Retinal architecture and melanopsin-mediated pupillary response characteristics

A putative pathophysiologic signature for the retino-hypothalamic tract in multiple sclerosis

Ethan Meltzer, Peter V. Sguigna, Adnan Subei, Shin Beh, Eric Kildebeck, Darrel Conger, Amy Conger, Marlen Lucero, Benjamin S. Frohman, Ashley N. Frohman, Shiv Saidha, Steven Galetta, Peter Calabresi, Robert Rennaker, Teresa C. Frohman, Randy H. Kardon, Laura J. Balcer, Elliot M. Frohman

Research output: Contribution to journalArticle

Abstract

IMPORTANCE A neurophysiologic signature of the melanopsin-mediated persistent constriction phase of the pupillary light reflexmay 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. OBJECTIVE To characterize abnormalities of retinal architecture in patients with multiple sclerosis (MS) and corresponding alterations in the melanopsin-mediated sustained pupillary constriction response. DESIGN, SETTING, AND PARTICIPANTS The case-control studywas an experimental assessment of various stimulus-induced pupillary response characteristics and was conducted at a university clinical center forMS 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). MAIN OUTCOMES AND MEASURES Association of pupillary response characteristics with alterations in retinal architecture. RESULTS 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). CONCLUSIONS AND RELEVANCE 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.

Original languageEnglish (US)
Pages (from-to)574-582
Number of pages9
JournalJAMA Neurology
Volume74
Issue number5
DOIs
StatePublished - May 1 2017

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Multiple Sclerosis
Constriction
Optical Coherence Tomography
Light
Retina
Optic Neuritis
Retinal Ganglion Cells
Brain Diseases
Ganglia
melanopsin
Case-Control Studies
Biomarkers
Outcome Assessment (Health Care)
Health

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Retinal architecture and melanopsin-mediated pupillary response characteristics : A putative pathophysiologic signature for the retino-hypothalamic tract in multiple sclerosis. / Meltzer, Ethan; Sguigna, Peter V.; Subei, Adnan; Beh, Shin; Kildebeck, Eric; Conger, Darrel; Conger, Amy; Lucero, Marlen; Frohman, Benjamin S.; Frohman, Ashley N.; Saidha, Shiv; Galetta, Steven; Calabresi, Peter; Rennaker, Robert; Frohman, Teresa C.; Kardon, Randy H.; Balcer, Laura J.; Frohman, Elliot M.

In: JAMA Neurology, Vol. 74, No. 5, 01.05.2017, p. 574-582.

Research output: Contribution to journalArticle

Meltzer, E, Sguigna, PV, Subei, A, Beh, S, Kildebeck, E, Conger, D, Conger, A, Lucero, M, Frohman, BS, Frohman, AN, Saidha, S, Galetta, S, Calabresi, P, Rennaker, R, Frohman, TC, Kardon, RH, Balcer, LJ & Frohman, EM 2017, 'Retinal architecture and melanopsin-mediated pupillary response characteristics: A putative pathophysiologic signature for the retino-hypothalamic tract in multiple sclerosis', JAMA Neurology, vol. 74, no. 5, pp. 574-582. https://doi.org/10.1001/jamaneurol.2016.5131
Meltzer, Ethan ; Sguigna, Peter V. ; Subei, Adnan ; Beh, Shin ; Kildebeck, Eric ; Conger, Darrel ; Conger, Amy ; Lucero, Marlen ; Frohman, Benjamin S. ; Frohman, Ashley N. ; Saidha, Shiv ; Galetta, Steven ; Calabresi, Peter ; Rennaker, Robert ; Frohman, Teresa C. ; Kardon, Randy H. ; Balcer, Laura J. ; Frohman, Elliot M. / Retinal architecture and melanopsin-mediated pupillary response characteristics : A putative pathophysiologic signature for the retino-hypothalamic tract in multiple sclerosis. In: JAMA Neurology. 2017 ; Vol. 74, No. 5. pp. 574-582.
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abstract = "IMPORTANCE A neurophysiologic signature of the melanopsin-mediated persistent constriction phase of the pupillary light reflexmay 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. OBJECTIVE To characterize abnormalities of retinal architecture in patients with multiple sclerosis (MS) and corresponding alterations in the melanopsin-mediated sustained pupillary constriction response. DESIGN, SETTING, AND PARTICIPANTS The case-control studywas an experimental assessment of various stimulus-induced pupillary response characteristics and was conducted at a university clinical center forMS 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). MAIN OUTCOMES AND MEASURES Association of pupillary response characteristics with alterations in retinal architecture. RESULTS 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). CONCLUSIONS AND RELEVANCE 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.",
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T2 - A putative pathophysiologic signature for the retino-hypothalamic tract in multiple sclerosis

AU - Meltzer, Ethan

AU - Sguigna, Peter V.

AU - Subei, Adnan

AU - Beh, Shin

AU - Kildebeck, Eric

AU - Conger, Darrel

AU - Conger, Amy

AU - Lucero, Marlen

AU - Frohman, Benjamin S.

AU - Frohman, Ashley N.

AU - Saidha, Shiv

AU - Galetta, Steven

AU - Calabresi, Peter

AU - Rennaker, Robert

AU - Frohman, Teresa C.

AU - Kardon, Randy H.

AU - Balcer, Laura J.

AU - Frohman, Elliot M.

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N2 - IMPORTANCE A neurophysiologic signature of the melanopsin-mediated persistent constriction phase of the pupillary light reflexmay 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. OBJECTIVE To characterize abnormalities of retinal architecture in patients with multiple sclerosis (MS) and corresponding alterations in the melanopsin-mediated sustained pupillary constriction response. DESIGN, SETTING, AND PARTICIPANTS The case-control studywas an experimental assessment of various stimulus-induced pupillary response characteristics and was conducted at a university clinical center forMS 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). MAIN OUTCOMES AND MEASURES Association of pupillary response characteristics with alterations in retinal architecture. RESULTS 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). CONCLUSIONS AND RELEVANCE 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.

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