SUPPRESSION OF MELATONIN SECRETION IN SOME BLIND PATIENTS BY EXPOSURE TO BRIGHT LIGHT

Background. Complete blindness generally results in the loss of synchronization of circadian rhythms to the 24-hour day and in recurrent insomnia. However, some blind patients maintain circadian entrainment. We undertook this study to determine whether some blind patients’ eyes convey sufficient photic information to entrain the hypothalamic circadian pacemaker and suppress melatonin secretion, despite an apparently complete loss of visual function. Methods. We evaluated the input of light to the circadian pacemaker by testing the ability of bright light to decrease plasma melatonin concentrations in 11 blind patients with no conscious perception of light and in 6 normal subjects. We also evaluated circadian entrainment over time in the blind patients. Results. Plasma melatonin concentrations decreased during exposure to bright light in three sightless patients by an average ( SD) of 69 21 percent and in the normal subjects by an average of 66 15 percent. When two of these blind patients were tested with their eyes covered during exposure to light, plasma melatonin did not decrease. The three blind patients reported no difficulty sleeping and maintained apparent circadian entrainment to the 24-hour day. Plasma melatonin concentrations did not decrease during exposure to bright light in seven of the remaining blind patients; in the eighth, plasma melatonin was undetectable. These eight patients reported a history of insomnia, and in four the circadian temperature rhythm was not entrained to the 24hour day. Conclusions. The visual subsystem that mediates the light-induced suppression of melatonin secretion remains functionally intact in some sightless patients. The absence of photic input to the circadian system thus constitutes a distinct form of blindness, associated with periodic insomnia, that afflicts most but not all patients with no conscious perception of light. (N Engl J Med 1995; 332:6-11.) From the Section on Sleep Disorders and Circadian Medicine, Division of Endocrinology, Department of Medicine, Harvard Medical School and Brigham and Women’s Hospital (C.A.C., T.L.S., E.B.K., H.M., D.J.B., J.S.E., T.K.); and the Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary (J.F.R.) — all in Boston. Address reprint requests to Dr. Czeisler at the Section on Sleep Disorders and Circadian Medicine, Division of Endocrinology, Department of Medicine, Harvard Medical School and Brigham and Women’s Hospital, 221 Longwood Ave., Boston, MA 02115. Supported in part by grants (NIA-1-P01-AG09975 and NIA-1-R01-AG06072) from the National Institute on Aging, a grant (NIMH-1-R01-MH45130) from the National Institute of Mental Health, a General Clinical Research Center grant (NCRR-GCRC-M01-RR02635) from the National Center for Research Resources, and a fellowship (NHLBI-5-T32-HL07609) from the National Heart, Lung, and Blood Institute (to Dr. Klerman). Dr. Czeisler has served as a consultant and principal scientific advisor to Light Sciences, Inc., Brookline, Mass. , and ShiftWork Systems, Inc., Cambridge, Mass. B LINDNESS afflicts more than 1 million Americans, 1 ⁄ 10 of whom have no conscious perception of light. 1 The eyes of these blind persons are typically assumed to serve only a cosmetic function. However, besides mediating the perception of images, ocular input of light synchronizes the hypothalamic circadian pacemaker that regulates many physiologic and behavioral processes. 2,3 Given the current understanding that light is the primary synchronizer of the circadian pacemaker, it is not surprising that in most totally blind persons the pacemaker is not synchronized with the 24-hour day. Instead, it oscillates around an intrinsic period of close to 24 hours. Therefore, despite maintaining regular schedules of sleep, work, and social contact, many totally blind people have cyclic bouts of insomnia as their circadian pacemakers move in and out of phase with the 24-hour day. 4-9 Some totally blind persons, however, remain synchronized to the 24-hour day. 6,7 Nonphotic time cues, once regarded as the principal circadian synchronizer in humans, 10 have been presumed to be the only cues available to entrain the circadian rhythms of such persons to the 24-hour day. 11 We hypothesized that unrecognized photic input may continue to synchronize the circadian pacemaker in some blind persons with entrained rhythms, even in the absence of conscious light perception and pupillary reflexes to light. To evaluate this hypothesis, we tested the functional integrity of the photic-entrainment pathway in a group of completely blind patients. 12 The retinohypothalamic tract conveys photic information from the retina to the hypothalamic circadian pacemaker, located in the suprachiasmatic nucleus. 13,14 Such photic entrainment is lost after bilateral transection of the optic nerve or the retinohypothalamic tract, whereas it persists after bilateral transection of the primary optic tract. 13,14 Photic information is conveyed from the suprachiasmatic nucleus to the pineal gland through a circuitous neural pathway, 13,15 resulting in the suppression of melatonin secretion. 16 We reasoned that even in blind persons, we could evaluate the retinal input of light to the suprachiasmatic nucleus by measuring the neuroendocrine response of the pineal gland, the end-organ in this pathway, as has been suggested. 17 In humans, the pineal gland is the source of circulating melatonin, 18 plasma concentrations of which are higher during the biologic night than during the day. Retinal exposure to light produces short-term suppression of nighttime melatonin secretion in sighted human subjects in an intensity-dependent manner. 19,20 Since the only known photic input governing melatonin synthesis in the mammalian pineal gland is The New England Journal of Medicine Downloaded from nejm.org at SAN DIEGO (UCSD) on November 6, 2015. For personal use only. No other uses without permission. Copyright © 1995 Massachusetts Medical Society. All rights reserved. Vol. 332 No. 1 SUPPRESSION OF MELATONIN BY BRIGHT LIGHT IN SOME BLIND PATIENTS 7 *Positive denotes a decrease in the average plasma melatonin concentration during the final hour of the bright-light exposure to 33 percent or more below the average concentration 24 hours