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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.

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.

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.

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.

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.