title: Retinal Architecture and Melanopsin-Mediated Pupillary Response Characteristics: A Putative Pathophysiologic Signature for the Retino-Hypothalamic Tract in Multiple Sclerosis.
abstract: A neurophysiologic signature of the melanopsin-mediated persistent constriction phase of the pupillary light reflex may represent a surrogate biomarker for the integrity of the retinohypothalamic tract, with potential utility for investigating alterations in homeostatic mechanisms associated with brain disorders and implications for identifying new treatments.
  
  
  
  To characterize abnormalities of retinal architecture in patients with multiple sclerosis (MS) and corresponding alterations in the melanopsin-mediated sustained pupillary constriction response.
  
  
  
  The case-control study was an experimental assessment of various stimulus-induced pupillary response characteristics and was conducted at a university clinical center for MS from September 6, 2012, to February 2015. Twenty-four patients with MS (48 eyes) and 15 individuals serving as controls (30 eyes) participated. The melanopsin-mediated, sustained pupillary constriction phase response following cessation of a blue light stimulus was compared with the photoreceptor-mediated pupillary constriction phase response following cessation of a red light stimulus. Optical coherence tomography was used to characterize the association between pupillary response characteristics and alterations in retinal architecture, specifically, the thickness of the retinal ganglion cell layer and inner plexiform layer (GCL + IPL).
  
  
  
  Association of pupillary response characteristics with alterations in retinal architecture.
  
  
  
  Of 24 patients with MS included in the analysis, 17 were women (71%); mean (SD) age was 47 (11) years. Compared with eyes from individuals with MS who had normal optical coherence tomography-derived measures of retinal GCL + IPL thickness, eyes of patients who had GCL + IPL thickness reductions to less than the first percentile exhibited a correspondingly significant attenuation of the melanopsin-mediated sustained pupillary response (mean [SD] pupillary diameter ratios at a point in time, 0.18 [0.1] vs 0.33 [0.09]; P < .001, generalized estimating equation models accounting for age and within-patient intereye correlations).
  
  
  
  In this case-control study, attenuation of the melanopsin-mediated sustained pupillary constriction response was significantly associated with thinning of the GCL + IPL sector of the retina in the eyes of patients with MS, particularly those with a history of acute optic neuritis. Melanopsin-containing ganglion cells in the retina represent, at least in part, the composition of the retinohypothalamic tract. As such, our findings may signify the ability to elucidate a putative surrogate neurophysiologic signature that correlates with a constellation of homeostatic mechanisms in both health and illness.
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas.
authors.forename: Ethan
authors.initials: E
authors.lastname: Meltzer
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Sguigna
authors.affiliation: Department of Neurology, Michigan State University, East Lansing.
authors.forename: Adnan
authors.initials: A
authors.lastname: Subei
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas.
authors.forename: Shin
authors.initials: S
authors.lastname: Beh
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas3Center for Engineering Innovation, University of Texas at Dallas.
authors.forename: Eric
authors.initials: E
authors.lastname: Kildebeck
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas.
authors.forename: Darrel
authors.initials: D
authors.lastname: Conger
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas.
authors.forename: Amy
authors.initials: A
authors.lastname: Conger
authors.affiliation: Student, Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas.
authors.forename: Marlen
authors.initials: M
authors.lastname: Lucero
authors.affiliation: Student, Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas.
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Frohman
authors.affiliation: Student, Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas.
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Frohman
authors.affiliation: Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Shiv
authors.initials: S
authors.lastname: Saidha
authors.affiliation: Department of Neurology, Population Health, New York University School of Medicine, New York.
authors.forename: Steven
authors.initials: S
authors.lastname: Galetta
authors.affiliation: Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
authors.affiliation: Department of Bioengineering, University of Texas at Dallas.
authors.forename: Robert
authors.initials: R
authors.lastname: Rennaker
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas.
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Frohman
authors.affiliation: Department of Ophthalmology, University of Iowa, Iowa City9Iowa City Veterans Affairs Center for Prevention and Treatment of Visual Loss, Iowa City.
authors.forename: Randy H
authors.initials: RH
authors.lastname: Kardon
authors.affiliation: Department of Neurology, Population Health, New York University School of Medicine, New York10Department of Ophthalmology, New York University School of Medicine, New York.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Balcer
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas7Department of Bioengineering, University of Texas at Dallas11Department of Ophthalmology, University of Texas Southwestern Medical Center at Dallas.
authors.forename: Elliot M
authors.initials: EM
authors.lastname: Frohman
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007031:Hypothalamus / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000150:complications / Q000000981:diagnostic imaging* / Q000503:physiopathology*; D009434:Neural Pathways / Q000503:physiopathology; D011681:Pupil Disorders / Q000209:etiology / Q000503:physiopathology*; D012025:Reflex, Pupillary / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000473:pathology; D055351:Retinal Neurons / Q000473:pathology*; D017299:Rod Opsins; D041623:Tomography, Optical Coherence; D000099210:Melanopsin
chemical_list: D017299:Rod Opsins; D000099210:Melanopsin