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Objectives: To describe the clinical and electrophysiologic features of synaptotagmin II (SYT2) mutations, a novel neuromuscular syndrome characterized by foot deformities and fatigable ocular and lower limb weakness, and the response to modulators of acetylcholine release. Methods: We performed detailed clinical and neurophysiologic assessment in 2 multigenerational families with dominant SYT2 mutations (c.920T>G [p.Asp307Ala] and c.923G>A [p.Pro308Leu]). Serial clinical and electrophysiologic assessments were performed in members of one family treated first with pyridostigmine and then with 3,4-diaminopyridine. Results: Electrophysiologic testing revealed features indicative of a presynaptic deficit in neurotransmitter release with posttetanic potentiation lasting up to 60 minutes. Treatment with 3,4-diaminopyridine produced both a clinical benefit and an improvement in neuromuscular transmission. Conclusion: SYT2 mutations cause a novel and potentially treatable complex presynaptic congenital myasthenic syndrome characterized by motor neuropathy causing lower limb wasting and foot deformities, with reflex potentiation following exercise and a uniquely prolonged period of posttetanic potentiation.

Myasthenia gravis (MG) with antibodies to the muscle-specific tyrosine kinase receptor (MuSK) is characterized by prominent cranial and bulbar weakness. The disease course is often severe and some patients develop permanent, disabling symptoms despite long-term immunosuppression.1 In patients with MuSK MG, the administration of acetylcholinesterase inhibitors (AChE-I) is poorly effective and often associated with clinical and electrophysiologic signs of cholinergic hypersensitivity.2 3,4-Diaminopyridine (3,4-DAP) improves neuromuscular transmission (NMT) by increasing quantal release. We report the case of an adult patient with MuSK MG who was responsive to and tolerant of 3,4-DAP.

Several drugs that primarily act on gamma-aminobutyrate or muscarinic receptors have been used to treat downbeat nystagmus (DBN) syndrome despite their having only moderate success and causing several side effects that limit their effectiveness. These drugs were tested under the assumption that DBN was caused by a disinhibition of a physiologic inhibitory cerebellar input on vestibular nuclei.To evaluate the effects of a single dose of the potassium channel blocker 3,4-diaminopyridine (3,4-DAP), which is known to increase the excitability of Purkinje cells, on DBN in a prospective, placebo-controlled, double-blind study with a crossover design.Seventeen patients with DBN due to cerebellar atrophy (5), infarction (3), Arnold-Chiari malformation (1), or unknown etiology (8) were included in the study (1 of 18 patients had to be excluded). Mean peak slow-phase velocity (PSPV) was measured before and 30 minutes after randomized ingestion of 20 mg of 3,4-DAP or placebo orally; at least 1 week later, the treatments were switched.3,4-DAP reduced mean PSPV of DBN from 7.2 +/- 4.2 degrees /s (mean +/- SD) before treatment to 3.1 +/- 2.5 degrees/s 30 minutes after ingestion of the 3,4-DAP (p0.001, two-way analysis of variance). Placebo had no measurable effect. In 10 of 17 subjects, the mean PSPV decreased by50% and in 12 of 17 by40%. In parallel, the subjects had less oscillopsia and felt more stable while standing and walking. Nine of the subjects continued to take the drug with success. Except for transient minor perioral or digital paresthesia reported by three subjects and nausea and headache reported by one, no other side effects were observed.In this study, the authors demonstrated that a single dose of 3,4-DAP significantly improved DBN. In view of animal studies reporting that micromolar concentrations of 4-aminopyridine increased the excitability of Purkinje cells, it is suggested that the efficacy of 3,4-DAP may be due to an increase of the physiologic inhibitory influence of the vestibulocerebellum on the vestibular nuclei.

3,4-Diaminopyridine (3,4-DAP) is a potassium channel blocker that has recently demonstrated an antioscillatory effect in humans by significantly reducing downbeat nystagmus. Based on the presumed role of intrinsic oscillations in the pathophysiology of essential tremor (ET), the authors conducted a double-blind, placebo-controlled crossover study assessing the antitremor effect of a single dose of 3,4-DAP in 19 patients with ET. They did not find any significant change in tremor severity as measured by clinical ratings or accelerometry.

3,4-diaminopyridine (3,4-DAP), a potassium (K+) channel blocker, improves fatigue and motor function in multiple sclerosis (MS). Although it was thought to do so by restoring conduction to demyelinated axons, recent experimental data show that aminopyridines administered at clinical doses potentiate synaptic transmission.To investigate motor cerebral activity with fMRI and transcranial magnetic stimulation (TMS) after a single oral dose of 3,4-DAP in patients with MS.Twelve right-handed women (mean +/- SD age 40.9 +/- 9.3 years) underwent fMRI on two separate occasions (under 3,4-DAP and under placebo) during a simple motor task with the right hand. FMRI data were analyzed with SPM99. After fMRI, patients underwent single-pulse TMS to test motor threshold, amplitude, and latency of motor evoked potentials, central conduction time, and the cortical silent period; paired-pulse TMS to investigate intracortical inhibition (ICI) and intracortical facilitation (ICF); and quantitative electromyography during maximal voluntary contraction.FMRI motor-evoked brain activation was greater under 3,4-DAP than under placebo in the ipsilateral sensorimotor cortex and supplementary motor area (p0.05). 3,4-DAP decreased ICI and increased ICF; central motor conduction time and muscular fatigability did not change.3,4-DAP may modulate brain motor activity in patients with MS, probably by enhancing excitatory synaptic transmission.

In order to see clearly enough to read a book or drive a car, visual images must be held quite still upon the central part of the retina, the fovea, which has the highest density of photoreceptors. Patients with nystagmus cannot hold the line of sight steady; the drift of visual images across the retina blurs vision and may cause oscillopsia—the illusion that the visual scene is moving. A variety of forms of nystagmus may disrupt vision and lead to postural instability. Initial progress in identifying drugs to suppress various forms of nystagmus came from clinical reports. Controlled clinical trials have indicated that certain drugs are useful: gabapentin1 and memantine2 have both been reported to suppress acquired pendular nystagmus in patients with MS. The appendix summarizes agents that have been reported effective in some …

Article abstract The authors reviewed the incidence of cancer, repetitive nerve stimulation findings, and response to treatment in 73 patients with Lambert-Eaton myasthenic syndrome. Thirty-one patients (42%) had lung cancer, 29 small cell. Doubling of the compound motor action potential amplitude in three tested distal muscles was seen in only 41% of patients. Treatment with 3,4-diaminopyridine produced moderate to marked self-reported functional improvement in 79% of the 53 treated patients.

To examine the efficacy and toxicity of oral 3,4 diaminopyridine (DAP) in dosages up to 100 mg/day, 36 patients with multiple sclerosis (MS) enrolled in a randomized, double-blind, placebo-controlled, crossover trial. The primary outcome measure was improvement of a prospectively defined neurologic deficit, which was leg weakness in 34 patients. Secondary outcome measures included the patient's subjective response, scored manual motor testing (MMT) of leg strength, scored leg strength from videotaped motor testing (VMT), quadriceps and hamstrings strength (QMT) measured by isometric dynamometry, neuropsychological testing (NPT), ambulation index (AI), and Expanded Disability Status Scale (EDSS) score. Paresthesias and abdominal pain were common and were dose limiting in eight patients. Three patients had episodes of confusion, and one patient had a seizure while on DAP. Eight patients withdrew from the study, leaving 28 evaluable patients for the efficacy analysis. The prospectively defined neurologic deficit improved in 24 patients-22 on DAP and 2 on placebo (p = 0.0005). All improvements were in leg weakness. Subjective response and measures of leg strength and function (MMT, VMT, QMT, and AI) improved on DAP compared with placebo. Neither NPT nor EDSS scores improved. DAP treatment can induce improvements in leg strength in MS patients, but toxicity is limiting in many patients.

Respiratory failure is a common manifestation of myasthenia gravis but is infrequent in Lambert-Eaton myasthenic syndrome (LEMS), where it is often related to the use of paralytic agents or intercurrent pulmonary pathology. Therapies that are effective acutely in myasthenia gravis are usually of minimal benefit in LEMS. We describe a patient with respiratory failure secondary to LEMS who responded to 3,4-diaminopyridine and review the 12 previously reported cases of ventilatory failure in LEMS.

Objective: To examine the pharmacogenomics of amifampridine phosphate in healthy volunteers. Background Amifampridine phosphate, a potassium channel blocking agent, is used in the treatment of Lambert Eaton myasthenic syndrome. We recently identified 3 N-acetyl amifampridine as its major metabolite. Genetic polymorphisms in N-acetyl-transferase 2 (NAT 2) genes determine acetylator status (“fast” or “slow”) and influence both toxicity and efficacy profiles of acetylated drugs. Design/Methods: An open label single center study enrolled 26 healthy subjects, half fast and half slow acetylators based on NAT 2 genotyping and pattern of caffeine metabolism. We examined the effect of acetylator status on pharmacokinetics (PK) of single ascending and multiple (QID) oral doses of amifampridine phosphate. Results: Subjects9 mean age was 29±11 years; 18(69%) were male and 23(88%) Caucasian. PKc analysis revealed that slow acetylators had 3-4x higher plasma drug levels than fast acetylators. After a single 20 mg dose, C max was 56.7 ± 16.1 ng/ml in slow vs 16.2 ± 4.56 ng/ml in fast acetylators (p 0-inf was 142 ± 32.1 ng-h/ml in slow vs 24.7 ± 2.47 ng-h/ml in fast acetylators ( p Conclusions: This is the first clinical study of the pharmacogenomics of amifampridine. Polymorphisms in the N-acetyltransferase system create 3-4-fold differences in plasma levels and alter the frequency of adverse events. Supported by: BioMarin Pharmaceuticals Inc. Disclosure: Dr. Haroldsen has received personal compensation for activities with BioMarin Pharmaceutical as an employee.Dr. Haroldsen has received research support from BioMarin Pharmaceutical Inc. Dr. Garovoy has received research support from BioMarin Pharmaceuticals Inc.

We evaluated the outcome in 16 patients with Lambert-Eaton myasthenic syndrome (LEMS) associated with histologically verified small-cell carcinoma (SCC). Thirteen patients received specific tumor therapy (chemotherapy, radiation therapy, or resection) and most also received pharmacologic and immunologic treatment for LEMS. Seven of 11 patients surviving for more than 2 months after tumor therapy showed substantial neurologic improvement (1 patient being in complete remission at 7 years); in 3 of 11 improvement was transient. An EMG index of disease severity (compound muscle action potential amplitude in abductor digiti minimi) was significantly increased at final follow-up (p less than 0.01; n = 11). A pretreatment amplitude greater than 3.0 mV was a good prognostic sign. We conclude that a combined treatment approach in SCC-LEMS usually results in neurologic improvement.

We used a new drug, 3,4-diaminopyridine, to treat five patients with the Lambert-Eaton syndrome, one with a carcinoma and four cryptogenic. The effects of intravenous, oral, and rectal administration were evaluated clinically and electrophysiologically after single doses and during continuous treatment for up to 21 months. 3,4-Diaminopyridine effectively ameliorated the neuromuscular and autonomic nervous system disorders without severe side effects. Anticholinesterase drugs strongly potentiated the benefit of 3,4-diaminopyridine.

Four patients with Eaton-Lambert syndrome, four patients with congenital myasthenia, and one patient with myasthenia gravis were treated with oral 4-aminopyridine for periods of up to 10 months, doses varying from 40 to 200 mg per day. Clinical and electrophysiologic assessment confirmed the effectiveness of the drug when given alone or in conjunction with anticholinesterases. At therapeutically effective doses, central side effects were frequent and unpredictable. Three patients had a generalized fit and one patient developed a confusional state. Adverse side effects must severely limit the place of 4-aminopyridine in the treatment of patients with these conditions.

We undertook serial clinical and electromyographic muscle action potential (MAP) amplitude assessments in nine patients with the Lambert-Eaton myasthenic syndrome (LEMS) over 0.5 to 2.5 years who received plasma exchange (PE; 5 to 15 exchanges over 4 to 19 days) and immunosuppressive drug (IS) treatment (prednisolone 60 to 100 mg on alternate days, azathioprine 2.5 mg/kg for 0.5 to 2.5 years), and who had no signs of carcinoma at entry. Eight patients responded to PE. The peak MAP response occurred 10 to 15 days post-PE, representing a 2.5-fold mean increase and was significant (p less than 0.01). Two of three patients who developed carcinoma responded initially to IS. Three of six noncarcinoma patients developed sustained clinical and MAP remission after 0.5 to 1 year; the three others, of whom two were intolerant of azathioprine, improved. IS and PE may benefit LEMS patients, but caution is required when carcinoma risk is high.