Elsevier

Experimental Eye Research

Volume 91, Issue 5, November 2010, Pages 578-583
Experimental Eye Research

Evaluation of functional integrity of the retinohypothalamic tract in advanced glaucoma using multifocal electroretinography and light-induced melatonin suppression

https://doi.org/10.1016/j.exer.2010.07.012Get rights and content

Abstract

The aim of the study was to investigate the survival of melanopsin-expressing retinal ganglion cells (mRGCs) and the functional integrity of the retinohypothalamic tract in patients with bilateral advanced glaucomatous optic neuropathy by measuring the neuroendocrine light response of the pineal gland. Nine patients with bilateral advanced primary open-angle glaucoma (glaucoma group) and nine normal control subjects (control group) were included in this pilot observational, prospective, case-control study. The best-corrected visual acuity logMAR, standard automated perimetry mean deviation, and the retinal nerve fiber layer thickness determined by optical coherence tomography and multifocal electroretinography were used to evaluate the changes. Melatonin was analyzed in the saliva by radioimmunoassay before and after exposure to bright light (600 lux) for 60 min at night. The advanced glaucoma group did not have any significant nocturnal melatonin suppression after exposure to bright light (14.28 ± 3.07 pg/ml pre-light melatonin concentration vs. 15.22 ± 3.56 pg/ml after light exposure; p = 0.798) unlike the marked melatonin suppression in the control group (22.43 ± 4.37 pg/ml pre-light melatonin concentration vs. 11.25 ± 1.89 pg/ml after light exposure; p < 0.002). Response density estimates by the scalar product amplitude measure for the interval 0–80 ms of the first-order kernel responses were similar in both groups, indicating that outer retinal function was significantly unchanged in the glaucoma group (5.95 ± 0.54 nV/dg^2) compared with the control group (6.20 ± 0.22 nV/dg^2) (p = 0.689). Our findings are consistent with the interpretation that the rhythmic secretion of melatonin was affected in advanced glaucoma, suggesting that attention should be paid to non-image-forming visual functions, such as control of circadian rhythm and the clinical impact in patients with glaucoma.

Research highlights

►Retinal ganglion cells (RGC) damage in glaucoma might result in melanopsin-RGC death. ►Melanopsin-RGC death leads to the alteration of rhythmic secretion of melatonin. ►Loss of synchronization of circadian rhythms and recurrent insomnia might be established.

Introduction

The hypothalamic suprachiasmatic nucleus (SCN), the primary circadian oscillator in mammals, functions as a biologic clock (Klein et al., 1991). Light can phase-shift the endogenous oscillator in the SCN, synchronizing it with the environmental day–night cycle (Moore and Lenn, 1972, Hannibal et al., 2000). Recently, in mammalian eyes including humans, a subtype of retinal ganglion cells (RGCs) that expresses melanopsin has been reported to be intrinsically light sensitive independent of input from the rods and cones (Berson et al., 2002, Berson, 2003, Hattar et al., 2002, Foster and Bellingham, 2004). These cells may be the primary photoreceptors mediating the effects of light on the SCN circadian system (Provencio et al., 2000, Berson et al., 2002) via the retinohypothalamic tract (RHT) and contributes to non-visual photoreception. Non-visual photoreception includes photoentrainment of circadian cycles, photic suppression of activity, acute light-activated suppression of pineal melatonin secretion, and control of pupillary light responses (Ruby et al., 2002, Hattar et al., 2002, Hannibal et al., 2002, Gooley et al., 2001, Berson et al., 2002, Hankins and Lucas, 2002, Lucas et al., 2003, Panda et al., 2002). These non-visual functions are retained in blind subjects lacking a functional outer retina, confirming in humans the recent remarkable discovery of a novel photoreceptor system in the mammalian eye (Czeisler et al., 1995, Lockley et al., 1997, Klerman et al., 2002).

Glaucoma is the principal ophthalmic disease in which investigators are exploring whether light transmission to the SCN is compromised as a result of melanopsin retinal ganglion cells (mRGCs) loss. In severe cases, patients with glaucoma can lose up to 95% of their RGCs (Blumenthal and Weinreb, 2001, Haefliger et al., 2000). Severe visual loss and blindness due to advanced glaucomatous optic neuropathy may result in loss of synchronization of circadian rhythms and recurrent insomnia, since RGC damage in glaucoma might result in mRGC death. However, no conclusive evidence supports a cause-and-effect relationship between various ophthalmic diseases and circadian-rhythm functions (Leger et al., 1999, Sack et al., 1992, Tabandeh et al., 1998).

The synthesis and secretion of melatonin are inhibited by light and stimulated during darkness via the multisynaptic neural pathway that connects the retina through the SCN of the hypothalamus to the pineal gland (Klein and Moore, 1979, Webb and Puig-Domingo, 1995, Larsen et al., 1998). In humans, the pineal hormone melatonin has a distinct daily secretory pattern in which the circulating and salivary melatonin concentration is low during the day, abruptly increases close to habitual bedtime, remains high throughout the night, and decreases to low daytime levels close to the time of awakening. In normal subjects, retinal exposure to light produces short-term suppression of nighttime melatonin secretion in an intensity-dependent manner (Lewy et al., 1980, McIntyre et al., 1989).

In the current report, we analyzed the functional integrity of the RHT in patients with bilateral advanced glaucomatous optic neuropathy by measuring the neuroendocrine light response of the pineal gland. Retinal thickness was measured by optical coherence tomography (OCT) and photoreceptor function integrity was evaluated by multifocal electroretinography (mfERG) to validate if the outer retinal function is unchanged in patients with advanced glaucoma.

Section snippets

Study subjects

Nine patients with bilateral advanced primary open-angle glaucoma (POAG) (glaucoma group; mean age, 69.66 ± 2.46 years; range, 58–77 years) (Table 1) and nine normal control subjects (control group; mean age, 66.89 ± 2.71 years; range, 54–77 years) were selected for this prospective pilot observational, case-control study. For the purpose of this study, “advanced glaucoma” was considered as a combination of both an optic disc with a vertical cup-to-disc ratio of 0.9 or greater, marked rim

Results

The baseline ophthalmologic data for the glaucoma group is shown in Table 1. The follow-up time from POAG diagnosis in our case group was 11.96 ± 0.82 years (range, 8–15.3 years). Most eyes in the glaucoma group had trabeculectomy or deep sclerectomy surgery, and were under topical treatment with prostaglandins eye drops. The mean BCVA (0.37 ± 0.06) was significantly lower (p < 0.003) in the glaucoma group than in the control group (0.07 ± 0.01) due to selection of cases with very advanced

Discussion

In the present work, we showed that the pre-light melatonin levels in the glaucoma patients were lower but not significantly so from the pre-light melatonin levels in control subjects (p = 0.147). Moreover, patients with glaucoma did not have any significant (p = 0.798) suppression of nocturnal melatonin after exposure to bright light compared to the marked melatonin suppression in normal subjects (p < 0.002). These results could be interpreted as implying that the melatonin rhythm in the

Acknowledgements

This study was supported by the Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, the Spanish Ministerio de Educación y Ciencia (SAF2007-66175) to PdlV and Instituto de Salud Carlos III (RD07/0062/0008).

References (43)

  • E. Drouyer et al.

    Glaucoma alters the circadian timing system

    PLoS ONE

    (2008)
  • R.G. Foster et al.

    Inner retinal photoreceptors (IRPs) in mammals and teleost fish

    Photochem. Photobiol. Sci.

    (2004)
  • R.G. Foster et al.

    Circadian photoreception in the retinally degenerate mouse (rd/rd)

    J. Comp. Physiol.

    (1991)
  • M.S. Freedman et al.

    Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors

    Science

    (1999)
  • J.J. Gooley et al.

    Melanopsin in cells of origin of the retinohypothalamic tract

    Nat. Neurosci.

    (2001)
  • I.O. Haefliger et al.

    In glaucoma, should enthusiasm about neuroprotection be tempered by the experience obtained in other neurodegenerative disorders?

    Eye

    (2000)
  • J. Hannibal et al.

    The photopigment melanopsin is exclusively present in pituitary adenylate cyclase-activating polypeptide-containing retinal ganglion cells of the retinohypothalamic tract

    J. Neurosci.

    (2002)
  • J. Hannibal et al.

    PACAP and glutamate are co-stored in the retinohypothalamic tract

    J. Comp. Neurol.

    (2000)
  • S. Hattar et al.

    Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity

    Science

    (2002)
  • D.C. Klein et al.

    Suprachiasmatic Nucleus: The Mind’s Clock

    (1991)
  • E.B. Klerman et al.

    Photic resetting of the human circadian pacemaker in the absence of conscious vision

    J. Biol. Rhythms.

    (2002)
  • Cited by (45)

    • Suppression of Melatonin Secretion in Totally Visually Blind People by Ocular Exposure to White Light: Clinical Characteristics

      2018, Ophthalmology
      Citation Excerpt :

      A number of studies examining damage to the inner retina, including the ganglion cell layer, have shown mixed results.36–39 For example, one study has reported impaired melatonin suppression responses in patients with optic neuropathy due to glaucoma.37 The salivary melatonin suppression response to 60 minutes of 600-lux white LE was reportedly absent in grouped analyses of 9 patients with bilateral advanced primary open-angle glaucoma, but who retained visual light perception, compared with normally sighted controls who exhibited an approximately 50% suppression of melatonin.

    • Melanopsin-expressing retinal ganglion cells are resistant to cell injury, but not always

      2017, Mitochondrion
      Citation Excerpt :

      Moreover, there is consistent evidence that mRGCs are more resistant to injury such as axotomy and survive different paradigms of stress (Cui et al., 2015; Rovere et al., 2016) and metabolic dysfunction such as in mitochondrial optic neuropathies (La Morgia et al., 2010, 2011). However, in other pathological conditions such as Alzheimer's disease and glaucoma, these cells are affected (La Morgia et al., 2016; Drouyer et al., 2008; Pérez-Rico et al., 2010; Obara et al., 2016; Valiente-Soriano et al., 2015). In this paper, we will review this dichotomy, in addition to present unpublished data on the topic.

    • Marshall M. Parks Memorial Lecture: Ocular Motor Misbehavior in Children: Where Neuro-Ophthalmology Meets Strabismus

      2017, Ophthalmology
      Citation Excerpt :

      Intrinsically sensitive retinal ganglion cells have now been implicated in a number of other neurologic disorders,14 including the photophobia of migraine15 and in seasonal affective disorder (an OPN4 melanopsin gene mutation being found in some individuals with this condition).16 The melanopsin system tends to be relatively spared when mitochondrial disease affects the retina, but it is more severely affected in glaucomatous optic neuropathy, contributing to circadian dysfunction.17,18 As a side note, this recurrent theme of subcortical visual pathways coming to life when higher pathways fail to develop on time also underlies the ocular motor misbehavior in infantile nystagmus19 and infantile esotropia.20

    View all citing articles on Scopus
    View full text