Search

Introduction Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin‐antibody–positive double‐seronegative myasthenia gravis (DNMG). Methods DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. Results Of 181 DNMG patients, 27 (14.9%) were positive for either low‐density lipoprotein receptor–related protein 4 (LRP4) or agrin antibodies. Twenty‐three DNMG patients (12.7%) were positive for both antibodies. More antibody‐positive patients presented with generalized symptoms (69%) compared with antibody‐negative patients (43%) (P ≤ .02). Antibody‐positive patients’ maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody‐negative patients (P ≤ .005). Seventy percent of antibody‐positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody‐negative patients. Most LRP4‐ and agrin‐antibody–positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow‐up of 11 years. Discussion Antibody‐positive patients had more severe clinical disease than antibody‐negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.

Aim: The skeletal muscle Cl− channels, the ClC-1 channels, stabilize the resting membrane potential and dampen muscle fibre excitability. This study explored whether ClC-1 inhibition can recover nerve-stimulated force in isolated muscle under conditions of compromised neuromuscular transmission akin to disorders of myasthenia gravis and Lambert–Eaton syndrome. Methods: Nerve-muscle preparations were isolated from rats. Preparations were exposed to pre-or post-synaptic inhibitors (ω-agatoxin, elevated extracellular Mg2+, α-bungarotoxin or tubocurarine). The potential of ClC-1 inhibition (9-AC or reduced extracellular Cl−) to recover nerve-stimulated force under these conditions was assessed. Results: ClC-1 inhibition recovered force in both slow-twitch soleus and fast-twitch EDL muscles exposed to 0.2 µmol/L tubocurarine or 3.5 mmol/L Mg2+. Similarly, ClC-1 inhibition recovered force in soleus muscles exposed to α-bungarotoxin or ω-agatoxin. Moreover, the concentrations of tubocurarine and Mg2+ required for reducing force to 50% rose from 0.14 ± 0.02 µmol/L and 4.2 ± 0.2 mmol/L in control muscles to 0.45 ± 0.03 µmol/L and 4.7 ± 0.3 mmol/L in muscles with 9-AC respectively (P + channels (4-AP) relieve symptoms in myasthenia gravis and Lambert–Eaton syndrome, respectively. Neostigmine and 9-AC additively increased the tubocurarine concentration required to reduce nerve-stimulated force to 50% (0.56 ± 0.05 µmol/L with 9-AC and neostigmine) and, similarly, 4-AP and 9-AC additively increased the Mg2+ concentration required to reduce nerve-stimulated force to 50% (6.5 ± 0.2 mmol/L with 9-AC and 4-AP). Conclusion: This study shows that ClC-1 inhibition can improve neuromuscular function in pharmacological models of compromised neuromuscular transmission.

Resumen La debilidad producida por la patologia del musculo o de la transmision neuromuscular tiene multiples causas. La aproximacion a este problema comienza por una anamnesis exhaustiva y sistematica que identifique patron de herencia, factores desencadenantes, edad y forma de inicio y sintomas especificos. La exploracion neurologica y general nos aportara datos fundamentales para ir restringiendo las posibilidades diagnosticas. Los estudios neurofisiologicos son una extension de la exploracion clinica, pueden sugerir el origen miopatico y son diagnosticos en las enfermedades de la transmision neuromuscular. Distintos anticuerpos son diagnosticos en enfermedades como miopatias inflamatorias o miastenia gravis. La biopsia muscular muestra rasgos caracteristicos de distintas miopatias y puede ser diagnostica o reducir el diagnostico diferencial a unas cuantas entidades. En las miopatias hereditarias y sindromes miastenicos congenitos, el diagnostico de certeza viene dado, muchas veces, por el estudio genetico que identifica el defecto molecular subyacente. Several causes are involved on muscle or neuromuscular transmission disorders causing muscle weakness. Exhaustive and systematic anamnesis, looking for inheritance pattern, triggering factors, age, onset form and specific symptoms, constitute the first approach. Neurological and general examination will bring us fundamental data focusing diagnostic alternatives. Neurophysiological tests, as an extension of the clinical exploration, can suggest myopathic origin, as well as they are a diagnostic tool for neuromuscular transmission disorders. In some cases, serological tests allow the diagnosis of several inflammatory myopathies or myasthenia gravis. In other myopathies, muscle biopsy shows characteristic features playing diagnostic role or supporting differential diagnosis. The certainty for diagnosis of inherited myopathies and congenital myasthenic syndromes is achieved, in many cases, by genetic examination revealing underlying molecular defect.

Congenital myasthenic syndrome (CMS) is a heterogenous group of inherited disorders caused by genetic defects that affect transmission of signals from nerve terminals to muscle endplates at the neuromuscular junction (NMJ) [1–4]. Based on the site and biochemical mechanism of the underlying defect, they are classified in presynaptic, synaptic (basal lamina-associated), and postsynaptic subcategories of CMS. The recent classification takes into account defects in protein glycosylation causing CMS [2]. These abnormal proteins are located at different sites of the endplate.

Congenital myasthenic syndromes (CMS) are neuromuscular transmission disorders caused by mutations in genes encoding neuromuscular junction proteins. CMS due to choline acetyltransferase (CHAT) gene is characterized by episodic apnea. We report a case of a 12-month-old female patient presented with recurrent episodic apnea carrying a mutation in CHAT gene, p.I336T. Furthermore, we describe the genetic and clinical findings in 44 CMS patients due to CHAT mutations in the literature up to date. Episodes of apnea and respiratory insufficiency are the hallmarks of CHAT mutations. Clinical manifestations usually provoked by infections and fever. CMS due to CHAT mutations are rare, but it is important to diagnosis. Early diagnosis and appropriate treatment can improve morbidity and mortality.

It is a great pleasure to be asked to honour the memory of Dr. Baldev Singh by reviewing the field of autoantibodies in myasthenia gravis and other neurotransmission disorders. The neuromuscular junction (NMJ) is the site of a number of different autoimmune and genetic disorders, and it is also the target of many neurotoxins from venomous snakes, spiders, scorpions and other species. The molecular organization of the NMJ is graphically represented in [Figure 1A], where different ion channels, receptors and other proteins are shown. Four of the ion channels or receptors are directly involved in autoimmune diseases. This brief review will not only concentrate on these conditions but also illustrate how their study is helping us to understand the etiology of rare but treatable neurological syndromes of the central nervous system.

Durch eine fruhere Diagnosestellung und verbesserte Therapie wurden die Mortalitat und der Verlauf einer erworbenen neuromuskularen Ubertragungsstorung deutlich verbessert. Trotzdem bleiben die Erkennung und die Aufklarung der Pathogenese neuromuskularer Transmissionsstorungen eine klinische und wissenschaftliche Herausforderung. Die Abgrenzung seronegativer erworbener Myasthenien gegenuber den kongenitalen myasthenen Syndromen (CMS) ist im Hinblick auf eine differenzierte Therapie und zur Vermeidung einer nichtindizierten immunsuppressiven Therapie bei Patienten mit kongenitalen Formen wichtig. An ein CMS sollte insbesondere immer dann gedacht werden, wenn bei Patienten mit seronegativer Myasthenie die Anamnese einer belastungsabhangigen Muskelschwache bis in die Kindheit oder Jugendzeit zuruckreicht oder aber eine Spatmanifestation mit einem Gliedergurtelphanotyp oder klinischen Besonderheiten eines autosomal-dominanten „Slow-channel“-Syndroms vorliegt, hier mit selektiven Paresen der zervikalen Muskulatur sowie der Finger- und Unterarmstreckermuskulatur. Die Familienanamnese bei den zumeist rezessiv vererbten CMS ist nicht immer wegweisend. Daher kann eine molekulargenetische Untersuchung zur Diagnosesicherung oder auch zum Ausschluss von haufigeren, potenziell symptomatisch behandelbaren CMS hilfreich sein.

Introduction Despite advances in antibody testing, electrodiagnostic testing still plays a crucial role in diagnosing disorders of the neuromuscular transmission (NMT). Existing criteria for NMT disorders are derived from consensus, while no evidence-based criteria have been published. The aim of this study was to derive evidence-based criteria for the electrodiagnosis of NMT disorders, supported on clinical diagnosis as agreed by consensus (gold standard) in an expert group. Methods A group of experienced physicians in the European multicentre project ESTEEM representing six different European countries reviewed samples of their patients diagnosed with NMT disorder. A total of 164 examinations obtained a consensus diagnosis of definite (105), probable (44), or possible (15) NMT disorder. In these examinations 405 repetitive nerve stimulation (RNS) and 116 single fibre electromyography (SFEMG) studies were performed. The average numbers of abnormal RNS and SFEMG studies in the patients with a probable consensus diagnosis of NMT disorder served as basis for recommendation of minimal electrodiagnostic criteria. Results The average number of performed RNS studies per patient from each of eight physicians ranged from 1.9 to 5.2, while the average number of abnormal RNS studies ranged from 0.7 to 3.2. For SFEMG the average number ranged from 0.09 to 1.6 for performed studies and from 0.09 to 1.5 for abnormal studies. In the 99 patients diagnosed with generalised myasthenia, the sensitivity of RNS varied from 43% (abductor digiti minimi muscle) to 78% (nasalis muscle), while the sensitivity of SFEMG ranged from 80% (orbicularis oculi muscle) to 100% (anconeus and frontalis muscles). As minimal electrodiagnostic criteria, the ESTEEM group recommends that either (a) 2 abnormal RNS studies, or (b) 1 abnormal RNS study and 1 abnormal SFEMG study, or (c) 2 abnormal SFEMG should be required to diagnose a NMT disorder. To evaluate the electrodiagnostic tests, the routinely used limits for decrement at the different centres should be applied. Conclusion Electrodiagnostic consensus recommendations for the minimum number of RNS and SFEMG studies to diagnose disorders of the neuromuscular junction are suggested. The recommendations encourage use of different limits according to the muscle examined and the relevant age group (e.g. children vs. adults), preferably obtained locally at each diagnostic centre. These are the first electrodiagnostic criteria for NMT based on clinical evidence of diagnosis as agreed by consensus.

Introduction Repetitive nerve stimulation (RNS) is the standard procedure to evaluate neuromuscular transmission disorders. The cut-off level is often arbitrary and is usually the same for every test, despite the peculiarities of each nerve-muscle setting. Our objective was to perform a ROC curve analysis of four different RNS techniques and define the best cut-off level for them. Methods We did a retrospective study of RNS with 20 patients with positive serologic confirmation of Myasthenia Gravis and 20 patients with negative acetylcholine receptor binding antibodies and normal jitter studies of both orbicularis oculi and of another symptomatic muscle. All patients were submitted to RNS with six stimuli at 3 or 2 Hz of the following nerves (muscles): ulnar (abductor digiti minimi), accessory (trapezius), facial (nasal), and axillary (deltoid). The decrement was calculated using the negative amplitude of the fourth potential in relation to the first. Recordings after maximal contraction were not considered for analysis. We calculated sensitivity and specificity at four different cut-off levels for each technique: 10%, 7.5%, 5%, and >0%. We constructed the ROC curve, compared the techniques, and suggested the best cut-off point for each test. Results The specificity was 100% for all tests using the classical decrement cut-off of 10%. Using this, sensitivity was: 5% (ulnar), 30% (accessory), 65% (facial), and 60% (axillary). The area bellow curve was 0.52 (ulnar), 0.58 (accessory), 0.83 (facial), and 0.86 (axillary). The best cut-off was a decrement above 7.5% for all tests, keeping specificity at 100% for all except accessory, which was 95%. Using this, sensitivity was: 20% (ulnar), 40% (accessory), 65% (facial), and 70% (axillary). Conclusion RNS of facial and axillary nerves had a better performance than ulnar and accessory nerves. The cut-off level suggested by our study is a decrement above 7.5% for all tests. Larger studies can propose different cut-off levels for each technique.

The repetitive nerve stimulation test is the most commonly used technique for studying neuromuscular transmission disorders because of its relative simplicity and rapid results. The classic pattern in myasthenia gravis (MG) is normal compound muscle action potential (CMAP) amplitude and decremental response at low-rate stimulation (LRS), being observed in 75% of cases. The classic pattern in Lambert–Eaton myasthenic syndrome (LEMS) is low CMAP amplitude, decremental response at LRS, and incremental response at high-rate stimulation, being observed in 100% of cases. The single-fiber electromyography is abnormal in 88–100% of MG cases and in 100% of LEMS and botulism cases.

Neuromuscular jitter is a sensitive measure of the safety factor of neuromuscular transmission. Nevertheless, the actual relationship between jitter and the safety factor is unknown because these parameters have not been simultaneously measured. In order to explore the theoretical relationship between them, a computer model of mammalian neuromuscular transmission has been developed. If the safety factor is expressed as the absolute value of the natural logarithm of the probability of a block, the model predicts a double exponential relationship between the safety factor and jitter, except when the percentage of blocks is greater than 90%. In that case, the jitter value decreases. Simulation of acetylcholinesterase inhibition shows that this treatment decreases the neuromuscular transmission blocks more effectively in postsynaptic than in presynaptic disorders. In contrast, when the percentage of blocks is greater than 60%, the jitter value increases in both conditions.

En este capítulo se describen las enfermedades de la placa neuromuscular, su epidemiología, hallazgos clínicos, métodos diagnósticos y tratamiento de cada una de ellas In this chapter we describe the neuromuscular transmission disorders, the epidemiology, clinical features, diagnosis and treatment

Electrophysiologic tests in neuromuscular transmission disorders are valuable aids in the clinical assessment of patients with suspected disease. The techniques of RNS and SFEMG are most reliable when the electromyographer is aware of their pitfalls and when they are interpreted in relation to the overall clinical setting. RNS is the most widely used technique to assess the integrity of neuromuscular transmission but may be normal in many patients. Among the techniques used to assess abnormality of neuromuscular transmission, SFEMG is the most sensitive.

Repetitive nerve stimulation (RNS) is a simple and rapid method for evaluation of neuromuscular transmission defects. Although the effect of exercise in conjunction with RNS is well recognized, it has not been standardized in actual patient and control groups. In a prospective study over a period of 1 year, the authors evaluated the effect of exercise in conjunction with RNS in comparison with conventional 3-Hz RNS at rest in the clinical setting. Fifty-four patients who were referred for possible neuromuscular transmission disorders, in addition to 35 healthy control subjects, were studied. Amplitude and area decremental responses with RNS at rest and after 20 seconds of maximal exercise at 1-minute intervals up to 3 minutes were evaluated. The use of RNS with exercise resulted in additional diagnostic yield of up to 36.4% compared with conventional 3-Hz RNS at rest. The standardized use of exercise with RNS is advocated for increasing its diagnostic yield in the neurophysiologic laboratory.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of neuromuscular disorders that share clinical features with other neuromuscular transmission disorders but differ from acquired syndromes and among each other by their underlying molecular, genetic, and cellular pathogenesis. CMS may present in infancy or may not be recognized until childhood or later. Thus, a CMS may resemble neonatal or adult-onset myasthenia gravis (MG) or Lambert-Eaton syndrome (LES). Although impairment of neuromuscular transmission gives rise to similar clinical presentations, the sophisticated analysis of biopsied intact, muscle ifbers from CMS patients using electrophysiologic, microscopic, and molecular techniques has identified several varieties of CMS in which impairment of neuromuscular transmission occurs through distinct molecular and cellular mechanisms. In many cases, recording of evoked or spontaneous miniature endplate potentials (MEPPs) or miniature endplate currents (MEPCs) or single channel currents has identified the presence and type of pre- or postsynaptic defect of neuromuscular transmission. Coupled with electron microscopic, biochemical, and genetic data, these studies have led to the identification of the affected protein, gene, and mutation in several patients. This detailed molecular information has provided insights into disease mechanisms that have begun to guide the development of therapeutic strategies.

The diagnostic performance of the medical expert system MUNIN for diagnosis of neuromuscular disorders was evaluated on a set of 30 test cases. The cases were provided by 7 experienced electromyographers who were subsequently invited to participate in the evaluation. To reasonably cover the range of disorders, the electromyographers were asked to provide cases from patients with different types of muscular dystrophy, with neuromuscular transmission disorders, with motor neurone disease, and with different types of polyneuropathies. In addition, patients with a range of local neuropathies were provided. Out of the 30 cases, 11 cases were evaluated by an “almost peer review” method and the remaining 19 cases were evaluated by a “silver standard” method. The number of cases evaluated by “almost peer review” was limited to 11 due to time constraints on the evaluation procedure. During the “almost peer review”, each electromyographer was asked to diagnose patients, using a vocabulary that closely resembled MUNIN's vocabulary. Subsequently, we attempted to provide a consensus diagnosis for the patients based on discussion among the participating electromyographers. The electromyographers were also asked to assess how well MUNIN had performed in each case. The remaining 19 cases were evaluated by a “silver standard” procedure, where MUNIN's diagnosis was compared to the diagnosis of the expert who provided the case. The results indicated that MUNIN performed well, and the electromyographers considered “that MUNIN performed at the same level as an experienced neurophysiologist.” In particular, it was noted that MUNIN handled cases with conflicting findings well, and that it was able to diagnose patients with multiple diseases.

Repetitive nerve stimulation of the anconeus muscle is described. Control studies showed the test to be reliable and well tolerated over a range of stimulus frequencies and train lengths. Sixty-one patients with primary disorders of neuromuscular transmission were tested. Repetitive nerve stimulation of anconeus was abnormal in 2 of 21 patients with ocular myasthenia, but showed a significant decrementing response in 16 of 30 patients with generalized myasthenia gravis. In comparison with other muscles, repetitive nerve stimulation of anconeus was more sensitive than abductor digiti minimi, but equally sensitive as deltoid. The test may also be used to help characterize other disorders of neuromuscular transmission such as congenital myasthenia or the Lambert-Eaton myasthenic syndrome. Compared with single fibre EMG on extensor digitorum communis, repetitive stimulation of anconeus was usually, but not always, a less sensitive method of detecting a neuromuscular transmission disorder.

Ampicillin is considered a 'safe' drug in patients with neuromuscular transmission disorders although recently some doubt has been raised. The effect of ampicillin on neuromuscular transmission was studied in healthy subjects by means of single-fiber electromyography. A statistically significant increase of mean jitter value and of recordings with abnormally high jitter occurred after ampicillin treatment in comparison to basal examinations. Such results reaffirm that ampicillin might not be completely harmless in patients with neuromuscular transmission disturbances.

A patient with a known history of pernicious anemia had the combined features of autoimmune myasthenia gravis (MG) and the Eaton-Lambert syndrome (ELS). Initially, this patient had all the features typical of MG, and after thymectomy developed all the typical features of ELS. In view of the coexistence of two autoimmune neuromuscular transmission disorders in one patient, we termed this disorder "overlap myasthenic syndrome."