TEST CATALOG ORDERING & RESULTS SPECIMEN HANDLING CUSTOMER SERVICE EDUCATION & INSIGHTS
Test Catalog

Test ID: ENC2    
Encephalopathy, Autoimmune Evaluation, Spinal Fluid

Useful For Suggests clinical disorders or settings where the test may be helpful

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 cerebrospinal 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

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

If client requests or if immunofluorescence (IFA) patterns suggest CRMP-5-IgG, then CRMP-5-IgG Western blot is performed at an additional charge.

 

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

 

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

 

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

 

If IFA pattern suggests AMPA-receptor antibody, and AMPA-receptor antibody CBA is positive, then AMPA-receptor antibody IFA titer assay is performed at an additional charge.

 

If IFA pattern suggests GABA-B-receptor antibody, and GABA-B-receptor antibody CBA is positive, then GABA-B-receptor antibody IFA titer assay is performed at an additional charge.

 

If IFA pattern suggests GFAP antibody, then GFAP IFA titer and GFAP CBA are performed at an additional charge.

 

If IFA pattern suggests 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 DPPX antibody, then DPPX antibody CBA and DPPX titer are performed at an additional charge.

 

If IFA pattern suggests mGluR1 antibody, then mGluR1 antibody CBA and mGluR1 titer are performed at an additional charge.

 

If IFA pattern suggests 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-Spinal Fluid in Special Instructions.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

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 Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

 Test ID

Reporting name

Methodology

Reference value

AMPCC

AMPA-R Ab CBA, CSF

Cell-binding assay (CBA)

Negative

AMPHC

Amphiphysin Ab, CSF

Indirect Immunofluorescence (IFA)

<1:2

AGN1C

Anti-Glial Nuclear Ab, Type 1

IFA

<1:2

ANN1C

Anti-Neuronal Nuclear Ab, Type 1

IFA

<1:2

ANN2C

Anti-Neuronal Nuclear Ab, Type 2

IFA

<1:2

ANN3C

Anti-Neuronal Nuclear Ab, Type 3

IFA

<1:2

CS2CC

CASPR2-IgG CBA, CSF

CBA

Negative

CRMC

CRMP-5-IgG, CSF

IFA

<1:2

DPPIC

DPPX Ab IFA, CSF

IFA

Negative

GABCC

GABA-B-R Ab CBA, CSF

CBA

Negative

GD65C

GAD65 Ab Assay, CSF

Radioimmunoassay (RIA)

< or =0.02 nmol/L

Reference values apply to all ages.

GFAIC

GFAP IFA, CSF

IFA

Negative

IG5IC

IgLON5 IFA, CSF

IFA

Negative

LG1CC

LGI1-IgG CBA, CSF

CBA

Negative

GL1IC

mGluR1 Ab IFA, CSF

IFA

Negative

NIFIC

NIF IFA, CSF

IFA

Negative

NMDCC

NMDA-R Ab CBA, CSF

CBA

Negative

PCTRC

Purkinje Cell Cytoplasmc Ab Type Tr

IFA

<1:2

PCA1C

Purkinje Cell Cytoplasmic Ab Type 1

IFA

<1:2

PCA2C

Purkinje Cell Cytoplasmic Ab Type 2

IFA

<1:2

 

Reflex Information:

Test ID

Reporting name

Methodology

Reference value

AGNBC

AGNA-1 Immunoblot, CSF

Immunoblot (IB)

Negative

AINCC

Alpha Internexin CBA, CSF

CBA

Negative

AMPIC

AMPA-R Ab IF Titer Assay, CSF

IFA

<1:2

AMIBC

Amphiphysin Immunoblot, CSF

IB

Negative

AN1BC

ANNA-1 Immunoblot, CSF

IB

Negative

AN2BC

ANNA-2 Immunoblot, CSF

IB

Negative

CRMWC

CRMP-5-IgG Western Blot, CSF

Western Blot

Negative

DPPCC

DPPX Ab CBA, CSF

CBA

Negative

DPPTC

DPPX Ab IFA Titer, CSF

IFA

<1:2

GABIC

GABA-B-R Ab IF Titer Assay, CSF

IFA

<1:2

GFACC

GFAP CBA, CSF

CBA

Negative

GFATC

GFAP IFA Titer, CSF

IFA

<1:2

IG5CC

IgLON5 CBA, CSF

CBA

Negative

IG5TC

IgLON5 IFA Titer, CSF

IFA

<1:2

GL1CC

mGluR1 Ab CBA, CSF

CBA

Negative

GL1TC

mGluR1 Ab IFA Titer, CSF

IFA

<1:2

NFLCC

NIF Light Chain CBA, CSF

CBA

Negative

NMDIC

NMDA-R Ab IF Titer Assay, CSF

IFA

Negative at <1:2

PC1BC

PCA-1 Immunoblot, CSF

IB

Negative

PCTBC

PCA-Tr Immunoblot, CSF

IB

Negative

 

Neuron-restricted patterns of IgG staining that do not fulfill criteria for ANNA-1, ANNA-2, ANNA-3, 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 1:2 are detectable by recombinant CRMP-5 Western blot analysis. CRMP-5 Western blot analysis will be done on request on stored spinal fluid (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 Provides information to assist in interpretation of the test results

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: 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, GAD65, or striational.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Negative results do not exclude autoimmune encephalopathy or cancer.

 

This test does not detect Ma1 or Ma2 antibodies (alias MaTa), which are sometimes associated with brainstem and limbic encephalitis in the context of testicular germ cell neoplasms. Scrotal ultrasound is advised for men who present with unexplained subacute encephalitis.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. McKeon A, Lennon, VA, Pittock, SJ: Immunotherapy Responsive Dementias and Encephalopathies. Continuum Lifelong Learning 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

Special Instructions Library of PDFs including pertinent information and forms related to the test