3,4-Diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome. A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome. 3,4-Diaminopyridine is more effective than placebo in a randomized, double-blind, cross-over drug study in LEMS. Treatment of myasthenia gravis exacerbation with intravenous immunoglobulin: a randomized double-blind clinical trial.
Lambert-Eaton myasthenic syndrome is characterized by muscle weakness, hyporeflexia, and autonomic dysfunction, which result from impaired release of acetylcholine from cholinergic nerve terminals. It is frequently associated with cancer, it is autoimmune-mediated, and treatment has been unsatisfactory. 3,4-Diaminopyridine enhances the release of acetylcholine. In this prospective, double-blind, placebo-controlled crossover study of 12 patients with Lambert-Eaton myasthenic syndrome (7 of whom had cancer), 3,4-diaminopyridine in doses up to 100 mg per day was effective in treating both the motor and the autonomic deficits of the syndrome. Muscle strength increased from an average of 70 percent of normal to 81 percent of normal in the upper extremities, and from 45 to 65 percent of normal in the lower extremities. The amplitudes of compound-muscle-action potentials nearly doubled, increasing from an average of 2.9 mV to 5.0 mV in the arm and from 1.6 mV to 3.1 mV in the leg. Autonomic symptoms were relieved. One patient had a seizure after 10 months of treatment, but other side effects from the drug were minimal and dose-related. We conclude that 3,4-diaminopyridine, either alone or in conjunction with other therapies, may be useful in the treatment of Lambert-Eaton myasthenic syndrome. The authors report the results of a prospective, placebo-controlled, randomized study to evaluate the effectiveness of 3,4-diaminopyridine (DAP) in patients with Lambert-Eaton myasthenic syndrome (LEMS) and to determine the acute and long-term side effects of DAP.
                Twenty-six patients with LEMS completed a two-arm parallel treatment protocol in which DAP, 20 mg three times daily, or placebo was given blindly for 6 days, and a quantitative examination of muscle strength (the quantitative myasthenia gravis [QMG] score) was used as the primary measure of efficacy. After the blinded study, patients were given open-label DAP and monitored for side effects as long as there was symptomatic improvement.
                Twelve patients took DAP, and 14 took placebo. There was no difference in the age of LEMS onset, gender distribution, incidence of lung cancer, or baseline muscle strength between the patients who were randomly assigned to receive placebo and those randomly assigned to DAP. Statistical analysis using the Wilcoxon's rank sum test demonstrated that patients who received DAP had a significantly greater improvement in the QMG score and in the summated amplitude of compound muscle action potentials recorded from three sentinel limb muscles. All but one LEMS patient had significant symptomatic improvement from subsequent open-label DAP. Side effects of DAP were negligible, consisting of perioral and digital paresthesia. Laboratory measurements demonstrated no evidence of toxicity affecting liver, renal, hematologic, endocrinologic, encephalographic, or electrocardiologic function acutely or after 6 months of open-label DAP.
                This study corroborates previous studies and many years of clinical experience showing that DAP is an effective and safe treatment for LEMS. The purpose of this study was to investigate the clinical and electrophysiological efficacy of 3,4-diaminopyridine (DAP) in patients with Lambert-Eaton myasthenic syndrome (LEMS) in a randomized, double-blind, cross-over drug trial. The diagnosis of LEMS was made based on the combination of fluctuating muscle weakness, diminished or absent reflexes, and more than 60% increment of the compound muscle action potential (CMAP) amplitude after brief exercise or 50-HZ stimulation on a repetitive nerve stimulation (RNS) test. Evaluations were done at baseline, with placebo, and with 3,4-DAP (up to 75-80 mg/day). Assignment of placebo or 3,4-DAP was done in a double-blinded manner. Measurements included subjective symptoms score, objective clinical measurements [LEMS classification, muscle strength score, quantitative myasthenia gravis (QMG) score] and RNS test and single-fiber electromyography (SFEMG). The differences between placebo and baseline values (placebo change) were compared with the differences between 3,4-DAP and baseline or placebo values (DAP change). Seven patients with LEMS (QMG score >9) participated in the study. One patient had major side-effects with 3,4-DAP and withdrew from the study. Statistically significant efficacy was noted with DAP change (N = 13) compared with placebo change (N = 7) according to the subjective symptoms score (P = 0.01), LEMS classification (P < 0.001), muscle strength score (P < 0.006), QMG score (P = 0.02), and CMAP (P = 0.03). For long-term treatment, 2 patients preferred 3,4-DAP, 1 chose guanidine hydrochloride, 1 preferred pyridostigmine, and 2 chose no treatment. A randomized, double-blind, cross-over drug trial of 3,4-DAP showed significant efficacy over placebo in patients with LEMS. As a long-term treatment, however, not all patients preferred this drug. The optimal dose of intravenous immunoglobulin (IVIG) in acute exacerbation of myasthenia gravis remains unknown. Increasing the treatment duration might provide added efficacy.
                To determine the optimal dose of IVIG for treating myasthenia gravis exacerbation.
                Randomized double-blind placebo-controlled multicenter trial designed to demonstrate superiority of the 2 g/kg dose over the 1 g/kg dose of IVIG, conducted between November 13, 1996, and October 26, 2002.
                One hundred seventy-three patients aged 15 to 85 years with acute exacerbation of myasthenia gravis.
                Participants were randomly assigned to receive 1 g/kg of IVIG on day 1 and placebo on day 2 (group 1) vs 1 g/kg of IVIG on 2 consecutive days (group 2).
                Improvement in the myasthenic muscular score after 2 weeks.
                The mean improvements in the myasthenic muscular scores after 2 weeks were 15.49 points (95% confidence interval, 12.09-18.90 points) in group 1 and 19.33 points (95% confidence interval, 15.82-22.85 points) in group 2. However, the difference between the 2 groups was not significant (effect size, 3.84 [95% confidence interval, -1.03 to 8.71]; P = .12).
                This trial found no significant superiority of 2 g/kg over 1 g/kg of IVIG in the treatment of myasthenia gravis exacerbation.
Limited but moderate to high quality evidence from randomised controlled trials showed that over days 3,4-diaminopyridine, or for up to 8 weeks IVIg, improved muscle strength scores and CMAP amplitudes in participants with Lambert-Eaton myasthenic syndrome. There are insufficient data at present to quantify this effect. Other possible treatments have not been tested in randomised controlled trials.