Clinical Focus
Paraneoplastic Neurological Syndromes
Laboratory Support of Diagnosis
Individuals suitable for testing
Test availability and selection
Appendix: Laboratory Tests for Diagnosis of PNSs and Identification of Related Tumors
Clinical background [return to contents]
Paraneoplastic neurological syndromes (PNSs) occur when cancer triggers an immune response that attacks the nervous system. Symptoms vary based on the part of the nervous system that is attacked and can include cognitive, psychiatric, autonomic, and sensorimotor effects.1,2
The prevalence of most PNSs is very low, but symptoms often precede discovery of cancer. Thus, diagnosis of a PNS and its cause may lead to earlier cancer treatment.2 However, because PNS-associated antibodies may cause permanent damage, successful treatment of a tumor does not always result in neurological improvement.2
The exact mechanisms of autoantibody-caused dysfunction in PNSs are often unclear. For extracellular antigens (eg, channels and receptors), pathogenesis may involve interference with synaptic transmission. For intracellular antigens, pathogenesis may involve T-cell–mediated cellular immunity.
A suggested approach for the diagnosis of PNS involves a clinical and neurologic examination followed by a laboratory investigation to evaluate paraneoplastic causes.3 Careful consideration should be given to the specific antibodies that are associated with the observed syndrome and support the diagnosis. Appropriate antibody testing in the blood and/or cerebrospinal fluid (CSF) can then be carried out to identify these antibodies,3 which can guide the search for an underlying malignancy.
A single antibody, however, can be associated with multiple syndromes and cancer types, and a single syndrome or cancer type can be associated with multiple antibodies. Furthermore, these antibodies can occur in the absence of an underlying cancer; that is, conditions such as autoimmune encephalitis, rapidly progressing dementia, and epilepsy can be paraneoplastic or nonparaneoplastic. In certain clinical circumstances it may be helpful to simultaneously test for multiple autoantibodies in the serum and/or CSF4; for some patients, detection of antibodies is more robust with CSF than serum.5-8
This Clinical Focus discusses the role of autoantibody testing in the diagnosis of PNSs and associated cancer and tumor types. It is intended as an overview. Complete diagnostic criteria, prognosis, follow-up studies, and treatment options (eg, immune modulation) of PNSs are beyond the scope of this Clinical Focus. These topics are covered in review articles and guidelines.1,2,4 The information provided in this Clinical Focus is not intended as medical advice. Test selection and interpretation, diagnosis, and patient management decisions should be based on the physician’s education, clinical expertise, and assessment of the patient.
Individuals suitable for testing [return to contents]
Table 1. Clinical Presentation and Associated Tumors of Paraneoplastic Neurological Syndromes [return to contents]
Neurological syndrome |
Clinical presentation |
Associated tumors (common cancer and tumor types are in bold) |
Brainstem encephalitis/ opsoclonus-myoclonus4,a |
Large-amplitude synchronic and chaotic eye movements (opsoclonus), spontaneous muscle jerks (myoclonus), and ataxia1,2 |
Breast cancer, ovarian cancer, testicular tumor, SCLC, neuroblastoma (children)4 |
Cerebellar degeneration4,a |
Ataxia, diplopia, dysarthria; early symptoms include dizziness, nausea, vomiting1,2 |
SCLC, ovarian cancer, breast cancer, Hodgkin lymphoma, thymoma4 |
Encephalomyelitis/ limbic encephalitis4,a |
Encephalomyelitis: subacute sensory neuropathy, limbic encephalitis, cerebellar ataxia; 30% of patients have autonomic neuropathy (eg, orthostatic hypotension, urinary retention, pupillary abnormalities, impotence, dry mouth)1,2 Limbic encephalitis: short-term memory loss, seizures, mood changes, hallucinations; less common symptoms include hypothalamic symptoms (eg, hyperthermia, somnolence, endocrine dysfunction)1,2 |
SCLC, testicular tumor, thymoma, neuroblastoma, prostate carcinoma, breast cancer, Hodgkin lymphoma4 |
Lambert-Eaton myasthenic syndrome4,a |
Proximal muscle weakness in lower extremities, fatigue, diaphragmatic weakness, bulbar symptoms; later symptoms include autonomic symptoms (eg, ptosis, impotence, dry mouth)1,2 |
SCLC4 |
Myasthenia gravis4,a |
Weakness and fatigue of voluntary muscles (eg, ocular-bulbar, limbs) and diaphragm1,2 |
Thymoma4 |
Neuromyotonia (Isaac syndrome)4,a |
Twitching, muscle rippling, stiffness, cramps, slowed movement1,2 |
Thymoma, SCLC4 |
Subacute autonomic neuropathy/ dysautonomia4,a |
Orthostatic hypotension, gastrointestinal dysfunction, dry eyes or mouth, bowel or bladder dysfunction, altered pupillary light reflexes, loss of sinus arrhythmia, chronic gastrointestinal pseudo-obstruction (constipation, nausea or vomiting, dysphagia, weight loss, abdominal distention)1,2 |
SCLC, thymoma4 |
Subacute sensory neuropathy4,a |
Paresthesia or pain (in upper before lower extremities), ataxia, multifocal or asymmetric distribution of neuropathy, decreased sensory modalities, pseudoathetosis of hands, decreased or absent deep tendon reflexes1,2 |
SCLC, breast cancer, ovarian cancer4 |
Stiff-person syndrome4,a |
Severe muscle stiffness, mainly in spine and legs; muscle spasms1,2 |
Breast cancer, SCLC4 |
| SCLC, small-cell lung cancer. | |
| a | These syndromes can occur in the absence of cancer or tumors. |
Test availability and selection [return to contents]
If a specific syndrome is suspected based on clinical presentation, individual antibody tests may help identify the presence of an underlying malignancy. However, there is consensus that limiting testing to a single methodology could contribute to low diagnostic yield.4
Quest Diagnostics offers several tests and panels (Appendix) that may help identify an underlying PNS or antibodies associated with specific autoimmune neurological disease. Selecting the appropriate test or panel depends on clinical indications (Table 1).
The panels offered by Quest come in 3 general categories; the main differences between categories are the numbers of antibodies tested and the reflex patterns of testing (see Tables 2 and 3 and the relevant figures):
Many components are available individually, but some tests are only offered as components of line blots or mosaics (Table 2, Appendix).
Table 2. Test Availability for PNS-Related Antibodies [return to contents]
Antibody |
Single antibody tests |
Basic test, serum (93876) |
Basic test, CSF (94536) |
Expanded test, serum (94957) |
Expanded test, CSF (94960) |
Comprehensive test, serum (93888) |
Tissue IFA panela (see Table 3 for antibodies) |
|
●b |
●c |
●d |
●d |
●e |
RIA |
||||||
AChR, binding |
● |
● |
|
|
|
● |
AChR, blocking |
● |
|
|
|
|
Reflex |
AChR, modulating |
● |
Reflex |
|
|
|
Reflex |
gAChR |
● |
● |
|
● |
|
● |
VGCC, N-type |
● |
● |
|
● |
|
● |
VGCC, P/Q-type |
● |
● |
|
● |
|
● |
VGKC |
● |
● |
Reflex |
● |
● |
● |
CBA |
||||||
Aquaporin 4 (NMO) |
● |
Reflex |
Reflexc |
●d |
●d |
Reflexe |
DPPX |
● |
●d |
●d |
●e |
||
AMPAR (1 & 2) |
|
Reflex |
Reflexc |
●d |
●d |
●e |
GABABR |
|
Reflex |
Reflexc |
●d |
●d |
●e |
NMDAR1 |
● |
Reflex |
Reflexc |
●d |
●d |
●e |
LGI1 |
● |
Reflexc |
●d |
●d |
●e |
|
CASPR2 |
● |
Reflexc |
●d |
●d |
●e |
|
Line blot |
||||||
AGNA (SOX1) |
|
Reflex |
Reflex |
Reflex |
● |
|
Amphiphysin |
● |
Reflex |
Reflex |
Reflex |
Reflex |
● |
ANNA1 (Hu) |
● |
Reflex |
Reflex |
Reflex |
Reflex |
● |
ANNA2 (Ri) |
● |
Reflex |
Reflex |
Reflex |
Reflex |
● |
CRMP5 (CV2) |
● |
Reflex |
Reflex |
Reflex |
Reflex |
● |
GAD65 |
● |
Reflex |
Reflex |
Reflex |
Reflex |
● |
Ma2/Ta |
● |
Reflex |
Reflex |
● |
||
PCA1 (Yo) |
● |
Reflex |
Reflex |
Reflex |
Reflex |
● |
PCA-Tr (DNER) |
● |
Reflex |
Reflexd |
Reflexd |
●e |
|
Recoverin |
● |
|
|
|
|
● |
Titin |
● |
|
|
|
|
● |
Zic4 |
● |
Reflex |
Reflex |
● |
||
IFA |
||||||
PCA-Tr (DNER) |
● |
|
Reflexd |
Reflexd |
Reflexe |
|
MAG IgM |
● |
|
|
Reflex |
Reflex |
Reflex |
MAG-SGPG |
● |
|
|
Reflex |
Reflex |
|
MAG |
● |
|
|
Reflex |
Reflex |
|
Striated muscle |
● |
●a |
|
|
|
●e |
| AChR, acetylcholine receptor; AGNA, anti-glial nuclear antibody; AMPAR, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor; ANNA, anti-neuronal nuclear antibody; CASPR2, contactin-associated protein-like 2; CBA, cell-binding assay; CRMP5, collapsin response mediator protein 5; CAR, cancer-associated retinopathy; CSF, cerebrospinal fluid; DNER, delta/notch-like epidermal growth factor-related receptor; DPPX, dipeptidyl-peptidase-like protein-6; GABABAR, gamma-aminobutyric acid receptor B; gAChR, ganglionic acetylcholine receptor; GAD65, glutamic acid decarboxylase 65 kD protein; IFA, immunofluorescence assay; LGl1, leucine-rich glioma inactivated-1; MAG, myelin-associated glycoprotein; MG, myasthenia gravis; MGUS, monoclonal gammopathy of uncertain significance; NMDAR1, N-methyl-D-aspartate receptor; NMO, neuromyelitis optica; NMOSD, neuromyelitis spectrum disorder; PCA, Purkinje cell cytoplasmic antibody; PCA-Tr, Purkinje cell cytoplasmic antibody type Tr; RIA, radioimmunoassay; RyR, ryanodine receptor; SCLC, small-cell lung cancer; VGCC, voltage-gated calcium channel; VGKC, voltage-gated potassium channel. | |
| a | Quest uses IFAs that employ nonhuman primate tissue rather than tissues from other animals. |
| b | In addition to reflex tests listed in this column, this IFA panel reflexes to ANNA3 and PCA2 titers if the respective antibodies are suggested by IFA. The individual IFA test for striated muscle antibody also reflexes to titer. |
| c | In addition to reflex tests listed in this column, this IFA panel reflexes to ANNA3 and PCA2 titers if the respective antibodies are suggested by IFA. The CBA tests also reflex to titers of respective antibodies. |
| d | In addition to reflex tests listed in this column, this IFA panel reflexes to ANNA3, PCA2, or myelin titer if the respective antibodies are suggested by IFA. The CBA tests also reflex to titers of respective antibodies. If PCA-Tr antibody is suggested by IFA, and both PCA-1 and PCA-Tr (DNER) are negative by line blot, the panel reflexes to PCA-Tr CBA IFA; if positive, the test reflexes to PCA-Tr titer. |
| e | In addition to reflex tests listed in this column, this IFA panel reflexes to ANNA3, PCA2, or myelin titer if the respective antibodies are suggested; the individual IFA test for striated muscle antibody also reflexes to titer. The CBA tests reflex to titers of respective antibodies. If PCA-Tr antibody is suggested by IFA, and both PCA-1 and PCA-Tr (DNER) are negative by line blot, the panel reflexes to PCA-Tr CBA IFA; if positive, the test reflexes to PCA-Tr titer. |
Table 3. Antibodies Included on Tissue IFA Panels [return to contents]
Antibody |
Basic, serum (93876)a |
Basic, CSF (94536)a |
Expanded, serum (94957)a |
Expanded, CSF (94960)a |
Comprehensive, serum (93888)a |
AGNA (SOX1) |
● |
● |
● |
● |
● |
Amphiphysin |
● |
● |
● |
● |
● |
ANNA1 |
● |
● |
● |
● |
● |
ANNA2 |
● |
● |
● |
● |
● |
ANNA3 |
● |
● |
● |
● |
● |
CRMP5 (CV2) |
● |
● |
● |
● |
● |
PCA1 |
● |
● |
● |
● |
● |
PCA2 |
● |
● |
● |
● |
● |
PCA-Tr (DNER) |
● |
● |
● |
● |
● |
Aquaporin 4 (NMO) |
|
● |
● |
● |
● |
GAD65 |
|
● |
● |
● |
● |
Ma2/Ta |
|
|
● |
● |
● |
Myelin |
|
|
● |
● |
● |
| AGNA, anti-glial nuclear antibody; ANNA, anti-nuclear nuclear antibody; CSF, cerebrospinal fluid; CRMP5, collapsin response mediator protein 5; DNER, delta/notch-like epidermal growth factor-related receptor; GAD65, glutamic acid decarboxylase 65 kD protein; PCA, Purkinje cell cytoplasmic antibody; PCA-Tr, Purkinje cell cytoplasmic antibody type Tr. | |
| a | Many, but not all, antibody tests are available individually (Table 2, Appendix); some tests are only offered as components of line blots or mosaics. |
Many, but not all, antibody tests are available individually (Table 2, Appendix); some tests are only offered as components of line blots or mosaics. If a clinician would like to order individual tests related to a particular syndrome or cancer type, Table 4 and information in the Test Interpretation section can help identify which antibodies would be most appropriate. Table 4 includes PNS-related antibodies and associated syndromes and cancer types. The Test Interpretation section contains information about the antibodies.
Test interpretation [return to contents]
The presence of an antibody is associated with certain PNSs and malignancies (Tables 4 and 5).4,9-19,21-55 Diagnostic criteria combine assignment of high-risk (>70%), intermediate-risk (30%-70%), and lower-risk (<30%) antibodies (risk defined by prevalence of cancer association) with phenotype and presence or absence of cancer.4 A points-based “PNS score” for diagnostic certainty (definite, probably, possible, or non-PNS) is based on these criteria.4
However, antibodies and syndromes can occur in the absence of cancer or a tumor; in such situations, they can help diagnose nonparaneoplastic forms of conditions. To confirm the presence of an underlying malignancy, positive antibody test results must be followed with imaging (eg, computed tomography [CT], fluorodeoxyglucose-positron emission tomography [FDG-PET], magnetic resonance imaging [MRI], ultrasound, mammography) or other laboratory tests (eg, biopsy, other antigen testing).2
The absence of an antibody rarely confirms the absence of an associated syndrome or cancer type. Table 5 provides specific information for each PNS-related antibody.
Table 5. Association of PNS Antibodies With Cancers and Neurological Syndromes [return to contents]
Antibody |
Associated syndrome/condition |
Associated cancer |
Positive result interpretation |
AChR |
MG |
Thymoma |
Found in almost all patients with MG and thymoma but with low specificity (one study found 23% vs MG with thymic atrophy or normal thyroid histology and 0% vs hyperplasia)15; most patients with MG have binding and modulating AChR but about 4% test positive for only modulating AChR44; blocking AChR is present in about 1% of patients without binding antibody56 |
AGNA (SOX1) |
LEMS, sensory neuropathy, limbic encephalitis, cerebellar degeneration28 |
SCLC (most common), lung28 |
Found in 43%-64% of patients with LEMS and SCLC (vs 0% without SCLC)28,57; >90% frequency of cancer(s) in AGNA-positive PNS4 |
AMPAR |
Limbic encephalitis11 |
SCLC, lung, thymoma, breast, ovarian11 |
Found in 0.2% of all patients with suspected PNS11 (9% of patients with limbic encephalitis58); patients with encephalitis59 have been shown to have titers ≥1:10; >50% frequency of cancer(s) in AMPAR-positive PNS4 |
Amphiphysin |
Brainstem encephalitis/ opsoclonus-myoclonus, sensory neuropathy, encephalomyelitis/ limbic encephalitis, stiff-person syndrome10 |
SCLC and breast (most common), lung40 |
Found in 0.026% of all patients with suspected PNS10; often found with other PNS-related antibodies (eg, CRMP5, ANNA1, VGCC)13,40; 80% frequency of cancer(s) in amphiphysin-positive PNS4 |
ANNA1 (Hu) |
Sensory neuropathy, cerebellar ataxia, limbic encephalitis, brainstem encephalitis, autonomic neuropathy39,45,46 |
SCLC (most common), lung, bladder, breast, GI tract, prostate, pancreas, ovary13,39,45,46 |
Found in 0.4% of patients with suspected PNS13 (54%-86% of patients with confirmed PNS and neuropathy39,45,46); cancer develops in 80%-98% of patients13,39,45,46 |
ANNA2 (Ri) |
Opsoclonus-myoclonus, cerebellar ataxia, stiff-person syndrome24 |
Lung and breast (most common), SCLC24 |
Found in 0.02% of patients with suspected PNS10; >70% frequency of cancer(s) in ANNA2-positive PNS4 |
ANNA3 |
Sensory neuropathy, limbic encephalopathy (often multifocal)9 |
SCLC (most common), adenocarcinoma (lung, esophagus)9 |
Found in 0.02% of patients with suspected PNS9 (one large study found among ANNA3-positive patients with oncological data, 5 had SCLC, 2 adenocarcinoma, 1 lung mass, 1 thoracic and abdominal masses)9 |
Aquaporin 4 (NMO) |
NMOSD19 |
Breast, lung, thymic, cervical, B-cell lymphoma, and others19 |
Found in 0.02% of patients with suspected PNS19 (one study found 93% with NMOSD and 29% with neoplasms)19; <5% frequency of cancer(s) in AQP4-positive PNS4 |
CRMP5 (CV2) |
Sensory neuropathy, cerebellar ataxia, autonomic neuropathy, limbic encephalitis, chorea23 |
SCLC, thymoma13,23,45 |
Found in 0.02% of patients with suspected PNS23 (prevalent in paraneoplastic chorea, which is commonly associated with SCLC); overall frequency of cancer(s) in CRMP5-positive PNS4 is >80%; over 50% of patients also test positive for other PNS-related antibodies, including ANNA1, N-type VGCC, and P/Q type VGCC13 |
GABABR |
Limbic encephalitis12 |
SCLC (most common), lung48 |
Found in 71% of patients with limbic encephalitis and SCLC12; median titers have been reported in the range of 1:40-1:2,000 in serum, 1:20-1:640 in the CSF60; >80% frequency of cancer(s) in GABABR -positive PNS4 |
gAChR |
Autonomic neuropathy, sensorimotor polyneuropathy, neuropsychiatric manifestations22 |
Adenocarcinoma (breast, prostate, lung, GI), B-cell lymphoma, melanoma, and others22 |
Found in 1% of patients with suspected PNS22; one study found 30% of patients had cancer and 25% of these had multiple malignant neoplasms22 |
GAD65 |
Stiff-person syndrome, cerebellar ataxia, limbic encephalitis30 |
SCLC, lung, thymoma, breast, pancreatic, thymic, hematological cancers41 |
Few reports of GAD65 in PNS, mainly SCLC41; >100 times higher in stiff-person syndrome than in type 1 diabetes49; <15% frequency of cancer(s) in GAD65-positive PNS4 |
Ma2/Ta |
Limbic encephalitis, brainstem encephalitis, cerebellar degeneration25 |
Testicular germ-cell tumors (especially men <50 years of age), lung, breast50 |
Among Ma2/Ta-positive patients, 90% present with limbic, brainstem, and/or diencephalic syndromes25; >75% frequency of cancer(s) in Ma2/Ta-positive PNS4 |
MAG |
Sensory or sensorimotor neuropathy21,51 |
MGUS, WM21,51 |
Among MAG-positive patients, 93% present with sensory or sensorimotor neuropathy21; 81%-85% have MGUS21,51 |
NMDAR1 |
Encephalitis with prominent psychiatric symptoms, seizures, dyskinesias, autonomic instability37 |
Ovarian teratoma (most common), testicular37 |
In one study, all NMDAR2-positive patients with encephalitis presented with psychiatric symptoms37; CSF and serum titers are higher in patients with poor outcomes or teratoma compared to patients with good outcomes or without teratomas61; 38% frequency of cancer(s) in NMDAR-positive PNS4 |
PCA1 (Yo) |
Cerebellar degeneration31,42 |
Ovarian (most common), breast31,42 |
PCA1-positive patients with paraneoplastic cerebellar degeneration are almost always women and 79%-95% develop cancer31,42 |
PCA2 |
Encephalomyelitis, limbic encephalitis, cerebellar ataxia10 |
Lung (SCLC, NSCLC), breast10 |
Found in 0.24% of patients with suspected PNS (80% of these patients with SCLC have high titers62); cancer is found in 79% of PCA2-positive patients10; frequently found with other antibodies (CRMP5, P/Q-type VGCC, GAD65, ANNA1)10 |
PCA-Tr (DNER) |
Cerebellar degeneration20 |
Hodgkin lymphoma (most common)20 |
Found in 0.006% of patients with suspected PNS10; highly specific for Hodgkin lymphoma as the cause of paraneoplastic cerebellar degeneration52; 90% frequency of cancer(s) in PCA-Tr-positive PNS4 |
Recoverin |
CAR38 |
SCLC (most common), endometrial, breast, colon, skin38 |
Found in 6% of patients with suspected paraneoplastic or autoimmune retinopathy (all were confirmed to have paraneoplastic retinopathy)38 |
Striated muscle (RyR, Titin) |
MG14 |
Thymoma (most common)14 |
Found in 69% of MG patients with thymoma but more specific (97% vs MG with thymic atrophy, hyperplasia, or normal thyroid histology) compared to AChR antibody14,15; titin is considered a biomarker for thymoma in MG15 |
VGCC (P/Q-type and N-type) |
LEMS, cerebellar degeneration29,53-55 |
SCLC (most common)29,53-55 |
Found in almost all patients (96%-100%29,53) with LEMS and cancer (primary marker for LEMS; 85%-95% of patients test positive)29,53,55; 70%-78% frequency of SCLC in VGCC-positive patients with LEMS29,55 |
VGKC (LGl1 and CASPR2; DPPX) |
LGl1 and CASPR2: limbic encephalitis, seizures, cognitive decline neuromyotonia, Morvan syndrome, neuropathic pain, sleep disturbance, personality change16-18 DPPX: multifocal neurological disorders, most prominently encephalopathy, myelopathy, weight loss, autonomic dysfunction34 |
LGl1 and CASPR2: thymoma16 DPPX: B-cell neoplasms34
|
Found in 0.06% of patients with suspected PNS63; LGI1 is more associated with CNS symptoms than peripheral nervous system symptoms; CASPR2 with peripheral and CNS symptoms16; Morvan syndrome is usually associated with high CASPR2 titers, which are accompanied by lower LG1 titers17 |
Zic4 |
Cerebellar degeneration33 |
SCLC (most common)33 |
Found in 13% of patients with PNS; 90% frequency of SCLC in Zic4-positive patients33; frequently found with ANNA1 or CRMP533 |
| AChR, acetylcholine receptor; AGNA, anti-glial nuclear antibody; AMPAR; alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor; ANNA, anti-nuclear nuclear antibody; CASPR2, contactin-associated protein-like 2; CRMP5, collapsin response mediator protein 5; CAR, cancer-associated retinopathy; DPPX, dipeptidyl-peptidase-like protein-6; GABABAR, gamma-aminobutyric acid receptor B; gAChR, ganglionic acetylcholine receptor; GAD65, glutamic acid decarboxylase 65 kD protein; LGl1, leucine-rich glioma inactivated-1; LEMS, Lambert-Eaton myasthenic syndrome; MAG, myelin-associated glycoprotein; MG, myasthenia gravis; MGUS, monoclonal gammopathy of uncertain significance; NMDAR1, N-methyl-D-aspartate receptor; NMOSD, neuromyelitis spectrum disorder; NSCLC, non small-cell lung cancer; PCA, Purkinje cell cytoplasmic antibody type 1; PCA-Tr, Purkinje cell cytoplasmic antibody type Tr; RyR, ryanodine receptor; SCLC, small-cell lung cancer; VGCC, voltage-gated calcium channel; VGKC, voltage-gated potassium channel; WM, Waldenström macroglobulinemia. |
Laboratory Tests for Diagnosis of PNSs and Identification of Related Tumors
(for clinical use [ie, associated syndromes and tumors], refer to Table 4)
Test code |
Test name |
Single antibody tests |
|
AChR |
|
Acetylcholine Receptor Binding Antibody |
|
Acetylcholine Receptor Blocking Antibody |
|
Acetylcholine Receptor Modulating Antibody |
|
Amphiphysin |
|
4674b |
Recombx® Amphiphysin Autoantibody Test |
ANNA1 (Hu) |
|
37053a,c |
Hu Antibody Screen With Reflex to Titer and Western Blot Includes ANNA1 (Hu) antibody (IFA) with reflex to WB with reflex to titer. |
37710a,c |
Hu Antibody Screen With Reflex to Titer and Western Blot, CSF Includes ANNA1 (Hu) antibody (IFA) with reflex to WB with reflex to titer. |
ANNA2 (Ri) |
|
10140a,c |
Ri Antibody Screen With Reflex to Titer and WB Includes ANNA2 (Ri) antibody (IFA) with reflex to WB with reflex to titer. |
90121a,c |
Ri Antibody Screen With Reflex to Titer and Western Blot, CSF Includes ANNA2 (Ri) antibody (IFA) with reflex to WB with reflex to titer. |
Aquaporin 4 (NMO) |
|
Aquaporin-4 (AQP4) (NMO-IgG) Antibody With Reflex to Titer, CSF Includes AQP4 antibody with reflex to titer. |
|
Aquaporin-4 (AQP4) (NMO-IgG) Antibody With Reflex to Titer, Serum Includes AQP4 antibody with reflex to titer. |
|
Aquaporin-4 (AQP4) Antibody (NMO-IgG), ELISA |
|
Aquaporin-4 Antibody (IgG), CBA |
|
CASPR2 |
|
CASPR2 Antibody Test |
|
CRMP5 (CV2) |
|
4681b |
Recombx® CV2 Autoantibody Test |
DPPX |
|
DPPX Receptor Antibody, CBA IFA |
|
gACHR |
|
Acetylcholine Receptor Ganglionic (Alpha 3) Antibody |
|
GAD65 |
|
GAD65 Neurological Syndrome Antibody Test |
|
LGI1 |
|
LGI1 Antibody Test |
|
Myelin and MAG |
|
4639d |
Myelin Antibody (IgG), IFA |
Myelin Associated Glycoprotein (MAG) Antibody (IgM), EIA |
|
Myelin Associated Glycoprotein (MAG)-SGPG Antibody (IgM) |
|
NMDAR1 |
|
NMDA Receptor (NR1-subunit) Autoantibody Test |
|
PCA1 (Yo) |
|
90119a,c |
Yo Antibody Screen With Reflex to Titer and Western Blot Includes PCA1 (Yo) antibody with reflex to WB with reflex to titer. |
90117a,c |
Yo Antibody Screen With Reflex to Titer and Western Blot, CSF Includes PCA1 (Yo) antibody with reflex to WB with reflex to titer. |
PCA-Tr |
|
Purkinje Cell Cytoplasmic Antibody Type Tr (DNER), CBA IFA |
|
Recoverin |
|
4684b |
Recombx® CAR (Anti-Recoverin) Autoantibody Test |
RyR |
|
RyR Autoantibody Test |
|
Striated muscle |
|
266a |
Striated Muscle Antibody With Reflex to Titer |
Titin |
|
Titin Autoantibody Test |
|
VGCC (N -type) |
|
Voltage-Gated Calcium Channel (VGCC) Type N Antibody |
|
VGCC (P/Q-type) |
|
Voltage-Gated Calcium Channel (VGCC) Type P/Q Antibody |
|
VGKC |
|
Voltage-Gated Potassium Channel (VGKC) Antibody |
|
Zic4 |
|
Recombx® Zic4 Autoantibody Test |
|
Multiple antibody tests (panels)e |
|
90133a,c |
Autoimmune Cerebellar Ataxia Panel Includes IgA level with reflex to tissue transglutaminase IgG; PCA1 (Yo) antibody (IFA) with reflex to WB with reflex to titer; tissue transglutaminase IgA antibody with reflex to endomysial IgA with reflex to endomysial IgA titer; and VGCC type P/Q antibody. |
94605b,c |
Autoimmune Epilepsy Evaluation Includes CASPR2, GAD65, LGI1, NMDAR, and VGKC antibodies. |
93888a,c |
Autoimmune Neurology Antibody Comprehensive Panel With Reflexes, Serum Includes a tissue IFA screen for AGNA (SOX1), amphiphysin, ANNA1 (Hu), ANNA2 (Ri), ANNA3, AQP4, CRMP5 (CV2), GAD65, Ma2/Ta, myelin, PCA1 (Yo), PCA2, and PCA-Tr (DNER) antibodies; a CBA screen for AMPAR1, AMPAR2, CASPR2, GABA-B receptor, LGI1, and NMDAR antibodies; and a line blot for AGNA (SOX1), amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CRMP5 (CV2), GAD65, Ma2/Ta, PCA1 (Yo), PCA-Tr (DNER), recoverin, titin, and Zic4 antibodies. Results suggesting AMPAR1, AMPAR2, ANNA3, CASPR2, GABA-B receptor, LGI1, NDMAR, or PCA2 antibodies reflex to respective titers; results suggesting AQP4 antibody reflex to AQP4 antibody (CBA) with reflex to titer; results suggesting myelin antibody reflex to titer and MAG antibody (WB) with reflex to MAG-SGPG antibody and MAG antibody (EIA); tissue IFA results suggesting PCA-Tr (DNER) antibody with negative PCA-Tr (DNER) and Yo line blot results reflex to PCA-Tr (DNER) CBA with reflex to titer. Also includes DPPX receptor antibody with reflex to titer; striated muscle antibody with reflex to titer; AChR binding antibody with reflexes to AChR modulating antibody (if AChR binding is negative or equivocal) and/or AChR blocking antibody (if AChR binding is positive or equivocal); and AChR ganglionic (alpha 3), VGCC type N, VGCC type P/Q, and VGKC antibodies. |
94958a,c |
Encephalitis Antibody Evaluation With Reflex to Titer and Line Blot, CSF Includes a tissue IFA screen for AGNA (SOX1), amphiphysin, ANNA1 (Hu), ANNA2 (Ri), ANNA3, AQP4, CRMP5 (CV2), GAD65, Ma2/Ta, myelin, PCA1 (Yo), PCA2, and PCA-Tr (DNER) antibodies with reflex to a line blot for AGNA (SOX1), amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CRMP5 (CV2), GAD65, Ma2/Ta, PCA1 (Yo), PCA-Tr (DNER), and Zic4 antibodies; and a CBA screen for AMPAR1, AMPAR2, CASPR2, GABA-B receptor, LGI1, and NMDAR antibodies. Results suggesting AMPAR1, AMPAR2, ANNA3, CASPR2, GABA-B receptor, LGI1, NMDAR, or PCA2 antibodies reflex to respective titers; results suggesting myelin antibody reflex to titer; tissue IFA results suggesting PCA-Tr (DNER) antibody with negative PCA-Tr (DNER) and Yo line blot results reflex to PCA-Tr (DNER) CBA with reflex to titer. Also includes AQP4 antibody (CBA) with reflex to titer, DPPX receptor antibody with reflex to titer; and VGKC antibody. |
94955a,c |
Encephalitis Antibody Evaluation With Reflex to Titer and Line Blot, Serum Includes a tissue IFA screen for AGNA (SOX1), amphiphysin, ANNA1 (Hu), ANNA2 (Ri), ANNA3, AQP4, CRMP5 (CV2), GAD65, Ma2/Ta, myelin, PCA1 (Yo), PCA2, and PCA-Tr (DNER) antibodies with reflex to a line blot for AGNA1/SOX1, amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CRMP5 (CV2), GAD65, Ma2/Ta, PCA1 (Yo), PCA-Tr (DNER), and Zic4 antibodies; and a CBA screen for AMPAR1, AMPAR2, CASPR2, GABA-B receptor, LGI1, and NMDAR antibodies. Results suggesting AMPAR1, AMPAR2, ANNA3, CASPR2, GABA-B receptor, LGI1, NMDAR, or PCA2 antibodies reflex to respective titers; results suggesting myelin antibody reflex to titer and MAG antibody (WB) with reflex to MAG-SGPG antibody and MAG antibody (EIA); tissue IFA results suggesting PCA-Tr (DNER) antibody with negative PCA-Tr (DNER) and Yo line blot results reflex to PCA-Tr (DNER) CBA with reflex to titer. Also includes AQP4 antibody (CBA) with reflex to titer, DPPX receptor antibody with reflex to titer; and AChR ganglionic (alpha 3), VGCC type N, VGCC type P/Q, and VGKC antibodies. |
94959a,c |
Epilepsy Antibody Evaluation With Reflex to Titer and Line Blot, CSF Includes a tissue IFA screen for AGNA (SOX1), amphiphysin, ANNA1 (Hu), ANNA2 (Ri), ANNA3, AQP4, CRMP5 (CV2), GAD65, Ma2/Ta, myelin, PCA1 (Yo), PCA2, and PCA-Tr (DNER) antibodies with reflex to a line blot for AGNA1/SOX1, amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CRMP5 (CV2), GAD65, Ma2/Ta, PCA1 (Yo), PCA-Tr (DNER), and Zic4 antibodies; and a CBA screen for AMPAR1, AMPAR2, CASPR2, GABA-B receptor, LGI1, and NMDAR antibodies. Results suggesting AMPAR1, AMPAR2, ANNA3, CASPR2, GABA-B receptor, LGI1, NMDAR, or PCA2 antibodies reflex to respective titers; results suggesting myelin antibody reflex to titer; tissue IFA results suggesting PCA-Tr (DNER) antibody with negative PCA-Tr (DNER) and Yo line blot results reflex to PCA-Tr (DNER) CBA with reflex to titer. Also includes AQP4 antibody (CBA) with reflex to titer, DPPX receptor antibody with reflex to titer; and VGKC antibody. |
94956a,c |
Epilepsy Antibody Evaluation With Reflex to Titer and Line Blot, Serum Includes a tissue IFA screen for AGNA (SOX1), amphiphysin, ANNA1 (Hu), ANNA2 (Ri), ANNA3, AQP4, CRMP5 (CV2), GAD65, Ma2/Ta, myelin, PCA1 (Yo), PCA2, and PCA-Tr (DNER) antibodies with reflex to a line blot for AGNA1/SOX1, amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CRMP5 (CV2), GAD65, Ma2/Ta, PCA1 (Yo), PCA-Tr (DNER), and Zic4 antibodies; and a CBA screen for AMPAR1, AMPAR2, CASPR2, GABA-B receptor, LGI1, and NMDAR antibodies. Results suggesting AMPAR1, AMPAR2, ANNA3, CASPR2, GABA-B receptor, LGI1, NMDAR, or PCA2 antibodies reflex to respective titers; results suggesting myelin antibody reflex to titer and MAG antibody (WB) with reflex to MAG-SGPG antibody and MAG antibody (EIA); tissue IFA results suggesting PCA-Tr (DNER) antibody with negative PCA-Tr (DNER) and Yo line blot results reflex to PCA-Tr (DNER) CBA with reflex to titer. Also includes AQP4 antibody (CBA) with reflex to titer, DPPX receptor antibody with reflex to titer; and AChR ganglionic (alpha 3), VGCC type N, VGCC type P/Q, and VGKC antibodies. |
90138a,c |
Hu, Yo, and Ri Antibodies With Reflex to Titers and Western Blot Includes ANNA1 (Hu), ANNA2 (Ri), and PCA1 (Yo) antibodies (IFA) with reflexes for each analyte to WB with reflex to titer. |
90122a,c |
Hu, Yo, and Ri Antibodies With Reflex to Titers and Western Blot, CSF Includes ANNA1 (Hu), ANNA2 (Ri), and PCA1 (Yo) antibodies (IFA) with reflexes for each analyte to WB with reflex to titer. |
11306a,c |
Lambert-Eaton Syndrome Antibody Panel Includes AChR binding and modulating antibodies; striated muscle antibody screen with reflex to titer; and VGCC type P/Q antibody. |
7550(X)a,c |
Myasthenia Gravis Panel 1 Includes AChR binding antibody and striated muscle antibody with reflex to titer. |
Myasthenia Gravis Panel 2 Includes AChR binding, blocking, and modulating antibodies. |
|
93859a,c |
Myasthenia Gravis Panel 2 With Reflex to MuSK Antibody Includes AChR binding, blocking, and modulating antibodies with reflex to MuSK antibody. |
10211(X)a,c |
Myasthenia Gravis Panel 3 Includes AChR binding, blocking, and modulating antibodies; and striated muscle antibody with reflex to titer. |
NeoCerebellar Degeneration Paraneoplastic Evaluation With Recombx® Includes amphiphysin, ANNA1 (Hu), ANNA2 (Ri) CRMP5 (CV2), GAD65, MaTa, PCA1 (Yo), and Zic4 antibodies. |
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NeoComplete Paraneoplastic Evaluation With Recombx® Includes AChR ganglionic, amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CASPR2, CRMP5 (CV2), GAD65, LGI1, MaTa, NMDAR (NR1), PCA1 (Yo), recoverin, VGCC, and Zic4 antibodies. |
|
NeoEncephalitis Paraneoplastic Evaluation With Recombx® Includes amphiphysin, ANNA1 (Hu), CASPR2, CRMP5 (CV2), GAD65, LGI1, MaTa, NMDAR (NR1), and VGKC antibodies. |
|
4725f |
NeoSensory Neuropathy Paraneoplastic Profile With Recombx® Includes Recombx® amphiphysin,CV2 and Hu antibodies. |
Neurology Antibody, CBA IFA Includes AMPAR1, AMPAR2, CASPR2, GABA-B-R, LGI1, and NMDAR1 antibodies. |
|
Neurology Antibody, Line Blot Includes AGNA (SOX1), amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CRMP5 (CV2), GAD65, Ma2/Ta, PCA1 (Yo), PCA-Tr (DNER), recoverin, titin, and Zic4 antibodies. |
|
93876a,c |
Paraneoplastic Antibody Evaluation With Reflex to Titer and Line Blot, Basic Includes AChR binding antibody with reflex to AChR modulating antibody; striated muscle antibody with reflex to titer; and AChR (ganglionic), VGCC type N, VGCC type P/Q, and VGKC antibodies. Also includes a tissue IFA screen for AGNA (SOX1), amphiphysin, ANNA1 (Hu), ANNA2 (Ri), ANNA3, CRMP5 (CV2), PCA1 (Yo), PCA2, and PCA-Tr (DNER) antibodies; positive or equivocal AChR binding antibody results and/or tissue IFA results that are positive, indeterminate, and/or suggesting GAD65 or CRMP5 (CV2) antibodies reflex to a line blot for amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CRMP5 (CV2), GAD65, and PCA1 (Yo); tissue IFA results positive for ANNA3 or PCA2 antibodies reflex to respective titers; tissue IFA results suggesting AQP4 antibody reflex to AQP4 antibody (CBA); tissue IFA results suggesting AMPAR1/2, GABA-B receptor, or NMDAR antibodies reflex to a CBA for AMPAR1, AMPAR2, GABA-B receptor, and NDMAR antibodies. |
94536a,c |
Paraneoplastic Antibody Evaluation With Reflex to Titer and LB, Basic, CSF Includes a tissue IFA screen for AGNA (SOX1), amphiphysin, ANNA1 (Hu), ANNA2 (Ri), ANNA3, AQP4, CRMP5 (CV2), GAD65, PCA1 (Yo), PCA2, and PCA-Tr (DNER) antibodies; tissue IFA results positive or indeterminate for amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CRMP5 (CV2), GAD65, PCA1 (Yo), or PCA-Tr (DNER) antibodies reflex to a line blot for amphiphysin, ANNA1 (Hu), ANNA2 (Ri), AQP4, CRMP5 (CV2), GAD65, PCA1 (Yo), PCA2, and PCA-Tr (DNER); tissue IFA results positive for ANNA3 or PCA2 antibodies reflex to respective titers; tissue IFA results positive for AQP4 antibody reflex to AQP4 antibody (CBA) with reflex to titer; tissue IFA results suggesting LGI1, CASPR2, or voltage-gated ion channel antibodies reflex to VGKC antibody; tissue IFA results suggesting AMPAR1, AMPAR2, CASPR2, GABA-B receptor, LGI1, NMDAR, or voltage-gated ion channel antibodies reflex to a CBA for AMPAR1, AMPAR2, CASPR2, GABA-B receptor, LGI1, and NMDAR. CBA results positive for AMPAR1, AMPAR2, CASPR2, GABA-B receptor, LGI1, or NMDAR reflex to respective titers. |
Paraneoplastic Autoantibody Evaluation With Recombx®, CSF Includes amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CASPR2, CRMP5 (CV2), LGI1, MaTa, NMDAR, PCA1 (Yo), recoverin, and Zic4 antibodies. |
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94957a,c |
Paraneoplastic Antibody Expanded Evaluation With Reflex to Titer and LB, Serum Includes a tissue IFA screen for AGNA (SOX1), amphiphysin, ANNA1 (Hu), ANNA2 (Ri), ANNA3, AQP4, CRMP5 (CV2), GAD65, Ma2/Ta, myelin, PCA1 (Yo), PCA2, and PCA-Tr (DNER) antibodies; a CBA screen for AMPAR1, AMPAR2, CASPR2, GABA-B receptor, LGI1, and NMDAR antibodies; and a line blot for AGNA (SOX1), amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CRMP5 (CV2), GAD65, Ma2/Ta, PCA1 (Yo), PCA-Tr (DNER) , and Zic4 antibodies. Results suggesting AMPAR1, AMPAR2, ANNA3, CASPR2, GABA-B receptor, LGI1, NDMAR, or PCA2 antibodies reflex to respective titers; results suggesting AQP4 antibody reflex to AQP4 antibody (CBA) with reflex to titer; results suggesting myelin antibody reflex to titer and MAG antibody (WB) with reflex to MAG-SGPG antibody and MAG antibody (EIA); tissue IFA results suggesting PCA-Tr (DNER) antibody with negative PCA-Tr (DNER) and Yo line blot results reflex to PCA-Tr (DNER) CBA with reflex to titer. Also includes DPPX receptor antibody with reflex to titer; and AChR ganglionic (alpha 3), VGCC type N, VGCC type P/Q, and VGKC antibodies. |
94960a,c |
Paraneoplastic Antibody Expanded Evaluation With Reflex to Titer and Line Blot, CSF Includes a tissue IFA screen for AGNA (SOX1), amphiphysin, ANNA1 (Hu), ANNA2 (Ri), ANNA3, AQP4, CRMP5 (CV2), GAD65, Ma2/Ta, myelin, PCA1 (Yo), PCA2, and PCA-Tr (DNER) antibodies with reflex to a line blot for AGNA1 (SOX1), amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CRMP5 (CV2), GAD65, Ma2/Ta, PCA1 (Yo), PCA-Tr (DNER), and Zic4 antibodies; and a CBA screen for AMPAR1, AMPAR2, CASPR2, GABA-B receptor, LGI1, and NMDAR antibodies. Results suggesting AMPAR1, AMPAR2, ANNA3, CASPR2, GABA-B receptor, LGI1, NMDAR, or PCA2 antibodies reflex to respective titers; results suggesting myelin antibody reflex to titer; tissue IFA results suggesting PCA-Tr (DNER) antibody with negative PCA-Tr (DNER) and Yo line blot results reflex to PCA-Tr (DNER) CBA with reflex to titer. Also includes AQP4 antibody (CBA) with reflex to titer, DPPX receptor antibody with reflex to titer; and VGKC antibody. |
4683b |
Recombx® MaTa Autoantibody Test Includes Ma and Ta antibodies. |
SensoriMotor Neuropathy Profile With Recombx® Complete Includes ANNA1 (Hu), Co-asialo-GM-1, GALOP, GD1a, Co-GD1b, Co-GM-1, SGPG, MAG, and sulfatide antibodies. |
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90136a,c |
Sensory-Motor Neuropathy Complete Antibody Panel Includes ANA Screen (IFA) with reflex to titer and pattern; ANCA screen with reflex to C-ANCA, P-ANCA, and/or atypical P-ANCA titer; ANNA1 (Hu) antibody screen with reflex to WB with reflex to titer; cryoglobulin screen with reflex to % cryoglobulin (cryocrit) and cryoglobulin immunofixation and immunodiffusion; ganglioside asialo-GM-1 IgG and IgM antibodies; ganglioside GD1a IgG and IgM, ganglioside GD1b IgG and IgM, ganglioside GM-1 IgG and IgM, and ganglioside GQ1b IgG antibodies; IgA level with reflex to tissue transglutaminase IgG; IgG level; IgM level; immunofixation; MAG IgM antibody (WB) with reflexes to MAG-SGPG IgM and MAG IgM (EIA) antibodies; MPO antibody, PR3 antibody, RF, SS-A, and SS-B antibodies; and tissue transglutaminase IgA antibody with reflexes to endomysial antibody and titer. |
15977a,c |
Sensory Neuropathy Complete Antibody Panel Includes ANA Screen (IFA) with reflex to titer and pattern; ANCA screen with reflex to C-ANCA, P-ANCA, and/or atypical P-ANCA titer; ANNA1 (Hu) antibody with reflex to WB with reflex to titer; cryoglobulin screen with reflex to % cryoglobulin (cryocrit) and cryoglobulin immunofixation and immunodiffusion; ganglioside GD1b IgG and IgM and ganglioside GQ1b IgG antibodies; IgA level with reflex to tissue transglutaminase IgG; IgG level; IgM level; immunofixation; MAG IgM antibody (WB) with reflexes to MAG-SGPG IgM and MAG IgM (EIA) antibodies; MPO antibody; PR3 antibody; RF; SS-A and SS-B antibodies; and tissue transglutaminase IgA antibody with reflexes to endomysial antibody with reflex to titer. |
| CBA, cell-binding assay; CSF, cerebrospinal fluid; IFA, immunofluorescence assay; LB, line blot; WB, Western blot. | |
| a | This test was developed and its analytical performance characteristics have been determined by Quest. It has not been cleared or approved by the US Food and Drug Administration. This assay has been validated pursuant to the CLIA regulations and is used for clinical purposes. |
| b | This test was developed and its analytical performance characteristics have been determined by Athena Diagnostics. It has not been cleared or approved by the US Food and Drug Administration. This assay has been validated pursuant to the CLIA regulations and is used for clinical purposes. |
| c | Reflex tests are performed at an additional charge and are associated with additional CPT® codes. |
| d | This test was performed using a kit that has not been cleared or approved by the FDA. The analytical performance characteristics of this test have been determined by Quest. This test should not be used for diagnosis without confirmation by other medically established means. |
| e | Some panel components may be ordered separately (see preceding list of single antibody tests). |
| f | Refer to Athena Diagnostics for test information. This test is performed by Athena Diagnostics. |
References [return to contents]
Content reviewed 4/2026
Detection of antineuronal autoantibodies aids the diagnosis of autoimmune paraneoplastic syndromes, encephalopathies, and other autoimmune neurological conditions. Identification of specific antineuronal autoantibodies may also help in the diagnostic workup for occult malignancies. Finally, knowledge of the specific identity of antineuronal autoantibodies aids greatly in making therapeutic decisions for patients. Antineuronal antibodies are detected and identified by Indirect Immunofluorescence, using multiple neuronal tissues, non-neuronal tissues, and transfected substrate cells, as well as Radioimmunoassays. Line Blot assays are used for confirmatory reflex testing.
Myasthenia Gravis is a neurological disorder characterized by a decrease in acetylcholine receptors. Patients exhibit skeletal muscle weakness and fatigability. Approximately 80% of patients with Myasthenia Gravis, excluding ocular involvement only, have detectable acetylcholine receptor antibody.
Myasthenia Gravis is a neurological disorder characterized by a decrease in acetylcholine receptors. Patients exhibit skeletal muscle weakness and fatigability. Approximately 80% of patients with Myasthenia Gravis, excluding ocular involvement only, have detectable acetylcholine receptor antibody. There is a strong correlation between the presence of striated muscle antibody and the presence of thymoma.
Reference ranges are provided as general guidance only. To interpret test results use the reference range in the laboratory report.
The tests listed by specialty and category are a select group of tests offered. For a complete list of Quest Diagnostics tests, please adjust the filter options chosen, or refer to our Directory of Services.