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].

• Weakness

  Conversely, LEMS patients never presented initially with ocular weakness; 5% presented with bulbar weakness, and 95% presented with limb weakness. [emedicine.medscape.com]

  Here, we describe a patient with a 5-year history of cervical myelopathy who presented with recurrent limb weakness of her limbs and complained of recent progressive weakness. [ncbi.nlm.nih.gov]

• Fatigue

  An African 41 years-old SLE patient presented with persisting fatigue, myalgia and dyspnea, abolished reflexes and a bilateral ptosis. [ncbi.nlm.nih.gov]

  These proximal muscles are more likely to fatigue with use, and muscle fatigue and sometimes stiffness may be more prominent than actual weakness. The legs are particularly affected. [mda.org]

• Pain

  The most common side effects experienced by patients in the clinical trials were burning or prickling sensation (paresthesia), upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension [fda.gov]

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 13, 2019 [patientslikeme.com]

  Patients with LEMS typically suffer from fatigue, muscle pain, and stiffness. The weakness is generally more marked in the proximal muscles particularly of the legs and trunk. [biomarin.com]

  Patients with LEMS typically present with fatigue, muscle pain and stiffness. The weakness is generally more marked in the lower extremity muscles, particularly of the legs and hip-girdle. [globalgenes.org]

  The most common side effects of the drug experienced by both adult and pediatric patients included burning or prickling sensation, abdominal pain, indigestion, dizziness, and nausea. [ajmc.com]

• Weight Loss

  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 [ncbi.nlm.nih.gov]

  Review of symptoms was notable for a 10-lb unintentional weight loss over one month before presentation. Past medical history was significant for chronic obstructive pulmonary disease and a 75-pack year smoking history. [n.neurology.org]

  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% [symptoma.com]

  She also experienced a 5-pound unintentional weight loss over a 2-month period. She denied smoking, drinking alcohol, or abusing any drugs. Her medications were aspirin 81 mg oral daily and amlodipine 5 mg oral daily. [journals.sagepub.com]

  LEMS patients with or without cancer may also undergo significant weight loss. The tendon reflexes are diminished or absent on examination. [rarediseases.org]

• Limb Pain

  Almost all patients receiving intravenous 3,4-DAP in one study reported upper limb pain on the side of the infusions, leading to trial withdrawal in two patients. 31 Monitoring of routine blood tests, electrocardiography, and electroencephalography did [dovepress.com]

• Constipation

  The Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular disease; its unique symptoms of LEMS include dry mouth with a metallic taste, constipation, and erectile dysfunction. [ncbi.nlm.nih.gov]

  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. [symptoma.com]

  Patients often report a dry mouth, impotence, and constipation. Very rarely these problems can be life-threatening when the weakness involves respiratory muscles. I have been undergoing infusions monthly for six years. [globalgenes.org]

  Autonomic dysfunction includes dry mouth, constipation, and erectile dysfunction. Deep tendon reflexes are usually decreased or absent. [ime.acponline.org]

• Xerostomia

  Autonomic dysfunctions, mostly xerostomia, occur in approximately 80% of the patients; other symptoms include impotence in men and loss of the libido in women 2,11. Both patients in this report presented xerostomia and reduction of the libido. [scielo.br]

  A 68‑year‑old male patient presented with a 6‑month history of progressive weakness of the proximal limbs and a 2‑month history of xerostomia. [spandidos-publications.com]

• Decreased Sweating

  Mestinon is indicated for the treatment of MG, but is often used in combination with Firdapse to treat symptoms of autonomic dysfunction (dry mouth, dry eyes, constipation, impotence and, decreased sweating). [rarediseases.org]

• Diplopia

  She recently developed unilateral ptosis and diplopia which dramatically improved with pyridostigmine suggesting concomitant MG. [ncbi.nlm.nih.gov]

  Some degree of eyelid ptosis or diplopia, usually mild, is found in 25% of patients. Occasionally, difficulty chewing, dysphagia, or dysarthria is present. Most patients have a dry mouth, eyes, or skin. [emedicine.medscape.com]

  Case report: Herein we report an 82 year old man a known case of adenocarcinoma of bladder who came with ptosis in left eye, diplopia, and dysphagia, weakness of both lower extremities and autonomic dysfunction. [imminv.com]

• Blepharoptosis

  옛 대한의협 3 의학용어 사전 검색 맞춤 검색 결과 : 15 페이지: 1 muscle weakness 근무력(筋無力). asthenia bulbar paralysis 근무력성 구(연수)마비(筋無力性球延髓 痺). blepharoptosis myasthenica 근무력성 안검하수. myasthenic fatigability 근무력성 피로증(筋無力性疲勞症). myasthenic nystagmus 근무력안진 muscular asthenia 근무력증(筋無力症 [kmle.co.kr]

  Titulaer et al. n 97 Male:female 32:18 84:26 55:42 Median age at onset (years) 54 62 57 Neurological findings (%) Weakness of upper extremities 82 80 82 Weakness of lower extremities 90 97 100 Decreased deep tendon reflex 92 85 92 Ophthalmoplegia NA 5 38 Blepharoptosis [onlinelibrary.wiley.com]

• Muscle Weakness

  The main clinical feature is potentially disabling limb muscle weakness. Clinical signs of autonomic nervous system involvement are frequent. [ncbi.nlm.nih.gov]

  From Wikidata Jump to navigation Jump to search an autoimmune, presynaptic disorder of neuromuscular transmission characterized by fluctuating muscle weakness and autonomic dysfunction frequently associated with small-cell lung cancer (SCLC) Eaton-Lambert [wikidata.org]

• Myopathy

  Lambert-Eaton myasthenic syndrome (LEMS) is a rare condition, which may mimic myopathy. [ncbi.nlm.nih.gov]

  EMG helps to differentiate LEMS from other causes of cancer-associated weakness, such as myopathy and polyneuropathy. [cmaj.ca]

  […] additional information about LEMS, please visit the following websites and others listed in the Patient/Physician Resource Library: LEMS.com European Society for Immunodeficiencies Myasthenia Gravis Association (UK) Association Française contre les Myopathies [biomarin.com]

• Neck Weakness

  Neurological examination revealed ptosis, dysarthria, neck weakness, hyporeflexia of all limbs, and autonomic failure. Electrophysiologic study showed a 400% increment response to high-rate repetitive nerve stimulation. [ncbi.nlm.nih.gov]

  The disease began with neck weakness, followed by asymmetric, bilateral lid ptosis. [docksci.com]

• Proximal Muscle Weakness of the Lower Extremity

  The most common initial complaint is proximal muscle weakness involving the lower extremities more than the upper extremities. Depressed deep tendon reflexes and autonomic dysfunction are frequently present. [ncbi.nlm.nih.gov]

• Limb Weakness

  A 27-year-old man as initially having the diagnosis of Addison's disease was admitted to the hospital because of fatigue, dry-mouthness and proximal limb weakness for 1 year. A diagnosis of LEMS was made from electrophysiological studies. [ncbi.nlm.nih.gov]

  Limb weakness confined to the arms is only found in generalised myasthenia gravis and not in LEMS. [jnnp.bmj.com]

• Dysarthria

  Neurological examination revealed ptosis, dysarthria, neck weakness, hyporeflexia of all limbs, and autonomic failure. Electrophysiologic study showed a 400% increment response to high-rate repetitive nerve stimulation. [ncbi.nlm.nih.gov]

• Paresthesia

  The side effects of 3,4-DAP are generally mild and most frequently consist of paresthesias, but epileptic seizures and arrhythmias have been described in patients using high doses. [ncbi.nlm.nih.gov]

  Side effects are usually mild, and the most frequently reported are paresthesias. The most common serious adverse events are epileptic seizures. 3,4-DAP is currently the treatment of choice in patients with Lambert–Eaton myasthenic syndrome. [doi.org]

  Results: A 64-year-female with LCNEC(stage-1A) status post wedge resection presented with one week history of encephalopathy, diplopia, generalized weakness and paresthesia. [n.neurology.org]

  The most common side effects experienced by patients in the clinical trials were burning or prickling sensation (paresthesia), upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension [fda.gov]

• Hyporeflexia

  Neurological examination revealed ptosis, dysarthria, neck weakness, hyporeflexia of all limbs, and autonomic failure. Electrophysiologic study showed a 400% increment response to high-rate repetitive nerve stimulation. [ncbi.nlm.nih.gov]

  History In 1953 Anderson and colleagues reported the case of a 47-year-old man with a bronchial neoplasm, progressive proximal muscle weakness and hyporeflexia who developed prolonged apnoea following administration of succinylcholine. [pmj.bmj.com]

  It is characterized clinically by muscle weakness, hyporeflexia or areflexia, and autonomic dysfunction. [cancerjournal.net]

• Absent Deep Tendon Reflex

  Debilitating muscle weakness, which is the main clinical manifestation of patients suffering from LEMS, is accompanied by reduced or absent deep tendon reflexes, and by various autonomic disturbances such as constipation, impaired sexual functions, or [symptoma.com]

  History and Physical The most frequent clinical manifestations of Lambert-Eaton myasthenic syndrome are proximal muscle weakness, autonomic dysfunction, and absent deep tendon reflexes. [statpearls.com]

  LEMS is characterized by depressed or absent deep tendon reflexes which helps to distinguish it from the myopathies and myositis diseases in which deep tendon reflexes are typically preserved. [cancertherapyadvisor.com]

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].

• Superior Mediastinal Mass

  A total body CT-scan revealed an antero-superior mediastinal mass, compatible with thymoma. The tumour was surgically removed with a final diagnosis of follicular thymic hyperplasia. [ncbi.nlm.nih.gov]

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.

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