For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
29
views
11
references
 Top references
cited by
108
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      409
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Results from a phase 1 study of nusinersen (ISIS-SMN Rx) in children with spinal muscular atrophy

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Objective:

          To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMN Rx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA).

          Methods:

          Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2–14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6–10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory.

          Results:

          A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4–6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9–14 months postdose (5.8 points; p = 0.008) during the extension study.

          Conclusions:

          Results from this study support continued development of nusinersen for treatment of SMA.

          Classification of evidence:

          This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.

          Related collections

          Most cited references11

          • Record: found
          • Abstract: found
          • Article: not found

          Spinal muscular atrophy.

          Mitchell R Lunn, Ching H Wang (2008)
          Spinal muscular atrophy is an autosomal recessive neurodegenerative disease characterised by degeneration of spinal cord motor neurons, atrophy of skeletal muscles, and generalised weakness. It is caused by homozygous disruption of the survival motor neuron 1 (SMN1) gene by deletion, conversion, or mutation. Although no medical treatment is available, investigations have elucidated possible mechanisms underlying the molecular pathogenesis of the disease. Treatment strategies have been developed to use the unique genomic structure of the SMN1 gene region. Several candidate treatment agents have been identified and are in various stages of development. These and other advances in medical technology have changed the standard of care for patients with spinal muscular atrophy. In this Seminar, we provide a comprehensive review that integrates clinical manifestations, molecular pathogenesis, diagnostic strategy, therapeutic development, and evidence from clinical trials.
          Article 0 comments Cited 262 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients.

            Jessica M. O’Hagen, Allan Glanzman, Michael McDermott … (2007)
            To develop and evaluate an expanded version of the Hammersmith Functional Motor Scale allowing for evaluation of ambulatory SMA patients.
            Article 0 comments Cited 87 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Age-related volumetric changes of brain gray and white matter in healthy infants and children.

              T Konishi, J Matsuzawa, Taka-aki Noguchi … (2001)
              To date there is little information about brain development during infancy and childhood, although several quantitative studies have shown volume changes in adult brains. We performed three-dimensional magnetic resonance imaging (3D-MRI) in 28 healthy children aged 1 month to 10 years. We examined the volumes of whole brain and frontal and temporal lobes with an advanced method for segmenting images into gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) compartments. Growth spurts of whole brain and frontal and temporal lobes could be seen during the first 2 years after birth. During this period the frontal lobes grew more rapidly than the temporal lobes, the right--left asymmetry was more noticeable in the temporal lobes than in the frontal lobes and the increase in GM was larger than that in WM in the temporal lobes. Subsequently, WM volume increased at a higher rate than GM volume throughout childhood. Quantitative information on normal brain development may play a pivotal role in clarifying brain neurodevelopmental abnormalities.
              Article 0 comments Cited 62 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Claudia A. Chiriboga:
                Comment :

                Scientific Advisory Boards:

                1. F. Hoffmann-La Roche Pharmaceuticals Advisory board Biogen Pharmaceuticals Advisory Board

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NeuroNEXT: Network for Excellence in Neuroscience Clinical Trials co-PI 09/01/11-08/31/16 DOD award W81XWH-11-1-0753 #10259004 Co-PI 7/30/11-8/01/14

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. SMA Foundation

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Kathryn J. Swoboda:
                Comment :

                Scientific Advisory Boards:

                1. 1. Avexis 2. Genzyme

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other activities:

                1. ISIS pharmaceuticals: PI for phase I and Phase II trials of ISIS SMNRx when I was employed at the University of Utah, through end of December 2014.

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. (1) Isis Pharmaceuticals, Inc., (2) Pfizer, Inc. (3) Orphamed, Inc. (4) Roche TCRC, Inc.

                Research Support, Government Entities:

                1. NIH RO1-HD69045 grant to fund a newborn screening pilot study for SMA, PI, 2011-16, NICHD.

                Research Support, Academic Entities:

                1. Employed previously at the University of Utah, through March 2015, before moving to MGH Boston.

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License fee payments, Technology or Inventions:

                1. (1) SMA Study Analysis Data, Orphamed, Inc.

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Basil T. Darras:
                Comment :

                Scientific Advisory Boards:

                1. (1) Hoffman LaRoche (2) Cytokinetics, Inc. (3) Audentes, Inc (4) Sarepta Therapeutics

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. (1) Various titles, UpToDate, 1999-present (2) 2 videotaped presentations, “Hypotonia”, “Congenital Myopathies”, Oakstone Medical Publishing, 2014

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. (1) Leerink Partners, LLC (2) Cowen and Company (3) Guidepoint Global Consultation (4) Vertex Pharma (5) Clearview Healthcare Partners (6) Gershon Lehrman Group (7) Putnam Associates (8) Wallachbeth Capital, LLC (9) Frankel Group (10) Voyager Therapeutics (11) Noble Insights (12) Jefferies and Company (13) Krog & Partners, Inc.

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. (1) PTC Therapeutics (2) Valerion Therapeutics (MTM) (3) Isis Pharmaceuticals (4) Serepta Therapeutics

                Research Support, Government Entities:

                1. (1) NIH/NIAMS, 2P01 NS040828-6A11, Co-PI, 2000-2012. (2) NIH/NINDS, 1U10NS077269, Site-PI/PD, 2011-2018. (3) NIH/NIAMS, 1R01AR060850, Co-PI, 2011-2015. (4) NIH/NINDS, 5U01NS061799, FOR-DMD, Site-PI, 2012-2016. (5) NIH/NINDS via Skulpt Inc., 5RNS073188, Site-PI, 2015- 2016.

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. (1) SMA Foundation (2) Muscular Dystrophy Association (3) Slaney Family Fund for SMA

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Susan T. Iannaccone:
                Comment :

                Scientific Advisory Boards:

                1. Lilly Scientific Advisory Board, 2013 $2500 Audentes Advisory Board, 2015 no payment Biogen Global Medical Steering Committee, 2015, $4500 Member DSMB, Congenital Muscular Dystrophy Ascending Multiple Dose Cohort Study anaLyzing Pharmacokinetics at three dose Levels In Children and Adolescents with Assessment of Safety and Tolerability of Omigapil Santhera, no payment, 2015 - present Cytokinetics Advisory Board for SMA drug development, CK- 2127107 HoffmanLaRoche Ltd Advisory Board for SMA drug, Olesoxime

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. Editorial board: Neuromuscular Disorders, Journal of Pediatric Rehabilitation Medicine

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. Member, Steering committee for planning preclinical IND enabling toxicology studies for scAAV9-SMN gene therapy of SMA, to be conducted at Nationwide Childrens Hospital, 2011-2014

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. Site PI for: PTC sponsored clinical trial of Ataluren in Duchenne muscular dystrophy: A Phase 2b Efficacy and Safety Study of PTC124 in Subjects with Nonsense-Mutation-Mediated Duchenne and Becker Muscular Dystrophy Extension Study of Ataluren in Subjects with Nonsense- Mutation-Mediated Duchenne and Becker Muscular Dystrophy, PTC Therapeutics, 3 patients previously enrolled now in open label. 2011 - present DMD 114876: An exploratory study to assess two doses of GSK2402968 in the treatment of ambulant boys with Duchenne Muscular Dystrophy GlaxoSmthKline 2012- 2014 A Phase III Double-Blind, Randomised, Placebo-Controlled Study of the Efficacy, Safety and Tolerability of Idebenone in 10 ? 18 Year Old Patients with Duchenne Muscular Dystrophy Santhera Pharmaceuticals 2012- 2014 An Open-label, Escalating Dose Study to Assess the Safety, Tolerability and Dose-range Finding of a Single Intrathecal Dose of ISIS 396443 in Patients with Spinal Muscular Atrophy (CS1) ISIS Pharmaceuticals Inc 2011 ? 2012 An Open-Label Study to Assess the Safety, Tolerability and Dose-Range Finding of Multiple Doses of ISIS 396443 Delivered Intrathecally to Patients with Spinal Muscular Atrophy (CS2, CS10, CS12) ISIS Pharmaceuticals Inc 2012 ? present A Phase 3, Randomized, Double-blind, Sham-Procedure Controlled Study to Assess the Clinical Efficacy and Safety of ISIS 396443 Administered Intrathecally in Patients with Later-onset Spinal Muscular Atrophy ISIS Pharmaceuticals Inc 2015 ? present A Phase 3, Randomized, Double-Blind, Sham-Procedure Controlled Study to Assess the Clinical Efficacy and Safety of ISIS 396443 Administered Intrathecally in Patients with Infantile-onset Spinal Muscular Atrophy ISIS Pharmaceuticals Inc 2014 ? present A Randomized Double Blind, Placebo Controlled, Phase 3 Trial of Tadalafil for Duchenne Muscular Dystrophy Lilly 2013 - present An Open-Label, Multi-Center, 48-Week Study with a Concurrent Untreated Control Arm to Evaluate the Efficacy and Safety of Eteplirsen in Duchenne Muscular Dystrophy Sarepta 2014 - present

                Research Support, Government Entities:

                1. Site CoPI for NIH sponsored NeuroNEXT 2010-2017 Site CoPI for NeuroNEXT (NIH) sponsored Biomarker in SMA study 2012-2015 Site CoPI for Wellstone Center for Muscular Dystrophy (NIH U54 AR068791-01 ) 2015-2020

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. Muscular Dystrophy Association, clinic grant SMA Foundation, International Coordinating Committee Families of SMA, Advisory Board Muscular Dystrophy Association, DMD Clinical Research Network, Sub-contract from Ohio State University, Site PI 11.2012-11.2017

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Jacqueline Montes:
                Comment :

                Scientific Advisory Boards:

                1. (1) Roche Pharmaceuticals (2) Biogen (3)Cytokinetics

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. (1) Isis Pharmaceuticals

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. (1) SMA Foundation

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Darryl C. De Vivo:
                Comment :

                Scientific Advisory Boards:

                1. (1)Member, Grace Wilsey Foundation?s Scientific Advisory Board (non-profit entity) (2)Medical Advisor, The Colleen Giblin Foundation for Pediatric Neurological Research(non-profit entity) (3)Medical Advisor, Spinal Muscular Atrophy (SMA) Foundation(non-profit entity) (4) Medical Advisor, Glut1 Disease Foundation (non-profit entity)

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. 1. Member, Editorial Board, Journal of the National Reye's Syndrome Foundation 2. Member, Editorial Board, European Journal of Pediatric Neurology 3. Member, Editorial Board, Brain & Development 4. Member, Editorial Board, Turkish Journal of Pediatric Neurology 5. Member, Editorial Board, Current Opinion in Neurology

                Patents:

                1. Patent pending- Glut1 gene therapy

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. Biogen, commercial AveXis, commercial

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. 2010-2014 USPHS Department of Defense # W81XWH-10-1- 0127 ?A Randomized, Control Trial of Exercise in Patients with Spinal Muscular Atrophy?(Principal Investigator) 1995-2019 USPHS #1 PO1 HD 32062 “Mitochondrial Encephalomyopathies and Mental Retardation”(Project 1) (Principal Investigator)

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. 2004-2014 Pediatric Neuromuscular Clinical Research Network for SMA Clinical Trials (Principal Investigator) 2012-2014 Glut1 Deficiency Syndrome Foundation Support for Longitudinal Studies (Principal Investigator) 1991-2014 Will Foundation ? ?Pathophysiology and Treatment of Glut1 Deficiency? 1985- present Colleen Giblin Foundation for Pediatric Neurological Research (Principal Investigator)

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Daniel A. Norris:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. Isis Pharmaceuticals, Carlsbad, CA, Director of Pharmacokinetics and Clinical Pharmacology, 2007 to present

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. Isis Pharmaceuticals, Carlsbad, CA, 2007 to 2015

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                C. Frank Bennett:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. Inventor on several issued and pending patents covering ISIS SMNRx and antisense technology

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. Employee of Isis Pharmaceuticals

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. 1. Isis Pharmaceuticals, 1989-2015

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Kathie M. Bishop:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. I was a full-time employee of Isis Pharmaceuticals from to September 2009 to March 2015.

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Journal
                Journal ID (nlm-ta): Neurology
                Journal ID (iso-abbrev): Neurology
                Journal ID (hwp): neurology
                Journal ID (publisher-id): neur
                Journal ID (pmc): neurology
                Journal ID (publisher-id): NEUROLOGY
                Title: Neurology
                Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )
                ISSN (Print): 0028-3878
                ISSN (Electronic): 1526-632X
                Publication date (Print): 08 March 2016
                Publication date PMC-release: 08 March 2016
                Volume: 86
                Issue: 10
                Pages: 890-897
                Affiliations
                From the Departments of Neurology (C.A.C., J.M., D.C.D.) and Rehabilitative and Regenerative Medicine (J.M.), Columbia University, New York, NY; Department of Neurology (K.J.S.), University of Utah, Salt Lake City; Department of Neurology (B.T.D.), Boston Children's Hospital, Boston, MA; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical School, Dallas; and Ionis Pharmaceuticals, Inc. (formerly Isis Pharmaceuticals, Inc.) (D.A.N., C.F.B., K.M.B.), Carlsbad, CA.
                Author notes
                Correspondence to Dr. Chiriboga: cac3@ 123456cumc.columbia.edu

                Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was paid by Ionis Pharmaceuticals Inc.

                Article
                Publisher ID: NEUROLOGY2015663500
                DOI: 10.1212/WNL.0000000000002445
                PMC ID: 4782111
                PubMed ID: 26865511
                SO-VID: 62ec6abf-8c8b-441e-8816-76a81d8d9974
                Copyright © © 2016 American Academy of Neurology
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

                History
                Date received : 28 April 2015
                Date accepted : 22 October 2015
                Categories
                Subject: 19
                Subject: 324
                Subject: 117
                Subject: 227
                Subject: 252
                Subject: Article
                Custom metadata
                OPEN-ACCESS TRUE
                cme yes
                special-property triangle

                Data availability:

                Comments

                Comment on this article

                scite_

                Similar content409

                See all similar

                Cited by222

                See all cited by

                Most referenced authors455

                See all reference authors