Publications by authors named "Richard Bedlack"

69 Publications

ALSUntangled 59: Tamoxifen.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Jan 21:1-4. Epub 2021 Jan 21.

Department of Neurology, McGill University Health Centre, Montreal, Canada.

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.
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http://dx.doi.org/10.1080/21678421.2021.1876731DOI Listing
January 2021

Continuing Non-Invasive Ventilation During Amyotrophic Lateral Sclerosis-Related Hospice Care Is Medically, Administratively, and Financially Feasible.

Am J Hosp Palliat Care 2020 Dec 17:1049909120982291. Epub 2020 Dec 17.

Department of Neurology, Duke University Medical Center, Durham, NC, USA.

Background: Amyotrophic Lateral Sclerosis (ALS) is a terminal neuromuscular disease with patients dying within 3-5 years of diagnosis. Most patients choose to forego invasive life sustaining measures. Timing of hospice referral can be challenging given the advancement of non-invasive ventilation (NIV) technology.

Objective: To describe the characteristics of patients enrolled in hospice from an ALS clinic at 1 academic medical center and to perform a cost analysis for patients who remained on ventilator support.

Methods: Retrospective cross-sectional study of patients enrolled in hospice over a 2-year period. Clinical characteristics included ALS Functional Rating Scale Revised (ALSFRS-R) score, Forced Vital Capacity (FVC), use of NIV and mechanical insufflation-exsufflation (MIE), riluzole use, and length of stay in hospice. A cost analysis was performed for patients enrolled in Duke Home Care and Hospice.

Results: 85 of 104 patients who died were enrolled in hospice. Median days enrolled in hospice was 84. Patients who continued on NIV had similar hospice length of stay as those on no respiratory support (88 versus 80 days, p = 0.83). Bulbar patients had a trend toward shorter length of stay in hospice than limb onset patients (71 versus 101 days, p = 0.49). Cost analysis showed that hospice maintained a mean net operating revenue of $3234.50 per patient who continued on NIV.

Conclusions: Hospice referrals for ALS patients on NIV can be challenging. This study shows that even with continued NIV use, most ALS patients die within the expected 6 months on home hospice, and care remains cost effective for hospice agencies.
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http://dx.doi.org/10.1177/1049909120982291DOI Listing
December 2020

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

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

The Sean M. Healey and AMG Center for ALS and the Neurological Clinical Research Institute, Department of Neurology, Massachusetts General Hospital, Boston.

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

Identification of a pathogenic intronic KIF5A mutation in an ALS-FTD kindred.

Neurology 2020 12 19;95(22):1015-1018. Epub 2020 Oct 19.

From the Neuromuscular Diseases Research Section (S.S-A, B.J.T.), Laboratory of Neurogenetics, NIA, NIH; Department of Anatomy (C.L.D.), Physiology & Genetics, Uniformed Services University of the Health Sciences; The American Genome Center (C.L.D., C.A., D.N.H., M.D.W.), Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences; Computational Biology Core (J.D.), Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD; Rita Levi Montalcini Department of Neuroscience (A.C.), University of Turin, Italy and AOU Città della Salute e della Scienza, Turin, Italy; Division of Neurology and Neurobiology (R. Bowser), Barrow Neurological Institute, Phoenix, AZ; Department of Neurology (E.P.P.), Neuromuscular Center, Neurological Institute, Cleveland Clinic, OH; Department of Neurology (R. Bedlack), Duke University and the Durham VA Medical Center, NC; and Department of Neurology (B.J.T.), Johns Hopkins University, Baltimore, MD.

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http://dx.doi.org/10.1212/WNL.0000000000011064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734922PMC
December 2020

Engaging ALS patients and caregivers (the ALS research ambassadors) to help design the REFINE-ALS biomarker study.

Amyotroph Lateral Scler Frontotemporal Degener 2020 Aug 24:1-4. Epub 2020 Aug 24.

Mitsubishi Tanabe Pharma America, Inc., Jersey City, NJ, USA.

In the planning and design of the adicava/daravone indings Biomarkrs From myotrophic ateral clerosis (REFINE-ALS) study, we sought to elicit feedback from patients with ALS and their caregivers to ensure that patient-centric issues would be addressed. Ten ALS Clinical Research Learning Institute (ALS-CRLI) Research Ambassadors participated in 2 meetings. They provided perspectives on patients' interest in the study, the schedule of study visits, and data sharing. The findings were used to help revise the study design, as appropriate. Key concerns identified were (1) the frequency of sample collections, (2) participant travel burden, (3) enrollment criteria, and (4) data reporting and sharing with participants. Several of the identified issues were promptly addressed. The number of visits was reduced, travel optimized, entry criteria clarified, and plans for sharing participants' data with them were codified. The feedback from the Ambassadors was substantive and resulted in constructive patient-centric changes to the study protocol.
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http://dx.doi.org/10.1080/21678421.2020.1804939DOI Listing
August 2020

Disease-modifying effects of an structural variant in a predominantly ALS cohort.

Neurol Genet 2020 Aug 1;6(4):e470. Epub 2020 Jul 1.

Centre for Neuromuscular and Neurological Disorders (J.P., L.L.F., R.S.A., F.L.M., F.T., A.P., S.K., P.A.A.), University of Western Australia, Crawley; Perron Institute for Neurological and Translational Science (J.P., L.L.F., R.S.A., F.L.M., F.T., A.P., S.K., P.A.A.), Nedlands; Centre for Molecular Medicine and Innovative Therapeutics (L.L.F., A.P., S.K., P.A.A.), Murdoch University; School of Health Sciences (R.S.A.), and Institute for Health Research (R.S.A.), University of Notre Dame Australia, Fremantle; Institute for Immunology and Infectious Diseases (I.J.), Murdoch University, Australia; Department of Neurology (A.M.S., R.B., M.W.L., A.D.R.), Duke University School of Medicine, Durham, NC; Zinfandel Pharmaceuticals, Inc. (A.M.S., D.K.B., A.D.R.), Durham, NC; ALS Clinic (R.B.), Duke University, Durham, NC; Departments of Neurology, Pathology and Cell and Molecular Biology (N.S., T.S.), the Les Turner ALS Center, Northwestern University Feinberg School of Medicine; and the Northwestern University Interdepartmental Neuroscience Program (N.S., T.S.), Chicago, IL.

Objective: To test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 () familial amyotrophic lateral sclerosis (fALS), we characterized rs573116164 within a cohort of 190 patients with fALS and 560 healthy age-matched controls to assess the variant for association with various measures of disease.

Methods: Using a previously described bioinformatics evaluation algorithm, a polymorphic short structural variant associated with was identified according to its theoretical effect on gene expression. An 12-18 poly-T repeat (rs573116164) within the 3' untranslated region of serine and arginine rich proteins-related carboxy terminal domain associated factor 4 (), a gene that is adjacent to , was assessed for disease association and influence on survival and age at onset in an fALS cohort using PCR, Sanger sequencing, and capillary separation techniques for allele detection.

Results: In a North American cohort of predominantly fALS patients (n =190) and age-matched healthy controls (n = 560), we showed that carriage of an 18T allele was associated with disease within this cohort (odds ratio [OR] 6.6; 95% confidence interval [CI] 3.9-11.2; = 4.0e-11), but also within non- cases (n = 27; OR 5.3; 95% CI 1.9-14.5; = 0.0014). This finding suggests genetically -independent effects of SCAF4 on fALS susceptibility. Furthermore, carriage of an 18T allele was associated with a 26-month reduction in survival time (95% CI 6.6-40.8; = 0.014), but did not affect age at onset of disease.

Conclusions: The findings in this fALS cohort suggest that rs573116164 could have -independent and broader relevance in ALS, warranting further investigation in other fALS and sporadic ALS cohorts, as well as studies of functional effects of the 18T variant on gene expression.
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http://dx.doi.org/10.1212/NXG.0000000000000470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357414PMC
August 2020

Total serum immunoglobulin A in ALS.

Amyotroph Lateral Scler Frontotemporal Degener 2020 Jul 16:1-5. Epub 2020 Jul 16.

Department of Neurology, Duke University, Durham, NC, USA.

Introduction: Amyotrophic lateral sclerosis (ALS) can have marked phenotypic variability. To date, no biomarker explains this variability. This study tested the hypothesis that immunoglobulin A (IgA) levels might help explain the variability seen in ALS clinical presentations. A database of the electronic health record at a tertiary referral academic medical center was used to extract data from the charts of patients with ALS-spectrum disease ( = 489), other neurodegenerative diseases ( = 174), select chronic autoimmune neurologic diseases ( = 154), and those neurologically healthy ( = 17475). There was no significant association of disease and total IgA serum concentrations when controlling for age and sex. No significant association was found between extremes of IgA serum concentrations and various clinical features of ALS. This is the largest study published to-date exploring total serum IgA levels in ALS and provides more conclusive evidence that total serum IgA concentration cannot be used as a standalone biomarker in ALS.
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http://dx.doi.org/10.1080/21678421.2020.1790608DOI Listing
July 2020

ALS clinical research learning institutes (ALS-CRLI): empowering people with ALS to be research ambassadors.

Amyotroph Lateral Scler Frontotemporal Degener 2020 05 15;21(3-4):216-221. Epub 2019 Nov 15.

MDA/ALS Center of Hope, Temple Health, Philadelphia, PA, USA.

: Patient engagement in research is increasingly recognized as important across many countries and fields. In 2008, we conducted surveys that suggested a need for improved patient engagement in ALS research. We decided to create an ALS Clinical Research Learning Institute (ALS-CRLI) to facilitate direct interactions between researchers and people with ALS and their caregivers, toward ultimately improving engagement. : Initially modeled after a similar program in Parkinson's disease, our ALS-CRLI is a multi-day collection of formal courses for people with ALS and their caregivers, moderated by clinicians, scientists and patient advocates. Previous graduates (called ALS Research Ambassadors) engage with the current class participants before, during and after the courses. Prior to the courses, Research Ambassadors serve as "mentors" to the participants, offering guidance and setting expectations. Feedback during the courses is used to change the way researchers design and advertise studies, and feedback after the courses is used to improve the agenda for subsequent ALS-CRLIs. Funding is provided by patient advocacy groups including the ALS Association and ALS Hope Foundation. Research Ambassadors are provided with ongoing mentoring and notifications about opportunities for engagement via regular teleconferences with the Northeast ALS Consortium's Patient Education and Advocacy Committee and their own Facebook page. Engagement and advocacy efforts are tracked using a tool on the Northeast ALS Consortium's website. : We have now held 15 ALS-CRLIs at various locations within the United States, resulting in over 320 graduated ALS Research Ambassadors. From these engagements, researchers have been prompted to formally include patients in the design process, to design more patient-centric trials and to create new ways to help patients find trials. Research ambassadors are improving awareness and clearing up misconceptions about participation in research, improving research availability, and helping to create more patient-centric trial designs. In addition, we are now creating an ALS-CRLI Toolkit that will facilitate ALS-CRLIs throughout the world. This will be housed on the Northeast ALS Consortium website.
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http://dx.doi.org/10.1080/21678421.2019.1690519DOI Listing
May 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.
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http://dx.doi.org/10.1002/mus.26989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283687PMC
August 2020

Understanding the needs of people with ALS: a national survey of patients and caregivers.

Amyotroph Lateral Scler Frontotemporal Degener 2020 08 12;21(5-6):355-363. Epub 2020 May 12.

Healey Center for ALS, Massachusetts General Hospital, Boston, MA, USA.

: Amyotrophic lateral sclerosis (ALS) has profound effects on people with ALS (PALS) and caregivers. There is a paucity of research detailing and comparing PALS and caregiver day-to-day perspectives of ALS. : A survey developed collaboratively by The ALS Association and a panel of experts in ALS care was designed to broadly sample the experience of PALS and caregivers with respect to physical and emotional symptoms, the efficacy of treatment approaches, and goals for future treatments. Specific physical symptoms assessed consisted of fatigue, pain, weakness, shortness of breath, difficulty sleeping, speech problems, depression and other mood changes, and cognitive changes. PALS, caregivers of living patients with ALS (C-LPALS), and caregivers of deceased patients with ALS (C-DPALS) were contacted by email to participate in a 30-minute online survey. : 887 PALS, 444 C-LPALS, and 193 C-DPALS responded to the survey. In comparison to PALS, C-LPALS perceived that PALS had significantly higher rates of all surveyed symptoms except for pain and weakness. Caregivers self-reported higher stress levels than PALS ( < 0.001). 35% (135/383) of caregivers reported experiencing a devastating or near devastating financial impact of ALS and 64% (247/383) of caregivers felt their own health had worsened. Caregivers were significantly less likely to perceive a positive response to treatment in comparison to PALS ( < 0.001). : PALS and caregivers report a number of symptoms beyond weakness that affect daily life which may be targets of future interventions. There are opportunities to improve services and care for caregivers to reduce the burden of illness.
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http://dx.doi.org/10.1080/21678421.2020.1760889DOI Listing
August 2020

ALSUntangled 55: vitamin E (α-tocopherol).

Amyotroph Lateral Scler Frontotemporal Degener 2020 May 2:1-7. Epub 2020 May 2.

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http://dx.doi.org/10.1080/21678421.2020.1754024DOI Listing
May 2020

Plasma creatinine and oxidative stress biomarkers in amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2020 05 10;21(3-4):263-272. Epub 2020 Apr 10.

Department of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA.

To determine the associations between plasma creatinine (PCr), plasma uric acid (PUA), and urinary oxidative stress (OS) biomarkers with the ALSFRS-R at baseline and survival in a large epidemiological cohort study (ALS COSMOS) with a well-phenotyped patient population ( = 355). Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival. At baseline, PCr correlated with ALSFRS-R (Spearman  = 0.30), percent (%) FVC ( = 0.20), PUA ( = 0.37), and 8-oxodG ( = -0.13, all  < 0.05). Baseline PCr significantly predicted survival (adjusted hazard ratio 0.28,  < 0.001). Time to death from baseline was shortest for those in the lowest two PCr quartiles relative to the highest two quartiles. PCr and ALSFRS-R values were significantly correlated at all three time points (baseline:  = 0.29, midpoint:  = 0.23, final:  = 0.38, all  < 0.001). PCr and PUA significantly declined over time, whereas OS biomarkers significantly increased over time. To date, PCr predicted survival the best, compared to PUA, 8-oxodG, and IsoP. Although PCr represents the degree of muscle mass, it may also represent complex biochemical changes in ALS. Because the field has no reliable prognostic biomarkers, the importance of PCr warrants further investigation through clinical studies in ALS.
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http://dx.doi.org/10.1080/21678421.2020.1746810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373369PMC
May 2020

Association of a structural variant within the gene with amyotrophic lateral sclerosis.

Neurol Genet 2020 Apr 27;6(2):e406. Epub 2020 Feb 27.

University of Western Australia (J.P., R.S.A., L.L.F., F.T., L.J., F.L.M., P.A.A.), Centre for Neuromuscular and Neurological Disorders, Crawley; Perron Institute for Neurological and Translational Science (J.P., R.S.A., L.L.F., F.T., L.J., I.P., F.L.M., P.A.A.), Nedlands; University of Notre Dame Australia (R.S.A.), School of Health Sciences; University of Notre Dame Australia (R.S.A.), Institute for Health Research, Fremantle; Murdoch University (L.L.F., I.P., P.A.A.), Centre for Molecular Medicine and Innovative Therapeutics; Murdoch University, Institute for Immunology and Infectious Diseases (I.J.), Western Australia, Australia; Department of Neurology (R.B.), Duke University School of Medicine, Durham, NC; Zinfandel Pharmaceuticals (A.M.S.), Inc.; Duke University (R.B.), ALS Clinic, Durham, NC; and Departments of Neurology, Pathology and Cell and Molecular Biology (T.S., N.S.), Northwestern University Feinberg School of Medicine, the Les Turner ALS Center and the Northwestern University Interdepartmental Neuroscience Program, Chicago, IL.

Objective: As structural variations may underpin susceptibility to complex neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), the objective of this study was to investigate a structural variant (SV) within sequestosome 1 ().

Methods: A candidate insertion/deletion variant within intron 5 of the gene was identified using a previously established SV evaluation algorithm and chosen according to its subsequent theoretical effect on gene expression. The variant was systematically assessed through PCR, polyacrylamide gel fractionation, Sanger sequencing, and reverse transcriptase PCR.

Results: A reliable and robust assay confirmed the polymorphic nature of this variant and that the variant may influence transcript levels. In a North American cohort of patients with familial ALS (fALS) and sporadic ALS (sALS) (n = 403) and age-matched healthy controls (n = 562), we subsequently showed that the variant is associated with fALS ( = 0.0036), particularly in familial superoxide dismutase 1 mutation positive patients ( = 0.0005), but not with patients with sALS ( = 0.97).

Conclusions: This disease association highlights the importance and implications of further investigation into SVs that may provide new targets for cohort stratification and therapeutic development.
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http://dx.doi.org/10.1212/NXG.0000000000000406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061286PMC
April 2020

Development and Validation of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS).

JAMA Neurol 2020 04;77(4):480-488

Emory University, Atlanta, Georgia.

Importance: A new outcome measure for overall disability level with improved responsiveness is needed for amyotrophic lateral sclerosis (ALS) clinical trials.

Objective: To describe the creation and development of a new self-reported ALS disability scale with improved item targeting and psychometric properties that used a mathematically rigorous Rasch methodology.

Design, Setting, And Participants: A preliminary ALS disability questionnaire with 119 questions was created based on literature review, clinical judgement of an expert panel, and patient input. Patients with ALS were recruited from January 2017 to June 2019 from the Emory University and Atlanta VA Medical Center ALS clinics, both in Atlanta, Georgia, during regularly scheduled clinic appointments to complete the draft questionnaire and standard ALS outcome measures. All consecutive patients seen at the Emory University and Atlanta VA Medical Center ALS clinics during the recruitment period with a diagnosis of ALS who were able to provide informed consent were invited to participate in the study. Rasch analyses were performed, and items were systematically removed based on missing data, model fit, disordered thresholds, item bias, and clinical judgment. A total of 509 patients with ALS were seen at the 2 sites during the recruitment period, and 264 patients provided informed consent.

Interventions: Participants completed the draft Rasch questionnaire and the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).

Main Outcomes And Measures: Rasch analyses and standard scale metrics were performed to create the new scale, and Rasch analyses were performed on the ALSFRS-R for comparison.

Results: Overall, 243 participants with ALS completed the draft questionnaire, and 230 participants were included for Rasch analyses. The mean (SD) age for study participants was 61.9 (11.1) years, 146 (60.1%) were men, and site of onset was 23.0% bulbar (n = 56), 36.2% upper extremity (n = 88), and 39.5% lower extremity (n = 96). A 28-question Rasch-Built Overall ALS Disability Scale (ROADS) was constructed with each item scored 0, 1, or 2. The ROADS fulfilled Rasch model requirements, demonstrated improved item targeting compared with the ALSFRS-R, and had test-retest reliability of 0.97. Individual question fit statistics demonstrated infit values from 0.68 to 1.37 and outfit values from 0.66 to 1.43. The difference between the empirical variance explained by the measures and the modeled variance was 0.1%. The ALSFRS-R violated Rasch model expectations and demonstrated disordered thresholds for 9 of 12 questions; 13 of 48 answer choices on the ALSFRS-R were never the most probable answer choice for any overall disability level.

Conclusions And Relevance: In this study, the 28-question, self-reported ROADS, which is linearly weighted, had improved item targeting compared with the ALSFRS-R, had high test-retest reliability, and was validated. ROADS may serve as a valuable and easily accessible outcome measure for use in ALS trials and in the clinic with improved responsiveness compared with the ALSFRS-R.
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http://dx.doi.org/10.1001/jamaneurol.2019.4490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990811PMC
April 2020

Study protocol for a randomised, double-blind, placebo-controlled study evaluating the Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease: the EMERALD trial.

BMJ Open 2019 11 11;9(11):e029449. Epub 2019 Nov 11.

Neurology, Gold Coast Hospital and Health Service, Southport, Queensland, Australia

Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no known cure and with an average life expectancy of 3-5 years post diagnosis. The use of complementary medicine such as medicinal cannabis in search for a potential treatment or cure is common in ALS. Preclinical studies have demonstrated the efficacy of cannabinoids in extending the survival and slowing of disease progression in animal models with ALS. There are anecdotal reports of cannabis slowing disease progression in persons with ALS (pALS) and that cannabis alleviated the symptoms of spasticity and pain. However, a clinical trial in pALS with these objectives has not been conducted.

Methods And Analysis: The Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease trial is a randomised, double-blind, placebo-controlled cannabis trial in pALS conducted at the Gold Coast University Hospital, Australia. The investigational product will be a cannabis-based medicine extract (CBME) supplied by CannTrust Inc., Canada, with a high-cannabidiol-low-tetrahydrocannabinol concentration. A total of 30 pALS with probable or definite ALS diagnosis based on the El Escorial criteria, with a symptom duration of <2 years, age between 25 and 75years and with at least 70% forced vital capacity (FVC) will be treated for 6 months. The primary objective of the study is to evaluate the efficacy of CBME compared with placebo in slowing the disease progression measured by differences in mean ALS Functional Rating Scale-Revised and FVC score between the groups at the end of treatment. The secondary objectives are to evaluate the safety and tolerability of CBME by summarising adverse events, the effects of CBME on spasticity, pain, weight loss and quality of life assessed by the differences in mean Numeric Rating Scale for spasticity and Numeric Rating Scale for pain, percentage of total weight loss and ALS specific quality of life-Revised questionnaire.

Ethics And Dissemination: The study has been approved by the local Institutional Review Board. The results of this study will be published in a peer-reviewed journal.

Trial Registration Number: NCT03690791.
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http://dx.doi.org/10.1136/bmjopen-2019-029449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858175PMC
November 2019

ALSUntangled No. 47: RT001.

Authors:
Richard Bedlack

Amyotroph Lateral Scler Frontotemporal Degener 2019 05 28;20(3-4):294-297. Epub 2019 Jan 28.

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http://dx.doi.org/10.1080/21678421.2018.1549531DOI Listing
May 2019

Longitudinal Screening Detects Cognitive Stability and Behavioral Deterioration in ALS Patients.

Behav Neurol 2018 31;2018:5969137. Epub 2018 Oct 31.

Department of Neurology, Eleanor and Lou Gehrig MD/ALS Research Center, CUMC, USA.

Objective: To evaluate longitudinal cognitive/behavioral change over 12 months in participants enrolled in the ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS).

Methods: We analyzed data from 294 ALS participants, 134 of whom were studied serially. Change over time was evaluated controlling for age, sex, symptom duration, education, race, and ethnicity. Using multiple regression, we evaluated associations among decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores, forced vital capacity (FVC), and cognitive/behavioral changes. Change in cognitive/behavioral subgroups was assessed using one-way analyses of covariance.

Results: Participants with follow-up data had fewer baseline behavior problems compared to patients without follow-up data. We found significant worsening of behavior (ALS Cognitive Behavioral Screen (ALS CBS) behavioral scale, < 0.001; Frontal Behavioral Inventory-ALS (FBI-ALS) disinhibition subscale, = 0.044). Item analysis suggested change in frustration tolerance, insight, mental rigidity, and interests ( < 0.05). Changes in ALSFRS-R correlated with the ALS CBS. Worsening disinhibition (FBI-ALS) did not correlate with ALSFRS-R, FVC, or disease duration.

Conclusion: We did not detect cognitive change. Behavioral change was detected, and increased disinhibition was found among patients with abnormal baseline behavioral scores. Disinhibition changes did not correlate with disease duration or progression. Baseline behavioral problems were associated with advanced, rapidly progressive disease and study attrition.
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http://dx.doi.org/10.1155/2018/5969137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234441PMC
April 2019

ALSUntangled 46: penicillin G/hydrocortisone.

Amyotroph Lateral Scler Frontotemporal Degener 2019 02 15;20(1-2):126-131. Epub 2018 Nov 15.

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http://dx.doi.org/10.1080/21678421.2018.1512704DOI Listing
February 2019

Independent home use of a brain-computer interface by people with amyotrophic lateral sclerosis.

Neurology 2018 07 27;91(3):e258-e267. Epub 2018 Jun 27.

From the Department of Neurology (J.R.W., D.S.H.), Albany Stratton Veterans Affairs Medical Center; Wadsworth Center (J.R.W., T.M.V., S.M.H., L.M.M., C.S.C., S.W., D.J.M., E.W.S.), National Center for Adaptive Neurotechnologies, New York State Department of Health, Albany; Durham Veterans Affairs Medical Center (R.S.B.) and Department of Neurology (R.S.B.), Duke University School of Medicine, NC; Veterans Affairs Cooperative Studies Program Coordinating Center (D.J.R., H.S., T.P.), Hines VA Medical Center, IL; Veterans Affairs Cooperative Studies Program Clinical Research Pharmacy Coordinating Center (R.J.R.) and University of New Mexico College of Pharmacy; Department of Neurology (P.G.B.), Louis Stokes Cleveland Veterans Affairs Medical Center, OH; Providence Veterans Affairs Medical Center (A.C.L.) and Department of Neurology, Brown University, RI; Veterans Affairs Connecticut Healthcare System (H.S.P.) and Department of Neurology, Yale School of Medicine, New Haven, CT; Department of Communication Science and Disorders (K.J.H.), University of Pittsburgh, PA; Cooperative Studies Program Central Office (D.G.H.), Department of Veterans Affairs Office of Research & Development, Washington, DC; and Louis Stokes Cleveland Veterans Affairs Medical Center (R.L.R.) and Department of Neurology, Case Western Reserve University School of Medicine, OH.

Objective: To assess the reliability and usefulness of an EEG-based brain-computer interface (BCI) for patients with advanced amyotrophic lateral sclerosis (ALS) who used it independently at home for up to 18 months.

Methods: Of 42 patients consented, 39 (93%) met the study criteria, and 37 (88%) were assessed for use of the Wadsworth BCI. Nine (21%) could not use the BCI. Of the other 28, 27 (men, age 28-79 years) (64%) had the BCI placed in their homes, and they and their caregivers were trained to use it. Use data were collected by Internet. Periodic visits evaluated BCI benefit and burden and quality of life.

Results: Over subsequent months, 12 (29% of the original 42) left the study because of death or rapid disease progression and 6 (14%) left because of decreased interest. Fourteen (33%) completed training and used the BCI independently, mainly for communication. Technical problems were rare. Patient and caregiver ratings indicated that BCI benefit exceeded burden. Quality of life remained stable. Of those not lost to the disease, half completed the study; all but 1 patient kept the BCI for further use.

Conclusion: The Wadsworth BCI home system can function reliably and usefully when operated by patients in their homes. BCIs that support communication are at present most suitable for people who are severely disabled but are otherwise in stable health. Improvements in BCI convenience and performance, including some now underway, should increase the number of people who find them useful and the extent to which they are used.
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http://dx.doi.org/10.1212/WNL.0000000000005812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059033PMC
July 2018

"ALS reversals": demographics, disease characteristics, treatments, and co-morbidities.

Amyotroph Lateral Scler Frontotemporal Degener 2018 11 2;19(7-8):495-499. Epub 2018 Apr 2.

f Department of Neurology , Duke University and Durham VA Medical Center , Durham , NC , USA.

Objective: To identify differences in demographics, disease characteristics, treatments, and co-morbidities between patients with "amyotrophic lateral sclerosis (ALS) reversals" and those with typically progressive ALS.

Methods: Cases of possible ALS reversals were found in prior publications, in the Duke ALS clinic, through self-referral or referral from other Neurologists, and on the internet. Of 89 possible reversals identified, 36 cases were included because chart or literature review confirmed their diagnosis and a robust, sustained improvement in at least one objective measure. Controls were participants in the Pooled Resource Open-Access ALS Clinical Trials database and the National ALS Registry. Cases and controls were compared using descriptive statistics.

Results: ALS reversals were more likely to be male, have limb onset disease, and initially progress faster. The prevalences of myasthenia gravis (MG) and purely lower motor neuron disease in cases were higher than estimates of these prevalences in the general population. The odds of taking curcumin, luteolin, cannabidiol, azathioprine, copper, glutathione, vitamin D, and fish oil were greater for cases than controls.

Conclusions: When compared to patients with typically progressive ALS, patients with reversals differed in their demographics, disease characteristics, and treatments. While some of these patients may have had a rare antibody-mediated ALS mimicker, such as atypical myasthenia gravis, details of their exams, EMGs and family histories argue that this was unlikely. Instead, our data suggest that ALS reversals warrant evaluation for mechanisms of disease resistance and that treatments associated with multiple ALS reversals deserve further study.
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http://dx.doi.org/10.1080/21678421.2018.1457059DOI Listing
November 2018

ALSUntangled 44: curcumin.

Amyotroph Lateral Scler Frontotemporal Degener 2018 11 1;19(7-8):623-629. Epub 2018 Mar 1.

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http://dx.doi.org/10.1080/21678421.2018.1440738DOI Listing
November 2018

A spatial analysis of amyotrophic lateral sclerosis (ALS) cases in the United States and their proximity to multidisciplinary ALS clinics, 2013.

Amyotroph Lateral Scler Frontotemporal Degener 2018 02 20;19(1-2):126-133. Epub 2017 Dec 20.

a Agency for Toxic Substances and Disease Registry/Centers for Disease Control and Prevention , Atlanta , GA , USA.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that typically results in death within 2-5 years of initial symptom onset. Multidisciplinary ALS clinics (MDCs) have been established to provide specialty care to people living with the disease.

Objective: To estimate the proximity of ALS prevalence cases to the nearest MDC in the US to help evaluate one aspect of access to care.

Methods: Using 2013 prevalence data from the National ALS Registry, cases were geocoded by city using geographic information system (GIS) software, along with the locations of all MDCs in operation during 2013. Case-to-MDC proximity was calculated and analyzed by sex, race, and age group.

Results: During 2013, there were 72 MDCs in operation in 30 different states. A total of 15,633 ALS cases were geocoded and were distributed throughout all 50 states. Of these, 62.6% were male, 77.9% were white, and 76.2% were 50-79 years old. For overall case-to-MDC proximity, nearly half (44.9%) of all geocoded cases in the US lived >50 miles from an MDC, including approximately a quarter who lived >100 miles from an MDC. There was a statistically significant difference between distance to MDC by race and age group.

Conclusions: The high percentage of those living more than 50 miles from the nearest specialized clinic underscores one of the many challenges of ALS. Having better access to care, whether at MDCs or through other modalities, is likely key to increasing survivability and obtaining appropriate end-of-life treatment and support for people with ALS.
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http://dx.doi.org/10.1080/21678421.2017.1406953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815888PMC
February 2018

Refractory myasthenia gravis exacerbation triggered By pembrolizumab.

Muscle Nerve 2018 04 7;57(4):E120-E121. Epub 2017 Dec 7.

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

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http://dx.doi.org/10.1002/mus.26021DOI Listing
April 2018

Perspective: Untangling the ALS X-Files.

Authors:
Richard Bedlack

Nature 2017 10;550(7676):S122

University in Durham, North Carolina.

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http://dx.doi.org/10.1038/550S122aDOI Listing
October 2017

Retinal thinning in amyotrophic lateral sclerosis patients without ophthalmic disease.

PLoS One 2017 25;12(9):e0185242. Epub 2017 Sep 25.

Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States of America.

Importance: Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease that primarily affects motor neurons. Recently, three causative genes have been implicated in both ALS and glaucoma. However, it is still uncertain whether patients with ALS have neurodegeneration in their retinas. If so, retinal thickness measurements might be a useful biomarker for ALS progression. Previous work in this area has been inconclusive, as it has not taken into account the effect of ophthalmic diseases on retinal thinning.

Objective: To determine whether there are differences in retinal neurons in ALS patients utilizing spectral-domain optical coherence tomography (SD-OCT). We tested the hypothesis that ALS patients exhibit retinal neurodegeneration that is not associated with ophthalmic diseases.

Design, Settings And Participants: Observational, comparative, cross-sectional study performed on patients recruited from the Duke University Medical Center ALS clinic. Patients underwent a comprehensive ophthalmologic examination to rule out ocular pathology. 21 patients met inclusion criteria. Two eyes with ocular pathology were excluded, leading to a total of 40 eyes of 21 patients included in the study. Retinal neurodegeneration was assessed by retinal nerve fiber layer (RNFL) thickness measurement using SD-OCT (Spectralis; Heidelberg Engineering).

Main Outcomes And Measures: ALS disease severity, determined through the ALS Functional Rating Scale (ALSFRS-R); mean and six sector RNFL thickness values compared to age-adjusted values in the normative database provided by Heidelberg Engineering; RNFL thickness correlation with ALSFRS-R, ALSFRS-R progression rate, forced vital capacity (FVC), and visual acuity.

Results: ALSFRS-R mean score was 30+/-10. Mean RNFL thickness in ALS patients was 88.95 +/- 10.8 microns, significantly thinner than values in the normative database (95.81 +/- 0.8). These RNFL thickness values did not demonstrate correlation to ALSFRS-R score, ALSFRS-R progression rate, FVC, intraocular pressure, or visual acuity.

Conclusions: Using SD-OCT, our study shows that ALS patients without ocular pathology exhibit thinned retinal layers. Future studies are warranted to clarify the clinical relationship between retinal thinning and motor neuron loss in ALS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185242PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612691PMC
October 2017

ALSUntangled 42: Elysium health's "basis".

Amyotroph Lateral Scler Frontotemporal Degener 2018 05 18;19(3-4):317-319. Epub 2017 Sep 18.

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http://dx.doi.org/10.1080/21678421.2017.1373978DOI Listing
May 2018

Cognitive-behavioral screening reveals prevalent impairment in a large multicenter ALS cohort.

Neurology 2016 Mar 22;86(9):813-20. Epub 2016 Jan 22.

From the Department of Neurology (J.M., C.L.-H.), UCSF; Department of Epidemiology (P.F.-L.), Mailman School of Public Health, Columbia University Medical Center (CUMC); Department of Psychiatry (R.G.), New York State Psychiatric Institute and CUMC; Department of Pathology and Cell Biology (P.L.N), Columbia University; Eleanor and Lou Gehrig MDA/ALS Research Center (J.H., J.S., H.M.), Department of Neurology, CUMC, New York, NY; California Pacific Medical Center (S.W., J.S.K.), San Francisco, CA; Departments of Biostatistics and Psychiatry (H.A.), Mailman School of Medicine, CUMC, New York, NY; Texas Neurology (D.H.), P.A., Dallas, TX; Duke University (R.S.B.), Durham, NC; Department of Neurology (R.J.B.), University of Kansas; Mayo Clinic (E.J.S.), Rochester, MN; University of California, Davis (B.O.), Sacramento, CA; University of Nebraska Medical Center (J.A.M.F.F.), Omaha, NE; University of Kentucky (E.J.K.), Lexington, KY; University of California, Irvine (T.M.), Orange, CA; University of Colorado, Denver (Y.D.R.), Aurora, CO; University of Texas-Southwestern (S.P.N.), Dallas, TX; University of Iowa (A.J.S.), Iowa City, IA; and Hospital for Special Care (B.A.K.-J.), New Britain, CT.

Objectives: To characterize the prevalence of cognitive and behavioral symptoms using a cognitive/behavioral screening battery in a large prospective multicenter study of amyotrophic lateral sclerosis (ALS).

Methods: Two hundred seventy-four patients with ALS completed 2 validated cognitive screening tests and 2 validated behavioral interviews with accompanying caregivers. We examined the associations between cognitive and behavioral performance, demographic and clinical data, and C9orf72 mutation data.

Results: Based on the ALS Cognitive Behavioral Screen cognitive score, 6.5% of the sample scored below the cutoff score for frontotemporal lobar dementia, 54.2% scored in a range consistent with ALS with mild cognitive impairment, and 39.2% scored in the normal range. The ALS Cognitive Behavioral Screen behavioral subscale identified 16.5% of the sample scoring below the dementia cutoff score, with an additional 14.1% scoring in the ALS behavioral impairment range, and 69.4% scoring in the normal range.

Conclusions: This investigation revealed high levels of cognitive and behavioral impairment in patients with ALS within 18 months of symptom onset, comparable to prior investigations. This investigation illustrates the successful use and scientific value of adding a cognitive-behavioral screening tool in studies of motor neuron diseases, to provide neurologists with an efficient method to measure these common deficits and to understand how they relate to key clinical variables, when extensive neuropsychological examinations are unavailable. These tools, developed specifically for patients with motor impairment, may be particularly useful in patient populations with multiple sclerosis and Parkinson disease, who are known to have comorbid cognitive decline.
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http://dx.doi.org/10.1212/WNL.0000000000002305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793785PMC
March 2016

How common are ALS plateaus and reversals?

Neurology 2016 Mar 9;86(9):808-12. Epub 2015 Dec 9.

From the Department of Neurology (R.S.B.), Duke University and Durham VA Medical Center, Durham, NC; PatientsLikeMe (T.V., P.W., J.H.), Cambridge, MA; Massachusetts General Hospital (E.S., R.S., E.A.M., D.S., M.C., A.S.), Boston; and Harvard Medical School (E.A.M.), Boston, MA.

Objective: To determine the frequency of amyotrophic lateral sclerosis (ALS) plateaus and reversals in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.

Methods: We analyzed Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) and ALSFRS-revised (ALSFRS-R) data from PRO-ACT participants. The frequencies of participants experiencing plateaus (periods where scores did not change) were calculated over 6-, 12-, and 18-month epochs. The percentage of participants ever experiencing reversals (periods where scores improved) of different lengths were also calculated and plotted.

Results: Over 6 months, 25% of 3,132 participants did not decline. Over 12 months, 16% of 2,105 participants did not decline. Over 18 months, 7% of 1,218 participants did not decline. Small ALS reversals were also common, especially over shorter follow-up intervals; 14% of 1,343 participants had a 180-day interval where their ALSFRS-R slope was greater than zero. Fewer than 1% of participants ever experienced improvements of 4 or more ALSFRS-R points lasting at least 12 months.

Conclusion: ALS plateaus and small reversals are common, especially over brief intervals. In light of these data, stable disease, especially for a short period of time, should not be interpreted as an ALS treatment effect. Large sustained ALS reversals, on the other hand, are rare, potentially important, and warrant further study.
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http://dx.doi.org/10.1212/WNL.0000000000002251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793781PMC
March 2016