Method: Qualitative Immunofluorescence

May be useful in evaluation of certain types of new-onset cryptogenic epilepsy (eg, associated with movement disorders, psychiatric manifestations, history of autoimmune diseases)