N-type Voltage-gated Calcium Channel Antibodies Research Articles

Initial screening for neuronal autoantibodies and their putative impact on survival in patients with small-cell lung cancer.

Small-cell lung cancer (SCLC) may be associated with neuronal autoantibodies and paraneoplastic neurological syndromes. It has been suggested that neuronal autoantibodies, especially antineuronal nuclear antibody type 1 (Hu) autoantibodies, are associated with longer survival of patients with SCLC. The objective of this study was to determine the frequency and distribution of neuronal autoantibodies at the time of diagnosis of SCLC patients and assess survival rates in relation to autoimmunity. In this retrospective study, serum from 40 patients with biopsy-proven SCLC at the time of diagnosis was studied prior to treatment. The sera originated from a cancer registry at the Oncology Department, Vejle Hospital from 2007 to 2010. The sera were analyzed blindly to clinical status for the presence of neuronal autoantibodies. Medical records were reviewed for neurological symptoms. Neuronal autoantibodies were detected in 22/40 (55%) of the SCLC patients. A broad range of neurological symptoms was recorded in 28/40 (70%) patients, of which 14/28 (50%) were positive for neuronal autoantibodies. The most frequently detected autoantibodies were Hu (7/40, 17.5%) followed by GAD65 (6/22, 15.0%). Striational and P/Q- or N-type voltage-gated calcium channel antibodies were less common, with each found in five patients (12.5%). Eight patients (20%) had coexisting autoantibodies. Autoantibody-positivity was not associated with survival. Neuronal autoantibodies were at time of diagnosis found in approximately half of the treatment-naïve SCLC patients. Neither autoantibody positivity at diagnosis nor neurological manifestations correlated with survival and their clinical importance requires further studies in larger, prospective cohorts.

Testing for N-type Voltage Gated Calcium Channel Antibody has Limited Utility in Evaluating Patients With Suspected Lambert-Eaton Myasthenic Syndrome

Objective To determine if testing for N-type voltage-gated calcium channel antibody improves diagnostic performance of serological testing for Lambert-Eaton Myasthenic Syndrome. Background Patients with suspected autoimmune neuromuscular junction transmission disorders are commonly tested for both P/Q-type (VGCC-P/Q) and N-type (VGCC-N) voltage-gated calcium channel antibodies to aid the diagnosis of Lambert-Eaton Myasthenic Syndrome (LEMS). Design/Methods This retrospective cross-sectional study included 93 patients diagnosed at Mayo Clinic with LEMS based on electrodiagnostic findings, clinical presentation and positive serology for VGCC-P/Q and/or VGCC-N. Results Forty-five patients (48.4%) were female, of median age 61 years (range 11- 99). Twenty-five (26.9%) were positive for both VGCC antibody types (reference interval <0.04 nmol/L [VGCC-N] and <0.03 nmol/L [VGCC-P/Q]); 67 (72.0%) were positive for VGCC-P/Q only and one (1.1%) was positive for VGCC-N only. The single VGCC-N positive only result [VGCC-N = 0.10 nmol/L; VGCC-PQ = 0.02 nmol/L] was from a patient with classic LEMS presentation and no evidence of malignancy by Chest CT. The prevalence of VGCC-N only positivity was lower than in the healthy population or other disease control populations. VGCC-P/Q antibody titers were higher in patients who had detectable co-existing VGCC-N antibody (median titer 1.58 versus 0.39 nmol/L, P = 0.02) and there was a positive correlation (r = 0.762, P < 0.001) between VGCC-N and VGCC-P/Q titers in double positive cases. Dual positivity did not significantly increase the likelihood of an underlying cancer (40.9% versus 30.1%, P = 0.33). Conclusions Testing for VGCC-P/Q antibodies alone is sufficient in the serological evaluation of suspected LEMS cases. Inclusion of VGCC-N antibody testing does not improve diagnostic performance. A positive VGCC-N antibody did not significantly increase the risk of paraneoplastic LEMS.

Performance evaluation of a radioimmunoprecipitation assay for the detection of N-type voltage-gated calcium channel antibodies

BackgroundIn this study, we assessed the performance characteristics of a laboratory-developed radioimmunoassay (RIA) to detect N-type voltage-gated calcium channel (N-VGCC) antibodies found in several autoimmune neurologic diseases. MethodsFour hundred and forty-five (n = 445) sera were evaluated, including 156 sera (50 positive and 106 negative for N-VGCC antibodies) previously tested at Mayo Clinic Laboratories (MCL) and 289 controls (n = 187 disease and n = 102 healthy). Specimens were analyzed with the RIA using N-VGCC labeled with 125I-ω-conotoxin GVIA. The RIA was compared to the predicate MCL assay using a tiered positive predictive value (PPV) approach. Other performance characteristics evaluated included specificity, precision, interference, and stability. ResultsQualitative inter-laboratory agreement based on tiered PPVs was 100% for results >1.00 nmol/L (71% PPV), 48% for results of 0.10–0.99 nmol/L (24% PPV) and 22% for results of 0.04–0.10 nmol/L (19% PPV). Negative results showed 90% agreement (n = 106). Specificity in controls positive for other neural autoantibodies and healthy controls were 87% and 100%, respectively. Acceptable results were observed for other performance characteristics. ConclusionsInter-laboratory correlations demonstrate equivalence between assays with some discrepancies between low positive results. Collaborative efforts aimed at assessing the clinical spectrum associated with these antibodies and consensus for harmonizing test performance are required for optimal categorization of patients.

Performance Evaluation of a Radioimmunoprecipitation Assay for the Detection of N-Type Voltage-gated Calcium Channel Antibodies in Patient and Control Groups (4968)

Performance Evaluation of a Radioimmunoprecipitation Assay for the Detection of N-Type Voltage-gated Calcium Channel Antibodies in Patient and Control Groups (4968)

Clinical Features of Neuromuscular Disorders in Patients with N-Type Voltage-Gated Calcium Channel Antibodies.

Neuromuscular junction disorders affect the pre- or postsynaptic nerve to muscle transmission due to autoimmune antibodies. Members of the group like myasthenia gravis and Lambert-Eaton syndrome have pathophysiologically distinct characteristics. However, in practice, distinction may be difficult. We present a series of three patients with a myasthenic syndrome, dropped-head syndrome, bulbar and respiratory muscle weakness and positive testing for anti-N-type voltage-gated calcium channel antibodies. In two cases anti-acetylcholin receptor antibodies were elevated, anti-P/Q-type voltage-gated calcium channel antibodies were negative. All patients initially responded to pyridostigmine with a non-response in the course of the disease. While one patient recovered well after treatment with intravenous immunoglobulins, 3,4-diaminopyridine, steroids and later on immunosuppression with mycophenolate mofetil, a second died after restriction of treatment due to unfavorable cancer diagnosis, the third patient declined treatment. Although new antibodies causing neuromuscular disorders were discovered, clinical distinction has not yet been made. Our patients showed features of pre- and postsynaptic myasthenic syndrome as well as severe dropped-head syndrome and bulbar and axial muscle weakness, but only anti-N-type voltage-gated calcium channel antibodies were positive. When administered, one patient benefited from 3,4-diaminopyridine. We suggest that this overlap-syndrome should be considered especially in patients with assumed seronegative myasthenia gravis and lack of improvement under standard therapy.

N-type calcium channel antibody-mediated autoimmune encephalitis: An unlikely cause of a common presentation.

We report, to our knowledge, the only known pediatric case with encephalopathy and significantly elevated titers of N-type voltage-gated calcium channel antibody (N-type VGCC). The patient, an 8th grader, was previously healthy and presented with a one-week history of confusion, aphasia, transient fever, headaches, and dizziness. An underlying autoimmune process was suspected because of inflammatory changes in the brain MRI and multiple focal electrographic seizures captured in the EEG in the absence of CSF pleocytosis. Within 24 h of presentation, the patient was empirically started on immune-modulatory therapy, and a full recovery was achieved within 3 months of the initial presentation. Immune therapy included high-dose intravenous (IV) methylprednisolone followed by a 2-week course of dexamethasone and 2 monthly courses of IV immunoglobulin (IVIG). He was also treated with anticonvulsants for one month. No tumor has been found to date. There is a paucity of reports on autoimmune epilepsy or encephalopathy associated with N-type VGCC. Complete resolution of brain lesion, seizure freedom, and full recovery of function following early and aggressive immunotherapy demonstrate that a high index of suspicion is crucial for early recognition and treatment of autoimmune encephalitis.

Paraneoplastic neurological syndromes associated with gastric cancer: a case report and review of the literature.

Paraneoplastic neurological syndromes (PNS) are associated with small-cell lung cancer, breast and gynecological cancers. We describe a gastric neoplasm presented with neurological symptoms. A 74-year-old male presented with tonic-clonic seizures. Initial investigations were normal; however, brain magnetic resonance imaging showed abnormal signal intensity in the hippocampi. A diagnosis of PNS was suspected. The patient was then diagnosed with a gastric neuroendocrine carcinoma with N-type voltage-gated calcium channel antibodies. The neurological impairments improved after the primary was resected and the patient remains free of cancer and paraneoplastic syndrome. We reviewed 10 cases of PNS associated with gastric cancer and found several characteristics: (1) older men, (2) neuroendocrine component or predominance, (3) oncological outcome for patients with PNS is better than for patients without PNS, and (4) neurological impairment is diagnosed 6months prior to the diagnosis of gastric malignancy. In conclusion, elderly men with symptoms suggestive of PNS should be investigated for a gastric neuroendocrine malignancy.

VGCC antibody-positive paraneoplastic cerebellar degeneration presenting with positioning vertigo

A 70-year-old woman developed paraneoplastic cerebellar degeneration (PCD) due to P/Q-type and N-type voltage-gated calcium channel antibodies and small cell lung cancer, the main clinical manifestations of which were severe positioning vertigo and vomiting. Loss of the visual suppression of caloric nystagmus, spontaneous downbeat nystagmus, periodic alternating nystagmus, and positioning vertigo in our patient most probably corresponds to the cerebellar flocculus/paraflocculus lesion caused by PCD.

Paraneoplastic limbic encephalitis presenting as a neurological emergency: a case report

IntroductionParaneoplastic limbic encephalitis remains a challenging clinical diagnosis with poor outcome if it is not recognized and treated early in the course of the disease.Case PresentationA 65-year-old Caucasian woman presented with generalized tonic-clonic seizures and increasing confusion shortly after a lung biopsy that led to the diagnosis of small-cell lung cancer. She had a complicated hospital course, and had recurrent respiratory distress due to aspiration pneumonia, and fluctuating mental status and seizures that were refractory to anti-epileptic drug treatment. Routine laboratory testing, magnetic resonance imaging of the brain, electroencephalogram, lumbar puncture, serum and cerebrospinal fluid tests for paraneoplastic antibodies, and chest computed tomography were performed on our patient. The diagnosis was paraneoplastic limbic encephalitis in the setting of small-cell lung cancer with positive N-type voltage-gated calcium channel antibody titer. Anti-epileptic drugs for seizures, chemotherapy for small-cell lung cancer, and intravenous immunoglobulin and steroids for paraneoplastic limbic encephalitis led to a resolution of her seizures and improved her mental status.ConclusionEarly recognition of paraneoplastic limbic encephalitis and prompt intervention with immune therapies at the onset of presentation will probably translate into more favorable neurological outcomes.

MG and LEMS overlap syndrome: case report with electrophysiological and immunological evidence

Objective: To report the clinical, electrophysiological, and immunological findings in one patient with MG and LEMS overlap syndrome (myasthenia gravis and Lambert-Eaton myasthenic syndrome). Methods: Evaluation of clinical, electrophysiological, and immunological findings in one patient with this disease. Results: A female patient with pernicious anemia had clinical findings of ptosis, diplopia, proximal leg weakness, areflexia and a positive edrophonium test as well as the classic patterns initially of MG and later of LEMS on successive repetitive nerve stimulation (RNS) tests. Immunologically she demonstrated positive acetylcholine receptor antibody (ACh-ab) and positive N-type voltage-gated calcium-channel antibody (VGCC-ab) titers. Conclusions: Among five reported cases combining the features of MG and LEMS and having positive AChR- and VGCC-ab titers, our patient provides the most convincing clinical, electrophysiological, and immunological evidence for the existence of MG and LEMS overlap syndrome. Significance: MG and LEMS overlap syndrome is a distinct entity.

Antibodies against the calcium channel beta-subunit in Lambert-Eaton myasthenic syndrome.

The sera of patients with Lambert-Eaton myasthenic syndrome (LEMS) contain autoantibodies against several extracellular and intracellular components of the voltage-gated calcium channel (VGCC)/synaptic vesicle release complex. An example of the latter are anti-beta-subunit antibodies (anti-MysB antibodies). We constructed a full-length cDNA clone of a human VGCC beta-subunit to produce purified beta-subunit fusion protein (MysB protein). Using this protein, we demonstrated that anti-beta-subunit antibodies are present in the sera of 23% of LEMS patients and only, in low titer, in 2% of small cell lung cancer patients without LEMS. The presence of anti-beta-subunit antibodies was closely associated with high titers of P/Q- and N-type VGCC antibodies. Immunization of rats with the purified MysB protein induced high antibody titers, but no signs of neurologic dysfunction were found. We conclude that anti-beta-subunit antibodies are not likely to interfere with ion channel function, but their presence could explain the cross-reactivity of LEMS sera with several subtypes of VGCCs and the lack of correlation between anti-VGCC antibody titer and clinical severity of disease.