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To evaluate the Dutch-English Lambert-Eaton Myasthenic Syndrome (LEMS) Tumour Association Prediction (DELTA-P) score in a prospective cohort of patients with newly diagnosed LEMS to assess the clinical validity of this tool in a real-world setting. Clinical features from 87 patients with LEMS, occurring within three months from disease onset, were collated to produce a DELTA-P score for each patient. Lung cancer was detected in 44/87 (51%) LEMS patients. Weight loss ≥ 5%, tobacco use at LEMS onset and age at onset ≥ 50 years were independent predictors for the development of small-cell lung cancer (SCLC) in LEMS patients in multivariable analysis. Median DELTA-P scores were significantly higher in SCLC-LEMS patients (3.5, 95% CI 3 to 4) compared to non-tumour-LEMS (2, 95% CI 1 to 2) (P < 0.0001). Higher DELTA-P scores increased the risk of SCLC stepwise (score 0 = 0%, 1 = 18.8%, 2 = 45%, 3 = 55.5%, 4 = 85.7%, 5 = 87.5%, 6 = 100%). The area under the curve of the receiver operating curve was 82.5% (95% CI 73.9% to 91%). The DELTA-P cancer prediction score, calculated at the time of LEMS diagnosis, is an effective tool for cancer screening in an independent, prospective study setting.

Since approximately 50% of patients with Lambert-Eaton myasthenic syndrome (LEMS) subsequently develop small-cell lung cancer (SCLC), it is important to be able to predict cancer occurrence in these patients at neurological presentation. We aimed to determine whether circulating biomarkers were effective and objective predictors of cancer development in LEMS. We found that the presence of either SOX2, N-type voltage gated calcium channel or GABAb antibodies at LEMS diagnosis was highly sensitive (84%) and specific (87%) for the detection of SCLC. Screening for SOX2 and neuronal antibodies is a useful adjunct to clinical predictive scoring tools in predicting SCLC in LEMS., Competing Interests: Declaration of Competing Interest Bethan Lang is a co-applicant and receives royalties on patent application WO/2010/046716 entitled ‘Neurological Autoimmune Disorders’. The patent has been licensed to Euroimmun AG for the development of assays for LGI1 and other VGKC-complex antibodies., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Merkel cell carcinoma is a rare cutaneous, aggressive tumor. Although it shares many neuroendocrine features with small cell lung carcinoma, it has only occasionally been reported with paraneoplastic neurological syndromes., Methods: A healthy 67-year-old man developed acute ataxia, vertigo, and nausea. Subsequently he also developed dysarthria, diplopia, xerostomia, fatigability and progressive anorexia. He underwent a full diagnostic workup and was found to have a high titer of voltage-gated calcium channel antibodies in serum and cerebrospinal fluid, neurophysiological findings compatible with Lambert-Eaton myasthenia and neurological signs compatible with cerebellar degeneration., Results: A positron emission tomography study revealed a hypermetabolic lesion in the axilla, subsequently biopsied and consistent with Merkel cell carcinoma., Conclusions: In most previous reports, neurological symptoms preceded the Merkel cell carcinoma diagnosis, and the primary localization was in lymph nodes. This tumor should be considered in patients with paraneoplastic syndrome, and particularly Lambert-Eaton myasthenia after exclusion of small cell lung carcinoma. Muscle Nerve 56: 998-1000, 2017., (© 2016 Wiley Periodicals, Inc.)

Objective: To establish whether improved tumor survival in patients with Lambert-Eaton myasthenic syndrome (LEMS) and small-cell lung cancer (SCLC) was due to known prognostic risk factors or an effect of LEMS independently, perhaps as a result of circulating factors., Methods: We undertook a prospective observational cohort study of patients with LEMS attending Nottingham University Hospitals, UK, or via the British Neurological Surveillance Unit. In parallel, patients with a new diagnosis of biopsy-proven SCLC were enrolled, examined for neurologic illness, and followed up until death or study end., Results: Between May 2005 and November 2014, we recruited 31 patients with LEMS and SCLC and 279 patients with SCLC without neurologic illness. Allowing for known SCLC survival prognostic factors of disease extent, age, sex, performance status, and sodium values, multivariate Cox regression analysis showed that the presence of LEMS with SCLC conferred a significant survival advantage independently of the other prognostic variables (hazard ratio 1.756, 95% confidence interval 1.137-2.709, p = 0.011)., Conclusions: Improved SCLC tumor survival seen in patients with LEMS and SCLC may not be due solely to lead time bias, given that survival advantage remains after allowing for other prognostic factors and that the same degree of survival advantage is not seen in patients with paraneoplastic neurologic syndromes other than LEMS presenting before SCLC diagnosis., (© 2017 American Academy of Neurology.)

Objective: To determine whether immunoglobulin G (IgG) from patients with Lambert-Eaton myasthenic syndrome (LEMS) decreases action potential–evoked synaptic vesicle exocytosis,and whether the effect is mediated by P/Q-type voltage-gated calcium channels (VGCCs)., Methods: IgG was obtained from 4 patients with LEMS (3 males, 1 female), including 2 patients with lung malignancy. Antibodies against P/Q-type VGCCs were detected in all 4 patients, and against N-type VGCCs in 2. We incubated neuronal cultures with LEMS IgG and determined the size of the total recycling pool of synaptic vesicles and the rate of action potential–evoked exocytosis using fluorescence imaging of the amphiphilic dye SynaptoRed C1. Pooled IgG from healthy volunteers was used as a control. We repeated the experiments on synapses lacking P/Q-type calcium channels from a Cacna1a knockout mouse to determine whether these channels account for the pathogenic effect of LEMS IgG., Results: LEMS IgG had no effect on the total recycling pool size but significantly reduced the rate of action potential–evoked synaptic exocytosis in wild-type neurons when compared with neurons treated with control IgG. In contrast, LEMS IgG had no effect on the rate of synaptic vesicle exocytosis in neurons lacking P/Q-type channels., Conclusions: These data provide direct evidence that LEMS IgG inhibits neurotransmitter release by acting on P/Q-type VGCCs.

Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular autoimmune disease that has served as a model for autoimmunity and tumour immunology. In LEMS, the characteristic muscle weakness is thought to be caused by pathogenic autoantibodies directed against voltage-gated calcium channels (VGCC) present on the presynaptic nerve terminal. Half of patients with LEMS have an associated tumour, small-cell lung carcinoma (SCLC), which also expresses functional VGCC. Knowledge of this association led to the discovery of a wide range of paraneoplastic and non-tumour-related neurological disorders of the peripheral and central nervous systems. Detailed clinical studies have improved our diagnostic skills and knowledge of the pathophysiological mechanisms and association of LEMS with SCLC, and have helped with the development of a protocol for early tumour detection., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: Approximately one half of patients with Lambert-Eaton myasthenic syndrome (LEMS) have small-cell lung carcinomas (SCLC), aggressive tumors with poor prognosis. In view of its profound impact on therapy and survival, we developed and validated a score to identify the presence of SCLC early in the course of LEMS., Patients and Methods: We derived a prediction score for SCLC in LEMS in a nationwide cohort of 107 Dutch patients, and validated it in a similar cohort of 112 British patients. A Dutch-English LEMS Tumor Association Prediction (DELTA-P) score was developed based on multivariate logistic regression., Results: Age at onset, smoking behavior, weight loss, Karnofsky performance status, bulbar involvement, male sexual impotence, and the presence of Sry-like high-mobility group box protein 1 serum antibodies were independent predictors for SCLC in LEMS. A DELTA-P score was derived allocating 1 point for the presence of each of the following items at or within 3 months from onset: age at onset ≥ 50 years, smoking at diagnosis, weight loss ≥ 5%, bulbar involvement, erectile dysfunction, and Karnofsky performance status lower than 70. The area under the curve of the receiver operating curve was 94.4% in the derivation cohort and 94.6% in the validation set. A DELTA-P score of 0 or 1 corresponded to a 0% to 2.6% chance of SCLC, whereas scores of 4, 5, and 6 corresponded to chances of SCLC of 93.5%, 96.6%, and 100%, respectively., Conclusion: The simple clinical DELTA-P score discriminated patients with LEMS with and without SCLC with high accuracy early in the course of LEMS.

Paraneoplastic cerebellar degeneration may occur in association with Lambert-Eaton myasthenic syndrome (LEMS), but to our knowledge, the co-occurrence of paraneoplastic opsoclonus-myoclonus syndrome and LEMS has not been previously reported. A 67-year-old woman presented with a complex partial seizure and evolving ocular flutter, opsoclonus, myoclonus and 'cerebellar' signs, all of which improved spontaneously within 6 weeks. Approximately 8 weeks after symptom onset, the patient became encephalopathic, she had a further complex partial seizure, and she became areflexic with potentiation of deep tendon reflexes. Radiological, bronchoscopic and histological investigations revealed small-cell lung cancer, and neurophysiological investigations confirmed a diagnosis of LEMS. High-titre anti-P/Q-type voltage-gated calcium-channel antibodies were identified in the serum, which increased as the signs of opsoclonus and myoclonus resolved. The encephalopathy and clinical features of LEMS responded dramatically to chemotherapy and radiotherapy. Spontaneous improvement of paraneoplastic opsoclonus-myoclonus syndrome may occur, and this syndrome may occur in association with LEMS. Antivoltage-gated calcium-channel antibodies are not implicated in the pathogenesis of paraneoplastic opsoclonus-myoclonus syndrome.

Introduction: The Lambert Eaton myasthenic syndrome (LEMS) is a paraneoplastic disorder associated with raised serum voltage-gated calcium channel (VGCC) antibodies in patients with small cell lung cancer (SCLC). VGCC can also be found in patients with SCLC and cerebellar ataxia. This was a prospective study to assess the incidence of clinical and subclinical LEMS or other neurologic disease in patients with SCLC., Patients and Methods: Sixty-three unselected patients with cytologically or histologically confirmed SCLC consented to participate. Pretreatment assessment included a neurologic symptom questionnaire, examination for physical signs of LEMS or ataxia, measurement of serum titers of antibodies to P/Q-type VGCCs by radioimmunoassay in all patients and electrophysiological examination where appropriate., Results: Neurologic symptoms unrelated to LEMS occurred in 26% of patients. Five patients (8%) had raised serum VGCC antibodies (range, 69-1553 pM/l) diagnostic of LEMS, two (3%) of whom had LEMS on clinical and electrophysiological grounds. Both also had mild cerebellar ataxia. There was no association between serum VGCC antibody titer and survival., Conclusion: Routine measurement of VGCC antibodies in patients without clinical LEMS is unlikely to assist either in management of SCLC or in assessment of prognosis.

Lambert-Eaton myasthenic syndrome (LEMS) is an immune-mediated disorder of the neuromuscular junction that rarely is associated with cerebellar ataxia (CA). We describe two patients with non-paraneoplastic LEMS associated with CA who showed high levels of anti-P/Q-type voltage-gated calcium channels antibodies in the serum and cerebrospinal fluid, and reduced CMAP with increment after brief maximum voluntary contraction in electrophysiological studies. We suggest that LEMS should be considered in the differential diagnosis of patients with CA.

To assess the survival impact of the presence of P/Q-type calcium channel antibodies in patients with small cell lung carcinoma (SCLC), we examined the frequency of the antibodies and Lambert-Eaton myasthenic syndrome (LEMS) in 148 consecutive patients with SCLC, and in 30 patients with paraneoplastic cerebellar degeneration and SCLC, and studied their relation with survival. In both series, only patients with LEMS had a remarkably long survival, whereas presence of the antibodies without LEMS did not result in a better prognosis.

Patients with small cell lung cancer (SCLC) survive longer if they have the antibody-mediated Lambert-Eaton myasthenic syndrome (LEMS), making this autoimmune disorder a prototype disease for studying cancer immunosurveillance. Patients with nontumor LEMS (NT-LEMS) never develop SCLC but are otherwise indistinguishable clinically. Therefore, we have compared immunogenetic factors in SCLC-LEMS and NT-LEMS and studied their role in the pathogenesis of LEMS and survival from SCLC. In 48 British and 29 Dutch Caucasian LEMS patients, we studied clinical symptoms, antibody titers, HLA types and alleles at six nearby located microsatellite loci. Highly significant associations were found in NT-LEMS, which appeared strongest with HLA-B8, but also involved HLA-DQ2, -DR3 and six flanking microsatellite alleles. SCLC-LEMS patients were not different from controls. Smoking was a strong predictor of SCLC. In contrast, HLA-B8 positivity correlated with a decreased risk of SCLC even among the smokers. Moreover, in SCLC-LEMS patients, HLA-B8 positivity correlated with prolonged survival after LEMS onset. We propose that two distinct immunopathogenetic routes can lead to one clinically and serologically indistinguishable autoimmune myasthenic syndrome. HLA-DR3-B8 is strongly associated with LEMS in nontumor patients only. In other LEMS patients, SCLC apparently provides a powerful autoimmunogenic stimulus that overrides HLA restrictions in breaking tolerance to calcium channels. Moreover, negativity for HLA-B8 combined with smoking behavior points more strongly to an underlying SCLC and predicts a worse prognosis in SCLC-LEMS patients.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular transmission in which antibodies are directed against voltage-gated calcium channels (VGCCs). We studied the action of LEMS immunoglobulin G (IgG) on cloned human VGCCs stably transfected into human embryonic kidney cells (HEK293). All LEMS IgGs tested bound to the surface of the P/Q-type VGCC cell line and caused a significant reduction in whole-cell calcium currents in these cells. By contrast, only 2 out of 6 IgGs bound extracellularly to the N-type VGCC cell line, and none of the LEMS IgGs tested was able to reduce whole-cell calcium currents in these cells. We used this apparent specificity of LEMS IgG for the P/Q-type VGCC to investigate the action of these IgGs on model systems where a number of different VGCC populations exist in equilibrium. LEMS IgG caused a significant downregulation in the omega-agatoxin IVA-sensitive P/Q-type VGCCs of cultured rat cerebellar neurons, but this was accompanied by a concomitant rise in the "resistant" R-type VGCCs. By using the passive transfer model of LEMS, similar results were observed at the mouse neuromuscular junction, where a significant reduction in P/Q-type VGCCs was paralleled by an increase in L- and R-type VGCCs. These results demonstrate an unexpected plasticity in the expression of VGCCs in mammalian neurons and may represent a mechanism by which the pathogenic effects of LEMS IgG are reduced.

In the Lambert-Eaton myasthenic syndrome (LEMS), immunoglobulin G (IgG) autoantibodies to presynaptic voltage-gated calcium channels (VGCCs) at the neuromuscular junction lead to a reduction in nerve-evoked release of neurotransmitter and muscle weakness. We have examined the action of LEMS IgGs on cloned human VGCCs stably expressed in transfected human embryonic kidney (HEK293) cell lines: 10-13 (alpha(1A-2), alpha(2b)delta, beta(4a)) and C2D7 (alpha(1B-1), alpha(2b)delta, beta(1b)). All LEMS IgGs studied showed surface binding to [(125)I]-omega-CTx-MVIIC-labeled VGCCs in the alpha(1A) cell line and two of six IgGs showed surface binding to [(125)I]-omega-CTx-GVIA-labeled VGCCs in the alpha(1B) cell line. We next studied the effect of LEMS IgGs (2 mg/ml) on whole-cell calcium currents in the alpha(1A) and alpha(1B) cell lines. Overnight treatment of alpha(1A) (10-13) cells with LEMS IgGs led to a significant reduction in peak current density without alteration of the current-voltage relationship or the voltage dependence of steady-state inactivation. In contrast, LEMS IgGs did not reduce peak current density in the alpha(1B) cell line. Overall these data demonstrate the specificity of LEMS IgGs for the alpha(1A) cell line and suggest that LEMS IgGs bind to and downregulate VGCCs in this cell line. Although several LEMS IgGs can be shown to bind to the alpha(1B) (C2D7) cell line, no functional effects were seen on this channel., (Copyright 2002 Wiley Periodicals, Inc. Muscle Nerve 25: 000-000, 2002)

Abstract: The autoimmune disorder of Lambert–Eaton myasthenic syndrome (LEMS) associates with small cell lung carcinoma (SCLC) in 50–60% of cases. It has been postulated that patients who harbour paraneoplastic neurological syndromes such as LEMS have an improved tumour prognosis compared to other patients with the tumour but without neurological deficit. In this intermediate report of an ongoing prospective study, 100 consecutive patients with biopsy-proven SCLC underwent full neurological examination and serum was taken for autoantibody analysis. Antibodies to voltage-gated calcium channels were detected in 10 patients, however only 4 had clinical and electrophysiological features of LEMS, 1 had limbic encephalitis, whilst the remaining 5 had no neurological signs. A further 6 patients had onconeural antibodies; only one had a paraneoplastic syndrome, sensory neuropathy. The median survival of the four antibody positive LEMS patients (19.6 months) was considerably greater than that for the antibody negative (8.9 months) or antibody positive patients as a whole (10.5 months). Although preliminary, these results suggest that functionally effective antibodies present in the sera of patients with LEMS may confer a survival advantage. [Copyright &y& Elsevier]