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HelpTest ID: EPS2 Epilepsy, Autoimmune/Paraneoplastic Evaluation, Serum
Ordering Guidance
Multiple neurological phenotype-specific autoimmune/paraneoplastic evaluations are available. For more information as well as phenotype-specific testing options, see Autoimmune Neurology Test Ordering Guide.
When more than one evaluation is ordered on the same order number, the duplicate test will be canceled.
For a list of antibodies performed with each evaluation, see Autoimmune Neurology Antibody Matrix.
This test should not be requested for patients who have recently received radioisotopes, therapeutically or diagnostically, because of potential assay interference. The specific waiting period before specimen collection will depend on the isotope administered, the dose given, and the clearance rate in the individual patient. Specimens will be screened for radioactivity prior to analysis. Radioactive specimens received in the laboratory will be held 1 week and assayed if sufficiently decayed or canceled if radioactivity remains.
Necessary Information
Provide the following information:
-Relevant clinical information
-Ordering provider name, phone number, mailing address, and e-mail address
Specimen Required
Patient Preparation: For optimal antibody detection, specimen collection is recommended prior to initiation of immunosuppressant medication or intravenous immunoglobulin (IVIg) treatment.
Supplies: Sarstedt Aliquot Tube, 5 mL (T914)
Collection Container/Tube:
Preferred: Red top
Acceptable: Serum gel
Submission Container/Tube: Plastic vial
Specimen Volume: 4 mL
Collection Instructions: Centrifuge and aliquot serum into a plastic vial.
Forms
If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen.
Useful For
Investigating new onset cryptogenic epilepsy with incomplete seizure control and duration of less than 2 years, using serum specimens
Investigating new onset cryptogenic epilepsy plus 1 or more of the following accompaniments:
-Psychiatric accompaniments (psychosis, hallucinations)
-Movement disorder (myoclonus, tremor, dyskinesias)
-Headache
-Cognitive impairment/encephalopathy
-Autoimmune stigmata (personal history or family history or signs of diabetes mellitus, thyroid disorder, vitiligo, premature graying of hair, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, idiopathic adrenocortical insufficiency), or multiple sclerosis
-History of cancer
-Smoking history (20 or more pack-years) or other cancer risk factors
-Investigating seizures occurring within the context of a subacute multifocal neurological disorder without obvious cause, especially in a patient with a past or family history of cancer
-A rising autoantibody titer in a previously seropositive patient suggests cancer recurrence
Profile Information
| Test ID | Reporting Name | Available Separately | Always Performed |
|---|---|---|---|
| AEPSI | Epilepsy, Interpretation, S | No | Yes |
| AMPCS | AMPA-R Ab CBA, S | No | Yes |
| AMPHS | Amphiphysin Ab, S | No | Yes |
| AGN1S | Anti-Glial Nuclear Ab, Type 1 | No | Yes |
| ANN1S | Anti-Neuronal Nuclear Ab, Type 1 | No | Yes |
| ANN2S | Anti-Neuronal Nuclear Ab, Type 2 | No | Yes |
| ANN3S | Anti-Neuronal Nuclear Ab, Type 3 | No | Yes |
| CS2CS | CASPR2-IgG CBA, S | No | Yes |
| CRMS | CRMP-5-IgG, S | No | Yes |
| DPPCS | DPPX Ab CBA, S | No | Yes |
| GABCS | GABA-B-R Ab CBA, S | No | Yes |
| GD65S | GAD65 Ab Assay, S | Yes | Yes |
| GFAIS | GFAP IFA, S | No | Yes |
| LG1CS | LGI1-IgG CBA, S | No | Yes |
| GL1IS | mGluR1 Ab IFA, S | No | Yes |
| NCDIS | Neurochondrin IFA, S | No | Yes |
| NMDCS | NMDA-R Ab CBA, S | No | Yes |
| PCAB2 | Purkinje Cell Cytoplasmic Ab Type 2 | No | Yes |
| PCATR | Purkinje Cell Cytoplasmic Ab Type Tr | No | Yes |
| PDEIS | PDE10A Ab IFA, S | No | Yes |
| T46IS | TRIM46 Ab IFA, S | No | Yes |
Reflex Tests
| Test ID | Reporting Name | Available Separately | Always Performed |
|---|---|---|---|
| AGNBS | AGNA-1 Immunoblot, S | No | No |
| AMPIS | AMPA-R Ab IF Titer Assay, S | No | No |
| AMIBS | Amphiphysin Immunoblot, S | No | No |
| AN1BS | ANNA-1 Immunoblot, S | No | No |
| AN2BS | ANNA-2 Immunoblot, S | No | No |
| CRMWS | CRMP-5-IgG Western Blot, S | Yes | No |
| DPPTS | DPPX Ab IFA Titer, S | No | No |
| GABIS | GABA-B-R Ab IF Titer Assay, S | No | No |
| GFACS | GFAP CBA, S | No | No |
| GFATS | GFAP IFA Titer, S | No | No |
| GL1CS | mGluR1 Ab CBA, S | No | No |
| GL1TS | mGluR1 Ab IFA Titer, S | No | No |
| NMDIS | NMDA-R Ab IF Titer Assay, S | No | No |
| PCTBS | PCA-Tr Immunoblot, S | No | No |
| AGNTS | AGNA-1 Titer, S | No | No |
| AN1TS | ANNA-1 Titer, S | No | No |
| AN2TS | ANNA-2 Titer, S | No | No |
| AN3TS | ANNA-3 Titer, S | Yes | No |
| APHTS | Amphiphysin Ab Titer, S | No | No |
| CRMTS | CRMP-5-IgG Titer, S | No | No |
| NCDCS | Neurochondrin CBA, S | No | No |
| NCDTS | Neurochondrin IFA Titer, S | No | No |
| PC2TS | PCA-2 Titer, S | No | No |
| PCTTS | PCA-Tr Titer, S | No | No |
| PDETS | PDE10A Ab IFA Titer, S | No | No |
| T46CS | TRIM46 Ab CBA, S | No | No |
| T46TS | TRIM46 Ab IFA Titer, S | No | No |
Testing Algorithm
To determine the necessity of laboratory testing for patients with suspected autoimmune encephalitis, epilepsy or dementia, see the Antibody Prevalence in Epilepsy and Encephalopathy (APE2) scorecard.
If the client requests or the immunofluorescence assay (IFA) patterns suggest collapsin response-mediator protein-5 (CRMP-5)-IgG, then the CRMP-5-IgG IFA titer and CRMP-5-IgG Western blot will be performed at an additional charge.
If the IFA patterns suggest amphiphysin antibody, then the amphiphysin immunoblot and amphiphysin IFA titer will be performed at an additional charge.
If the IFA pattern suggests antiglial nuclear antibody (AGNA)-1, then the AGNA-1 immunoblot and AGNA-1 IFA titer will be performed at an additional charge.
If the IFA pattern suggests antineuronal nuclear antibody type 1 (ANNA-1), then the ANNA-1 IFA titer, ANNA-1 immunoblot, and ANNA-2 immunoblot will be performed at an additional charge.
If the IFA pattern suggests ANNA-2 antibody, then the ANNA-2 IFA titer, ANNA-2 immunoblot, ANNA-1 immunoblot will be performed at an additional charge.
If the client requests or if the IFA pattern suggests ANNA-3 antibody, then the ANNA-3 IFA titer will be performed at an additional charge.
If the IFA pattern suggests Purkinje cytoplasmic antibody type 2 (PCA-2), then the PCA-2 IFA titer will be performed at an additional charge.
If the IFA pattern suggests PCA-Tr antibody, then the PCA-Tr immunoblot and PCA-Tr IFA titer will be performed at an additional charge.
If the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor antibody cell-binding assay (CBA) result is positive, then the AMPA receptor antibody IFA titer will be performed at an additional charge.
If the gamma-aminobutyric acid B (GABA-B) receptor antibody CBA result is positive, then the GABA-B-receptor antibody IFA titer assay will be performed at an additional charge.
If the IFA pattern suggests glial fibrillary acidic protein (GFAP) antibody, then the GFAP IFA titer and GFAP CBA will be performed at an additional charge.
If the N-methyl-D-aspartate (NMDA) receptor antibody CBA result is positive, then the NMDA-receptor antibody IFA titer assay will be performed at an additional charge.
If the dipeptidyl-peptidase-like protein-6 (DPPX) antibody CBA result is positive, then the DPPX IFA titer will be performed at an additional charge.
If the IFA pattern suggests metabotropic glutamate receptor 1 (mGluR1) antibody, then the mGluR1 antibody CBA and mGluR1 IFA titer will be performed at an additional charge.
If the IFA pattern suggests neurochondrin antibody, then the neurochondrin antibody CBA and neurochondrin IFA titer will be performed at an additional charge.
If the IFA pattern suggests tripartite motif-containing protein 46 (TRIM46) antibody, then TRIM46 antibody CBA and TRIM46 IFA titer will be performed at an additional charge.
If the IFA pattern suggests phosphodiesterase 10A (PDE10A) antibody, then PDE10A antibody IFA titer will be performed at an additional charge.
For more information see Autoimmune/Paraneoplastic Epilepsy Evaluation Algorithm-Serum.
Method Name
AGN1S, AGNTS, AMPIS, AMPHS, APHTS, ANN1S, AN1TS, ANN2S, AN2TS, ANN3S, AN3TS, CRMTS, CRMS, DPPTS, GABIS, GFAIS, GFATS, GL1IS, GL1TS, NCDIS, NCDTS, NMDIS, PCAB2, PC2TS, PCATR, PCTTS, PDEIS, PDETS, T46IS, T46TS: Indirect Immunofluorescence Assay (IFA)
AMPCS, CS2CS, DPPCS, GABCS, GFACS, LG1CS, GL1CS, NCDCS, NMDCS, T46CS: Cell Binding Assay (CBA)
CRMWS: Western Blot (WB)
AGNBS, AMIBS, AN1BS, AN2BS, PCTBS: Immunoblot (IB)
GD65S: Radioimmunoassay (RIA)
Reporting Name
Epilepsy, Autoimm/Paraneo, SSpecimen Type
SerumSpecimen Minimum Volume
2.5 mL
Specimen Stability Information
| Specimen Type | Temperature | Time | Special Container |
|---|---|---|---|
| Serum | Refrigerated (preferred) | 28 days | |
| Frozen | 28 days | ||
| Ambient | 72 hours |
Clinical Information
Antiepileptic drugs (AED) are the mainstay of treatment for epilepsy, but seizures continue in one-third of patients despite appropriate AED therapeutic trials. The etiology of epilepsy often remains unclear. Seizures are a common symptom in autoimmune neurological disorders, including limbic encephalitis and multifocal paraneoplastic disorders. Seizures may be the exclusive manifestation of an autoimmune encephalopathy without evidence of limbic encephalitis.
Autoimmune epilepsy is increasingly recognized in the spectrum of neurological disorders characterized by detection of neural autoantibodies in serum or spinal fluid (CSF) and responsiveness to immunotherapy. The advent of more sensitive and specific serological detection methods is increasingly revealing previously underappreciated autoimmune epilepsies. Neural autoantibodies specific for intracellular and plasma membrane antigens aid the diagnosis of autoimmune epilepsy, but no single antibody is specific for this diagnosis.
Autoantibody specificities most informative for autoimmune epilepsies include leucine-rich glioma inactivated protein-1 (LGI1), glutamic acid decarboxylase-65 (GAD65), N-methyl-D-aspartate receptor (NMDA-R), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-R), and gamma-aminobutyric acid type B receptor (GABA-B-R) antibodies.
Autoantibodies recognizing onconeural proteins shared by neurons, glia, or muscle (eg, antineuronal nuclear antibody, type 1 [ANNA 1]; collapsin response-mediator protein-5 neuronal [CRMP-5-IgG]; N-type calcium channel antibody), also serve as markers of paraneoplastic or idiopathic autoimmune epilepsies. A specific neoplasm is often predictable by the individual patient's autoantibody profile.
Suspicion for autoimmune epilepsy on clinical grounds justifies comprehensive evaluation of CSF and serum for neural autoantibodies. Selective testing for individual autoantibodies is not advised because each is individually rare, and a timely diagnosis is critical. Collectively, the antibodies tested for in the autoimmune epilepsy evaluations represent a broad spectrum of treatable disorders, some of which are associated with occult cancer. Testing of CSF for autoantibodies is particularly helpful when serum testing is negative, although, in some circumstances, testing both serum and CSF simultaneously is pertinent. Testing of CSF is recommended for some antibodies (eg, NMDA-R antibody and glial fibrillary acidic protein [GFAP]-IgG) because CSF testing is both more sensitive and specific. In contrast, serum testing for LGI1 antibody is more sensitive than CSF testing. Failure to detect a neural antibody does not exclude the diagnosis of autoimmune epilepsy when other clinical clues exist. A trial of immunotherapy is justifiable in those cases.
Reference Values
|
Test ID |
Reporting Name |
Methodology* |
Reference Value |
|
AEPSI |
Epilepsy, Interpretation, S |
Medical interpretation |
Interpretive report |
|
AMPCS |
AMPA-R Ab CBA, S |
CBA |
Negative |
|
AMPHS |
Amphiphysin Ab, S |
IFA |
Negative |
|
AGN1S |
Anti-Glial Nuclear Ab, Type 1 |
IFA |
Negative |
|
ANN1S |
Anti-Neuronal Nuclear Ab, Type 1 |
IFA |
Negative |
|
ANN2S |
Anti-Neuronal Nuclear Ab, Type 2 |
IFA |
Negative |
|
ANN3S |
Anti-Neuronal Nuclear Ab, Type 3 |
IFA |
Negative |
|
CS2CS |
CASPR2-IgG CBA, S |
CBA |
Negative |
|
CRMS |
CRMP-5-IgG, S |
IFA |
Negative |
|
DPPCS |
DPPX Ab CBA, S |
CBA |
Negative |
|
GABCS |
GABA-B-R Ab CBA, S |
CBA |
Negative |
|
GD65S |
GAD65 Ab Assay, S |
RIA |
≤0.02 nmol/L Reference values apply to all ages |
|
GFAIS |
GFAP IFA, S |
IFA |
Negative |
|
LG1CS |
LGI1-IgG CBA, S |
CBA |
Negative |
|
GL1IS |
mGluR1 Ab IFA, S |
IFA |
Negative |
|
NCDIS |
Neurochondrin IFA, S |
IFA |
Negative |
|
NMDCS |
NMDA-R Ab CBA, S |
CBA |
Negative |
|
PCAB2 |
Purkinje Cell Cytoplasmic Ab Type 2 |
IFA |
Negative |
|
PCATR |
Purkinje Cell Cytoplasmic Ab Type Tr |
IFA |
Negative |
|
PDEIS |
PDE10A Ab IFA, S |
IFA |
Negative |
|
T46IS |
TRIM46 Ab IFA, S |
IFA |
Negative |
Reflex Information:
|
Test ID |
Reporting Name |
Methodology* |
Reference Value |
|
AGNBS |
AGNA-1 Immunoblot, S |
IB |
Negative |
|
AGNTS |
AGNA-1 Titer, S |
IFA |
<1:240 |
|
AMPIS |
AMPA-R Ab IF Titer Assay, S |
IFA |
<1:240 |
|
AMIBS |
Amphiphysin Immunoblot, S |
IB |
Negative |
|
AN1BS |
ANNA-1 Immunoblot, S |
IB |
Negative |
|
AN1TS |
ANNA-1 Titer, S |
IFA |
<1:240 |
|
AN2BS |
ANNA-2 Immunoblot, S |
IB |
Negative |
|
AN2TS |
ANNA-2 Titer, S |
IFA |
<1:240 |
|
AN3TS |
ANNA-3 Titer, S |
IFA |
<1:240 |
|
APHTS |
Amphiphysin Ab Titer, S |
IFA |
<1:240 |
|
CRMTS |
CRMP-5-IgG Titer, S |
IFA |
<1:240 |
|
CRMWS |
CRMP-5-IgG Western Blot, S |
WB |
Negative |
|
DPPTS |
DPPX Ab IFA Titer, S |
IFA |
<1:240 |
|
GABIS |
GABA-B-R Ab IF Titer Assay, S |
IFA |
<1:240 |
|
GFACS |
GFAP CBA, S |
CBA |
Negative |
|
GFATS |
GFAP IFA Titer, S |
IFA |
<1:240 |
|
GL1CS |
mGluR1 Ab CBA, S |
CBA |
Negative |
|
GL1TS |
mGluR1 Ab IFA Titer, S |
IFA |
<1:240 |
|
NCDCS |
Neurochondrin CBA, S |
CBA |
Negative |
|
NCDTS |
Neurochondrin IFA Titer, S |
IFA |
<1:240 |
|
NMDIS |
NMDA-R Ab IF Titer Assay, S |
IFA |
<1:240 |
|
PC2TS |
PCA-2 Titer, S |
IFA |
<1:240 |
|
PCTBS |
PCA-Tr Immunoblot, S |
IB |
Negative |
|
PCTTS |
PCA-Tr Titer, S |
IFA |
<1:240 |
|
PDETS |
PDE10A Ab IFA Titer, S |
IFA |
<1:240 |
|
T46CS |
TRIM46 Ab CBA, S |
CBA |
Negative |
|
T46TS |
TRIM46 Ab IFA Titer, S |
IFA |
<1:240 |
*Methodology abbreviations:
Immunofluorescence assay (IFA)
Cell-binding assay (CBA)
Western blot (WB)
Radioimmunoassay (RIA)
Immunoblot (IB)
Neuron-restricted patterns of IgG staining that do not fulfill criteria for ANNA-1, ANNA-2, ANNA-3, 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 1:240 are detectable by recombinant CRMP-5 Western blot analysis. CRMP-5 Western blot analysis will be done on request on stored serum (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
Antibodies specific for neuronal, glial, or muscle proteins are valuable serological markers of autoimmune epilepsy and of a patient's immune response to cancer. These autoantibodies are not found in healthy subjects and are usually accompanied by subacute neurological symptoms and signs. It is not uncommon for more than 1 of the following autoantibodies to be detected in patients with autoimmune dementia.
-Plasma membrane antibodies (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). These autoantibodies are all potential effectors of dysfunction.
-Antineuronal nuclear antibody, type 1 (ANNA-1) or type 3 (ANNA-3).
-Neuronal or muscle cytoplasmic antibodies (amphiphysin, Purkinje cell antibody-type 2 [PCA-2], collapsin response-mediator protein-5 neuronal [CRMP-5-IgG], or glutamic acid decarboxylase [GAD65] antibody).
Clinical Reference
1. Smith KM, Britton JW, Thakolwiboon S, et al. Seizure characteristics and outcomes in patients with neurological conditions related to high-risk paraneoplastic antibodies. Epilepsia. 2023;64(9):2385-2398. doi:10.1111/epi.17695
2. Garrido Sanabria ER, Zahid A, Britton J, et al. CASPR2-IgG-associated autoimmune seizures. Epilepsia. 2022;63(3):709-722. doi:10.1111/epi.17164
3. Smith KM, Zalewski NL, Budhram A, et al. Musicogenic epilepsy: Expanding the spectrum of glutamic acid decarboxylase 65 neurological autoimmunity. Epilepsia. 2021;62(5):e76-e81. doi:10.1111/epi.16888
4. Steriade C, Britton J, Dale RC, et al. Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: Conceptual definitions. Epilepsia. 2020;61(7):1341-1351. doi:10.1111/epi.16571
5. Dubey D, Singh J, Britton JW, et al. Predictive models in the diagnosis and treatment of autoimmune epilepsy. Epilepsia. 2017;58(7):1181-1189. doi:10.1111/epi.13797
Day(s) Performed
Profile tests: Monday through Sunday; Reflex tests: Varies
Report Available
8 to 12 daysTest Classification
This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.CPT Code Information
86255 x 19
86341
84182-AGNBS (if appropriate)
86256-AGNTS (if appropriate)
86256-AMPIS (if appropriate)
84182-AMIBS (if appropriate)
84182-AN1BS (if appropriate)
86256-AN1TS (if appropriate)
84182-AN2BS (if appropriate)
86256-AN2TS (if appropriate)
86256-AN3TS (if appropriate)
86256-APHTS (if appropriate)
86256-CRMTS (if appropriate)
84182-CRMWS (if appropriate)
86256-DPPTS (if appropriate)
86256-GABIS (if appropriate)
86255-GFACS (if appropriate)
86256-GFATS (if appropriate)
86255-GL1CS (if appropriate)
86256-GL1TS (if appropriate)
86255-NCDCS (if appropriate)
86256-NCDTS (if appropriate)
86256-NMDIS (if appropriate)
86256-PC2TS (if appropriate)
84182-PCTBS (if appropriate)
86256-PCTTS (if appropriate)
86256-PDETS (if appropriate)
86255-T46CS (if appropriate)
86256-T46TS (if appropriate)
LOINC Code Information
| Test ID | Test Order Name | Order LOINC Value |
|---|---|---|
| EPS2 | Epilepsy, Autoimm/Paraneo, S | 94698-8 |
| Result ID | Test Result Name | Result LOINC Value |
|---|---|---|
| 61516 | NMDA-R Ab CBA, S | 93503-1 |
| 61518 | AMPA-R Ab CBA, S | 93489-3 |
| 61519 | GABA-B-R Ab CBA, S | 93428-1 |
| 34259 | Epilepsy, Interpretation, S | 69048-7 |
| 89080 | AGNA-1, S | 84927-3 |
| 81722 | Amphiphysin Ab, S | 72327-0 |
| 80150 | ANNA-1, S | 33615-6 |
| 80776 | ANNA-2, S | 43187-4 |
| 83137 | ANNA-3, S | 43102-3 |
| 83077 | CRMP-5-IgG, S | 72504-4 |
| 81596 | GAD65 Ab Assay, S | 30347-9 |
| 83138 | PCA-2, S | 84925-7 |
| 83076 | PCA-Tr, S | 84926-5 |
| 64279 | LGI1-IgG CBA, S | 94287-0 |
| 64281 | CASPR2-IgG CBA, S | 94285-4 |
| 64933 | DPPX Ab CBA, S | 94676-4 |
| 64928 | mGluR1 Ab IFA, S | 94347-2 |
| 605155 | GFAP IFA, S | 94346-4 |
| 615867 | Neurochondrin IFA, S | 101452-1 |
| 616445 | TRIM46 Ab IFA, S | 103843-9 |
| 620068 | PDE10A Ab IFA, S | 103842-1 |
| 618898 | IFA Notes | 48767-8 |
Special Instructions
mml-neuroimmunology, mml-Epilepsy,