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ALSUntangled reviews alternative and off label treatments with a goal of helping patients make more informed decisions about them. Here we review ketogenic diets. We shows that these have plausible mechanisms, including augmenting cellular energy balance and reducing excitotoxicity, neuroinflammation and oxidative stress. We review a mouse model study, anecdotal reports and trials in ALS and other diseases. We conclude that there is yet not enough data to recommend ketogenic diets for patients with ALS, especially in light of the many side effects these can have.

Summary Background There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. Methods The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178 ) has also been completed, but will be reported separately. Findings Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. Interpretation Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation. Funding Orion Corporation.

An intravenous (IV) formulation of edaravone has been shown to slow the rate of physical functional decline in amyotrophic lateral sclerosis (ALS). An oral suspension formulation of edaravone was recently approved by the United States Food and Drug Administration for use in patients with ALS. This study assessed the safety and tolerability of oral edaravone.This global, open-label, phase 3 study evaluated the long-term safety and tolerability of oral edaravone in adults with ALS who had a baseline forced vital capacity ≥70% of predicted and disease duration ≤3 y. The primary safety analysis was assessed at weeks 24 and 48. Patients received a 105-mg dose of oral edaravone in treatment cycles replicating the dosing of IV edaravone.The study enrolled 185 patients (64.3% male; mean age, 59.9 y; mean disease duration, 1.56 y). The most common treatment-emergent adverse events (TEAEs) at week 48 were fall (22.2%), muscular weakness (21.1%) and constipation (17.8%). Serious TEAEs were reported by 25.9% of patients; the most common were worsening ALS symptoms, dysphagia, dyspnea, and respiratory failure. Twelve TEAEs leading to death were reported. Forty-six (24.9%) patients reported TEAEs that were considered related to study drug; the most common were fatigue, dizziness, headache, and constipation. Sixteen (8.6%) patients discontinued study drug due to TEAEs. No serious TEAEs were related to study drug.This study indicated that oral edaravone was well tolerated during 48 wk of treatment, with no new safety concerns identified.

Comprehensive and valid bulbar assessment scales for use within amyotrophic lateral sclerosis (ALS) clinics are critically needed. The aims of this study are to develop the Clinical Bulbar Assessment Scale (CBAS) and complete preliminary validation.The authors selected CBAS items from among the literature and expert opinion, and content validity ratio (CVR) was calculated. Following consent, the CBAS was administered to a pilot sample of English-speaking adults with El Escorial defined ALS (N = 54) from a multidisciplinary clinic, characterizing speech, swallowing, and extrabulbar features. Criterion validity was assessed by correlating CBAS scores with commonly used ALS scales, and internal consistency reliability was obtained.Expert raters reported strong agreement for the CBAS items (CVR = 1.00; 100% agreement). CBAS scores yielded a moderate, significant, negative correlation with ALS Functional Rating Scale-Revised (ALSFRS-R) total scores (r = -0.652, p .001), and a strong, significant, negative correlation with ALSFRS-R bulbar subscale scores (r = -0.795, p .001). There was a strong, significant, positive correlation with Center for Neurologic Studies Bulbar Function Scale (CNS-BFS) scores (r = 0.819, p .001). CBAS scores were significantly higher for bulbar onset (mean = 38.9% of total possible points, SD = 22.6) than spinal onset (mean = 18.7%, SD = 15.8; p = .004). Internal consistency reliability (Cronbach's alpha) values were: (a) total CBAS, α = 0.889; (b) Speech subscale, α = 0.903; and (c) Swallowing subscale, α = 0.801.The CBAS represents a novel means of standardized bulbar data collection using measures of speech, swallowing, respiratory, and cognitive-linguistic skills. Preliminary evidence suggests the CBAS is a valid, reliable scale for clinical assessment of bulbar dysfunction.

Vitamin C is one of the most common supplements taken by people with ALS. As an antioxidant, it has a plausible mechanism for slowing disease progression and there are some flawed pre-clinical studies and case reports suggesting benefit. However, a small human trial showed no benefit. Given this negative trial, we do not currently advise vitamin C as an ALS treatment.

Here we use the ALSUntangled methodology to review Tamoxifen as an ALS treatment. We show that it has plausible mechanisms, a positive preclinical study, a case report and 2 small trials suggesting benefits. We show that it appears reasonably safe, though there is a small risk of developing cancer with long term use. While we cannot yet endorse this as an ALS treatment, there is enough evidence to warrant another larger ALS trial.

An orally administered, fixed‐dose coformulation of sodium phenylbutyrate‐taurursodiol (PB‐TURSO) significantly slowed functional decline in a randomized, placebo‐controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long‐term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB‐TURSO or placebo. Participants completing the 6‐month (24‐week) randomized phase were eligible to receive PB‐TURSO in the open‐label extension. An all‐cause mortality analysis (35‐month maximum follow‐up post‐randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow‐up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB‐TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34‐0.92; P = .023). Initiation of PB‐TURSO treatment at baseline resulted in a 6.5‐month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB‐TURSO has both functional and survival benefits in ALS.

To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow...

IntroductionEarly detection and tracking of bulbar dysfunction in amyotrophic lateral sclerosis (ALS) are critical for directing management of the disease. Current clinical bulbar assessment tools are lacking, while existing physiological instrumental assessments are often inaccessible and cost-prohibitive for clinical application. The goal of our research is to develop and validate a brief and reliable, clinician-administered assessment tool—the ALS-Bulbar Dysfunction Index (ALS-BDI). This publication describes the study protocol that has been established to ascertain the tools’ psychometric properties.Methods and analysisThe ALD-BDI’s development closely follows guidelines outlined by the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). Through the proposed study protocol, we expect to establish psychometric properties of both individual test items of the ALS-BDI as well as the final version of the entire tool, including test–retest and inter-rater reliability, construct validity using gold-standard assessment methods and responsiveness.Ethics and disseminationThis study has been reviewed and approved by research ethics boards at two data collection sites: Sunnybrook Health Science Centre, primary (Toronto, Canada; ID3080) and Mass General Brigham (#2013P001746, Boston, USA). Prior to participation in the study, the participants sign the informed consent in accordance with the Declaration of Helsinki. Once validated, the ALS-BDI will be disseminated to key stakeholders. Following validation, the ALS-BDI and any required training material will be implemented for clinical use in a context of a multidisciplinary ALS clinic and used as an outcome measure for clinical trials in ALS research.

BackgroundCoformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS).ObjectiveDetermine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial.MethodsAdults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation.ResultsRisk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO.ConclusionsEarly PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS.Trial registration numberNCT03127514;NCT03488524.

BackgroundGenetically polymorphic Superoxide Dismutase 1 G93A (SOD1-G93A) underlies one form of familial Amyotrophic Lateral Sclerosis (ALS). Exposures from viruses may also contribute to ALS, possibly by stimulating immune factors, such as IL-6, Interferon Stimulated Genes, and Nitric Oxide. Recently, chlorovirus ATCV-1, which encodes a SOD1, was shown to replicate in macrophages and induce inflammatory factors.ObjectiveThis study aimed to determine if ATCV-1 influences development of motor degeneration in an ALS mouse model and to assess whether SOD1 of ATCV-1 influences production of inflammatory factors from macrophages.MethodsSera from sporadic ALS patients were screened for antibody to ATCV-1. Active or inactivated ATCV-1, saline, or a viral mimetic, polyinosinic:polycytidylic acid (poly I:C) were injected intracranially into transgenic mice expressing human SOD1-G93A- or C57Bl/6 mice. RAW264.7 mouse macrophage cells were transfected with a plasmid vector expressing ATCV-1 SOD1 or an empty vector prior to stimulation with poly I:C with or without Interferon-gamma (IFN-γ).ResultsSerum from sporadic ALS patients had significantly more IgG1 antibody directed against ATCV-1 than healthy controls. Infection of SOD1-G93A mice with active ATCV-1 significantly accelerated onset of motor loss, as measured by tail paralysis, hind limb tucking, righting reflex, and latency to fall in a hanging cage-lid test, but did not significantly affect mortality when compared to saline-treated transgenics. By contrast, poly I:C treatment significantly lengthened survival time but only minimally slowed onset of motor loss, while heat-inactivated ATCV-1 did not affect motor loss or survival. ATCV-1 SOD1 significantly increased expression of IL-6, IL-10, ISG promoter activity, and production of Nitric Oxide from RAW264.7 cells.ConclusionATCV-1 chlorovirus encoding an endogenous SOD1 accelerates pathogenesis but not mortality, while poly I:C that stimulates antiviral immune responses delays mortality in an ALS mouse model. ATCV-1 SOD1 enhances induction of inflammatory factors from macrophages.

We propose a cloud-based multimodal dialog platform for the remote assessment and monitoring of Amyotrophic Lateral Sclerosis (ALS) at scale. This paper presents our vision, technology setup, and an initial investigation of the efficacy of the various acoustic and visual speech metrics automatically extracted by the platform. 82 healthy controls and 54 people with ALS (pALS) were instructed to interact with the platform and completed a battery of speaking tasks designed to probe the acoustic, articulatory, phonatory, and respiratory aspects of their speech. We find that multiple acoustic (rate, duration, voicing) and visual (higher order statistics of the jaw and lip) speech metrics show statistically significant differences between controls, bulbar symptomatic and bulbar pre-symptomatic patients. We report on the sensitivity and specificity of these metrics using five-fold cross-validation. We further conducted a LASSO-LARS regression analysis to uncover the relative contributions of various acoustic and visual features in predicting the severity of patients' ALS (as measured by their self-reported ALSFRS-R scores). Our results provide encouraging evidence of the utility of automatically extracted audiovisual analytics for scalable remote patient assessment and monitoring in ALS.

To develop a multidimensional facial surface electromyographic (EMG) analysis for assessing bulbar involvement in amyotrophic lateral sclerosis (ALS).Fifty-four linear and nonlinear features were extracted from the surface EMG recordings for masseter, temporalis, and anterior belly of digastric in 13 patients with ALS and 10 healthy controls, each performed a speech task three times. The features were factor analyzed and then evaluated in terms of internal consistency, relation to functional speech outcomes, and efficacy for patient-control classification.Five internally consistent, interpretable factors were derived, representing the functioning of masseter, temporalis, digastric, antagonists, and agonists, respectively. These factors explained 40-43% of the variance in the functional speech outcomes and were ≥90% accurate in patient-control classification. The jaw muscle performance of individuals with ALS was characterized by (1) reduced complexity and coherence of antagonist muscle activities, and (2) increased complexity and irregularity of temporalis activity.Two important bulbar muscular changes were identified in ALS, related to both upper and lower motor neuron pathologies. These changes reflected (1) decreased motor unit recruitment and synchronization for jaw antagonists, and (2) a potential neuromuscular adaptation for temporalis.The surface EMG-based framework shows promise as an objective bulbar assessment tool.

Introduction: Universally established comprehensive clinical bulbar scales objectively assessing disease progression in amyotrophic lateral sclerosis (ALS) are currently lacking. The goal of this working group project is to design a best practice set of provisional bulbar ALS guidelines, available for immediate implementation within all ALS clinics. Methods: ALS specialists across multiple related disciplines participated in a series of clinical bulbar symposia, intending to identify and summarize the currently accepted best practices for the assessment and management of bulbar dysfunction in ALS Results: Summary group recommendations for individual speech, Augmentative and Alternative Communication (AAC), and swallowing sections were achieved, focusing on the optimal proposed level of care within each domain. Discussion: We have identified specific clinical recommendations for each of the 3 domains of bulbar functioning, available for incorporation within all ALS clinics. Future directions will be to establish a formal set of bulbar guidelines through a methodological and evidence-based approach. Muscle Nerve 59:531–531, 2019. Fil: Pattee, Gary L.. No especifíca; Fil: Plowman, Emily K.. University of Florida; Estados Unidos Fil: Garand, Kendrea L.. University of Alabama at Birmingahm; Estados Unidos Fil: Costello, John. No especifíca; Fil: Brooks, Benjamin Rix. No especifíca; Fil: Berry, James D.. No especifíca; Fil: Smith, Richard A.. No especifíca; Fil: Atassi, Nazem. No especifíca; Fil: Chapin, Jennifer L.. University of Florida; Estados Unidos Fil: Yunusova, Yana. University of Toronto; Canadá Fil: McIlduff, Courtney E.. No especifíca; Fil: Young, Eufrosina. No especifíca; Fil: Macklin, Eric A.. No especifíca; Fil: Locatelli, Eduardo R.. No especifíca; Fil: Silani, Vincenzo. Università degli Studi di Milano; Italia Fil: Heitzman, Daragh. No especifíca; Fil: Wymer, James. University of Florida; Estados Unidos Fil: Goutman, Stephen A.. No especifíca; Fil: Gelinas, Deborah F.. No especifíca; Fil: Perry, Bridget. No especifíca; Fil: Nalipinski, Paige. No especifíca; Fil: Stipancic, Kaila. Children's Hospital Boston; Estados Unidos Fil: O'Brien, Meghan. Children's Hospital Boston; Estados Unidos Fil: Sullivan, Stacey L.. No especifíca; Fil: Pioro, Erik P.. No especifíca; Fil: Gargiulo Monachelli, Gisella Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Green, Jordan R.. No especifíca

ALSUntangled reviews alternative and off-label treatments for people with ALS. Here we review light therapy. We show that it has theoretically plausible mechanisms, three flawed pre-clinical data, studies, and one incompletely documented case report supporting its use. We explain why further studies are needed to determine whether any specific light therapy protocol can help people with ALS.

To identify a novel, quantitative bulbar measure in amyotrophic lateral sclerosis (ALS) based on jaw muscle coherence. Methods: The myoelectric activities of masseter, anterior temporalis, and anterior belly of digastric were recorded bilaterally during a speech task in 12 individuals with ALS and 10 neurologically healthy controls, using surface electromyography. Coherence and directed coherence were calculated for all muscle pairs. The muscle pairs showing significant coherence and directed coherence in the beta-band (15–35 Hz) were identified and their mean beta-band coherence were (1) correlated with the kinematic (i.e. jaw acceleration time) and functional speech (i.e. speaking rate) measures that have been previously identified to be affected by bulbar ALS, across all participants, and (2) evaluated in terms of their efficacy in differentiating individuals with ALS from healthy controls. Results: Beta-band coherence was in general reduced in ALS relative to healthy controls, with the antagonistic and homologous muscle pairs being more affected than the agonistic pairs. Among all muscle pairs, the coherence between masseter and digastric (1) showed the strongest correlations with jaw acceleration time and speaking rate, and (2) differentiated individuals with ALS from healthy controls with the highest sensitivity (i.e. 0.92) and specificity (i.e. 0.90). Conclusions: Reduced beta-band coherence between masseter and digastric in ALS reflects weakened neural linkage between these muscles resulting from the disrupted cortical drive to the bulbar musculature. These findings provide preliminary evidence for jaw muscle coherence as a novel, quantitative measure of corticobulbar involvement, designed to improve bulbar assessment in ALS.

Here we use the ALSUntangled methodology to review Tamoxifen as an ALS treatment. We show that it has plausible mechanisms, a positive preclinical study, a case report and 2 small trials suggesting benefits. We show that it appears reasonably safe, though there is a small risk of developing cancer with long term use. While we cannot yet endorse this as an ALS treatment, there is enough evidence to warrant another larger ALS trial.

Objective: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength megascore, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898)

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.)

Background: Pseudobulbar affect (PBA) is associated with neurological disorders or injury affecting the brain, and characterized by frequent, uncontrollable episodes of crying and/or laughing that are exaggerated or unrelated to the patient’s emotional state. Clinical trials establishing dextromethorphan and quinidine (DM/Q) as PBA treatment were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). This trial evaluated DM/Q safety in patients with PBA secondary to any neurological condition affecting the brain. Objective: To evaluate the safety and tolerability of DM/Q during long-term administration to patients with PBA associated with multiple neurological conditions. Methods: Fifty-two-week open-label study of DM/Q 30/30 mg twice daily. Safety measures included adverse events (AEs), laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations. Clinical trial registration: #NCT00056524. Results: A total of 553 PBA patients with >30 different neurological conditions enrolled; 296 (53.5%) completed. The most frequently reported treatment-related AEs (TRAEs) were nausea (11.8%), dizziness (10.5%), headache (9.9%), somnolence (7.2%), fatigue (7.1%), diarrhea (6.5%), and dry mouth (5.1%). TRAEs were mostly mild/moderate, generally transient, and consistent with previous controlled trials. Serious AEs (SAEs) were reported in 126 patients (22.8%), including 47 deaths, mostly due to ALS progression and respiratory failure. No SAEs were deemed related to DM/Q treatment by investigators. ECG results suggested no clinically meaningful effect of DM/Q on myocardial repolarization. Differences in AEs across neurological disease groups appeared consistent with the known morbidity of the primary neurological conditions. Study interpretation is limited by the small size of some disease groups, the lack of a specific efficacy measure and the use of a DM/Q dose higher than the eventually approved dose. Conclusions: DM/Q was generally well tolerated over this 52 week trial in patients with PBA associated with a wide range of neurological conditions.

AIMS A recent double-blind placebo-controlled crossover 70-day trial demonstrated that a fixed combination of dextromethorphan and quinidine (DM/Q) improves speech and swallowing function in most patients with amyotrophic lateral sclerosis. In this study, a subset of participants, many of whom did not substantially improve while on DM/Q, were re-evaluated using computer-based speech analyses and expert clinician ratings of the overall severity of speech impairment. METHODS Speech samples were recorded from the subset of 10 patients at four visits made at approximately 30-day intervals. The recordings were analysed by automated computer-based analysis of speech pausing patterns. Severity of speech impairment was rated by three experienced speech-language pathologists using direct magnitude estimation. Scores on patient-reported and clinician-administered scales of bulbar motor involvement were obtained at each visit. RESULTS The effects of DM/Q were detected on several of the objective speech measures, including total pause duration (s) (Cohen's d = 0.73, 95% confidence interval (CI) -1.70, 0.24), pause time (%) (d = 0.77, 95% CI -1.75, 0.21), and mean speech event duration (s) (d = 0.52, 95% CI -0.44, 1.47), but not on clinician ratings of speech or the speech components of the self-report or clinician-administered scales. CONCLUSIONS These findings suggest that even patients with modest improvement while on DM/Q may experience quantifiable improvements in speech when assessed using sensitive and objective measures. This study provides additional evidence of the positive impact of DM/Q on one or more of the neural systems that control bulbar motor function and production of speech.

OBJECTIVE: Speech and Swallowing impairments are highly prevalent in individuals with amyotrophic lateral sclerosis (ALS) and contribute to reduced quality of life, malnutrition, aspiration, pneumonia and death. Established practice parameters for bulbar dysfunction in ALS do not currently exist. The aim of this study was to identify current practice patterns for the evaluation of speech and swallowing function within participating Northeast ALS clinics in the United States. METHODS & RESULTS: A 15-item survey was emailed to all registered NEALS centers. Thirty-eight sites completed the survey. The majority (92%) offered Speech-Language Pathology, augmentative and alternative communication (71%), and dietician (92%) health care services. The ALS functional rating scale-revised and body weight represented the only parameters routinely collected in greater then 90% of responding sites. Referral for modified barium swallow study was routinely utilized in only 27% of sites and the use of percutaneous gastrostomy tubes in ALS patient care was found to vary considerably. CONCLUSIONS: This survey reveals significant variability and inconsistency in the management of bulbar dysfunction in ALS across NEALS sites. We conclude that a great need exists for the development of bulbar practice guidelines in ALS clinical care to accurately detect and monitor bulbar dysfunction.

Infections and inflammatory responses may contribute to motor neuron diseases (MND), such as Amyotrophic Lateral Sclerosis (ALS). A portion of familial ALS is caused by polymorphic Superoxide Dismutase (SOD)1 gene (SOD1G93A). As chloroviruses (CV) infect macrophages inducing inflammatory cytokines, they may contribute to ALS. Moreover, ATCV-1 is one of several chlorovirus types that encodes its own SOD1. Thus we evaluated serum from human ALS patients compared with controls for antibody against ATCV-1. In addition, we i.c. injected saline or ATCV-1 into SOD1G93A-transgenic and C57Bl/6 control mice and assessed development of ALS-like MND. Sera from ALS patients and controls had antibody to ATCV-1. However, ALS patients had significantly greater IgG1 anti-ATCV-1 compared with controls. This was accompanied by elevated IL-6, IFN-γ, and anti-Tetanus toxin antibody, but not IL-17. SOD1G93A mice inoculated with ATCV-1 had significantly accelerated development of MND, including tail paralysis, hindlimb tucking, decreased righting reflex, and latency to fall in a hanging cage lid test, compared with saline injected SOD1G93A mice. Splenic T cells of SOD1G93A and control mice showed similar IFN-γ and IL-17 responses to anti-CD3/-CD28, while Foxp3 expression overall was significantly higher in T cells of SOD1G93A compared with control mice. Inoculation with ATCV-1 decreased Foxp3 expression in SOD1G93A T cells compared with mice not given ATCV-1. These results indicate that chloroviruses, ubiquitous in fresh waters worldwide, induce antibody responses in humans that are elevated in ALS and may accelerate MND in the SOD1G93A type of familial ALS. Funding was generously provided by the Stuart Nichols ALS Research Foundation.

17 pags., 8 figs., We investigated the Central Nervous System (CNS) and skeletal muscle tissue from A woman was clinically diagnosed with amyotrophic lateral sclerosis (ALS) at the age of 22. Neuropathologic evaluation showed upper and lower motor neuron loss, corticospinal tract degeneration and skeletal muscle denervation. Analysis of the patient's Deoxyribonucleic acid (DNA) revealed a AGT>GGT change resulting in an S375G substitution in the C-terminal region of TDP-43. This variant was previously reported as being benign. Considering the early onset and severity of the disease in this patient, we tested the effects of this genetic variant on TDP-43 localization, pre-mRNA splicing activity and toxicity, in parallel with the effects on known neighboring disease-associated mutations. In cell lines, expressed in culture, S375G TDP-43 appeared to be more significantly localized in the nucleus and to exert higher toxicity than wild-type TDP-43. Strikingly, a phosphomimic mutant at the same residue (S375E) showed a strong tendency to accumulate in the cytoplasm, especially under stress conditions, and molecular dynamics simulations suggest that phosphorylation of this residue can disrupt TDP-43 intermolecular interactions. The results of the current study highlight the importance of phosphorylation and regulation of TDP-43 nuclear-cytoplasmic shuttling/redistribution, in relation to the pathogenetic mechanisms involved in different forms of ALS., This work was supported by the International Scientific Co-operation Agreement between Italy and Israel (SCREENCELLS4ALS, Ministero Affari Esteri, MAE, Italy) and SAF-2016-76678-C2-2-R (DVL). BG is supported by grant P30 AG010133. KN is supported by grant P30 AG035982.

People with such severe and complex communication needs that they require speech-generating devices (SGDs) to meet daily communication needs come from all age groups and socioeconomic backgrounds (Beukelman & Mirenda, 2013). Among this group are people eligible for Medicare, which will provide payment for a percentage (typically 80 percent) of covered health care costs, including SGDs. Medicare eligibility extends to people age 65 and older and younger people who became disabled from non-work related causes. In this article, the authors first review Medicare coverage for augmentative and alternative communication (AAC) devices beginning in the 1980s and subsequently document the SGD acquisition and access of 64 people with amyotrophic lateral sclerosis (ALS) whose speech became so severely limited that they required an SGD to support functional communication.

This study investigated speaking rate effects on articulatory pattern consistency in talkers with mild amyotrophic lateral sclerosis (ALS) to better understand speech rate declines during the early stages of speech deterioration. Eight talkers with mild ALS and 11 controls repeated a sentence at their typical rate, an accelerated rate, and a reduced rate. Lip and jaw movements were captured using a 3-D motion capture system. Results showed that talkers with ALS produced more consistent articulatory patterns during typical speech than did controls. Further, rate reduction resulted in diminished pattern consistency in both groups. Fast speech also elicited less consistent articulatory patterns in talkers with ALS. Controls, by contrast, tended to produce more consistent patterns during fast speech. Relatively inconsistent patterns during fast speech suggest that ALS may negatively affect articulatory control when the speech motor system operates near its performance limit. Relatively consistent patterns during typical speech indicate a successful adaption to disease-related articulatory deficits. Rate reduction does not appear to benefit articulatory stability during early stages of speech decline.

Bulbar motor deterioration due to amyotrophic lateral sclerosis (ALS) leads to the eventual impairment of speech and swallowing functions. Despite these devastating consequences, no standardized diagnostic procedure for assessing bulbar dysfunction in ALS exists and adequate objective markers of bulbar deterioration have not been identified. In this paper, we consider objective measures of speech motor function, which show promise for forming the basis of a comprehensive, quantitative bulbar motor assessment in ALS. These measures are based on the assessment of four speech subsystems: respiratory, phonatory, articulatory, and resonatory. The goal of this research is to design a non-invasive, comprehensive bulbar motor assessment instrument intended for early detection, monitoring of disease progression, and clinical trial application. Preliminary data from an ongoing study of bulbar motor decline are presented, which demonstrate the potential clinical efficacy of the speech subsystem approach.

Purpose To determine the mechanisms of speech intelligibility impairment due to neurologic impairments, intelligibility decline was modeled as a function of co-occurring changes in the articulatory, resonatory, phonatory, and respiratory subsystems. Method Sixty-six individuals diagnosed with amyotrophic lateral sclerosis (ALS) were studied longitudinally. The disease-related changes in articulatory, resonatory, phonatory, and respiratory subsystems were quantified using multiple instrumental measures, which were subjected to a principal component analysis and mixed effects models to derive a set of speech subsystem predictors. A stepwise approach was used to select the best set of subsystem predictors to model the overall decline in intelligibility. Results Intelligibility was modeled as a function of five predictors that corresponded to velocities of lip and jaw movements (articulatory), number of syllable repetitions in the alternating motion rate task (articulatory), nasal airflow (resonatory), maximum fundamental frequency (phonatory), and speech pauses (respiratory). The model accounted for 95.6% of the variance in intelligibility, among which the articulatory predictors showed the most substantial independent contribution (57.7%). Conclusion Articulatory impairments characterized by reduced velocities of lip and jaw movements and resonatory impairments characterized by increased nasal airflow served as the subsystem predictors of the longitudinal decline of speech intelligibility in ALS. Declines in maximum performance tasks such as the alternating motion rate preceded declines in intelligibility, thus serving as early predictors of bulbar dysfunction. Following the rapid decline in speech intelligibility, a precipitous decline in maximum performance tasks subsequently occurred.

The goal of this study was to determine if talkers with ALS are limited in their ability to increase lower lip and jaw speed at an early stage of the disease when their speaking rate and intelligibility are only minimally or not affected.A novel metronome paced fixed-target task was used to assess movement speed capacities during lower lip and jaw oscillations in seven talkers with ALS and seven age and gender matched controls.Lower lip peak speeds were significantly lower in talkers with mild ALS than in healthy talkers suggesting a lower lip speed constraint in talkers with mild ALS. Jaw peak speeds tended to be lower, but jaw displacements tended to be larger in talkers with mild ALS than in healthy talkers. Because greater speeds are typically expected for larger displacements, outcomes also suggest a jaw speed constraint in talkers with mild ALS.Lower lip and jaw peak speeds may be sensitive measures to identify bulbar motor performance decline at an early stage of the disease when speaking rate and intelligibility are only minimally affected.The reader will be able to explain two different articulatory strategies to increase speaking rate and understand why fast speech tasks and diadochokinetic pseudo-speech tasks are not suited to assess articulatory speed capacity in healthy and impaired talkers. The reader will also be able to explain how orofacial movement speed capacity can be tested using a fixed-target task and how ALS affects lower lip and jaw speed capacities during the early stages of the disease.

The aim of this Symposium was to develop a consensus based, bulbar assessment protocol for implementation within NEALS clinics.A one-day symposium, held in April 2017, was organized into Speech and Swallowing sections to establish summary recommendations for the assessment of bulbar dysfunction within each group.Summary recommendations included speech referrals and AAC evaluations at initial visit, CNS-BFS, maximum sustained phonation, and speaking rate. Dysarthria evaluation included the speech subsystem involvement of respiration, phonation, resonance, and articulation. Specific recommendations for swallowing were established for each of the following domains: dietary/oral intake, airway defense physiologic capacity, swallow safety screen, patient-reported swallow-related outcomes, oral sensorimotor exam, and pulmonary function. Practice parameters focused upon patient education and unresolved questions included the use of videofluoscopy, monitoring diet progression, and swallow safety screening.The working goal is to establish a clinical bulbar protocol, designed to be incorporated within ALS clinics and ultimately to formulate a best practice set of bulbar ALS guidelines, available for implementation throughout the international ALS community.

The purpose of this study was to investigate the self-perceived attention allocation of listeners as they transcribed the speech samples of speakers with mild to severe dysarthria as a result of amyotrophic lateral sclerosis. Listeners reported that their perceived attention allocation increased consistently as speech intelligibility for sentences decreased from 100% to 75%. In this study, self-perceptions of attention allocation peaked between 75% and 80% intelligibility. These results support the conclusion that listeners experience a considerable perceptual load as they attempt to comprehend the messages of persons whose speech has relatively high intelligibility but distorted due to dysarthria.

Background and purpose Impaired bulbar functions of speech and swallowing are among the most serious consequences of amyotrophic lateral sclerosis (ALS). Despite this, clinical trials in ALS have rarely emphasized bulbar function as an endpoint. The rater‐administered Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised (ALSFRS‐R) or various quality‐of‐life measures are commonly used to measure symptomatic benefit. Accordingly, we sought to evaluate the utility of measures specific to bulbar function in ALS. Methods We assessed bulbar functions in 120 patients with ALS, with clinicians first making direct observations of the degree of speech, swallowing and salivation impairment in these subjects. Clinical diagnosis of bulbar impairment was then compared with ALSFRS‐R scores, speech rate, time to swallow liquids and solids, and scores obtained when patients completed visual analog scales (VASs) and the newly‐developed 21‐question self‐administered Center for Neurologic Study Bulbar Function Scale (CNS‐BFS). Results The CNS‐BFS, ALSFRS‐R, VAS and timed speech and swallowing were all concordant with clinician diagnosis. The self‐report CNS‐BFS and ALSFRS‐R bulbar subscale best predicted clinician diagnosis with misclassification rates of 8% and 14% at the optimal cut‐offs, respectively. In addition, the CNS‐BFS speech and swallowing subscales outperformed both the bulbar component of the ALSFRS‐R and speech and swallowing VASs when correlations were made between these scales and objective measures of timed reading and swallowing. Conclusions Based on these findings and its relative ease of administration, we conclude that the CNS‐BFS is a useful metric for assessing bulbar function in patients with ALS., Click https://www.ean.org/CME.2714.0.html for the corresponding questions to this CME article.