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Progressive retinal ganglion cell loss in primary open-angle glaucoma is associated with temperature circadian rhythm phase delay and compromised sleep

01 янв января 2019

Background: Advanced primary open-angle glaucoma (POAG) is characterized by progressive retinal ganglion cell complex (RGCC) damage thatmay cause subsequent disruption of the circadian rhythms.

Therefore, we evaluated circadian body temperature (BT) rhythm and sleep characteristics of 115 individuals (38 men and 77 women) diagnosed with POAG.

GLV (global loss volume; %), a measure of RGCC damage, was
estimated by high-definition optical coherence tomography, and RGC functional ability was assessed by pattern electroretinogram amplitude (PERGA). Depending on dynamics of POAG progression criteria, two groups were formed that were distinctively different in GLV: Stable POAG group (S-POAG; GLV = 5.95 ± 1.84, n = 65) and Progressive POAG group (P-POAG; GLV = 24.27 ± 5.09, n = 50). S-POAG and P-POAG groupswere not different in mean age (67.61 ± 7.56 versus 69.98 ± 8.15) or body mass index (24.66 ± 3.03 versus 24.77 ± 2.90).


All subjects performed 21 around-the-clock BT self-measurements
during a 72-h period and kept activity/sleep diaries. Results showed pronounced disruption of circadian physiology in POAG and its progression with increasing severity of the disease. The dailymean of BT was unusually low, compared to age-matched controls.

Moreover, our results revealed distinctive features of
BT circadian rhythmalterations in POAG development and POAG progression. S-POAG is associated with lowered BT circadian rhythm robustness and inter-daily phase stability compared to controls. In the P-POAG group, the mean phase of the circadian BT rhythm was delayed by about 5 h and phases were highly scattered among individual patients, which led to reduced group mean amplitude. Circadian amplitudes of individuals were not different between the groups.


Altogether, these results suggest that the body clock stillworks in POAG patients, but its entrainment to the 24-h environment is compromised.
Probably because of the internal desynchronization, bedtime is delayed, and sleep duration is accordingly shortened by about 55 min in P-POAG compared to S-POAG patients. In the entire POAG cohort (both groups), later sleep phase and shorter mean sleep duration correlate with the delayed BT phase (r = 0.215; p = 0.021 and r = 0.322; p = 0.0004, respectively). An RGCC GLV of 15% apparently constitutes a threshold above which a delay of the circadian BT rhythm and a shortening of sleep duration occur.

   Introduction In mammals, including humans, circadian rhythms are generated by a central pacemaker system located in the suprachiasmatic nuclei (SCN) (Weaver 1998). Themain synchronizer, which entrains the endogenous rhythms to the 24-h environment is the lightdark (LD) cycle. The photic information is perceived by a subpopulation of retinal ganglion cells (RGCs), namely by intrinsically photosensitive RGCs (ipRGCs) (Berson et al. 2003; Panda et al. 2003,2002). The axons of these neurons form the retinohypothalamic tract (RHT), the main afferent pathway to the SCN (Freedman et al. 1999; Golombek and Rosenstein 2010; Markwell et al. 2010).

 Any damage of these neurons leads to an impairment of photic synchronization. Such circadian disruption has consequences for subjects´ performance and wellbeing and may cause several diseases (Escobar et al. 2011; Waterhouse and DeCoursey 2004; Vaze and Sharma 2013).Primary open-angle glaucoma (POAG) is a progressive optic neuropathy, one of the most common forms of glaucoma and the leading cause of irreversible blindness, estimated to affect 70 million people worldwide (Weinreb et al. 2014). POAG affects predominantly urban residents; its incidence is growing steadily and is expected to increase further (Tham et al. 2014).

 Though pathophysiology of POAG is not fully understood, mechanical stress due to elevated intraocular pressure (IOP) is related to progressive RGCs damage, dysfunction and death (Weinreb et al. 2014). Numerous studies have shown that glaucoma may affect also the number and the function of ipRGCs (Drouyer et al. 2008; Feigl et al. 2011). This mean that not only image forming vision is impaired in glaucoma patients, but also the transmission of the photic synchronizing signal to the central pacemaker, which has adverse consequences for photic synchronization and masking (Drouyer et al. 2008; Girardin et al. 2008; Göz et al. 2008).


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