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

Anti-N-methyl-D-aspartate (NMDA) 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

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 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-N-methyl-D-aspartate (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, AMPAR, GABABR, LGI1, mGluR5)
      • Human herpesvirus (HHV6/HHV7) 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

Monitoring

  • Monitor treatment response (in individuals who are antibody positive)
    • Serum anti-N-methyl-D-aspartate (anti-NMDA) receptor antibodies – decreasing levels may be associated with therapeutic response
  • Females – magnetic resonance imaging (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

ARUP Laboratory Tests

Primary Tests

Confirm diagnosis of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis

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

Confirm diagnosis of anti-NMDAR encephalitis in cerebrospinal fluid (CSF)

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

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

Detect unique IgG oligoclonal bands in CSF in conjunction with a matched serum specimen

Calculate CSF IgG index

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

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

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

Presence of VGKC antibodies should be used in conjunction with clinical manifestations for neuromyotonia spectrum of disorders and VGKC antibody-associated limbic encephalitis

Should not be used as the sole criterion for diagnosis

VGKC receptor-complex proteins may be coprecipitated by anti-VGKC antibodies, including LGI1, CASPR2, and other unidentified targets

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

For extended version of this panel, refer to autoimmune encephalitis extended panel

For adults and patients with suspicion of cancer, additional evaluation of paraneoplastic autoantibodies is recommended; refer to paraneoplastic antibodies (PCCA/ANNA) reflex test

Individual tests in panel may also be ordered separately

Panel includes NDMA receptor antibody, IgG with reflex to titer; glutamic acid decarboxylase (GAD) antibody; VGKC antibody; aquaporin-4 receptor antibody; aquaporin-4 receptor antibody, IgG by indirect fluorescent antibody (IFA) with reflex to titer; LGI1 antibody, IgG with reflex to titer; and CASPR2 antibody, IgG with reflex to titer

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

Individual tests in panel may also be ordered separately

Serum is the preferred specimen

Panel includes NDMA receptor antibody, IgG with reflex to titer; GAD antibody; VGKC antibody; aquaporin-4 receptor antibody; aquaporin-4 receptor antibody, IgG by IFA with reflex to titer; leucine-rich, glioma-inactivated protein 1 antibody, IgG with reflex to titer; alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antibody, IgG by IFA with reflex to titer; and contactin-associated protein-2 antibody, IgG with reflex to titer

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

Detect antibodies in addition to those included in the autoimmune encephalitis reflexive panel 

Testing for LGI1 and CASPR2 antibodies is always performed rather than only as a reflex

For adults and patients with suspicion of cancer, additional evaluation of paraneoplastic autoantibodies is recommended; refer to the paraneoplastic reflexive panel

Components include NMDA receptor antibody, IgG, glutamic acid decarboxylase antibody, VGKC antibody, aquaporin-4 receptor antibody, LG1 antibody, CASPR2 antibody, AMPA receptor antibody, GABA receptor antibody, and MOG antibody

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

Individual tests in panel may also be ordered separately

Panel includes Purkinje cell (PCCA) antibody and neuronal nuclear (ANNA) antibody IgG by IFA with reflex to titer and immunoblot (Hu, Ri, Yo, Tr/DNER); amphiphysin; antibody IgG; CV2.1 antibody IgG by IFA with reflex to titer; NDMA receptor antibody, IgG with reflex to titer; GAD antibody; VGKC antibody; aquaporin-receptor antibody; aquaporin-4 receptor antibody, IgG by IFA with reflex to titer; LGI1 antibody, IgG with reflex to titer; CASPR2 antibody, IgG with reflex to titer; N-type voltage-gated calcium channel (VGCC) antibody; P/Q type VGCC antibody; acetylcholine receptor binding antibody with reflex to acetylcholine receptor modulating antibody; titin antibody; and striated muscled antibody

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

Individual tests in panel may also be ordered separately

Serum is the preferred specimen

Panel includes Purkinje cell (PCCA) antibody and neuronal nuclear (ANNA) antibody IgG by IFA with reflex to titer and immunoblot (Hu, Ri, Yo); amphiphysin antibody IgG; CV2.1 antibody IgG by IFA with reflex to titer; NDMA receptor antibody, IgG with reflex to titer; GAD antibody; VGKC antibody; aquaporin-4 receptor antibody; aquaporin-4 receptor antibody, IgG by IFA with reflex to titer; LGI1 antibody, IgG with reflex to titer; CASPR2 antibody, IgG with reflex to titer; N-type voltage-gated calcium channel (VGCC) antibody; P/Q type VGCC antibody; acetylcholine receptor binding antibody with reflex to acetylcholine receptor modulating antibody; titin antibody; and striated muscled antibody; SOX1 antibody, IgG

Aid in diagnosis of limbic encephalitis

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

The presence of AMPA receptor antibodies may be associated with psychosis, with or without seizures; AMPA encephalitis may be paraneoplastic but tumor type is variable (thymic, lung and breast cancer)

Related Tests

Screening test for voltage-gated potassium channel (VGKC) antibody receptor complex-associated autoantibodies with test reflex to CASPR2 and LGI1 antibodies. Antibodies are associated with acquired neuromyotonia, limbic encephalitis, painful neuropathy, Morvan syndrome, and rare tumors (eg, thymoma, small-cell lung cancer) Serum is the preferred specimen type

Identify bacteria in cerebrospinal fluid (CSF)

Important informationLimited to the University of Utah Health Sciences Center only

May be helpful in diagnosing infectious etiology

May be helpful in diagnosing infectious etiology

May be helpful in diagnosing infectious etiology

May be helpful in diagnosing infectious etiology

Aid in ruling out metabolic encephalopathy

Gold standard test to diagnose fungi as agent of infection in blood

Gold standard test to diagnose fungi as agent of infection in blood

Aids in the diagnosis of paraneoplastic syndromes associated with ANNA-1 (Hu), ANNA-2 (Ri), PCCA-1 (Yo), amphiphysin, SOX1 antibody, and CV2.1 antibodies

Panel includes Purkinje cell/neuronal nuclear IgG and titer; neuronal nuclear (Hu, Ri, Yo, Tr/DNER) IgG; neuronal nuclear antibody (ANNA) IgG titer; CV2.1 antibody and titers; amphiphysin antibody; SOX1 antibody, IgG

Aid in the diagnosis of paraneoplastic neurologic syndromes associated with malignancy

Order based on clinical presentation

Aids in diagnosis of stiff-person syndrome, limbic encephalitis, and other autoimmune neurologic disorders

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

Aids in diagnosis of stiff-person syndrome, limbic encephalitis, and other autoimmune neurologic disorders

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

Screening test for voltage-gated potassium channel (VGKC) antibody receptor complex-associated autoantibodies

Assay does not identify contactin associated protein 2 (CASPR2) antibody or leucine-rich glioma inactivated 1 protein (LGI1) antibodies individually

Use to manage antibody-positive (VGKC, LGI1, or CASPR2) individual following immunotherapy and/or plasmapheresis

Presence of VGKC antibodies should be used in conjunction with clinical manifestations for neuromyotonia spectrum of disorders or VGKC antibody-associated limbic encephalitis

Should not be used as the sole criterion for diagnosis

VGKC receptor-complex proteins may be coprecipitated by anti-VGKC antibodies, including LGI1, CASPR2, or other unidentified targets

Screening test for voltage-gated potassium channel (VGKC) antibody receptor complex-associated autoantibodies

Does not identify contactin associated protein 2 (CASPR2) antibody or leucine-rich glioma inactivated 1 protein (LGI1) antibodies

Manage antibody-positive (VGKC, LGI1, or CASPR2) individual following immunotherapy and/or plasmapheresis

Results are not intended to be used as the sole means for clinical diagnosis or patient management decisions

Serum is the preferred specimen type

Aid in evaluation of neuromyelitis optica (NMO) and NMO spectrum disorders

Absence of antibodies to the AQP4 receptor does not rule out the diagnosis of NMO

A negative result can occur in the setting of immunosuppression

Test performance may vary due to differences in methods and/or disease states (new versus established)

Useful for initial evaluation of NMO spectrum disorders

Aid in evaluation of NMO and NMO spectrum disorders

Absence of antibodies to the AQP4 receptor does not rule out the diagnosis of NMO

A negative result can occur in the setting of immunosuppression

Test performance may vary due to differences in methods and/or disease states (new versus established)

Aid in diagnosis of CNS demyelinating disease or autoimmune encephalitis

The presence of myelin oligodendrocyte glycoprotein (MOG) antibody may be associated with neuromyelitis optica spectrum disorders including optic neuritis and transverse myelitis, brainstem encephalitis and acute disseminated encephalomyelitis

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

Aid in diagnosis of LGI1 antibody disorders associated with limbic encephalitis, hyponatremia, myoclonic movements

Disorders are rarely associated with tumors

Use to manage antibody-positive (LGI1) individual following immunotherapy and/or plasmapheresis

Aid in diagnosis of LGI1 antibody disorders associated with limbic encephalitis, hyponatremia, myoclonic movements

Disorders are rarely associated with tumors

Use to manage antibody-positive (LGI1) individual following immunotherapy and/or plasmapheresis

Serum is the preferred specimen

Aid in diagnosis of CASPR2 antibody disorders associated with acquired neuromyotonia, limbic encephalitis, painful neuropathy, and Morvan syndrome

Use to manage antibody-positive (CASPR2) individual following immunotherapy and/or plasmapheresis

Aid in diagnosis of CASPR2 antibody disorders associated with acquired neuromyotonia, limbic encephalitis, painful neuropathy, and Morvan syndrome

Use to manage antibody-positive (CASPR2) individual following immunotherapy and/or plasmapheresis

Aid in diagnosis of limbic encephalitis

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

The presence of AMPA receptor antibodies may be associated with psychosis, with or without seizures; AMPA encephalitis may be paraneoplastic but tumor type is variable (thymic, lung and breast cancer)

Aid in diagnosis of limbic encephalitis

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

The presence of GABA-BR antibodies may be associated with seizures; GABA-BR encephalitis may be paraneoplastic as about 50% of cases are associated with small-cell lung cancer

Medical Experts

Contributor

Fisher

Mark A. Fisher, PhD, D(ABMM)
Associate Professor of Clinical Pathology, University of Utah
Medical Director, Bacteriology, Special Microbiology, and Antimicrobial Susceptibility Testing, ARUP Laboratories
Contributor
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®