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Test ID: ENCES    
Encephalopathy, Autoimmune Evaluation, Serum

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

 

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

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. Misdiagnosed 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 identifying 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, 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 Ab, Type 1 (ANNA-1)

<1:240

Antineuronal Nuclear Ab, Type 2 (ANNA-2)

<1:240

Antineuronal Nuclear Ab, Type 3 (ANNA-3)

<1:240

Anti-Glial/Neuronal Nuclear Ab, Type 1 (AGNA-1)

<1:240

 

NEURONAL AND MUSCLE CYTOPLASMIC ANTIBODIES

Purkinje Cell Cytoplasmic Ab, Type1 (PCA-1)

<1:240

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

<1:240

Purkinje Cell Cytoplasmic Ab, Type Tr (PCA-Tr)

<1:240

Amphiphysin Antibody

<1:240

CRMP-5-IgG

<1:240

 

WESTERN BLOT

Paraneoplastic Western Blot

Negative

CRMP-5-IgG Western Blot

Negative

Amphiphysin Western Blot

Negative

 

ISLET CELL ANTIBODIES

Glutamic Acid Decarboxylase (GAD65) Antibody

< or =0.02 nmol/L

 

CATION CHANNEL ANTIBODIES

N-Type Calcium Channel Antibody

< or =0.03 nmol/L

P/Q-Type Calcium Channel Antibody

< or =0.02 nmol/L

AChR Ganglionic Neuronal Antibody

< or =0.02 nmol/L

Neuronal VGKC Autoantibody

< or =0.02 nmol/L

 

ACHR RECEPTOR ANTIBODIES

ACh Receptor (Muscle) Binding Antibody

< or =0.02 nmol/L

 

N-Methyl-D-aspartate receptor (NMDA-R)

CBA: Negative

IFA: <1:120

2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid receptor (AMPA-R)

CBA: Negative

IFA: <1:120

Gamma-Amino Butyric acid-type B receptor (GABA-B-R)

CBA: Negative

IFA: <1:120

NMO/AQP4-IgG

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.

1. Plasma membrane autoantibodies: voltage-gated potassium channel 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. These are all potential effectors of neurological dysfunction

2. Neuronal nuclear autoantibodies, type 1 (ANNA-1), type 2 (ANNA-2), or type 3 (ANNA-3).

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 Provides recommendations for further 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 and Forms Describes specimen collection and preparation information, test algorithms, and other information pertinent to test. Also includes pertinent information and consent forms to be used when requesting a particular test