Autoimmune Dysautonomia Evaluation, Serum
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Autoimmune dysautonomia encompasses disorders of peripheral autonomic synapses, ganglionic neurons, autonomic nerve fibers, and central autonomic pathways mediated by neural-specific IgG or effector T cells. These disorders may be idiopathic or paraneoplastic, subacute or insidious in onset, and may present as a limited disorder or generalized pandysautonomia. Pandysautonomia is usually subacute in onset and severe, and includes impaired pupillary light reflex, anhidrosis, orthostatic hypotension, cardiac arrhythmias, gastrointestinal dysmotility, sicca manifestations, and bladder dysfunction. Limited dysautonomia is confined to 1 or just a few domains, is often mild and may include sicca manifestations, postural orthostatism and cardiac arrhythmias, bladder dysfunction or gastrointestinal dysmotilities. Diagnosis of limited dysautonomia requires documentation of objective abnormalities by autonomic reflex testing, thermoregulatory sweat test, or gastrointestinal motility studies.
The most commonly encountered autoantibody marker of autoimmune dysautonomia is the neuronal ganglionic alpha-3- (acetylcholine receptor: AChR) autoantibody. This autoantibody to date is the only proven effector of autoimmune dysautonomia. A direct relationship has been demonstrated between antibody titer and severity of dysautonomia in both alpha-3-AChR-immunized animals and patients with autoimmune dysautonomia. Patients with high alpha-3-AChR autoantibody values (>1.0 nmol/L) generally have profound pandysautonomia. Dysautonomic patients with lower alpha-3-AChR autoantibody values (0.03-0.99 nmol/L) have limited dysautonomia.
Importantly, cancer is detected in 30% of patients with alpha-3-AChR autoantibody. Cancers recognized most commonly include small-cell lung carcinomas, thymoma, adenocarcinomas of breast, lung, prostate, and gastrointestinal tract, and lymphoma. Cancer risk factors include a past or family history of cancer, history of smoking, or social/environmental exposure to carcinogens. Early diagnosis and treatment of the neoplasm favors neurologic improvement and lessens morbidity.
Autoantibodies to other onconeural proteins shared by neurons, glia or muscle (eg, antineuronal nuclear antibody-type 1: ANNA-1, CRMP-5-IgG, N-type voltage-gated calcium channel, muscle AChR and sarcomeric [striational antigens]) serve as additional markers of paraneoplastic or idiopathic dysautonomia. A specific neoplasm is often predictable by the individual patient’s autoantibody profile.
Investigating idiopathic dysautonomic symptoms
Directing a focused search for cancer in patients with idiopathic dysautonomia
Investigating autonomic symptoms that appear in the course or wake of cancer therapy, and are not explainable by recurrent cancer or metastasis (detection of autoantibodies in this profile helps differentiate autoimmune dysautonomia from the effects of chemotherapy)
Antibodies directed at onconeural proteins shared by neurons, muscle, and glia are valuable serological markers of a patient's immune response to cancer. These autoantibodies are not found in healthy subjects, and are usually accompanied by subacute neurological symptoms and signs. It is not uncommon for more than 1 autoantibody to be detected in patients with autoimmune dysautonomia. These include:
-Plasma membrane cation channel antibodies (neuronal ganglionic [alpha-3] and muscle [alpha-1] acetylcholine receptor; neuronal calcium channel N-type or P/Q-type, and neuronal voltage-gated potassium channel antibodies). All of these autoantibodies are potential effectors of autonomic dysfunction.
-Antineuronal nuclear autoantibody-type 1
-Neuronal and muscle cytoplasmic antibodies (CRMP-5 IgG, glutamic acid decarboxylase and striational)
A rising autoantibody titer in previously seropositive patients suggests cancer recurrence.
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 dysautonomia or cancer.
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.
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
Glutamic Acid Decarboxylase (GAD65) Antibody
< or =0.02 nmol/L
NEURONAL NUCLEAR ANTIBODIES
Antineuronal Nuclear Antibody-Type 1 (ANNA-1)
Antineuronal Nuclear Antibody-Type 2 (ANNA-2)
Antineuronal Nuclear Antibody-Type 3 (ANNA-3)
Anti-Glial/Neuronal Nuclear Antibody-Type 1 (AGNA-1)
NEURONAL AND MUSCLE CYTOPLASMIC ANTIBODIES
Purkinje Cell Cytoplasmic Antibody, Type 1 (PCA-1)
Purkinje Cell Cytoplasmic Antibody, Type 2 (PCA-2)
Purkinje Cell Cytoplasmic Antibody, Type Tr (PCA-Tr)
Note: 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 or 507-266-5700 to request CRMP-5 Western blot.
Striational (Striated Muscle) Antibodies
ACHR RECEPTOR ANTIBODIES
ACh Receptor (Muscle) Binding Antibody
< or =0.02 nmol/L
AChR Receptor (Muscle) Modulating Antibody
0-20% loss of AChR
NEUROMYELITIS OPTICA (NMO)/AQUAPORIN-4-IGG CELL-BINDING ASSAY
Paraneoplastic Western Blot
CRMP-5-IgG Western Blot
Amphiphysin Western Blot
N-Methyl-D-aspartate receptor (NMDA-R) CBA
2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid receptor (AMPA-R) CBA
Gamma-Amino Butyric acid-type B receptor (GABA-B-R) CBA
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Vernino S, Low PA, Fealey RD, et al: Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000;343:847-855
2. O'Suilleabhain P, Low PA, Lennon VA: Autonomic dysfunction in the Lambert-Eaton myasthenic syndrome: serologic and clinical correlates. Neurology 1998;50:88-93
3. Dhamija R, Tan KM, Pittock SJ, et al: Serological profiles aiding the diagnosis of autoimmune gastrointestinal dysmotility. Clin Gastroenterol Hepatol 2008;6:988-992
4. McKeon A, Lennon VA, Lachance DH, et al: The ganglionic acetylcholine receptor autoantibody: oncological, neurological and serological accompaniments. Arch Neurol 66(6):735-741