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Test ID: ENS2 Encephalopathy, Autoimmune 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 or intravenous immunoglobulin 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.

3. Patient should have no general anesthetic or muscle-relaxant drugs in the previous 24 hours.

Container/Tube:

Preferred: Red top

Acceptable: Serum gel

Specimen Volume: 4 mL


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 serum 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 cerebral spinal 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
AEESI Encephalopathy, 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
DPPIS DPPX Ab IFA, 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
IG5IS IgLON5 IFA, S No Yes
LG1CS LGI1-IgG CBA, S No Yes
GL1IS mGluR1 Ab IFA, S No Yes
NIFIS NIF IFA, S No Yes
NMDCS NMDA-R Ab CBA, S No Yes
PCABP Purkinje Cell Cytoplasmic Ab Type 1 No Yes
PCAB2 Purkinje Cell Cytoplasmic Ab Type 2 No Yes
PCATR Purkinje Cell Cytoplasmic Ab Type Tr No Yes

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
ARBI ACh Receptor (Muscle) Binding Ab Yes No
AGNBS AGNA-1 Immunoblot, S No No
AINCS Alpha Internexin 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
CRMWS CRMP-5-IgG Western Blot, S Yes No
DPPCS DPPX Ab CBA, S No 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
IG5CS IgLON5 CBA, S No No
IG5TS IgLON5 IFA Titer, S No No
GL1CS mGluR1 Ab CBA, S No No
GL1TS mGluR1 Ab IFA Titer, S No No
NFHCS NIF Heavy Chain CBA, S No No
NIFTS NIF IFA Titer, S No No
NFLCS NIF Light Chain CBA, S No No
NMDIS NMDA-R Ab IF Titer Assay, S No No
PC1BS PCA-1 Immunoblot, S No No
PCTBS PCA-Tr Immunoblot, S No No

Testing Algorithm

If client requests or if immunofluorescence (IFA) patterns suggest collapsin response-mediator protein-5-IgG (CRMP-5-IgG), then CRMP-5-IgG Western blot, and ACh receptor (muscle) binding antibody are performed at an additional charge.

 

If IFA patterns suggest amphiphysin antibody, then amphiphysin immunoblot is performed at an additional charge.

 

If IFA pattern suggests antiglial nuclear antibody (AGNA)-1, then AGNA-1 immunoblot is performed at an additional charge.

 

If IFA pattern suggests antineuronal nuclear antibody (ANNA)-1, 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 Purkinje cytoplasmic antibody (PCA)-1, 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 and IgLON5 cell-binding assay (CBA) is performed at an additional charge.

 

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

 

If AMPA-receptor antibody CBA is positive, then CRMP-5-IgG Western blot, and acetylcholine (Ach) receptor (muscle) binding antibody are performed at an additional charge.

 

If contactin-associated protein-like-2 (CASPR2)-receptor antibody CBA is positive, then CRMP-5-IgG Western blot, and ACh receptor (muscle) binding antibody are performed at an additional charge.

 

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

 

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

 

If IFA pattern suggests N-methyl-D-aspartate (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 dipeptidyl-peptidase-like protein-6 (DPPX) antibody, then DPPX antibody CBA and DPPX titer are performed at an additional charge.

 

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

 

If IFA pattern suggests neuronal intermediate filament (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-Serum in Special Instructions.

Method Name

AGN1S, AMPHS, AMPIS, ANN1S, ANN2S, ANN3S, CRMS, DPPIS, DPPTS, GABIS, GFAIS, GFATS, GL1IS, GL1TS, IG5IS, IG5TS, NIFIS, NIFTS, NMDIS, PCAB2, PCABP, PCATR: Indirect Immunofluorescence Assay (IFA)

 

AINCS, AMPCS, CS2CS, DPPCS, GABCS, GFACS, GL1CS, IG5CS, LG1CS, NFHCS, NFLCS, NMDCS: Cell-Binding Assay (CBA)

 

CRMWS: Western Blot (WB)

 

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

 

ARBI, GD65S: Radioimmunoassay (RIA)

Reporting Name

Encephalopathy-Autoimmune Eval, S

Specimen Type

Serum

Specimen 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

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

AMPCS

AMPA-R Ab CBA, S

Cell-binding assay (CBA)

Negative

AMPHS

Amphiphysin Ab, S

Indirect Immunofluorescence Assay (IFA)

<1:240

AGN1S

Anti-Glial Nuclear Ab, Type 1

IFA

<1:240

ANN1S

Anti-Neuronal Nuclear Ab, Type 1

IFA

<1:240

ANN2S

Anti-Neuronal Nuclear Ab, Type 2

IFA

<1:240

ANN3S

Anti-Neuronal Nuclear Ab, Type 3

IFA

<1:240

CS2CS

CASPR2-IgG CBA, S

CBA

Negative

CRMS

CRMP-5-IgG, S

IFA

<1:240

DPPIS

DPPX Ab IFA, S

IFA

Negative

GABCS

GABA-B-R Ab CBA, S

CBA

Negative

GD65S

GAD65 Ab Assay, S

Radioimmunoassay (RIA)

≤0.02 nmol/L

Reference values apply to all ages.

GFAIS

GFAP IFA, S

IFA

Negative

IG5IS

IgLON5 IFA, S

IFA

Negative

LG1CS

LGI1-IgG CBA, S

CBA

Negative

GL1IS

mGluR1 Ab IFA, S

IFA

Negative

NIFIS

NIF IFA, S

IFA

Negative

NMDCS

NMDA-R Ab CBA, S

CBA

Negative

PCABP

Purkinje Cell Cytoplasmic Ab Type 1

IFA

<1:240

PCAB2

Purkinje Cell Cytoplasmic Ab Type 2

IFA

<1:240

PCATR

Purkinje Cell Cytoplasmic Ab Type Tr

IFA

<1:240

 

Reflex Information:

Test ID

Reporting name

Methodology

Reference value

ARBI

ACh Receptor (Muscle) Binding Ab

RIA

≤0.02 nmol/L

AGNBS

AGNA-1 Immunoblot, S

Immunoblot (IB)

Negative

AINCS

Alpha Internexin CBA, S

CBA

Negative

AMPIS

AMPA-R Ab IF Titer Assay, S

IFA

<1:120

AMIBS

Amphiphysin Immunoblot, S

IB

Negative

AN1BS

ANNA-1 Immunoblot, S

IB

Negative

AN2BS

ANNA-2 Immunoblot, S

IB

Negative

CRMWS

CRMP-5-IgG Western Blot, S

Western blot (WB)

Negative

DPPCS

DPPX Ab CBA, S

CBA

Negative

DPPTS

DPPX Ab IFA Titer, S

IFA

<1:240

GABIS

GABA-B-R Ab IF Titer Assay, S

IFA

<1:120

GFACS

GFAP CBA, S

CBA

Negative

GFATS

GFAP IFA Titer, S

IFA

<1:240

IG5CS

IgLON5 CBA, S

CBA

Negative

IG5TS

IgLON5 IFA Titer, S

IFA

<1:240

GL1CS

mGluR1 Ab CBA, S

CBA

Negative

GL1TS

mGluR1 Ab IFA Titer, S

IFA

<1:240

NFHCS

NIF Heavy Chain CBA, S

CBA

Negative

NIFTS

NIF IFA Titer, S

IFA

<1:240

NFLCS

NIF Light Chain CBA, S

CBA

Negative

NMDIS

NMDA-R Ab IF Titer Assay, S

IFA

<1:120

PC1BS

PCA-1 Immunoblot, S

IB

Negative

PCTBS

PCA-Tr Immunoblot, S

IB

Negative

 

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."

 

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

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: 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. These are all potential effectors of neurological dysfunction.

-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

1. McKeon A, Lennon, VA, Pittock, SJ: Immunotherapy responsive dementias and encephalopathies. Continuum (Minneap Minn). 2010 Apr;16(2):80-101

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 Sep;81(9):1207-1214

4. Lancaster E, Martinez-Hernandez E, Dalmau J: Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology. 2011 Jul 12;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 Feb;70(2):229-234

Day(s) Performed

AGN1S, AMPHS, AMPIS, ANN1S, ANN2S, ANN3S, ARBI, CRMS, DPPIS, DPPTS, GABIS, GD65S, GFAIS, GFATS, GL1IS, GL1TS, IG5IS, IG5TS, NIFIS, NIFTS, NMDIS, PCAB2, PCABP, PCATR:

Monday through Sunday

 

AMPCS, CS2CS, DDPCS, GABCS, LG1CS, NMDCS:

Monday through Friday, Sunday

 

GL1CS, IG5CS:

Monday, Thursday

 

AINCS, NFHCS, NFLCS:

Tuesday, Thursday

 

GFACS:

Monday, Wednesday, Friday

 

CRMWS:

Monday through Thursday

 

AGNBS, AMIBS, AN1BS, AN2BS, PC1BS, PCTBS:

Monday through Friday

Report Available

10 to 13 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 US Food and Drug Administration.

CPT Code Information

86255 x 19

86341 x 1

83519-ARBI (if appropriate)

84182-AGNBS (if appropriate)

86255-AINCS (if appropriate)

86256-AMPIS (if appropriate)

84182-AMIBS (if appropriate)

84182-AN1BS (if appropriate)

84182-AN2BS (if appropriate)

84182-CRMWS (if appropriate)

86255-DPPCS (if appropriate)

86256-DPPTS (if appropriate)

86256-GABIS (if appropriate)

86255-GFACS (if appropriate)

86256-GFATS (if appropriate)

86255-IG5CS (if appropriate)

86256-IG5TS (if appropriate)

86255-GL1CS (if appropriate)

86256-GL1TS (if appropriate)

86255-NFHCS (if appropriate)

86256-NIFTS (if appropriate)

86255-NFLCS (if appropriate)

86256-NMDIS (if appropriate)

84182-PC1BS (if appropriate)

84182-PCTBS (if appropriate)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
ENS2 Encephalopathy-Autoimmune Eval, S 94697-0

 

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
34257 Encephalopathy, Interpretation, S 69048-7
64279 LGI1-IgG CBA, S 94287-0
64281 CASPR2-IgG CBA, S 94285-4
64930 DPPX Ab IFA, S 82976-2
64928 mGluR1 Ab IFA, S 94347-2
605155 GFAP IFA, S 94346-4
606946 IgLON5 IFA, S 96476-7
606964 NIF IFA, S 96486-6
89080 AGNA-1, S 94341-5
81722 Amphiphysin Ab, S 94340-7
80150 ANNA-1, S 94342-3
80776 ANNA-2, S 94343-1
83137 ANNA-3, S 94344-9
83077 CRMP-5-IgG, S 94815-8
81596 GAD65 Ab Assay, S 94345-6
83138 PCA-2, S 94351-4
9477 PCA-1, S 94350-6
83076 PCA-Tr, S 94352-2
36349 Reflex Added 77202-0
Mayo Clinic Laboratories | Neurology Catalog Additional Information:

mml-neuroimmunology