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Mayo Clinic Laboratories

Test 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 healthcare professional's name, phone number, mailing address, and email address

Specimen Required

Patient Preparation: For optimal antibody detection, collect specimen before starting 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 Serum

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
AK5IS	AK5 Ab IFA, 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
GBACS	GABA-A-R Ab CBA, S	Yes	Yes
GABCS	GABA-B-R Ab CBA, S	No	Yes
GD65S	GAD65 Ab Assay, S	Yes	Yes
KLHCS	KLHL11-IgG CBA, S	Yes	Yes
LG1CS	LGI1-IgG CBA, S	No	Yes
MA2ES	Ma2 Ab ELISA, S	Yes	Yes
GL1IS	mGluR1 Ab IFA, S	No	Yes
GL5IS	mGluR5 Ab IFA, S	No	Yes
NCDIS	Neurochondrin IFA, S	No	Yes
NMDCS	NMDA-R Ab CBA, S	No	Yes
PDEIS	PDE10A Ab IFA, S	No	Yes
PCAB2	Purkinje Cell Cytoplasmic Ab Type 2	No	Yes
PCATR	Purkinje Cell Cytoplasmic Ab Type Tr	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
DPPTS	DPPX Ab IFA Titer, S	No	No
GABIS	GABA-B-R Ab IF Titer Assay, 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
AK5CS	AK5 Ab CBA, S	No	No
AK5TS	AK5 Ab IFA Titer, S	No	No
K11TS	KLHL11 Ab IFA Titer, S	No	No
MP1BS	MAP1B Immunoblot, S	No	No
GL5CS	mGluR5 Ab CBA, S	No	No
GL5TS	mGluR5 Ab IFA Titer, S	No	No
CRMWS	CRMP-5-IgG Western Blot, 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 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 pattern suggests adenylate kinase 5 protein (AK5) antibody, then the AK5 IFA titer and AK5 cell binding assay (CBA) 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 and MAP1B immunoblot 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 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-receptor antibody 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 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 Kelch-like protein 11 (KLHL11) CBA result is reactive, then the KLHL11 antibody 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 metabotropic glutamate receptor 5 (mGluR5) antibody, then the mGluR5 antibody CBA and mGluR5 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

-Epilepsy: Unexplained Refractory and/or Familial Testing Algorithm

Method Name

AEPSI: Technical Interpretation

AGN1S, AK5IS AMPHS, ANN1S, ANN2S, ANN3S, CRMS, GL1IS, GL5IS, NCDIS, PCAB2, PCATR, PDEIS, T46IS, AGNTS, AK5TS, AMPIS, AN1TS, AN2TS, AN3TS, APHTS, CRMTS, DPPTS, GABIS, GL1TS, GL5TS, K11TS, NCDTS, NMDIS, PC2TS, PCTTS, PDETS, T46TS: Indirect Immunofluorescence Assay (IFA)

AMPCS, CS2CS, DPPCS, GABCS, GBACS, LG1CS, NMDCS, AK5CS, KLHCS, GL1CS, GL5CS, NCDCS, T46CS: Cell Binding Assay (CBA)

MA2ES: Enzyme-Linked Immunosorbent Assay (ELISA)

CRMWS: Western Blot (WB)

GD65S: Radioimmunoassay (RIA)

AGNBS, AMIBS, AN1BS, AN2BS, MP1BS, PCTBS: Immunoblot (IB)

Reporting Name

Epilepsy, Autoimm/Paraneo, S

Specimen Type

Serum

Specimen Minimum Volume

Serum: 2.5 mL

Specimen Stability Information

Specimen Type	Temperature	Time
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	Technical interpretation	Interpretive report
AK5IS	AK5 Ab IFA, S	IFA	Negative
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
GBACS	GABA-A-R Ab CBA, S	CBA	Negative
GABCS	GABA-B-R Ab CBA, S	CBA	Negative
GD65S	GAD65 Ab Assay, S	RIA	≤0.02 nmol/L
KLHCS	KLHL11-IgG CBA, S	CBA	Negative
LG1CS	LGI1-IgG CBA, S	CBA	Negative
MA2ES	Ma2 Ab ELISA, S	ELISA	Negative
GL1IS	mGluR1 Ab IFA, S	IFA	Negative
GL5IS	mGluR5 Ab IFA, S	IFA	Negative
NCDIS	Neurochondrin IFA, S	IFA	Negative
NMDCS	NMDA-R Ab CBA, S	CBA	Negative
PDEIS	PDE10A Ab IFA, S	IFA	Negative
PCAB2	Purkinje Cell Cytoplasmic Ab Type 2	IFA	Negative
PCATR	Purkinje Cell Cytoplasmic Ab Type Tr	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
AK5CS	AK5 Ab CBA, S	CBA	Negative
AK5TS	AK5 Ab IFA Titer, S	IFA	<1:240
AMPIS	AMPA-R Ab IF Titer Assay, S	IFA	<1:120
APHTS	Amphiphysin Ab Titer, 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
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
K11TS	KLHL11 Ab IFA Titer, S	IFA	<1:240
MP1BS	MAP1B Immunoblot, S	IB	Negative
GL1CS	mGluR1 Ab CBA, S	CBA	Negative
GL1TS	mGluR1 Ab IFA Titer, S	IFA	<1:240
GL5CS	mGluR5 Ab CBA, S	CBA	Negative
GL5TS	mGluR5 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:

Cell-binding assay (CBA)

Enzyme-linked immunosorbent assay (ELISA)

Immunoblot (IB)

Immunofluorescence assay (IFA)

Radioimmunoassay (RIA)

Western Blot (WB)

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 days

Test 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 21

86341

0432U

83516

84182 AGNBS (if appropriate)

86256 AGNTS (if appropriate)

86255 AK5CS (if appropriate)

86256 AK5TS (if appropriate)

86256 AMPIS (if appropriate)

86256 APHTS (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 CRMTS (if appropriate)

84182 CRMWS (if appropriate)

86256 DPPTS (if appropriate)

86256 GABIS (if appropriate)

86256 K11TS (if appropriate)

84182 MP1BS (if appropriate)

86255 GL1CS (if appropriate)

86256 GL1TS (if appropriate)

86255 GL5CS (if appropriate)

86256 GL5TS (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
620232	GABA-A-R Ab CBA, S	101874-6
623395	mGluR5 Ab IFA, S	In Process
623399	AK5 Ab IFA, S	In Process
616445	TRIM46 Ab IFA, S	105525-0
620068	PDE10A Ab IFA, S	103842-1
622117	KLHL11-IgG CBA, S	99072-1
34259	Epilepsy, Interpretation, S	69048-7
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
615867	Neurochondrin IFA, S	101452-1
605970	Ma2 Ab ELISA, S	101868-8
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	94345-6
83138	PCA-2, S	84925-7
83076	PCA-Tr, S	84926-5
618898	IFA Notes	48767-8

Special Instructions

Mayo Clinic Laboratories | Neurology Catalog Additional Information:

mml-neuroimmunology, mml-Epilepsy,