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

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
    • Herpes simplex virus (HSV) polymerase chain reaction (PCR)
    • Varicella-Zoster virus (VZV) PCR
    • Enterovirus PCR
    • VDRL
    • Viral culture from CSF not indicated (perform nucleic-acid amplification testing)
  • 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
    • Does not differentiate from multiple sclerosis
• Consider evaluation for other etiologies once infection has been ruled out
  • Autoimmune evaluation
    • Antiphospholipid syndrome
    • Sjögren syndrome
    • Thyroiditis (eg, Graves disease, Hashimoto thyroiditis)
    • Multiple sclerosis
    • Systemic lupus erythematosus
  • Metabolic evaluation
    • Porphyria
    • Hepatic encephalopathy
    • Drug intoxication
    • Mitochondrial disorders
    • Amino/organic acid metabolism disorders
• 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 [GABA_BR], 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
    • Arbovirus serology
    • Toxoplasma gondii serology

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

• Viral encephalitis
  • HSV
  • VZV
  • Epstein-Barr virus
  • Cytomegalovirus
  • HHV-6/HHV-7
  • HIV
  • Arbovirus
  • Rabies virus
• Autoimmune encephalitis
  • Paraneoplastic encephalitis
  • Limbic encephalitis
  • Systemic lupus erythematosus
  • Antiphospholipid syndrome
  • Sjögren syndrome
  • Thyroiditis (eg, Graves disease, Hashimoto thyroiditis)
  • Vasculitis
• Toxics and metabolic disorders
  • Drug ingestion (salicylates, amphetamines, cocaine, phencyclidine, carbon monoxide, methanol, cyanide)
  • Porphyria
  • Mitochondrial disorders
  • Amino/organic acid metabolism disorders (primarily children)

Monitoring

• 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

Background

Epidemiology

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

Pathophysiology

• 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