Objective To evaluate the safety, tolerability, and pharmacokinetics of an antisense oligonucleotide designed to inhibit SOD1 expression (ISIS 333611) following intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis (ALS). Background Mutations in SOD1 cause 13% of familial ALS. In animal studies, ISIS 333611 delivered to the cerebrospinal fluid (CSF) distributed to the brain and spinal cord, decreased SOD1 mRNA and protein levels in spinal cord tissue, and prolonged survival in the SOD1G93A rat ALS model. Methods In a randomized, placebo controlled Phase 1 trial, ISIS 333611 was delivered by intrathecal infusion using an external pump over 11.5 hours at increasing doses to four cohorts of eight SOD1 positive ALS subjects (randomized 6 drug: 2 placebo/cohort). Subjects were allowed to re-enroll in subsequent cohorts. Safety and tolerability assessments were made during the infusion and periodically over 28 days following the infusion. CSF and plasma drug levels were measured. Findings No dose-limiting toxicities were identified at doses up to 3.0 mg. No safety or tolerability concerns related to ISIS 333611 were identified. There were no serious adverse events (AEs) in ISIS 333611-treated subjects. Re-enrollment and re-dosing of subjects with ISIS 333611 was also well tolerated. Dose-dependent CSF and plasma concentrations were observed. Interpretation In this first clinical study to report intrathecal delivery of an antisense oligonucleotide, ISIS 333611 was well tolerated when administered as an intrathecal infusion in subjects with SOD1 familial ALS. CSF and plasma drug levels were consistent with levels predicted from preclinical studies. These results suggest that antisense oligonucleotide delivery to the central nervous system may be a feasible therapeutic strategy for neurological disorders. Source of funding ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals
Expanding use of immune-checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune-related adverse events (irAE-N). We evaluate the real-world frequency, phenotypes, co-occurring immune-related adverse events (irAEs), and long-term outcomes of severe, grade III to V irAE-N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE-N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE-N reporting are outlined.
IntroductionCoronavirus disease 2019 (COVID‐19) has rapidly become a global pandemic, but little is known about its potential impact on patients with myasthenia gravis (MG).MethodsWe studied the clinical course of COVID‐19 in five hospitalized patients with autoimmune MG (four with acetylcholine receptor antibodies, one with muscle‐specific tyrosine kinase antibodies) between April 1, 2020‐April 30‐2020.ResultsTwo patients required intubation for hypoxemic respiratory failure, whereas one required significant supplemental oxygen. One patient with previously stable MG had myasthenic exacerbation. One patient treated with tocilizumab for COVID‐19 was successfully extubated. Two patients were treated for MG with intravenous immunoglobulin without thromboembolic complications.DiscussionOur findings suggest that the clinical course and outcomes in patients with MG and COVID‐19 are highly variable. Further large studies are needed to define best practices and determinants of outcomes in this unique population.
Objective: To review the current evidence and make practice recommendations regarding the diagnosis and treatment of limb-girdle muscular dystrophies (LGMDs).Methods: Systematic review and practice recommendation development using the American Academy of Neurology guideline development process.
Objective: To study activin signaling and its blockade in sporadic inclusion body myositis (sIBM) through translational studies and a randomized controlled trial. Methods:We measured transforming growth factor b signaling by SMAD2/3 phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 with sIBM). We tested inhibition of activin receptors IIA and IIB (ActRII) in 14 patients with sIBM using one dose of bimagrumab (n 5 11) or placebo (n 5 3). The primary outcome was the change in right thigh muscle volume by MRI at 8 weeks. Lean body mass, strength, and function were secondary outcomes. Twelve of the patients (10 bimagrumab, 2 placebo) participated in a subsequent 16-week observation phase.Results: Muscle SMAD2/3 phosphorylation was higher in sIBM than in other muscle diseases studied (p 5 0.003). Eight weeks after dosing, the bimagrumab-treated patients increased thigh muscle volume (right leg 16.5% compared with placebo, p 5 0.024; left leg 17.6%, p 5 0.009) and lean body mass (15.7% compared with placebo, p 5 0.014). Subsequently, bimagrumabtreated patients had improved 6-minute walking distance, which peaked at 16 weeks (114.6%, p 5 0.008) compared with placebo. There were no serious adverse events; the main adverse events with bimagrumab were mild acne and transient involuntary muscle contractions.Conclusions: Transforming growth factor b superfamily signaling, at least through ActRII, is implicated in the pathophysiology of sIBM. Inhibition of ActRII increased muscle mass and function in this pilot trial, offering a potential novel treatment of sIBM. Classification of evidence:This study provides Class I evidence that for patients with inclusion body myositis, bimagrumab increases thigh muscle volume at 8 weeks. Neurology ® 2014;83:2239-2246 GLOSSARY ActRII 5 activin receptors IIA and IIB; DXA 5 dual-energy x-ray absorptiometry; LBM 5 lean body mass; pSMAD2/3 5 phosphorylated SMAD2/3; QMT 5 quantitative muscle testing; sIBM 5 sporadic inclusion body myositis; 6MWD 5 6-minute walking distance; TGFb 5 transforming growth factor b; TMV 5 thigh muscle volume.Sporadic inclusion body myositis (sIBM) is a slowly progressive degenerative and inflammatory skeletal muscle disease beginning in middle or later life.1 Its clinical features include a specific pattern of muscle involvement (preferential weakness of finger flexors and knee extensors) accompanied by progressive muscle atrophy, distinctive microscopic pathology including endomysial inflammation and rimmed vacuoles, and a recently identified serum autoantibody (against cytosolic 59-nucleotidase 1A) biomarker.2-4 Despite a prominent adaptive immune response characterized by antigen-stimulated B-and T-cell maturation and prominent infiltration into muscle of immune system cells, sIBM is highly refractory to immunosuppressive therapies studied to date. 2Members of the transforming growth factor b (TGFb) superfamily of ligands signal through a heterodimeric receptor system.5 They first bind a type II receptor, such as the TGFb...
At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.
Patients who undergo mechanical ventilation for severe asthma are at risk of developing diffuse muscle weakness because of acute myopathy. The relative importance of corticosteroids and neuromuscular paralysis in causing the myopathy is controversial, and it is uncertain whether the chemical structure of the drug used to induce paralysis influences the risk of myopathy. Using a retrospective cohort study design, we evaluated 107 consecutive episodes of mechanical ventilation for severe asthma to assess (1) the incidence of clinically significant weakness in patients treated with corticosteroids alone versus corticosteroids with neuromuscular paralysis, (2) the influence of the duration of paralysis on the incidence of muscle weakness, and (3) the relative risk of weakness in patients paralyzed with the nonsteroidal drug atracurium versus an aminosteroid paralytic agent (pancuronium, vecuronium). The use of corticosteroids and a neuromuscular blocking agent was associated with a much higher incidence of muscle weakness as compared with the use of corticosteroids alone (20 of 69 versus O of 38, p < 0.001). The 20 weak patients were paralyzed significantly longer than the 49 patients who received a neuromuscular blocking agent without subsequent weakness (3.4 +/- 2.4 versus 0.6 +/- 0.7 d, p < 0.001). Eighteen of the 20 weak patients had been paralyzed for more than 24 h. The incidence of weakness was not reduced when paralysis was achieved with atracurium as opposed to an aminosteroid neuromuscular blocking agent. In conclusion, corticosteroid-treated patients with severe asthma who undergo prolonged neuromuscular paralysis are at significant risk for the development of muscle weakness, and the risk of weakness is not reduced by use of atracurium.
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