Gerald M. Fenichel

Long‐term benefit from prednisone therapy in Duchenne muscular dystrophy

Two successive, 6-month, randomized, double-blind, controlled trials of prednisone showed that 0.75 ing/kg/d was the optimal dose to improve strength in boys with Duchenne muscular dystrophy (DMD). We attempted to maintain 93 boys on that dose for an additional 2 years. During the 3 years of observation, the decline in average muscle strength scores of all boys taking prednisone was 0.072 units/yr, as compared with an expected decline of 0.341 units/yr from natural history controls. The occurrence of side effects in some boys prevented maintenance of the full dose, which may have lessened the response. At the time of last visit, dosages ranged from 0.15 mg/kg to 0.75 mg/kg. In addition to maintaining their strength, several of the boys actually improved their performance in lifting kilogram weights and in some timed function tests. Treatment of DMD with prednisone significantly slows the progression of weakness and loss of function for at least 3 years.

Duchenne dystrophy: randomized, controlled trial of prednisone (18 months) and azathioprine (12 months)

Prednisone has been shown to improve strength in Duchenne dystrophy. Azathioprine often benefits corticosteroid-responsive diseases and can reduce the dose of prednisone needed. The present study reports a randomized, controlled trial of prednisone and azathioprine designed to assess the longer-term effects of prednisone and to determine whether azathioprine alone, or in combination with prednisone, improves strength. Ninety-nine boys (aged five to 15 years) with Duchenne dystrophy were randomized to one of three groups: (I) placebo; (II) prednisone 0.3 mg/kg/d; or (III) prednisone 0.75 mg/kg/d. After 6 months, azathioprine 2 to 2.5 mg/kg/d was added in groups I and II and placebo added in group III. The study showed that the beneficial effect of prednisone (0.75 mg/kg/d) is maintained for at least 18 months and is associated with a 36% increase in muscle mass. There was weight gain, growth retardation, and other side effects. Azathioprine did not have a beneficial effect. This study suggests that prednisones beneficial effect is not due to immunosuppression.

Limb-Girdle Muscular Dystrophy in the United States

Limb-girdle muscular dystrophy (LGMD) has been linked to 15 chromosomal loci, 7 autosomal-dominant (LGMD1A to E) and 10 autosomal-recessive (LGMD2A to J). To determine the distribution of subtypes among patients in the United States, 6 medical centers evaluated patients with a referral diagnosis of LGMD. Muscle biopsies provided histopathology and immunodiagnostic testing, and their protein abnormalities along with clinical parameters directed mutation screening. The diagnosis in 23 patients was a disorder other than LGMD. Of the remaining 289 unrelated patients, 266 had muscle biopsies sufficient for complete microscopic evaluation; 121 also underwent Western blotting. From this combined evaluation, the distribution of immunophenotypes is 12% calpainopathy, 18% dysferlinopathy, 15% sarcoglycanopathy, 15% dystroglycanopathy, and 1.5% caveolinopathy. Genotypes distributed among 2 dominant and 7 recessive subtypes have been determined for 83 patients. This study of a large racially and ethnically diverse population of patients with LGMD indicates that establishing a putative subtype is possible more than half the time using available diagnostic testing. An efficient approach to genotypic diagnosis is muscle biopsy immunophenotyping followed by directed mutational analysis. The most common LGMDs in the United States are calpainopathies, dysferlinopathies, sarcoglycanopathies, and dystroglycanopathies.

Chronic inhibition of cholinesterase as a cause of myopathy

The concept has been evolving that myopathy and dystrophy may be the result of an abnormal neural influence on muscle rather than a primary defect in the muscle fiber.’ When skeletal muscle is denervated, the initial abnormality is a reduction in fiber size with relative integrity of fiber structure.2 ,3 “Myopathic” fibers, characterized by fragmentation of fiber structure and phagocytosis, have been noted in chronically denervated skeletal niuscle4 and acutely denervated ocular muscle.’ Although myopathic changes are noted in these situations, it is not reasonable t o assume that most myopathies and dystrophies are secondary t o simple denervating processes. Rather, it seems more likely that muscle fiber fragmentation is related t o a subtle alteration in the trophic influence of nerve o n muscle than t o the complete cessation of neuromuscular transmission. Of specific interest in this regard was the demonstration by Ariens et al.6j7 of necrosis in the striated muscles of the albino rat by the single intravenous infusion of paraoxon (diethylparanitrophenyl phosphate), the active metabolite of the insecticide parathion (0,Od i e t h y 1 0-[ p-nitrophenyl] thiophosphate).8 Paraoxon is an organophosphorous compound that acts as an irreversible inhibitor of cholinesterase (ChE) and is not known t o have any direct action upon the nerve. The experiments reported here demonstrate the production of a progressive and extensive

Pediatric manifestations of Hashimoto’s encephalopathy

Hashimotos encephalopathy is a steroid-responsive encephalopathy associated with elevated blood concentrations of antithyroid antibodies. The patients are usually euthyroid or mildly hypothyroid. The authors report two pediatric patients with Hashimotos encephalopathy and review the literature. The clinical picture in adolescents, as with adults, is pleomorphic but frequently associated with seizures, confusion, and hallucinations. Alternatively, progressive cognitive decline manifested by a drop in school performance can be observed. The diagnosis of Hashimotos thyroiditis is often overlooked at presentation and a high degree of suspicion is necessary for proper diagnosis.

A randomized efficacy and safety trial of oxandrolone in the treatment of Duchenne dystrophy

Background: A pilot study suggested that oxandrolone, an anabolic steroid, improved strength in boys with Duchenne dystrophy (DD) and indicated the need for a more definitive study. Methods: A 6-month, randomized, double-blind, placebo-controlled study of oxandrolone in boys with an established diagnosis of DD, using the change from baseline to 6 months in the average muscle strength score (MMT) as the primary efficacy measure. Results: The mean change from baseline for the oxandrolone group was +0.035 and that for the placebo group was −0.140. Although the oxandrolone group did not get worse and the placebo patients showed some deterioration in strength, the difference was not significant (p = 0.13). The average of the four quantitative muscle tests (QMT) showed a significant improvement in the oxandrolone-treated boys as compared with placebo. No adverse reactions attributable to oxandrolone were recorded. Conclusions: Although oxandrolone did not produce a significant change in the average manual muscle strength score as compared with placebo, the mean change in QMT was significant. Because oxandrolone is safe, accelerates linear growth, and may have some beneficial effect in slowing the progress of weakness, it may be useful before initiating corticosteroid therapy.

An autosomal‐dominant dystrophy with humeropelvic distribution and cardiomyopathy

A father and his two children developed a slowly progressive humeropelvic weakness and contractures in childhood and cardiomyopathy after age 20. The disorder in this family is similar to, but not identical with, Emery-Dreifuss dystrophy.

Hemiplegic atrophy: Histoiogical and etiologic considerations

LOSS OF MUSCLE BULK may result from primary diseases of muscle (myopathy), disorders of the lower motor neuron (neural atrophy), disturbances of suprasegmental influences (“central” atrophy), and a heterogenous group of conditions in which debilitation or immobilization are present (“disuse” atrophy). Myopathy and neural atrophy are readily diagnosed by histological examination, and much is known about their pathophysiology. In contrast, the histological observations in central atrophy and disuse atrophy are sparse, and the two frequently are grouped together as possessing a common etiologic mechanism. The purpose of this report is to describe the histopathology of atrophy, secondary to hemiplegia, resulting from a cerebral vascular accident. This atrophy is usually considered to be the result of disuse of the paralyzed extremity. In some instances, parietal lobe dysfunction with a resulting loss of “trophic” influences on muscle is held as causal. Evidence is presented to question the importance of disuse as a major factor, and the literature concerning atrophy of suprasegmental origin is reviewed.

A beneficial effect of oxandrolone in the treatment of Duchenne muscular dystrophy: A pilot study

We treated 10 boys with Duchenne muscular dystrophy with oxandrolone, an anabolic steroid, for 3 months. The mean of the changes in the average muscle score was an improvement of 0.315 ± 0.097. The expected mean change in muscle score after 3 months from natural history data is a loss of 0.1. The difference of 0.415 between the actual and expected values is significant at p < 0.01. This preliminary evidence suggests that oxandrolone treatment may provide a degree of functional benefit for children with Duchenne muscular dystrophy that is similar to that after prednisone administration.

An experimental myopathy secondary to excessive acetylcholine release

Daily injection of guanidine, which enhances the release of acetylcholine, rapidly produces a severe myopathy in the soleus muscle of the Sprague-Dawley rat. The myopathy is inhibited by prior sciatic nerve section and is accentuated by cholinesterase inhibition. Carbamylcholine, an acetylcholine analogue that depolarizes the end-plate and causes contraction, does not induce myopathy in rats when given in almost lethal doses. These results suggest that excessive acetylcholine can induce skeletal muscle necrosis even when the cholinesterase system is intact. The myopathy is not just the result of excessive depolarization and contraction but more likely is related to a disturbance in the trophic effect mediated by acetylcholine.