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Objective: To compare the effect of riluzole on median survival in population studies of patients with amyotrophic lateral sclerosis (ALS) with that observed in clinical trials. Methods : Two independent PubMed searches were conducted, to identify population studies that reported median survival for ALS patients who were either treated with riluzole or remained riluzole-free. Results : We identified 14 studies that met the inclusion criteria of reporting median survival and an additional study that reported mean survival of both riluzole and riluzole-free patients. Analysis of the 15 studies found that a majority reported increased survival of riluzole vs. riluzole-free patients. In 8 studies, the median survival for patients treated with riluzole was 6-19 months longer compared with patients not treated with riluzole ( p  < 0.05). Three additional studies reported a clinically meaningful treatment effect (range 3-5.9 months) but did not meet statistical significance. The remaining 4 studies did not show a meaningful treatment effect between riluzole and riluzole-free groups (<3 months), and differences among the groups were not significant. Also, 5 of the studies used multivariate regression analysis to investigate the level of association between treatment with riluzole and survival; these analyses supported the positive effect of riluzole on survival. Conclusions : A majority of population studies that compared riluzole vs. riluzole-free ALS patients found significant differences in median survival between the two groups, ranging from 6 to 19 months. This is substantially longer than the 2- to 3-month survival benefit observed in the pivotal clinical trials of riluzole.

Background: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known., Methods: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization., Results: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal., Conclusions: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: In a Phase 3 study, amyotrophic lateral sclerosis (ALS) patients experienced significantly less physical functional decline with 24-week edaravone vs placebo, followed by open-label treatment for an additional 24 weeks., Methods: Outcome (the change in ALS Functional Rating Scale-Revised, ALSFRS-R, from baseline) was projected for placebo patients through 48 weeks and compared with 48-week edaravone or 24-week edaravone after switching from placebo., Results: A total of 123 patients received open-label treatment (65 edaravone-edaravone; 58 placebo-edaravone). The projected ALSFRS-R decline for placebo from baseline through week 48 was greater than for 48-week edaravone (P < .0001). For patients switching from placebo to edaravone, ALSFRS-R slope approached that of continued edaravone for 48 weeks. ALSFRS-R decline did not differ between actual and projected edaravone through week 48., Conclusions: Compared with placebo, these analyses suggest that edaravone is beneficial in ALS patients even after 6 mo of receiving placebo, and efficacy is maintained for up to 1 year., (© 2019 The Authors. Muscle & Nerve published by Wiley Periodicals, Inc.)

Background : Radicava ® (edaravone), approved for the treatment of amyotrophic lateral sclerosis (ALS) in 2017, may be administered intravenously at clinic sites, infusion centers or at home. Objective : To gain insights into the utilization of Radicava ® at 1 year post-launch. Methods : Radicava ® usage data were collected, and a survey was conducted among 75 physicians. Adverse events (AEs) were identified from a post-marketing safety database from 8 August 2017 through 3 August 2018 (cutoff date). Results : As of 6 August 2018, 3007 ALS patients were treated with Radicava ® . Survey results indicated that 43% of patients received infusions at home, 32% in a clinician's office, and 26% at a referred site. Infusions were administered mainly via implanted port. The most commonly reported AEs were drug ineffective, death (not specified), therapeutic response unexpected, asthenia, fatigue, gait disturbance, disease progression, muscular weakness, fall, and dyspnea. Conclusions : The first year of Radicava ® availability to ALS patients in the US provided many key learnings that will help shape strategies for improved patient care.

Goal: There is limited research on intracerebral hemorrhage in young urban populations. There is reduced access to healthcare and a high prevalence of multiple comorbidities in this vulnerable population. We studied the etiologies and outcomes of spontaneous intracerebral hemorrhage in an urban North Philadelphia cohort aged 50 years old and younger., Materials and Methods: A retrospective chart review of subjects 50 years old and younger who presented with spontaneous intracerebral hemorrhage at Temple University Hospital was conducted. A novel scoring system was used to classify the cause of each intracerebral hemorrhage. This system was used to assign a degree of likelihood that hypertension, amyloid angiopathy, tumor, oral anticoagulants, vascular malformations, infrequent causes, or cryptogenic etiologies were present. Aneurysmal subarachnoid hemorrhage was excluded. The prevalence of each risk factor and outcomes were analyzed., Findings: Of the 110 patients in the study, the most common etiology was hypertension (82.7%). There was no statistically significant difference in mortality between patients with multiple possible etiologies for their hemorrhage. Vascular malformations and cavernomas were rare (5.5%)., Conclusions: Hypertension was the most common cause of intracerebral hemorrhage in a young urban population. The presence of multiple possible etiologies does not correlate with a worse prognosis of mortality. There is a need for further research into hemorrhagic stroke in young populations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: The goals of this study were to characterize clinical and electrophysiologic findings of subjects with upper motor neuron disease and to explore feasibility of clinical trials in this population., Methods: Twenty northeast amyotrophic lateral sclerosis consortium (northeast amyotrophic lateral sclerosis) sites performed chart reviews to identify active clinical pure upper motor neuron disease patients. Patients with hereditary spastic paraplegia or meeting revised El Escorial electrodiagnostic criteria for amyotrophic lateral sclerosis were excluded. Patients were classified into 2 groups according to the presence or absence of minor electromyography (EMG) abnormalities., Results: Two hundred thirty-three subjects with upper motor neuron disease were identified; 217 had available EMG data. Normal EMGs were seen in 140 subjects, and 77 had minor denervation. Mean disease duration was 84 (±80) months for the entire cohort with no difference seen between the 2 groups. No difference was seen in clinical symptoms, disability, or outcome measures between the 2 groups after correcting for multiple comparisons., Conclusions: Minor EMG abnormalities were not associated with phenotypic differences in a clinical upper motor neuron disease population. These findings suggest that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical upper motor neuron disease. This study also demonstrates the availability of a large number of patients with upper motor neuron diseases within the northeast amyotrophic lateral sclerosis network and suggests feasibility for conducting clinical trials in this population.

Background: Amyotrophic lateral sclerosis (ALS) is a serious and rapidly fatal neurodegenerative disorder with an annual incidence of 1-2.6/100,000 persons. Few known risk factors exist although gene-environment interaction is suspected. We investigated the relationship between suspected neurotoxicant hazardous air pollutants (HAPs) exposure and ALS., Methods: A case-control study involving sporadic ALS cases (n = 51) and matched controls (n = 51) was conducted from 2008 to 2011. Geocoded residential addresses were linked to U.S. EPA NATA data (1999, 2002, and 2005) by census tract. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression., Results: Residential exposure to aromatic solvents significantly elevated the risk of ALS among cases compared to controls in 2002 (OR = 5.03, 95% CI: 1.29, 19.53) and 1999 (OR = 4.27, 95% CI: 1.09, 16.79) following adjustment for education, smoking, and other exposure groups. Metals, pesticides, and other HAPs were not associated with ALS., Conclusions: A potential relationship is suggested between residential ambient air aromatic solvent exposure and risk of ALS in this study., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Mitochondrial myopathies belong to a larger group of systemic diseases caused by morphological or biochemical abnormalities of mitochondria. Mitochondrial disorders can be caused by mutations in either the mitochondrial or nuclear genome. Only 5% of all mitochondrial disorders are autosomal dominant. We analyzed DNA from members of the previously reported Puerto Rican kindred with an autosomal dominant mitochondrial myopathy (Heimann-Patterson et al. 1997). Linkage analysis suggested a putative locus on the pericentric region of the long arm of chromosome 22 (22q11). Using the tools of integrative genomics, we established chromosome 22 open reading frame 16 (C22orf16) (later designated as CHCHD10) as the only high-scoring mitochondrial candidate gene in our minimal candidate region. Sequence analysis revealed a double-missense mutation (R15S and G58R) in cis in CHCHD10 which encodes a coiled coil-helix-coiled coil-helix protein of unknown function. These two mutations completely co-segregated with the disease phenotype and were absent in 1,481 Caucasian and 80 Hispanic (including 32 Puerto Rican) controls. Expression profiling showed that CHCHD10 is enriched in skeletal muscle. Mitochondrial localization of the CHCHD10 protein was confirmed using immunofluorescence in cells expressing either wild-type or mutant CHCHD10. We found that the expression of the G58R, but not the R15S, mutation induced mitochondrial fragmentation. Our findings identify a novel gene causing mitochondrial myopathy, thereby expanding the spectrum of mitochondrial myopathies caused by nuclear genes. Our findings also suggest a role for CHCHD10 in the morphologic remodeling of the mitochondria.

Background: Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with few therapeutic options. Mild obesity is associated with greater survival in patients with the disease, and calorie-dense diets increased survival in a mouse model. We aimed to assess the safety and tolerability of two hypercaloric diets in patients with amyotrophic lateral sclerosis receiving enteral nutrition., Methods: In this double-blind, placebo-controlled, randomised phase 2 clinical trial, we enrolled adults with amyotrophic lateral sclerosis from participating centres in the USA. Eligible participants were aged 18 years or older with no history of diabetes or liver or cardiovascular disease, and who were already receiving percutaneous enteral nutrition. We randomly assigned participants (1:1:1) using a computer-generated list of random numbers to one of three dietary interventions: replacement calories using an isocaloric tube-fed diet (control), a high-carbohydrate hypercaloric tube-fed diet (HC/HC), or a high-fat hypercaloric tube-fed diet (HF/HC). Participants received the intervention diets for 4 months and were followed up for 5 months. The primary outcomes were safety and tolerability, analysed in all patients who began their study diet. This trial is registered with ClinicalTrials.gov, number NCT00983983., Findings: Between Dec 14, 2009, and Nov 2, 2012, we enrolled 24 participants, of whom 20 started their study diet (six in the control group, eight in the HC/HC group, and six in the HF/HC group). One patient in the control group, one in the HC/HC group, and two in the HF/HC group withdrew consent before receiving the intervention. Participants who received the HC/HC diet had a smaller total number of adverse events than did those in the other groups (23 in the HC/HC group vs 42 in the control group vs 48 in the HF/HC group; overall, p=0.06; HC/HC vs control, p=0.06) and significantly fewer serious adverse events than did those on the control diet (none vs nine; p=0.0005). Fewer patients in the HC/HC group discontinued their study diet due to adverse events (none [0%] of eight in the HC/HC group vs three [50%] of six in the control group). During the 5 month follow-up, no deaths occurred in the nine patients assigned to the HC/HC diet compared with three deaths (43%) in the seven patients assigned to the control diet (log-rank p=0.03). Adverse events, tolerability, deaths, and disease progression did not differ significantly between the HF/HC group and the control group., Interpretation: Our results provide preliminary evidence that hypercaloric enteral nutrition is safe and tolerable in patients with amyotrophic lateral sclerosis, and support the study of nutritional interventions in larger randomised controlled trials at earlier stages of the disease., Funding: Muscular Dystrophy Association, National Center for Research Resources, National Institutes of Health, and Harvard NeuroDiscovery Center., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background and Aims: Enteral nutrition (EN) is commonly prescribed for dysphagia and weight loss in amyotrophic lateral sclerosis (ALS), but there are currently no ALS-specific EN guidelines. We aimed to survey current practices prescribing EN to ALS patients., Methods: An online survey was distributed using list servers administered by the Academy of Nutrition and Dietetics (AND), Muscular Dystrophy Association (MDA), and ALS Association (ALSA)., Results: A total of 148 dietitians, nurses, and physicians participated in the survey, of whom 50% were dietitians and 68% were associated with an ALS clinic. Only 47% of respondents reported their patients to be fully compliant with EN recommendations. Side effects (fullness, diarrhea, constipation, and bloating) were the most important reason for patient noncompliance, followed by dependence on caregivers. By contrast, only 3% of providers rated depression/hopelessness as the most important reason for noncompliance. Half of those surveyed reported that more than 25% of patients continued to lose weight after starting EN., Conclusions: Our survey results show a high frequency of gastrointestinal side effects and weight loss in ALS patients receiving EN. These findings may be limited by sampling error and non-response bias. Prospective studies are needed to help establish EN guidelines for ALS.

Transgenic mice expressing multiple copies of the G93A mutant form of SOD1 develop motor neuron pathology and clinical symptoms similar to those seen in patients with amyotrophic lateral sclerosis (ALS). The phenotype of these mice is dependent on the number of transgene copies in their genome. Changes in transgene copy number, although rare, can sometimes occur while mating due to intra locus recombination events during meiosis. The objective of this study was to develop a real time quantitative PCR method to determine changes in transgene copy number in these mice and to evaluate the effect of transgene copy number on the phenotype of the G93A SOD1 mouse model of ALS.

Objective: To assess the utility of standard equations for calculating caloric requirements in patients with amyotrophic lateral sclerosis (ALS)., Background: Malnutrition substantially increases the risk of death in ALS. Weight loss can be stabilized and survival prolonged with early gastrostomy feeding. However the use of standard nutrition equations has not been validated in this population. We therefore compared measured caloric expenditure to 2 predictive equations in patients with varying stages of ALS., Methods: Thirty-four patients were studied. Caloric expenditure and respiratory quotient (R) were measured using indirect calorimetry. Results were compared with the Harris-Benedict equation., Results: The prediction error for the Harris-Benedict equation was 18.6 + 14.9%. Limits of agreement showed this equation could overestimate caloric expenditure by 591 kcal/d and underestimate requirements by 677 kcal/d. R was >0.86 in 11 patients, suggesting overfeeding, and <0.8 in 15 patients, suggesting underfeeding. The difference between predicted and measured caloric expenditure did not correlate with disease severity, disease duration, or body mass index. Mechanically ventilated patients had higher than predicted energy expenditure., Conclusions: We found that standard equations used to calculate energy expenditure were not valid for patients with ALS. Moreover, the majority of our patients were either overfed or underfed. As underfeeding can cause diaphragm impairment, and overfeeding can increase ventilatory load, indirect calorimetry should be considered in ALS patients to determine optimal caloric requirement.