Test ID: ENC2 Encephalopathy, Autoimmune Evaluation, Spinal Fluid
Necessary Information
Provide the following information:
-Relevant clinical information
-Ordering provider name, phone number, mailing address, and e-mail address
Specimen Required
Container/Tube: Sterile vial
Specimen Volume: 4 mL
Forms
If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen.
Useful For
Evaluating new onset encephalopathy (noninfectious or metabolic) comprising confusional states, psychosis, delirium, memory loss, hallucinations, movement disorders, sensory or motor complaints, seizures, dyssomnias, ataxias, nausea, vomiting, inappropriate antidiuresis, coma, dysautonomias, or hypoventilation in spinal fluid specimens
The following accompaniments should increase of suspicion for autoimmune encephalopathy:
-Headache
-Autoimmune stigmata (personal or family history or signs of diabetes mellitus, thyroid disorder, vitiligo, poliosis [premature graying], myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus)
-History of cancer
-Smoking history (20+ pack years) or other cancer risk factors
-Inflammatory cerebrospinal fluid (or isolated protein elevation)
-Neuroimaging signs suggesting inflammation
Evaluating limbic encephalitis (noninfectious)
Directing a focused search for cancer
Investigating encephalopathy appearing in the course or wake of cancer therapy and not explainable by metastasis or drug effect
Profile Information
Test ID | Reporting Name | Available Separately | Always Performed |
---|---|---|---|
AEECI | Encephalopathy, Interpretation, CSF | No | Yes |
AMPCC | AMPA-R Ab CBA, CSF | No | Yes |
AMPHC | Amphiphysin Ab, CSF | No | Yes |
AGN1C | Anti-Glial Nuclear Ab, Type 1 | No | Yes |
ANN1C | Anti-Neuronal Nuclear Ab, Type 1 | No | Yes |
ANN2C | Anti-Neuronal Nuclear Ab, Type 2 | No | Yes |
ANN3C | Anti-Neuronal Nuclear Ab, Type 3 | No | Yes |
CS2CC | CASPR2-IgG CBA, CSF | No | Yes |
CRMC | CRMP-5-IgG, CSF | No | Yes |
DPPIC | DPPX Ab IFA, CSF | No | Yes |
GABCC | GABA-B-R Ab CBA, CSF | No | Yes |
GD65C | GAD65 Ab Assay, CSF | Yes | Yes |
GFAIC | GFAP IFA, CSF | No | Yes |
IG5IC | IgLON5 IFA, CSF | No | Yes |
LG1CC | LGI1-IgG CBA, CSF | No | Yes |
GL1IC | mGluR1 Ab IFA, CSF | No | Yes |
NIFIC | NIF IFA, CSF | No | Yes |
NMDCC | NMDA-R Ab CBA, CSF | No | Yes |
PCTRC | Purkinje Cell Cytoplasmc Ab Type Tr | No | Yes |
PCA1C | Purkinje Cell Cytoplasmic Ab Type 1 | No | Yes |
PCA2C | Purkinje Cell Cytoplasmic Ab Type 2 | No | Yes |
Reflex Tests
Test ID | Reporting Name | Available Separately | Always Performed |
---|---|---|---|
AGNBC | AGNA-1 Immunoblot, CSF | No | No |
AINCC | Alpha Internexin CBA, CSF | No | No |
AMPIC | AMPA-R Ab IF Titer Assay, CSF | No | No |
AMIBC | Amphiphysin Immunoblot, CSF | No | No |
AN1BC | ANNA-1 Immunoblot, CSF | No | No |
AN2BC | ANNA-2 Immunoblot, CSF | No | No |
CRMWC | CRMP-5-IgG Western Blot, CSF | Yes | No |
DPPCC | DPPX Ab CBA, CSF | No | No |
DPPTC | DPPX Ab IFA Titer, CSF | No | No |
GABIC | GABA-B-R Ab IF Titer Assay, CSF | No | No |
GFACC | GFAP CBA, CSF | No | No |
GFATC | GFAP IFA Titer, CSF | No | No |
IG5CC | IgLON5 CBA, CSF | No | No |
IG5TC | IgLON5 IFA Titer, CSF | No | No |
GL1CC | mGluR1 Ab CBA, CSF | No | No |
GL1TC | mGluR1 Ab IFA Titer, CSF | No | No |
NFHCC | NIF Heavy Chain CBA, CSF | No | No |
NIFTC | NIF IFA Titer, CSF | No | No |
NFLCC | NIF Light Chain CBA, CSF | No | No |
NMDIC | NMDA-R Ab IF Titer Assay, CSF | No | No |
PC1BC | PCA-1 Immunoblot, CSF | No | No |
PCTBC | PCA-Tr Immunoblot, CSF | No | No |
Testing Algorithm
If client requests or if immunofluorescence (IFA) patterns suggest CRMP-5-IgG, then CRMP-5-IgG Western blot is performed at an additional charge.
If IFA patterns suggest amphiphysin antibody, then amphiphysin immunoblot is performed at an additional charge.
If IFA pattern suggests AGNA-1 antibody, then AGNA-1 immunoblot is performed at an additional charge.
If IFA pattern suggests ANNA-1 antibody, then ANNA-1 immunoblot is performed at an additional charge.
If IFA pattern suggests ANNA-2 antibody, then ANNA-2 immunoblot is performed at an additional charge.
If IFA pattern suggests PCA-1 antibody, then PCA-1 immunoblot is performed at an additional charge.
If IFA pattern suggests PCA-Tr antibody, then PCA-Tr immunoblot is performed at an additional charge.
If IFA pattern suggests IgLON5 antibody, then IgLON5 IFA titer IgLON5 cell-binding assay (CBA) is performed at an additional charge.
If IFA pattern suggests AMPA-receptor antibody, and AMPA-receptor antibody CBA is positive, then AMPA-receptor antibody IFA titer assay is performed at an additional charge.
If IFA pattern suggests GABA-B-receptor antibody, and GABA-B-receptor antibody CBA is positive, then GABA-B-receptor antibody IFA titer assay is performed at an additional charge.
If IFA pattern suggests GFAP antibody, then GFAP IFA titer and GFAP CBA are performed at an additional charge.
If IFA pattern suggests NMDA-receptor antibody, and NMDA-receptor antibody CBA is positive, then NMDA-receptor antibody IFA titer assay is performed at an additional charge.
If IFA pattern suggests DPPX antibody, then DPPX antibody CBA and DPPX titer are performed at an additional charge.
If IFA pattern suggests mGluR1 antibody, then mGluR1 antibody CBA and mGluR1 titer are performed at an additional charge.
If IFA pattern suggests NIF antibody, then alpha internexin CBA, NIF heavy chain CBA, NIF light chain CBA, and NIF titer are performed at an additional charge.
See Encephalopathy Autoimmune Evaluation Algorithm-Spinal Fluid in Special Instructions.
Special Instructions
Method Name
AGN1C, AMPHC, AMPIC, ANN1C, ANN2C, ANN3C, CRMC, DPPIC, DPPTC, GABIC, GFAIC, GFATC, GL1IC, GL1TC, IG5IC, IG5TC, NIFIC, NIFTC, NMDIC, PCA1C, PCA2C, PCTRC: Indirect Immunofluorescence Assay (IFA)
AINCC, AMPCC, CS2CC, DPPCC, GABCC, GFACC, GL1CC, IG5CC, LG1CC, NFHCC, NFLCC, NMDCC: Cell-Binding Assay (CBA)
CRMWC: Western Blot (WB)
AGNBC, AMIBC, AN1BC, AN2BC, PC1BC, PCTBC: Immunoblot (IB)
GD65C: Radioimmunoassay (RIA)
Reporting Name
Encephalopathy-Autoimmune Eval, CSFSpecimen Type
CSFSpecimen Minimum Volume
2 mL
Specimen Stability Information
Specimen Type | Temperature | Time | Special Container |
---|---|---|---|
CSF | Refrigerated (preferred) | 28 days | |
Frozen | 28 days | ||
Ambient | 72 hours |
Clinical Information
Autoimmune encephalopathies extend beyond the classically recognized clinical and radiological spectrum of "limbic encephalitis." They encompass a diversity of neurological presentations with subacute or insidious onset, including confusional states, psychosis, delirium, memory loss, hallucinations, movement disorders, sensory or motor complaints, seizures, dyssomnias, ataxias, eye movement problems, nausea, vomiting, inappropriate antidiuresis, coma, dysautonomias, or hypoventilation. A diagnosis of autoimmune encephalopathy should be suspected on the basis of clinical course, coexisting autoimmune disorder (eg, thyroiditis, diabetes), serological evidence of autoimmunity, spinal fluid evidence of intrathecal inflammation, neuroimaging or electroencephalographic abnormalities, and favorable response to trial of immunotherapy.
Detection of one or more neural autoantibodies aids the diagnosis of autoimmune encephalopathy and may guide a search for cancer. Pertinent autoantibody specificities include: 1) neurotransmitter receptors and ion channels such as neuronal voltage-gated potassium channels (and interacting synaptic and axonal proteins, leucine-rich glioma inactivated protein: LGI1 and contactin associated protein 2: CASPR2), ionotropic glutamate receptors (N-methyl-D-aspartate receptor: NMDA and 2-amino-3-[5-methyl-3-oxo-1,2- oxazol-4-yl] propanoic acid: AMPA), metabotropic gamma-aminobutyric acid (GABA)-B receptors; 2) enzymes, signaling molecules and RNA-regulatory proteins in the cytoplasm and nucleus of neurons (glutamic acid decarboxylase 65: GAD65, collapsin response-mediator protein-5 neuronal: CRMP-5, antineuronal nuclear antibody-type 1: ANNA-1, and ANNA-2).
Importantly, autoimmune encephalopathies are reversible. Misdiagnosis as a progressive (currently irreversible) neurodegenerative condition is not uncommon and has devastating consequences for the patient. Clinicians must consider the possibility of an autoimmune etiology in the differential diagnoses of encephalopathy. For example, a potentially reversible disorder justifies a trial of immunotherapy for the detection of neural autoantibodies in patients presenting with symptoms of personality change, executive dysfunction, and psychiatric manifestations.
A triad of clues helps to identify patients with an autoimmune encephalopathy: 1) clinical presentation (subacute symptoms, onset rapidly progressive course, and fluctuating symptoms) and radiological findings consistent with inflammation, 2) detection of neural autoantibodies in serum or cerebrospinal fluid (CSF), and 3) favorable response to a trial of immunotherapy.
Detection of neural autoantibodies in serum or CSF informs the physician of a likely autoimmune etiology, and may heighten suspicion for a paraneoplastic basis and guide the search for cancer. Neurological accompaniments of neural autoantibodies are generally not syndromic, but diverse and multifocal. For example, LGI1 antibody was initially considered to be specific for autoimmune limbic encephalitis, but over time other presentations have been reported, including rapidly progressive course of cognitive decline mimicking neurodegenerative dementia.
Comprehensive antibody testing is more informative than selective testing for 1 or 2 neural antibodies. Some antibodies strongly predict an underlying cancer. For example; small-cell lung carcinoma (ANNA-1; CRMP-5-IgG), ovarian teratoma (NMDA-R), and thymoma (CRMP-5-IgG).
An individual patient's profile autoantibody may be informative for a specific cancer type. For example, in a patient presenting with encephalitis who has CRMP-5-IgG, and subsequent reflex reveals muscle acetylcholine receptor (AChR) binding antibody, the findings should raise a high suspicion for thymoma. Testing of CSF for autoantibodies is particularly helpful when serum testing is negative, though in some circumstances testing both serum and CSF simultaneously is pertinent. Testing of CSF is recommended for some antibodies in particular (such as NMDA-R antibody and GFAP-IgG) because CSF testing is both more sensitive and specific. In contrast, serum testing for LGI1 antibody is more sensitive than CSF testing.
Reference Values
Test ID |
Reporting name |
Methodology |
Reference value |
AMPCC |
AMPA-R Ab CBA, CSF |
Cell-binding assay (CBA) |
Negative |
AMPHC |
Amphiphysin Ab, CSF |
Indirect Immunofluorescence (IFA) |
<1:2 |
AGN1C |
Anti-Glial Nuclear Ab, Type 1 |
IFA |
<1:2 |
ANN1C |
Anti-Neuronal Nuclear Ab, Type 1 |
IFA |
<1:2 |
ANN2C |
Anti-Neuronal Nuclear Ab, Type 2 |
IFA |
<1:2 |
ANN3C |
Anti-Neuronal Nuclear Ab, Type 3 |
IFA |
<1:2 |
CS2CC |
CASPR2-IgG CBA, CSF |
CBA |
Negative |
CRMC |
CRMP-5-IgG, CSF |
IFA |
<1:2 |
DPPIC |
DPPX Ab IFA, CSF |
IFA |
Negative |
GABCC |
GABA-B-R Ab CBA, CSF |
CBA |
Negative |
GD65C |
GAD65 Ab Assay, CSF |
Radioimmunoassay (RIA) |
≤0.02 nmol/L Reference values apply to all ages. |
GFAIC |
GFAP IFA, CSF |
IFA |
Negative |
IG5IC |
IgLON5 IFA, CSF |
IFA |
Negative |
LG1CC |
LGI1-IgG CBA, CSF |
CBA |
Negative |
GL1IC |
mGluR1 Ab IFA, CSF |
IFA |
Negative |
NIFIC |
NIF IFA, CSF |
IFA |
Negative |
NMDCC |
NMDA-R Ab CBA, CSF |
CBA |
Negative |
PCTRC |
Purkinje Cell Cytoplasmc Ab Type Tr |
IFA |
<1:2 |
PCA1C |
Purkinje Cell Cytoplasmic Ab Type 1 |
IFA |
<1:2 |
PCA2C |
Purkinje Cell Cytoplasmic Ab Type 2 |
IFA |
<1:2 |
Reflex Information:
Test ID |
Reporting name |
Methodology |
Reference value |
AGNBC |
AGNA-1 Immunoblot, CSF |
Immunoblot (IB) |
Negative |
AINCC |
Alpha Internexin CBA, CSF |
CBA |
Negative |
AMPIC |
AMPA-R Ab IF Titer Assay, CSF |
IFA |
<1:2 |
AMIBC |
Amphiphysin Immunoblot, CSF |
IB |
Negative |
AN1BC |
ANNA-1 Immunoblot, CSF |
IB |
Negative |
AN2BC |
ANNA-2 Immunoblot, CSF |
IB |
Negative |
CRMWC |
CRMP-5-IgG Western Blot, CSF |
Western Blot |
Negative |
DPPCC |
DPPX Ab CBA, CSF |
CBA |
Negative |
DPPTC |
DPPX Ab IFA Titer, CSF |
IFA |
<1:2 |
GABIC |
GABA-B-R Ab IF Titer Assay, CSF |
IFA |
<1:2 |
GFACC |
GFAP CBA, CSF |
CBA |
Negative |
GFATC |
GFAP IFA Titer, CSF |
IFA |
<1:2 |
IG5CC |
IgLON5 CBA, CSF |
CBA |
Negative |
IG5TC |
IgLON5 IFA Titer, CSF |
IFA |
<1:2 |
GL1CC |
mGluR1 Ab CBA, CSF |
CBA |
Negative |
GL1TC |
mGluR1 Ab IFA Titer, CSF |
IFA |
<1:2 |
NFLCC |
NIF Light Chain CBA, CSF |
CBA |
Negative |
NMDIC |
NMDA-R Ab IF Titer Assay, CSF |
IFA |
Negative at <1:2 |
PC1BC |
PCA-1 Immunoblot, CSF |
IB |
Negative |
PCTBC |
PCA-Tr Immunoblot, CSF |
IB |
Negative |
Neuron-restricted patterns of IgG staining that do not fulfill criteria for ANNA-1, ANNA-2, ANNA-3, CRMP-5-IgG, PCA-1, PCA-2, or PCA-Tr may be reported as "unclassified anti-neuronal IgG." Complex patterns that include nonneuronal elements may be reported as "uninterpretable."
Note: CRMP-5 titers lower than 1:2 are detectable by recombinant CRMP-5 Western blot analysis. CRMP-5 Western blot analysis will be done on request on stored spinal fluid (held 4 weeks). This supplemental testing is recommended in cases of chorea, vision loss, cranial neuropathy, and myelopathy. Call the Neuroimmunology Laboratory at 800-533-1710 to request CRMP-5 Western blot.
Interpretation
Neuronal, glial, and muscle autoantibodies are valuable serological markers of autoimmune encephalopathy and of a patient's immune response to cancer. These autoantibodies are usually accompanied by subacute neurological symptoms and signs are not found in healthy subjects. It is not uncommon for more than 1 of the following autoantibody specificities to be detected in patients with an autoimmune encephalopathy:
-Plasma membrane autoantibodies: These are all potential effectors of neurological dysfunction: N-methyl-D-aspartate (NMDA) receptor; 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid (AMPA) receptor; gamma-amino butyric acid (GABA-B) receptor; neuronal ACh receptor.
-Neuronal nuclear autoantibodies: type 1 (ANNA-1), type 2 (ANNA-2), or type 3 (ANNA-3)
-Neuronal or muscle cytoplasmic antibodies: amphiphysin, Purkinje cell antibodies (PCA-1 and PCA-2), CRMP-5, GAD65, or striational.
Clinical Reference
2. Lucchinetti CF, Kimmel DW, Lennon VA: Paraneoplastic and oncological profiles of patients seropositive for type 1 anti-neuronal nuclear autoantibodies. Neurology 1998;50:652-657
3. Pittock SJ, Yoshikawa H, Ahlskog JE, et al: Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal and spinal cord dysfunction. Mayo Clin Proc 2006;81:1207-1214
4. Lancaster E, Martinez-Hernandez E, Dalmau J: Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 2011;77(2):179-189
5. Klein CJ, Lennon VA, Aston PA, et al: Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol 2013;70(2):229-234
Day(s) and Time(s) Performed
AGN1C, AMPHC, AMPIC, ANN1C, ANN2C, ANN3C, CRMC, DPPIC, DPPTC, GABIC, GFAIC, GFATC, GL1IC, GL1TC, IG5IC, IG5TC, NIFIC, NIFTC, NMDIC, PCA1C, PCA2C, PCTRC:
Monday through Friday; 5 a.m., 7 a.m., 5 p.m.
Saturday, Sunday; 6 a.m.
AMPCC, CS2CC, DPPCC, GABCC, LG1CC, NMDCC:
Monday through Friday; 10 p.m.
Sunday; 3 p.m.
GL1CC, IG5CC:
Monday, Thursday; 6 p.m.
AINCC, NFHCC, NFLCC:
Tuesday, Thursday; 6 p.m.
GFACC:
Monday, Wednesday, Friday; 6 p.m.
CRMWC:
Monday through Thursday; 8 a.m.
AGNBC, AMIBC, AN1BC, AN2BC, PC1BC, PCTBC:
Monday through Friday; 6 p.m.
GD65C:
Monday through Friday; 5 a.m., 2 p.m.
Saturday, Sunday; 7 a.m.
Analytic Time
8 daysTest Classification
This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.CPT Code Information
86255 x19
86341 x1
84182 AGNBC (if appropriate)
86255 AINCC (if appropriate)
86256 AMPIC (if appropriate)
84182 AMIBC (if appropriate)
84182 AN1BC (if appropriate)
84182 AN2BC (if appropriate)
84182 CRMWC (if appropriate)
86255 DPPCC (if appropriate)
86256 DPPTC (if appropriate)
86256 GABIC (if appropriate)
86255 GFACC (if appropriate)
86256 GFATC (if appropriate)
86255 IG5CC (if appropriate)
86256 IG5TC (if appropriate)
86255 GL1CC (if appropriate)
86256 GL1TC (if appropriate)
86255 NFHCC (if appropriate)
86256 NIFTC (if appropriate)
86255 NFLCC (if appropriate)
86256 NMDIC (if appropriate)
84182 PC1BC (if appropriate)
84182 PCTBC (if appropriate)
LOINC Code Information
Test ID | Test Order Name | Order LOINC Value |
---|---|---|
ENC2 | Encephalopathy-Autoimmune Eval, CSF | 94708-5 |
Result ID | Test Result Name | Result LOINC Value |
---|---|---|
61513 | NMDA-R Ab CBA, CSF | 93502-3 |
61514 | AMPA-R Ab CBA, CSF | 93491-9 |
61515 | GABA-B-R Ab CBA, CSF | 93426-5 |
34256 | Encephalopathy, Interpretation, CSF | 69048-7 |
64280 | LGI1-IgG CBA, CSF | 94288-8 |
64282 | CASPR2-IgG CBA, CSF | 94286-2 |
64929 | DPPX Ab IFA, CSF | 82989-5 |
64927 | mGluR1 Ab IFA, CSF | 94361-3 |
605156 | GFAP IFA, CSF | 94360-5 |
606965 | NIF IFA, CSF | 96490-8 |
606947 | IgLON5 IFA, CSF | 96479-1 |
89079 | AGNA-1, CSF | 94355-5 |
5906 | Amphiphysin Ab, CSF | 94354-8 |
3852 | ANNA-1, CSF | 94356-3 |
7472 | ANNA-2, CSF | 94357-1 |
21633 | ANNA-3, CSF | 94358-9 |
21650 | CRMP-5-IgG, CSF | 94706-9 |
3988 | PCA-1, CSF | 94363-9 |
21632 | PCA-2, CSF | 94364-7 |
21631 | PCA-Tr, CSF | 94362-1 |
21702 | GAD65 Ab Assay, CSF | 94359-7 |
36429 | Reflex Added | 77202-0 |
mml-neuroimmunology