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FeedbackAnti-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
- CBC – rule out meningitis
- 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
- Autoimmune evaluation
- 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
- Psychotic 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
- 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
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
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
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody
Confirm diagnosis of anti-NMDAR encephalitis in cerebrospinal fluid (CSF)
May be used in monitoring treatment response in individuals who are antibody positive
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody
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
Qualitative Isoelectric Focusing/Electrophoresis/Quantitative Immunoturbidimetry
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
Quantitative Radioimmunoassay/Semi-Quantitative Cell-Based Indirect Fluorescent Antibody
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
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody/Quantitative Radioimmunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Panel includes NMDA 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; contactin-associated protein-2 antibody, IgG with reflex to titer; and dipeptidyl aminopeptidase-like protein 6 (DPPX) 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
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody/Quantitative Radioimmunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Components: NMDA receptor antibody, IgG; glutamic acid decarboxylase antibody; VGKC antibody; aquaporin-4 receptor antibody; LGI1 antibody; CASPR2 antibody; AMPA receptor antibody; GABA receptor antibody; MOG antibody; and DPPX 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
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody/Qualitative Immunoblot/Quantitative Radioimmunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Components: 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; glutamic acid decarboxylase (GAD) antibody; voltage-gated potassium channel (VGKC) antibody; aquaporin-4 receptor antibody, IgG by IFA with reflex to titer; leucine-rich, glioma-inactivated protein 1 antibody, IgG with reflex to titer; contactin-associated protein-2 antibody, IgG with reflex to titer; acetylcholine receptor binding antibody; striated muscled antibody; AMPA receptor antibody, IgG by IFA with reflex to titer; GABA-BR antibody IgG by IFA with reflex to titer; MOG antibody, IgG by IFA with reflex to titer; SOX1 antibody, IgG by immunoblot; P/Q type voltage-gated calcium channel (VGCC) antibody; ganglionic acetylcholine receptor antibody; dipeptidyl aminopeptidase-like protein 6 (DPPX) antibody, IgG by IFA with reflex to titer, serum
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
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody/Qualitative Immunoblot/Quantitative Radioimmunoassay/Semi-quantitative Enzyme-Linked Immunosorbent Assay
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-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; striated muscled antibody; SOX1 antibody, IgG; dipeptidyl aminopeptidase-like protein 6 (DPPX) antibody, IgG with reflex to titer; and amphiphysin 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)
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody
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
Quantitative Radioimmunoassay/Semi-Quantitative Cell-Based Indirect Fluorescent Antibody
May be helpful in diagnosing infectious etiology
Enzymatic Assay
May be helpful in diagnosing infectious etiology
Reflectance Spectrophotometry
Quantitative Ion-Selective Electrode/Enzymatic Assay
Aid in ruling out metabolic encephalopathy
Quantitative Enzymatic Assay/Quantitative Spectrophotometry
Gold standard test to diagnose fungi as agent of infection in blood
Culture/Identification
Gold standard test to diagnose fungi as agent of infection in blood
Continuous Monitoring Blood Culture/Identification
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
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody/Qualitative Immunoblot
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
Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot
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
Semi-quantitative Enzyme-Linked Immunosorbent Assay
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
Semi-quantitative Enzyme-Linked Immunosorbent Assay
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
Quantitative Radioimmunoassay
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
Quantitative Radioimmunoassay
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)
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
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)
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody
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
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody
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
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody
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
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody
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
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody
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
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody
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)
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody
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
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody
References
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Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091-1098.
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Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.
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Hacohen Y, Wright S, Waters P, et al. 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):748-755.
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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 1615-1616.
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Peery HE, Day GS, Dunn S, et al. Anti-NMDA receptor encephalitis. The disorder, the diagnosis and the immunobiology. Autoimmun Rev. 2012;11(12):863-872.
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Ramanathan S, Mohammad SS, Brilot F, et al. Autoimmune encephalitis: recent updates and emerging challenges. J Clin Neurosci. 2014;21(5):722-730.
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Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the International Encephalitis Consortium. Clin Infect Dis. 2013;57(8):1114-1128.
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Vincent A, Bien CG. Anti-NMDA-receptor encephalitis: a cause of psychiatric, seizure, and movement disorders in young adults. Lancet Neurol. 2008;7(12):1074-1075.
Medical Experts
Fisher
Peterson
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