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Test Code ENC1 Encephalopathy, Autoimmune Evaluation, Spinal Fluid

Secondary ID

48404

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 spinal fluid 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
AEECI Encephalopathy, Interpretation, CSF No Yes
NMDCC NMDA-R Ab CBA, CSF No Yes
VGKCC VGKC-complex Ab IPA, CSF No Yes
LG1CC LGI1-IgG CBA, CSF No Yes
CS2CC CASPR2-IgG CBA, CSF No Yes
GD65C GAD65 Ab Assay, CSF Yes Yes
GABCC GABA-B-R Ab CBA, CSF No Yes
AMPCC AMPA-R Ab CBA, CSF No Yes
ANN1C Anti-Neuronal Nuclear Ab, Type 1 No Yes
ANN2C Anti-Neuronal Nuclear Ab, Type 2 No Yes
ANN3C Anti-Neuronal Nuclear Ab, Type 3 No Yes
AGN1C Anti-Glial Nuclear Ab, Type 1 No Yes
PCA1C Purkinje Cell Cytoplasmic Ab Type 1 No Yes
PCA2C Purkinje Cell Cytoplasmic Ab Type 2 No Yes
PCTRC Purkinje Cell Cytoplasmc Ab Type Tr No Yes
AMPHC Amphiphysin Ab, CSF No Yes
CRMC CRMP-5-IgG, CSF No Yes

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
WBNC Paraneoplas Autoantibody WBlot,CSF No No
CRMWC CRMP-5-IgG Western Blot, CSF Yes No
ABLTC Amphiphysin Western Blot, CSF No No
NMOFC NMO/AQP4 FACS, CSF Yes No
NMOTC NMO/AQP4 FACS Titer, CSF No No
AMPIC AMPA-R Ab IF Titer Assay, CSF No No
GABIC GABA-B-R Ab IF Titer Assay, CSF No No
NMDIC NMDA-R Ab IF Titer Assay, CSF No No

Testing Algorithm

If indirect immunofluorescence assay (IFA) (ANN1C, ANN2C, ANN3C, AGN1C, PCA2C, PCTRC, AMPHC, CRMC) is indeterminate, then WBNC is performed at an additional charge.

 

If client requests or if IFA patterns suggest CRMP-5-IgG, then CRMWC is performed at an additional charge.

 

If IFA pattern suggest amphiphysin antibody, then ABLTC is performed at an additional charge.

 

If IFA pattern suggest NMO/AQP4-IgG, then NMOFC is performed at an additional charge.

 

If NMO/AQP4-IgG FACS screen assay requires further investigation, then NMO/AQP4-IgG FACS titration assay is performed at an additional charge.

 

If IFA pattern suggest AMPA-R Ab and AMPCC is positive, then AMPIC is performed at an additional charge.

 

If IFA pattern suggest GABA-B-R Ab and GABCC is positive, then GABIC is performed at an additional charge.

 

If IFA pattern suggest NMDA-R Ab and NMDCC is positive, then NMDIC is performed at an additional charge.

 

See Encephalopathy Autoimmune Evaluation Algorithm, Spinal Fluid in Special Instructions

Method Name

ANN1C, ANN2C, ANN3C, AGN1C, PCA1C, PCA2C, PCTRC, AMPHC, CRMC, AMPIC, GABIC, NMDIC: Indirect Immunofluorescence Assay (IFA)

AMPCC, GABCC, NMDCC, LG1CC, CS2CC: Cell-Binding Assay (CBA)

GD65C: Immunoprecipitation Assay

VGKCC: Radioimmunoassay (RIA)

WBNC, ABLTC: Western Blot

AEECI: Interpretive Comments

Reporting Name

Encephalopathy-Autoimmune Eval, CSF

Specimen Type

CSF


Necessary Information


Include name, phone number, mailing address, and e-mail address (if applicable) of ordering physician.



Specimen Required


Container/Tube: Sterile vial

Specimen Volume: 4 mL


Specimen Minimum Volume

2 mL

Specimen Stability Information

Specimen Type Temperature Time
CSF Refrigerated (preferred) 28 days
  Frozen  28 days
  Ambient  72 hours

Reject Due To

Hemolysis

Mild OK; Gross reject

Lipemia

Mild OK; Gross reject

Icterus

NA

Other

NA

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 1 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, LGI1 and CASPR2), ionotropic glutamate receptors (NMDA and AMPA), metabotropic GABA-B receptors; 2) enzymes, signaling molecules and RNA-regulatory proteins in the cytoplasm and nucleus of neurons (GAD65, CRMP-5, 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 cerebral spinal 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, neuronal voltage-gated potassium channel (VGKC)-complex antibodies were initially considered specific for autoimmune limbic encephalitis or disorders of peripheral nerve hyperexcitability. However, more diverse presentations are now recognized, including rapidly progressive cognitive decline mimicking frontotemporal dementia and Creutzfeldt-Jakob disease.

 

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 (antineuronal nuclear antibody-type 1: ANNA-1; collapsin response-mediator protein-5 neuronal: CRMP-5-IgG), ovarian teratoma (N-methyl-D-aspartate receptor: NMDA-R), and thymoma (CRMP-5 IgG).

 

An individual patient's profile autoantibody may be informative for a specific cancer type. For example, detection of muscle acetylcholine receptor (AChR) binding, alpha 3 ganglionic AChR, and CRMP-5 IgG in a patient presenting with encephalopathy suggests thymoma. When an associated tumor is found, its resection or ablation optimizes the neurological outcome.

 

Testing of CSF for autoantibodies is particularly helpful when serum testing is negative. Simultaneous testing of serum and CSF is recommended for NMDA-R antibody, because CSF is usually more informative.

Reference Values

NEURONAL NUCLEAR ANTIBODIES

Antineuronal Nuclear Antibody-Type 1 (ANNA-1)

<1:2

Antineuronal Nuclear Antibody-Type 2 (ANNA-2)

<1:2

Antineuronal Nuclear Antibody-Type 3 (ANNA-3)

<1:2

Anti-Glial/Neuronal Nuclear Antibody-Type 1 (AGNA-1)

<1:2

 

NEURONAL AND MUSCLE CYTOPLASMIC ANTIBODIES

Purkinje Cell Cytoplasmic Antibody, Type 1 (PCA-1)

<1:2    

Purkinje Cell Cytoplasmic Antibody, Type 2 (PCA-2)

<1:2    

Purkinje Cell Cytoplasmic Antibody, Type TR (PCA-TR)

<1:2

Amphiphysin Antibody

<1:2

Collapsin Response-Mediator Protein-5 Neuronal (CRMP-5-IGG)

<1:2

 

ISLET CELL ANTIBODIES

Glutamic Acid Decarboxylase (GAD65) Antibody Assay

≤0.02 nmol/L

 

AMPA-RECEPTOR ANTIBODY BY CBA

CBA: Negative

IFA: <1:2

GABA-B-RECEPTOR ANTIBODY BY CBA

CBA: Negative

IFA: <1:2

NMDA-RECEPTOR ANTIBODY BY CBA

CBA: Negative

IFA: <1:2

LGI1-IgG CBA: Negative

CASPR2-IgG CBA: Negative

 

Neuronal Voltage-Gated Potassium Channel-Complex Autoantibody

≤0.02 nmol/L

 

WESTERN BLOT

Paraneoplastic Autoantibody, Western Blot Confirmation

Negative

Collapsin Response-Mediator Protein-5-IGG (CRMP-5-IGG) Western Blot

Negative

Amphiphysin Antibody Western Blot

Negative

 

Neuromyelitis Optica (NMO)/Aquaporin-4-Igg FACS Assay

Negative

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: These are all potential effectors of neurological dysfunction: neuronal voltage-gated potassium channel (VGKC)-complex, 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.

-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, GA65, or striational.

Clinical Reference

1. McKeon A, Lennon, VA, Pittock, SJ: Immunotherapy responsive dementias and encephalopathies. Continuum Lifelong Learning Neurol 2010;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;81:1207-1214

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

Day(s) and Time(s) Performed

ANNA-1, ANNA-2, ANNA-3, AGNA-1, PCA-1, PCA-2, PCA-Tr, Amphiphysin, CRMP-5-IgG, AMPIC, GABIC, NMDIC:

Monday through Friday; 11:30 a.m. and 8:00 p.m.; Saturday and Sunday 8:00 a.m.

 

AMPCC, GABCC, NMDCC LG1CC, CS2CC: Monday through Friday; 6 a.m.

Paraneoplastic autoantibody Western blot confirmation, CRMP-5-IgG Western blot, Amphiphysin Western blot: Monday, Wednesday, Friday; 8 a.m.

GAD65: : Monday to Friday; 6:00 a.m. and 4:00 p.m.

VGKC: Monday through Friday 11:00 a.m. and 6:00 p.m.; Saturday 6:00 a.m.; Sunday 6:00 a.m.

Analytic Time

3 days if negative/5 days if positive

Performing Laboratory

Mayo Medical Laboratories in Rochester

Test Classification

See Individual Test IDs

CPT Code Information

83519-Neuronal VGKC autoantibody

86255-AGNA-1

86255-Amphiphysin

86255-ANNA-1

86255-ANNA-2

86255-ANNA-3

86255-CRMP-5-IgG

86255-PCA-1

86255-PCA-2

86255-PCA-Tr

86255-AMPAR-Ab

86255-GABAR-Ab

86255-NMDAR-Ab

86341-GAD65

86255-LG1CC

86255- CS2CC

84182-Amphiphysin Western blot (if appropriate)

84182-CRMP-5 Western blot confirmation (if appropriate)

84182-Paraneoplastic autoantibody Western blot confirmation (if appropriate)

86255-NMO/AQP4-IgG FACS (if appropriate)

86256-AMPAR-Ab titer (if appropriate)

86256-GABAR-Ab titer (if appropriate)

86256-NMDAR-Ab titer (if appropriate)

86256- NMO/AQP4-IgG FACS titer (if appropriate)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
ENC1 Encephalopathy-Autoimmune Eval, CSF In Process

 

Result ID Test Result Name Result LOINC Value
61513 NMDA-R Ab CBA, CSF No LOINC Needed
61514 AMPA-R Ab CBA, CSF No LOINC Needed
61515 GABA-B-R Ab CBA, CSF No LOINC Needed
34256 Encephalopathy, Interpretation, CSF 69048-7
61729 VGKC-complex Ab IPA, CSF 68913-3
64280 LGI1-IgG CBA, CSF In Process
64282 CASPR2-IgG CBA, CSF In Process
89079 AGNA-1, CSF 53714-2
5906 Amphiphysin Ab, CSF 56531-7
3852 ANNA-1, CSF 24400-4
7472 ANNA-2, CSF 24401-2
21633 ANNA-3, CSF 35144-5
21650 CRMP-5-IgG, CSF 35385-4
3988 PCA-1, CSF 14248-9
21632 PCA-2, CSF 35143-7
21631 PCA-Tr, CSF 51748-2
21702 GAD65 Ab Assay, CSF 53708-4
36429 Reflex Added No LOINC Needed

Forms

If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen (http://www.mayomedicallaboratories.com/it-mmfiles/neurology-request-form.pdf)