Publications by authors named "Stephen N Scelsa"

18 Publications

  • Page 1 of 1

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.

Sean M. Healey & AMG Center for ALS & the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

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

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

COVID-19-associated Guillain-Barré syndrome: The early pandemic experience.

Muscle Nerve 2020 10 11;62(4):485-491. Epub 2020 Aug 11.

Department of Neurology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, USA.

Guillain-Barré syndrome (GBS) is an inflammatory polyradiculoneuropathy associated with numerous viral infections. Recently, there have been many case reports describing the association between coronavirus disease-2019 (COVID-19) and GBS, but much remains unknown about the strength of the association and the features of GBS in this setting. We reviewed 37 published cases of GBS associated with COVID-19 to summarize this information for clinicians and to determine whether a specific clinical or electrodiagnostic (EDx) pattern is emerging. The mean age (59 years), gender (65% male), and COVID-19 features appeared to reflect those of hospitalized COVID-19 patients early in the pandemic. The mean time from COVID-19 symptoms to GBS symptoms was 11 days. The clinical presentation and severity of these GBS cases was similar to those with non-COVID-19 GBS. The EDx pattern was considered demyelinating in approximately half of the cases. Cerebrospinal fluid, when assessed, demonstrated albuminocytologic dissociation in 76% of patients and was negative for severe acute respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) in all cases. Serum antiganglioside antibodies were absent in 15 of 17 patients tested. Most patients were treated with a single course of intravenous immunoglobulin, and improvement was noted within 8 weeks in most cases. GBS-associated COVID-19 appears to be an uncommon condition with similar clinical and EDx patterns to GBS before the pandemic. Future studies should compare patients with COVID-19-associated GBS to those with contemporaneous non-COVID-19 GBS and determine whether the incidence of GBS is elevated in those with COVID-19.
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http://dx.doi.org/10.1002/mus.27024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405390PMC
October 2020

Does anxiety trigger fasciculations?

Muscle Nerve 2018 12 23;58(6):749-750. Epub 2018 Sep 23.

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

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http://dx.doi.org/10.1002/mus.26321DOI Listing
December 2018

Frequency of Radiculopathy in Patients With Carpal Tunnel Syndrome and Paracervical Pain.

J Clin Neuromuscul Dis 2016 Jun;17(4):187-9

*Department of Neurology, Emory University School of Medicine, Atlanta, GA; and †Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine, New York, NY.

Objectives: Patients with carpal tunnel syndrome (CTS) and paracervical pain (PCP) are often incorrectly diagnosed with cervical radiculopathy. The objective of the study is to determine how frequently such patients have electrophysiologic evidence of radiculopathy.

Methods: We reviewed charts of patients with clinical features of CTS and at least 1 median nerve conduction parameter showing slowing across the wrist. Patients were divided into those with and without PCP. Radiculopathy was defined electrophysiologically. We assessed group differences in the frequency of radiculopathy and how radiculopathy frequency varied with median nerve entrapment severity.

Results: Of 108 patients meeting criteria, 56 had PCP and 52 did not. Eight of 56 patients with PCP and 4 of 52 without pain had cervical radiculopathy (P = 0.36). There was no difference in the frequency of radiculopathy related to the severity of median nerve entrapment (P = 0.64).

Discussion: In patients with CTS, PCP is not associated with cervical radiculopathy. Cervical radiculopathy is not more frequent in more severe CTS.
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http://dx.doi.org/10.1097/CND.0000000000000114DOI Listing
June 2016

Rapid improvement of hereditary neuropathy with liability to pressure palsies following cubital tunnel release.

Muscle Nerve 2015 Nov 8;52(5):910-1. Epub 2015 Aug 8.

Department of Neurology, Mount Sinai Beth Israel, New York, New York.

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http://dx.doi.org/10.1002/mus.24762DOI Listing
November 2015

A 23-year-old man with acute onset paresthesias and gait ataxia.

J Clin Neuromuscul Dis 2014 Jun;15(4):192-3

Department of Neurology, Mt. Sinai Beth Israel Medical Center, New York, NY.

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http://dx.doi.org/10.1097/CND.0000000000000035DOI Listing
June 2014

Clinical reasoning: a 79-year-old man with polyneuropathy and dysautonomia.

Neurology 2011 May;76(19):e93-7

Neuromuscular Division and ALS Center, Beth Israel Medical Center, Albert Einstein College of Medicine, Phillips Ambulatory Care Center, New York, NY 10003, USA.

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http://dx.doi.org/10.1212/WNL.0b013e318219fa63DOI Listing
May 2011

Can vitamin D delay the progression of ALS?

Med Hypotheses 2011 May;76(5):643-5

Albert Einstein College of Medicine, Beth Israel Medical Center, 10 Union Square East, New York, NY 10003, USA.

The pathogenesis of amyotrophic lateral sclerosis (ALS) is multifactorial and a treatment targeting only one aspect of the disease is unlikely to be beneficial. Vitamin D is safe and may delay progression of ALS by acting on several aspects of the disease. In this article we explore how vitamin D may promote VGEF, IGF-1 and axonal regeneration delaying ALS progression. In addition, we discuss how vitamin D may increase calcium binding protein in motor neuron cells conferring a greater resistance to the underlying disease process, as seen in the oculomotor nerve and Onuf's nucleus. Finally, we discuss vitamin D immunomodulator role, decreasing the reactive gliosis in ALS.
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http://dx.doi.org/10.1016/j.mehy.2011.01.021DOI Listing
May 2011

Clinical Reasoning: A 48-year-old woman with generalized weakness.

Neurology 2010 May;74(18):e76-80

Neuromuscular Division and ALS Center, Beth Israel Medical Center, Albert Einstein College of Medicine, Phillips Ambulatory Care Center, 10 Union Square East, Suite 5 D, New York, NY 10003, USA.

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http://dx.doi.org/10.1212/WNL.0b013e3181dc1aacDOI Listing
May 2010

Sensory neuronopathy with Ro antibodies: response to combination immunosuppression.

J Clin Neuromuscul Dis 2010 Mar;11(3):120-3

Beth Israel Medical Center, New York, NY, USA.

The objective of this study was to describe a case of sensory neuronopathy syndrome (SNS) with Ro antibodies who had nearly complete functional recovery with combination immunosuppression. Plasma exchange, azathioprine, and hydroxychloroquine were used in combination. The gait ataxia, kinesthetic sensation, and sensory response amplitudes showed considerable recovery with excellent functional outcomes. Prompt combined therapy with azathioprine and hydroxychloroquine is a promising therapy for patients with sensory neuronopathy syndrome and Ro antibodies.
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http://dx.doi.org/10.1097/CND.0b013e3181d05980DOI Listing
March 2010

Clinical Reasoning: a 34-year-old woman with recurrent bouts of acral paresthesias.

Neurology 2010 Mar;74(9):775-8

Neuromuscular Division and ALS Center, Beth Israel Medical Center, Albert Einstein College of Medicine, New York, NY, USA.

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http://dx.doi.org/10.1212/WNL.0b013e3181d25b1cDOI Listing
March 2010

The clinical course of progressive bulbar palsy.

Amyotroph Lateral Scler 2010 Aug;11(4):364-8

Neuromuscular Division and ALS Center, Beth Israel Medical Center, Albert Einstein College of Medicine, New York, New York, USA.

Our objective was to study the clinical course of patients diagnosed with progressive bulbar palsy (PBP). We reviewed all 392 medical records of ALS patients seen between 1 January 2000 and 31 July 2007. Patients with isolated PBP at presentation were selected and classified into those with normal EMG of the limbs (PBP-N) and those with active denervation on EMG (PBP-A). We studied the time to progression of these patients to ALS. We compared patients with PBP-N to patients with PBP-A. Fifteen patients were diagnosed with PBP-N. The remaining 17 had PBP-A. Thirteen of the 15 patients with PBP-N (87%) progressed to definite ALS. The two patients who did not progress to ALS died at 22 and 60 months, respectively. The median survival time was 35 months for the PBP-N group and 40 months for the PBP-A group (p = 0.92). Except for the rate of depression, patients with PBP-N did not differ from patients with PBP-A in the basic demographics, time of presentation, clinical course, survival and treatment received. All patients with FTD died within 40 months of onset of symptoms. In conclusion, almost all PBP patients progress to ALS regardless of the presence of upper motor signs or generalized denervation on EMG of the limbs.
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http://dx.doi.org/10.3109/17482960903513159DOI Listing
August 2010

Familial, demyelinating sensory and motor polyneuropathy with conduction block.

Authors:
Stephen N Scelsa

Muscle Nerve 2010 Apr;41(4):558-62

Neuromuscular Division, Department of Neurology, Beth Israel Medical Center, Albert Einstein College of Medicine, Phillips Ambulatory Care Center, 10 Union Square East, Suite 5D, New York, New York 10003, USA.

Both multifocal, demyelinating features and prednisone responsiveness are rare in Charcot-Marie-Tooth (CMT) disease. We report a mother and son with a prednisone-responsive, multifocal, demyelinating, predominantly sensory polyneuropathy that was associated with an isoleucine92valine polymorphism of lipopolysaccharide-induced TNF-alpha factor (LITAF). The mother had a multifocal, acquired, demyelinating sensory and motor polyneuropathy (MADSAM)-like presentation. The son developed left peroneal neuropathy during acute Lyme disease with a subsequent relapsing, MADSAM-like illness, despite antibiotic treatment. Both shared prednisone responsiveness and multifocal, demyelinating features electrophysiologically. MADSAM may be familial (FaDSAM) and respond to prednisone.
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http://dx.doi.org/10.1002/mus.21558DOI Listing
April 2010

A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS.

Amyotroph Lateral Scler 2008 Aug;9(4):212-22

Department of Neurology, Columbia University, New York, USA.

Combining agents with different mechanisms of action may be necessary for meaningful results in treating ALS. The combinations of minocycline-creatine and celecoxib-creatine have additive effects in the murine model. New trial designs are needed to efficiently screen the growing number of potential neuroprotective agents. Our objective was to assess two drug combinations in ALS using a novel phase II trial design. We conducted a randomized, double-blind selection trial in sequential pools of 60 patients. Participants received minocycline (100 mg)-creatine (10 g) twice daily or celecoxib (400 mg)-creatine (10 g) twice daily for six months. The primary objective was treatment selection based on which combination best slowed deterioration in the ALS Functional Rating Scale-Revised (ALSFRS-R); the trial could be stopped after one pool if the difference between the two arms was adequately large. At trial conclusion, each arm was compared to a historical control group in a futility analysis. Safety measures were also examined. After the first patient pool, the mean six-month decline in ALSFRS-R was 5.27 (SD=5.54) in the celecoxib-creatine group and 6.47 (SD=9.14) in the minocycline-creatine group. The corresponding decline was 5.82 (SD=6.77) in the historical controls. The difference between the two sample means exceeded the stopping criterion. The null hypothesis of superiority was not rejected in the futility analysis. Skin rash occurred more frequently in the celecoxib-creatine group. In conclusion, the celecoxib-creatine combination was selected as preferable to the minocycline-creatine combination for further evaluation. This phase II design was efficient, leading to treatment selection after just 60 patients, and can be used in other phase II trials to assess different agents.
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http://dx.doi.org/10.1080/17482960802195632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354803PMC
August 2008

Sensory symptoms in acquired neuromyotonia.

Neurology 2005 Oct;65(8):1330-1

Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.

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http://dx.doi.org/10.1212/01.wnl.0000180688.06885.6fDOI Listing
October 2005

Blood gammadelta T cells, Campylobacter jejuni, and GM1 titers in Guillain-Barré syndrome.

Muscle Nerve 2004 Oct;30(4):423-32

Department of Neurology, Beth Israel Medical Center, New York, NY, USA.

The gammadelta T cells participate in microbial defense, are prevalent in intestinal epithelia, and are activated in autoimmune diseases. We studied whether peripheral blood gammadelta cells and gammadelta subsets are increased in Guillain-Barré syndrome (GBS) and whether elevations are associated with Campylobacter jejuni infection or GM1 elevations. In 20 GBS patients, we performed serial flow cytometry studies of blood gammadelta, Vdelta1, and Vdelta2 cells (+/- CD8+), C jejuni, and ganglioside titers. There was no significant difference in median gammadelta T-cell percentages between GBS patients and controls at onset and at convalescence. However, 5 patients had marked Vdelta1/CD8+ elevations. Elevated Vdelta1 or Vdelta1/CD8+ cells occurred in 3 of 6 patients with C jejuni or GM1 titer elevations. A minority of GBS patients have elevations of Vdelta1/CD8+ cells, possibly associated with elevated C jejuni or GM1 titers. The gammadelta T cells may have a cytotoxic (or suppressor) role in the disease.
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http://dx.doi.org/10.1002/mus.20105DOI Listing
October 2004

Dyspnea-fasciculation syndrome: early respiratory failure in ALS with minimal motor signs.

Amyotroph Lateral Scler Other Motor Neuron Disord 2002 Dec;3(4):239-43

Department of Neurology, Beth Israel Medical Center, New York, NY 10003, USA.

Background: Respiratory failure (RF) in ALS typically occurs as a late manifestation. While there are uncommon patient reports of early RF, most had moderate limb and bulbar weakness.

Design/methods: We reviewed clinical and laboratory data from 3 patients with ALS, early RF, and minor motor signs.

Results: Patients were male, ages 62, 75 and 80 years. The patients presented with 6 months to 2 years of exertional and nocturnal dyspnea, daytime hypersomnolence, limb fatigability, and weight loss. Exam showed tachypnea, slight distal limb weakness, and hyperreflexia. All three patients had prominent fasciculations, insomnia, supportive EMG findings, FVC (32-74% predicted), PO2 (50-80 mmHg), PCO2(52-76 mmHg) and required BiPAP (Bi-level positive airway pressure). One patient had a reduced FEV1/FVC of 0.55 and a 15% increase in FEV1 post-bronchodilator suggesting concurrent chronic obstructive pulmonary disease (COPD). However, his P(A-a)O2 was only 7 mmHg suggesting COPD was not the major factor causing respiratory failure; his extreme hypercapnea could not be explained by ALS or COPD alone.

Conclusions: ALS may present with unexplained RF, or sleep disturbance resembling sleep apnea, without significant bulbar or limb weakness. In our experience, such patients are elderly with dyspnea, fasciculations, and other minor motor signs: the Dyspnea-Fasciculation Syndrome. Concurrent COPD may augment the effect of ALS, resulting in earlier RF. FVC may be relatively preserved, despite hypercapnia.
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http://dx.doi.org/10.1080/146608202760839011DOI Listing
December 2002