Test Catalog

Test ID: ENC1    
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 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

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

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.

 

The following algorithms are available in Special Instructions:

-Encephalopathy Autoimmune Evaluation Algorithm, Spinal Fluid

-Meningitis/Encephalitis Panel Algorithm

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 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 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.

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

< or =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

< or =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 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: 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.

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 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

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