Paraneoplastic Autoantibody Evaluation, Serum
Serological evaluation of patients who present with a subacute neurological disorder of undetermined etiology, especially those with known risk factors for cancer
Directing a focused search for cancer
Investigating neurological symptoms that appear in the course of, or after, cancer therapy, and are not explainable by metastasis
Differentiating autoimmune neuropathies from neurotoxic effects of chemotherapy
Monitoring the immune response of seropositive patients in the course of cancer therapy
Detecting early evidence of cancer recurrence in previously seropositive patients
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Paraneoplastic autoimmune neurological disorders reflect a patient's humoral and cellular immune responses to cancer. The cancer may be new or recurrent, is usually limited in metastatic volume, and is often occult by standard imaging procedures. Autoantibodies specific for onconeural proteins found in the plasma membrane, cytoplasm, and nucleus of neurons, glia, or muscle are generated in this immune response and serve as serological markers of paraneoplastic autoimmunity. Cancers recognized in this context most commonly are small-cell lung carcinoma, thymoma, ovarian (or related mullerian) carcinoma, breast carcinoma, and Hodgkin lymphoma. Pertinent childhood neoplasms recognized thus far include neuroblastoma, thymoma, Hodgkin lymphoma, and chondroblastoma. An individual patient's autoantibody profile can predict a specific neoplasm with 90% certainty, but not the neurological syndrome.
Four classes of autoantibodies are recognized in this evaluation:
-Neuronal nuclear (ANNA-1, ANNA-2, ANNA-3)
-Anti-glial/neuronal nuclear (AGNA-1; also known as Sox1)
-Neuronal and muscle cytoplasmic (PCA-1, PCA-2, PCA-Tr, CRMP-5, amphiphysin, and striational)
-Plasma membrane cation channel, calcium channels, P/Q-type and N-type calcium channel, dendrotoxin-sensitive potassium channels, and neuronal (ganglionic) and muscle nicotinic acetylcholine receptors (AChR). These autoantibodies are potential effectors of neurological dysfunction.
Seropositive patients usually present with subacute neurological symptoms and signs such as encephalopathy; cerebellar ataxia; myelopathy; radiculopathy; plexopathy; or sensory, sensorimotor, or autoimmune neuropathy, with or without a neuromuscular transmission disorder: Lambert-Eaton syndrome, myasthenia gravis, or neuromuscular hyperexcitability. Initial signs may be subtle, but a subacute multifocal and progressive syndrome usually evolves. Sensorimotor neuropathy and cerebellar ataxia are common presentations, but the clinical picture in some patients is dominated by striking gastrointestinal dysmotility, limbic encephalopathy, basal ganglionitis, or cranial neuropathy (especially loss of vision, hearing, smell, or taste).
Cancer risk factors include past or family history of cancer, history of smoking, or social or environmental exposure to carcinogens. Early diagnosis and treatment of the neoplasm favor less neurological morbidity and offer the best hope for survival.
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)
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
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
Neuron-restricted patterns of IgG staining that do not fulfill criteria for amphiphysin, ANNA-1, ANNA-2, ANNA-3, AGNA-1, PCA-1, PCA-2, PCA-Tr, or CRMP-5-IgG may be reported as "unclassified antineuronal IgG." Complex patterns that include non-neuronal elements may be reported as "uninterpretable."
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
Antibodies directed at onconeural proteins shared by neurons, glia, muscle, and certain cancers are valuable serological markers of a patient's immune response to cancer. They are not found in healthy subjects, and are usually accompanied by subacute neurological symptoms and signs. Several autoantibodies have a syndromic association, but no autoantibody predicts a specific neurological syndrome. Conversely, a positive autoantibody profile has 80% to 90% predictive value for a specific cancer. It is not uncommon for more than 1 paraneoplastic autoantibody to be detected, each predictive of the same cancer.
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 cancer.
This evaluation does not include Ma2 autoantibody (alias: MaTa). Ma2 autoantibody has been described in patients with brainstem and limbic encephalitis in the context of testicular germ cell neoplasms. Scrotal ultrasound is advisable in men who present with unexplained subacute encephalitis. N-methyl-D-asparate receptor antibodies have been reported in women with paraneoplastic encephalitis related to ovarian teratoma.
This test should not be requested for patients who have recently received radioisotopes, therapeutically or diagnostically, because of potential assay interference. The specific waiting period before specimen collection will depend on the isotope administered, the dose given, and the clearance rate in the individual patient. Specimens will be screened for radioactivity prior to analysis. Radioactive specimens received in the laboratory will be held 1 week and assayed if sufficiently decayed, or canceled if radioactivity remains.
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Lennon VA: Calcium channel and related paraneoplastic disease autoantibodies. In Textbook of Autoantibodies. Edited by JB Peter, Y Schoenfeld. The Netherlands, Elsevier Science Publishers, B.V., 1996, pp 139-147
2. Voltz R, Gultekin SH, Rosenfeld MR, et al: A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N Engl J Med 1999 June 10;340(23):1788-1795
3. Vernino S, Tuite P, Adler CH, et al: Paraneoplastic chorea associated with CRMP-5 neuronal antibody and lung carcinoma. Ann Neurol 2002 May;51(1):625-630
4. Pittock SJ, Kryzer TJ, Lennon VA: Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol 2004;56(5):715-719
5. Sabater L, Saiz A, Titulaer MG, et al: Sox 1 antibodies are markers of paraneoplastic Lambert-Eaton myasthenic syndrome. Neurology 2007;68(Suppl 1):A290-A291
6. Dalmau J, Tuzun E, Wu H-Y, et al: Paraneoplastic anti-N-methyl-D-asparate receptor encephalitis associated with ovarian teratome. Ann Neurol 2007;61:25-36
7. Tan K. Lennon V, Pittock S: Voltage-gated potassium channel (VGKC) autoimmunity, Abstract, Annual Meeting of American Neurological Association, Washington DC, (October) 2007
8. Pittock SJ, Lucchinetti DF, Parisi JE, et al: Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann Neurol 2005:58(1):96-107