Paraneoplastic Neurological Syndromes

Transcription

1 Paraneoplastic Neurological Syndromes Laboratory Support of Diagnosis CLINICAL BACKGROUND 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 the cancer. Thus, diagnosis of a PNS and its cause can lead to earlier cancer treatment and better chances of good cancer-related outcomes. However, because PNS-associated antibodies may cause permanent damage, successful treatment of a tumor does not always result in neurologic improvement. 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. Diagnosis can be complicated because signs and symptoms of the different syndromes overlap. In addition, autoimmune neurological syndromes are not always paraneoplastic (ie, caused by cancer); they can be caused by infectious agents, toxins, or metabolic conditions. The diagnosis of a PNS and identification of an underlying malignancy can involve imaging and laboratory tests. 3 Laboratory tests can identify specific autoantibodies that indicate possible PNSs and can guide the search for an underlying malignancy. However, a single antibody 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, they are also associated with non-paraneoplastic conditions, such as autoimmune encephalitis, rapidly progressing dementia, and epilepsy. Testing for many autoantibodies at the same time may be appropriate in certain clinical circumstances. 4 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; thus, it focuses on studies involving larger cohorts and generally does not discuss case reports unless necessary. 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. 1-4 INDIVIDUALS SUITABLE FOR TESTING Individuals who have signs and symptoms consistent with a PNS (Table 1) Individuals who have a PNS with an unidentified underlying malignancy TEST AVAILABILITY AND SELECTION 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 Quest Diagnostics offers several tests and panels (Table 2, Appendix) that may help identify an underlying PNS. Panels offered by Quest Diagnostics include the following: Paraneoplastic Antibody Evaluation with Reflex to Titer and Western Blot, Basic (test code 93876, Figure 1): for use with serum specimens Paraneoplastic Antibody Evaluation with Reflex to Titer and Western Blot, Basic, CSF (test code 94536, Figure 2): for some patients, detection of antibodies in CSF is more robust than in serum 5-8 Autoimmune Neurology Antibody Comprehensive Panel with Reflexes, Serum (test code 93888, Figure 3): for use with serum specimens Many, but not all, antibody tests are available individually (Table 2); 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 3 and information in the Test Interpretation section can help identify which antibodies would be most appropriate. Table 3 includes PNS-related antibodies and associated syndromes and cancer types. The Test Interpretation section contains information about the antibodies.

2 TEST INTERPRETATION The presence of an antibody is associated with certain PNSs and malignancies (see Table 3 and below). However, antibodies and syndromes can occur in the absence of cancer or a tumor and are associated with other non-paraneoplastic conditions, such as autoimmune encephalitis, rapidly progressing dementia, and epilepsy. 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. Specific information for each PNS-related antibody follows Table 3. Table 1. Clinical Presentation and Associated Tumors of Paraneoplastic Neurological Syndromes Neurological Syndrome a.4 Clinical Presentation 1,2 Associated Tumors 4 (common cancer and tumor types are in bold) Brainstem encephalitis/ opsoclonus-myoclonus Cerebellar degeneration Encephalomyelitis/limbic encephalitis Lambert-Eaton myasthenic syndrome Myasthenia gravis Neuromyotonia (Isaac syndrome) Subacute autonomic neuropathy/dysautonomia Subacute sensory neuropathy Stiff-person syndrome Large-amplitude synchronic and chaotic eye movements (opsoclonus), spontaneous muscle jerks (myoclonus), and ataxia Ataxia, diplopia, dysarthria; early symptoms include dizziness, nausea, vomiting Encephalomyelitis: subacute sensory neuropathy, limbic encephalitis, cerebellar ataxia; 30% of patients have autonomic neuropathy (eg, orthostatic hypotension, urinary retention, pupillary abnormalities, impotence, dry mouth) Limbic encephalitis: short-term memory loss, seizures, mood changes, hallucinations; less common symptoms include hypothalamic symptoms (eg, hyperthermia, somnolence, endocrine dysfunction) Proximal muscle weakness in lower extremities, fatigue, diaphragmatic weakness, bulbar symptoms; later symptoms include autonomic symptoms (eg, ptosis, impotence, dry mouth) Weakness and fatigue of voluntary muscles (eg, ocular-bulbar, limbs) and diaphragm Twitching, muscle rippling, stiffness, cramps, slowed movement 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) Paresthesias 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 reflexes Severe muscle stiffness, mainly in spine and legs, muscle spasms SCLC, small-cell lung cancer. a These syndromes can occur in the absence of cancer or tumors. Breast cancer, ovarian cancer, testicular tumor, SCLC, neuroblastoma (children) SCLC, ovarian cancer, breast cancer, Hodgkin lymphoma, thymoma SCLC, testicular tumor, thymoma, neuroblastoma, prostate carcinoma, breast cancer, Hodgkin lymphoma SCLC Thymoma Thymoma, SCLC SCLC, thymoma SCLC, breast cancer, ovarian cancer Breast cancer, SCLC

3 Table 2. Test Availability for PNS-Related Antibodies Antibody Single Antibody Tests (see Appendix for test codes) Basic Panel, Serum (test code 93876) Basic Panel, CSF (test code 94536) Comprehensive Panel, Serum (test code 93888) AChR, binding AChR, blocking a AChR, modulating a a AGNA/SOX1 AMPAR a a Amphiphysin ANNA1 (Hu) ANNA2 (Ri) ANNA3 Aquaporin 4 (NMO) a CASPR2 a CRMP5/CV2 DPPX GABA B R a a gachr GAD65 a LGI1 a Ma2/Ta MAG IgM a MAG-SGPG a Myelin NMDAR1 a a PCA1 (Yo) PCA2 PCA-Tr (DNER) Recoverin RyR Striated muscle Titin VGCC, N-type VGCC, P/Q-type VGKC a Zic4 a Reflex test.

4 Figure 1. Interpretation of Paraneoplastic Antibody Evaluation, Basic, Serum (Test Code 93876) Panel Patient with suspected paraneoplastic neurological syndrome Paraneoplastic Antibody Evaluation, Basic, Serum Reflex Tests AChR binding antibody positive or equivocal AChR modulating antibody CRMP5/CV2 Western line blot Positive ( 32% binding inhibition) Positive (signal intensity 11) Myasthenia gravis Cerebellar degeneration, encephalomyelitis/limbic encephalitis, sensory neuropathy, chorea, or optic neuritis AMPAR, GABABR, or NMDAR1 suggested by tissue IFA AMPAR1, AMPAR2, GABABR, NMDAR1 (CBA) AMPAR1, AMPAR2, or GABABR positive NMDAR1 positive Encephalomyelitis or limbic encephalitis Encephalitis with psychiatric manifestations, seizures, dyskinesias, dystonia, and autonomic instability ANNA3 positive by tissue IFA ANNA3 titer 1:40 Encephalomyelitis or sensory neuropathy NMO antibody suggested by tissue IFA pattern Aquaporin 4 (NMO) Positive Neuromyelitis optica PCA2 positive by tissue IFA PCA2 titer 1:40 Encephalomyelitis, cerebellar degeneration Striated muscle antibody positive Striated muscle antibody titer 1:40 Myasthenia gravis AGNA/SOX1, amphiphysin, ANNA1, ANNA2, CRMP5/CV2, GAD65, PCA1, or PCA-Tr (DNER) positive, indeterminate, or suggested by IFA Western line blot, quantitative Positive (signal intensity 11) Refer to Table 3 for interpretation gachr, VGCC (N-type), VGCC (P/Q-type), or VGKC positive Refer to Table 3 for interpretation This figure was developed by Quest Diagnostics based on the following references: 4 and It is provided for informational purposes only and is not intended as medical advice. A physician s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.

5 Figure 2. Interpretation of Paraneoplastic Antibody Evaluation, Basic, CSF (Test Code 94536) Panel Patient with suspected paraneoplastic neurological syndrome Paraneoplastic Antibody Evaluation, Basic, CSF Reflex Tests AMPAR1, AMPAR2, GABABR, NMDAR1, CASPR2, LGI1 suggested by tissue IFA AMPAR1, AMPAR2, GABABR, NMDAR1, CASPR2, LGI1 (CBA) AMPAR1, AMPAR2, or GABABR titer 1:10 Encephalomyelitis or limbic encephalitis Positive (any test) Titer for positive antibody NMDAR1 titer 1:10 Encephalitis with psychiatric manifestations, seizures, dyskinesias, dystonia, and autonomic instability CASPR2 or LGI1 titer 1:10 Limbic encephalitis, neuromyotonia, or Morvan syndrome ANNA3 positive by tissue IFA ANNA3 titer 1:10 Encephalomyelitis or sensory neuropathy NMO antibody suggested by tissue IFA pattern Aquaporin 4 (NMO), CBA Positive Aquaporin 4 (NMO), Titer 1:10 Neuromyelitis optica PCA2 positive by tissue IFA PCA2 titer 1:10 Encephalomyelitis, cerebellar degeneration AGNA/SOX1, amphiphysin, ANNA1, ANNA2, CRMP5/CV2, GAD65, PCA1, or PCA- Tr (DNER) positive, indeterminate, or suggested by IFA Western line blot, Quantitative Positive (signal intensity 11) Refer to Table 3 for interpretation VGKC, LGI1, CASPR2 antibody positive by tissue IFA Neuronal (V-G) K+ Channel Ab, CSF 20 pmol/l Refer to Table 3 for interpretation This figure was developed by Quest Diagnostics based on the following references: 4, 9, 10, and 13. This figure is provided for informational purposes only and is not intended as medical advice. A physician s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.

6 Figure 3. Interpretation of Autoimmune Neurology Antibody Comprehensive Panel, Serum (Test Code 93888) Patient with suspected paraneoplastic neurological syndrome Autoimmune Neurology Antibody Comprehensive Panel, Serum Reflex Tests AChR binding antibody positive AChR blocking antibody Positive Myasthenia gravis AChR binding antibody equivocal AChR blocking and modulating antibodies Positive (either test) Myasthenia gravis AChR binding antibody negative AChR modulating antibody Positive Myasthenia gravis AMPAR1, AMPAR2, or GABABR titer 1:10 Encephalomyelitis or limbic encephalitis AMPAR1, AMPAR2, GABABR, NMDAR1, CASPR2, or LGI1 positive by CBA Titer for positive antibody NMDAR1 titer 1:10 CASPR2 or LGI1 titer 1:10 ANNA3 suggested by tissue IFA ANNA3 titer 1:40 DPPX positive by IFA DPPX titer 1:10 Encephalitis with psychiatric manifestations, seizures, dyskinesias, dystonia, and autonomic instability Limbic encephalitis, neuromyotonia, or Morvan syndrome Encephalomyelitis or sensory neuropathy Encephalopathy, myelopathy Myelin antibody suggested by tissue IFA pattern MAG antibody, with reflex to MAG-SGPG and MAG, EIA Myelin titer Positive 1:40 Autoimmune peripheral neuropathy Autoimmune peripheral neuropathy NMO antibody suggested by tissue IFA pattern Aquaporin 4 (NMO), CBA IFA Positive NMO titer 1:10 Neuromyelitis optica PCA2 suggested by tissue IFA PCA2 titer 1:40 Encephalomyelitis, cerebellar degeneration PCA-Tr antibody suggested by tissue IFA pattern AND line blot shows DNER AND PCA1 (Yo) negative PCA-Tr, CBA IFA Positive PCA-Tr titer 1:10 Cerebellar degeneration Striated muscle antibody positive Striated muscle antibody titer 1:40 Myasthenia gravis Other antibodies positive: AGNA/SOX1, amphiphysin, ANNA1, ANNA2, CRMP5/CV2, gachr, GAD65, Ma2/Ta, PCA1, recoverin, titin, VGCC (N-type), VGCC (P/Q-type), VGKC, or Zic4 Refer to Table 3 for interpretation This figure was developed by Quest Diagnostics based on the following references: 4, 11, 12, and 14. It is provided for informational purposes only and is not intended as medical advice. A physician s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.

7 Table 3. Paraneoplastic Neurological Syndromes and Tumor/Cancer Types Associated with Autoantibodies 4,9-24 Associated Neurologic Syndrome a Associated Tumor or Cancer Type Autoantibody Target a Autonomic neuropathy Brainstem encephalitis/ opsoclonus-myoclonus Cerebellar degeneration LE / Encephalomyelitis LEMS Myasthenia gravis Neuromyelitis optica Neuromyotonia AChR AGNA/SOX1 AMPAR Amphiphysin ANNA1 (Hu) Sensory neuropathy Stiff-person Others Breast cancer Hodgkin lymphoma Lung cancer Ovarian cancer Prostate cancer Renal cell cancer SCLC Testicular tumor Thymoma Other bladder, GI, pancreas ANNA2 (Ri) gynecological ANNA3 b Aquaporin 4 (NMO) CRMP5/CV2 c DPPX GABA B R d gachr e GAD65 NMDAR f g g PCA1 (Yo) PCA2 b PCA-Tr (DNER) RyR Striated muscle Titin VGCC, N-type VGCC, P/Q-type VGKC h GI, lymphoid, melanoma, bladder pancreatic, thymic cancer indicates tumor type(s) most frequently associated with the antibody; GI, gastrointestinal; LE, limbic encephalitis; LEMS, Lambert-Eaton myasthenia gravis; SCLC, small-cell lung cancer. a Autoantibodies and syndromes can occur in the absence of cancer or a tumor. b Case report c Chorea, optic neuritis d Tumor e Cortical and neuropsychiatric presentation f Encephalitis with psychiatric manifestations, seizures, dyskinesias, dystonia, and autonomic instability g Teratoma h Morvan syndrome

8 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. 11,12,25 Among patients confirmed as not having MG (but initially suspected of having MG), 0% test positive, indicating 100% specificity for MG. 12 In side-by-side comparisons with other MG-related antibodies (ryanodine receptor [RyR], striated muscle, and titin), 11,12 AChR antibody was generally more sensitive for thymoma in MG patients, though one study demonstrated a 95% sensitivity for titin antibody. 11 However, AChR antibody was less specific than RyR, striated muscle, or titin antibodies (Table 4). 11,12 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. 26 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 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 Table 4. Sensitivity and Specificity of MG-related Antibodies for Thymoma in MG Patients a,5,6 Antibody Sensitivity, % Specificity, % AChR RyR Striated muscle Titin a One study included 146 MG patients, of which 20 had thymoma 11 ; the other study included 44 patients, of which 13 had thymoma. 12 (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). 16 In patients who have SCLC but no PNS, 22% to 32% test positive for AGNA. 27,28 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. 16,27 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 with suspected PNS, 0.2% test positive for AMPAR antibody. 17 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. 17 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. 29 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, 0.06% test positive for amphiphysin antibody. 21 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. 21 Amphiphysin antibody has also been reported in patients with stiff-person syndrome, though GAD antibody is much more common in those patients. 19

9 Among patients who test positive for amphiphysin antibody, 51% have lung cancer (84% are SCLC) and 25% have breast cancer. 21 Ovarian cancer has also been reported, but at a much lower rate than SCLC and breast cancer. 30 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 most frequently coexisting antibodies. 21,31 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. Among patients with suspected PNS, 0.4% test positive for ANNA1 antibody. 31 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. 15,32,33 Cancer develops in 80% to 98% of patients who test positive. 15,31 In 80% to 86% of cancer patients with ANNA1, cancer is found in the lung (SCLC develops in 66% to 82%). 15,31-33 Cancer in the bladder, breast, gastrointestinal tract, pancreas, prostate, or ovary each develop in 1% to 4% of patients. 15 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%. 31 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. 34,35 Among patients with suspected PNS, 0.05% test positive for ANNA2. 20 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%. 20 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. 20,31 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. 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. 9 Six of the 11 patients also tested positive for other PNSrelated antibodies: VGCC (3), gachr (2), or ANNA2 (1). 9 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 PNS-related antibodies, 0.02% test positive for aquaporin 4 antibody. Among those who test positive, 93% have NMO. 10 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. 10 CASPR2 (contactin-associated proteinlike 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, autonomic neuropathy, limbic encephalitis, and chorea. SCLC and thymoma are the most commonly associated cancer types.

10 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. 23 In a study of 16 patients with paraneoplastic chorea, all patients tested positive for CRMP5/CV2. 26 Among CRMP5/CV2-positive patients, 53% to 77% have lung cancer (47% to 62% have SCLC) and 6% to 15% have thymoma. 23,31,32 CRMP5/CV2 antibodies rarely occur in healthy individuals (0.6%) but occur in 5% of patients with SCLC and 12% of patients with thymoma. 37 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%). 31 DPPX (dipeptidyl-peptidase-like protein-6) See VGKC (voltage-gated potassium channel) section. GABA B R (gamma-aminobutyric acid receptor B) A positive test result for GABA B R 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 GABA B R antibody. 38 In a study that included 7 patients with suspected autoimmune encephalitis who tested positive for GABA B R 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. 38 In a study that included 15 patients with suspected paraneoplastic encephalitis who tested positive for GABA B R 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). 39 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 PNS-related antibodies, 1% test positive for gachr antibody. 18 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 central nervous system manifestations, most commonly cortical or neuropsychiatric. Manifestations are multifocal in 29% of patients. 18 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: 11 adenocarcinoma (breast [4], prostate [3], lung [2], gastrointestinal [2]), 5 lymphoid (B cell lymphoma [3]), 2 renal cell carcinoma, 2 melanoma, and 2 bladder. 18 Small studies have also reported SCLC and thymoma. 40,41 Coexisting antibodies are detected in 26% of gachr antibodypositive patients: GAD65, muscle AChR, N-type VGCC, VKCC, P/Q-type VGCC, striational, ANNA1, and CRMP5/CV2. 18 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 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. 42 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 antibodypositive 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). 43 GAD antibodies are also present in ~80% of patients with type 1 diabetes. 45 However, titers of GAD antibody are usually >100 times higher in patients with stiff-person syndrome than in those with type 1 diabetes. 46

11 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. 47 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. 47,48 In a study of 25 patients with Ma2/Ta-positive encephalitis who were <50 years of age, 19 (76%) had germ-cell tumors. 49 Testicular tumors are more common when Ma2/Ta is not accompanied by Ma1 or Ma3 antibodies. 48,50 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, 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, 14 81% to 85% have MGUS, and 8% to 19% have Waldenström macroglobulinemia. 14,51 Among patients with MGUS and neuropathy, 69% test positive for MAG antibody. 14 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 or SCLC. 52 PCA1 (Yo; Purkinje cell cytoplasmic antibody type 1) A positive test result for PCA1 is consistent with cerebellar degeneration. Breast and ovarian cancers are 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 cancer 34,53 ; ovarian cancer accounts for 43% to 47% of cancers and breast cancer accounts for 25% to 40%. 53,54 Among patients who test positive for PCA1, 9% test positive for other autoantibodies (voltage-gated channel or acetylcholine receptor antibodies). 31 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. Among patients with suspected PNS, 0.07% test positive for PCA2. 31 In a case series, 10 PCA2-positive patients had various neurological presentations, including brainstem or limbic encephalitis in 5 patients and cerebellar ataxia in 3. Lung malignancies were identified in 9 patients, 8 of whom had SCLC. 55 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, 15 (79%) had lung cancer (10 SCLC, 5 NSCLC). 31 Among PCA2-positive patients, 63% have coexisting PNSrelated 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. 31 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. 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

12 11%. 56 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. 57 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. 58 Of the recoverin antibodypositive patients, 6 had lung cancer (5 had SCLC) and 2 (17%) had endometrial cancer; other patients had breast, colon, or skin cancer. 58 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. 60 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 European Federation of Neurological Societies (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. 11,12 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 5). 11 In side-by-side comparisons with AChR (Table 4), 11,12 sensitivity for thymoma in MG patients is generally lower for striated muscle, RyR, and titin antibodies (usually around 75%) compared to that of AChR (100%), though titin sensitivity has been shown to be as high as 95%. 11 In contrast, specificity for thymoma in MG patients is higher for these antibodies (58% to 97%) than that of AChR (17% to 23%). Titin See striated muscle section. 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. 24,61,62 Among LEMS patients with lung cancer, 40% to 73% test positive for N-type VGCC antibody. 24 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. 24,61 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/Qtype VGCC antibody. 24,61,63 In contrast, 2% of healthy patients test positive. 24,61 Among LEMS patients who test positive, 70% to 78% have SCLC. 24,63 Among LEMS patients with cancer, 96% to 100% test positive. 24,61 P/Q-type VGCC antibody is present in 92% to 100% of LEMS patients who test positive for N-type VGCC antibody. 24,61,62 Table 5. Frequency of Muscle-Related Antibodies in Myasthenia Gravis (MG) Patients 11 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%

13 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. 65 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 neurologic disorders. B-cell neoplasms occur in some patients who test positive for DPPX antibody. Among patients with suspected PNS, 0.06% test positive for VGKC antibody. 66 Among those who test positive, 67% have limbic encephalitis, 11% have neuromyotonia, 5% have Morvan syndrome, 4% have epilepsy, and 13% have other disorders. 13 In a study that included 72 VGKC antibodypositive 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. 66 The epitopes recognized by VGKC autoantibodies are often on proteins bound to the calcium channels, such as LGI1, CASPR2, and DPPX. Among patients who test positive for VGKC antibody, 57% test positive for LGI1, 20% test positive for CASPR2, and 5% test positive for DPPX antibodies. 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). 13,67 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 thymomas. 13 In a study of 20 patients who tested positive for DPPX, all patients had multifocal neurologic disorders; encephalopathy, myelopathy, weight loss, and autonomic dysfunction were most prominent. Of the 20 patients, 2 had B-cell neoplasms. 22 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. 68 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%. 68 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. 68

14 APPENDIX Laboratory Tests for Paraneoplastic Neurological Syndrome Diagnosis and Identification of Related Tumors (for associated clinical use, refer to Table 3 and information in the Test Interpretation section) Test Code Test Name Single Antibody Tests AChR 206 Acetylcholine Receptor Binding Antibody Acetylcholine Receptor Blocking Antibody Acetylcholine Receptor Modulating Antibody Amphiphysin 4674 a Recombx Amphiphysin Antibody Test ANNA1 (Hu) b,c Hu Antibody Screen with Reflex to Titer and Western Blot Includes Hu antibody screen (IFA) with reflexes to WB and antibody titer b,c Hu Antibody Screen with Reflex to Titer and Western Blot, CSF Includes Hu antibody screen (IFA) with reflexes to WB and antibody titer. ANNA2 (Ri) b,c Ri Antibody Screen with Reflex to Titer and WB Includes Ri antibody screen (IFA) with reflexes to WB and antibody titer b,c Ri Antibody Screen with Reflex to Titer and Western Blot, CSF Includes Ri antibody screen (IFA) with reflexes to WB and antibody titer. Aquaporin 4 (NMO) d Aquaporin 4 Antibody (IgG), CBA CASPR a CASPR2 Antibody Test CRMP5/CV a Recombx CV2 Antibody Test DPPX d DPPX Receptor Antibody, CBA gachr d Ganglionic nachr Antibody Test GAD a GAD65 Neurological Syndrome Antibody Test LGI a LGI1 Antibody Test Myelin and MAG 4639 e Myelin Antibody (IgG), IFA d Myelin Associated Glycoprotein (MAG) Antibody (IgM), EIA d Myelin Associated Glycoprotein (MAG)-SGPG Antibody (IgM) c Myelin Assoc. Glycoprotein (MAG) Ab w/reflex to MAG-SGPG and MAG, EIA Includes MAG antibody (Western blot) with reflexes to MAG-SGPG and MAG (EIA). (Continued)

15 APPENDIX (Continued) Laboratory Tests for Paraneoplastic Neurological Syndrome Diagnosis and Identification of Related Tumors (for associated clinical use, refer to Table 3 and information in the Test Interpretation section) Test Code NMDAR1 Test Name NMDA Receptor (NR1-subunit) Autoantibody Test PCA1 (Yo) b,c Yo Antibody Screen with Reflex to Titer and Western Blot Includes Yo antibody (IFA) with reflexes to WB and titer b,c Yo Antibody Screen with Reflex to Titer and Western Blot, CSF PCA-Tr Includes Yo antibody (IFA) with reflexes to WB and titer d Purkinje Cell Cytoplasmic Antibody Type Tr (DNER), CBA IFA Recoverin 4684 a Recombx CAR (Anti-Recoverin) Autoantibody Test RyR 1481 f RyR Autoantibody Test Striated Muscle 266 c Striated Muscle Antibody with Reflex to Titer VGCC (N -type) d Voltage-Gated Calcium Channel (VGCC) Type N Antibody VGCC (P/Q-type) Voltage-Gated Calcium Channel (VGCC) Type P/Q Antibody VGKC d Voltage-Gated Potassium Channel (VGKC) Antibody Zic a Recombx Zic4 Antibody Test Multiple Antibody Tests (Panels) b,c Autoimmune Cerebellar Ataxia Panel Includes IgA level with reflex to tissue transglutaminase IgG; tissue transglutaminase IgA antibody with reflex(es) to endomysial IgA and endomysial IgA titer; voltage-gated calcium channel (VGCC) antibody; and Yo antibody (IFA) with reflexes to Western blot and titer b,c Hu, Yo, and Ri Antibodies with Reflex to Titers and Western Blot b,c Hu, Yo, and Ri Antibodies with Reflex to Titers and Western Blot, CSF 11306X b,c Lambert-Eaton Syndrome Antibody Panel Includes AChR modulating, VGCC, and AChR binding antibodies; also includes striated muscle antibodies with reflex to titer. 7550(X) b,c Myasthenia Gravis Panel 1 Includes acetylcholine receptor binding antibody and striated muscle antibody screen with reflex to titer d Myasthenia Gravis Panel 2 Includes acetylcholine receptor binding, blocking, and modulating antibodies b,c Myasthenia Gravis Panel 2 with Reflex to MuSK Antibody Includes acetylcholine receptor binding, blocking, and modulating antibodies with reflex to MuSK antibody (test code 18842) (X) b,c Myasthenia Gravis Panel 3 Includes acetylcholine receptor binding, blocking, and modulating antibodies and striated muscle antibody screen with reflex to titer. (Continued)

16 APPENDIX (Continued) Laboratory Tests for Paraneoplastic Neurological Syndrome Diagnosis and Identification of Related Tumors (for associated clinical use, refer to Table 3 and information in the Test Interpretation section) Test Code Test Name a NeoCerebellar Degeneration Paraneoplastic Evaluation with Recombx Includes amphiphysin and GAD65 antibodies and Recombx CV2, Hu, MaTa, Ri, Yo, and Zic4 antibodies a NeoComplete Paraneoplastic Evaluation with Recombx Includes amphiphysin, CASPR2, gachr, GAD65, LGI1, NMDA Receptor (NR1), VGCC, and VGKC antibodies and Recombx CAR (antirecoverin), CV2, Hu, Ma1 and Ma2, Ri, Yo, and Zic4 antibodies a NeoEncephalitis Paraneoplastic Profile with Recombx Includes amphiphysin, CASPR2, GAD65, LGI1, NMDA receptor (NR1), and VGKC antibodies and Recombx TM CV2, Hu, and MaTa antibodies f NeoSensory Neuropathy Paraneoplastic Evaluation with Recombx Includes amphiphysin and Recombx CV2 and Hu antibodies d Neurology Antibody, CBA IFA Includes AMPAR1, AMPAR2, CASPR2, GABA-B-R, LGI1, and NMDAR1 antibodies d 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 b,c Paraneoplastic Antibody Evaluation with Reflex to Titer and Western Blot, Basic Includes IFA test for the following antibodies: AGNA/SOX1, amphiphysin, ANNA1 (Hu), ANNA2 (Ri), ANNA3 with reflex to titer, CRMP5/CV2, PCA1 (Yo), PCA2 with reflex to titer, and PCA-Tr (DNER). Also includes reflex to NMO-5 IgG, AMPAR, GABABR, NMDAR, and a line blot panel. Includes striated muscle antibody with reflex to titer and acetylcholine receptor binding antibody with reflexes to modulating antibody and a Western blot panel. The line blot panel includes 6 antibodies: amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CRMP5/CV2, GAD65, and PCA1 (Yo) b,d Paraneoplastic Antibody Evaluation with Reflex to Titer and Western Blot, Basic, CSF Includes IFA test for the following antibodies: AGNA/SOX1, amphiphysin, ANNA1 (Hu), ANNA2 (Ri), ANNA3 with reflex to titer, aquaporin 4 (NMO) with reflex to CBA then titer, CRMP5/CV2, GAD65, PCA1 (Yo), PCA2 with reflex to titer, PCA-Tr (DNER). Also includes reflex to VGKC antibody, line blot panel, or CBA IFA panel. Line blot panel includes 8 antibodies: AGNA/SOX1, amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CRMP5/CV2, GAD65, PCA1, and PCA-Tr (DNER). CBA IFA panel includes AMPAR1/2, CASPR2, GABABR, LGI1, NMDAR and reflexes to individual titers for antibodies b,c Autoimmune Neurology Antibody Comprehensive Panel with Reflexes, Serum Includes IFA panel, CBA IFA panel, line blot panel, and tests for individual antibodies. IFA panel includes antibodies for the following: AGNA/ SOX1, AMPAR, amphiphysin, ANNA1 (Hu), ANNA2 (Ri), ANNA3, aquaporin 4 (NMO), CRMP5/CV2, GABABR, GAD65, LGI1, Ma2/Ta, myelin, NMDAR, PCA1, PCA2, and PCA-Tr (DNER). CBA IFA panel includes antibodies for AMPAR1/2, CASPR2, GABABR, LGI1, and NMDAR. Line blot panel includes AGNA/SOX1, amphiphysin, ANNA1 (Hu), ANNA2 (Ri), CRMP5/CV2, GAD65, PCA1 (Yo), PCA2, PCA-Tr (DNER), recoverin, titin, and Zic4. Tests for individual antibodies include the following: DPPX, striated muscle with reflex to titer, AChR binding antibody, gachr, VGCC (N-type), VGCC (P/Q-type), and VGKC. Also includes reflex tests to AChR blocking antibody, AChR modulating antibody, aquaporin 4 antibody, PCA-Tr (DNER), and MAG antibody (Western blot) with reflexes to MAG-SGPG and MAG (EIA) a Recombx MaTa Autoantibody Test Includes Ma and Ta antibodies a SensoriMotor Neuropathy Profile with Recombx Complete Includes ANNA1 (Hu), asialo-gm1, GALOP IgM, GD1a, GD1b, GM1, MAG, SGPG, and sulfatide antibodies b,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 atypical P-ANCA titer; cryoglobulin screen with reflex to % cryoglobulin (cryocrit) and cryoglobulin immunofixation and immunodiffusion; ganglioside asialo- GM-1 IgG and IgM; ganglioside GD1a IgG and IgM; ganglioside GD1b IgG and IgM; ganglioside GM-1 IgG and IgM; ganglioside GQ1b IgG; Hu antibody screen with reflex to Wstern blot with reflex to titer; IgA level with reflex to tissue transglutaminase IgG; IgG level; IgM level; immunofixation; MAG IgM antibody (Western blot) with reflexes to MAG-SGPG IgM and MAG IgM (EIA); myeloperoxidase, proteinase-3, rheumatoid factor, SS-A, and SS-B antibodies; and tissue transglutaminase IgA with reflexes to endomysial antibody and titer. (Continued)

17 APPENDIX (Continued) Laboratory Tests for Paraneoplastic Neurological Syndrome Diagnosis and Identification of Related Tumors (for associated clinical use, refer to Table 3 and information in the Test Interpretation section) Test Code Test Name b,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 atypical P-ANCA titer; cryoglobulin screen with reflex to % cryoglobulin (cryocrit) and cryoglobulin immunofixation and immunodiffusion; ganglioside GD1b IgG and IgM; ganglioside GQ1b IgG; Hu antibody screen with reflex to Western blot with reflex to titer; IgA level with reflex to tissue transglutaminase IgG; IgG level; IgM level; immunofixation; MAG IgM antibody (Western blot) with reflexes to MAG-SGPG IgM and MAG IgM (EIA); myeloperoxidase antibody; proteinase-3 antibody; rheumatoid factor; SS-A and SS-B antibodies; and tissue transglutaminase IgA with reflexes to endomysial antibody and titer. a This test was developed and its analytical performance characteristics have been determined by Athena Diagnostics. It has not been cleared or approved by the FDA. This assay has been validated pursuant to the CLIA regulations and is used for clinical purposes. b Reflex tests are performed at an additional charge and are associated with additional CPT codes. c This test was developed and its performance characteristics have been determined by Quest Diagnostics. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. Performance characteristics refer to the analytical performance of the test. d This test was developed and its analytical performance characteristics have been determined by Quest Diagnostics. It has not been cleared or approved by the U.S. Food and Drug Administration. The assay has been validated pursuant to the CLIA regulations and is used for clinical purposes. e This test was performed using a kit that has not been approved or cleared by the FDA. The analytical performance characteristics of this test have been determined by Quest Diagnostics. This test should not be used for diagnosis without confirmation by other medically established means. f Refer to the Athena Diagnostics website ( for test information. This test is performed by Athena Diagnostics. References 1. Didelot A, Honnorat J. Update on paraneoplastic neurological syndromes. Curr Opin Oncol. 2009;21: Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2010;85: Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004;75: Titulaer MJ, Soffietti R, Dalmau J, et al. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol. 2011;18:19-e Dreessen J, Jeanjean AP, Sindic CJ. Paraneoplastic limbic encephalitis: diagnostic relevance of CSF analysis and total body PET scanning. 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Paraneoplastic myasthenia gravis: detection of anti-mgt30 (titin) antibodies predicts thymic epithelial tumor. Neurology. 1997;49: Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan s syndrome and acquired neuromyotonia. Brain. 2010;133: Nobile-Orazio E, Manfredini E, Carpo M, et al. Frequency and clinical correlates of anti-neural IgM antibodies in neuropathy associated with IgM monoclonal gammopathy. Ann Neurol. 1994;36: Graus F, Keime-Guibert F, Rene R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain. 2001;124: Graus F, Vincent A, Pozo-Rosich P, et al. Anti-glial nuclear antibody: marker of lung cancer-related paraneoplastic neurological syndromes. J Neuroimmunol. 2005;165: Hoftberger R, van Sonderen A, Leypoldt F, et al. Encephalitis and AMPA receptor antibodies: Novel findings in a case series of 22 patients. Neurology. 2015;84: McKeon A, Lennon VA, Lachance DH, et al. Ganglionic acetylcholine receptor autoantibody: oncological, neurological, and serological accompaniments. Arch Neurol. 2009;66: