Pentoxifylline as a rescue treatment for DMD: a randomized double-blind clinical trial.

OBJECTIVE: To determine whether pentoxifylline (PTX) slows the decline of muscle strength and function in ambulatory boys with Duchenne muscular dystrophy (DMD). METHODS: This was a multicenter, randomized, double-blinded, controlled trial comparing 12 months of daily treatment with PTX or placebo in corticosteroid-treated boys with DMD using a slow-release PTX formulation (~20 mg/kg/day). The primary outcome was the change in mean total quantitative muscle testing (QMT) score. Secondary outcomes included changes in QMT subscales, manual muscle strength, pulmonary function, and timed function tests. Outcomes were compared using Student t tests and a linear mixed-effects model. Adverse events (AEs) were compared using the Fisher exact test. RESULTS: A total of 64 boys with DMD with a mean age of 9.9 ± 2.9 years were randomly assigned to PTX or placebo in 11 participating Cooperative International Neuromuscular Research Group centers. There was no significant difference between PTX and the placebo group in total QMT scores (p = 0.14) or in most of the secondary outcomes after a 12-month treatment. The use of PTX was associated with mild to moderate gastrointestinal or hematologic AEs. CONCLUSION: The addition of PTX to corticosteroid-treated boys with DMD at a moderate to late ambulatory stage of disease did not improve or halt the deterioration of muscle strength and function over a 12-month study period. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that treatment with PTX does not prevent deterioration in muscle function or strength in corticosteroid-treated boys with DMD.

Intraoperative pediatric laryngeal electromyography: experience and caveats with monopolar electrodes.

We report our experience with intraoperative laryngeal electromyography (L-EMG) using direct laryngoscopy and placement of monopolar electrodes under general anesthesia in the evaluation and management of laryngeal dysfunction in pediatric patients. In this series of case studies, we present clinical data on 30 pediatric patients with known or suspected anatomic or neurologic laryngotracheal disorders evaluated with placement of shielded monopolar electrodes into the thyroarytenoid muscles during direct laryngoscopy under general anesthesia. Diagnoses included congenital vocal fold paralysis (VFP), laryngotracheal stenosis, cerebral palsy, laryngeal tumors, traumatic vocal fold dysfunction, and postsurgical VFP. The impact of L-EMG on patient management was assessed. We found that L-EMG objectively supported clinical findings, but provided new objective data relevant toward management recommendations in only a few selected pediatric patients with new-onset vocal fold paralysis or paresis or infiltrative laryngeal tumors, and in selected postsurgical cases involving decannulation decisions. The prognostic utility of L-EMG in newborns with congenital VFP has not been established. A normal L-EMG recording indicates an intact neuromuscular axis, but does not guarantee vocal fold mobility or guarantee muscle function in a partially denervated or deconditioned muscle. The potential for false-negative recordings is the major limitation of this technique.

Charcot-Marie-Tooth disease type I diagnosed in a 5-year-old boy after vincristine neurotoxicity, resulting in maternal diagnosis.

Charcot-Marie-Tooth disease type 1, also known as hereditary motor sensory neuropathy type 1, is an uncommon autosomal dominant disease that causes destruction of peripheral nerves with a varied clinical course, but often leads to muscle weakness. If the peroneal muscle is involved, the patient may develop a characteristic slapping gait. The dose-limiting side effect of the chemotherapeutic agent vincristine is usually its neurotoxicity. We report the case of a 5-year-old patient with leukemia who developed an acute polyneuropathy after treatment with vincristine. Charcot-Marie-Tooth disease type 1 was diagnosed in the patient and, subsequently, in his mother only after vincristine toxicity was observed.

Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis.

We performed a retrospective multicenter chart review to compare the efficacy and tolerance of plasma exchange (PE) and intravenous immunoglobulin (i.v.Ig) in treatment of 54 episodes of myasthenic crisis. After adjustment for other variables, PE (compared with i.v.Ig) was associated with a superior ventilatory status at 2 weeks (partial F = 6.2, p = 0.02) and 1 month functional outcome (partial F = 4.5, p = 0.04). However, the complication rate was higher with PE compared with i.v.Ig (13 versus 5 episodes, p = 0.07).

Neutropenia in a patient receiving intravenous immune globulin.

A child with Guillain-Barre syndrome treated with intravenous immune globulin (IVIG) developed neutropenia (absolute neutrophil count = 390), which resolved 3 days after completion of the therapy. Potential mechanisms for the development of neutropenia during the use of IVIG therapy are discussed. In this case, testing of the IVIG used revealed the presence of a high concentration of anti-neutrophil antibodies compared to other samples. It is recommended that white blood cell and neutrophil counts be monitored daily during the use of such therapy.

Possible radiation-induced dural fibrosarcoma with an unusually short latent period: case report.

We report a case of radiation-induced dural fibrosarcoma in a 9.5-year-old male patient who was treated with radiation for medulloblastoma. He received a total dose of 53.2-Gy radiation, delivered at 1.6 and 1.8 Gy per fraction with a 6 MV linear accelerator using the standard cranial-spinal technique. A sequential magnetic resonance image at 15 months after the completion of radiation therapy showed a mass above the cerebral convexity that increased two-fold in size within a period of 4 months. The tumor showed characteristics of a low-grade fibrosarcoma. This case emphasizes the potential risk of early development of a second neoplasm after therapeutic radiation, especially in children, and also documents what is to our knowledge the shortest latent period between the administration of radiation therapy and the development of an intracranial fibrosarcoma that has been reported.

Stroke in purine nucleoside phosphorylase deficiency.

The first documented case of cerebrovascular disease occurring in a 13-year-old girl with purine nucleoside phosphorylase deficiency is reported. This patient, the oldest known survivor with purine nucleoside phosphorylase deficiency, had previously experienced multiple sequential neurologic problems. She presented with episodes of transient left hemiparesis, followed shortly thereafter by dense left hemiplegia. Magnetic resonance imaging revealed a right internal capsule infarct; cerebral angiography revealed vasculopathy of the proximal vessels. Proposed mechanisms for neurologic dysfunction and cerebrovascular disease in purine nucleoside phosphorylase deficiency are discussed.

Dietary erucic acid therapy for X-linked adrenoleukodystrophy.

We investigated the biochemical and clinical efficacy of dietary erucic acid (C22:1) therapy for X-linked adrenoleukodystrophy (ALD). In a double-blind crossover study of patients who were on chronic oleic acid (C18:1) therapy, addition of erucic acid to the diet led to a further reduction in plasma hexacosanoic acid (C26:0) concentration. We treated 12 newly diagnosed ALD patients with a diet enriched with erucic acid and oleic acid for 2 to 19 months. Mean plasma C26:0 concentration decreased to normal by 4 weeks, and the C26:0 composition of plasma sphingomyelin and phosphatidylcholine became normal by 4 months on therapy. Fatty acid analysis of postmortem tissues from 1 boy treated for 10 months suggested that dietary erucic acid entered the heart, liver, adrenal gland, and brain. Eight patients remained on treatment long enough (mean, 12 +/- 3 months) to evaluate their clinical response; 6 of these patients with moderate to advanced disease deteriorated neurologically or showed progression of white matter disease on brain magnetic resonance imaging whereas 2 mildly affected patients remained clinically stable after 10 and 19 months. No adverse effects of the diet occurred. We conclude that dietary erucic acid therapy is effective in lowering plasma C26:0 to normal in ALD patients, and may prevent further demyelination in some mildly affected boys.

Remyelination in the human central nervous system.

Remyelination, albeit incomplete, has been demonstrated in human central nervous system (CNS). However, information about the initial stage and the final extent of such remyelination is not available. We describe the morphologic findings of a demyelinating lesion with evidence of early remyelination in a biopsy obtained from a 15-year-old boy about two weeks after the onset of neurologic symptoms. The demyelinated area appeared hypercellular with a relatively large number of oligodendrocytes frequently seen in the process of new myelin formation. In addition to the usual reactive changes, the astrocytes were often seen to contain otherwise normal-looking oligodendrocytes within their cytoplasm. In the ensuing months, the patient made apparently total functional recovery accompanied by nearly complete resolution of the white matter lesions demonstrated by the subsequent magnetic resonance studies. These observations suggested that the initial remyelination seen in the biopsy eventually succeeded in producing extensive remyelination in the lesion. Although the exact nature of the demyelinating disorder in our patient remains undetermined, this study indicates that clinically significant remyelination is possible in human CNS. Also, our findings appeared strikingly similar to those described in certain experimental animal models in which widespread remyelination is known to occur.

Use of DNA probes in detecting carriers of Duchenne muscular dystrophy: selected case studies.

Detection of Duchenne muscular dystrophy carriers by genetic analysis is illustrated by four case studies. The technique is most useful in obligate families, in excluding carrier status in isolated cases, and in families in which the affected child demonstrates a molecular deletion. A major limitation of this technique is that the accuracy of carrier status in isolated (i.e., no family history) cases is limited by the probability that the affected child may represent a new mutation. To improve the carrier risk estimate generated by the DNA data, particularly in isolated cases, we suggest that measuring creatine kinase activities in the serum and performing the genetic analysis on the nonaffected males may be helpful.

Intraoperative electroneurography: management of ulnar neuropathy at the elbow.

At the elbow the ulnar nerve may be compressed either in the retrocondylar groove or at the cubital tunnel. Optimal surgical therapy should be directed at the specific site of involvement. Intraoperative electroneurography performed in conjunction with 19 ulnar nerve explorations helped localize the precise site of compression. Of the primary procedures, abnormality was at the retrocondylar groove in 9, cubital tunnel in 4, both locations in 3, and at an unusual distal point in 1; 12 anterior subcutaneous transpositions, 4 cubital tunnel releases, and 1 distal decompression resulted. Intraoperative studies helped identify residual compression in two patients undergoing reexploration. Although routine electrodiagnosis may localize an ulnar neuropathy to the elbow, reliably separating retrocondylar from cubital tunnel compression is more difficult. Preoperatively, percutaneous serial short increment studies were more accurate than simple "inching" in predicting the site of compression.

Adrenoleukodystrophy: dietary oleic acid lowers hexacosanoate levels.

Adrenoleukodystrophy (ALD) is an X-linked disorder characterized by demyelination, adrenal insufficiency, and accumulation of saturated very-long-chain fatty acids (VLFA), particularly hexacosanoate (C26:0). We treated 5 patients with adrenoleukodystrophy (3 males and 2 symptomatic female carriers) for 6 months with a diet enriched in oleic acid (C18:1) and moderately restricted in C26:0. Elevated plasma and erythrocyte levels of C26:0 decreased in a time-dependent manner during treatment. Total plasma C26:0 concentration was lowered by 50 +/- 9% (p less than 0.01); it became normal in the female carriers. The total erythrocyte level of C26:0 decreased (44 +/- 5%; p less than 0.001) into the normal range in all patients. Significant decreases were noted in the saturated VLFA composition of plasma and erythrocyte sphingomyelin and erythrocyte phosphatidylcholine during dietary treatment. In general, decreases in saturated VLFA levels were accompanied by increases in monounsaturated VLFA levels, while total VLFA values did not change. This novel approach to the treatment of adrenoleukodystrophy, in which there is an exchange of monounsaturated VLFA for the more toxic saturated VLFA, may prove clinically beneficial in this disorder.

CT-guided stereotactic biopsies of lesions in the medulla and a case of Leigh's disease.

CT-guided stereotactic biopsy of lower brain stem lesions in 7 consecutive cases is discussed. A frontal transincisural approach was used. Five patients had astrocytomas histologically. The single patient who had undergone empirical radiation therapy prior to tissue diagnosis revealed only necrosis. One patient was found to have pathology suggestive of Leigh's disease. This patient was not radiated and is the first alive adult to have this diagnosis confirmed. Although controversy still exists in the management of brain stem lesions, we intend to demonstrate the value of tissue diagnosis in the management of such lesions.

Malignant thymoma with dysautonomia and disordered neuromuscular transmission.

A 42-year-old man had prominent dysautonomia accompanied by clinical and electrophysiological features of both myasthenia gravis and the Lambert-Eaton myasthenic syndrome. Antiacetylcholine receptor antibodies were present in high titer. Invasive thymoma was found at thymectomy; later, a solitary metastasis to the spleen required a splenectomy. Complete remission followed surgery. There was evidence of antibody activity directed against postsynaptic acetylcholine receptors, presynaptic somatic motor terminals, and autonomic effector junctions. To our knowledge, the association of thymoma with a myasthenia gravis-Lambert-Eaton overlap syndrome has not been reported previously.

Autosomal dominant humeroperoneal myopathy.

Emery-Dreifuss muscular dystrophy is a syndrome with five salient features: early and unusual contractures; humeroperoneal muscle wasting; the slow progression of weakness, beginning in childhood; cardiac conduction defects; and X-linked inheritance. We present two cases and detail other reports with a similar constellation of findings with apparent autosomal dominant inheritance. We postulate separate genetic disorders with similar phenotypic expression.

Information processing speed of children with Friedreich's ataxia.

Two children with Friedreich's ataxia and six controls matched for age and Verbal IQ were administered a measure of short-term memory scanning and tests of attention, memory, language and abstraction. The patients demonstrated a deficit in information processing speed, decreased sustained attention and variable memory performance. The findings suggest that a deficit in information processing speed occurs early in the clinical course of Friedreich's ataxia and progresses as neurological status deteriorates.

Nocardia asteroides brain abscess following mastoidectomy.

Nocardia asteroides brain abscess occurred after mastoidectomy and tympanoplasty in a previously healthy 10-year-old boy. Combined surgical excision and trimethoprim/sulfamethoxazole therapy resulted in significant improvement.

Hypertrophia musculorum vera in familial ataxia.

A kindred with dominantly inherited ataxia demonstrated hypertrophia musculorum vera as a phenotypic feature of the disease. The proband had fasciculations, cramps, absent sensory nerve action potentials, an increased creatine kinase level, dramatic enlargement of calf muscles, and a muscle biopsy specimen showing denervation accompanied by true muscle fiber hypertrophy; ataxia and other clinical signs of spinocerebellar degeneration were also present. Other family members displayed progressive ataxia and calf muscle enlargement to varying degrees. Though peroneal atrophy is a more common feature of the familial ataxias, some kindreds may have muscle enlargement simulating the pseudohypertrophy of muscular dystrophy that is due instead to denervation-induced compensatory individual fiber hypertrophy.

Prediction of carrier status in Duchenne dystrophy by creatine kinase measurement.

Serum creatine kinase (CK) was measured in 515 healthy white women and 28 obligate carriers for Duchenne muscular dystrophy. There was substantial overlap between the control and carrier populations. To analyze the impact of the degree of overlap, the predictive value of a CK result was determined by (1) using sensitivity and specificity analysis, which assumes dichotomization into a positive or negative result based on a particular cut-off value; and (2) using likelihood ratio analysis, which evaluates an individual result based on the continuum observed for control and carrier populations. There was no clinically important difference whether an observed 57% or a hypothetical 33% overlap between control and carrier results was used. Because of the substantial overlap, the CK test utility is limited to those suspected carriers whose results fall above the healthy population interval. A low CK result does not provide sufficient assurance of noncarrier status.