title: Retinal thickness measured with optical coherence tomography and risk of disability worsening in multiple sclerosis: a cohort study.
abstract: BACKGROUND
  Most patients with multiple sclerosis without previous optic neuritis have thinner retinal layers than healthy controls. We assessed the role of peripapillary retinal nerve fibre layer (pRNFL) thickness and macular volume in eyes with no history of optic neuritis as a biomarker of disability worsening in a cohort of patients with multiple sclerosis who had at least one eye without optic neuritis available.
  
  
  METHODS
  In this multicentre, cohort study, we collected data about patients (age ≥16 years old) with clinically isolated syndrome, relapsing-remitting multiple sclerosis, and progressive multiple sclerosis. Patients were recruited from centres in Spain, Italy, France, Germany, Czech Republic, Netherlands, Canada, and the USA, with the first cohort starting in 2008 and the latest cohort starting in 2013. We assessed disability worsening using the Expanded Disability Status Scale (EDSS). The pRNFL thickness and macular volume were assessed once at study entry (baseline) by optical coherence tomography (OCT) and was calculated as the mean value of both eyes without optic neuritis for patients without a history of optic neuritis or the value of the non-optic neuritis eye for patients with previous unilateral optic neuritis. Researchers who did the OCT at baseline were masked to EDSS results and the researchers assessing disability with EDSS were masked to OCT results. We estimated the association of pRNFL thickness or macular volume at baseline in eyes without optic neuritis with the risk of subsequent disability worsening by use of proportional hazards models that included OCT metrics and age, disease duration, disability, presence of previous unilateral optic neuritis, and use of disease-modifying therapies as covariates.
  
  
  RESULTS
  879 patients with clinically isolated syndrome (n=74), relapsing-remitting multiple sclerosis (n=664), or progressive multiple sclerosis (n=141) were included in the primary analyses. Disability worsening occurred in 252 (29%) of 879 patients with multiple sclerosis after a median follow-up of 2·0 years (range 0·5-5 years). Patients with a pRNFL of less than or equal to 87 μm or less than or equal to 88 μm (measured with Spectralis or Cirrus OCT devices) had double the risk of disability worsening at any time after the first and up to the third years of follow-up (hazard ratio 2·06, 95% CI 1·36-3·11; p=0·001), and the risk was increased by nearly four times after the third and up to the fifth years of follow-up (3·81, 1·63-8·91; p=0·002). We did not identify meaningful associations for macular volume.
  
  
  CONCLUSIONS
  Our results provide evidence of the usefulness of monitoring pRNFL thickness by OCT for prediction of the risk of disability worsening with time in patients with multiple sclerosis.
  
  
  BACKGROUND
  Instituto de Salud Carlos III.
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Elena H
authors.initials: EH
authors.lastname: Martinez-Lapiscina
authors.affiliation: University of California, San Francisco, CA, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Arnow
authors.affiliation: University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Wilson
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Shiv
authors.initials: S
authors.lastname: Saidha
authors.affiliation: Charles University, Prague, Czech Republic.
authors.forename: Jana Lizrova
authors.initials: JL
authors.lastname: Preiningerova
authors.affiliation: Experimental and Clinical Research Center and NeuroCure Clinical Research Center, Charité University Medicine and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Timm
authors.initials: T
authors.lastname: Oberwahrenbrock
authors.affiliation: Experimental and Clinical Research Center and NeuroCure Clinical Research Center, Charité University Medicine and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Alexander U
authors.initials: AU
authors.lastname: Brandt
authors.affiliation: Hospital Miguel Servet, Zaragoza, Spain.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Pablo
authors.affiliation: San Raffaele Hospital, Milan, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Guerrieri
authors.affiliation: Hospital Clinico San Carlos, Madrid, Spain.
authors.forename: Ines
authors.initials: I
authors.lastname: Gonzalez
authors.affiliation: University of Lille, Lille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Outteryck
authors.affiliation: University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Mueller
authors.affiliation: University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Phillip
authors.initials: P
authors.lastname: Albrecht
authors.affiliation: University of Calgary, Calgary, AB, Canada.
authors.forename: Wesley
authors.initials: W
authors.lastname: Chan
authors.affiliation: University of Zurich, Zurich, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lukas
authors.affiliation: VU Medical Center, Amsterdam, Netherlands.
authors.forename: Lisanne J
authors.initials: LJ
authors.lastname: Balk
authors.affiliation: Save Sight Institute, University of Sydney, NSW, Australia.
authors.forename: Clare
authors.initials: C
authors.lastname: Fraser
authors.affiliation: Glostrup Hospital, University of Copenhagen, Denmark.
authors.forename: Jette L
authors.initials: JL
authors.lastname: Frederiksen
authors.affiliation: Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Resto
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Frohman
authors.affiliation: University of California, San Francisco, CA, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Cordano
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Irati
authors.initials: I
authors.lastname: Zubizarreta
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Magi
authors.initials: M
authors.lastname: Andorra
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Sanchez-Dalmau
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Saiz
authors.affiliation: Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Bermel
authors.affiliation: Save Sight Institute, University of Sydney, NSW, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Klistorner
authors.affiliation: VU Medical Center, Amsterdam, Netherlands; Moorfields Eye Hospital, London, UK.
authors.forename: Axel
authors.initials: A
authors.lastname: Petzold
authors.affiliation: University of Zurich, Zurich, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Schippling
authors.affiliation: University of Calgary, Calgary, AB, Canada.
authors.forename: Fiona
authors.initials: F
authors.lastname: Costello
authors.affiliation: University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Orhan
authors.initials: O
authors.lastname: Aktas
authors.affiliation: University of Lille, Lille, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Vermersch
authors.affiliation: Hospital Clinico San Carlos, Madrid, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Oreja-Guevara
authors.affiliation: San Raffaele Hospital, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: San Raffaele Hospital, Milan, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Leocani
authors.affiliation: Hospital Miguel Servet, Zaragoza, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Garcia-Martin
authors.affiliation: Experimental and Clinical Research Center and NeuroCure Clinical Research Center, Charité University Medicine and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Paul
authors.affiliation: Charles University, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Havrdova
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Elliot
authors.initials: E
authors.lastname: Frohman
authors.affiliation: University of Pennsylvania, Philadelphia, PA, USA; New York University, New York, NY, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Balcer
authors.affiliation: University of California, San Francisco, CA, USA.
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Green
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain; University of California, San Francisco, CA, USA. Electronic address: pvilloslada@clinic.ub.es.
authors.forename: Pablo
authors.initials: P
authors.lastname: Villoslada
mesh_terms: D000328:Adult; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008266:Macula Lutea / Q000000981:diagnostic imaging*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000150:complications / Q000503:physiopathology*; D011379:Prognosis; D012164:Retinal Diseases / Q000000981:diagnostic imaging* / Q000209:etiology; D055351:Retinal Neurons / Q000473:pathology*; D012720:Severity of Illness Index; D041623:Tomography, Optical Coherence / Q000379:methods*