title: Monocular and binocular low-contrast visual acuity and optical coherence tomography in pediatric multiple sclerosis.
abstract: BACKGROUND
  Low-contrast letter acuity and optical coherence tomography (OCT) capture visual dysfunction and axonal loss in adult-onset multiple sclerosis (MS), and have been proposed as secondary outcome metrics for therapeutic trials. Clinical trials will soon be launched in pediatric MS, but such outcome metrics have not been well-validated in this population.
  
  
  OBJECTIVE
  To determine whether MS onset during childhood and adolescence is associated with measurable loss of visual acuity and thinning of the retinal nerve fiber layer (RNFL), whether such features are noted only in the context of clinical optic nerve inflammation (optic neuritis, ON) or are a feature of MS even in the absence of optic nerve relapses, and to define the optimal methods for such detection.
  
  
  METHODS
  Cross-sectional study.
  
  
  METHODS
  Monocular and binocular high- and low-contrast letter acuity and contrast sensitivity were assessed in a cross-sectional cohort of children (ages 5 to 17 years) with MS (N=22 patients, 44 eyes; 8 patients with a history of ON) and disease-free controls (N=29 patients; 58 eyes) from three academic centers. Binocular summation was determined by calculating the number of letters correctly identified using the binocular score minus the better eye score for each visual test. RNFL thickness was measured using OCT (Stratus OCT-3). Results were analyzed in terms of "eyes" as: MS ON+, MS ON-, and control eyes. Generalized estimating equation (GEE) regression models were used to compare patients to controls.
  
  
  RESULTS
  Traditional high-contrast visual acuity scores did not differ between MS ON+, MS ON-, and controls eyes. MS ON+ eyes had decreased monocular (p<0.001) and decreased binocular (p=0.007) low-contrast letter acuity (Sloan 1.25% contrast charts) scores. Monocular visual acuity did not differ when comparing MS ON- and control eyes. The magnitude of binocular summation using low-contrast charts was similar for pediatric MS participants and controls and was not diminished in children with a history of ON. While the mean RNFL thickness for all MS eyes (103±17 μm) trended lower when compared to corresponding measures in control eyes (109±9 μm,p=0.085), we confirmed a highly significant reduction in mean RNFL thickness in MS eyes with a history of ON (86±22 μm,p<0.001). RNFL thickness of MS ON- eyes in pediatric MS patients (109±11 μm) did not differ from controls (p=0.994).
  
  
  CONCLUSIONS
  Low-contrast letter acuity detects subtle visual loss in MS patients with prior ON, consistent with incomplete recovery, a finding further supported by RNFL loss in ON affected eyes. In MS patients with prior unilateral ON, binocular acuity is decreased; however, the magnitude of binocular summation is preserved, unlike adult-onset MS who exhibit a reduced capacity for visual compensation in the context of unilateral injury. Also unlike findings in adult-onset MS, we did not demonstrate RNFL thinning in ON- eyes of children and adolescents with MS. Further validation is required to confirm whether neurodegeneration of visual pathways occurs in the absence of relapse, and thus whether OCT will serve as a sensitive metric for such pathology in the pediatric and adolescent MS context.
authors.affiliation: The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania ; Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania ; Department of Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Amy T
authors.initials: AT
authors.lastname: Waldman
authors.affiliation: Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Girish
authors.initials: G
authors.lastname: Hiremath
authors.affiliation: The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania ; Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania ; Department of Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Avery
authors.affiliation: Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Amy
authors.initials: A
authors.lastname: Conger
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania ; Department of Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Pineles
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Loguidice
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Lauren S
authors.initials: LS
authors.lastname: Talman
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Galetta
authors.affiliation: The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shumski
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: James
authors.initials: J
authors.lastname: Wilson
authors.affiliation: Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: E'tona
authors.initials: E
authors.lastname: Ford
authors.affiliation: The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Lavery
authors.affiliation: Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Darrel
authors.initials: D
authors.lastname: Conger
authors.affiliation: Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Greenberg
authors.affiliation: Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Jonas H
authors.initials: JH
authors.lastname: Ellenberg
authors.affiliation: Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Elliot M
authors.initials: EM
authors.lastname: Frohman
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania ; Department of Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania ; Department of Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Balcer
authors.affiliation: Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
keywords: demyelinating disease; multiple sclerosis; optic neuritis; pediatric