Letter of Medical Necessity for Paraneoplastic Syndrome Testing<Date>

ATTN: <Medical Director/ Physician Name>, M.D.<Institution/Insurance Company>

<Street Address><City>, <State>, <Zip>

RE: <Patient Name>DOB: <MM/DD/YYYY>Member ID: <Insurance ID Number>Group #: <Enter Group #>

Dear Medical Director:

I am writing this letter on behalf of my patient <Patient Name> to request coverage for the Paraneoplastic Syndrome (PNS) testing offered by Quest Diagnostics to determine <state what test is being used for>. The characterization of autoantibodies by this test can assist in establishing a specific diagnosis, and in selecting the most appropriate course of clinical management. This letter provides background documentation for the medical necessity for Paraneoplastic Syndrome (PNS) testing in light of the patient’s medical history. Results from the test will be used to guide appropriate medical care for this patient.

I have determined that this test is medically necessary because of the following aspects of this patient’s history:

<Patient name> is a <age> year old <gender > with a suspected diagnosis of <disease name>. The following symptoms and clinical findings are consistent with this diagnosis:1. <Symptom #1 with ICD-10 code>2. <Symptom #2 with ICD-10 code>

[Provide summary statement indicating that the patient's medical and family history are consistent with a specific diagnosis, indicate the need for additional testing, etc.]

Rationale for TestingMultiple neoplastic diseases are associated with production of antibodies that target brain and nervous system structures directly or target non-neurological tissues, but cross-react with brain and other neurological tissues. These autoantibodies cause neurological symptoms and signs that suggest the presence of underlying, occult, or

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known malignancies, hence the term “paraneoplastic.” However, the presence of autoantibodies resulting from other conditions such as other idiopathic autoimmune conditions can cause syndromes with similar neurological symptoms in the absence of cancer. Thus, it is important to differentiate cancer-related paraneoplastic antibodies from other autoimmune antibodies and to use available data from testing to guide the search for an underlying neoplasm. Further, characterization of autoantibody specificity may allow syndromic classification and assist in diagnosis and management. (See reference 1 below, table 1)

Table 1

Laboratory tests can identify specific autoantibodies that indicate possible PNSs and can guide the search for an underlying malignancy or tumor. However, the same antibody can be associated with multiple syndromes and cancer types, and the same syndrome or cancer type can be associated with multiple antibodies. Thus, simultaneously testing for many autoantibodies is often the most appropriate testing approach to avoid the loss of time to diagnosis and improve the testing yield as recommended by the European Federation of Neurological Societies (EFNS) Task Force.4 The prevalence of most PNSs is very low, but symptoms often precede discovery of tumors. Diagnosis of a PNS and its cause can lead to earlier cancer treatment and the opportunity for better cancer-related outcomes.

Quest Diagnostics offers several panels to specifically evaluate patients, as appropriate based on PNS clinical presentations (Figure 1 above). The specific value of the individual elements of those panels is shown in the attached appendix. The information from the

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individual tests is most informative when used both individually and collectively in the evaluation and management of my patient.

[Provide a brief overview of the specific test for which coverage is requested. Include the antibody specificities and their relationship to the patient’s clinical presentation]

The results may provide several important benefits for my patient: [E.g. RI/RO the suspicion of an occult cancer, direct next steps toward diagnosis and/or treatment, etc.]

1. Benefit 1 2. Benefit 2

I am requesting that <Patient Name> be approved for the <Test Name> test <Test Code; CPT codes> offered by Quest Diagnostics. [Specify any reasons for recommending this specific test/panel or Quest Diagnostics.]

In summary, [add brief summary recapping expected benefit from this test.] I hope you will support this letter of medical necessity for <Patient Name>. Please feel free to contact me at <Physician Phone> if you have additional questions.

Sincerely,

<Physician Name>, MDNPI #: <Physician NPI#>

Contact information: < Address><City>, <State>, <Zip>Contact Phone No.: <phone number>

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Appendix: Discussion Regarding Individual PNS ComponentsThe presence of an antibody is associated with certain PNSs and malignancies. To confirm the presence of an underlying malignancy or tumor, positive antibody test results must be followed with imaging (e.g., computed tomography [CT], fluorodeoxyglucose-positron emission tomography [FDG-PET], magnetic resonance imaging [MRI], ultrasound, mammography, or other laboratory tests (e.g., 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. For additional information, please see http://www.questdiagnostics.com/testcenter/testguide.action?dc=CF_Paraneoplastic_Syndromes.

AChR (acetylcholine receptor)

A positive test result for AChR 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.5-7 Among patients confirmed as not having MG (but initially suspected of having MG), 0% test positive, indicating 100% specificity for MG.6 Among MG patients who test positive, 16% have thymoma, 32% have late-onset MG, and 42% have early-onset MG.5

In a side-by-side comparison, AChR antibody was more sensitive for thymoma in MG patients that striated muscle, another MG-related antibody; however, AChR antibody was less specific (2).5,6

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.8 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 identify some additional cases and improve specificity.

Table 2. Sensitivity and Specificity of MG-related Antibodies for Thymoma in MG Patients5,6

Antibody Sensitivity, % Specificity, %

AChR 100 17-23

Striated muscle 75-77 58-73

AGNA/SOX1 (anti-glial nuclear antibody)

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A positive test result for AGNA/SOX1 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).9 In patients who have SCLC, but no PNS, 22% to 32% test positive for AGNA.18,19

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.9,18 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 antibody is consistent with limbic encephalitis. Lung (SCLC), thymoma, breast, and ovarian cancer types are associated with AMPAR antibody.

Among patients suspected of PNS, 0.2% test positive for AMPAR antibody.10 In a study of 22 AMPAR antibody-positive patients, 59% had limbic encephalitis and 36% had limbic dysfunction and encephalopathy; the rest (1 patient) had psychosis with bipolar features. Cancer was identified in 64% of patients (14 of 22): 6 patients had lung cancer (5 had SCLC), 4 had thymoma, 2 had breast cancer, and 2 had ovarian teratoma.10

In a study of 109 patients who had limbic encephalitis, 10 (9%) tested positive for AMPAR antibody. Of the 10 patients, 7 had neoplasms: 3 had thymus cancer, 2 had breast cancer, and 2 had lung cancer.20

Amphiphysin

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

Among patients suspected of PNS, 0.06% test positive for amphiphysin antibody.11 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. Lambert-Eaton syndrome, opsoclonus, cranial neuropathies, optic neuritis/retinitis, and pruritus are also reported.11 Amphiphysin antibody has also been reported in patients with stiff-person syndrome, though GAD antibody is much more common in those patients.21

Among patients who test positive for amphiphysin antibody, 51% have lung cancer (84% are SCLC) and 25% have breast cancer.11 Ovarian cancer has also been reported, but at a much lower rate than SCLC and breast cancer.22

Other PNS-related antibodies coexist with amphiphysin in a substantial proportion of patients (38% to 70%). CRMP5/CV2, ANNA1, and voltage-gated calcium channels are the

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most frequently coexisting antibodies.11,23

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

A positive test result for ANNA1 is consistent with sensory neuropathy, cerebellar ataxia, limbic encephalitis, brainstem encephalitis, and autonomic neuropathy. SCLC is the most commonly associated cancer type.

In patients suspected of PNS, 0.4% test positive for ANNA1 antibody.23 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.24-26 Cancer develops in 80% to 98% of patients who test positive.23,24 In 80% to 86% of cancer patients with ANNA1, cancer is found in the lung (SCLC develops in 66% to 82%).23-26 Cancer in the bladder, breast, gastrointestinal tract, pancreas, prostate, or ovary each develop in 1% to 4% of patients.24

ANNA1 coexists with other PNS-related antibodies in 43% of patients. Antibodies to CRMP5/CV2, P/Q-type voltage-gated calcium channels (VGCC), or N-type VGCC coexist in 14% to 17% of ANNA1-positive patients. Other antibodies coexist at frequencies between 1% and 5%.23

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

A positive test result for ANNA2 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.27,28

Among patients suspected of having a PNS, 0.05% test positive for ANNA2.16 In a study that included 34 patients who tested positive, 59% presented with manifestations indicating brainstem involvement (e.g., ataxia, opsoclonus-myoclonus), and 41% presented with manifestations, indicating cerebellum involvement (e.g., ataxia with nystagmus). Lung cancer occurred in 36% of ANNA2-positive patients, breast cancer in 32%, and other cancer types in 15%.16

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.16,23

ANNA3 (anti-neuronal nuclear antibody type 3)

A positive test result for ANNA3 is consistent with sensory neuropathy and limbic encephalopathy. SCLC is the most commonly associated cancer.29

In a study of 68,000 patients suspected of having a 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

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(lung, esophagus), 1 had a lung mass, and 1 had thoracic and abdominal masses.29

Six of the 11 patients also tested positive for other PNS-related antibodies: VGCC (3), gAChR (2), or ANNA2 (1).29

Aquaporin 4 (NMO)

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

Among patients tested for paraneoplastic antibodies, 0.02% test positive for aquaporin 4 antibody. Among those who test positive, 93% have NMO.15 In a study that included 31 patients who tested positive for aquaporin 4 antibody, 9 (29%) were diagnosed with neoplasms: 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.15

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 antibody is consistent with multiple PNSs: sensory neuropathy, cerebellar ataxia, 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.17 In a study of 16 patients with paraneoplastic chorea, all patients tested positive for CRMP5/CV2.30

Among CRMP5/CV2-positive patients, 53% to 77% have lung cancer (47% to 62% have SCLC) and 6% to 15% have thymoma.17,23,25 CRMP5/CV2 antibodies rarely occur in healthy individuals (0.6%), but occur in 5% of patients with SCLC and 12% of patients with thymoma.31

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%).23

GABABR (gamma-aminobutyric acid receptor B)

A positive test result for GABABR 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

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antibody.32 In a study that included 7 patients suspected of autoimmune encephalitis who tested positive for GABABR antibody, all 7 were confirmed to have limbic encephalitis. Of the 7, 5 had SCLC and 1 had a lung mass that was not biopsied; the patient without cancer was 16 years old.32

In a study that included 15 patients suspected of having paraneoplastic encephalitis who tested positive for GABABR antibody, 7 had tumors, 5 of which were SCLC. Of the 15 patients, 7 tested positive for antibodies to other antigens (N-type VGCC, GAD65, thyroid peroxidase, or thyroglobulin).33

gAChR (ganglionic acetylcholine receptor)

A positive test result for gAChR 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 paraneoplastic antibodies, 1% test positive for gAChR antibody.14 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 dysmotitilty; and 17% have central nervous system manifestations, most commonly cortical or neuropsychiatric. Manifestations are multifocal in 29% of patients.14

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.14 Small studies have also reported SCLC and thymoma.34,35

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/CV2.14

GAD65 (glutamic acid decarboxylase 65 kD protein)

A positive test result for GAD65 antibody is associated with stiff-person syndrome, cerebellar ataxia or degeneration, and limbic encephalitis. Many cancer types are associated with GAD65 antibody.12,36,37

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

Many cancers have been reported in GAD65 antibody-positive patients, though many of them are from case studies or single patients within a study. In a study that included 15 GAD65 antibody-positive patients, the authors also summarized cancer types in 19 GAD65-positive patients in the literature. Of these 34 total patients, 10 had lung cancer (7 of which were SCLC), 10 had thymoma (3 of which were malignant), 6 had breast

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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).12

GAD antibodies are also present in ~80% of patients with type 1 diabetes.38 However, titers of GAD antibody are usually >100 times higher in patients with stiff-person syndrome than in those with type 1 diabetes.39

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.40 Tumors are identified in 89% to 97% of Ma2/Ta antibody-positive patients. Among patients with cancer, 53% to 57% have testicular 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.40,41 In a study of 25 patients with Ma2/Ta -positive encephalitis who were <50 years of age, 19 (76%) had germ-cell tumors.42

Testicular tumors are more common when Ma2/Ta is not accompanied by Ma1 or Ma3 antibodies.41,43

Myelin-associated glycoprotein (MAG)

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, 56% of those with neuropathy test positive for MAG antibody compared to 7% of those without neuropathy. Among patients with IgM monoclonal gammopathy and MAG antibody, 93% display sensory or sensorimotor neuropathy, 81% to 85% have MGUS, and 8% to 19% have Waldenström macroglobulinemia.44,45 Among patients with MGUS and neuropathy, 69% test positive for MAG antibody.44

NMDAR1 (N-methyl-D-aspartate receptor)

A positive test result for NMDAR1 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

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or SCLC.13

PCA1 (Yo; Purkinje cell cytoplasmic antibody type 1)

A positive test result for PCA1 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 cancer27,46; ovarian cancer accounts for 43% to 47% of cancers and breast cancer accounts for 25% to 40%.46,47

Among patients who test positive for PCA1, 9% test positive for other autoantibodies (voltage-gated channel or acetylcholine receptor antibodies).23

PCA2 (Purkinje cell cytoplasmic antibody type 2)

A positive test result for PCA2 is consistent with encephalomyelitis, limbic encephalitis, and cerebellar ataxia. Lung cancer (SCLC) is the most commonly associated cancer type.48

Among patients suspected of PNS, 0.07% test positive for PCA2.23 In a case report, 10 PCA2-positive patients had various neurological presentations, including 5 patients with brainstem or limbic encephalitis and 3 with cerebellar ataxia. Lung malignancies were identified in 9 patients, 8 of whom had SCLC.48 The high incidence of lung cancer in PCA2-positive patients is supported by a study that included 19 PCA2-positive patients with adequate clinical information. Of those patients, 79% had lung cancer in a 2-to-1 ratio of SCLC to NSCLC.23

Among PCA2-positive patients, 63% have coexisting PNS-related antibodies: 44% have CRMP5, 14% have P/Q-type VGCC, 12% have ANNA1, 9% have N-type VGCC, 9% have VKGC, and 11% have amphiphysin, ANNA3, muscle AChR, or striated muscle.23

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

A positive test result for PCA-Tr is consistent with cerebellar degeneration. Hodgkin lymphoma is the most commonly associated cancer type.49

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% were diagnosed with Hodgkin lymphoma; no tumor was found in the other 11%.49 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.50

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.51 Of the recoverin antibody-positive patients, 6

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had lung cancer (5 had SCLC) and 2 (17%) had endometrial cancer; other patients had breast, colon, or skin cancer.51

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.52 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.53

Striated muscle

A positive test result for striated muscle antibody is consistent with MG. Thymoma is the most commonly associated tumor type.

Among patients with MG, 34% to 58% test positive for striated muscle antibody.5,6 Among those who test positive, 31% have thymoma, 39% have late-onset MG, and 27% have early-onset MG.5

In a side-by-side comparison, the sensitivity and specificity of striated muscle antibody for thymoma in MG patients was less sensitive but more specific than another MG-related antibody, AChR (Table 2).6

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

A positive test result for N-type VGCC 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.54-56 Among LEMS patients with lung cancer, 40% to 73% test positive for N-type VGCC antibody.54 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.54,55

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.54,55,57 In contrast, ≤2% of normal patients test positive.54,55 Among LEMS patients who test positive, 70% to 78% have SCLC.54,57 Among LEMS patients with cancer, 96% to 100% test positive.54,55 P/Q-type VGCC antibody is present in 92% to 100% of LEMS patients who test positive for N-type VGCC antibody.54-56

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.58 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.59

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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.

In patients suspected of PNS, 0.06% test positive for VGKC antibody.60 Among those who test positive, 67% have limbic encephalitis, 11% have neuromyotonia, 5% have Morvan syndrome, 4% have epilepsy, and 13% have other disorders.61 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.60

The epitopes recognized by VGKC autoantibodies are often on proteins bound to the calcium channels, such as LGI1 and CASPR2. Among patients who test positive for VGKC antibody, 57% test positive for LGI1 and 20% test positive for CASPR2. Among patients who test positive for VGKC and LGI1 antibodies, 89% to 100% have limbic encephalitis; however, only up to 11% have tumors (thyroid, lung, renal cell, ovarian teratoma, thymoma).61,62 In a study that included 19 patients who tested positive for VGKC and CASPR2 antibodies, 7 (37%) had limbic encephalitis, 7 (37%) had neuromyotonia, and 3 (16%) had Morvan syndrome. Tumors were identified in 6 of the 19 patients, 5 of which were thymoma.61

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.63 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%.63

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 (e.g., sensory neuropathy, limbic encephalitis, sensorimotor neuropathy) or multifocal syndromes.63

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