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Lung cancer prediction in Lambert-Eaton myasthenic syndrome in a prospective cohort.

ABSTRACT: 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?

SUBMITTER: Maddison P

PROVIDER: S-EPMC7324357 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Lung cancer prediction in Lambert-Eaton myasthenic syndrome in a prospective cohort.

Maddison Paul P Lipka Alexander F AF Gozzard Paul P Sadalage Girija G Ambrose Philip A PA Lang Bethan B Verschuuren Jan J JJ

Scientific reports 20200629 1

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 ons ...[more]

PMID: 32601396

Similar Datasets

Adenocarcinoma of Lung Presenting as Lambert-Eaton Myasthenic Syndrome.

Project description:Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic neuromuscular junction disorder. LEMS presents with muscular weakness and fatigability, mainly involving the proximal lower limbs. There are 2 types of LEMS depending on the etiology: paraneoplastic and idiopathic. The paraneoplastic form, which constitutes more than a half of the cases, is mostly associated with intrathoracic neoplasms. Most cases are seen in patients with small cell lung cancer; other subtypes of lung cancer are extremely rare. In this article, we report a case of LEMS as a rare association with adenocarcinoma of the lung.

| S-EPMC5521354 | biostudies-other

Long-term follow-up, quality of life, and survival of patients with Lambert-Eaton myasthenic syndrome.

Project description:ObjectiveTo study survival and to characterize long-term functional impairments and health-related quality of life (HRQOL) of patients with Lambert-Eaton myasthenic syndrome (LEMS).MethodsIn this observational study, survival of patients with LEMS, separately for nontumor (NT) and small cell lung cancer (SCLC), was compared to that of the Dutch general population and patients with SCLC. Disease course in patients with LEMS was recorded retrospectively. Several scales for functional impairments and health-related quality of life were assessed.ResultsWe included 150 patients with LEMS. Survival was similar to that of the general population in 65 patients with NT-LEMS. Tumor survival was significantly longer in 81 patients with SCLC-LEMS compared to patients with non-LEMS SCLC (overall median survival 17 vs 7.0 months, p < 0.0001). At diagnosis, 39 (62%) of 63 patients with complete follow-up data were independent for activities of daily living, improving to 85% at the 1-year follow-up. The physical HRQOL composite score (55.9) was significantly lower than in the general population (76.3, p < 0.0001) and comparable to that of patients with myasthenia gravis (60.5). The mental HRQOL composite score was 71.8 in patients with LEMS, comparable to that of the general population (77.9, p = 0.19) and patients with myasthenia gravis (70.3).ConclusionsThis study shows that patients with NT-LEMS have normal survival. Patients with SCLC-LEMS have an improved tumor survival, even after correction for tumor stage. A majority of patients with LEMS report a stable disease course and remain or become independent for self-care after treatment.

| S-EPMC7080283 | biostudies-literature

Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy.

Project description:Synaptotagmin 2 is a synaptic vesicle protein that functions as a calcium sensor for neurotransmission but has not been previously associated with human disease. Via whole-exome sequencing, we identified heterozygous missense mutations in the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two multigenerational families presenting with peripheral motor neuron syndromes. An essential calcium-binding aspartate residue, Asp307Ala, was disrupted by a c.920A>C change in one family that presented with an autosomal-dominant presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome. A c.923C>T variant affecting an adjacent residue (p.Pro308Leu) produced a presynaptic neuromuscular junction defect and a dominant hereditary motor neuropathy in a second family. Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis using this transgenic model. These findings indicate that Synaptotagmin 2 regulates neurotransmitter release at human peripheral motor nerve terminals. In addition, mutations in the Synaptotagmin 2 C2B domain represent an important cause of presynaptic congenital myasthenic syndromes and link them with hereditary motor axonopathies.

| S-EPMC4157148 | biostudies-literature

Lowering the cutoff value for increment increases the sensitivity for the diagnosis of Lambert-Eaton myasthenic syndrome.

Project description:BACKGROUND:Increment of compound muscle action potential amplitude is a diagnostic hallmark of Lambert-Eaton myasthenic syndrome (LEMS). Making a diagnosis can be challenging, therefore, a proper cutoff for abnormal increment is highly relevant for improved recognition of this rare disease. METHODS:We determined the sensitivity and specificity of 60% and 100% cutoff values in all consecutive patients who underwent increment testing in our hospital from 1999 to 2016. RESULTS:We included 156 patients, 63 with LEMS and 93 without LEMS. Sensitivity of a 60% cutoff for increment testing was 77.8% (95% confidence interval 65.5%-87.3%) and 58.7% (45.6%-71.0%) for 100%. Specificity was 98.9% (94.2%-100%) and 100% (96.1%-100%) using a threshold of 60% and 100%, respectively. CONCLUSIONS:Lowering the cutoff value for abnormal increment to 60% greatly increases sensitivity to diagnose LEMS without an overt loss in specificity.

| S-EPMC7318278 | biostudies-literature

Lambert-Eaton syndrome IgG inhibits transmitter release via P/Q Ca2+ channels.

Project description:ObjectiveTo 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).MethodsIgG 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.ResultsLEMS 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.ConclusionsThese data provide direct evidence that LEMS IgG inhibits neurotransmitter release by acting on P/Q-type VGCCs.

| S-EPMC4335987 | biostudies-literature

3,4-diaminopyridine base effectively treats the weakness of Lambert-Eaton myasthenia.

Project description:INTRODUCTION:3,4-diaminopyridine has been used to treat Lambert-Eaton myasthenia (LEM) for 30 years despite the lack of conclusive evidence of efficacy. METHODS:We conducted a randomized double-blind placebo-controlled withdrawal study in patients with LEM who had been on stable regimens of 3,4-diaminopyridine base (3,4-DAP) for???3 months. The primary efficacy endpoint was >30% deterioration in triple timed up-and-go (3TUG) times during tapered drug withdrawal. The secondary endpoint was self-assessment of LEM-related weakness (W-SAS). RESULTS:Thirty-two participants were randomized to continuous 3,4-DAP or placebo groups. None of the 14 participants who received continuous 3,4-DAP had?>?30% deterioration in 3TUG time versus 72% of the 18 who tapered to placebo (P?<?0.0001). W-SAS similarly demonstrated an advantage for continuous treatment over placebo (P?<?0.0001). Requirement for rescue and adverse events were more common in the placebo group. DISCUSSION:This trial provides significant evidence of efficacy of 3,4-DAP in the maintenance of strength in LEM. Muscle Nerve 57: 561-568, 2018.

| S-EPMC5900968 | biostudies-literature

Validation of the triple timed up-and-go test in Lambert-Eaton myasthenia.

Project description:INTRODUCTION:There are no validated, practical, and quantitative measures of disease severity in Lambert-Eaton myasthenia (LEM). METHODS:Data from the Effectiveness of 3,4-Diaminopyridine in Lambert-Eaton Myasthenic Syndrome (DAPPER) trial were analyzed to assess triple timed up-and-go (3TUG) reproducibility and relationships between 3TUG times and other measures of LEM severity. RESULTS:The coverage probability technique showed ?0.90 probability for an acceptable 3TUG difference of ?0.2, indicating that it is reproducible in LEM patients. The correlation between 3TUG times and lower extremity function scores was significant in subjects who continued and in those who were withdrawn from 3,4-diaminopyridine free base. Worsening patient-reported Weakness Self-Assessment Scale and Investigator Assessment of Treatment Effect scores corresponded with prolongation of 3TUG times. DISCUSSION:The 3TUG is reproducible, demonstrates construct validity for assessment of lower extremity function in LEM patients, and correlates with changes in patient and physician assessments. These findings, along with prior reliability studies, indicate 3TUG is a valid measure of disease severity in LEM.

| S-EPMC7357813 | biostudies-literature

Population Pharmacokinetics/Pharmacodynamics of 3,4-Diaminopyridine Free Base in Patients With Lambert-Eaton Myasthenia.

Project description:Lambert-Eaton myasthenia (LEM) is a rare autoimmune disorder associated with debilitating muscle weakness. There are limited treatment options and 3,4-diaminopyridine (3,4-DAP) free base is an investigational orphan drug used to treat LEM-related weakness. We performed a population pharmacokinetic/pharmacodynamic (PK/PD) analysis using 3,4-DAP and metabolite concentrations collected from a phase II study in patients with LEM. The Triple Timed Up & Go (3TUG) assessment, which measures lower extremity weakness, was the primary outcome measure. A total of 1,270 PK samples (49 patients) and 1,091 3TUG data points (32 randomized patients) were included in the PK/PD analysis. A two-compartment and one-compartment model for parent and metabolite, respectively, described the PK data well. Body weight and serum creatinine partially explained the variability in clearance for the final PK model. A fractional inhibitory maximum effect (Emax ) model characterized the exposure-response relationship well. The PK/PD model was applied to identify a suggested dosing approach for 3,4-DAP free base.

| S-EPMC5613184 | biostudies-literature

Lung cancer prediction

Project description:We generated a blood-derived transcriptional signature that discriminates patients with lung cancer from non-affected smokers. When applied to blood samples from one of the largest prospective population-based cancer studies (the European Prospective Investigation into Cancer and Nutrition), this signature accurately predicted the occurrence of lung cancer in smokers within two years before the onset of clinical symptoms. Such a blood test could be used as a screening tool to enable early diagnosis of lung cancer at a curable stage. All samples were taken from smokers. EPIC cases were taken from the EPIC trial (a large prospective epidemiological trial in Europe, and are incident cases), Cosmos and BC cases are prevalent cases from a Cologne, Germany based epidemiological trial.

2010-02-28 | E-GEOD-12771 | biostudies-arrayexpress

Myasthenic syndrome caused by plectinopathy.

Project description:Plectin crosslinks intermediate filaments to their targets in different tissues. Defects in plectin cause epidermolysis bullosa simplex (EBS), muscular dystrophy (MD), and sometimes pyloric atresia. Association of EBS with a myasthenic syndrome (MyS) was documented in a single patient in 1999.To analyze the clinical, structural, and genetic aspects of a second and fatal case of EBS associated with a MyS and search for the genetic basis of the disease in a previously reported patient with EBS-MD-MyS.Clinical observations; histochemical, immunocytochemical, and electron microscopy studies of skeletal muscle and neuromuscular junction; and mutation analysis.An African American man had EBS since early infancy, and progressive muscle weakness, hyperCKemia, and myasthenic symptoms refractory to therapy since age 3 years. Eventually he became motionless and died at age 42 years. At age 15 years, he had a marked EMG decrement, and a reduced miniature endplate potential amplitude. The myopathy was associated with dislocated muscle fiber organelles, structurally abnormal nuclei, focal plasmalemmal defects, and focal calcium ingress into muscle fibers. The neuromuscular junctions showed destruction of the junctional folds, and remodeling. Mutation analysis demonstrated a known p.Arg2319X and a novel c.12043dupG mutation in PLEC1. The EBS-MD-MyS patient reported in 1999 also carried c.12043dupG and a novel p.Gln2057X mutation. The novel mutations were absent in 200 Caucasian and 100 African American subjects.The MyS in plectinopathy is attributed to destruction of the junctional folds and the myopathy to defective anchoring of muscle fiber organelles and defects in sarcolemmal integrity.

| S-EPMC3034415 | biostudies-literature

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