Effects of Natural Products on Neuromuscular Junction.

Neuromuscular junction (NMJ) disorders result from damage, malfunction or absence of one or more key proteins involved in neuromuscular transmission, comprising a wide range of disorders. The most common pathology is antibody-mediated or downregulation of ion channels or receptors, resulting in Lambert-Eaton myasthenic syndrome, myasthenia gravis, and acquired neuromyotonia (Isaac's syndrome), and rarely congenital myasthenic syndromes caused by mutations in NMJ proteins. A wide range of symptomatic treatments, immunomodulating therapies, or immunosuppressive drugs have been used to treat NMJ diseases. Future research must be directed at a better understanding of the pathogenesis of these diseases, and developing novel disease-specific treatments. Numerous secondary metabolites, especially alkaloids isolated from plants, have been used to treat NMJ diseases in traditional and clinical practices. An ethnopharmacological approach has provided leads for identifying new treatments for NMJ diseases. In this review, we performed a literature survey in Pubmed, Science Direct, and Google Scholar to gather information on drug discovery from plant sources for NMJ disease treatments. To date, most research has focused on the effects of herbal remedies on cholinesterase inhibitory and antioxidant activities. This review provides leads for identifying potential new drugs from plant sources for the treatment of NMJ diseases.

Lambert-Eaton myasthenia syndrome: specified description of a response pattern to low-frequency repetitive nerve stimulation.

OBJECTIVE: 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). PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Amifampridine for the treatment of Lambert-Eaton myasthenic syndrome.

Introduction: The present status of amifampridine (AFP) for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) is reviewed. Areas covered: All relevant literature identified through a PubMed search under treatment of LEMS, aminopyridine, and amifampridine are reviewed. An expert opinion on AFP was formulated. Expert opinion: AFPs, 3,4-DAP and 3,4-DAPP, are the most studied drugs in neuromuscular diseases. Randomized and non-randomized studies showed the most effective drug as symptomatic medication for LEMS. AFPs are safe and tolerable. Thus, AFPs should be the drug of choice for the symptomatic treatment in LEMS. As long as the daily dose is less than 80 mg a day, there is no concern for the serious side-reaction, seizure. Because of short-acting drug effects, it should be given three or four times a day. Peri-oral and finger paresthesia, the most common side-reaction, is accepted as a sign of drug-intake by many patients. Gastro-intestinal side reactions, the next common side-reaction of AFPs, are tolerable. AFPs are also the drug of choice and life-saving for LEMS crisis. For the long-term usage, it is proven to be safe and AFPs can be supplemented with liberal amount of pyridostigmine to sustain a symptomatic improvement without any undue side-reaction.

[P/Q-type Calcium Channel Antibodies in Lambert-Eaton Myasthenic Syndrome].

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of the neuromuscular junction. Approximately 50-60% of patients with LEMS have a tumor, most often small cell lung cancer (SCLC), making LEMS a paraneoplastic neurological syndrome. In Japan, the clinical picture is a male: female ratio of 3:1; mean age, 62 years (17-80 years); and 61% of LEMS patients have SCLC (SCLC-LEMS), with the remainder of patients having no cancer. Patients with LEMS develop a unique set of clinical characteristics, which include proximal muscle weakness, depressed tendon reflexes with post-tetanic potentiation, and autonomic symptoms. Interestingly, less than 10% of patients with LEMS have cerebellar ataxia (LEMS with paraneoplastic cerebellar degeneration). Considering its pathomechanisms, LEMS is a presynaptic disorder of neuromuscular transmission in which quantal release of acetylcholine is impaired by autoantibodies against P/Q-type voltage-gated calcium channels (P/Q-VGCCs) at active zones reducing quantal release of acetylcholine, although an animal model using immunization with purified P/Q-VGCCs has not yet been established. The diagnosis can be confirmed by finding a reduced compound muscle action potential amplitude that increases by over 60% following maximum voluntary activation or 50 Hz nerve stimulation. Approximately 90% of patients who satisfy the above electrophysiological diagnostic criteria are positive for P/Q-VGCC antibodies have their diagnosis confirmed. Specific tumor therapy in SCLC-LEMS will often improve the neurologic deficit. Tumor removal is the primary treatment for LEMS. If primary tumor screening is negative, screening should be repeated after 3-6 months, followed by screening every 6 months until 2 years post diagnosis. Most patients benefit from 3,4-diaminopyridine being administered with pyridostigmine. In those with severe weakness, high-dose intravenous gamma-globulin (IVIg) or plasmapheresis confers short-term benefits. Prednisone, alone or combined with immunosuppressive drugs, can achieve long-term control of the disorder. The results of a prospective cohort study showed that the presence of LEMS with SCLC had a significant survival advantage independent of other prognostic factors including disease extent, age, sex, performance status, and serum sodium values.

[Decrement pattern of M-response amplitude in the low-frequency repetitive nerve stimulation in the muscles of patients with myasthenia gravis and Lambert-Eaton myasthenic syndrome]. / Dekrement amplitudy M-otveta pri nizkochastotnoi stimulyatsii myshts bol'nykh miasteniei i miastenicheskim sindromom Lamberta­Itona.

AIM: To investigate the pattern of decrement in the muscles of patients with myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS). MATERIAL AND METHODS: Twenty-seven patients with MG and 39 patients with LEMS were studied using low frequency repetitive nerve stimulation (3/ sec). RESULTS AND CONCLUSION: The decrease of safety factor of neuromuscular transmission was equal in both groups. At the same time, a significant difference in the decrease of pattern of the amplitude compound of muscle action potential (CMAP) was found. In LEMS, by contrast with MG, another sequence of amplitude variability of CMAP from the second stimulus to the first and from the fifth stimulus to the fourth was noted. In LEMS patients, progressive decrement, manifesting by increasing ratios of late A9/A1 to early A4/A1 was found, whereas the MG patients showed retrogressive decrement expressed by the reduction in decrement ratio (from late to early). These differences reflect the mechanisms and status of acetylcholine mobilization and release from the axon terminal.

Modelling the response to low-frequency repetitive nerve stimulation of myasthenia gravis and Lambert-Eaton myasthenic syndrome.

Myasthenia gravis (MG) is an autoimmune postsynaptic disorder of neuromuscular transmission caused, in most patients, by antibodies against postsynaptic acetylcholine receptors. Lambert-Eaton myasthenic syndrome (LEMS) is a presynaptic autoimmune disease in which there is a reduction in Ca2+ entry with each impulse due to the action of antibodies against Ca2+ channels. These diseases have a distinct pattern of response to low-frequency repetitive nerve stimulation which allows its recognition in a particular subject. Nevertheless, the physiologic basis of this response is not entirely known. A model of the time-course of release probability of neuromuscular junctions that incorporates facilitation and a depression-recovery mechanism has been developed with the aim to investigate these response patterns. When the basal value of release probability was in the physiologic range, as in MG, release probability showed an increment after its initial decrease only if the recovery from depression was accelerated by presynaptic residual Ca2+. Otherwise, when the basal release probability was low, as in LEMS, a progressive reduction in the release probability without any late increase was only obtained if the efficacy of Facilitation and Ca2+-dependent recovery from depression were reduced.

[Autoantibody against the presynaptic P/Q-type voltage-gated calcium channel in Lambert-Eaton myasthenic syndrome].

Antibodies against the muscle acetylcholine receptor (AChR) were recognized as the cause of myasthenia gravis in the 1970s'. Since then, other neurological disorders associated with autoantibodies have been identified, each associated with an antibody against a ligand- or voltage-gated ion channel. Autoantibodies against P/Q-type voltage-gated calcium channels (VGCCs) are detected in patients with Lambert-Eaton myasthenic syndrome (LEMS). These antibodies interfere with the calcium-dependent release of acetylcholine from the presynaptic membrane. LEMS is an autoimmune disorder affecting the neuromuscular junction, and is characterized by proximal muscle weakness, reduction of tendon reflex, and autonomic dysfunction. Electrophysiological examinations show small-amplitude compound muscle action potentials and increments on rapid repetitive nerve stimulation. Fifty to sixty percent of LEMS patients present with tumors, mostly small cell lung carcinoma (SCLC), as a paraneoplastic syndrome. SCLC is a neuroendocrine tumor, which expresses neuronal VGCCs. Some patients present cerebellar ataxia, which is always accompanied by SCLC. These patients tend to show higher titers of VGCC antibodies than that by LEMS patients with no ataxia. The diagnosis can be confirmed by finding reduced compound muscle action potential amplitudes at rest that shows increments greater than 100% with repetitive nerve stimulation and antibody detection by using radioimmunoprecipitation assays. The treatment options are generally categorized as anti-tumor, immunomodulating, immunosuppressing, and symptomatic treatments. In cases with SCLC, effective treatment against the tumor can improve LEMS. Plasmapheresis and intravenous administration of high-dose immunoglobulins have a short effect. Prednisone, alone or in combination with immunosuppressants can achieve long-term control of the disorder.

Lambert-Eaton myasthenic syndrome following H1N1-influenza vaccination: a case report.

BACKGROUND: The outbreak of influenza A (H1N1) pandemic during the year 2009 led to the development of several vaccinations against H1N1 virus. In Finland, 2.6 million citizens were vaccinated during pandemic 2009 - 2010 with adjuvanted influenza vaccine, Pandemrix(®) . CLINICAL PRESENTATION: In this case report, we describe a patient with non-paraneoplastic Lambert-Eaton myasthenic syndrome following Pandemrix(®) vaccination. CONCLUSION: Development of various autoimmune diseases in genetically predisposed subjects following exposure to certain environmental factors, including vaccinations, is a well-known entity. Clinicians should be aware of the possibility of the induction of autoimmune diseases following vaccinations and actively ask the relevant clinical history in a newly diagnosed patient with an autoimmune disorder.

[A case of the Lambert-Eaton syndrome of non-neoplastic origin. Ten-year follow-up]. / Przypadek zespolu Lamberta-Eatona pochodzenia nienowotworowego. Obserwacja 10-letnia.

A case is presented of a 34-year-old man who developed weakness of the proximal muscles of the extremities, particularly lower, slight myalgia, and vegetative symptoms (dryness in the mouth). Those symptoms progressed within a month. On examination weakness of the muscles of the extremities was found as well as weak tendon reflexes, slight atrophy of muscles of the arms and thighs and apokamnosis. Edrophonium test was slightly positive. Electrostimulation revealed changes typical of the Lambert-Eaton syndrome: low amplitude of the compound muscle action potential on single stimulus, decreasing amplitude of the subsequent responses to 3 Hz stimulation, marked facilitation on 30 Hz stimulation. Neoplastic etiology was excluded by chest X-ray and CT, as well as by bronchoscopy, abdominal and prostatic USG, and thyroid USG and scintigraphy. Antibodies to AChR were not found in the serum. The titre of the antibodies against voltage-gated calcium channels was highly positive which was decisive in the diagnosing of the Lambert-Eaton syndrome. The patient was treated with pyridostigmine, corticosteroids, cyclophosphamide and immunoglobulins. Ten years of follow-up have fully confirmed the diagnosis of a non-neoplastic Lambert-Eaton syndrome.

Estudios neurofisiológicos de la unión neuromuscular / Neurophysiological studies of the neuromuscular junction

Introducción. El papel de los estudios neurofisiológicos (ENF) en el diagnóstico de las enfermedades de la transmisión neuromuscular (TNM) se fundamenta en el estudio del fallo de la fibra muscular para alcanzar una despolarización suficiente para que el potencial de placa alcance el umbral adecuado y conseguir un potencial de acción muscular. Este impulso bloqueado total o parcialmente originará los distintos tipos de respuestas en los tests neurofisiológicos. Objetivo. Analizar los distintos ENF aplicados como método diagnóstico en las enfermedades que alteran la TNM. Desarrollo. Se revisa el concepto de margen de seguridad de la placa motora y se describen las técnicas neurofisiológicas más utilizadas en la actualidad –estimulación repetitiva, electromiografía (EMG) convencional, de fibra aislada con activación voluntaria y con activación eléctrica axonal– y los hallazgos más frecuentes en las enfermedades de la TNM. Conclusiones. Los ENF servirán para confirmar o no el diagnóstico clínico, excluir otras enfermedades neuromusculares concomitantes, determinar si el proceso es pre o postsináptico, monitorizar el curso clínico de la enfermedad, tanto si es natural o en respuesta al tratamiento médico o quirúrgico, y permiten, además, determinar el estado de la TNM en los casos de remisión clínica, así como detectar trastornos subclínicos. Los estudios de EMG de fibra aislada son el diagnóstico neurofisiológico que muestra una mayor sensibilidad en el diagnóstico de estas enfermedades (AU)

Introduction. The role played by neurophysiological studies (NPS) in the diagnosis of diseases affecting neuromuscular transmission (NMT) is based on the study of the failure of muscle fibres to achieve a sufficient degree of depolarisation for the junction potential to reach the appropriate threshold and attain a muscular action potential. This totally or partially blocked impulse will give rise to different types of responses in neurophysiological tests. Aims. To analyse the different NPS as diagnostic methods in diseases that affect NMT. Development. The article offers a review of the concept of the safety margin at the neuromuscular junction and a description of the most common neurophysiological techniques currently in use –repetitive stimulation, as well as conventional or single fibre electromyography (EMG) with voluntary activation or axonal electrical activation–. The most frequent findings in diseases affecting NMT are also discussed. Conclusions. NPS will be useful to confirm or reject the clinical diagnosis, to exclude other concomitant neuromuscular diseases, to establish whether the process is pre- or post-synaptic, to monitor the clinical course of the disease (when it is both natural or in response to the medical or surgical treatment) and also to enable the physician to determine the status of NMT in cases of clinical remission, as well as to detect subclinical disorders. Single fibre EMG studies are the most sensitive method of neurophysiological diagnosis when dealing with these diseases (AU)

Lambert-eaton myasthenic syndrome: diagnosis and treatment.

A high index of suspicion is essential in arriving at the correct diagnosis of Lambert-Eaton myasthenic syndrome (LEMS). LEMS should be considered in the differential in any patient who has proximal weakness, reduced or absent muscle stretch reflexes, and dry mouth. Weakness predominates in hip and shoulder muscles, but may also affect ocular and oropharyngeal muscles to a lesser extent. The diagnosis is confirmed by demonstrating characteristic electromyographic findings-low-amplitude muscle responses that increase dramatically after activation. Most patients also have circulating antibodies to the voltage-gated calcium channel. Half the patients with LEMS have a malignancy, usually small-cell lung cancer. The diagnosis should trigger an intensive search for malignancy, especially in older patients with a history of smoking. Younger, nonsmoking patients are likely to have LEMS as part of a more general autoimmune state. Successful treatment of the underlying cancer leads to improvement in many patients. More than 85% of patients have clinically significant benefit from 3,4-diaminopyridine (DAP). In over half of these, the improvement is marked. If severe weakness persists despite DAP, immunotherapy should be considered. Plasma exchange and high-dose immunoglobulin induce transient improvement in many patients, but function rarely becomes normal. Combinations of prednisone, azathioprine, or cyclosporine have been used with variable success. Improvement, if any, occurs only after many months and requires chronic administration of immunosuppressive medications at significant doses. The long-term prognosis in LEMS is determined by the presence of cancer or other autoimmune disease.

Cloning and characterization of a Lambert-Eaton myasthenic syndrome antigen.

Lambert-Eaton myasthenic syndrome is a paraneoplastic neuromuscular disorder in which an immune response directed against a small-cell lung tumor crossreacts with antigens in the neuromuscular junction. To isolate and characterize the antigens, we screened a human fetal brain expression library with a high-titer serum from a patient with Lambert-Eaton myasthenic syndrome. This screening resulted in the isolation of a complementary DNA clone encoding an antigen we call myasthenic syndrome antigen B (MysB). Approximately 43% (3 of 7) of Lambert-Eaton myasthenic syndrome sera specifically recognized MysB fusion protein, whereas none of 34 control sera did. The predicted amino acid sequence of this clone shows a high degree of homology to the beta subunit of calcium channel complexes. The MysB pre-messenger RNA is alternatively spliced to yield 3 forms of the protein differing in the domain between two highly conserved alpha-helical segments.