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 seizures
  • Monitor treatment response in individuals who are antibody positive

Laboratory Testing

  • Nonspecific testing
    • CBC – not usually helpful, although leukocytosis may point to bacterial etiology; relative lymphocytosis may suggest a viral etiology
    • Electrolyte panel, liver function studies – rule out metabolic encephalopathy
  • Cerebrospinal fluid (CSF) exam – necessary to determine presence of meningitis
    • CSF opening pressure – limited value if normal; usually >300mm in bacterial but ≤300 in all others
    • Microscopic exam – white count >1,000 cells/µL in >90% of patients with bacterial meningitis
      • Neutrophils usually predominate in bacterial meningitis; monocytes predominate in viral and fungal meningitis
      • Normal result does not exclude bacterial meningitis
    • Protein
    • Glucose
    • Gram stain
    • Bacterial culture
    • CSF antigen antibody testing, when appropriate (eg, pneumococcal antigen, dimorphic fungi serology, cryptococcal antigen)
    • Fungal and/or AFB culture (when clinically indicated) requires a HIGH VOLUME tap (at least 10cc fluid [minimum 5cc for each test])
    • Viral culture from CSF not indicated (perform nucleic-acid amplification testing)
    • Oligoclonal band testing – often elevated later in disease
      • Does not differentiate from MS
  • Consider testing for other etiologies once infectious process is ruled out
  • Anti-NMDA receptor antibodies, serum – confirm diagnosis

Imaging Studies

  • Head MRI/CT
    • Rule out anatomic abnormality or infection (eg, abscess)
    • In syndrome, MRI/CT are typically normal or have nonspecific findings (eg, white matter lesions, cerebritis) without focal lesions
  • Abdominal ultrasound/MRI – rule out ovarian pathology in females
    • Testicular ultrasound to replace abdominal ultrasound in males – rule out testicular tumor
  • EEG – seizure activity, generalized slowing common

Differential Diagnosis

Monitoring

  • Anti-NMDA receptor antibodies, serum – decreasing levels may be associated with therapeutic response
  • MRI and abdominal ultrasound in females for at least two years after diagnosis
    • Guidelines in males not available – 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

Pathophysiology

  • N-methyl-D-aspartate receptor (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
  • NMDAR is a heteromeric tetramer protein made up of two subunits (NR1 and either NR2 or NR3) that contain extracellular epitopes
  • Anti-NMDAR 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

Clinical Presentation

  • Prodromal symptoms   
    • Initial-low-grade fever, headache, and nonspecific viral-like illness
  • Rapid progression to other neurologic symptoms
    • Hallucinations
    • Delusions, psychoses
    • Memory issues
    • Paranoia
    • Unresponsiveness
    • Seizures
    • Dyskinesia, movement disorders
    • Cardiac dysrhythmias
    • Autonomic dysfunction (hypoventilation, tachycardia, hypertension, hyperthermia)
  • May have relapses; better course if tumor present and is 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

   
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

Aid in ruling out metabolic encephalopathy

   
Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Aid in ruling out metabolic encephalopathy

   
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

   
Fungal Culture 0060149
Method: Culture/Identification

May be helpful in evaluation of encephalitis if fungal etiology suspected

Need 5cc fluid to culture for fungus

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

May be helpful in evaluation of encephalitis if fungal etiology suspected

   
Fungal Culture, Skin, Hair or Nails 0060728
Method: Culture/Identification

May be helpful in evaluation of encephalitis if fungal etiology suspected

   
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
   
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