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.

Pediatric manifestations of Hashimoto's encephalopathy.

Hashimoto's 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 Hashimoto's 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 Hashimoto's thyroiditis is often overlooked at presentation and a high degree of suspicion is necessary for proper diagnosis.

Dystonia and unique muscle features. A 23-year follow-up and correction of diagnosis in two brothers.

OBJECTIVE: To provide follow-up information and a corrected diagnosis on two brothers who were primarily described in the ARCHIVES in 1971 as having had a genetic dystonia with unusual muscle biopsy features. MEASURES: Clinical observation of response to treatment and muscle histologic findings. RESULTS: These brothers are an unusual example of dopa-responsive dystonia that was present since birth. The muscle histopathologic features were caused by an abnormal cerebral influence on the developing motor unit and were not a primary abnormality. A repeated muscle biopsy performed 1 year after treatment continued to show the same pattern of fiber-type abnormalities. CONCLUSIONS: Dopa-responsive dystonia can be present from birth or early infancy. The response to levodopa is excellent even after a delay in treatment of more than 20 years. Intrauterine dystonia can cause a predominance of small type 2 fibers. A trial of levodopa/carbidopa is indicated in all patients with a childhood-onset dystonia or gait disturbance.

Sneddon and antiphospholipid antibody syndromes causing bilateral thalamic infarction.

A child suffered bilateral thalamic infarction secondary to Sneddon and antiphospholipid antibody syndromes. Her initial findings of hypersomnolence, mood disturbance, and amnesia are characteristic of bilateral thalamic infarction. Clinical and laboratory evaluation confirmed the diagnosis of both Sneddon and antiphospholipid antibody syndromes as the cause of her unusual stroke. The treatment of this patient, based on experience with adult patients, was long-term, high-intensity warfarin anticoagulation.

Thymectomy for the myasthenia gravis patient: factors influencing outcome.

Thymectomy is a therapeutic option for patients with myasthenia gravis with moderate to severe disability. To document the efficacy of thymectomy coupled with medical therapy to treat this disease and to identify clinical factors that influence outcome, the clinical courses of all 46 patients (12 male and 34 female; mean age, 30 +/- 16 years) with myasthenia gravis who underwent thymectomy through a median sternotomy at a single institution over a 21-year period were reviewed. Clinical staging was determined preoperatively, at 1 month, 6 months, and 12 months postoperatively, and at last follow-up (mean time, 75 months postoperatively) using the Oosterhuis classification. Changes in severity of illness were graded as "deteriorated," "unchanged," "improved," or "much improved." Preoperative Oosterhuis classification was 3.3 +/- 1.1 and at last follow-up, 1.4 +/- 1.2 (p = 0.022). At last follow-up, 40 patients (87%) were in the improved or much improved category, and 6 patients were in the deteriorated or unchanged category. Status at 1 month, 6 months, and 12 months after operation predicted outcome at last follow-up visit (p = 0.007, p = 0.005, and p = 0.001, respectively). Clinical factors that positively influenced outcome were age less than 45 years (p = 0.004), female sex (p = 0.0309), and preoperative stage (p = 0.021).

Three new mutations in patients with myophosphorylase deficiency (McArdle disease).

We report three new mutations in patients with myophosphorylase deficiency (McArdle disease). A splice-junction mutation (G-to-A transition at the 5' end of intron 14) and a missense mutation (CTG to CCG at codon 291, changing an encoded leucine to a proline) were identified in Caucasian patients who were heterozygous for a common mutation reported elsewhere (CGA [Arg] to TGA [stop]) at codon 49. The splice-junction mutation destroyed the consensus sequence at the 5' splice site, and a cryptic splice site 67 bp upstream was recognized instead. As a result, there was a 67-bp deletion in the 3'-terminal region of exon 14 in the transcript, resulting in a frameshift with premature translation termination. A deletion of a single codon, 708/709 (TTC, specifying phenylalanine) was identified in Japanese patients. Two affected siblings were homozygotes, and their parents were heterozygotes. A third, unrelated patient was heterozygous for the same mutation, while the myophosphorylase gene on the other allele was only faintly expressed.

Neurological examination of the newborn.

Sophisticated technology for neurodiagnosis supplements, but does not replace, the neurological examination. Physical examination remains the standard for assessing the normal or abnormal function of the nervous system, the localization of neurological injury, and the severity of impairment. An experienced examiner can rapidly perform this assessment and then exercise the best judgement in selecting laboratory investigations.

Prolongation of ambulation in children with Duchenne muscular dystrophy by subcutaneous lower limb tenotomy.

To assess the effect of subcutaneous (s.c.) lower limb tenotomies on the ambulatory ability of patients with Duchenne muscular dystrophy (DMD), 54 patients were followed. Twenty-nine patients underwent hip, knee, and ankle tenotomies at a mean age of 10 2/12 years and were followed postoperatively for an average of 3 9/12 years. These children continued ambulation in long-leg braces to a mean age of 12 8/12 years and stood to an average of 13 5/12 years. Contracture correction was 49% at the hip, 58% at the knee, and 100% at the ankle. A separate group of 25 children to whom operation was offered but declined, was followed: these children ceased ambulating at a mean age of 10 years and ceased standing at a mean age of 10 2/12 years. Thus, we propose that s.c. tenotomy is effective in allowing braced ambulation well beyond what the natural history would allow.

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 prednisone's beneficial effect is not due to immunosuppression.

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 mg/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.

Risk of seizures after measles-mumps-rubella immunization.

To evaluate the risks of seizures and other neurologic events following measles-mumps-rubella (MMR) or measles-rubella (MR) immunization, a retrospective cohort study was conducted among 18,364 Tennessee children enrolled in Medicaid who received MMR or MR immunizations in their first 3 years of life. One hundred children had seizures at some time between immunization and 36 months; there were no encephalopathies during this period. Four children had febrile seizures in the 7 through 14 days following MMR or MR immunization compared with 72 in the interval 30 or more days following MMR or MR immunization yielding a relative risk (95% confidence interval) of 2.1 (0.7 to 6.4). Although not statistically significant, this increase in febrile seizures in the 7- through 14-day interval following MMR immunization is coincident with the occurrence of fever following MMR immunization and is consistent with reports of other investigators.

A comparison of daily and alternate-day prednisone therapy in the treatment of Duchenne muscular dystrophy.

We previously reported the results of a randomized, double-blind 6-month trial of prednisone therapy in which 102 boys aged 5 to 15 years with Duchenne muscular dystrophy received daily doses of 1.5 and 0.75 mg/kg per day and were compared with those receiving placebo. The strength and function in both prednisone-treated groups improved equally and were significantly better than in the placebo group. To compare alternate-day and daily dosing of prednisone with respect to benefits and adverse side effects, the placebo group was started on alternate-day prednisone therapy, and the treatment group regimens were changed to equivalent doses of alternate-day prednisone without breaking the double-blind nature. At the end of 6 months, the group that was changed from daily to alternate-day therapy had declined in strength back to levels observed 12 months previously, at the start of daily therapy. The group in which alternate-day therapy was started showed a significant improvement in strength at 3 months, similar in magnitude to the response of boys treated with daily therapy. However, their strength declined significantly in the subsequent 3 months compared with boys who received daily therapy. The frequency of side effects was not significantly different for alternate-day therapy compared with daily therapy. We conclude that alternate-day prednisone therapy effectively increases strength but does not sustain the improvement to the same extent as daily therapy or mitigate side effects.

Prednisone in Duchenne dystrophy. A randomized, controlled trial defining the time course and dose response. Clinical Investigation of Duchenne Dystrophy Group.

A randomized, controlled trial of daily prednisone was conducted in 99 boys (aged 5 to 15 years) with Duchenne dystrophy to define the time course of improvement and the dose response to treatment. Prednisone at 0.3 mg/kg (n = 33), prednisone at 0.75 mg/kg (n = 34), and placebo (n = 32) were administered for 6 months. Patients were examined using manual muscle and myometry testing, timed functional testing, pulmonary function testing, and laboratory measurements at 10 days, 1 month, 2 months, 3 months, and 6 months of treatment. Boys treated with prednisone had stronger average muscle strength scores, than did boys treated with placebo as early as 10 days after starting therapy. At the 3-month visit, the boys in the group given 0.75 mg/kg of prednisone were significantly stronger than those in the group given 0.3 mg/kg of prednisone, indicating a dose response. At 6 months, significant side effects occurred in the group treated with 0.75 mg/kg of prednisone, including weight gain, cushingoid appearance, and excessive hari growth. Only weight gain was observed in the group taking prednisone at a dose of 0.3 mg/kg. Importantly, no side effects were evident at 10 days or 1 month of treatment, despite improvement in muscle strength and function. We conclude that prednisone produces a rapid increase in muscle strength in patients with Duchenne dystrophy and that this improvement is maximal at a prednisone dosage of 0.75 mg/kg or less.

Randomized, double-blind trial of mazindol in Duchenne dystrophy.

There is evidence that growth hormone may be related to the progression of weakness in Duchenne dystrophy. We conducted a 12-month controlled trial of mazindol, a putative growth hormone secretion inhibitor, in 83 boys with Duchenne dystrophy. Muscle strength, contractures, functional ability and pulmonary function were tested at baseline, and 6 and 12 months after treatment with mazindol (3 mg/d) or placebo. The study was designed to have a power of greater than 0.90 to detect a slowing to 25% of the expected rate of progression of weakness at P less than 0.05. Mazindol did not benefit strength at any point in the study. Side effects attributable to mazindol included decreased appetite (36%), dry mouth (10%), behavioral change (22%), and gastrointestinal symptoms (18%); mazindol dosage was reduced in 43% of patients. The effect of mazindol on GH secretion was estimated indirectly by comparing the postabsorptive IGF-I levels obtained following 3, 6, 9, and 12 months in the mazindol treated to those in the placebo groups. Although mazindol-treated patients gained less weight and height than placebo-treated patients, no significant effect on IGF-I levels was observed. Mazindol doses not slow the progression of weakness in Duchenne dystrophy.

Risk of seizures and encephalopathy after immunization with the diphtheria-tetanus-pertussis vaccine.

We evaluated the risks of seizures and other neurological events following diphtheria-tetanus-pertussis (DTP) immunization for 38,171 Tennessee Medicaid children who received 107,154 DTP immunizations in their first 3 years of life. There were 2 children with encephalitis; both had disease onset more than 2 weeks following DTP immunization. There were 277 children who had febrile seizures, 42 with afebrile seizures, and 37 with seizures associated with other acute neurological illness (acute symptomatic). The risk of febrile seizures in the 0 to 3 days following DTP immunization (n = 6) was 1.5 (95% confidence interval, 0.6 to 3.3) times that of the control period 30 or more days following DTP immunization. There was no evidence that in the 0 to 3 days following DTP immunization the risk of afebrile seizures (n = 1) or acute symptomatic seizures (n = 0) was increased. No child who was previously normal without a prior history of seizures had a seizure in the 0 to 3 days following immunization that marked the onset of either epilepsy or other neurological or developmental abnormality.