Profound Muscle Weakness and Pain after One Dose of Actonel

The World Health Organization (WHO) defines osteopenia as a bone density between 1 and 2.5 standard deviation (SD) below the bone density of a normal young adult Iqbal 2000. Osteoporosis is defined as 2.5 SD or more below that reference point Iqbal 2000. Bisphosphonates are a group of medications used to treat osteoporosis, Padget's disease of bone, and osteopenia. We report a woman who developed profound muscle weakness and pain after one dose of Risedronate (Actonel)

Serum Ferritin and Metal Levels as Risk Factors for Amyotrophic Lateral Sclerosis

Metal toxicity has been identified as a possible risk factor for amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. We conducted a retrospective chart review of urinary, hair and blood metal levels and serum ferritin in 321 people with ALS seen over a ten-year period at the Massachusetts General Hospital (MGH). We found that hair lead levels and serum ferritin levels were elevated in ALS patients compared to published normal values. Metal levels of arsenic, lead, mercury, cadmium, thallium, cobalt and aluminum in 24-hour urine specimens and lead, mercury and arsenic in serum were within the normal range. We conclude that twenty-four hour urine or blood testing for metals is not warranted as part of the evaluation of ALS. Elevated levels of serum ferritin in ALS population could reflect an underlying perturbation in iron metabolism

Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS

Objective: To examine the safety and tolerability as well as the preliminary efficacy of arimoclomol, a heat shock protein co-inducer that promotes nascent protein folding, in patients with rapidly progressive SOD1 amyotrophic lateral sclerosis (ALS). Methods: This was a double-blind, placebo-controlled trial in which patients with rapidly progressive SOD1-mutant ALS were randomized 1:1 to receive arimoclomol 200 mg tid or matching placebo for up to 12 months. Study procedures were performed using a mix of in-person and remote assessments. Primary outcome was safety and tolerability. Secondary outcome was efficacy, with survival as the principal measure. Additional efficacy measures were the rates of decline of the Revised ALS Functional Rating Scale (ALSFRS-R) and percent predicted forced expiratory volume in 6 seconds (FEV6), and the Combined Assessment of Function and Survival (CAFS). Results: Thirty-eight participants were randomized. Thirty-six (19 placebo, 17 arimoclomol) were included in the prespecified intent-to-treat analysis. Apart from respiratory function, groups were generally well-balanced at baseline. Adverse events occurred infrequently, and were usually mild and deemed unlikely or not related to study drug. Adjusting for riluzole and baseline ALSFRS-R, survival favored arimoclomol with a hazard ratio of 0.77 (95% confidence interval [CI] 0.32–1.80). ALSFRS-R and FEV6 declined more slowly in the arimoclomol group, with treatment differences of 0.5 point/month (95% CI −0.63 to 1.63) and 1.24 percent predicted/month (95% CI −2.77 to 5.25), respectively, and the CAFS similarly favored arimoclomol. Conclusions: This study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. Although not powered for therapeutic effect, the consistency of results across the range of prespecified efficacy outcome measures suggests a possible therapeutic benefit of arimoclomol. Clinicaltrials.gov identifier NCT00706147. Classification of evidence This study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. The study lacked the precision to conclude, or to exclude, an important therapeutic benefit of arimoclomol

Respiratory Measures in Amyotrophic Lateral Sclerosis

Objective: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that causes skeletal muscle weakness, including muscles involved with respiration. Death often results from respiratory failure within 3€“5 years. Monitoring respiratory status is therefore critical to ALS management, as respiratory/pulmonary function tests (PFTs) are used to make decisions including when to initiate noninvasive ventilation. Understanding the different respiratory and PFTs as they relate to disease progression and survival may help determine which tests are most suitable. Methods: This review describes the tests used to assess respiratory muscle and pulmonary function in patients with ALS and the correlations between different respiratory measures and clinical outcomes measures. Results: The most commonly used measurement, forced vital capacity (VC), has been shown to correlate with clinical milestones including survival, but also requires good motor coordination and facial strength to form a tight seal around a mouthpiece. Other tests such as slow VC, sniff inspiratory pressure, or transdiaphragmatic pressure with magnetic stimulation are also associated with distinct advantages and disadvantages. Conclusions: Therefore, how and when to use different tests remains unclear. Understanding how each test relates to disease progression and survival may help determine which is best suited for specific clinical decisions

A Phase III Trial of Tirasemtiv as a Potential Treatment for Amyotrophic Lateral Sclerosis

Objective: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo in patients with amyotrophic lateral sclerosis. Methods: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled clinical trial. Participants tolerating 2 weeks of open-label tirasemtiv (125 mg twice daily) were randomized 3:2:2:2 to placebo or one of three target tirasemtiv dose levels, using an escalating dosage protocol lasting 28 days. The primary outcome measure was changed in slow vital capacity (SVC) at 24 weeks. Secondary endpoints included a change in muscle strength and time to respiratory milestones of disease progression. Results: Of 744 participants, 565 tolerated open-label tirasemtiv and received randomized treatment. By 24 weeks, 23 (12.2%) placebo-treated participants discontinued study treatment vs. 129 (34.2%) randomized to tirasemtiv. SVC declined by 14.4% (95% CI: ˆ’16.8, ˆ’11.9) in the placebo group and 13.4% (95% CI: ˆ’15.3, ˆ’11.6) in the tirasemtiv group (p = 0.56). Secondary endpoints did not show significant differences. However, participants who tolerated tirasemtiv at their randomized dose showed a numeric trend toward a dose-related slowing of decline in SVC (p = 0.11). Dizziness, fatigue, nausea, weight loss, and insomnia occurred more frequently on tirasemtiv. Serious adverse events were similar across groups. Conclusions: Tirasemtiv did not alter the decline of SVC or significantly impact secondary outcome measures. Poor tolerability of tirasemtiv may have contributed to this result. However, participants tolerating their intended dose exhibited a trend toward treatment benefit on SVC, suggesting the underlying mechanism of action may still hold promise, as is being tested with a different fast skeletal muscle troponin activator (NCT03160898)

Mexiletine for muscle cramps in amyotrophic lateral sclerosis: A randomized, double-blind crossover trial

INTRODUCTION:More than 90% of amyotrophic lateral sclerosis (ALS) patients have muscle cramps, but evidence-based treatments have not been available.METHODS:A multicenter, double-blind, placebo-controlled crossover trial of mexiletine 150 mg twice daily was conducted in ALS patients requesting treatment of symptomatic muscle cramps.RESULTS:Muscle cramp frequency was reduced in 18 of 20 patients; 13 reductions were attributed to treatment (P < 0.05). The average reduction, based on t tests, was 1.8 cramps per day (a reduction from 5.3 with placebo to 3.5 with mexiletine). The estimated reduction of cramp severity was 15 units on a 100-unit scale (P = 0.01) from a baseline average of 46. No effect on fasciculations was noted. One patient discontinued the study because of dizziness, and another patient discontinued the study to start open-label mexiletine therapy. No serious adverse event occurred.DISCUSSION:Mexiletine is a well tolerated and effective medication for controlling the symptom of muscle cramps 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

Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: Assessed with [11C]-PBR28

Evidence from human post mortem, in vivo and animal model studies implicates the neuroimmune system and activated microglia in the pathology of amyotrophic lateral sclerosis. The study aim was to further evaluate in vivo neuroinflammation in individuals with amyotrophic lateral sclerosis using [11C]-PBR28 positron emission tomography. Ten patients with amyotrophic lateral sclerosis (seven males, three females, 38–68 years) and ten age- and [11C]-PBR28 binding affinity-matched healthy volunteers (six males, four females, 33–65 years) completed a positron emission tomography scan. Standardized uptake values were calculated from 60 to 90 min post-injection and normalized to whole brain mean. Voxel-wise analysis showed increased binding in the motor cortices and corticospinal tracts in patients with amyotrophic lateral sclerosis compared to healthy controls (pFWE < 0.05). Region of interest analysis revealed increased [11C]-PBR28 binding in the precentral gyrus in patients (normalized standardized uptake value = 1.15) compared to controls (1.03, p < 0.05). In patients those values were positively correlated with upper motor neuron burden scores (r = 0.69, p < 0.05), and negatively correlated with the amyotrophic lateral sclerosis functional rating scale (r = –0.66, p < 0.05). Increased in vivo glial activation in motor cortices, that correlates with phenotype, complements previous histopathological reports. Further studies will determine the role of [11C]-PBR28 as a marker of treatments that target neuroinflammation