As the release of acetylcholine at the neuromuscular junction is impaired, numerous symptoms may appear. Debilitating muscle weakness, which is the main clinical manifestation of patients suffering from LEMS [13], is accompanied by reduced or absent deep tendon reflexes [7], and by various autonomic disturbances such as constipation, impaired sexual functions, or dry mouth [5]. Muscle weakness usually starts at the proximal lower extremities and is progressive in nature, eventually spreading to both upper and lower distal extremities [1]. Respiratory failure may be observed in severe cases in whom the diagnosis is made when advanced stages of the disease have been reached. Ocular and bulbar symptoms may be present as well and their frequency ranges between 0-80% [1].

The two most important steps in the diagnostic workup are a meticulous physical examination and EMG studies [5]. EMG will confirm a low CMAP, in which case further evaluation for SCLC through the use of chest CT, bronchoscopy and PET should be carried out as soon as possible [8]. Between 85-90% of patients test positive for VGCC antibodies, with numbers reaching 100% if LEMS is associated with SCLC [7]. Because SCLC and LEMS are strongly correlated, a prediction score has been proposed in order to aid physicians in making the diagnosis early on. More than 50 years of age at onset of symptoms, positive history for smoking, weight loss, bulbar symptoms, male sexual impotence and Karnofsky performance status lower than 70 were established as valid predictors of SCLC, as the chances of 93.5%, 96.6% and 100% for this malignancy were observed if patients had 4,5 or all 6 symptoms, respectively [9].

Current treatment principles rely on symptomatic and causative therapy, with 3,4 - DAP being currently considered as first-line therapy [6] [14]. 3,4 - DAP acts by blocking voltage-gated potassium channels, thus causing a prolonged depolarization phase at the presynaptic terminal and providing more time for acetylcholine to be released into the synaptic cleft [10]. Recent studies have additionally suggested that this drug also directly influences the activity of VGCCs, but this theory remains to be solidifies [1]. Guidelines suggest dosages of 5 milligrams every 8 hours, but up to 60 mg/day can be given [10]. This drug, however, is contraindicated in patients who suffer from epilepsy, since seizures are the most significant adverse effect. Additionally, its combination with drugs that prolong the QT interval is prohibited [10], as the drug can further cause QT prolongation. It was shown that 3,4 diaminopyridine can improve muscle strength within days after its initiation, whereas positive effects were seen with intravenous immunoglobulins over the course of weeks [9]. Corticosteroids, used together with azathioprine or cyclosporine, have proved to be successful in long-term management [15]. In addition to described therapeutic agents, a novel calcium channel agonist (GV-58) has shown significant success in animal models, especially when used together with 3,4 DAP [13]. Efficient treatment of the underline malignant disease (if present) is equally important when it comes to long-term survival rates [6].

The prognosis varies from patient to patient, but the majority of individuals have a reduced life expectancy. Non neoplastic forms have been associated with a much better prognosis compared to those in whom SCLC was discovered as the underlying cause [11], but in any case, intensive immunosuppressive therapy is necessary to maintain an adequate quality of life [11]. Although between 20 and 50% of patients enter long-term remission with appropriate therapy, studies have confirmed that the severity of symptoms at the time of diagnosis is a valid predictor of outcome, which is why an diagnosis is essential in achieving better results [11].

LEMS occurs due to suppressed presynaptic neurotransmitter release by antibodies acting on the VGCCs. Since the activity of these channels are essential for secretion of acetylcholine into the synaptic cleft, their inactivity will invariably lead to reduced signal transmission and cause numerous symptoms. In 50-90% of patients, some form of malignancy is discovered, by far the most common being SCLC [2], which is encountered in the vast majority of tumor-related LEMS [1]. Its exact role in the pathogenesis, however, remains unknown.

LEMS is considered to be a rare disease, with prevalence rates of 2.3 per 1 million individuals and an incidence of 0.5 per 1 million [7]. Other studies suggest that this disease affects approximately 1 per 100,000 individuals in the United States and Europe [8]. SCLC is by far the most important risk factor and this condition is often divided into SCLC-induced and non-SCLC induced LEMS [11]. In patients with SCLC, The onset of symptoms is most frequent > 50 years of age, with a slight predilection toward male gender [7]. On the other hand, non-SCLC LEMS Is more frequently seen in women, with the onset being most common at 35 and 60 years of age [7]. Ethnic predilection has not been established, as this condition affect all races [12].

Under physiological circumstances, neurotransmitter release at the neuromuscular junction is mediated by opening and closing of presynaptic P or Q type voltage-gated Ca+ channels (VGCCs), which are regulated by the activity and impulse of the presynaptic action potential [13]. In the setting of LEMS, the production of IgG-class antibodies that target the extracellular VGCCs leads to downregulation of calcium dependent release of acetylcholine in the presynaptic terminal [5]. Consequently, depressed tendon reflexes, proximal weakness and impairment of autonomic functions develop [11]. Apart from VGCC, other targets have been discussed, since up to 10-15% of patients have negative antibody titers, with the most prominent candidates being synaptotagmin (a synaptic vesicle protein) and muscarinic presynaptic acetylcholine receptors [8].

Because almost 100% of patients with LEMS were diagnosed with SCLC within 1 year [3], and because the diagnosis is often made several years after the onset of symptoms [12], a screening protocol consisting of chest CT and PET scans has been proposed in order to facilitate an early diagnosis [3], which can significantly prolong survival rates and be even life-saving for many patients. The prevention of LEMS is currently not possible, as the exact cause of antibody production is unknown.

Since its initial description more than 50 years ago [1], much has been revealed about Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disease featured by production of antibodies against voltage-gated calcium channels (VGCCs) at the neuromuscular junction [2]. In a substantial amount of patients (50-90%, depending on the study) [2] [3] [4], the underlying cause was determined to be small cell lung carcinoma (SCLC) [1], one of the most aggressive lung tumors encountered in clinical practice. LEMS was established as the common paraneoplastic disorders identified in SCLC patients, with a prevalence rate reaching up to 6% [5]. On the other hand, a nonparaneoplastic form of LEMS (also known as non-SCLC LEMS) comprises 10-15% of cases [6], in which the underlying cause remains unknown. In these patient, anti-VGCC antibodies are not found, consequently leading to the search for other molecules involved in the pathogenesis [7]. So far, synaptotagmin (a protein involved in the formation of synaptic vesicles) and muscarinic acetylcholine receptors located on the presynaptic terminal have been listed as potential targets [8]. The pathogenesis of SCLC-LEMS starts with delayed presynaptic signaling as a result of antibody activity and suppression of VGCCs, leading to impaired conduction of action potentials and secretion of acetylcholine into the synaptic cleft [2]. As a result, numerous neurological deficits appear, most important being progressive muscle weakness, usually starting at the lower extremities, together with diminished or completely absent deep tendon reflexes and autonomic dysfunction that manifests as dry mouth, constipation and erectile dysfunction [1]. LEMS is rarely seen in medical practice, as studies have determined an incidence rate of 0.5 per 1 million individuals [7], whereas approximately 1 in 100,000 individuals in Europe and the United States were shown to suffer from this diseases [8]. SCLC is, by far, the single most important risk factor for LEMS, but the roles of gender and age are considered to be important as well. Males are more commonly affected by SCLC-related LEMS, while non-SCLC LEMS is more frequently observed among women [7]. In terms of age, SCLC-related cases appear almost universally after 50 years of age, while the remaining patients are diagnosed at two age peaks, 35 and 60 years [1], and the exact cause for such results remains unknown. To make the diagnosis, a thorough physical examination and various laboratory and imaging studies are necessary. Electromyography (EMG) results showing low compound muscle action potential (CMAP) and elevated serum values of VGCC antibodies are diagnostic hallmarks of LEMS, in which case a detailed and prompt inspection of the chest through computed tomography (CT), positron emission tomography (PET) and bronchoscopy is pivotal to confirm SCLC [1]. A recent study has composed a predictive score for SCLC in patients with suspected LEMS, including factors such as age of > 50 years at onset, smoking, erectile dysfunction, weight loss and functional impairment assessed through the Karnofsky scale, and has shown to be highly specific in the presence of 4 or more factors [9]. Treatment principles aim to suppress the activity of antibodies, primarily through use of 3,4 - diaminopyridine (3,4-DAP). Less effective drugs include intravenous immunoglobulins (IVIG) and plasmapheresis [10]. For chronic, long-term suppression, azathioprine and corticosteroids are of significant benefit [1]. If the presence of SCLC is confirmed, its management is equally important in ensuring longer survival rates. The severity of symptoms at the time of diagnosis is established to be the most valid predictor of life expectancy [11], which is why an early diagnosis based on high clinical suspicion is of essential importance.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease most frequently appearing in the presence of a malignant tumor, most commonly small lung cell carcinoma. LEMS is, in fact, considered to be the most common paraneoplastic syndrome in small lung cell carcinoma (SCLC). In a small subset of patients (10-15%), however, LEMS is not related to any malignant tumor and its cause remains unknown. For reasons yet to be determined, production of antibodies against calcium channels that are essential cogs in proper conduction of nervous signals occurs and these antibodies are identified in high titers in the vast majority of patients. When antibodies suppress the activity of these channel, the main neurotransmitter, acetylcholine, cannot perform its physiological function and diminished nervous signaling triggers numerous deficits. Symptoms such as muscle weakness, diminished tendon reflexes and impaired autonomic functions that manifest as dry mouth, constipation or erectile dysfunction are manifestations of LEMS. To make the diagnosis, it is important to perform a full physical examination, together with electromyography (EMG) and various imaging studies to confirm or exclude the presence of small lung cell carcinoma. Computed tomography (CT scan) of the chest, positron emission tomography (PET scan) and bronchoscopy are all indicated in the setting of high clinical suspicion toward LEMS. Treatment involves administration of various drugs, but 3,4 - diaminopyridine is considered as first-line therapy. Intravenous immunoglobulins and plasmapheresis are also considered as good alternatives, especially in patients suffering from epilepsy, in whom 3,4 -diaminopyrine is contraindicated due to the fact that its most prominent adverse effect is seizures. Corticosteroids and azathioprine are used for long-term suppression. The prognosis of LEMS significantly depends on the promptness of the diagnosis, as much longer survival rates have been observed in patients with milder symptoms at their initial presentation. Although LEMS is considered to be a rare disease, appearing in 2 per 1 million individuals, it should be taken into consideration in individuals older than 50 years of age who present with progressive muscle weakness and autonomic dysfunction as the underlying cause may lead to fatal outcomes if not recognized early on.

1. Titulaer, Maarten J et al. Lambert–Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2014;10(12):1098-1107.
2. Wirtz PW, Bradshaw J, Wintzen AR, et al. Associated autoimmune diseases in patients with the Lambert-Eaton myasthenic syndrome and their families. J Neurol. 2004;251:1255-1259.
3. Titulaer MJ, Wirtz PW, Willems LN, et al. Screening for small-cell lung cancer: a follow-up study of patients with Lambert-Eaton myasthenic syndrome. J Clin Oncol. 2008;26:4276-4281.
4. Wirtz PW, Smallegange TM, Wintzen AR, et al. Differences in clinical features between the Lambert-Eaton myasthenic syndrome with and without cancer: an analysis of 227 published cases. Clin Neurol Neurosurg. 2002;104:359-363.
5. Payne M, Bradbury P, Lang B, et al. Prospective study into the incidence of Lambert Eaton myasthenic syndrome in small cell lung cancer. J Thorac Oncol. 2010;5(1):34–38.
6. Newsom-Davis J. Therapy in myasthenia gravis and Lambert-Eaton myasthenic syndrome. Semin Neurol. 2003;23:191-198.
7. Bekircan-Kurt CE, Çiftçi ED, Kurne AT, et al. Voltage gated calcium channel antibody-related neurological diseases. World J Clin Cases. 2015;3(3):293–300.
8. Keogh M, Sedehizadeh S, Maddison P. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev. 2011;CD003279.
9. Titulaer MJ, Maddison P, Sont JK et al. Clinical Dutch-English Lambert-Eaton myasthenic syndrome (LEMS) tumor association prediction score accurately predicts small-cell lung cancer in the LEMS. J Clin Oncol. 2011;29:902–908.
10. Lindquist S, Stangel M. Update on treatment options for Lambert-Eaton myasthenic syndrome: focus on use of amifampridine. Neuropsychiatr Dis Treat. 2011;7:341–349
11. Maddison P, Lang B, Mills K, et al. Long term outcome in Lambert-Eaton myasthenic syndrome without lung cancer. J Neurol Neurosurg Psychiatry. 2001;70:212-217.
12. Harms L, Peter Sieb J-P, Williams AE, et al. Long-term disease history, clinical symptoms, health status, and healthcare utilization in patients suffering from Lambert Eaton myasthenic syndrome: results of a patient interview survey in Germany. J Med Econ. 2012;15(3):521–530.
13. Tarr TB, Wipf P, Meriney SD. Synaptic Pathophysiology and Treatment of Lambert-Eaton Myasthenic Syndrome. Molecular Neurobiology Mol Neurobiol. 2014;52(1):456-463.
14. Skeie GO, Apostolski S, Evoli A, et al. Guidelines for the treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol. 2006;13:691-699.
15. Newsom-Davis J. Lambert–Eaton myasthenic syndrome. Rev Neurol (Paris). 2004;160(2):177–180.