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.

Tabs Content

Clinical Overview

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 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-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
  - 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
- HHV6/HHV7
- HIV
- Arbovirus
- Rabies virus
Autoimmune encephalitis
- Paraneoplastic encephalitis
- Limbic encephalitis
- Systemic lupus erythematosus
- Antiphospholipid syndrome
- Sjögren syndrome
- Thyroiditis (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-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 Lab Tests

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.

N-methyl-D-Aspartate Receptor Antibody, IgG, Serum with Reflex to Titer 2004221
Method: Semi-Quantitative Indirect Fluorescent Antibody

Recommended Use

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

Reflex pattern – If NMDA antibody IgG is positive, then an NMDA antibody IgG titer is reported

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

Recommended Use

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

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

Reflex pattern – if NMDA CSF antibody IgG is positive, then an NMDA CSF antibody IgG titer is reported

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

Recommended Use

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

Voltage-Gated Potassium Channel (VGKC) Antibody with Reflex to LGI1 and CASPR2 Screen and Titer 2009463
Method: Quantitative Radioimmunoassay/Semi-Quantitative Indirect Fluorescent Antibody

Recommended Use

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)

Reflex pattern – if VGKC is indeterminate or positive, LGI1 antibody IgG and CASPR2 antibody IgG will be added; if LGI1 antibody IgG is positive, then LGI1 antibody IgG titer will be added; if CASPR2 antibody IgG is positive, then CASPR2 antibody IgG titer will be added

Limitations

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

Autoimmune Encephalitis Reflexive Panel 2013601
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Radioimmunoassay

Recommended Use

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

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

Individual tests in panel may also be ordered separately

Autoimmune Encephalitis Extended Panel 3001431
Method: Semi-Quantitative Indirect Fluorescent Antibody/Quantitative Radioimmunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Recommended Use

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

Autoimmune Neurologic Disease Reflexive Panel 2013944
Method: Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot/Quantitative Radioimmunoassay/Semi-quantitative Enzyme-Linked Immunosorbent Assay

Recommended Use

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

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; voltage-gated calcium channel (VGCC) antibody; acetylcholine receptor binding antibody with reflex to acetylcholine receptor modulating antibody; titin antibody; and striated muscled antibody

Individual tests in panel may also be ordered separately

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antibody, IgG by IFA with Reflex to Titer, Serum 3001260
Method: Semi-Quantitative Indirect Fluorescent Antibody

Recommended Use

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)

Test Fact Sheet(s)

Voltage-Gated Potassium Channel Antibody Disorders

Medical Experts

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

Peterson, Lisa K., PhD, D(ABMLI), Medical Director, Immunology, at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Tebo, Anne E., PhD, D(ABMLI), Medical Director, Immunology at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

Venkatesan A, Tunkel AR, Bloch KC, Lauring AS, Sejvar J, Bitnun A, Stahl J, Mailles A, Drebot M, Rupprecht CE, Yoder J, Cope JR, Wilson MR, Whitley RJ, Sullivan J, Granerod J, Jones C, Eastwood K, Ward KN, Durrheim DN, Solbrig MV, Guo-Dong L, Glaser CA, International Encephalitis Consortium. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis. 2013; 57(8): 1114-28. PubMed

General References

Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, Dessain SK, Rosenfeld MR, Balice-Gordon R, Lynch DR. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008; 7(12): 1091-8. PubMed

Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Höftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Prüss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostásy K, Saiz A, Venkatesan A, Vincent A, Wandinger K, Waters P, Dalmau J. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016; 15(4): 391-404. PubMed

Hacohen Y, Wright S, Waters P, Agrawal S, Carr L, Cross H, De Sousa C, Devile C, Fallon P, Gupta R, Hedderly T, Hughes E, Kerr T, Lascelles K, Lin J, Philip S, Pohl K, Prabahkar P, Smith M, Williams R, Clarke A, Hemingway C, Wassmer E, Vincent A, Lim MJ. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens. J Neurol Neurosurg Psychiatry. 2013; 84(7): 748-55. PubMed

Lafond P, Varvat J, Tardy B. N-methyl-D-aspartate limbic encephalitis: diagnosis should respect well-recognized criteria. Crit Care Med. 2010; 38(7): 1615; author reply 1615-6. PubMed

Lazar-Molnar E, Tebo AE. Autoimmune NMDA receptor encephalitis. Clin Chim Acta. 2015; 438: 90-7. PubMed

Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies. Ann N Y Acad Sci. 2015; 1338: 94-114. PubMed

Leypoldt F, Wandinger K. Paraneoplastic neurological syndromes. Clin Exp Immunol. 2014; 175(3): 336-48. PubMed

Lim M, Hacohen Y, Vincent A. Autoimmune encephalopathies. Pediatr Clin North Am. 2015; 62(3): 667-85. PubMed

Miya K, Takahashi Y, Mori H. Anti-NMDAR autoimmune encephalitis. Brain Dev. 2014; 36(8): 645-52. PubMed

Peery HE, Day GS, Dunn S, Fritzler MJ, Prüss H, De Souza C, Doja A, Mossman K, Resch L, Xia C, Sakic B, Belbeck L, Foster WG. Anti-NMDA receptor encephalitis. The disorder, the diagnosis and the immunobiology. Autoimmun Rev. 2012; 11(12): 863-72. PubMed

Ramanathan S, Mohammad SS, Brilot F, Dale RC. Autoimmune encephalitis: recent updates and emerging challenges. J Clin Neurosci. 2014; 21(5): 722-30. PubMed

Vincent A, Bien CG. Anti-NMDA-receptor encephalitis: a cause of psychiatric, seizure, and movement disorders in young adults. Lancet Neurol. 2008; 7(12): 1074-5. PubMed

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Lazar-Molnar E, Tebo AE. Autoimmune NMDA receptor encephalitis. Clin Chim Acta. 2015; 438: 90-7. PubMed

McMillin GA, Wood KE, Strathmann FG, Krasowski MD. Patterns of drugs and drug metabolites observed in meconium: What do they mean? Ther Drug Monit. 2015; 37(5): 568-80. PubMed

Educational Videos

Content Review:

January 2018

Last Update: March 2019

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

Diagnosis

Indications for Testing

Laboratory Testing

Imaging Studies

Differential Diagnosis

Monitoring

Background

Epidemiology

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Test Fact Sheet(s)

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult


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

Diagnosis

Indications for Testing

Laboratory Testing

Imaging Studies

Differential Diagnosis

Monitoring

Background

Epidemiology

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Test Fact Sheet(s)

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult