A randomized controlled trial of resistance and endurance exercise in amyotrophic lateral sclerosis.

OBJECTIVE: Evaluate the safety and tolerability of resistance and endurance exercise in ALS participants as measured by their ability to complete this six-month study. METHODS: Participants were randomized to Resistance, Endurance, or Stretching/Range of Motion (SROM the exercise regimen prescribed for most ALS patients) exercises. All exercises were performed at home with an individualized regimen designed by a physical therapist trained in ALS management. Primary outcome measures were tolerability of the exercises at 24 weeks defined by 50% of participants completing at least 50% of the prescribed exercise regimen. Secondary outcome measures included the ALSFRS-R, pulmonary FVC, and other measures of ALS function. RESULTS: At 12 and 24 weeks, all three exercise regimens were tolerated according to our pre-specified criteria. Compliance to the prescribed exercise regimen was the highest in the resistance and SROM arms of the study. All three forms of exercise were considered safe as there were no differences in the rates of disease progression among groups. There were no differences in the secondary outcome measures and feasibility for evaluating these measures was successful. In a post-hoc analysis, there was a trend towards fewer falls in the Resistance and Endurance groups. CONCLUSIONS: This study demonstrates that SROM, resistance, and endurance exercise are all safe to be performed with the specified regimen without any worsening of outcomes as related to ALS function. All three forms of exercise were tolerated with resistance and SROM exercises showing the highest compliance over the 24 week-period.

Systemic pharmacokinetics and cerebrospinal fluid uptake of intravenous ceftriaxone in patients with amyotrophic lateral sclerosis.

The cephalosporin antibiotic ceftriaxone was evaluated as a potential therapeutic agent for the treatment of amyotrophic lateral sclerosis (ALS). The pharmacokinetics (PK) of ceftriaxone in plasma and cerebrospinal fluid (CSF) were investigated in 66 participants in a previously reported clinical trial. Their mean age was 51 years, and 65% were male. Participants were randomly assigned to 1 of 3 treatment groups receiving intravenous infusions (mean duration: 25 minutes) every 12 hours of either: placebo and placebo; 2 g ceftriaxone and placebo; or 2 g ceftriaxone twice. Mean steady-state plasma PK variables were: volume of distribution, 14 L (0.17 L/kg); elimination half-life, 8-9 h; total clearance, 17-21 mL/min (0.22-0.25 mL/min/kg). Values were not different between dosage groups. CSF PK analysis, determined through sparse CSF sampling, indicated apparent entry and elimination half-life values of 1.0 and 34 hours, respectively. With both dosage regimens, CSF concentrations were maintained above the target threshold of 1.0 µM (0.55 µg/mL) as determined from in vitro models. The plasma and CSF PK profiles of ceftriaxone were used as a basis for planning the Phase 3 clinical trial of ceftriaxone in ALS.

Design and initial results of a multi-phase randomized trial of ceftriaxone in amyotrophic lateral sclerosis.

OBJECTIVES: Ceftriaxone increases expression of the astrocytic glutamate transporter, EAAT2, which might protect from glutamate-mediated excitotoxicity. A trial using a novel three stage nonstop design, incorporating Phases I-III, tested ceftriaxone in ALS. Stage 1 determined the cerebrospinal fluid pharmacokinetics of ceftriaxone in subjects with ALS. Stage 2 evaluated safety and tolerability for 20-weeks. Analysis of the pharmacokinetics, tolerability, and safety was used to determine the ceftriaxone dosage for Stage 3 efficacy testing. METHODS: In Stage 1, 66 subjects at ten clinical sites were enrolled and randomized equally into three study groups receiving intravenous placebo, ceftriaxone 2 grams daily or ceftriaxone 4 grams daily divided BID. Participants provided serum and cerebrospinal fluid for pharmacokinetic analysis on study day 7. Participants continued their assigned treatment in Stage 2. The Data and Safety Monitoring Board (DSMB) reviewed the data after the last participants completed 20 weeks on study drug. RESULTS: Stage 1 analysis revealed linear pharmacokinetics, and CSF trough levels for both dosage levels exceeding the pre-specified target trough level of 1 µM (0.55 µg/mL). Tolerability (Stages 1 and 2) results showed that ceftriaxone at dosages up to 4 grams/day was well tolerated at 20 weeks. Biliary adverse events were more common with ceftriaxone but not dose-dependent and improved with ursodeoxycholic (ursodiol) therapy. CONCLUSIONS: The goals of Stages 1 and 2 of the ceftriaxone trial were successfully achieved. Based on the pre-specified decision rules, the DSMB recommended the use of ceftriaxone 4 g/d (divided BID) for Stage 3, which recently closed. TRIAL REGISTRATION: ClinicalTrials.gov NCT00349622.

Muscle power failure in mobility-limited older adults: preserved single fiber function despite lower whole muscle size, quality and rate of neuromuscular activation.

This study investigated the physiological and gender determinants of the age-related loss of muscle power in 31 healthy middle-aged adults (aged 40-55 years), 28 healthy older adults (70-85 years) and 34 mobility-limited older adults (70-85 years). We hypothesized that leg extensor muscle power would be significantly lower in mobility-limited elders relative to both healthy groups and sought to characterize the physiological mechanisms associated with the reduction of muscle power with aging. Computed tomography was utilized to assess mid-thigh body composition and calculate specific muscle power and strength. Surface electromyography was used to assess rate of neuromuscular activation and muscle biopsies were taken to evaluate single muscle fiber contractile properties. Peak muscle power, strength, muscle cross-sectional area, specific muscle power and rate of neuromuscular activation were significantly lower among mobility-limited elders compared to both healthy groups (P ≤ 0.05). Mobility-limited older participants had greater deposits of intermuscular adipose tissue (P < 0.001). Single fiber contractile properties of type I and type IIA muscle fibers were preserved in mobility-limited elders relative to both healthy groups. Male gender was associated with greater decrements in peak and specific muscle power among mobility-limited participants. Impairments in the rate of neuromuscular activation and concomitant reductions in muscle quality are important physiological mechanisms contributing to muscle power deficits and mobility limitations. The dissociation between age-related changes at the whole muscle and single fiber level suggest that, even among older adults with overt mobility problems, contractile properties of surviving muscle fibers are preserved in an attempt to maintain overall muscle function.

Relationship between force and size in human single muscle fibres.

When the contractile properties of single muscle fibres are studied, force is typically normalized by fibre cross-sectional area and expressed as specific force. We studied a set of 2725 chemically skinned human single muscle fibres from 119 healthy adults to determine whether specific force is the optimal way to express the relationship between single-fibre force and size. A linear mixed effects model was used to estimate the slope and slope variability among individuals of log-log plots of force and diameter. For type I fibres, the slope estimate was 0.99 (95% confidence interval 0.36-1.62), and for type IIa fibres it was 0.94 (95% confidence interval 0.77-1.11), indicating that force is proportional to fibre diameter, rather than to cross-sectional area. If force were proportional to cross-sectional area, the slope estimate would be 2.0. In future studies using the chemically skinned single fibre preparation, force may be normalized to fibre diameter rather than cross-sectional area. We propose that a new term, 'normalized force', be used for this variable, with units of newtons per metre. We demonstrate using our data set that when populations of single fibres are compared with one another, the determination of whether the size and force relationship is the same or different is dependent upon the method used to account for fibre size (i.e. specific force versus 'normalized force').

Dysferlin overexpression in skeletal muscle produces a progressive myopathy.

OBJECTIVE: The dose-response effects of dysferlin transgenesis were analyzed to determine if the dysferlin-deficient myopathies are good candidates for gene replacement therapy. METHODS: We have generated 3 lines of transgenic mice, expressing low, mid, and high levels of full-length human dysferlin from a muscle-specific promoter. Transgenic skeletal muscle was analyzed and scored for morphological and functional deficits. RESULTS: Overexpression of dysferlin in mice resulted in a striking phenotype of kyphosis, irregular gait, and reduced muscle mass and strength. Moreover, protein dosage correlated with phenotype severity. In contrast to dysferlin-null skeletal muscle, no evidence of sarcolemmal impairment was revealed. Rather, increased levels of Ca(2+)-regulated, dysferlin-binding proteins and endoplasmic reticulum stress chaperone proteins were observed in muscle lysates from transgenic mice as compared with controls. INTERPRETATION: Expression levels of dysferlin are important for appropriate function without deleterious or cytotoxic effects. As a corollary, we propose that future endeavors in gene replacement for correction of dysferlinopathy should be tailored to take account of this.

Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial. METHODS: We designed and implemented a multicenter trial with an adaptive, two-stage, bias-adjusted, randomized, placebo-controlled, double-blind, Phase II design (n = 185). The primary outcome in both stages was a decline in the ALS Functional Rating Scale-revised (ALSFRSr) score over 9 months. Stage 1 (dose selection, 35 participants per group) compared CoQ10 doses of 1,800 and 2,700 mg/day. Stage 2 (futility test, 75 patients per group) compared the dose selected in Stage 1 against placebo. RESULTS: Stage 1 selected the 2,700 mg dose. In Stage 2, the pre-specified primary null hypothesis that this dose is superior to placebo was not rejected. It was rejected, however, in an accompanying prespecified sensitivity test, and further supplementary analyses. Prespecified secondary analyses showed no significant differences between CoQ10 at 2,700 mg/day and placebo. There were no safety concerns. INTERPRETATION: CoQ10 at 2,700 mg daily for 9 months shows insufficient promise to warrant Phase III testing. Given this outcome, the adaptive Phase II design incorporating a dose selection and a futility test avoided the need for a much larger conventional Phase III trial.

Single muscle fiber contractile properties in adults with muscular dystrophy treated with MYO-029.

Myostatin inhibitors are being investigated as treatments for myopathies. We assessed single muscle fiber contractile properties before and after 6 months of study drug in 6 patients with facioscapulohumeral, Becker, and limb-girdle muscular dystrophy. Five of the patients received MYO-029, a myostatin inhibitor, and 1 received placebo. The chemically skinned single muscle fiber preparation was used to measure single fiber force, specific force, maximum unloaded shortening velocity, power, and specific power in type I and IIa fibers from each subject. In 4 of 5 patients who received MYO-029, improvement was seen in single muscle fiber contractile properties; thus, there may be a beneficial effect of myostatin inhibition on muscle physiology at the cellular level. No improvement was seen in the patient who received placebo. This finding may be clinically relevant in spite of the fact that quantitative muscle strength measurements in our patients did not improve. Further studies of myostatin inhibition as a treatment for muscular dystrophy are warranted, and single muscle fiber contractile studies are a useful assay for muscle function at the cellular level.

The amyotrophic lateral sclerosis center: a model of multidisciplinary management.

Amyotrophic lateral sclerosis (ALS) is a devastating, progressive motor neuron disorder that poses a myriad of clinical problems. Patients who have ALS are best cared for in a multidisciplinary fashion, with involvement of clinicians from various specialties, including neurology, physical medicine and rehabilitation, pulmonary medicine, clinical nurse specialists or nurse practitioners, physical and occupational therapists, speech language pathologists, dietitians, psychologists, social workers, and case managers. This article provides a summary of the current research into the rehabilitation of ALS, including the role of exercise, spasticity management, mood disorders, pain, and palliative care.

Muscle fiber size and function in elderly humans: a longitudinal study.

Cross-sectional studies are likely to underestimate age-related changes in skeletal muscle strength and mass. The purpose of this longitudinal study was to assess whole muscle and single muscle fiber alterations in the same cohort of 12 older (mean age: start of study 71.1+/-5.4 yr and end of study 80+/-5.3 yr) volunteers (5 men) evaluated 8.9 yr apart. No significant changes were noted at follow-up in body weight, body mass index, and physical activity. Muscle strength, evaluated using isokinetic dynamometry, and whole muscle specific force of the knee extensors were significantly lower at follow-up. This was accompanied by a significant reduction (5.7%) in cross-sectional area of the total anterior muscle compartment of the thigh as evaluated by computed tomography. Muscle histochemistry showed no significant changes in fiber type distribution or fiber area. Experiments with chemically skinned single muscle fibers (n=411) demonstrated no change in type I fiber size but an increase in IIA fiber diameter. A trend toward an increase in maximal force in both fiber types was observed. Maximum unloaded shortening velocity did not change. In conclusion, single muscle fiber contractile function may be preserved in older humans in the presence of significant alterations at the whole muscle level. This suggests that surviving fibers compensate to partially correct muscle size deficits in an attempt to maintain optimal force-generating capacity.

Evaluation and treatment of peroneal neuropathy.

Peroneal nerve compromise results in the clinical complaint of weakness of the ankle dorsiflexors and evertors. This peripheral origin of foot drop has been reported due to numerous traumatic and insidious causes. Traumatic causes of nerve injury occur in association with musculoskeletal injury or with isolated nerve traction, compression, or laceration. Insidious causes include mass lesions and metabolic syndromes. The peroneal nerve is most commonly interrupted at the knee. However, the sciatic and peroneal nerves may be compromised at the hip and ankle as well. This article reviews the anatomical origin of the nerve, the etiologies of possible nerve damage, evaluation of the patient with peroneal nerve injury, and treatment of this disorder.

Single skeletal muscle fiber elastic and contractile characteristics in young and older men.

The current investigation was designed to: (a) assess the impact of aging on elastic characteristics of single skeletal muscle fibers from young (N = 6) and older men (N = 6); and (b) correlate the potential changes, with the fiber contractile properties. Chemically skinned single muscle fibers (n = 235) from vastus lateralis muscle were maximally activated. Maximal force and cross-sectional area were measured, and specific force calculated. The slack test was used to measure maximal unloaded shortening velocity. A quick release of 0.15% of fiber length was applied to determine instantaneous stiffness. The myosin heavy chain isoform composition of each single fiber was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Aging induces changes in both fiber elasticity (i.e., increased instantaneous stiffness) and contractility (i.e., reduced specific force and unloaded shortening velocity) in type I and IIa fibers. However, the changes in fiber stiffness may not directly influence contractile characteristics alterations.

Neck and back pain: musculoskeletal disorders.

In this article, non-neurologic causes of neck and back pain are reviewed. Musculoskeletal pain generators include muscle, tendon, ligament, intervertebral disc, articular cartilage, and bone. Disorders that can produce neck and back pain include muscle strain, ligament sprain, myofascial pain, fibromyalgia, facet joint pain, internal disc disruption, somatic dysfunction, spinal fracture, vertebral osteomyelitis, and polymyalgia rheumatica. Atlantoaxial instability and atlanto-occipital joint pain are additional causes of neck pain. Back pain resulting from vertebral compression fracture, Scheuermann's disease, spondylolysis and spondylolisthesis, pregnancy, Baastrup's disease, sacroiliac joint dysfunction, and sacral stress fracture is discussed.

Single skeletal muscle fiber behavior after a quick stretch in young and older men: a possible explanation of the relative preservation of eccentric force in old age.

The origins of the smaller age-related decrease in eccentric force compared to isometric and concentric conditions in vivo remain unclear. Could this originate from contractile elements of muscle cells? The main intent of the current investigation was to assess the force behavior of muscle cells with aging, during lengthening. Chemically skinned single muscle fibers (n=235) from m. vastus lateralis of six young (mean age 31.6 years) and six older men (mean age 66.1 years) were maximally activated with pCa 4.5 at 15 degrees C. Maximal isometric force and cross-sectional area were measured allowing the calculation of the tension (T (0)). A quick stretch (2 nm per half-sarcomere length) was applied and caused an immediate increase in tension followed by a decrease and a secondary delayed and transient rise in tension (phase 3); finally, the tension recovered a steady state value (phase 4). The tension enhancements during phase 3 (DeltaT (3)) and phase 4 (DeltaT (4)) were evaluated. The myosin heavy-chain isoform composition of each single fiber was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. DeltaT (3) and DeltaT (4) were preserved in older men for both type I and IIa fibers despite a reduction in T (0). Therefore, the age-related preservation of the tension increments after a quick stretch in single muscle fibers could explain in part the smaller decrease in force during eccentric contractions compared to isometric and concentric conditions in vivo with aging usually observed.

Recurrent rhabdomyolysis in a collegiate athlete: a case report.

PURPOSE: Hereditary metabolic disorders can cause rhabdomyolysis in athletes. Team physicians should be aware of the presentation, workup, and management of the most common of these disorders, carnitine palmitoyltransferase (CPT) II deficiency and muscle phosphorylase deficiency. METHODS: The case of a collegiate athlete with recurrent bouts of rhabdomyolysis is presented, and the diagnostic workup is discussed. RESULTS: The patient described in this case has CPT II deficiency. The diagnosis and management of CPT II deficiency and muscle phosphorylase deficiency (McArdle's disease) are discussed. CONCLUSION: Athletes with rhabdomyolysis, in the absence of an obvious cause such as drug toxicity, severe trauma, or excessive exercise, should be evaluated for the presence of a metabolic myopathy.

Single muscle fiber size and contractility after spinal cord injury in rats.

Spinal cord injury (SCI) results in muscle weakness but the degree of impairment at the level of single fibers is not known. The purpose of this study was to examine the effects of T9-level SCI on single muscle fibers from the tibialis anterior of rats. Significant decreases in cross-sectional area (CSA), maximal force (Po), and specific force (SF = Po/CSA) were noted at 2 weeks. Atrophy and force-generating capacity were reversed at 4 weeks, but SF remained impaired. Maximum shortening velocity (Vo) did not change after injury. SCI thus appears to affect various contractile properties of single muscle fibers differently. Normal cage activity may partially restore function but new interventions are needed to restore muscle fiber quality.

Sex differences in single muscle fiber power in older adults.

PURPOSE: This study was conducted to determine whether differences in power at the single muscle fiber level contribute to sex differences in whole muscle power production in the elderly. METHODS: A total of 16 sedentary older persons (10 women, 6 men), mean age 72 yr, had percutaneous needle biopsy of musculus vastus lateralis. Chemically skinned single muscle fibers were activated with Ca for maximal isometric force measurement (Po). The slack test was performed to determine maximal unloaded shortening velocity (Vo). Force-velocity and power curves were generated via a series of isotonic contractions, allowing measurement of peak power and specific power. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was used to determine myosin heavy chain composition of single muscle fibers. Whole muscle strength, velocity, and power were measured for knee extension and double leg press. RESULTS: Men had greater whole muscle strength, power, and velocity compared with women. Studied were 274 type I and 33 type IIa single fibers. No significant sex differences were found for fiber size, Po, specific force, Vo, power, or specific power in type I or IIa fibers. CONCLUSIONS: Single muscle fiber quality in older women is equivalent to that in older men and can not explain the differences seen in whole muscle strength, power, or function.

Chronic inflammatory demyelinating polyradiculoneuropathy with tumefactive central demyelination.

A 46-year-old man with a 1-year history of distal paresthesias and mild distal weakness subacutely developed paralysis of the left hand. Electrodiagnostic evaluation revealed a demyelinating peripheral neuropathy that met criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Magnetic resonance imaging of the brain revealed a mass that enhanced with contrast, but revealed focal myelin loss with intense macrophage activity and axonal preservation on biopsy. The mass and hand weakness improved following steroid therapy. The combination of CIDP and central demyelination with mass effect broadens the spectrum of demyelinating disease in association with CIDP.