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Duchenne muscular dystrophy (DMD) is one of the most commonly recognized dystrophinopathies. There are no approved therapeutic options available for this disease but recent discoveries have led to hope that effective therapies might be forthcoming. With funding from patient advocacy groups, private investors, and governmental bodies such as the Food and Drug Administration Office of Orphan Product Development (FDA/OOPD), gene modification and other molecular therapies are being actively investigated. However, since DMD patients are few in number and disease manifestations vary considerably in early and late stages of disease, obtaining the data needed for full evaluation of putative therapies may prove challenging. Should ambulation remain the focus of Phase 2/3 studies or should consideration be given to the primary causes of late-stage morbidity and mortality, e.g., cardiac and respiratory dysfunction related to reduced or absent dystrophin production? It seems reasonable to argue that clinical trials planned for DMD should consider the entire population.

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BACKGROUND: We detected disproportionate reporting of amyotrophic lateral sclerosis (ALS) with HMG-CoA-reductase inhibitors (statins) in the Food and Drug Administration's (FDA) spontaneous adverse event (AE) reporting system (AERS). PURPOSE: To describe the original ALS signal and to provide additional context for interpreting the signal by conducting retrospective analyses of data from long-term, placebo-controlled clinical trials of statins. METHODS: The ALS signal was detected using the multi-item gamma Poisson shrinker (MGPS) algorithm. All AERS cases of ALS reported in association with use of a statin were individually reviewed by two FDA neurologists. Manufacturers of lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, and rosuvastatin were requested to provide the number of cases of ALS diagnosed during all of their placebo-controlled statin trials that were at least 6 months in duration. RESULTS: There were 91 US and foreign reports of ALS with statins in AERS. The data mining signal scores for ALS and statins ranged from 8.5 to 1.6. Data were obtained from 41 statin clinical trials ranging in duration from 6 months to 5 years and representing approximately 200,000 patient-years of exposure to statin and approximately 200,000 patient-years of exposure to placebo. Nine cases of ALS were reported in statin-treated patients and 10 cases in placebo-treated patients. CONCLUSIONS: Although we observed a data mining signal for ALS with statins in FDA's AERS, retrospective analyses of 41 statin clinical trials did not reveal an increased incidence of ALS in subjects treated with a statin compared with placebo.

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Electrodiagnosis has a prominent role in the diagnosis of common entrapment neuropathies (carpal tunnel syndrome and ulnar neuropathy at the elbow) and plexopathies (idiopathic brachial plexopathy and diabetic lumbar radiculoplexopathy). The relevant anatomy and pathology of these disorders is reviewed in the context of electrodiagnosis and prognosis.

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Repetitive nerve stimulation often shows responses with an abnormal decrement in patients with amyotrophic lateral sclerosis (ALS), suggesting instability of the neuromuscular junction; however, the pathophysiology and response characteristics of this instability are not clear. We evaluated response variability of 47 single motor units from 16 patients with ALS and 51 units from 10 normal subjects, acquired by delivering threshold stimuli sporadically at 0.5 HZ or less. In addition, in 46 other different single motor units obtained from 21 patients with ALS, variability was studied at both 1- and 3-HZ stimulation rates. Motor units from patients with ALS were significantly more variable than those from normal subjects, even when their larger amplitude was accounted for. This increased variability was not rate dependent. Response variability is a critical measure in the statistical method of motor unit number estimation and is attributed to variability in the number of units activated; the fact that variability of single motor units varies with disease state may be a potentially confounding factor in the application of the technique.

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Temporal dispersion and phase cancellation limit the utility of amplitude reduction in compound muscle action potential (CMAP) as a measure of focal conduction block but may not affect motor unit number estimation (MUNE). Hence, MUNE offers the potential of a specific measure of conduction block. We investigated the role of MUNE in 11 patients with ulnar neuropathy and conduction block at the elbow and also in 8 normal subjects. MUNE failed to detect motor unit dropout in the patient group because reduced values for surface-recorded motor unit potentials (SMUPs) were obtained at proximal locations, suggesting that focal compression selectively damages larger motor axons, an hypothesis that has support from animal studies. We conclude that, because MUNE is affected by the physiological characteristics of functional axons surviving the underlying pathological process, the utility of MUNE is limited to diseases in which the expected pathology affects motor axons uniformly.

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