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Test ID AIAES Autoimmune Axonal Evaluation, Serum


Necessary Information


Provide the following information:

-Relevant clinical information

-Ordering provider name, phone number, mailing address, and e-mail address



Specimen Required


Patient Preparation:

1. For optimal antibody detection, specimen collection is recommended prior to initiation of immunosuppressant medication.

2. This test should not be requested in 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.

Container/Tube:

Preferred: Red top

Acceptable: Serum gel

Specimen Volume: 4 mL


Useful For

Evaluation of patients who present with a subacute neurological disorder of undetermined etiology, especially those with known risk factors for cancer

 

Directing a focused search for cancer

 

Investigating neurological symptoms that appear in the course of, or after, cancer therapy, and are not explainable by metastasis

 

Differentiating autoimmune neuropathies from neurotoxic effects of chemotherapy

 

Detecting early evidence of cancer recurrence in previously seropositive patients

Profile Information

Test ID Reporting Name Available Separately Always Performed
AIAEI Autoimmune Axonal Interp, S No Yes
GANG AChR Ganglionic Neuronal Ab, S No Yes
AMPHS Amphiphysin Ab, S No Yes
ANN1S Anti-Neuronal Nuclear Ab, Type 1 No Yes
ANN3S Anti-Neuronal Nuclear Ab, Type 3 No Yes
AGN1S Anti-Glial Nuclear Ab, Type 1 No Yes
CS2CS CASPR2-IgG CBA, S No Yes
CRMWS CRMP-5-IgG Western Blot, S Yes Yes
CRMS CRMP-5-IgG, S No Yes
LG1CS LGI1-IgG CBA, S No Yes
PCABP Purkinje Cell Cytoplasmic Ab Type 1 No Yes
PCAB2 Purkinje Cell Cytoplasmic Ab Type 2 No Yes

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
AGNBS AGNA-1 Immunoblot, S No No
AMPCS AMPA-R Ab CBA, 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
ANN2S Anti-Neuronal Nuclear Ab, Type 2 No No
DPPCS DPPX Ab CBA, S No No
DPPTS DPPX Ab IFA Titer, S No No
GABCS GABA-B-R Ab CBA, S No No
GABIS GABA-B-R Ab IF Titer Assay, S No No
GD65S GAD65 Ab Assay, S Yes 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
NMDCS NMDA-R Ab CBA, S No No
NMDIS NMDA-R Ab IF Titer Assay, S No No
PC1BS PCA-1 Immunoblot, S No No
PCATR Purkinje Cell Cytoplasmic Ab Type Tr No No
PCTBS PCA-Tr Immunoblot, S No No

Testing Algorithm

If indirect immunofluorescence assay (IFA) patterns suggest antiglial nuclear antibody-1 (AGNA-1) antibody, then AGNA-1 antibody immunoblot is performed at an additional charge.

 

If IFA patterns suggest antineuronal nuclear antibodies (ANNA)-1, then ANNA-1 immunoblot and ANNA-2 immunoblot are performed at an additional charge.

 

If IFA patterns suggest ANNA-2 antibody, then ANNA-2 immunoblot, ANNA-1 immunoblot, and ANNA-2 antibody IFA are performed at an additional charged.

 

If IFA patterns suggest glutamic acid decarboxylase-65 (GAD65) antibody, then GAD65 radioimmunoassay is performed at an additional charge.

 

If IFA patterns suggest Purkinje cytoplasmic antibody (PCA)-1 antibody, then PCA-1 antibody immunoblot is performed at an additional charge.

 

If IFA patterns suggest PCA-Tr antibody, then PCA-Tr immunoblot is performed at an additional charge.

 

If IFA pattern suggests amphiphysin antibody, then amphiphysin antibody immunoblot is performed at an additional charge.

 

If IFA pattern suggests dipeptidyl-peptidase-like protein-6 antibody (DPPX) antibody, then DPPX antibody cell-binding assay (CBA) and DPPX antibody IFA titer are performed at an additional charge.

 

If IFA pattern suggests metabotropic glutamate receptor 1 (mGluR1) antibody, then mGluR1antibody CBA and mGluR1 antibody IFA titer are performed at an additional charge.

 

If IFA pattern suggests glial fibrillary acidic protein (GFAP) antibody, then GFAP antibody CBA and GFAP antibody IFA titer are performed at an additional charge.

 

If IFA pattern suggests N-methyl-D-aspartate receptor (NMDAR) antibody, then NMDAR antibody CBA and NMDAR antibody IFA titer are performed at an additional charge.

 

If IFA pattern suggests alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPA-R) antibody, then AMPA-R antibody CBA and AMPA-R antibody IFA titer are performed at an additional charge.

 

If IFA pattern suggests gamma-aminobutyric acid B receptor (GABA-B-R) antibody, then GABA-B-R antibody CBA and GABA-B-R antibody IFA titer are performed at an additional charge.

 

See Autoimmune Axonal Evaluation Algorithm in Special Instructions.

Method Name

AMPCS, CS2CS, DPPCS, GABCS, GFACS, GL1CS, LG1CS, NMDCS: Cell Binding Assay (CBA)

AGN1S, AMPHS, AMPIS, ANN1S, ANN2S, ANN3S, CRMS, DPPTS, GABIS, GFATS, GL1TS, NMDIS, PCAB2, PCABP, PCATR: Indirect Immunofluorescence (IFA)

GANG, GD65S: Radioimmunoassay (RIA)

CRMWS; Western Blot (WB)

AGNBS, AMIBS, AN1BS, AN2BS, PC1BS, PCTBS: Immunoblot (IB)

Reporting Name

Autoimmune Axonal Eval, S

Specimen Type

Serum

Specimen Minimum Volume

2 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Serum Refrigerated (preferred) 28 days
  Frozen  28 days
  Ambient  72 hours

Clinical Information

Neuropathy patients have variable sensory disturbance (loss or exaggerated sensation) with pain, weakness, and autonomic involvements such as sweat abnormalities, gastrointestinal dysfunction, and lightheadedness on standing. These symptoms are as a result of injury to the distal nerves, roots, ganglia or their gathering points (nerve plexus in the thighs and arms). Patients may have symmetric or asymmetric involvements of the extremities, trunk, and head including extraocular muscles. Subacute onsets and asymmetric involvements favor inflammatory or immune causes over inherited or metabolic forms. Depending on the specific inflammatory or immune mediated causes other parts of the nervous system may also be affected (brain, cerebellum, spinal cord).

 

In the evaluation of patients with immune mediated autoantibody neuropathies, nerve conduction studies and needle electromyography can help to classify the neuropathy as either: 1) primary axonal; 2) primary demyelinating; or 3) mixed axonal and demyelinating. This evaluation focuses on persons with primary axonal forms.

 

Well established neuronal autoantibodies responsible for axonal neuropathies include: antineuronal nuclear antibodies (ANNA1 and 3), Purkinje cytoplasmic antibody (PCA1 and 2), amphiphysin antibody, collapsin response mediator protein 5 (CRMP5) antibody, leucine-rich glioma inactivated 1 protein (LGI1) antibody, contactin-associated response protein 2 (CASPR2) antibody, and acetylcholine receptor (AChR) ganglionic neuronal antibody (Alpha-3). Other autoantibodies have preliminary evidence to support their association with neuropathy including: alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) antibody; antiglial nuclear antibody (AGNA); antineuronal nuclear antibody, type 2 antibody (ANNA2); gamma-aminobutyric acid B receptor (GABABR) antibody; glutamic acid decarboxylase 65 (GAD65) receptor antibody; glial fibrillary acidic protein (GFAP) antibody; N-methyl-D-aspartate receptor (NMDAR) antibody; Purkinje cell cytoplasmic TR (PCATR) antibody; dipeptidyl-peptidase-like protein-6 (DPPX) antibody; and metabotropic glutamate receptor 1 (mGluR1).

 

A patient's humoral and cellular immune response leads to the neurological syndrome. This may be related to an underlying cancer or unidentified antigen trigger. If related to cancer it may be a new or recurrent malignancy, is usually limited in metastatic volume, and is often occult by standard imaging procedures. Autoantibodies specific for onconeural proteins found in the plasma membrane, cytoplasm, and nucleus of neurons, glia, or muscle are generated in this immune response and serve as serological markers of paraneoplastic autoimmunity. Cancers recognized in this context most commonly are small-cell lung carcinoma, thymoma, ovarian (or related Mullerian) carcinoma, breast carcinoma, and Hodgkin lymphoma. Pertinent childhood neoplasms recognized thus far include neuroblastoma, thymoma, Hodgkin lymphoma, and chondroblastoma.

 

This evaluation focuses on those antibodies with known associations with varied forms of peripheral axonal neuropathy. Seropositive patients usually present with subacute neurological symptoms of radiculopathy; plexopathy; or sensory, sensorimotor, or autonomic neuropathy, with or without a neuromuscular transmission disorder such as neuromuscular hyperexcitability. Other peripheral manifestation includes cranial neuropathies, especially loss of vision, hearing, smell, or taste. Commonly beyond the peripheral manifestation are encephalopathy, seizures, cerebellar ataxia, and myelopathy. Initial signs may be subtle, but a subacute multifocal and progressive syndrome usually evolves. Sensorimotor neuropathy and cerebellar ataxia are common presentations, but the clinical picture in some patients is dominated by striking gastrointestinal dysmotility, and limbic encephalopathy.

 

Cancer risk factors include past or family history of cancer, history of smoking, or social or environmental exposure to carcinogens.

Reference Values

Test ID

Reporting name

Methodology

Reference value

AIAEI

Autoimmune Axonal Interp, S

Interpretation

N/A

AGN1S

Anti-Glial Nuclear Ab, Type 1

Indirect Immunofluorescence  (IFA)

<1:240

AMPHS

Amphiphysin Ab, S

IFA

<1:240

ANN1S

ANNA-1, S

IFA

<1:240*

ANN3S

ANNA-3, S

IFA

<1:240

CRMS

CRMP-5-IgG, S

IFA

<1:240**

CRMWS

CRMP-5-IgG Western Blot, S

Western Blot (WB)

Negative (reported as positive or negative)

CS2CS

CASPR2-IgG CBA, S

Cell Binding Assay (CBA)

Negative

GANG

AChR Ganglionic Neuronal Ab, S

Radioimmunoassay (RIA)

<0.02 nmol/L

LG1CS

LGI1-IgG CBA, S

CBA

Negative

PCAB2

PCA-2, S

IFA

<1:240*

PCABP

PCA-1, S

IFA

<1:240*

 

Reflex Information:

Test ID

Reporting name

Methodology

Reference value

AGNBS

AGNA-1 Immunoblot, S

Immunoblot (IB)

Negative

AMIBS

Amphiphysin Immunoblot, S

IB

Negative

AMPCS

AMPA-R Ab CBA, S

CBA

Negative

AMPIS

AMPA-R Ab IF Titer Assay, S

IFA

<1:120

AN1BS

ANNA-1 Immunoblot, S

IB

Negative

AN2BS

ANNA-2 Immunoblot, S

IB

Negative

ANN2S

ANNA-2, S

IFA

<1:240*

DPPCS

DPPX Ab CBA, S

CBA

Negative

DPPTS

DPPX Ab IFA, S

IFA

<1:240

GABCS

GABA-B-R Ab CBA, S

CBA

Negative

GABIS

GABA-B-R Ab IF Titer Assay, S

IFA

<1:120

GD65S

GAD65 Ab Assay, S

RIA

<0.02 nmol/L

Reference values apply to all ages

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, S

IFA

<1:240

NMDCS

NMDA-R Ab CBA, S

CBA

Negative

NMDIS

NMDA-R Ab IF Titer Assay, S

IFA

<1:120

PC1BS

PCA-1 Immunoblot, S

IB

Negative

PCATR

Purkinje Cell Cytoplasmic Ab Type Tr

IFA

<1:240*

PCTBS

PCA-Tr Immunoblot, S

IB

Negative

 

*Neuron-restricted patterns of IgG staining that do not fulfill criteria for ANNA-1, ANNA-2, 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."

Interpretation

Antibodies directed at onconeural proteins shared by neurons, glia, muscle, and certain cancers are valuable serological markers of a patient's immune response to cancer. They are not found in healthy subjects and are usually accompanied by subacute neurological symptoms and signs. Several autoantibodies have a syndromic association, but no autoantibody predicts a specific neurological syndrome. More than 1 paraneoplastic autoantibody may be detected and associated with specific cancers.

Clinical Reference

1. Klein CJ: Autoimmune-mediated peripheral neuropathies and autoimmune pain. In: Pittock SJ, Vincent A, eds. Handbook of Clinical Neurology; Autoimmune Neurology. Elsevier; 2016:417-446

2. Cutsforth-Gregory JK, McKeon A, Coon EA, et al: Ganglionic antibody level as a predictor of severity of autonomic failure. Mayo Clin Proc. 2018;93:1440-1447

3. Wei YC, Huang CC, Liu CH, Kuo HC, Lin JJ: Peripheral neuropathy in limbic encephalitis with anti-glutamate receptor antibodies: Case report and systematic literature review. Brain Behav. 2017;7:e00779

4. Lucchinetti CF, Kimmel DW, Lennon VA: Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology. 1998;50:652-657

5. Pittock SJ, Lucchinetti CF, Lennon VA: Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann Neurol. 2003;53:580-587

6. Chan KH, Vernino S, Lennon VA: ANNA-3 anti-neuronal nuclear antibody: marker of lung cancer-related autoimmunity. Ann Neurol. 2001;50:301-311

7. Dubey D, Lennon VA, Gadoth A, et al. Autoimmune CRMP5 neuropathy phenotype and outcome defined from 105 cases. Neurology. 2018;90:e103-e110

8. Gadoth A, Pittock SJ, Dubey D, et al: Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG-positive patients. Ann Neurol. 2017;82:79-92

9. Honnorat J, Trouillas P, Thivolet C, Aguera M, Belin MF: Autoantibodies to glutamate decarboxylase in a patient with cerebellar cortical atrophy, peripheral neuropathy, and slow eye movements. Arch Neurol. 1995;52:462-468

10. McKeon A, Tracy JA: GAD65 neurological autoimmunity. Muscle Nerve. 2017;56:15-27

11. Bradshaw MJ, Haluska P, McKeon A, Klein CJ: Multifocal neuropathy as the presenting symptom of Purkinje cell cytoplasmic autoantibody-1. Muscle Nerve. 2013;48:827-831

12. Pittock SJ, Lucchinetti CF, Parisi JE, et al: Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann Neurol. 2005;58:96-107

Day(s) and Time(s) Performed

AGN1S, AMPHS, AMPIS, ANN1S, ANN2S, ANN3S, CRMS, DPPTS, GABIS, GFATS, GL1TS, NMDIS, PCAB2, PCABP:

Monday through Friday; 5 a.m., 7 a.m., 5 p.m.

Saturday, Sunday; 6 a.m.

 

CS2CS, AMPCS, GABGS, LG1CS, NMDCS:

Monday through Thursday; 10 p.m.

Sunday; 3 p.m.

 

DPPCS, GL1CS:

Wednesday; 6 p.m.

 

GFACS:

Monday, Wednesday; 6 p.m.

 

GANG:

Monday through Friday; 6 a.m., 8 a.m., 6 p.m.

Saturday, Sunday; 7 a.m.

 

AGNBS, AMIBS, AN1BS, AN2BS, PC1BS,:

Monday through Friday; 6 p.m.

 

CRMWS:

Monday, Wednesday, Friday; 8 a.m.

 

PCTBS:

Monday through Friday; 8 a.m.

Analytic Time

10 days

Test 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 x9

84182

83519

LOINC Code Information

Test ID Test Order Name Order LOINC Value
AIAES Autoimmune Axonal Eval, S 94695-4

 

Result ID Test Result Name Result LOINC Value
606975 Autoimmune Axonal Interp, S 69048-7
89080 AGNA-1, S 94341-5
81722 Amphiphysin Ab, S 94340-7
80150 ANNA-1, S 94342-3
83137 ANNA-3, S 94344-9
83077 CRMP-5-IgG, S 94815-8
83107 CRMP-5-IgG Western Blot, S 47401-5
84321 AChR Ganglionic Neuronal Ab, S 94694-7
83138 PCA-2, S 94351-4
9477 PCA-1, S 94350-6
64279 LGI1-IgG CBA, S 94287-0
64281 CASPR2-IgG CBA, S 94285-4
36349 Reflex Added 77202-0