Test ID: AIAES Axonal Neuropathy, Autoimmune/Paraneoplastic Evaluation, Serum
Ordering Guidance
Multiple neuroimmunology profile tests are available. For testing that is performed with each profile, see Autoimmune Neurology Antibody Matrix.
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 or intravenous immunoglobulin (IVIg) treatment.
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.
Collection Container/Tube:
Preferred: Red top
Acceptable: Serum gel
Submission Container/Tube: Plastic vial
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 |
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/Paraneoplastic Axonal Neuropathy Evaluation Algorithm
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)
GD65S: Radioimmunoassay (RIA)
CRMWS; Western Blot (WB)
AGNBS, AMIBS, AN1BS, AN2BS, PC1BS, PCTBS: Immunoblot (IB)
Reporting Name
Axonal, Autoimm/Paraneo, SSpecimen Type
SerumSpecimen 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, and contactin-associated response protein 2 (CASPR2) antibody. 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 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 (PCA-Tr) 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. Some patients may present with mostly pain and have a limited small fiber neuropathy with or without autonomic symptoms.
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 |
Medical Interpretation |
NA |
AGN1S |
Anti-Glial Nuclear Ab, Type 1 |
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 |
WB |
Negative |
CS2CS |
CASPR2-IgG CBA, S |
CBA |
Negative |
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 |
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 |
*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, 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."
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 one 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 Oct;93(10):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 Aug;7(9):e00779
4. Lucchinetti CF, Kimmel DW, Lennon VA: Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology. 1998 Mar;50(3):652-657
5. Pittock SJ, Lucchinetti CF, Lennon VA: Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann Neurol. 2003 May;53(5):580-587
6. Chan KH, Vernino S, Lennon VA: ANNA-3 anti-neuronal nuclear antibody: marker of lung cancer-related autoimmunity. Ann Neurol. 2001 Sep;50(3):301-311
7. Dubey D, Lennon VA, Gadoth A, et al. Autoimmune CRMP5 neuropathy phenotype and outcome defined from 105 cases. Neurology. 2018 Jan;90(2):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 Jul;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 May;52(5):462-468
10. McKeon A, Tracy JA: GAD65 neurological autoimmunity. Muscle Nerve. 2017 Jul;56(1):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 Jul;58(1):96-107
Day(s) Performed
Profile tests: Monday through Sunday; Reflex tests: Varies
Report Available
5 to 10 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 US Food and Drug Administration.CPT Code Information
86255 x9
84182
84182 AGNBS (if appropriate)
86255 AMPCS (if appropriate)
86256 AMPIS (if appropriate)
84182 AMIBS (if appropriate)
84182 AN1BS (if appropriate)
84182 AN2BS (if appropriate)
86255 ANN2S (if appropriate)
86255 DPPCS (if appropriate)
86256 DPPTS (if appropriate)
86255 GABCS (if appropriate)
86256 GABIS (if appropriate)
86341 GD65S (if appropriate)
86255 GFACS (if appropriate)
86256 GFATS (if appropriate)
86255 GL1CS (if appropriate)
86256 GL1TS (if appropriate)
86255 NMDCS (if appropriate)
86256 NMDIS (if appropriate)
84182 PC1BS (if appropriate)
84182 PCTBS (if appropriate)
86255 PCATR (if appropriate)
LOINC Code Information
Test ID | Test Order Name | Order LOINC Value |
---|---|---|
AIAES | Axonal, Autoimm/Paraneo, 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 |
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 |
Special Instructions
Forms
If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen.
mml-neuroimmunology