Test availability and selection [return to contents]

If a specific syndrome is suspected based on the clinical presentation, individual antibody tests may help identify the presence of an underlying malignancy. However, the European Federation of Neurological Societies (EFNS) Task Force points out that most syndromes and tumors are associated with multiple antibodies. Thus, the EFNS recommends testing for several antibodies simultaneously to avoid the loss of time to diagnosis and improve the testing yield.4

A systematic review of current guidelines suggests that PNS-related antibody testing is helpful for defining the probability of whether a neurological disorder has a paraneoplastic origin but should not be used to screen for malignancy.5 The same review found that tests for "classical" tumor markers (eg, alpha-fetoprotein, carcinoembryonic antigen) in PNS are not useful or recommended, despite being commonly ordered in some neurological wards.5

Large retrospective studies in academic clinics highlighted the importance of selecting patients with the appropriate clinical indications for PNS-related antibody testing, broader testing results in low yields of true positive results for malignancy.6-8 In addition, others have shown that limiting testing to a single methodology could contribute to low diagnostic yield.9

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).

• The "basic" panels include the smallest number of antibodies and are available for serum and cerebrospinal fluid (CSF) specimens; for some patients, detection of antibodies is more robust with CSF than serum.10-13 The difference between the serum and CSF panels is that the CSF panels do not contain antibodies targeting gAChR, VGCC (N-type), and VGCC (P/Q-type). Notably, the immunofluorescence assays (IFA) employ nonhuman primate tissue rather than tissues from other animals (Table 2).
• Paraneoplastic Antibody Evaluation With Reflex to Titer and Western Blot, Basic, Serum (test code 93876, Figure 1)14-20
• Paraneoplastic Antibody Evaluation With Reflex to Titer and Western Blot, Basic, CSF (test code 94536, Figure 2)14-17,21-24
• The "expanded" panels include several additional antibodies (targeting aquaporin 4, CASPR2, Ma2/Ta, LGI1, myelin, and Zic4) not included in the "basic" panels and are available for serum and CSF specimens. With the expanded panels, cell-binding tests are always performed (rather than as a reflex to positive IFA results). This is because cell-binding tests have greater sensitivity than IFAs for select antibodies (eg, antibodies to membrane-embedded aquaporin 4 and NMDA1).25
• Paraneoplastic Antibody Expanded Evaluation With Reflex to Titer and Line Blot, Serum (test code 94957, Figure 3)14,15,26,27
• Paraneoplastic Antibody Expanded Evaluation With Reflex to Titer and Line Blot, CSF (test code 94960, Figure 3)
• The "comprehensive" panel includes the largest number of antibodies and is only available for serum specimens. It includes all of the antibodies in the smaller panels ("basic" and "expanded") but also adds antibodies targeting recoverin, titin, AChr, and striated muscle. Unlike with smaller panels, a line blot is performed for all specimens.
• Autoimmune Neurology Antibody Comprehensive Panel With Reflexes, Serum (test code 93888, Figure 4)14,15,19,20,24,26,27

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 panel (see Table 3 for antibodies)		•a	•b	•c	•c	•d
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	Reflexb	•c	•c	Reflexd
DPPX	•			•c	•c	•d
AMPAR (1 & 2)		Reflex	Reflexb	•c	•c	•d
GABABR		Reflex	Reflexb	•c	•c	•d
NMDAR1	•	Reflex	Reflexb	•c	•c	•d
LGI1	•		Reflexb	•c	•c	•d
CASPR2	•		Reflexb	•c	•c	•d
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	Reflexc	Reflexc	•d
Recoverin	•					•
Titin	•					•
Zic4	•			Reflex	Reflex	•
IFA
PCA-Tr (DNER)	•			Reflexc	Reflexc	Reflexd
MAG IgM	•			Reflex	Reflex	Reflex
MAG-SGPG	•			Reflex		Reflex
MAG	•			Reflex		Reflex
Striated muscle	•	•a				•d

CBA, cell-binding assay; CSF, cerebrospinal fluid; IFA, immunofluorescence assay; MAG, myelin-associated glycoprotein; RIA, radioimmunoassay.
a	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.
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 CBA tests also reflex to titers of respective antibodies.
c	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.
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; 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 test, serum (93876)a	Basic test, CSF (94536)a	Expanded, serum (94957)a	Expanded, CSF (94960)a	Comprehensive test, serum (93888)a
AGNA (SOX1)	•	•	•	•	•
Amphiphysin	•	•	•	•	•
ANNA1	•	•	•	•	•
ANNA2	•	•	•	•	•
ANNA3	•	•	•	•	•
CRMP5 (CV2)	•	•	•	•	•
PCA1	•	•	•	•	•
PCA2	•	•	•	•	•
PCA Tr (DNER)	•	•	•	•	•
Aquaporin 4 (NMO)		•	•	•	•
GAD65		•	•	•	•
Ma2/Ta			•	•	•
Myelin			•	•	•

CSF, cerebrospinal fluid.
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 (see Table 4 and below).3,4,14-17,19-22,24,27-49 Updated diagnostic criteria combine assignment of high-(>70%), intermediate-(30%-70%), and lower-(<30%) risk antibodies (risk defined by prevalence of cancer association), with phenotype and presence or absence of cancer.3 A points-based "PNS score" for diagnostic certainty (definite, probably, possible, or non-PNS) is based on these criteria.3

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).2,4

The absence of an antibody rarely confirms the absence of an associated syndrome or cancer type.
The text below provides specific information for each PNS-related antibody.

AChR (acetylcholine receptor)

A positive test result for AChR (acetylcholine receptor) antibody is consistent with myasthenia gravis (MG). Thymoma is the most commonly associated tumor type.

Among patients with MG, 79% to 85% test positive for AChR antibody.19,20,50 Among patients confirmed as not having MG (but initially suspected of having MG), 0% test positive, indicating 100% specificity for MG.20

In side-by-side comparisons with other MG-related antibodies (ryanodine receptor [RyR], striated muscle, and titin),19,20 AChR antibody was generally more sensitive for thymoma in MG patients, though one study demonstrated a 95% sensitivity for titin antibody.19 However, AChR antibody was less specific than RyR, striated muscle, or titin antibodies (Table 5).19,20

Table 5. Sensitivity and Specificity of MG-Related Antibodies for Thymoma in Individuals With MG
[return to contents]

Antibody	Sensitivity, %	Specificity, %
AChR19,20,51	99-100	17-25
RyR19,51	47-70	86-95
Striated muscle19,20	75-77	58-73
Titin19,20,51	51-95	76-97

MG, myasthenia gravis.
a	One study included 146 MG patients, of whom 20 had thymoma19; the second study included 44 patients, of whom 13 had thymoma20; the third study included 437 patients, of whom 128 had thymoma.51

 

Three types of AChR antibodies, which affect receptors in different ways, can help with MG diagnosis: binding, modulating, and blocking. Binding antibodies are present in 69% to 82% of patients with generalized MG.52 Modulating antibodies are found at approximately the same frequency, but ~4% of patients test positive for modulating antibody and negative for binding antibody. Thus, testing for modulating antibody may help identify more patients with MG. Blocking antibody is present in <1% of patients without binding antibodies and is rare in non-MG diseases; thus, it can confirm binding antibody positivity and improve specificity.

AGNA (SOX1, anti-glial nuclear antibody)

A positive test result for AGNA (SOX1, anti-glial nuclear antibody) is consistent with Lambert-Eaton myasthenic syndrome (LEMS), sensory neuropathy, limbic encephalitis, and cerebellar degeneration. Small-cell lung cancer (SCLC) is the most commonly associated cancer type.

In a study of 24 patients who tested positive for AGNA, 38% had LEMS, 21% had paraneoplastic cerebellar degeneration (of those, 1 patient also had LEMS), 13% had sensory neuropathy, 8% had limbic encephalitis, and 4% had sensorimotor neuropathy; 17% did not have a PNS. Of the 24 patients, 92% had lung cancer (79% had SCLC).34 In patients who have SCLC but no PNS, 22% to 32% test positive for AGNA.53,54

AGNA (SOX1) can be particularly useful for identifying SCLC in patients with LEMS. In patients with LEMS, 43% to 64% of those with SCLC test positive for AGNA, whereas 0% of those without SCLC test positive.34,53 Thus, in a patient with LEMS, a positive AGNA result is consistent with SCLC, while a negative result suggests absence of SCLC.

AMPAR (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor)

A positive test result for AMPAR (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor) antibody is consistent with limbic encephalitis. Lung (SCLC), thymoma, breast, and ovarian cancer types are associated with AMPAR antibody.

Among patients with suspected PNS, 0.2% test positive for AMPAR antibody.16 In a study of 22 AMPAR antibody-positive patients, 13 (59%) had limbic encephalitis and 8 (36%) had limbic dysfunction and encephalopathy; the remaining patient had psychosis with bipolar features. Cancer was identified in 14 (64%) of patients: 6 had lung cancer (5 had SCLC), 4 had thymoma, 2 had breast cancer, and 2 had ovarian teratoma.16

In a study of 109 patients who had limbic encephalitis, 10 (9%) tested positive for AMPAR antibody. Of these, 7 had neoplasms: 3 had thymus cancer, 2 had breast cancer, and 2 had lung cancer.55

Amphiphysin

A positive test result for amphiphysin antibody is consistent with sensory neuropathy, encephalomyelitis/limbic encephalitis, and stiff-person syndrome. SCLC and breast cancer are the most commonly associated cancer types.

Among patients with suspected PNS, 0.026% test positive for amphiphysin antibody.15 Among patients who test positive, 52% present with neuropathy, 30% with encephalopathy, 29% with encephalomyelitis with rigidity, 27% with myelopathy, 22% with generalized or focal pain, and 17% with cerebellar syndrome. Other conditions associated with amphiphysin antibody include Lambert-Eaton syndrome, opsoclonus, cranial neuropathies, optic neuritis/retinitis, and pruritus.46 Amphiphysin antibody has also been reported in patients with stiff-person syndrome, though GAD antibody is much more common in those patients.41

Among patients who test positive for amphiphysin antibody, 51% have lung cancer (84% are SCLC) and 25% have breast cancer.46 Ovarian cancer has also been reported, but at a much lower rate than SCLC and breast cancer.49

Other PNS-related antibodies coexist with amphiphysin in a substantial proportion of patients (38%-70%). CRMP5 (CV2), ANNA1, and voltage-gated calcium channels (VGCC) are the most frequently coexisting antibodies.18,46

ANNA1 (Hu; anti-neuronal nuclear antibody type 1)

A positive test result for ANNA1 (Hu; anti-neuronal nuclear antibody type 1) is consistent with sensory neuropathy, cerebellar ataxia, limbic encephalitis, brainstem encephalitis, and autonomic neuropathy. SCLC is the most commonly associated cancer type.

Among patients with suspected PNS, 0.4% test positive for ANNA1 antibody.18 In patients with confirmed PNS and ANNA1, 54% to 86% have neuropathy, 11% to 22% have cerebellar syndromes, 10% to 21% have limbic syndromes, 6% to 18% have brainstem syndromes or encephalitis, and 4% to 24% have dysautonomia.45,56,57 Cancer develops in 80% to 98% of patients who test positive.18,45 In 80% to 86% of cancer patients with ANNA1, cancer is found in the lung (SCLC develops in 66%-82% of patients).18,45,56,57 Cancer in the bladder, breast, gastrointestinal tract, pancreas, prostate, or ovary each develop in 1% to 4% of patients.45

ANNA1 coexists with other PNS-related antibodies in 43% of patients. Antibodies to CRMP5 (CV2), P/Q-type VGCC, or N-type VGCC coexist in 14% to 17% of ANNA1-positive patients. Other antibodies coexist at frequencies between 1% and 5%.18

ANNA2 (Ri, anti-neuronal nuclear antibody type 2)

A positive test result for ANNA2 (Ri, anti-neuronal nuclear antibody type 2) is consistent with opsoclonus-myoclonus and cerebellar syndrome. Lung and breast cancers are the most commonly associated cancer types. Gynecological tumors are also associated but much less commonly.38,58

Among patients with suspected PNS, 0.016% test positive for ANNA2.15 In a study that included 34 patients who tested positive, 59% presented with manifestations indicating brainstem involvement (eg, ataxia, opsoclonus-myoclonus) and 41% presented with manifestations indicating cerebellum involvement (eg, ataxia with nystagmus). Lung cancer occurred in 36% of ANNA2-positive patients, breast cancer in 32%, and other cancer types in 15%.30

Among patients who test positive for ANNA2 antibody, 35% also test positive for other PNS-related autoantibodies, most commonly ANNA1, GAD65, P/Q-type VGCC, or N-type VGCC.18,30

ANNA3 (anti-neuronal nuclear antibody type 3)

A positive test result for ANNA3 (anti-neuronal nuclear antibody type 3) is consistent with sensory neuropathy and limbic encephalopathy. SCLC is the most commonly associated cancer.

In a study of 68,000 patients with suspected PNS, 11 (0.02%) tested positive for ANNA3. ANNA3 was not present in any control patients (ANNA1-positive, ANNA2-positive, healthy, SCLC-positive but negative for neurological disorder). In the 11 ANNA3-positive patients, neurological presentations were often multifocal and included sensory neuropathy, limbic encephalopathy, cerebellar ataxia, and myelopathy. Oncological information was available for 9; all 9 had cancer: 5 had SCLC, 2 had adenocarcinomas (lung, esophagus), 1 had a lung mass, and 1 had thoracic and abdominal masses.14

Six of the 11 patients also tested positive for other PNS-related antibodies: VGCC (3), gAChR (2), or ANNA2 (1).14

Aquaporin 4 (NMO)

A positive test result for aquaporin 4 (NMO) antibody is consistent with neuromyelitis optica (NMO)-spectrum disorders; these disorders involve demyelination in the central nervous system (CNS) and can be misdiagnosed as multiple sclerosis. Many types of cancer have been observed in aquaporin 4 antibody-positive patients.

Among patients tested for PNS-related antibodies, 0.02% test positive for aquaporin 4 antibody. Among those who test positive, 93% have NMO.24 In a study that included 31 patients who tested positive for aquaporin 4 antibody, 9 (29%) had neoplasms diagnosed: 3 with breast, 2 with lung, 1 with thymic, 1 with cervical, 1 with seminoma, bladder, and B-cell lymphoma, and 1 with monoclonal gammopathy. Notably, 2 of the 9 patients with neoplasms (1 with breast cancer and 1 with lung cancer) did not have clinical evidence of NMO.24

CASPR2 (contactin-associated protein-like 2)

See VGKC (voltage-gated potassium channel) section.

CRMP5 (CV2, collapsin response mediator protein 5)

A positive test result for CRMP5 (CV2, collapsin response mediator protein 5) antibody is consistent with multiple PNSs: sensory neuropathy, cerebellar ataxia, autonomic neuropathy, limbic encephalitis, and chorea. SCLC and thymoma are the most commonly associated cancer types.

Among patients with suspected PNS, 0.2% test positive for CRMP5 (CV2) antibody. Among patients who test positive, 47% to 57% display sensory neuropathy, 26% to 46% display cerebellar ataxia, 31% display autonomic neuropathy, 25% display subacute dementia, 14% display myasthenic syndrome (LEMS or MG), 14% display limbic encephalitis, 12% display neuromuscular junction disorders, and 11% display chorea.29 In a study of 16 patients with paraneoplastic chorea, all tested positive for CRMP5 (CV2).59

Among CRMP5 (CV2)-positive patients, 53% to 77% have lung cancer (47%-62% have SCLC) and 6% to 15% have thymoma.18,29,56 CRMP5 (CV2) antibodies rarely occur in healthy individuals (0.6%) but occur in 5% of patients with SCLC and 12% of patients with thymoma.60

Among patients who test positive for CRMP5 (CV2), 57% also test positive for a range of other PNS-related antibodies; the most frequent antibodies are ANNA1 (17%), N-type VGCC (14%), and P/Q-type VGCC (13%).18

DPPX (dipeptidyl-peptidase-like protein-6)

See VGKC (voltage-gated potassium channel) section.

GABABR (gamma-aminobutyric acid receptor B)

A positive test result for GABABR (gamma-aminobutyric acid receptor B) antibody is consistent with limbic encephalitis. SCLC is the most commonly associated cancer type.

Among patients with suspected autoimmune encephalitis, 0.2% test positive for GABABR antibody.17 In a study that included 7 patients with suspected autoimmune encephalitis who tested positive for GABABR antibody, all 7 were confirmed to have limbic encephalitis. Of these, 5 had SCLC and 1 had a lung mass that was not biopsied; the patient without cancer was 16 years old.17

In a study that included 15 patients with suspected paraneoplastic encephalitis who tested positive for GABABR antibody, 7 had tumors, of which 5 were SCLC. Of the 15 patients, 7 tested positive for antibodies to other antigens (N-type VGCC, GAD65, thyroid peroxidase, or thyroglobulin).61

gAChR (ganglionic acetylcholine receptor)

A positive test result for gAChR (ganglionic acetylcholine receptor) antibody is consistent with multiple neurological presentations, including autonomic neuropathy, sensorimotor neuropathy, and cortical and neuropsychiatric manifestations. Many cancer types are associated with gAChR antibody.

Among patients tested for PNS-related antibodies, 1% test positive for gAChR antibody.28 Among those who test positive, 28% have somatic peripheral manifestations, most commonly sensorimotor polyneuropathy; 21% have peripheral autonomic manifestations, most commonly limited dysautonomia, pandysautonomia, and GI dysmotility; 17% have CNS manifestations, most commonly cortical or neuropsychiatric. Manifestations are multifocal in 29% of patients.28

In a study that included 78 gAChR antibody-positive patients, 24 (30%) had cancer, of which 6 had multiple malignant neoplasms. Eighteen types of cancer were observed. There were multiples cases of the following cancer types: 13 adenocarcinoma (breast [4], prostate [3], lung [2], gastrointestinal [2]), 5 lymphoid (B-cell lymphoma [3]), 2 renal cell carcinoma, 2 melanoma, and 2 bladder.28 Small studies have also reported SCLC and thymoma.62,63

Coexisting antibodies are detected in 26% of gAChR antibody-positive patients: GAD65, muscle AChR, N-type VGCC, VKCC, P/Q-type VGCC, striational, ANNA1, and CRMP5 (CV2).28

GAD65 (glutamic acid decarboxylase 65 kD protein)

A positive test result for GAD65 (glutamic acid decarboxylase 65 kD protein) antibody is associated with stiff-person syndrome, cerebellar ataxia or degeneration, and limbic encephalitis. Many cancer types are associated with GAD65 antibody.36,47,64

Among patients who test positive for GAD65 antibody, 36% have stiff-person syndrome, 33% have cerebellar ataxia or degeneration, and 7% have limbic encephalitis or encephalomyelitis.36

Although many cancers have been described in GAD65 antibody-positive patients, most reports represent case studies or single patients within a larger study. Ariño and colleagues summarized findings from 34 GAD65 antibody-positive patients (15 newly identified and 19 previously reported). Of these, 10 had lung cancer (including 7 SCLC), 10 had thymoma (3 malignant), 6 had breast cancer, 4 had hematological cancer (2 non-Hodgkin lymphoma, 1 multiple myeloma, 1 Hodgkin lymphoma), and 4 had other cancers (2 pancreas, 1 kidney, 1 cavum).47

GAD antibodies are also present in ~80% of patients with type 1 diabetes.65 However, titers of GAD antibody are usually >100 times higher in patients with stiff-person syndrome than in those with type 1 diabetes.66

LGI1 (leucine-rich glioma inactivated-1)

See VGKC (voltage-gated potassium channel) section.

Ma2/Ta

A positive test result for Ma2/Ta antibody is consistent with limbic encephalitis, brainstem encephalitis, and cerebellar degeneration. Testicular cancer is the most commonly associated cancer type.

Among patients who test positive for Ma2/Ta antibodies, 89% have limbic, brainstem, and/or diencephalic syndromes; 5% have cerebellar ataxia.31 Tumors are identified in 89% to 97% of Ma2/Ta antibody-positive patients. Among patients with cancer, 53% to 57% have testicular germ-cell tumors, 14% to 21% have lung cancer, and 6% to 7% have breast cancer. Other associated cancer types include parotid gland, ovary, colon, kidney, lymphoma, and choriocarcinoma.31,67 In a study of 25 patients with Ma2/Ta -positive encephalitis who were <50 years of age, 19 (76%) had germ-cell tumors.68

Testicular tumors are more common when Ma2/Ta is not accompanied by Ma1 or Ma3 antibodies.67,69

MAG (myelin-associated glycoprotein)

A positive test result for MAG antibody is consistent with sensory or sensorimotor neuropathy and monoclonal gammopathy of uncertain significance (MGUS).

Among patients with IgM monoclonal gammopathy, MAG antibody positivity is more frequent in those with neuropathy (56%) than those without (7%). Among patients with IgM monoclonal gammopathy and MAG antibody, 93% display sensory or sensorimotor neuropathy,27 81% to 85% have MGUS, and 8% to 19% have Waldenströlm macroglobulinemia.27,70 Among patients with MGUS and neuropathy, 69% test positive for MAG antibody.27

NMDAR1 (N-methyl-D-aspartate receptor)

A positive test result for NMDAR1 (N-methyl-D-aspartate receptor) antibody is consistent with encephalitis with psychiatric manifestations, seizures, dyskinesias, dystonia, and autonomic instability. Ovarian teratoma is the most commonly associated cancer type.

In a study of 100 patients (91 women) with encephalitis and a positive NMDAR1 antibody test, all displayed psychiatric symptoms: unresponsiveness (88%), dyskinesias (86%, includes dystonia), seizures (76%), autonomic instability (69%), and hypoventilation (66%). Of the 98 patients with available clinical information, 59% had a tumor; 91% of the tumors were ovarian teratomas. The 2 males with tumors had a testicular teratoma or SCLC.43

PCA1 (Yo; Purkinje cell cytoplasmic antibody type 1)

A positive test result for PCA1 (Yo; Purkinje cell cytoplasmic antibody type 1) is consistent with cerebellar degeneration. Breast and ovarian cancers are the most commonly associated cancer types.

Patients with paraneoplastic cerebellar degeneration who test positive for PCA1 are almost always women. Among PCA1-positive patients with paraneoplastic cerebellar degeneration, 79% to 95% develop cancer37,38; ovarian cancer accounts for 43% to 47% of cancers and breast cancer accounts for 25% to 40%.37,48

Among patients who test positive for PCA1, 9% test positive for other autoantibodies (voltage-gated channel or acetylcholine receptor antibodies).18

PCA2 (Purkinje cell cytoplasmic antibody type 2)

A positive test result for PCA2 (Purkinje cell cytoplasmic antibody type 2) is consistent with encephalomyelitis, limbic encephalitis, and cerebellar ataxia. Lung cancer (SCLC) is the most commonly associated cancer type.

Among patients with suspected PNS, 0.024% test positive for PCA2.15 Among patients who test positive for PCA2 antibodies, 53% have peripheral neuropathy, 38% have cerebellar dysfunction, and 27% have encephalopathy. Cancer is identified in 79% of PCA2 antibody-positive patients. Among patients with cancer, 58% have SCLC, 20% have NSCLC, 8% have breast cancer, 14% have another type of cancer (1%-3% per type).15

Among PCA2-positive patients, 67% have coexisting PNS-related antibodies: 26% have CRMP5, 21% have P/Q-type VGCC, 15% have GAD65, 13% have ANNA1, 7% have VGKC, 6% have gAChR, 3% have AChR or GABABR, and 2% have AGNA, AMPAR, amphiphysin, or N-type VGCC; 9% have more than 1 coexisting antibody.15 ANNA3 and striated muscle have also been reported as coexisting antibodies.18

PCA-Tr (DNER, Purkinje cell cytoplasmic antibody type Tr)

A positive test result for PCA-Tr (DNER, Purkinje cell cytoplasmic antibody type Tr) is consistent with cerebellar degeneration. Hodgkin lymphoma is the most commonly associated cancer type.

Among patients with suspected PNS, 0.006% test positive for PCA-Tr.15 In a study of 28 patients who tested positive for PCA-Tr, 93% had cerebellar degeneration, 4% had chronic, mild cerebellar ataxia, and 4% had limbic encephalitis. Of the 28 patients, 89% had Hodgkin lymphoma diagnosed; no tumor was found in the other 11%.26 A positive PCA-Tr test result may indicate the presence of both a cerebellar disorder and Hodgkin disease; in a study that looked at patients who had one or the other, none of the patients tested positive for PCA-Tr.71

Recoverin

A positive test result for recoverin antibody is consistent with cancer-associated retinopathy (CAR). SCLC is the most commonly associated cancer type.

In a study of 193 patients who had symptoms consistent with paraneoplastic or autoimmune retinopathy, 12 (6%) tested positive for recoverin antibody; all 12 of these patients had paraneoplastic retinopathy.44 Of the recoverin antibody-positive patients, 6 had lung cancer (5 had SCLC) and 2 (17%) had endometrial cancer; other patients had breast, colon, or skin cancer.44

In a study of 18 patients with CAR, all tested positive for recoverin antibodies (10 initially and all upon follow-up). Of the 18 patients, 10 had lung cancer (7 had SCLC), 2 had prostate cancer, and 2 had thymoma.72 Among patients with lung cancer (SCLC and NSCLC), 17% test positive for recoverin; only 1% of patients who are healthy or have nonmalignant pulmonary diseases test positive.73

RyR (ryanodine receptor)

See striated muscle section.

Striated muscle

A positive test result for striated muscle, RyR, or titin antibodies, is consistent with MG. Thymoma is the most commonly associated tumor type. The EFNS Task Force considers titin antibody a biomarker for thymoma.4

Among patients with MG, 34% to 58% test positive for striated muscle antibody, 14% test positive for RyR, and 30% to 34% test positive for titin antibody.19,20 Unlike AChR, which occurs in all patients with early-onset MG, late-onset MG, or thymoma, the frequencies of striated muscle, RyR, and titin antibodies vary by MG type: they are present more often in patients with thymoma (Table 6).19

Table 6. Frequency of Muscle-Related Antibodies in MG Patients19 [return to contents]

MG subtype	AChR	Striated muscle	RyR	Titin
Early-onset MG (n=52)	100%	25%	0%	10%
Late-onset MG (n=40)	100%	48%	14%	58%
Thymoma (n=20)	100%	75%	70%	95%

MG, myasthenia gravis.

In side-by-side comparisons in MG patients (Table 5),19,20 striated muscle, RyR, and titin antibodies had generally lower sensitivity for thymoma than did AChR.19 In contrast, specificity for thymoma in MG patients is higher for these antibodies than for AChR.

Titin

See striated muscle section.

VGCC, N-type (N-type voltage-gated calcium channel)

A positive test result for N-type VGCC (voltage-gated calcium channel) antibody is consistent with LEMS. SCLC is the most commonly associated cancer type.

Among patients with LEMS, 33% to 65% test positive for N-type VGCC antibody. Among LEMS patients who test positive, 59% to 85% have cancer; at least 95% of detected cancers are SCLC.35,74,75 Among LEMS patients with lung cancer, 40% to 73% test positive for N-type VGCC antibody.35 Healthy patients do not test positive, but up to 22% of SCLC patients without PNS and up to 27% of patients with paraneoplastic encephalomyeloneuropathies test positive.35,74

VGCC, P/Q-type (P/Q-type voltage-gated calcium channel)

A positive test result for P/Q-type VGCC antibody is consistent with LEMS and cerebellar degeneration. SCLC is the most commonly associated cancer type.

Among patients with LEMS, 85% to 95% test positive for P/Q-type VGCC antibody.35,74,76 In contrast, ≤2% of healthy patients test positive.35,74 Among LEMS patients who test positive, 70% to 78% have SCLC.35,76 Among LEMS patients with cancer, 96% to 100% test positive.35,74 P/Q-type VGCC antibody is present in 92% to 100% of LEMS patients who test positive for N-type VGCC antibody.35,74,75

Among patients with paraneoplastic cerebellar degeneration and lung cancer, 41% test positive for P/Q-type VGCC antibody; among those who test positive, 44% have LEMS.77 In a study that included 27 patients with paraneoplastic cerebellar degeneration and tumors other than SCLC (21 with ovarian or breast, 4 with Hodgkin lymphoma, 1 with non-Hodgkin lymphoma, 1 with bladder cancer), none tested positive.78

VGKC (voltage-gated potassium channel)

A positive test result for VGKC, LGI1, or CASPR2 antibody is consistent with limbic encephalitis, neuromyotonia, and Morvan syndrome. SCLC and thymoma are the cancer types associated with these antibodies. A positive test result for DPPX antibody is consistent with multiple neurological disorders. B-cell neoplasms occur in some patients who test positive for DPPX antibody.3

In patients with suspected PNS, 0.06% test positive for VGKC antibody.79 Among those who test positive, 67% have limbic encephalitis, 11% have neuromyotonia, 5% have Morvan syndrome, 4% have epilepsy, and 13% have other disorders.22 In a study that included 72 VGKC antibody-positive patients, 47% had suspected or histologically confirmed neoplasms; of the 12 types described, the most common were SCLC, adenoma, mass lesion or adenopathy, thymoma or thymic carcinoma, and prostate adenocarcinoma.79

The epitopes recognized by VGKC autoantibodies are often on proteins, such as LGI1 and CASPR2, that are bound to potassium channels. Among patients who test positive for VGKC antibody, 5.0% test positive for LGI1 and 1.4% test positive for CASPR2.21 DPPX is also a protein that binds a potassium channel subunit and is associated with PNSs; however, it is associated with a potassium channel (Kv4.2)80 distinct from that associated with LGI1 and CASPR2 (Kv1).22

Among patients who test positive for VGKC and LGI1 antibodies, 93% have CNS manifestations and 31% have peripheral nervous system manifestations.21 Reported CNS manifestations vary, but over half of patients have seizures (80%), cognitive decline (70%), or psychiatric manifestations (55%),21 and 43% to 100% have limbic encephalitis.21-23 Cancer has been reported in 11% to 13% of patients who test positive for LGI1, but the type varies.21-23 In one study, 12 types of cancer were detected in 22 of 166 patients who were positive for LGI1 and negative for CASPR2; only nonmelanoma skin (6 patients), prostate (4), colon (3), and breast (3) cancer occurred in more than 1 patient each.21

Among patients who test positive for VGKC and CASPR2 antibodies, 61% have CNS manifestations and 47% have peripheral nervous system manifestations. Over half of patients have sensory-motor symptoms, and large proportions have seizures (49%), neuropathic pain (46%), cognitive decline (39%), personality change (33%), or sleep disturbance (33%)21; 18% have limbic encephalitis,21 and neuromyotonia, and Morvan syndrome have also been reported.22 In one study, cancer was reported in 8 of 40 (20%) patients who were positive for CASPR2 and negative for LGI1; only thymoma (3) and melanoma (2) were reported in more than 1 patient. The study also found 9 patients positive for both antibodies, 4 of which had cancer; 2 of those patients had thymoma.21 In a separate study, tumors were identified in 6 of the 19 patients who were positive for CASPR2, of which 5 were thymomas.22

In a study of 20 patients who tested positive for DPPX antibodies, all patients had multifocal neurological disorders; encephalopathy, myelopathy, weight loss, and autonomic dysfunction were most prominent. Of the 20 patients, 2 had B-cell neoplasms.40

Zic4

A positive test result for Zic4 antibody is consistent with cerebellar degeneration. SCLC is the most commonly associated cancer type.

Among patients with PNSs, 13% test positive for Zic4 antibody.39 Among patients with a PNS and Zic4 antibodies, 67% have cerebellar syndromes, while the rest have multifocal syndromes. SCLC is present in 90% of Zic4 antibody-positive patients, and other tumor types are present in 8%.39

In Zic4 antibody-positive patients with PNS, 82% also test positive for ANNA1 or CRMP5 antibodies. The presence of Zic4 alone is often accompanied by cerebellar syndromes; in a study that included 9 PNS patients with Zic4 antibody alone, 8 had cerebellar syndromes; in contrast, 75% (30 of 40) of patients who tested positive for multiple antibodies displayed other (eg, sensory neuropathy, limbic encephalitis, sensorimotor neuropathy) or multifocal syndromes.39

 

Appendix [return to contents]

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
206	Acetylcholine Receptor Binding Antibody
34459	Acetylcholine Receptor Blocking Antibody
26474a	Acetylcholine Receptor Modulating Antibody
Amphiphysin
4674b	Recombx® Amphiphysin Antibody 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)
38323a	Aquaporin-4 (AQP4) (NMO-IgG) Antibody With Reflex to Titer, CSF Includes AQP4 antibody with reflex to titer.
38321a	Aquaporin-4 (AQP4) (NMO-IgG) Antibody With Reflex to Titer, Serum Includes AQP4 antibody with reflex to titer.
90382	Aquaporin-4 (AQP4) Antibody (NMO-IgG), ELISA
93893a	Aquaporin-4 Antibody (IgG), CBA
CASPR2
92413b	CASPR2 Antibody Test
CRMP5 (CV2)
4681b	Recombx® CV2 Autoantibody Test
DPPX
93891a	DPPX Receptor Antibody, CBA IFA
gACHR
93881a	Acetylcholine Receptor Ganglionic (Alpha 3) Antibody
GAD65
92414b	GAD65 Neurological Syndrome Antibody Test
LGI1
92416b	LGI1 Antibody Test
Myelin and MAG
4639d	Myelin Antibody (IgG), IFA
37438a	Myelin Associated Glycoprotein (MAG) Antibody (IgM), EIA
37078a	Myelin Associated Glycoprotein (MAG)-SGPG Antibody (IgM)
10063a	Myelin Associated Glycoprotein (MAG) Antibody, With Reflex to MAG-SGPG and MAG, EIA Includes MAG antibody (WB) with reflex to MAG-SGPG antibody and MAG antibody (EIA).
NMDAR1
92394	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
93894a	Purkinje Cell Cytoplasmic Antibody Type Tr (DNER), CBA IFA
Recoverin
4684b	Recombx® CAR (Anti-Recoverin) Autoantibody Test
RyR
94743b	RyR Autoantibody Test
Striated muscle
266a	Striated Muscle Antibody With Reflex to Titer
Titin
92792b	Titin Autoantibody Test
VGCC (N -type)
93882a	Voltage-Gated Calcium Channel (VGCC) Type N Antibody
VGCC (P/Q-type)
34057	Voltage-Gated Calcium Channel (VGCC) Type P/Q Antibody
VGKC
93883a	Voltage-Gated Potassium Channel (VGKC) Antibody
Zic4
4689b	Recombx® Zic4 Antibody 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 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.
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.
10104a	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.
91623b	NeoCerebellar Degeneration Paraneoplastic Evaluation With Recombx® Includes amphiphysin, ANNA1 (Hu), ANNA2 (Ri) CRMP5 (CV2), GAD65, MaTa, PCA1 (Yo), and Zic4 antibodies
91636b	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..
91622b	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.
93890a	Neurology Antibody, CBA IFA Includes AMPAR1, AMPAR2, CASPR2, GABA-B-R, LGI1, and NMDAR1 antibodies.
93892a	Neurology Antibody, Line Blot Includes AGNA (SOX1), amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CRMP (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.
94603b	Paraneoplastic Autoantibody Evaluation With Recombx®, CSF Includes amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CASPR2, CRMP5 (CV2), LGI1, MaTa, NMDAR, PCA1 (Yo), recoverin, and Zic4 antibodies.
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), 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.
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 antibodies.
4683b	Recombx® MaTa Autoantibody Test Includes Ma and Ta antibodies.
94604b	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.
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).
e	f Refer to the Athena Diagnostics website (AthenaDiagnostics.com/Content/Test-Catalog) for test information. This test is performed by Athena Diagnostics.