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Myasthenia gravis and Lambert-Eaton myasthenic syndrome are antibody-mediated autoimmune diseases of the neuromuscular junction that usually present with weakness in ocular muscles and in proximal muscles of the limb and trunk. Prognosis regarding muscle strength, functional abilities, quality of life, and survival is generally good. However, some patients do not respond to treatment. Symptomatic drugs, corticosteroids, and steroid-sparing immunosuppressive drugs remain the cornerstone of treatment. In the past few years, new biological agents against complement, the FcRn receptor, or B-cell antigens have been tested in clinical trials. These new therapies extend the possibilities for targeted immunotherapies and promise exciting new options with a relatively rapid mode of action. Challenges in their use might occur, with barriers due to an increase in cost of care and additional considerations in the choice of drugs, and potential consequences of infection and vaccination due to the COVID-19 pandemic.

Autoimmune neuromuscular junction disorders are rare. However, myasthenia gravis is being increasingly recognised in people older than 50 years. In the past 5-10 years, epidemiological studies worldwide suggest an incidence of acetylcholine receptor antibody-positive myasthenia gravis of up to 29 cases per 1 million people per year. Muscle-specific tyrosine kinase antibody-positive myasthenia gravis and Lambert-Eaton myasthenic syndrome are about 20 times less common. Several diagnostic methods are available for autoimmune neuromuscular junction disorders, including serological antibody, electrophysiological, imaging, and pharmacological tests. The course of disease can be followed up with internationally accepted clinical scores or patient-reported outcome measures. For prognostic purposes, determining whether the disease is paraneoplastic is of great importance, as myasthenia gravis can be associated with thymoma and Lambert-Eaton myasthenic syndrome with small-cell lung cancer. However, despite well defined diagnostic parameters to classify patients into subgroups, objective biomarkers for use in the clinic or in clinical trials to predict the course of myasthenia gravis and Lambert-Eaton myasthenic syndrome are needed.

Clinical Practice Points • Immune checkpoint inhibitor (ICI) therapy could exacerbate preexisting active autoimmune diseases (AIDs), and the presence of preexisting AIDs might be associated with a greater risk of developing new immune-related adverse events (irAEs). • The safety of ICIs for patients with Lambert-Eaton myasthenic syndrome (LEMS), a neuromuscular autoimmune disease known as a paraneoplastic syndrome mainly associated with small-cell lung cancer (SCLC), is fully unknown. • We experienced an extensive-stage (ES)-SCLC patient with LEMS successfully treated with chemotherapy in combination with ICI without a flare-up of LEMS. • Phase III trials have shown that ICIs in combination with platinum doublet therapy significantly improved the overall survival of patients with ES-SCLC in first-line settings, therefore, patients diagnosed with ES-SCLC with the complication of LEMS have the widespread opportunity to receive ICIs as standard care. This report suggests that treatment using ICIs may be a treatment option to consider for ES-SCLC patients with LEMS.

Myasthenia gravis (MG) is a relatively rare neurological disease that is usually associated with antibodies to the acetylcholine receptor (AChR). These antibodies (Abs) cause loss of the AChRs from the neuromuscular junction (NMJ), resulting in muscle weakness that can be life-threatening. Another form of the disease is caused by antibodies to muscle specific kinase (MuSK) that result in impaired AChR clustering and numbers at the NMJ, and may also interfere with presynaptic adaptive mechanisms. Other autoimmune disorders, Lambert Eaton myasthenic syndrome and acquired neuromyotonia, are associated with antibodies to presynaptic voltage-gated calcium and potassium channels respectively. All four conditions can be diagnosed by specific clinical features, electromyography and serum antibody tests, and can be treated effectively by a combination of pharmacological approaches and procedures that reduce the levels of the IgG antibodies. They form the first of a spectrum of diseases in which serum autoantibodies bind to extracellular domains of neuronal proteins throughout the nervous system and lead to constellations of clinical features including paralysis, sensory disturbance and pain, memory loss, seizures, psychiatric disturbance and movement disorders. This review will briefly summarize the ways in which this field has developed, since the 1970s when considerable contributions were made in Ricardo Miledi's laboratory at UCL.

In order to describe the clinical characteristics, treatment response and long-term follow up in Lambert–Eaton myasthenic syndrome (LEMS) patients with and without small cell lung cancer (SCLC) in East China, patients seen in Huashan Hospital from January 1997 to December 2017 were included. Clinical information was collected retrospectively and quantitative MG (QMG) score, manual muscle testing (MMT), activities of daily living (ADL) scale were evaluated when the patients were followed up. Of 50 patients, 23 (46%) were SCLC-LEMS and 20 (40%) were nontumor LEMS (NT-LEMS). The median onset age was 55.5 (18–86) years old and the gender ratio was about 1.8:1. It took less time to make the diagnosis (median time: 6 vs 22.5 months, p = 0.0003) and there were more patients with other paraneoplastic syndromes in SCLC-LEMS group than in NT-LEMS group (8/23 vs 0/20, p = 0.0042). Electrophysiologically, the peroneal compound motor action potential (CMAP) of rest showed difference between SCLC-LEMS and NT-LEMS (0.8 vs 1.6 mV, p = 0.0499). The median survival time of 19 SCLC-LEMS patients since the diagnosis of SCLC was 30 months. According to their survival time, SCLC patients with LEMS showed a more favorable prognosis than those without LEMS. In the time of follow-up, most NT-LEMS showed improvement or obtained status of CSR/PR/MM after immunosuppressive therapy and no significant difference in proportion of achieving CSR/PR/MM was found between SCLC-LEMS and NT-LEMS patients (0/5 vs 6/13, p = 0.114).

Paraneoplastic syndromes involving the visual system are a heterogeneous group of disorders occurring in the setting of systemic malignancy. They are unrelated to local tumor invasion or metastasis and unexplained by nutritional, metabolic, infectious or iatrogenic causes. The presence of antibodies may aid in the diagnosis of a paraneoplastic syndrome, although this is not an absolute requirement. Chorioretinal involvement is seen in CAR (cancer-associated retinopathy) syndrome, MAR (melanoma-associated retinopathy) syndrome, paraneoplastic vitelliform maculopathy, and bilateral diffuse uveal melanocytic proliferation. Paraneoplastic neurological syndromes with ophthalmologic involvement include optic neuropathy, opsoclonus-myoclonus, Eaton-Lambert myasthenic syndrome, paraneoplastic cerebellar degeneration (PCD) and rhombencephalitis.

Lambert-Eaton myasthenic syndrome is a paraneoplastic or primary autoimmune neuromuscular junction disorder characterized by proximal weakness, autonomic dysfunction and ariflexia. The characteristic symptoms are thought to be caused by antibodies generated against the P/Q-type voltage-gated calcium channels present on presynaptic nerve terminals and by diminished release of acetylcholine. More than half of Lambert-Eaton myasthenic syndrome cases are associated with small cell lung carcinoma. Diagnosis is confirmed by serologic testing and electrophysiologic studies. 3,4-diaminopyridine is effective symptomatic treatment of LEMS.

Background Pharmaceutical compounding preparations, produced by (hospital) pharmacies, usually do not have marketing authorization. As a consequence, some of these pharmaceutical compounding preparations can be picked-up by a pharmaceutical company to obtain marketing authorization, often leading to price increases. An example is the 3,4-diaminopyridine slow release (3,4-DAP SR) tablets for Lambert-Eaton Myasthenic Syndrome (LEMS). In 2009 marketing authorization was given for the commercial immediate release phosphate salt of the drug, including a fifty-fold price increase compared to the pharmaceutical compounding preparation. Obtaining marketing authorization for 3,4-DAP SR by academia might have been a solution to prevent this price increase. To determine whether the available data of a pharmaceutical compounding preparation with long-term experience in regular care are adequate to obtain marketing authorization, 3,4-DAP SR is used as a case study. Methods A retrospective qualitative case-study was performed. Initially, document analysis was executed by collecting the required data for marketing authorization in general and whether data of Firdapse® and 3,4-DAP SR met these requirements. Secondly, the (non-) available data of the two formulations were compared with each other to determine the differences in availability. Results At the time of approval, almost all data were available for both Firdapse® and 3,4-DAP SR. Conversely, much of the data used for the approval of Firdapse® originated from the 3,4-DAP immediate release (3,4-DAP IR) formulation. Only two bioequivalence studies and one pharmacology safety study was performed with Firdapse® before marketing authorization application. Conclusions In conclusion, at time Firdapse® obtained approval, the data available did not differ substantially from 3,4-DAP SR, indicating that approval with 3,4-DAP SR would have been possible. We make a plea for approval of orphan medicinal products developed and manufactured by academic institutions as to keep utilization of these products affordable.

Background In 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. Methods Four 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. Results Qualitative 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. Conclusions Inter-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.

Thymic small cell cancer is a very rare type of thymic epithelial tumor. Lambert-Eaton myasthenic syndrome is a rare paraneoplastic syndrome associated with thymic epithelial tumors. We report an extremely rare case of Lambert-Eaton myasthenic syndrome associated with thymic small cell carcinoma. A 71-year-old man was referred to our institution for a mediastinal tumor and a 2-month history of ptosis, fatigue, and gait disorder. Based on radiologic findings thymoma associated with Lambert-Eaton myasthenic syndrome was diagnosed, and extended thymectomy was performed. After surgery the patient's symptoms had not improved. Anticholinesterase treatment alleviated his symptoms.

The synapse between motor neurons and skeletal muscle is known as the neuromuscular junction (NMJ). Proper alignment of presynaptic and post-synaptic structures of motor neurons and muscle fibers, respectively, is essential for efficient motor control of skeletal muscles. The synaptic cleft between these two cells is filled with basal lamina. Laminins are heterotrimer extracellular matrix molecules that are key members of the basal lamina. Laminin α4, α5, and β2 chains specifically localize to NMJs, and these laminin isoforms play a critical role in maintenance of NMJs and organization of synaptic vesicle release sites known as active zones. These individual laminin chains exert their role in organizing NMJs by binding to their receptors including integrins, dystroglycan, and voltage-gated calcium channels (VGCCs). Disruption of these laminins or the laminin-receptor interaction occurs in neuromuscular diseases including Pierson syndrome and Lambert-Eaton myasthenic syndrome (LEMS). Interventions to maintain proper level of laminins and their receptor interactions may be insightful in treating neuromuscular diseases and aging related degeneration of NMJs.

Paraneoplastic syndromes (PNS) are commonly associated with neuroendocrine cancers, such as small cell lung cancer.We examined the association of PNS in Merkel cell carcinoma (MCC), a rare neuroendocrine skin cancer.We identified PNS associated with MCC based on chart review of a Seattle-based repository and examined the incidence of MCC-associated hyponatremia in an independent cohort within Kaiser Permanente Northern California.Eight PNS cases were identified from the Seattle repository. Three distinct PNS types were observed: cerebellar degeneration (1 case), Lambert-Eaton myasthenic syndrome (2 cases), and malignancy-associated hyponatremia (5 cases). Moreover, the incidence of severe hyponatremia (serum sodium125 mmol/L) coincident with MCC was identified among 4.3% (9 of 211) patients with MCC in the Kaiser Permanente Northern California cohort.We did not have access to complete medical records on all patients so it was not possible to determine the prevalence of PNS in MCC.MCC can be associated with PNS similar to those found in other neuroendocrine cancers. Clinicians should be aware of these presentations as PNS often precede the identification of the underlying malignancy and usually resolve with appropriate treatment of the cancer.

We aimed to specify and quantify the characteristics of the decrement in low-frequency repetitive nerve stimulation response in Lambert-Eaton myasthenia syndrome (LEMS) and compare it to those of myasthenia gravis (MG).We retrospectively reviewed 18 patients with LEMS and 24 patients with MG. Ten consecutive stimulations were applied at 3 Hz to the abductor pollicis brevis. We determined the position of the smallest wave in the stimulation sequence, and we calculated the decrement and recovery.The median sequential order of the minimum wave was 8 in the LEMS group and 5 in the MG group (p 0.001). The median decrement in the LEMS group was 36.7%, while that in the MG group was 21.0% (p = 0.047). The recovery percentage was 1.4% in the LEMS group and 3.5% in the MG group (p = 0.001). The area under the curve for the sequential order of the minimum wave was 0.90, and the reciprocal optimum cut-off point was 6.5.We elucidated a pattern with a delayed nadir and subsequent poor recovery, featuring a low-frequency decrement; furthermore, we determined the most likely sequential order of the minimum wave in patients with LEMS, and the indicator was useful for differentiation.

• Myasthenic crises is a potentially severe complication of COVID-19. • Hydroxychloroquine can aggravate myasthenia crises. • IVIg is a potential treatment for both Myasthenic crises and COVID-19. • IVIg treatment may cause thrombosis in susceptible patients.

Purpose Amifampridine (3,4-diaminopyridine) has been approved in the European Union for the treatment of Lambert-Eaton myasthenic syndrome. Amifampridine has a narrow therapeutic index, and supratherapeutic exposure has been associated with dose-dependent adverse events, including an increased risk for seizure. This study assessed the effect of food on the relative bioavailability of amifampridine in healthy subjects and informed on conditions that can alter exposure. Methods This randomized, open-labeled, 2-treatment, 2-period crossover study enrolled 47 healthy male and female subjects. Subjects were randomly assigned to receive 2 single oral doses of amifampridine phosphate salt (20 mg base equivalents per dose) under fed or fasted conditions separated by a washout period. Blood and urine samples for pharmacokinetic analyses were taken before and after dosing. Plasma concentrations of amifampridine and an inactive 3- N -acetyl metabolite were determined. The relative bioavailability values of amifampridine and metabolite were assessed based on the plasma PK parameters AUC 0–∞ , AUC 0–t , and C max in the fed and fasted states using noncompartmental pharmacokinetic analysis. Parent drug and metabolite excretion were calculated from urinary concentrations. A food effect on bioavailability would be established if the 90% CI of the ratio of population geometric mean value of AUC 0–∞ , AUC 0–t , or C max between fed and fasted administration was not within the bioequivalence range of 80% to 125%. Tolerability was assessed based on adverse-event reporting, clinical laboratory assessments, physical examination including vital sign measurements, 12-lead ECG, and concurrent medication use. Findings Food slowed and somewhat decreased the absorption of amifampridine. There was a decrease in exposure (C max , 44%; AUC, 20%) after oral administration of amifampridine phosphate salt in the presence of food, and mean T max was 2-fold longer in the fed state. The extent of exposure and plasma elimination half-life of the major metabolite was greater than those of amifampridine in the fed and fasted conditions. Mean AUCs in the fed and fasted states were slightly greater in women than men, with no difference in mean C max . Orally administered amifampridine was renally eliminated (>93%) as the parent compound and metabolite within 24 hours. Single oral doses of 20 mg of amifampridine phosphate salt were considered well tolerated in both the fed and fasted conditions. High intersubject variability (%CVs, >30%) in amifampridine pharmacokinetic parameter values was observed. Implications At the intended dose under fasting conditions, amifampridine exposure may be increased. European Union Drug Regulating Authorities Clinical Trials identifier: 2011-000596-13.

Lambert-Eaton myasthenic syndrome (LEMS) describes a rare human autoimmune disorder of the neuromuscular junction (NMJ). Clinically, LEMS patients suffer from characteristic muscle weakness that is caused by the presence of antibodies directed against their voltage-gated calcium channels (VGCC). These channels are localized in the presynaptic membrane of their motor nerve terminals. Binding of autoimmune antibodies to the VGCCs leads to reduced neuromuscular transmission. In approximately 50% of the patients, LEMS is reflected by a paraneoplastic manifestation and most commonly associated with a small cell lung carcinoma (SCLC) whose cells also express VGCCs in their plasma membrane. Better understanding of the pathophysiological mechanisms of LEMS has helped with the development of new diagnostic approaches and has led to targeted symptomatic and immunosuppressive therapy. For LEMS patients with an underlying malignancy, tumor therapy is the first choice to date.

Study Objective Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of the neuromuscular junction that manifests with muscle weakness, autonomic and bulbar dysfunction, and increased sensitivity to neuromuscular blocking drugs. The objective of this study is to review perioperative outcomes on a series of patients with LEMS. Design The medical records of surgical patients with LEMS from January 1, 1990, to December 31, 2012, were retrospectively reviewed. Setting Major academic hospital. Patients Surgical patients with LEMS. Measurements and Main Results Thirty-seven patients underwent 60 surgeries, with most performed to diagnose or treat lung malignancy (n = 31; 51.7%). Equal number of patients had LEMS associated with small cell lung cancer (n = 16; 43.2%) or an autoimmune process (n = 16; 43.2%), with the remainder having various malignancies. Neuromuscular blocking drug medications were used in 23 (38.3%) of cases, including 8 patients who were not treated for LEMS symptoms. Four patients (11%) had respiratory complications. Interestingly, 3 patients were either undiagnosed or not treated for LEMS at the time of perioperative complication, and developed weakness after use of neuromuscular blocking drugs. Conclusion Patients with LEMS have increased sensitivity to neuromuscular blocking drugs. The risk for the development of prolonged muscle weakness or postoperative respiratory failure after being exposed to neuromuscular blocking drugs is increased in patients with undiagnosed or untreated LEMS.

The Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disease of the neuromuscular transmission involving the presynaptic voltage-gated calcium channels (VGCCs). In most cases (60%), LEMS presents a paraneoplastic syndrome associated with small cell lung cancer, in the remaining an idiopathic, autoimmune diseases, with frequent overlap with other immune dysfunctions, including myasthenia gravis. The typical clinical triad in LEMS consists of weakness (predominantly affecting proximal muscles), autonomic dysfunctions (including xerostomia, pupillomotor dysfunction, constipation, impaired sweating) and hypo/areflexia. LEMS patients typically present a proximal lower > upper limb weakness that progressively involves axial, oculomotor and pharyngo-laryngeal muscles, thus leading to gait and upright alteration, ocular and bulbar symptoms in severely affected patients. We report the case of a 41-year-old woman diagnosed and treated from 2015. Due to the unusual initial symptoms and coexisting diseases, the patient remains under constant control and observation, including oncological monitoring.

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder affecting neuromuscular junctions. LEMS has served as a model of paraneoplastic neurological syndromes and antitumoral immunity, shedding light on the pathological role of autoantibodies directed against synaptic targets. Autoantibodies associated with LEMS are directed against voltage-gated calcium channels (VGCC) present on nerve terminals of neuromuscular synapses. Anti-VGGC antibodies play a direct pathological role in LEMS by blocking VGCC and calcium entry during depolarisation. Nearly half of patients with LEMS have small-cell lung cancer (SCLC), which also expresses VGCC. Diagnosis of LEMS frequently permits early detection and treatment of SCLC Knowledge of this syndrome has led to the discovery of a broad range of cancerous and non cancerous antibody-mediated neurological syndromes, and led to the concept of autoimmune synaptopathies.

Objectives To study post-exercise exhaustion by decrement (PEE-D) systematically in 24 repetitive nerve stimulation (RNS) tests in 14 patients with Lambert–Eaton myasthenic syndrome (LEMS). Methods In the abductor digiti quinti muscle, the compound muscle action potential (CMAP) amplitude and 3 Hz responses for 2 s were obtained with the supramaximal stimulation at rest, immediately after (PE0), 30 s after (PE30s), and at 1, 2, 3, and 4 m after 10-s exercise. Results There was a 377% increment in the CMAP amplitude at PE0 and a mild increment (+26%) at PE30s. A transient but significant improvement (−22%) in the decremental response was observed at PE0, and a gradual worsening of decrement in subsequent tests, with the worst decrement noted (−50%) at PE2m. Conclusion PEE-D was found 2 m after exercise in LEMS. Significance PEE-D may be physiologically closest to the reversible myasthenic fatigue after exercise observed in LEMS patients.

Background Lambert-Eaton myasthenic syndrome, a presynaptic neuromuscular junction autoimmune disorder, rarely occurs in children. Patients typically present with proximal lower extremity weakness with areflexia. Methods We report three children presenting between ages 9 and 10 years diagnosed with Lambert-Eaton myasthenic syndrome 2 years, 1 year, and 5 months later, respectively. Their clinical attributes are correlated with nine other pediatric Lambert-Eaton myasthenic syndrome patients found in our literature review. Results These patients were identified as having Lambert-Eaton myasthenic syndrome during their evaluation for proximal weakness. Low-amplitude compound muscle action potentials classically facilitating >100% with voluntary exercise and/or 50 Hz stimulation were essential to diagnosis. Three of the 12 children had associated malignancies, two of them had lymphoproliferative disorders with onset of symptoms more rapid than the rest, and the third had neuroblastoma. The nine nonparaneoplastic Lambert-Eaton myasthenic syndrome patients responded to immunomodulatory therapy with close return to their baseline function. Complete remission no longer necessitating medication was reported in two patients. Follow-up up to 17 years was available on two patients previously reported. Conclusion Lambert-Eaton myasthenic syndrome is a diagnosis that must be considered in children presenting with unidentified proximal muscle weakness. In most children, Lambert-Eaton myasthenic syndrome is a primary autoimmune disorder that is treatable. Nevertheless, a search for malignancy is recommended.

Objective Lambert-Eaton myasthenic syndrome (LEMS) is a rare condition, which may mimic myopathy. A few reports have described that EMG in LEMS may show changes compatible with myopathy, and muscle biopsies have been described with type II as well as type I atrophy. The EMG results were, however, based on qualitative EMG examination and the histopathological methods were not always clear. The objective of this study was to investigate if the previous EMG findings could be confirmed with quantitative EMG (QEMG) and to describe muscle histology in LEMS. Methods QEMG, nerve conduction studies and muscle biopsy were performed in four consecutive LEMS patients. Results QEMG showed significantly decreased mean MUP duration and muscle biopsy showed marked type II fiber atrophy. Conclusion EMG and biopsy abnormalities mimicking myopathy may often be found in patients with LEMS. Significance LEMS is a debilitating, but treatable disease, which often precedes detection of a malignancy and it is therefore of obvious importance to diagnose these patients with speed and certainty. Hence it is important that neurophysiologists and neurologists are aware that EMG and histological abnormalities mimicking myopathy may be found in LEMS patients so that these findings do not prolong or misdirect the diagnostic process in these patients.

Autoimmune ion channel disorders of the peripheral nervous system include myasthenia gravis, the Lambert–Eaton myasthenic syndrome, acquired neuromyotonia and autoimmune autonomic ganglionopathies. These disorders are characterized by the common feature of being mediated by IgG autoantibodies against identified target antigens, i.e. the acetylcholine receptor, the voltage-gated calcium and potassium channels, and the neuronal acetylcholine receptor. Moreover, experimental animal models have been identified for these diseases that respond to immunotherapy and are improved by plasmapheresis. On this basis, autoimmune ion channel disorders represent the ideal candidate for therapeutic apheresis. Immunoadsorption can be the treatment of choice when intensive apheretic protocols or long-term treatments must be performed, in patients needing frequent apheresis to keep a stable clinical condition, in case of unresponsiveness to corticosteroids and immunosuppressive treatments, or failure with TPE or intravenous immunoglobulins, and in patients with severe contraindications to long-term corticosteroids.

Lambert-Eaton myasthenic syndrome is a paraneoplastic phenomenon associated with neuroendocrine tumours, most frequently small cell lung carcinoma. Merkel cell carcinoma is a rare cause of Lambert-Eaton myasthenic syndrome. A 70-year old gentleman was referred with metastatic axillary nodal disease from a previously resected Merkel cell carcinoma of the left arm. Pre-operatively, the patient was wheelchair-bound from Lambert-Eaton myasthenic syndrome. Level I-III left axillary node clearance was performed and within 6 months, he had experienced full recovery of muscle power and mobility. We describe a case of complete cure of Lambert-Eaton myasthenic syndrome following axillary nodal clearance in a patient with metastatic Merkel cell carcinoma.

Our patient is a 7-year-old girl, who presented at the age of 3 years with features of droopy eyes, weakness in head-neck control, inability to hop and jump, and an abnormal gait. She was initially evaluated in an outside hospital (OSH) occupational safety and health and treatment with pyridostigmine with suspicion of myasthenia gravis. She was then referred to our center for further evaluation. At the time of her hospitalization, she was reported to have improvement in her ptosis and stamina with pyridostigmine, without much benefit in her gross motor activities, inability to run and jump, and difficulty in getting up from lying and sitting position. There was no history pain, fever, swallowing, or breathing difficulty. She was born full-term with an uneventful pregnancy, labor, and childbirth and had a previously normal development. There was no history suggestive of hypotonia or weakness in the neonatal period or thereafter. Medical history was not remarkable, and there was no evidence of neurologic, genetic, or rheumatologic disorders in the family. On examination, she was of average weight and built, with an unremarkable general, cardiac, pulmonary, and abdominal examination. Neurologic evaluation showed ptosis in neutral gaze, which disappeared with sustained upward gaze, no ophthalmoplegia, symmetric smile, and normal tongue movement without fasciculation. Axial and appendicular tone was low without any wasting or polyminimyoclonus. Motor strength test was notable for proximal muscle weakness more in the lower extremity compared with the upper, with power in range of 4-5 for most muscle groups. There was areflexia, intact sensation, and gait was of trendelenberg pattern with intact toe

Introduction Paraneoplastic neurological syndromes (PNS) are uncommon and imperfectly understood and, therefore, are frequently underdiagnosed. Methods We review the current literature on the clinical presentation, diagnosis, pathophysiology and treatment of PNS. Results PNS are a heterogeneous group of neurologic disorders caused by an immune response to an underlying malignancy. A 3-step diagnostic process is necessary to establish the diagnosis. We review the role of onconeural antibodies in the diagnosis and pathogenesis of PNS and describe recent advances in treatment, focusing on paraneoplastic encephalomyelitis, limbic encephalitis, paraneoplastic cerebellar degeneration, opsoclonus-myoclonus syndrome, subacute sensory neuronopathy and Lambert-Eaton myasthenic syndrome Conclusion PNS often antedate the diagnosis of cancer, offering an opportunity for detecting cancer at an earlier and curable stage. Tests for paraneoplastic antibodies are often negative and do not rule out the diagnosis of a paraneoplastic syndrome. Certain clinical presentations should suggest a paraneoplastic syndrome, even in the absence of paraneoplastic antibodies, and prompt a thorough search for occult malignancy.

We investigated the effect of IgG immunoadsorption (IA) on cytokine network in patients with treatment-resistant Myasthenia Gravis (MG) and Lambert-Eaton Syndrome (LEMS). We observed upregulation of interleukin (IL)-10, an anti-inflammatory and B cells growth factor, and reduction of pro-inflammatory factors such as IL-18 and IL-17, in both MG and LEMS after IA. Our observation suggests that the massive removal of antibodies might induce modifications of the cytokine balance linked to T and B cells mediated autoimmunity.

The Lambert–Eaton myasthenic syndrome (LEMS) is a disease of neuromuscular transmission in which autoantibodies against the P/Q-type voltage-gated calcium channel (VGCC) at the presynaptic nerve terminal play a major role in decreasing quantal release of acetylcholine (ACh), resulting in skeletal muscle weakness and autonomic symptoms. It is associated with cancer, particularly small-cell lung carcinoma (SCLC), in 50–60% of LEMS patients; the nerve terminal and carcinoma cells apparently share a common antigen (VGCC), suggesting an immunological cross-reactivity that may lead to the neurological abnormality. Non-tumor LEMS has a strong association with HLA-DR3-B8. In approximately 15% of LEMS patients, no anti-P/Q-type VGCC antibodies are found, suggesting recognition of other targets(s). The VGCC-associated protein synaptotagmin could be one candidate, because it acts as an exocytotic calcium receptor, is implicated in fast ACh release; its N-terminus is exposed extracellularly during exocytosis and it is expressed in SCLC. Antibodies against synaptotagmin-1 were detected in both anti-VGCC-positive and -negative LEMS patients (20%), and it can be immunogenic, allowing induction of an animal model of LEMS. Another candidate target is the M1-type presynaptic muscarinic ACh receptor (M1 mAChR), also expressed extracellularly on motor nerve terminals; it modulates cholinergic transmission, linking to P/Q-type VGCC. In our series of 25 LEMS patients with and without SCLC, anti-M1 mAChR antibodies were prevalent in both anti-VGCC-positive and -negative LEMS patients. Autonomic symptoms seemed more frequent in the latter; serum from one of them passively transferred LEMS-type electrophysiological defects to mice. As a compensatory mechanism, researchers in Oxford suggested a shift in the dependence of ACh release from the P/Q-type to other types of VGCC. We have also focused on G protein-coupled mAChRs and neurotrophins, which may affect both P/Q-type VGCC and clathrin-independent “kiss-and-run” synaptic vesicle recycling (fast-mode of endocytosis) via protein kinase C activation. We hypothesize that these signaling cascades help to compensate for the immune-mediated defects in calcium entry in LEMS, compensation that may frequently be restricted by the coincident anti-M1 mAChR antibodies in this disease.

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.

John Newsom-Davis was a key figure in the field of neuroimmunology and combined many outstanding personal qualities with considerable clinical and scientific expertise. His first report of plasma exchange in myasthenia in the late 1970s demonstrated its use both as a treatment and as an experimental tool to establish the pathogenic role of antibodies in neurological disorders. Subsequent investigations into the Lambert Eaton myasthenic syndrome and acquired neuromyotonia showed that these were caused by antibodies to specific ion channels. The field of autoimmune channelopathies is continuing to expand with identification of new antibody-mediated diseases including those affecting the central nervous system. This review will highlight some of his most seminal findings and those that are following on from his work.

Several reports have presented patients with subacute cerebellar ataxia (subacute CA) and Lambert-Eaton myasthenic syndrome (LEMS). Some clinical features of those patients have been described in the previous reports, such as priority of subacute CA to LEMS or a concurrent occurrence of both diseases, a high incidence of malignancy, less efficacy of the treatment for subacute CA compared with that for LEMS. Cerebellar ataxia in some patients with LEMS has been demonstrated to be caused by serum antibodies to P/Q-type voltage-gated calcium channels (VGCCs). Here, we report a 63-year-old woman with subacute CA and LEMS. Cerebellar ataxia appeared 15 months after the incidence of LEMS, and the onset of cerebellar ataxia was thought to be due to serum anti-P/Q-type VGCCs antibodies. The clinical course of this patient was atypical in that 1) LEMS preceded subacute CA which developed after intracranial aneurysm surgery, 2) no malignancy was detected when both diseases coexisted, 3) symptoms of LEMS did not progress with the onset of cerebellar ataxia, and 4) cerebellar ataxia showed a definite improvement in symptoms and by 123I-IMP SPECT imaging after steroid administration. In addition, it is remarkable that LEMS became aggravated in electrophysiological examinations in contrast to subacute CA. We suggest that these atypical features of subacute CA and the changes in LEMS may be associated with a balance between the amount of serum anti-P/Q-type VGCCs antibodies and the susceptibility of the cerebellum and presynaptic nerve terminals to the antibodies. More cases are needed to investigate the mechanisms involved. The subacute CA and LEMS in this patient have remained comparatively silent after the withdrawal of steroid, and we are continuing to observe her condition.

Introduction Lambert-Eaton Myasthenic Syndrome (LEMS) is an autoimmune channelopathy in which patients produce autoantibodies directed against voltage-gated calcium channels. LEMS is paraneoplastic in 50% of patients, most frequently associated with small cell lung carcinoma. We describe a case of paraneoplastic LEMS associated with a vocal cord carcinoma. Observation A 64-year-old man developed in five months muscle weakness affecting gait. Clinical examination showed proximal muscular deficiency, areflexia and dysphonia. Electrophysiologic study showed potentiation greater than 500% after post exercise facilitation and 76 percent increment response at high-rate repetitive nerve stimulation (20Hz). Diagnosis of LEMS was confirmed by electrophysiologic study and anti-voltage gated calcium channel antibodies (90pM, positive value greater or equal to 70pM). Left vocal cord lesion histology showed epidermoid carcinoma. A combination of vocal cord tumor removal by endoscopy and treatment by pyridostigmine, 3-4 diaminopyridine and intravenous human immunoglobulin improved neurological symptoms. Conclusion Paraneoplastic syndromes in association with cancers of the larynx and hypopharynx are unusual. Only two cases are reported with LEMS associated with larynx carcinoma. We describe an unusual case of LEMS associated with a left vocal cord carcinoma.

Resume Introduction Le syndrome de Lambert-Eaton (SLE) est une affection rare du versant presynaptique de la jonction neuromusculaire. Le diagnostic electrophysiologique s’etablit sur l’observation de reponses motrices d’amplitude reduite au repos, se normalisant apres effort bref ou stimulations nerveuses repetitives a haute frequence. L’activite electromyographique (EMG) en detection est classiquement rapportee comme normale ou myogene. Observation Nous rapportons le cas d’une jeune patiente presentant un SLE non paraneoplasique dont l’examen electroneuromyographique initial montrait la coexistence d’anomalies EMG neurogenes en detection et d’un tableau typique d’atteinte presynaptique de la jonction neuromusculaire en stimulo-detection. Discussion L’existence d’anomalies EMG neurogenes en detection n’a pas ete rapportee precedemment dans les SLE et pourrait etre liee a une denervation « fonctionnelle » reversible, dependante de la presence d’anticorps anti-canaux calciques de la terminaison axonale. Conclusion La presence d’un syndrome neurogene en detection EMG au cours d’un deficit moteur subaigu ne doit pas faire eliminer la possibilite d’une atteinte presynaptique de la jonction neuromusculaire tel que le SLE.

Background This chapter of the guidelines is intended to provide an evidence-based assessment of the initial evaluation of patients recognized as having lung cancer and the recognition of paraneoplastic syndromes. Methods The current medical literature that is applicable to this issue was identified by a computerized search and was evaluated using standardized methods. Recommendations were framed using the approach described by the Health and Science Policy Committee of the American College of Chest Physicians. Results Patients with lung cancer usually present with multiple symptoms, both respiratory related and constitutional. There is usually a time delay between symptom recognition by the patient and the ultimate diagnosis of lung cancer by the physician. Whether this time delay impacts prognosis is unclear, but delivering timely and efficient care is an important component in its own right. Lung cancer may be accompanied by a variety of paraneoplastic syndromes. These syndromes may not necessarily preclude treatment with a curative intent. Conclusions The initial evaluation of the patient with known or suspected lung cancer should include an assessment of symptoms, signs, and laboratory test results in a standardized manner as a screen for identifying those patients with paraneoplastic syndromes and a higher likelihood of metastatic disease.

Lambert-Eaton myasthenic syndrome is a paraneoplasic syndrome which can reveal a primitive tumor. Frequently, the first diagnosis is myasthenia gravis. This disease is extremely rare in children. Only 10 cases have been reported in the last 35 years. We report 2 new observations occurring in very young patients, aged 2 and 3 years, with a ganglioneurobastoma as primitive tumor.

The decrement pattern at low rates of repetitive nerve stimulation in myasthenia gravis (MG) is characterized by a decrease of compound muscle action potential size within the first 4-5 responses. With subsequent stimuli, compound muscle action potential size either increases or does not change. Following an observation that the pattern of decrement might be different in patients with Lambert-Eaton myasthenic syndrome (LEMS), we retrospectively studied traces from eight LEMS patients and 14 patients with seropositive generalized MG, calculating decrement percent from first to fourth and from first to ninth compound muscle action potential. In the LEMS patients, compound muscle action potential amplitude decreased progressively from first to ninth stimulus at 2, 3 or 5Hz in all traces but one. In contrast, MG patients demonstrated the expected improvement after the initial decrement in all traces except one. In the evaluation of patients suspected of having myasthenia gravis, the finding of progressive decrement pattern at low rates of repetitive nerve stimulation may alert the electromyographer to the possibility of Lambert-Eaton syndrome and prompt the performance of further electrodiagnostic tests.

Lambert-Eaton myasthenic syndrome (LEMS) is a neurological autoimmune disease in which downregulation of voltage-gated calcium channels (VGCCs) leads to reduced acetylcholine release from motoneuron terminals. 70% of cases are paraneoplastic and rapid diagnosis of LEMS can result in early detection of the underlying tumor. Serological assays based on the capacity of autoantibodies to precipitate VGCCs labeled with radioligands provide valuable data. We have established a novel assay using the spider venom peptide 125I-omega-Phonetoxin IIA (125I-omegaPtxIIA). 125I-omegaPtxIIA labeled recombinant Cav2.1 and Cav2.2 channels and endogenous VGCCs in rat brain membranes. Autoantibodies that immunoprecipitate a 125I-omegaPtxIIA/channel complex were detected in 26/31 (84%) LEMS patients. The patients that were seropositive in the 125I-omegaPtxIIA assay corresponded precisely to the population that was positive for Cav2.1 and/or Cav2.2 antibodies detected using two different omega-conotoxins. Thus, the 125I-omegaPtxIIA assay detects a broader spectrum of autoantibody specificities than current omega-conotoxin-based assays.

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.

Lambert-Eaton myasthenic syndrome, often associated with small-cell lung carcinoma, is a disease of neuromuscular transmission in which antibodies directed against voltage-gated calcium channel (VGCC)(P/Q-type) in the motor nerve terminal play a crucial role in causing a deficient quantal release of acetylcholine. The motor nerve terminal and carcinoma cell may share a common antigen. The study using synthetic peptides and recombinant protein specified the extracellular S5-S6 linker regions in 3 of 4 domains as immunodominant sites in the molecular structure of P/Q-type VGCC alpha1 subunit. Also, the study by use of peptides and recombinant protein corresponding to synaptotagmin I suggested that in this functionally VGCC-associated presynaptic protein, the segment which exposes extracellularly during exocytosis can be immunogenic for the syndrome.

Non-paraneoplastic Lambert-Eaton myasthenic syndrome (LEMS) is an antibody-mediated autoimmune disorder, in which genetically determined interleukin-10 (Il-10) and tumor necrosis factor-alpha (TNF-alpha) could play a role in the susceptibility for the disease. Therefore, we analyzed the production of Il-10 and TNF-alpha after whole-blood stimulation in first-degree family members of patients with LEMS without malignancy, as a measure of innate production in the patients. Thirty-six first-degree family members of 10 patients and 80 healthy controls were studied. Both Il-10 (p=0.037) and TNF-alpha (p=0.0016) production were increased in the family members, but had no relation with the severity of LEMS or HLA-B8DR3 carriership. Our findings suggest that high innate production of Il-10 and TNF-alpha is a susceptibility factor for non-paraneoplastic LEMS.

To compare the clinical features of patients with the Lambert-Eaton myasthenic syndrome (LEMS) associated with carcinoma, with patients having LEMS but no cancer, reports on LEMS patients were analyzed systematically. Cancer was detected (CD group) in 62% of the 227 included cases. This CD group showed a male predominance (70%). No sex difference was found in patients in whom no cancer was detected (NCD group). Median age at onset of LEMS in the CD group was higher than in the NCD group (58 and 49.5 years, P

Lambert–Eaton Myasthenic Syndrome (LEMS) is a rare autoimmune disorder characterized by autoantibodies that bind to P/Q voltage-gated calcium channels at the neuromuscular junction. Using cell-free direct peptide binding in 12 LEMS patients, we find linear B-cell epitopes that reside on the extracellular peptide linkers between the S5–S6 transmembrane peptides of Domains II and IV. A major epitope is located within the S5–S6 linker peptide of Domain IV defined by the acidic amino acid sequence EDEDSDEDE.