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.

Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy.

OBJECTIVE: To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD). METHODS: A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months. RESULTS: Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone. CONCLUSIONS: Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period.

Progressive amyotrophy as a late complication of myelopathy.

A delayed syndrome of progressive weakness has been described in survivors of paralytic poliomyelitis - "Post-Polio Muscular Atrophy (PPMA)". One proposed etiology is a drop-out of motor neurons due to increased metabolic demands of an enlarged motor unit territory. We report a patient with slowly progressive lower extremity weakness 20 years after recovery from an episode of myelopathy involving the lower lumbar and sacral segments of the spinal cord. Delayed progressive amyotrophy may complicate any significant injury to anterior horn cells.

HTLV-1 and its neurological complications.

BACKGROUND: Since its discovery in 1980, human T-cell lymphotropic virus type-1 (HTLV-1) has been associated with a number of neurological diseases. The distribution of HTLV-1-associated neurological disease is worldwide. In endemic areas, up to 30% of the population may be infected with HTLV-1; however, only a small percentage of infected persons develops neurological disease. REVIEW SUMMARY: In 1986, HTLV-1 infection was reported in patients of chronic progressive myelopathy of uncertain etiology, and the disease entity was called HTLV-1-associated myelopathy/tropical spastic paraparesis. Recently, HTLV-1 infection has been associated with polymyositis and uveitis. Interestingly, a single patient may display more than one syndrome. Although other neurological syndromes occur in HTLV-1-infected individuals, there is not enough epidemiologic data that show a strong association. Treatment of HTLV-1-associated neurological disease is challenging, and well-controlled studies are lacking. CONCLUSION: As neurologists and other scientists begin to understand the pathophysiology of HTLV-1 infection, improved therapies should be developed. Randomized trials with longer follow-up are required to understand the effect of treatment on disability and quality of life.

Diltiazem in the treatment of calcinosis in juvenile dermatomyositis.

Subcutaneous calcifications occur in a variety of diseases, including juvenile dermatomyositis. These calcifications cause disabling symptoms that do not always respond to immunosuppressant therapy. The calcium antagonist diltiazem reduces subcutaneous calcifications in CREST syndrome and in isolated cases of children with dermatomyositis. Our study was performed to determine the effects of diltiazem when used as adjunctive therapy in children with dermatomyositis.

Rapid growth of a basilar aneurysm.

We describe a patient who developed, over a 22-month period, a giant aneurysm of his basilar artery. A prior MRI of the brain done for nonspecific symptoms showed a normal brainstem and basilar artery. At presentation, he had a repeat MRI scan for a 4-month history of a partial right oculomotor nerve palsy and left hemiparesis. The MRI revealed a giant aneurysm of the top of the basilar artery. This was treated by angiographic placement of Guglielmi detachable coils (GDC) after surgical intervention was deemed unfeasible. This case illustrates the acquired nature of intracranial aneurysms. All inoperable intracranial aneurysms should be closely monitored and MRI and MR angiography may currently be the best noninvasive methods for this purpose. Intra-arterial GDC embolization of aneurysms is an alternative treatment when surgery is not possible.

Secondary reduction in calpain 3 expression in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy (primary dysferlinopathies).

Dysferlin is the protein product of the gene (DYSF) that is defective in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy. Calpain 3 is the muscle-specific member of the calcium activated neutral protease family and primary mutations in the CAPN3 gene cause limb girdle muscular dystrophy type 2A. The functions of both proteins remain speculative. Here we report a secondary reduction in calpain 3 expression in eight out of 16 patients with a primary dysferlinopathy and clinical features characteristic of limb girdle muscular dystrophy type 2B or Miyoshi myopathy. Previously CAPN3 analysis had been undertaken in three of these patients and two showed seemingly innocuous missense mutations, changing calpain 3 amino acids to those present in the sequences of calpains 1 and 2. These results suggest that there may be an association between dysferlin and calpain 3, and further analysis of both genes may elucidate a novel functional interaction. In addition, an association was found between prominent expression of smaller forms of the 80 kDa fragment of laminin alpha 2 chain (merosin) and dysferlin-deficiency.

Selective paraspinal muscle amyotrophy.

A 56-year-old female presented with mild low back pain. Examination revealed severe, selective atrophy of the thoracic and lumbar paraspinal muscles. Fibrillations were seen in the paraspinal muscles on EMG. Limb EMG was normal. Biopsy of the gluteus maximus was normal. Paraspinal muscle biopsy revealed neurogenic features. Atrophy of the thoracic and lumbar paraspinal muscles was noted on magnetic resonance imaging. This patient has selective amyotrophy of the thoracic and lumbar paraspinal muscles. This may be an addition to the spectrum of 'benign focal amyotrophy'. The differential diagnosis of paraspinal muscle weakness is discussed.

Long-term tracheostomy ventilation in neuromuscular diseases: patient acceptance and quality of life.

Domiciliary assisted ventilation has been used to prolong life in patients with neuromuscular diseases. Although earlier studies suggest that the majority of patients are satisfied with their lives, the physician's perception of a patient's poor quality of life on assisted ventilation is a major reason for discouraging assisted ventilation. In this study, the quality of life was assessed in 19 patients with neuromuscular diseases on domiciliary tracheal intermittent positive-pressure ventilation for a mean duration of 54 months. An attempt was made to compare the quality of life of Duchenne muscular dystrophy patients with that of amyotrophic lateral sclerosis patients. More than two-thirds of patients were satisfied with their lives. Eighty-four percent thought they had made the right choice. Patients with amyotrophic lateral sclerosis were somewhat more negative or ambiguous toward assisted ventilation and had lower life satisfaction scores as compared with Duchenne muscular dystrophy patients. Financial stresses were significant. Assisted ventilation should be offered as a viable option to patients with neuromuscular diseases. Larger studies may be useful in influencing insurance companies to make expenses associated with assisted ventilation reimbursable.

Hidden afterdischarges in slow channel congenital myasthenic syndrome.

Afterdischarges in motor nerve stimulation studies help distinguish slow channel congenital myasthenic syndrome (SCCMS) from acquired myasthenia gravis (MG) We present a patient with fatigable weakness in whom afterdischarges were not initially apparent. After she failed to respond to treatment for MG, afterdischarges were demonstrated in some, but not all, of her muscles. Genetic testing confirmed SCCMS. This case indicates that electrophysiological distinction between SCCMS and MG may require motor nerve stimulation studies in multiple muscles.

Muscle and nerve imaging techniques in neuromuscular diseases.

Imaging of muscle and nerve has become increasingly useful and of promising value in the evaluation of patients with various neuromuscular disorders. These techniques include ultrasonography, radionuclide scanning, computed tomography, and magnetic resonance imaging. They have different applications, advantages. and disadvantages. This review assesses these imaging modalities and describes the findings in pathologic conditions. The usefulness of these methods in the evaluation of various neuromuscular diseases is discussed.

Focal myositis presenting with radial nerve palsy.

Focal myositis is a rare inflammatory pseudotumor of skeletal muscle which usually has a benign course. We report a 56-year-old woman with a painful mass in the left arm with a radial nerve palsy. Magnetic resonance imaging (MRI) of the left arm showed a mass in the triceps muscle that was suggestive of a soft-tissue sarcoma. Electromyography showed a severe radial neuropathy involving both motor and sensory axons. An open biopsy showed focal myositis. Treatment with corticosteroids resulted in complete disappearance of the mass clinically and by MRI, without recurrence for more than 2 years. Radial nerve function also recovered completely. As a treatable cause of focal neuropathy, focal myositis should be included in the differential diagnosis of a muscle mass.

Bilateral ophthalmoplegia and exophthalmos complicating central hemodialysis catheter placement.

We describe a 58-year-old woman who presented with bilateral ophthalmoplegia, exophthalmos, and headache and was found to have retrograde internal jugular vein flow secondary to a high-grade obstruction of the ipsilateral brachiocephalic vein from a previous hemodialysis catheter placement. The patient had also a high-flow dialysis graft in the ipsilateral arm. The cranial and extracranial venous system congestion resolved, and the signs disappeared soon after a balloon angioplasty and stent placement at the level of the obstruction.

Single-fiber electromyography of the laryngeal muscles.

Single-fiber electromyography (SFEMG) is useful in the evaluation of disorders of neuromuscular transmission and the assessment of motor unit morphology. Standard EMG techniques are used routinely in the evaluation of laryngeal dysfunction, but the feasibility of laryngeal SFEMG has not been established. We, therefore, performed laryngeal SFEMG in 10 normal individuals to demonstrate the feasibility of the technique and generate preliminary normative data. We also studied 2 patients with amyotrophic lateral sclerosis and 1 patient previously treated with botulinum toxin for comparative purposes.

Inflammatory myopathies [polymyositis, dermatomyositis, inclusion body myositis].

Inflammatory myopathies are common treatable diseases of muscle that should be differentiated from similar but incurable conditions. This article discusses the diagnosis, laboratory studies, pathology, pathogenesis, differential diagnosis, and treatment of the different autoimmune myopathies.

Laminin alpha2 muscular dystrophy: genotype/phenotype studies of 22 patients.

OBJECTIVE: To determine the number of primary laminin alpha2 gene mutations and to conduct genotype/phenotype correlation in a cohort of laminin alpha2-deficient congenital muscular dystrophy patients. BACKGROUND: Congenital muscular dystrophies (CMD) are a heterogeneous group of muscle disorders characterized by early onset muscular dystrophy and a variable involvement of the CNS. Laminin alpha2 deficiency has been reported in about 40 to 50% of cases of the occidental, classic type of CMD. Laminin alpha2 is a muscle specific isoform of laminin localized to the basal lamina of muscle fibers, where it is thought to interact with myofiber membrane receptor, such as integrins, and possibly dystrophin-associated glycoproteins. METHODS: Seventy-five CMD patients were tested for laminin alpha2 expression by immunofluorescence and immunoblot. The entire 10 kb laminin alpha2 coding sequence of 22 completely laminin alpha2-deficient patients was screened for causative mutations by reverse transcription (RT)-PCR/single strand conformational polymorphisms (SSCP) analysis and protein truncation test (PTT) analysis followed by automatic sequencing of patient cDNA. Clinical data from the laminin alpha2-deficient patients were collected. RESULTS: Thirty laminin alpha2-negative patients were identified (40% of CMD patients tested) and 22 of them were screened for laminin alpha2 mutations. Clinical features of laminin alpha2-deficient patients were similar, with severe floppiness at birth, delay in achievement of motor milestones, and MRI findings of white matter changes with normal intelligence. Loss-of-function mutations were identified in 95% (21/22) of the patients studied. SSCP analysis detected laminin alpha2 gene mutations in about 50% of the mutant chromosomes; PTT successfully identified 75% of the mutations. A two base pair deletion mutation at position 2,096-2,097 bp was present in 23% of the patients analyzed. CONCLUSIONS: Our data suggest that the large majority of laminin alpha2-deficient patients show laminin alpha2 gene mutations.

Demyelinating neuropathy in a patient with multiple sclerosis and genotypical HMSN-1.

Patients with multiple sclerosis (MS) may develop a peripheral neuropathy, sometimes attributed to nutritional deficiency. Other patients present with a demyelinating neuropathy which is presumed to be the result of an autoimmune process that affects both the central and peripheral nervous systems. We report a case of concurring MS and demyelinating neuropathy, without a positive family history, in whom genetic testing proved the neuropathy to be hereditary and not autoimmune. Hereditary neuropathy should be a consideration in sporadic cases of peripheral neuropathy and MS.

Hypophosphatemia-induced neuropathy: clinical and electrophysiologic findings.

Severe hypophosphatemia has rarely been reported as a cause of acute paralysis. We present the clinical and electrophysiological findings on a patient who developed quadriparesis following several surgeries for complicated cholecystectomy. The paralysis was most likely the result of severe hypophosphatemia causing a neuropathy which improved readily after proper phosphate replacement. The possible pathogenic mechanisms of hypophosphatemic neuropathy are discussed.

Remission of myasthenia gravis caused by proteinuria in nephrotic syndrome.

Myasthenia gravis is caused by antibodies against acetylcholine receptors and is treated with inhibition or elimination of antibody production. We report a 43-year-old myasthenic female who was symptomatic until she developed proteinuria from nephrotic syndrome, which caused a marked drop in acetylcholine receptor antibody titer with remission of myasthenia. Treatment of the nephrotic syndrome produced exacerbation of her myasthenia and a rise in antibody level. This patient's improvement is the result of antibody elimination during proteinuria in nephrotic syndrome.