Publications by authors named "Jeremy M Shefner"

81 Publications

Estimation of forced vital capacity using speech acoustics in patients with ALS.

Amyotroph Lateral Scler Frontotemporal Degener 2021 ;22(sup1):14-21

Department of Speech Pathology, Arizona State University, Phoenix, AZ, USA.

In this study, we present and provide validation data for a tool that predicts forced vital capacity (FVC) from speech acoustics collected remotely via a mobile app without the need for any additional equipment (e.g. a spirometer). We trained a machine learning model on a sample of healthy participants and participants with amyotrophic lateral sclerosis (ALS) to learn a mapping from speech acoustics to FVC and used this model to predict FVC values in a new sample from a different study of participants with ALS. We further evaluated the cross-sectional accuracy of the model and its sensitivity to within-subject change in FVC. We found that the predicted and observed FVC values in the test sample had a correlation coefficient of .80 and mean absolute error between .54 L and .58 L (18.5% to 19.5%). In addition, we found that the model was able to detect longitudinal decline in FVC in the test sample, although to a lesser extent than the observed FVC values measured using a spirometer, and was highly repeatable (ICC = 0.92-0.94), although to a lesser extent than the actual FVC (ICC = .97). These results suggest that sustained phonation may be a useful surrogate for VC in both research and clinical environments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2020.1866013DOI Listing
September 2021

Prescription and acceptance of durable medical equipment in FORTITUDE-ALS, a study of in ALS: post hoc analyses of a randomized, double-blind, placebo-controlled clinical trial.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Jul 5:1-8. Epub 2021 Jul 5.

Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA.

: To evaluate the possible effect of , a fast skeletal muscle troponin activator, on prescription and acceptance of durable medical equipment (DME) in the FORTITUDE-ALS trial. Health economic outcome information was collected in FORTITUDE-ALS (NCT03160898); sites recorded if and when DME, specifically manual or power wheelchairs, gastrostomy tubes, noninvasive ventilators, or augmentative language devices, was prescribed by a physician and accepted by the patient (DME-PAP) during the trial. Acceptance was defined as the patient agreeing the item was needed. Cox regression analysis compared time to DME-PAP for each dose with placebo. Post hoc analyses evaluated all doses compared with placebo. At least one DME item was prescribed and accepted by 33/114 (28.9%) of placebo patients, 19/112 (17.0%) of patients receiving 150 mg bid, 24/113 (21.2%) receiving 300 mg bid, and 29/117 (24.8%) receiving 450 mg bid. The proportion of new DME-PAP was significantly lower in patients receiving 150 mg bid vs placebo (17.0% vs 28.9%,  = 0.032). The hazard ratio versus placebo for accepting at least one DME item for all doses combined was 0.61 (confidence interval: 0.39, 0.96,  = 0.032). 25% of placebo patients were prescribed and agreed to obtain a DME item by 84 days; this threshold was met for -treated patients at 120 days. Results suggest ALS patients receiving may have lower risk of and delayed need for DME related to impaired mobility, breathing, swallowing, or speaking; this delay is consistent with other measures indicating delay in disease progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2021.1946083DOI Listing
July 2021

Tocilizumab is safe and tolerable and reduces C-reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients.

Muscle Nerve 2021 09 24;64(3):309-320. Epub 2021 Jun 24.

Department of Neurology, Gregory W. Fulton ALS and Neuromuscular Disease Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.

Introduction/aims: We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients.

Methods: Twenty-two participants, whose peripheral blood mononuclear cell (PBMC) gene expression profile reflected high messenger ribonucleic acid (mRNA) expression of inflammatory markers, were randomized 2:1 to three tocilizumab or placebo treatments (weeks 0, 4, and 8; 8 mg/kg intravenous). Participants were followed every 4 wk in a double-blind fashion for 16 wk and assessed for safety, tolerability, plasma inflammatory markers, and clinical measures. Cerebrospinal fluid (CSF) was collected at baseline and after the third treatment. Participants were genotyped for Asp Ala polymorphism of the interleukin 6 receptor (IL-6R) gene.

Results: Baseline characteristics, safety, and tolerability were similar between treatment groups. One serious adverse event was reported in the placebo group; no deaths occurred. Mean plasma C-reactive protein (CRP) level decreased by 88% in the tocilizumab group and increased by 4% in the placebo group (-3.0-fold relative change, P < .001). CSF CRP reduction (-1.8-fold relative change, P = .01) was associated with IL-6R C allele count. No differences in PBMC gene expression or clinical measures were observed between groups.

Discussion: Tocilizumab treatment was safe and well tolerated. PBMC gene expression profile was inadequate as a predictive or pharmacodynamic biomarker. Treatment reduced CRP levels in plasma and CSF, with CSF effects potentially dependent on IL-6R Asp Ala genotype. IL-6 trans-signaling may mediate a distinct central nervous system response in individuals inheriting the IL-6R C allele. These results warrant further study in ALS patients where IL-6R genotype and CRP levels may be useful enrichment biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.27339DOI Listing
September 2021

Evaluation of Amyotrophic Lateral Sclerosis-Induced Muscle Degeneration Using Magnetic Resonance-Based Relaxivity Contrast Imaging (RCI).

Tomography 2021 05 5;7(2):169-179. Epub 2021 May 5.

Barrow Neuroimaging Innovation Center, Division of Neuroimaging Research, Barrow Neurological Institute, Phoenix, AZ 85013, USA.

(1) Background: This work characterizes the sensitivity of magnetic resonance-based Relaxivity Contrast Imaging (RCI) to Amyotrophic Lateral Sclerosis (ALS)-induced changes in myofiber microstructure. Transverse Relaxivity at Tracer Equilibrium (TRATE), an RCI-based parameter, was evaluated in the lower extremities of ALS patients and healthy subjects. (2) Methods: In this IRB-approved study, 23 subjects (12 ALS patients and 11 healthy controls) were scanned at 3T (Philips, The Netherlands). RCI data were obtained during injection of a gadolinium-based contrast agent. TRATE, fat fraction and T measures, were compared in five muscle groups of the calf muscle, between ALS and control populations. TRATE was also evaluated longitudinally (baseline and 6 months) and was compared to clinical measures, namely ALS Functional Rating Scale (ALSFRS-R) and Hand-Held Dynamometry (HHD), in a subset of the ALS population. (3) Results: TRATE was significantly lower ( < 0.001) in ALS-affected muscle than in healthy muscle in all muscle groups. Fat fraction differences between ALS and healthy muscle were statistically significant for the tibialis anterior ( = 0.01), tibialis posterior ( = 0.004), and peroneus longus ( = 0.02) muscle groups but were not statistically significant for the medial ( = 0.07) and lateral gastrocnemius ( = 0.06) muscles. T differences between ALS and healthy muscle were statistically significant for the tibialis anterior ( = 0.004), peroneus longus ( = 0.004) and lateral gastrocnemius ( = 0.03) muscle groups but were not statistically significant for the tibialis posterior ( = 0.06) and medial gastrocnemius ( = 0.07) muscles. Longitudinally, TRATE, averaged over all patients, decreased by 28 ± 16% in the tibialis anterior, 47 ± 18% in the peroneus longus, 25 ± 19% in the tibialis posterior, 29 ± 14% in the medial gastrocnemius and 35 ± 18% in the lateral gastrocnemius muscles between two timepoints. ALSFRS-R scores were stable in two of four ALS patients. HHD scores decreased in three of four ALS patients. (4) Conclusion: RCI-based TRATE was shown to consistently differentiate ALS-affected muscle from healthy muscle and also provide a quantitative measure of longitudinal muscle degeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/tomography7020015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162571PMC
May 2021

Putting the patient first: The validity and value of surface-based electrical impedance myography techniques.

Clin Neurophysiol 2021 07 20;132(7):1752-1753. Epub 2021 Apr 20.

Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinph.2021.03.020DOI Listing
July 2021

Noninvasive ventilation use by patients enrolled in VITALITY-ALS.

Amyotroph Lateral Scler Frontotemporal Degener 2021 11 1;22(7-8):486-494. Epub 2021 Apr 1.

St. Joseph's Hospital and Medical Cente, Barrow Neurological Institute, Phoenix, AZ, USA.

To evaluate the prescribing practices of noninvasive ventilation (NIV) and patient compliance during VITALITY-ALS. VITALITY-ALS enrolled patients with a slow vital capacity (SVC) ≥70% of predicted who were not using NIV at screening. Physicians prescribed NIV without restriction following randomization. Reason(s) for NIV prescription, dates prescribed and initiated, and compliance were recorded. Compliance was recorded as prescribed but never initiated, used ≥2 h/24 h, used ≥4 h/24 h, or used ≥22 h/24 h. In addition to other outcome measures, SVC and the revised ALS functional rating scale (ALSFRS-R) were performed at all visits. Patients were followed up to 56 weeks. 565 patients were randomized and dosed with placebo or in VITALITY-ALS; 195 (34.5%) were prescribed NIV: of these, 78.5% used it for ≥2 h/24 h, 71.3% for ≥4 h/24 h, and 11.8% for ≥22 h/24 h. The three most common reasons NIV was prescribed were decline in vital capacity, respiratory symptoms, and sleep-related symptoms. During the trial, 179/565 (31.7%) patients had a decline of SVC below 50%; of these patients, 122/179 (68.2%) were prescribed NIV. Reasons for prescribing NIV were different for patients from North America compared with Europe. Despite allowing for NIV initiation at any point following randomization in VITALITY-ALS, only slightly more than two out of three patients whose SVC fell below 50% were prescribed NIV; this was similar in Europe and in North America. Underutilization of NIV could influence survival outcomes in patients with ALS including those involved in clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2021.1904993DOI Listing
November 2021

Diagnostic Utility of Gold Coast Criteria in Amyotrophic Lateral Sclerosis.

Ann Neurol 2021 05 24;89(5):979-986. Epub 2021 Feb 24.

Westmead Clinical School, University of Sydney, Sydney, Australia.

Objective: The diagnosis of amyotrophic lateral sclerosis (ALS) remains problematic, with current diagnostic criteria (revised El Escorial [rEEC] and Awaji) being complex and prone to error. Consequently, the diagnostic utility of the recently proposed Gold Coast criteria was determined in ALS.

Methods: We retrospectively reviewed 506 patients (302 males, 204 females) to compare the diagnostic accuracy of the Gold Coast criteria to that of the Awaji and rEEC criteria (defined by the proportion of patients categorized as definite, probable, or possible ALS) in accordance with standards of reporting of diagnostic accuracy criteria.

Results: The sensitivity of Gold Coast criteria (92%, 95% confidence interval [CI] = 88.7-94.6%) was comparable to that of Awaji (90.3%, 95% CI = 86.69-93.2%) and rEEC (88.6, 95% CI = 84.8-91.7%) criteria. Additionally, the Gold Coast criteria sensitivity was maintained across different subgroups, defined by site of onset, disease duration, and functional disability. In atypical ALS phenotypes, the Gold Coast criteria exhibited greater sensitivity and specificity.

Interpretation: The present study established the diagnostic utility of the Gold Coast criteria in ALS, with benefits evident in bulbar and limb onset disease patients, as well as atypical phenotypes. The Gold Coast criteria should be considered in clinical practice and therapeutic trials. ANN NEUROL 2021;89:979-986.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.26045DOI Listing
May 2021

To Zoom or Not to Zoom: The Should I Travel Index Revisited during the Coronavirus Disease Pandemic.

Ann Neurol 2021 06 15;89(6):1057-1058. Epub 2021 Feb 15.

Department of Neurology, University of Miami, Miller School of Medicine, Miami, FL, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.26038DOI Listing
June 2021

Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase II randomized controlled trial.

Muscle Nerve 2021 03 31;63(3):371-383. Epub 2020 Dec 31.

Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Background: To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial.

Methods: Twenty ALS subjects were randomized to placebo and mexiletine 300 or 600 mg daily for 4 wk and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT).

Results: RMT was unchanged with 4 wk of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (P = .039). Reductions of motor evoked potential (MEP) amplitude (P = .013) and accommodation half-time (P = .002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 wk on mexiletine.

Conclusions: The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half-time supports the reduction of cortical and axonal hyperexcitability with mexiletine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.27146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513796PMC
March 2021

Improving clinical trial outcomes in amyotrophic lateral sclerosis.

Nat Rev Neurol 2021 02 18;17(2):104-118. Epub 2020 Dec 18.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Individuals who are diagnosed with amyotrophic lateral sclerosis (ALS) today face the same historically intransigent problem that has existed since the initial description of the disease in the 1860s - a lack of effective therapies. In part, the development of new treatments has been hampered by an imperfect understanding of the biological processes that trigger ALS and promote disease progression. Advances in our understanding of these biological processes, including the causative genetic mutations, and of the influence of environmental factors have deepened our appreciation of disease pathophysiology. The consequent identification of pathogenic targets means that the introduction of effective therapies is becoming a realistic prospect. Progress in precision medicine, including genetically targeted therapies, will undoubtedly change the natural history of ALS. The evolution of clinical trial designs combined with improved methods for patient stratification will facilitate the translation of novel therapies into the clinic. In addition, the refinement of emerging biomarkers of therapeutic benefits is critical to the streamlining of care for individuals. In this Review, we synthesize these developments in ALS and discuss the further developments and refinements needed to accelerate the introduction of effective therapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41582-020-00434-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747476PMC
February 2021

Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

JAMA Neurol 2021 02;78(2):186-196

Department of Neurology, University of California Irvine, Irvine.

Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials.

Objective: To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS.

Design, Setting, And Participants: This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements.

Interventions: Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks.

Main Outcomes And Measures: The primary outcome was change in short-interval intracortical inhibition (SICI; SICI-1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies.

Results: A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI-1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI-1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, -2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001).

Conclusions And Relevance: Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials.

Trial Registration: ClinicalTrials.gov Identifier: NCT02450552.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2020.4300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684515PMC
February 2021

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington's Disease Patients-A Randomized Phase 2 Clinical Trial.

J Clin Med 2020 Nov 16;9(11). Epub 2020 Nov 16.

Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington's disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington's Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9113682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696926PMC
November 2020

Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis.

Muscle Nerve 2021 01 30;63(1):31-39. Epub 2020 Oct 30.

Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, Iowa.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.27091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820979PMC
January 2021

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of In Patients With ALS.

Amyotroph Lateral Scler Frontotemporal Degener 2021 05 24;22(3-4):287-299. Epub 2020 Sep 24.

Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada.

Objective: To evaluate safety, dose response, and preliminary efficacy of over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to 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. Patients ( = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance ( = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R,  = 0.09; muscle strength mega-score,  = 0.31). Post hoc analyses pooling all active -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)). 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. Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring 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 on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2020.1822410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117790PMC
May 2021

Efficacy of Ciprofloxacin/Celecoxib combination in zebrafish models of amyotrophic lateral sclerosis.

Ann Clin Transl Neurol 2020 10 11;7(10):1883-1897. Epub 2020 Sep 11.

The Dead Sea Arava Science Center, Auspices of Ben Gurion University, Central Arava, 86815, Israel.

Objective: To evaluate the efficacy of a fixed-dose combination of two approved drugs, Ciprofloxacin and Celecoxib, as a potential therapeutic treatment for amyotrophic lateral sclerosis (ALS).

Methods: Toxicity and efficacy of Ciprofloxacin and Celecoxib were tested, each alone and in distinct ratio combinations in SOD1 G93R transgenic zebrafish model for ALS. Quantification of swimming measures following stimuli, measurements of axonal projections from the spinal cord, neuromuscular junction structure and morphometric analysis of microglia cells were performed in the combination- treated vs nontreated mutant larvae. Additionally, quantifications of touch-evoked locomotor escape response were conducted in treated vs nontreated zebrafish expressing the TARDBP G348C ALS variant.

Results: When administered individually, Ciprofloxacin had a mild effect and Celecoxib had no therapeutic effect. However, combined Ciprofloxacin and Celecoxib (Cipro/Celecox) treatment caused a significant increase of ~ 84% in the distance the SOD1 G93R transgenic larvae swam. Additionally, Cipro/Celecox elicited recovery of impaired motor neurons morphology and abnormal neuromuscular junction structure and preserved the ramified morphology of microglia cells in the SOD1 mutants. Furthermore, larvae expressing the TDP-43 mutation displayed evoked touch responses that were significantly longer in swim distance (110% increase) and significantly higher in maximal swim velocity (~44% increase) when treated with Cipro/Celecox combination.

Interpretation: Cipro/Celecox combination improved locomotor and cellular deficits of ALS zebrafish models. These results identify this novel combination as effective, and may prove promising for the treatment of ALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.51174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545590PMC
October 2020

Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis.

N Engl J Med 2020 09;383(10):919-930

From the Sean M. Healey and AMG Center for ALS and the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School (S.P., J.D.B., S.B., M.C., D.D., M.M., J.O., L.P., A.V.S., E.T., P.V., J. Walker, H.Y., R.E.T., M.E.C.), the Biostatistics Center, Massachusetts General Hospital, Harvard Medical School (E.A.M., J. Chan, D.S.), and Spaulding Rehabilitation Hospital, Harvard Medical School (S.P.), Boston, the University of Massachusetts Memorial Medical Center, Worcester (M.A.O.), and Amylyx Pharmaceuticals (J. Cohen, J. Klee, K.L., P.D.Y.) and Harvard University (W.G.), Cambridge - all in Massachusetts; Pentara, Millcreek, UT (S.H., S.P.D., N.E., K.H.); Swedish Neuroscience Institute, Seattle (M.A.E.); Hennepin Healthcare, Minneapolis (S.M.); the Department of Neurology, Oregon Health and Science University, Portland (C.K.); the Department of Neurology, Wake Forest School of Medicine, Winston-Salem, NC (J.B.C.); the Department of Neurology, Ohio State University College of Medicine, Columbus (A.Q.); the Department of Neurology, University of Florida College of Medicine, Gainesville (J. Wymer); the Department of Neurology, University of Michigan, Ann Arbor (S.A.G.); Texas Neurology, Dallas (D.H.); the Department of Neurology, Lewis Katz School of Medicine, Temple University (T.H.-P.), and the Department of Neurology, University of Pennsylvania Perelman School of Medicine (C.Q.) - both in Philadelphia; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Disease, University of Texas Health Science Center at San Antonio, San Antonio (C.E.J.); the Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore (J.D.R.); the Department of Neurology, University of Kentucky College of Medicine, Lexington (E.J.K.); California Pacific Medical Center and Forbes Norris MDA-ALS Research and Treatment Center, San Francisco (J. Katz, L.J.); Barrow Neurological Institute, Phoenix, AZ (S.L., M.H., G.K., R.R., J.M.S.); the Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis (T.M.M.); the Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York (S.N.S.); the Department of Neurology, University of South Florida Morsani College of Medicine, Tampa (T.H.V.); the Departments of Neurology and Pathology, Emory University School of Medicine, Atlanta (C.N.F., J.D.G.); Ochsner Health System, New Orleans (K.M.J.); the Department of Neurology, University of Iowa Carver College of Medicine, Iowa City (A.S.); the Department of Neurology, University of California, Irvine, School of Medicine, Irvine (N.A.G.); Neurology Associates, Lincoln, NB (G.L.P.); independent consultant, Nobleboro, ME (P.L.A.); and Statistics Collaborative, Washington, DC (J. Wittes).

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.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1916945DOI Listing
September 2020

Amyotrophic lateral sclerosis: a new diagnostic paradigm.

J Neurol Neurosurg Psychiatry 2020 09 23;91(9):903-904. Epub 2020 Jun 23.

Institute of Clinical Neurosciences, University of Sydney, Sydney, New South Wales, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2020-324006DOI Listing
September 2020

Improved ALS clinical trials through frequent at-home self-assessment: a proof of concept study.

Ann Clin Transl Neurol 2020 07 9;7(7):1148-1157. Epub 2020 Jun 9.

Barrow Neurological Clinic, Phoenix, AZ, USA.

Objective: To determine the potential for improving amyotrophic lateral sclerosis (ALS) clinical trials by having patients or caregivers perform frequent self-assessments at home.

Methods And Participants: We enrolled ALS patients into a nonblinded, longitudinal 9-month study in which patients and caregivers obtained daily data using several different instruments, including a slow-vital capacity device, a hand grip dynamometer, an electrical impedance myography-based fitness device, an activity tracker, a speech app, and the ALS functional rating scale-revised. Questions as to acceptability were asked at two time points.

Results: A total of 113 individuals enrolled, with 61 (43 men, 18 women, mean age 60.1 ± 9.9 years) collecting a minimum of 7 days data and being included in the analysis. Daily measurements resulted in more accurate assessments of the slope of progression of the disease, resulting in smaller sample size estimates for a hypothetical clinical trial. For example, by performing daily slow-vital capacity measurements, calculated sample size was reduced to 182 subjects/study arm from 882/arm for monthly measurements. Similarly, performing the ALS functional rating scale weekly rather than monthly led to a calculated sample size of 73/arm as compared to 274/arm. Participants generally found the procedures acceptable and, for many, improved their sense of control of their disease.

Interpretation: Frequent at-home measurements using standard tools holds the prospect of tracking progression and reducing sample size requirements for clinical trials in ALS while also being acceptable to the patients. Future studies in this and other neurological disorders should consider adopting this approach to data collection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.51096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359124PMC
July 2020

Amyotrophic lateral sclerosis care and research in the United States during the COVID-19 pandemic: Challenges and opportunities.

Muscle Nerve 2020 08 5;62(2):182-186. Epub 2020 Jun 5.

Department of Neurology, Duke University, Durham, North Carolina.

Coronavirus disease 2019 has created unprecedented challenges for amyotrophic lateral sclerosis (ALS) clinical care and research in the United States. Traditional evaluations for making an ALS diagnosis, measuring progression, and planning interventions rely on in-person visits that may now be unsafe or impossible. Evidence- and experience-based treatment options, such as multidisciplinary team care, feeding tubes, wheelchairs, home health, and hospice, have become more difficult to obtain and in some places are unavailable. In addition, the pandemic has impacted ALS clinical trials by impairing the ability to obtain measurements for trial eligibility, to monitor safety and efficacy outcomes, and to dispense study drug, as these also often rely on in-person visits. We review opportunities for overcoming some of these challenges through telemedicine and novel measurements. These can reoptimize ALS care and research in the current setting and during future events that may limit travel and face-to-face interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.26989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283687PMC
August 2020

Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

JAMA Neurol 2020 06;77(6):755-763

Columbia University Irving Medical Center, New York, New York.

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.

Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings.

Conclusions And Relevance: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2020.0367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483960PMC
June 2020

Clinical neurophysiology of anterior horn cell disorders.

Handb Clin Neurol 2019 ;161:317-326

Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, United States. Electronic address:

The development of neurophysiological techniques for clinical assessment in the 20th century is closely related to the study of anterior horn cell diseases. The effects of motor axon loss on nerve conduction velocity and compound motor amplitude were elucidated first in amyotrophic lateral sclerosis (ALS), as was the characterization of reinnervation as detected by needle electromyography. The same changes noted in early studies still play a major role in the diagnosis of anterior horn cell diseases. In addition, much of modern neurophysiological assessment of motor axon quantitation, ion channel changes in neurogenic disease, and cortical physiology studies to assess both network and excitability abnormalities have all been applied to ALS. In this chapter, we summarize the clinical attributes of ALS and Spinal Muscular Atrophy, and review how clinical neurophysiology is employed in the clinical and the research setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/B978-0-444-64142-7.00057-6DOI Listing
January 2020

ALS drug development guidances and trial guidelines: Consensus and opportunities for alignment.

Neurology 2019 07 6;93(2):66-71. Epub 2019 Jun 6.

From the Eleanor and Lou Gehrig ALS Center (J.A.A.), Columbia University, New York, NY; ALS Association (L.I.B.), Washington, DC; and Department of Neurology (J.M.S.), Barrow Neurological Institute, University of Arizona College of Medicine, Phoenix. Dr. Bruijn is currently at Bruijn-Yard Neuroscience R&D Consultant.

The US Food and Drug Administration (FDA) developed a draft guidance for drug development in amyotrophic lateral sclerosis (ALS) that was issued in February 2018. The FDA draft guidance considered the recommendations developed by the ALS community that incorporated the views of a large group of clinical investigators, industry representatives, advocacy groups, patients, and caregivers. This external input from the ALS community reviewed the current state of clinical research in ALS, made suggestions over a wide range of drug development topics, and served as an educational tool to provide the agency with additional inputs about ALS, the state of the science, and the community's views on key topics. In parallel to this effort, there was an independent effort to revise and update the ALS Clinical Trial Guidelines. We discuss the areas of agreement of these 3 documents and the areas that provide opportunities to improve the efficiency of drug development in ALS. It is likely that further research into biomarkers, efficacy endpoints, and predictive algorithms will provide greater alignment among community stakeholders and increase clarity on drug development efforts going forward. Continued patient engagement and inclusion of patient experience data in every aspect of the drug development process will further facilitate the approval of new treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000007695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656654PMC
July 2019

A phase III trial of as a potential treatment for amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2019 ;0(0):1-11

The Neurological Institute, Columbia University, New York, NY, USA.

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: −16.8, −11.9) in the placebo group and 13.4% (95% CI: −15.3, −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).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2019.1612922DOI Listing
July 2020

Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies.

Neurology 2019 05 24;92(21):e2492-e2506. Epub 2019 Apr 24.

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Objective: To report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA).

Methods: Analyses included children from a phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2-15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196-413 days). Assessments included the Hammersmith Functional Motor Scale-Expanded (HFMSE), Upper Limb Module (ULM), 6-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed.

Results: Twenty-eight children were included (SMA type II, n = 11; SMA type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1,150 visit (HFMSE: SMA type II, +10.8 points; SMA type III, +1.8 points; ULM: SMA type II, +4.0 points; 6MWT: SMA type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events.

Conclusions: Nusinersen treatment over ∼3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of nusinersen in later-onset SMA, including SMA type III.

Clinicaltrialsgov Identifier: NCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12).

Classification Of Evidence: This study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000007527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541434PMC
May 2019

ALS longitudinal studies with frequent data collection at home: study design and baseline data.

Amyotroph Lateral Scler Frontotemporal Degener 2019 02 28;20(1-2):61-67. Epub 2018 Nov 28.

b Department of Neurology , Barrow Neurological Institute , Phoenix , AZ , USA.

Objective: To design an ALS clinical study in which patients are remotely recruited, screened, enrolled and then assessed via daily data collection at home by themselves or caregivers.

Methods: This observational, natural-history study included two academic medical centers, one providing overall clinical management and the other overseeing computing and web-services design and management. Both healthy and ALS subjects were recruited on the Internet via advertisement on governmental and foundation websites as well as through Facebook and Google paid advertisements. Individuals underwent screening and enrollment remotely, including signing an electronic informed consent form. Participants were then provided self-measurement equipment and instructed on their use through a series of web-based videos. The equipment included a handgrip dynamometer, spirometer with smartphone connection, electrical impedance myography device, and an activity tracker. ALS Functional Rating Scale-Revised data were also collected. Subjects were asked to collect data daily for three months and twice-weekly for the subsequent six months.

Results: One hundred and eleven ALS patients and 30 healthy individuals enrolled in the study from across 41 states (74 men, 62 women). Baseline median ALSFRS-R score was 33. Seventy two percent of the ALS patients sent equipment and 88% of the healthy subjects sent equipment were able to complete a first set of measurements. Expected baseline differences between the ALS patients and healthy participants were identified for all measures.

Conclusions: It is possible to design and institute an at-home based study in ALS patients, using a number of state-of-the-art approaches, including web-based consenting and training and Internet-connected measurement devices.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2018.1541095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513689PMC
February 2019

Relationships between slow vital capacity and measures of respiratory function on the ALSFRS-R.

Amyotroph Lateral Scler Frontotemporal Degener 2018 11 31;19(7-8):506-512. Epub 2018 Oct 31.

f Cytokinetics, Inc ., South San Francisco , CA , USA.

Objective: As declining respiratory muscle function commonly leads to disability and death in amyotrophic lateral sclerosis (ALS), respiratory measurements such as slow vital capacity (SVC) may predict disease progression. This study evaluated the relationship between SVC and symptoms measured by the revised ALS Functional Rating Scale (ALSFRS-R).

Methods: About 453 ALS placebo-treated patients from the EMPOWER trial (NCT01281189) were evaluated. Correlations between %predicted SVC and individual respiratory ALSFRS-R subdomain items, respiratory subdomain score (maximum score of 12), and total ALSFRS-R score (maximum score of 48) were evaluated using the Pearson correlation coefficient. Pearson's chi-squared test was used to evaluate changes from baseline to week 48 in ALSFRS-R respiratory symptom and respiratory subdomain scores in patients with baseline %predicted SVC above/below the median at baseline and with more slowly/more rapidly decreasing %predicted SVC.

Results: The %predicted SVC showed significant correlations with dyspnea, orthopnoea, respiratory insufficiency, respiratory subdomain score, and total ALSFRS-R score (all p < 0.0001). Patients with baseline SVC values < median were significantly more likely than those with baseline SVC ≥ median to have a change in total ALSFRS-R respiratory subdomain score from 12 to <12 (40.9% vs. 30.2%, p = 0.0358) and from ≥10 to <10 (41.6% vs. 24.4%, p = 0.0005). Additionally, patients with smaller declines in SVC over time were significantly more likely to have smaller decreases in their respiratory subdomain scores (p < 0.0001).

Conclusions: The higher correlation between %predicted SVC and specific ALSFRS-R symptom scores in patients with rapidly versus more slowly progressing disease reinforces the importance of continually monitoring respiratory function throughout the disease course.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2018.1497658DOI Listing
November 2018

Reducing sample size requirements for future ALS clinical trials with a dedicated electrical impedance myography system.

Amyotroph Lateral Scler Frontotemporal Degener 2018 11 28;19(7-8):555-561. Epub 2018 Sep 28.

g Myolex, Inc , San Francisco , CA , USA.

Objective: In this longitudinal multicenter cohort study, we evaluated the potential of a dedicated electrical impedance myography (EIM) device to assess ALS progression and the system's basic reproducibility and diagnostic accuracy.

Methods: Forty-six ALS patients underwent up to five sequential measurements of multiple muscles over a period of 8 months at 2-month intervals using the mView EIM device (Myolex, Inc., San Francisco, CA). Standard measures of disease status were also obtained. A group of 30 healthy volunteers and 30 ALS-mimics were evaluated once to determine if the technique could assist with initial diagnosis. Several electrode arrays and EIM outcomes were assessed.

Results: EIM tracked ALS progression; power analyses suggested a 5.2-fold reduction in sample size requirements compared to ALSFRS-R by utilizing 50 kHz phase value from the muscle with the greatest EIM decline in each subject. This progression rate correlated to total ALSFRS-R progression, with R = 0.371, p = 0.021. Reproducibility was high, with both intra- and inter-rater intraclass correlation coefficients for individual muscles mostly greater than 0.90. The mean 50 kHz phase distinguished between ALS patients and healthy controls (area-under-curve 0.78, 95% confidence intervals (CIs) 0.68, 0.89), but not between mimics and ALS patients (area-under-curve 0.60, 95% CIs 0.47, 0.73).

Conclusions: While limited in its specificity to identify ALS versus disease mimics, these results support the hypothesis that single-muscle EIM can serve as a convenient, repeatable, and powerful outcome measure in ALS clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2018.1510008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438779PMC
November 2018

Effects of Strength Training in Amyotrophic Lateral Sclerosis: How Much Do We Know?

Authors:
Jeremy M Shefner

Muscle Nerve 2019 01 28;59(1):6-7. Epub 2018 Nov 28.

Department of Neurology, Barrow Neurological Institute and the University of Arizona College of Medicine-Phoenix, 240 West Thomas Road, Phoenix, Arizona, 85013, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.26347DOI Listing
January 2019
-->