Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

The Associations of Obstructive Sleep Apnea and Eye Disorders: Potential Insights into Pathogenesis and Treatment

The Associations of Obstructive Sleep Apnea and Eye Disorders: Potential Insights into... Purpose of Review Obstructive sleep apnea (OSA) patients are at significantly increased risks for cardiovascular and cerebro- vascular morbidities. Recently, there has been heightened interest in the association of OSA with numerous ocular diseases and possible improvement of these conditions with the initiation of OSA treatment. We reviewed the current evidence with an emphasis on the overlapping pathogeneses of both diseases. Recent Findings Currently available literature points to a substantial association of OSA with ocular diseases, ranging from those involving the eyelid to optic neuropathies and retinal vascular diseases. Since the retina is one of the highest oxygen-consuming tissues in the body, the intermittent hypoxia and hypercapnia ensuing in OSA can have deleterious effects on ocular function and health. Tissue hypoxia, autonomic dysfunction, microvascular dysfunction, and inflammation all play important roles in the pathogenesis of both OSA and ocular diseases. Whether OSA treatment is capable of reversing the course of associated ocular diseases remains to be determined. It is anticipated that future therapeutic approaches will target the common underlying pathophysiologic mechanisms and promote favorable effects on the treatment of known associated ocular diseases. Summary Emerging evidence supports the association of ocular diseases with untreated OSA. Future studies focusing on whether therapeutic approaches targeting the common pathophysiologic mechanisms will be beneficial for the course of both diseases are warranted. . . . Keywords Obstructive sleep apnea Floppy eyelid syndrome Optic neuropathy Nonarteritic anterior ischemic optic neuropathy (NAION) Retinal vascular disease Introduction in the eye that may shed light on the pathogenesis of ocular disorders in the context of OSA. As we better understand the Within the past 5 years, there have been several excellent metabolic, immune, and biological attributes of OSA, it is published reviews addressing the relationship of obstructive worthwhile to revisit these associations in order to better un- sleep apnea (OSA) and ocular disorders [1, 2�� , 3]. During this derstand potential models for the pathogeneses of these ocular period, there has also been an intensification of the relation- conditions and to potentially identify therapeutic interven- ship of OSA with ocular disorders that has been inspired by tions that might impact their management. This review will new imaging technologies that can identify structural changes attempt to summarize the evidence for the associations of OSA and ocular disorders, the newer structural and func- tional parameters of eye disorders and vision that may be This article is part of the Topical Collection on Sleep and Health linked to OSA, and attempt to consider the underlying met- Disparities abolic, genetic, and structural mechanisms that may inform our understanding of both OSA and ocular conditions * Michael B. Gorin gorin@jsei.ucla.edu (Table 1). In some instances, we will consider shared etiol- ogies and risk factors, while for others, we will consider Department of Ophthalmology, Seoul National University College of how the alterations caused by OSA may directly influence Medicine and Seoul Metropolitan Government Seoul National ocular function and disease. This third segment of the pa- University Boramae Medical Center, Seoul, Korea per, based on peer-reviewed publications, is ultimately UCLA Stein Eye Institute, Division of Retinal Disorders and speculative but gives us some hints for future research di- Ophthalmic Genetics, Department of Ophthalmology, David Geffen rections and potential therapies. School of Medicine, UCLA, Los Angeles, CA, USA 66 Curr Sleep Medicine Rep (2021) 7:65–79 Table 1 Evidence for, or a lack Association with OSA Response to OSA of, associations with various therapy ocular diseases and obstructive sleep apnea (OSA) and responses Yes No Yes No to OSA therapy External and surface eye disease Floppy eyelid [4–15][16][17–19] Keratoconus [20, 21� , 22–25][26] Dry eyes [11, 27, 28][11][29][30] Optic neuropathy Primary open-angle glaucoma [31–40][5, 41–45][46][32] Normal-tension glaucoma [35–38, 40, 42, 47–50][39][50] Non-arteritic ischemic optic neuropathy [51–58][59] Retinal vascular disease Diabetic retinopathy [60–82][74][60, 67, 83–85][85] Retinal vein occlusion [86–93] Central serous chorioretinopathy [94–100] Age-related macular degeneration [45, 101][102] Definition of OSA, Age-Dependent common disturbance in tissue perfusion and oxygenation as well Differences, and Implications for Eye as potential metabolic derangements that promote coagulation Disorders disorders. One can make a case that similar processes could underlie the association of OSA with both primary open-angle Obstructive sleep apnea (OSA) is a subset of sleep-disordered glaucoma and normal-tension glaucoma. However, it is certain- breathing that is characterized by episodic sleep state– ly possible that structural changes in connective tissue that con- dependent upper airway collapse, resulting in periodic reduc- tribute to the intermittent loss of airway integrity could act as a tions or cessations in ventilation, with subsequent hypoxia, hy- shared risk factor for floppy eyelid syndrome (FES), and also percapnia, or arousals from sleep [103]. Risk factors for OSA result in increased optic nerve vulnerability to damage from are conditions that reduce the size of the resting pharynx or elevated intraocular pressures or compression in high myopes increase airway collapsibility such as obesity, male sex, persons [107, 108]. These mechanisms do not seem to offer a clear with hypothyroidism or acromegaly, increased tonsillar and explanation for the associations of OSA with central serous adenoid tissue, and certain craniofacial abnormalities [104]. chorioretinopathy (CSR). While CSR is also intimately related In terms of OSA prevalence and age, although there is a to abnormalities of the choroidal circulation and closely associ- gradual increase, prevalence tends to level off after 65 years ated with choroidal thickening (known as pachychoroid), the [105]. Geriatric patients exhibit more severe and deeper noctur- distinct clinical features of CSR, the focal or multifocal character nal intermittent hypoxia compared to young adults, indepen- with considerable ocular asymmetry, its intermittent acute flares dent of OSA severity which could be reflective of the already and spontaneous remissions, and associations with endogenous present chronic hypoxemic conditions, due to the physiologic cortisol or exogenous steroid exposure seem to be outside of aging process [106]. When we consider the association of OSA known OSA risk factors. Yet, the association of OSA with with ocular conditions, we have to consider if these relation- CSR is so clearly established that some clinicians have even ships are due to pleiotropic effects of shared risk factors (such as suggested that every patient with CSR undergo testing for anatomic features and common physiologic pathways) and/or if OSA regardless of clinical symptoms [94]. the metabolic and systemic effects of the OSA itself contributes There is one study that indicates that the clinical response as a risk factor for these conditions, as illustrated in Fig. 1. to anti-vascular endothelial growth factor (VEGF) injections for treating exudative age-related macular degeneration (AMD) is impacted by whether or not an OSA patient is treat- Association of OSA with Specific Ocular ed with continuous positive airway pressure (CPAP) [101]. If such a finding were to be replicated, it would suggest a very Conditions dynamic relationship between the physiologic changes during sleep and potential exacerbations of retinal hypoxia and The association of OSA with microvascular eye diseases, in- cluding non-arteritic ischemic neuropathy, retinal vein occlu- secondary elevations of VEGF in the retina/choroid. Given our lack of therapies to prevent or slow the progression of sion, and diabetic retinopathy, seems to be strengthened by a Curr Sleep Medicine Rep (2021) 7:65–79 67 Obstructive Sleep Apnea Ocular Disease Shared etiologies Disorders of airway Disorders of ocular adnexa basement membrane and connective tissue integrity, inflammation structure and ocular structures Tissue Laxity FES � vasodilation Mast cell disease Dry Eye � vasoconstriction POAG � dysregulation of ocular perfusion pressure acute events Disorders of ocular blood flow Consequences of PCA Recurrent PCA NAION OSA on local and hypopnea/apnea RAO RVO systemic circulation DR POAG CRV CRA chronic events Optic nerve Disorders of ocular metabolism and immune system Metabolic/Immune CSR Shared etiologies Derangements AMD mast cells, inflammatory cytokines, POAG circadian dysfunction Fig. 1 The pleiotropic effects of shared etiologies on both obstructive CRV, central retinal vein; CRA, central retinal artery; NAION, non- sleep apnea (OSA) and ocular diseases, and the acute/chronic effects of arteritic ischemic optic neuropathy; RAO, retinal artery occlusion; OSA on ocular blood flow. FES, floppy eyelid syndrome; POAG, RVO, retinal vein occlusion; DR, diabetic retinopathy; CSR, central primary open-angle glaucoma; PR, prelaminar region; LC, lamina serous chorioretinopathy; AMD, age-related macular degeneration cribrosa; R, retina; C, choroid; S, sclera; PCA, posterior ciliary artery; nonexudative AMD and the relatively high percentage of pa- applied to the pretarsal skin in a vertical direction and found a tients with exudative AMD who demonstrate only a partial vertical lidpullof15 to 25mmfor FESpatients, 7to16mmfor response to anti-VEGF therapies, it would be invaluable to OSA,and5to10mmfor age- andgender-matchedcontrols explore the potential impact of OSA treatment on this [10]. Robert et al. found increased eyelid hyperlaxity in OSA condition. patients, and Mojon et al. found positive correlation between Figure 2 summarizes the effects of OSA on various ocular respiratory disturbance index (RDI) and eyelid distraction dis- structures and associated ocular diseases. tance [11, 13]. However, Fox et al. recently performed a cross- sectional observational study with individuals referred for over- night polysomnography and found no association between the The Association of OSA with Structural presence of OSA and eyelid laxity [16]. The authors enrolled a large number of patients (201 individuals, 402 eyes) and and Functional Changes of the Eye and Vision attempted to employ validated quantitative measurements to objectively determine the presence of eyelid laxity. The lack Eyelid and Ocular Surface Morphology of a gold standard for assessing and the relatively subjective Ever since Gonnering and Sonneland first reported a patient methods with which previous studies investigated structural with both obstructive sleep apnea (OSA) and floppy eyelid eyelid change are all possible reasons for the discrepancy in syndrome (FES) in 1987 [7], there have been numerous papers these study results. Age and body mass index (BMI) are both looking at the association between the two diseases [4, 8–12, important factors associated with increased eyelid laxity and 14, 16](Fig. 3). Lid laxity quantification is important in deter- OSA and may possibly act as a confounding factor, but previ- mining the presence or absence of structural eyelid change and ous studies controlling for these factors nonetheless found an there have been several methods suggested, such as measuring association between FES and OSA [8, 10, 11]. The number of elastin fibers has been found to be markedly the “vertical lid pull,”“vertical hyperlaxity of the lid,” or simply “horizontal eyelid distraction distance” [10, 11, 13]. McNab decreased in FES patients with increased expression of matrix metalloproteinases implicated as a possible cause [109, 110]. measured the excursion of the upper lid margin from traction 68 Curr Sleep Medicine Rep (2021) 7:65–79 FES DR RVO elasn fiber AMD disorganizaon OSA hypercapnia Mast Cell Fig. 3 A patient with floppy eyelid syndrome. There is significant lid Dysfuncon hypoxemia eversion (white arrow) with mild upward traction demonstrating extensive lid laxity. (Image credit: Dr. Robert A. Goldberg, UCLA oxidave Stein Eye Institute) stress features of OSA, can impact FES directly. This may also be autonomic due to inflammatory factors that appear to improve with OSA dysfuncon therapy and may contribute to the OSA severity, as well as to the severity of the lid swelling and laxity. Ocular Structural Changes Ocular surface changes have also been studied in conjunc- Opc disc Choroid Cornea RNFL tion with eyelid laxity in OSA patients. One study found that choroidal choroidal Surface drying RNFL thinning although 52% of OSA patients had abnormal eye findings and thinning thickening RDI correlated negatively with tear film break-up time (TBUT), corneal abnormalities were found in only 4.5%, with symptoms of ocular irritation being rare [11]. Another study NAION DED CSR NTG conducted a more comprehensive study focusing specifically POAG on ocular surface changes occurring in OSA patients and found that moderate and severe OSA is associated with lower Fig. 2 Summary of the effects of OSA on various ocular structures and Schirmer and TBUT, high scores on the ocular surface disease associated ocular diseases. Hypercapnia, hypoxemia, oxidative stress, index questionnaire, and corneal staining pattern stage [112]. and autonomic dysfunction, as a result of OSA, contribute to the pathogeneses of various retinal vascular diseases such as diabetic retinopathy, retinal vein occlusion, and age-related macular Corneal Hysteresis degeneration. Ocular structural changes arising in association with OSA result in various ocular diseases according to the different tissues affected. OSA, obstructive sleep apnea; DR, diabetic retinopathy; RVO, retinal Normal human corneal thickness is about 500 μm and diurnal vein occlusion; AMD, age-related macular degeneration; FES, floppy variation is present with overnight swelling and resolution by eyelid syndrome; RNFL, retinal nerve fiber layer; DED, dry eye early afternoon, possibly arising from hypoxia created by lid disease; NAION, non-arteritic ischemic optic neuropathy; NTG, normal-tension glaucoma; POAG, primary open-angle glaucoma; CSR, closure [113]. Both hypoxic and hypercapnic environments central serous chorioretinopathy are known to affect corneal thickness with 7% swelling per hour observed in the normal human cornea [114]. One study Interestingly, elastin fiber network disorganization in the distal analyzed changes in corneal thickness with/without CPAP uvula was found to be associated with the apnea-hypopnea application in OSA patients using an ultrasonic pachymeter index (AHI) [111] and such pathologic tissue changes may be and found a significant corneal thickness increase in only the the common pathophysiology underlying both FES and OSA. without-CPAP group [115]. Another study looked at central Therapeutic approaches that could mitigate these structural corneal thickness (CCT), TBUT, and Schirmer’stest in OSA changes to the tissues would potentially benefit patients with patients according to severity defined by AHI scores [116]. either FES or OSA. However, a more functional interrelation- CCT was significantly decreased in OSA patients compared to ship between these two conditions has been suggested by sev- that in the control group, and as OSA severity increased, CCT eral studies that reported that FES improved in a group of OSA decreased in a stepwise manner (mean CCT 570 mm, 561 patients with successful use of CPAP [18, 19]. The not-so- mm, and 534 mm in mild, moderate, and severe OSA, respec- clear-cut effects of CPAP therapy and OSA-related surgery tively, p < 0.05). There were no significant differences in on FES suggest that both shared factors related to the structural TBUT or Schirmer’s test results among different OSA sever- integrity of the palate and lid tissues, as well as dynamic ity groups. Dikkaya et al. used an ocular response analyzer to Curr Sleep Medicine Rep (2021) 7:65–79 69 study corneal biochemical properties in OSA patients and Optic Nerve Vasculature: Non-arteritic Ischemic Optic showed significantly lower corneal hysteresis and resistance Neuropathy in the severe OSA group, which implies possible corneal bio- chemical changes in OSA, especially in the severe type [117]. The perfusion of the retina by the central retinal artery and its branches is crucial for the maintenance of the inner retinal neu- Optic Disc rons. The outer retinal layers, specifically the photoreceptor layer, derive their vascular and metabolic support from the Retinal ganglion cells (RGCs) are responsible for conveying choroidal circulation. Effective blood flow and oxygenation synaptic input initiated by a visual stimulus to the visual cortex are achieved by having sufficient perfusion pressure of the within the brain. Ganglion cell axons converge at the optic disc retinal vasculature to overcome the resistance caused by the and exit through the lamina cribrosa to form the optic nerve. intraocular pressure. Reductions in nocturnal blood pressure, Optic nerve examination, as well as examination of the in conjunction with the impairment of central retinal artery peripapillary retinal nerve fiber layers (RNFL), consisting of blood flow and/or elevated intraocular pressures, can lead to ganglion cell axons, is useful for investigating the presence of acute ischemic events such as NAION (Fig. 4) and, more rare- neuroaxonal degeneration, either anterograde or retrograde. ly, central retinal artery occlusions (CRAO) [130, 131]. Among OSA has been reported to be associated with various optic nerve 925 episodes of NAION, 73% of patients first reported visual diseases, such as non-arteritic anterior ischemic optic neuropa- symptoms after waking from sleep, and nocturnal arterial hy- thy (NAION), primary open-angle glaucoma, normal-tension potension showed a significant correlation with progressive glaucoma, and papilledema [118, 119� , 120� , 121–123]. visual field deterioration in NAION, altogether implying that Huseyinoglu et al. looked specifically at changes in optic nocturnal blood pressure depression may precipitate NAION disc parameters in OSA patients, such as optic disc area, cup development in patients having additional risk factors [132, area, cup volume, cup/disc area ratio, and nerve head volume, 133]. In OSA, the imbalance between nitric oxide and using OCT to obtain 12 radial scans and 13 concentric rings, endothelin results in reduced autoregulatory ability of the optic centered on the disc, but were unable to detect any significant nerve microcirculation to compensate for fluctuations in blood differences [118]. pressure and decreased blood oxygen saturation during apnea Studies related to optic neuropathy/glaucoma and OSA have may cause direct injury to the optic nerve head [134, 135]. Such suggested that the negative effects of OSA on RNFL and nerve structural and functional changes occurring in OSA could act as oxygenation may be reversed by CPAP. However, to date, IOP the additional risk factor tipping the fine balance of perfusion control is the only proven treatment for glaucoma and there is towards ischemia for patients at risk for NAION. Prospective yet no evidence that IOP can be altered by CPAP therapy. studies also reported the prevalence of OSA in NAION patients Oxidative stress and lower oxygenation could also be contrib- to be 55.6~89% in comparison to that of 18~22% in the general uting factors for ischemic optic neuropathy, which also has population or a control group, while a 12-year nationwide implications for diabetic retinopathy (which also seems to re- population-based retrospective cohort study found an increased spond to CPAP therapy but not always consistently) [83], as risk of developing NAION in the OSA group compared to the well as complications of retinal vein occlusion (RVO). non-OSA group (HR 3.80; 95% CI 1.46 to 9.90) even after Idiopathic intracranial hypertension (IIH), a syndrome of adjusting for demographics, comorbidities, and co- increased intracranial pressure (ICP) with unknown etiology, medications [136, 57, 53, 105, 119]. Hence, individuals who hasalsobeenreported tobeassociated withOSA [124–126]. have experienced an episode of NAION or a CRAO should be Intermittent ICP elevation is not infrequently observed in carefully questioned regarding a history of OSA-related symp- OSA, and Sugita et al. hypothesized this to be due to a com- toms and a formal sleep study should be considered, even if bination of factors such as increased central venous pressure other OSA comorbidities are not present. There is no evidence and subsequent cerebrovascular volume increase, systemic at this time that suggests that treatment of OSA will alter the arterial hypertension with secondary increased cerebral perfu- recovery of the eye from one of these acute ischemic events sion pressure and cerebral vasodilation due to hypoxia and [59] although nonadherence to CPAP treatment in patients with hypercapnia, and resulting intracranial blood volume increase both OSA and unilateral NAION was found to increase the risk [127, 128]. Since IIH and OSA share a common risk factor of of fellow eye involvement [51]. obesity, it remains to be determined whether OSA itself is a comorbidity or an independent risk factor for IIH. There was a Choroidal Layer report of IIH symptom resolution after surgery for OSA in a pediatric patient and optic disc swelling resolution was ob- Choroidal circulation has autonomic regulation, sharing regu- served after CPAP, but as with the association between OSA latory properties as that of cerebral blood flow [137]. and IIH, there is no consensus at this time as to whether OSA Alternating hypoxia and arousal occurring in OSA is thought treatment affects IIH [126, 128, 129]. to stimulate the sympathetic nervous system leading to an 70 Curr Sleep Medicine Rep (2021) 7:65–79 Fig. 4 A 66-year-old male non-arteritic ischemic optic neuropathy patient (b). Humphrey visual field testing showed inferior visual field defect presenting with vision blurring in the right eye. Disc photograph of the (black arrows) in the right eye (c) corresponding to the area of optic right eye (a) showed blurring (white arrowheads) of the superotemporal disc swelling, while the left eye showed normal visual field (d) optic disc margin compared to a normal-looking optic disc in the left eye increase in choroidal blood flow following hypercapnia and in vessel permeability, and choroidal thinning. One study used expression of hypoxia-inducible factor and vascular growth choroidal laser Doppler flowmetry to study choroidal vascular factors, resulting in vascular endothelium damage, changes reactivity in OSA men with a mean age of 50.9 years, having Curr Sleep Medicine Rep (2021) 7:65–79 71 no cardiovascular comorbidities, and found no impairments, role in CSR, the activation and degranulation of mast cells that i.e., hypercapnia-induced blood flow increase and stable cho- are resident within the choriocapillaris may be a reasonable roidal blood flow in hyperoxia, suggesting long-term adaptive connection with other known associations of CSR such as mechanisms coming into play in the ocular microcirculation stress or low-dose (not high-dose) steroid exposure and [138]. As with RNFL, numerous studies have found thinner OSA, which can also modulate the immune system and trigger choroidal thickness while others have found no difference in mast cell degranulation. This hypothesis that CSR may be OSA patients compared to controls, although a meta-analysis driven and triggered by mast cell accumulation and degranu- was able to confirm significant choroidal thickness reduction, lation, as well as local inflammation, would also be consistent especially in severe OSA [94, 139–143]. In terms of reversal with the purported role of mast cell accumulation and activa- of choroidal thickness changes after treatment, one study re- tion in floppy eyelid syndrome [163]. ported significant increases in choroidal thickness after 12 months of CPAP institution with possible improvements in Retinal Nerve Fiber Layer and Ganglion Cell Layer choroidal function [144]. Different modalities and analysis techniques used to assess choroidal blood flow may be one Numerous studies have reported significant reduction, while oth- of the underlying reasons for varied results in previous studies. er studies have found no difference in RNFL thickness in OSA The biological basis between CSR, in which a thickened patients compared to normal controls [118, 121–123, 164–173]. choroid is the most distinct characteristic, and OSA is perhaps Recently, numerous meta-analyses have been published, in the most complicated and unclear (Fig. 5). CSR does not appear which all found a significant reduction of average RNFL thick- to be triggered by topical, periocular, or intravitreal exposures ness in OSA patients [122, 123, 166, 167, 174]. Recurrent ob- to steroids, even though there are multiple reports of activation struction of airflow occurring in OSA, leading to repeated hyp- associated with systemic steroids, as well as from intra-articu- oxemia, hypercapnia, and reduced perfusion in the optic nerve, lar, intranasal, and inhalant exposures. This paradox highlights would most likely result in retinal ganglion cell apoptosis and the fact that the underlying mechanism of CSR is poorly un- subsequent retinal nerve fiber layer reduction [118, 121]. derstood. The relationship of CSR and OSA becomes an even Sleep disturbance is one of the most prevalent non-motor more intriguing target for study. There is no evidence that the symptoms in Parkinson’sdisease (PD) [175]. Rapid eye move- choriocapillaris is thicker in OSA patients, suggesting that this ment sleep behavior disorder (RBD), characterized by the loss of “pachychoroid” feature is relatively independent of OSA. It is normal atonia during rapid eye movement (REM) sleep, has been possible that the association of OSA and CSR is not with the implicated as a precursor to α-synucleinopathies such as demen- underlying pathology that is required to develop CSR but may tiawithLewybody(DLB) andPD[176]. Peripapillary RNFL be related to factors that cause acute activation and/or persis- thickness, as well as inner retinal thickness in the macular area, tence of active CSR [94, 139, 141, 145]. has been reported to be reduced in both PD and RBD [177–181]. The initial activation and recurrences of CSR have sug- Melanopsin-containing retinal ganglion cells (mRGCs) are a sub- gested the possibility of an infectious and/or inflammatory set of RGCs that also participate in non-image-forming functions etiology for this condition. There is an association of OSA such as circadian rhythm regulation or pupillary light reflex acti- with activation of herpes zoster in patients which has been vation [182, 183]. Their degeneration and impairment are one of suggested to be due to modulation of the immune system the pathways in which sleep disturbance is hypothesized to occur [146, 147]. An infectious etiology for CSR has been proposed in PD [184]. Neither PD nor RBD has any overlapping patho- with an association of Helicobacter pylori [148], though the genic mechanisms with OSA; however, both neurodegenerative natural history of recurrent episodes would require either re- diseases result in sleep disturbance and have ocular manifesta- activation of infection or sensitization of the choroid with tions both functionally and anatomically, as in OSA, and are inflammatory cells that continue to reside in the choroid, and examples of a sleep-associated disease, such as OSA, in which which are vulnerable to sporadic activation. Other studies ophthalmic examination may reveal more than meets the eye. have shown that H. pylori can both promote the accumulation and degranulation of mast cells in different tissues [149–154]. There are even several studies that have focused on the asso- Metabolic, Structural, Genetic Correlates that ciation of H. pylori itself with OSA. Whether such infectious May Underlie the Association of OSA etiologies play an important role in the pathophysiology of with Ocular Disorders OSA and its comorbidities is a topic that requires further in- vestigations [155–162]. Hypoxia Some investigators have suggested that CSR activation may be due to the degranulation of mast cells that are resident In vitro model of intermittent hypoxia (IH)/reoxygenation in the choriocapillaris, and this could certainly be triggered by shows activation of the pro-inflammatory transcription factor low-dose steroid exposure. Whether or not H. pylori plays a NFκB. Circulating tumor necrosis factor-α levels which were 72 Curr Sleep Medicine Rep (2021) 7:65–79 Fig. 5 A patient with central serous chorioretinopathy. Subretinal fluid (arrowheads) is evident on fundus photograph (a) of the right eye and horizontal optical coherence tomography scan (b) shows subretinal fluid with elevated retina and thickened choroid (double head arrows) significantly higher in OSA patients normalized after CPAP chorioretinopathy, and age-related macular degeneration. therapy, demonstrating that selective activation of inflamma- However, treatments that would alter these autonomic states tory pathways as a result of intermittent hypoxia in OSA may have not been explored as potential treatments for these ocular be one of the molecular pathways underlying macro/ conditions as of yet. microvascular diseases associated with OSA [185]. The pro- 1)Elevated catecholamines and muscle sympathetic nerve inflammatory nature of OSA could potentially play important activity during apnea as while awake roles in the pathophysiology of floppy eyelids, dry eyes, dia- 2)Activation of the renin-angiotensin-aldosterone system betic retinopathy, and age-related macular degeneration. 3)Differing vascular reactivity between OSA and controls 4)Changes in sympathetic and vascular reactivity with OSA treatment Autonomic Dysfunction 5)Animals exposed to intermittent hypoxia or apnea show the above observations. High sympathetic tone, increase in baseline heart rate, and elevated muscle sympathetic nerve activity are all commonly observed in OSA patients [186]. The following phenomena all Microvascular Changes come into play in OSA patients, and such changes may affect the choroidal vascular supply, which is mainly controlled by One study used OSA patient skin biopsies to identify molec- the autonomic nervous system, pathologic changes in which ular biomarkers involved in the vascular dysfunction of OSA could have an impact on diabetic retinopathy, central serous and found endothelial nitric oxide synthase (eNOS), tumor Curr Sleep Medicine Rep (2021) 7:65–79 73 necrosis factor-α–induced protein 3, hypoxia-inducible factor therapeutic interventions for OSA and the impact of those treat- 1 α, and vascular cell adhesion molecule 1 (VCAM-1) expres- ments on ocular anatomy and metabolic states can help us better sions to be significantly upregulated [187]. All of these factors understand how the amelioration of OSA in patients with these have also been implicated in the pathogenesis of diabetic ret- ocular conditions may offer an adjunct to our current therapies. inopathy, retinal vascular occlusive disease, and exudative forms of age-related macular degeneration [188–190]. However, there is yet no study that has considered the role Compliance with Ethical Standards of these factors in the combined context of OSA patients with Conflict of Interest The authors report no conflicts of interest. any of these retinal diseases. Human and Animal Rights and Informed Consent This article does not Oxidative Stress contain any studies with human or animal subjects performed by any of the authors. When rats were exposed to 14 days of IH, superoxide ion Open Access This article is licensed under a Creative Commons expression in the ophthalmic artery (OA) wall and OA con- Attribution 4.0 International License, which permits use, sharing, adap- tractile response to endothelin-1 both increased, and nitric tation, distribution and reproduction in any medium or format, as long as oxide–mediated relaxation was significantly delayed [191]. you give appropriate credit to the original author(s) and the source, pro- vide a link to the Creative Commons licence, and indicate if changes were This shows the induction of oxidative stress in rat OA by made. The images or other third party material in this article are included chronic IH, combined with endothelial cell and nitric oxide in the article's Creative Commons licence, unless indicated otherwise in a synthase dysfunction. Given the known vulnerabilities of the credit line to the material. If material is not included in the article's optic nerve, as well as the retina, to damage from oxidative Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain stress for many of the conditions that we know are associated permission directly from the copyright holder. To view a copy of this with OSA, we need to consider if agents that reduce oxidative licence, visit http://creativecommons.org/licenses/by/4.0/. stress might be potentially useful in a subset of OSA patients and have a clinical impact on the ocular conditions in these individuals. References Conclusions and Future Directions Papers of particular interest, published recently, have been We can see that the ocular associations with OSA likely involve highlighted as: both structural comorbidities such as collagen mutations that � Of importance affect the structural integrity of the airways and the eyelids, as �� Of major importance well as the activation of mast cells that place a role in the atopic aspects of many cases of floppy eyelid syndrome as well as dry 1. West SD, Turnbull C. Obstructive sleep apnoea. Eye (Lond). 2018;32(5):889–903. https://doi.org/10.1038/s41433-017-0006-y. eye manifestations. At the same time, this modulation of mast 2.�� Mentek M, Aptel F, Godin-Ribuot D, Tamisier R, Pepin JL, cells and/or cortisol in patients with OSA may contribute to the Chiquet C. Diseases of the retina and the optic nerve associated risk of activation of CSR. Elevated inflammatory factors that with obstructive sleep apnea. Sleep Med Rev. 2018;38:113–30. have been reported in OSA may contribute to both AMD and https://doi.org/10.1016/j.smrv.2017.05.003 Comprehensive diabetic retinopathy. Microvascular changes may also play a role review of the effect of obstructive sleep apnea on specifically the retina and optic disc. in the severity and progression of diabetic retinopathy. The 3. Grover DP. Obstructive sleep apnea and ocular disorders. Curr chronic, intermittent hypoxia of untreated OSA may play a role Opin Ophthalmol. 2010;21(6):454–8. https://doi.org/10.1097/ in patients’ visual dysfunction and may offer a potential means of ICU.0b013e32833f00dc. functionally monitoring these patients both before and in re- 4. Chambe J, Laib S, Hubbard J, Erhardt C, Ruppert E, Schroder C, et al. sponse to treatment. Central serous chorioretinopathy appears Floppy eyelid syndrome is associated with obstructive sleep apnoea: a prospective study on 127 patients. J Sleep Res. 2012;21(3):308–15. to be ameliorated by the treatment of OSA and may be related https://doi.org/10.1111/j.1365-2869.2011.00968.x. to either cortisol modulation and/or mast cell activation. These 5. Kadyan A, Asghar J, Dowson L, Sandramouli S. Ocular findings in hypothetical connections offer new opportunities to better under- sleep apnoea patients using continuous positive airway pressure. Eye stand both OSA and the ocular conditions that are influenced by (Lond). 2010;24(5):843–50. https://doi.org/10.1038/eye.2009.212. 6. Ezra DG, Beaconsfield M, Sira M, Bunce C, Wormald R, Collin this disorder. They offer potential, testable interventions to limit R. The associations of floppy eyelid syndrome: a case control the damage from a number of these eye conditions by either study. Ophthalmology. 2010;117(4):831–8. https://doi.org/10. treating the underlying OSA or the shared pathways that may 1016/j.ophtha.2009.09.029. be contributory (even in individuals without clinical evidence of 7. Gonnering RS, Sonneland PR. Meibomian gland dysfunction in floppy eyelid syndrome. Ophthalmic Plast Reconstr Surg. OSA). Using ocular imaging and visual function to assess 74 Curr Sleep Medicine Rep (2021) 7:65–79 1987;3(2):99–103. https://doi.org/10.1097/00002341- 24. Pihlblad MS, Schaefer DP. Eyelid laxity, obesity, and obstructive sleep apnea in keratoconus. Cornea. 2013;32(9):1232–6. https:// 198703020-00009. doi.org/10.1097/ICO.0b013e318281e755. 8. Karger RA, White WA, Park WC, Rosales AG, McLaren JW, Olson EJ, et al. Prevalence of floppy eyelid syndrome in obstructive sleep 25. Saidel MA, Paik JY, Garcia C, Russo P, Cao D, Bouchard C. apnea-hypopnea syndrome. Ophthalmology. 2006;113(9):1669–74. Prevalence of sleep apnea syndrome and high-risk characteristics https://doi.org/10.1016/j.ophtha.2006.02.053. among keratoconus patients. Cornea. 2012;31(6):600–3. https:// doi.org/10.1097/ICO.0b013e318243e446. 9. Leibovitch I, Selva D. Floppy eyelid syndrome: clinical features and the association with obstructive sleep apnea. Sleep Med. 26. Gencer B, Ozgurhan EB, Kara S, Tufan HA, Arikan S, Bozkurt E, 2006;7(2):117–22. https://doi.org/10.1016/j.sleep.2005.07.001. et al. Obesity and obstructive sleep apnea in patients with 10. McNab AA. Floppy eyelid syndrome and obstructive sleep apnea. keratoconus in a Turkish population. Cornea. 2014;33(2):137– Ophthalmic Plast Reconstr Surg. 1997;13(2):98–114. https://doi. 40. https://doi.org/10.1097/ICO.0000000000000024. org/10.1097/00002341-199706000-00005. 27. Galor A, Feuer W, Lee DJ, Florez H, Carter D, Pouyeh B, et al. Prevalence and risk factors of dry eye syndrome in a United States 11. Mojon DS, Goldblum D, Fleischhauer J, Chiou AG, Frueh BE, veterans affairs population. Am J Ophthalmol. 2011;152(3):377– Hess CW, et al. Eyelid, conjunctival, and corneal findings in sleep 84 e2. https://doi.org/10.1016/j.ajo.2011.02.026. apnea syndrome. Ophthalmology. 1999;106(6):1182–5. https:// doi.org/10.1016/S0161-6420(99)90256-7. 28. Lim EWL, Chee ML, Sabanayagam C, Majithia S, Tao Y, Wong TY, et al. Relationship between sleep and symptoms of tear dys- 12. Muniesa MJ, Huerva V, Sanchez-de-la-Torre M, Martinez M, Jurjo function in Singapore Malays and Indians. Invest Ophthalmol Vis C, Barbe F. The relationship between floppy eyelid syndrome and Sci. 2019;60(6):1889–97. https://doi.org/10.1167/iovs.19-26810. obstructive sleep apnoea. Br J Ophthalmol. 2013;97(11):1387–90. https://doi.org/10.1136/bjophthalmol-2012-303051. 29. Acar M, Firat H, Yuceege M, Ardic S. Long-term effects of PAP 13. Robert PY, Adenis JP, Tapie P, Melloni B. Eyelid hyperlaxity and on ocular surface in obstructive sleep apnea syndrome. Can J obstructive sleep apnea (O.S.A.) syndrome. Eur J Ophthalmol. Ophthalmol. 2014;49(2):217–21. https://doi.org/10.1016/j.jcjo. 1997;7(3):211–5. 2013.11.010. 30. Hayirci E, Yagci A, Palamar M, Basoglu OK, Veral A. The effect 14. Woog JJ. Obstructive sleep apnea and the floppy eyelid syndrome. of continuous positive airway pressure treatment for obstructive Am J Ophthalmol. 1990;110(3):314–5. https://doi.org/10.1016/ sleep apnea syndrome on the ocular surface. Cornea. 2012;31(6): s0002-9394(14)76357-3. 604–8. https://doi.org/10.1097/ICO.0b013e31824a2040. 15. Wang P, Yu DJ, Feng G, Long ZH, Liu CJ, Li H, et al. Is floppy 31. Muniesa M, Sanchez-de-la-Torre M, Huerva V, Lumbierres M, eyelid syndrome more prevalent in obstructive sleep apnea syn- Barbe F. Floppy eyelid syndrome as an indicator of the presence drome patients? J Ophthalmol. 2016;2016:6980281. https://doi. org/10.1155/2016/6980281. of glaucoma in patients with obstructive sleep apnea. J Glaucoma. 2014;23(1):e81 –5. https://doi.org/10.1097/IJG. 16. Fox TP, Schwartz JA, Chang AC, Parvin-Nejad FP, Yim CK, 0b013e31829da19f. Feinsilver SH, et al. Association between eyelid laxity and ob- structive sleep apnea. JAMA Ophthalmol. 2017;135(10):1055– 32. Cohen Y, Ben-Mair E, Rosenzweig E, Shechter-Amir D, Solomon 61. https://doi.org/10.1001/jamaophthalmol.2017.3263. AS. The effect of nocturnal CPAP therapy on the intraocular pres- sure of patients with sleep apnea syndrome. Graefes Arch Clin 17. Bayir O, Acar M, Yuksel E, Yuceege M, Saylam G, Tatar EC, Exp Ophthalmol. 2015;253(12):2263–71. https://doi.org/10. et al. The effects of anterior palatoplasty on floppy eyelid syn- 1007/s00417-015-3153-5. drome patients with obstructive sleep apnea. Laryngoscope. 33. Fan YY, Su WW, Liu CH, Chen HS, Wu SC, Chang SHL, et al. 2016;126(9):2171–5. https://doi.org/10.1002/lary.25905. Correlation between structural progression in glaucoma and ob- 18. McNab AA. Reversal of floppy eyelid syndrome with treatment of structive sleep apnea. Eye (Lond). 2019;33(9):1459–65. https:// obstructive sleep apnoea. Clin Exp Ophthalmol. 2000;28(2):125– doi.org/10.1038/s41433-019-0430-2. 6. https://doi.org/10.1046/j.1442-9071.2000.00278.x. 34. Chen HY, Chang YC, Lin CC, Sung FC, Chen WC. Obstructive 19. Vieira MJ, Silva MJ, Lopes N, Moreira C, Carvalheira F, Sousa sleep apnea patients having surgery are less associated with glau- JP. Prospective evaluation of floppy eyelid syndrome at baseline coma. J Ophthalmol. 2014;2014:838912. https://doi.org/10.1155/ and after CPAP therapy. Curr Eye Res. 2020:1–4. https://doi.org/ 2014/838912. 10.1080/02713683.2020.1776332. 35. Aptel F, Chiquet C, Tamisier R, Sapene M, Martin F, Stach B, 20. Gupta PK, Stinnett SS, Carlson AN. Prevalence of sleep apnea in et al. Association between glaucoma and sleep apnea in a large patients with keratoconus. Cornea. 2012;31(6):595–9. https://doi. French multicenter prospective cohort. Sleep Med. 2014;15(5): org/10.1097/ICO.0b013e31823f8acd. 576–81. https://doi.org/10.1016/j.sleep.2013.11.790. 21.� Arriola-Villalobos P, Benito-Pascual B, Peraza-Nieves J, Perucho- Gonzalez L, Sastre-Ibanez M, Dupre-Pelaez MG, et al. Corneal 36. Bendel RE, Kaplan J, Heckman M, Fredrickson PA, Lin SC. Prevalence of glaucoma in patients with obstructive sleep topographic, anatomic, and biomechanical properties in severe obstructive sleep apnea-hypopnea syndrome. Cornea. apnoea–a cross-sectional case-series. Eye (Lond). 2008;22(9): 2020;39(1):88 –91. https://doi.org/10.1097/ICO. 1105–9. https://doi.org/10.1038/sj.eye.6702846. 0000000000002102 Comprehensive analysis of the corneal 37. Hashim SP, Al Mansouri FA, Farouk M, Al Hashemi AA, Singh topographic, anatomic, and biomechanical properties in R. Prevalence of glaucoma in patients with moderate to severe severe obstructive sleep apnea patients. obstructive sleep apnea: ocular morbidity and outcomes in a 3 year follow-up study. Eye (Lond). 2014;28(11):1304–9. https://doi. 22. Pedrotti E, Demasi CL, Fasolo A, Bonacci E, Brighenti T, Gennaro org/10.1038/eye.2014.195. N, et al. Obstructive sleep apnea assessed by overnight polysomnography in patients with keratoconus. Cornea. 2018;37(4): 38. Lin CC, Hu CC, Ho JD, Chiu HW, Lin HC. Obstructive sleep 470–3. https://doi.org/10.1097/ICO.0000000000001509. apnea and increased risk of glaucoma: a population-based matched-cohort study. Ophthalmology. 2013;120(8):1559–64. 23. Naderan M, Rezagholizadeh F, Zolfaghari M, Naderan M, Rajabi https://doi.org/10.1016/j.ophtha.2013.01.006. MT, Kamaleddin MA. Association between the prevalence of obstructive sleep apnoea and the severity of keratoconus. Br J 39. Wu X, Liu H. Obstructive sleep apnea/hypopnea syndrome in- Ophthalmol. 2015;99(12):1675–9. https://doi.org/10.1136/ creases glaucoma risk: evidence from a meta-analysis. Int J Clin bjophthalmol-2015-306665. Exp Med. 2015;8(1):297–303. Curr Sleep Medicine Rep (2021) 7:65–79 75 40. Perez-Rico C, Gutierrez-Diaz E, Mencia-Gutierrez E, Diaz-de- 55. Wu Y, Zhou LM, Lou H, Cheng JW, Wei RL. The association between obstructive sleep apnea and nonarteritic anterior ischemic Atauri MJ, Blanco R. Obstructive sleep apnea-hypopnea syn- drome (OSAHS) and glaucomatous optic neuropathy. Graefes optic neuropathy: a systematic review and meta-Analysis. Curr Arch Clin Exp Ophthalmol. 2014;252(9):1345–57. https://doi. Eye Res. 2016;41(7):987–92. https://doi.org/10.3109/02713683. org/10.1007/s00417-014-2669-4. 2015.1075221. 41. Cabrera M, Benavides AM, Hallaji NAE, Chung SA, Shapiro 56. Stein JD,Kim DS,Mundy KM,Talwar N,Nan B,ChervinRD, et al. CM, Trope GE, et al. Risk of obstructive sleep apnea in open- The association between glaucomatous and other causes of optic neu- angle glaucoma versus controls using the STOP-Bang question- ropathy and sleep apnea. Am J Ophthalmol. 2011;152(6):989–98 e3. naire. Can J Ophthalmol. 2018;53(1):76–80. https://doi.org/10. https://doi.org/10.1016/j.ajo.2011.04.030. 1016/j.jcjo.2017.07.008. 57. Mojon DS, Hedges TR 3rd, Ehrenberg B, Karam EZ, Goldblum 42. Bagabas N, Ghazali W, Mukhtar M, AlQassas I, Merdad R, D, Abou-Chebl A, et al. Association between sleep apnea syn- Maniyar A, et al. Prevalence of glaucoma in patients with obstruc- drome and nonarteritic anterior ischemic optic neuropathy. Arch tive sleep apnea. J Epidemiol Glob Health. 2019;9(3):198–203. Ophthalmol. 2002;120(5):601–5. https://doi.org/10.1001/ https://doi.org/10.2991/jegh.k.190816.001. archopht.120.5.601. 43. Salzgeber R, Iliev ME, Mathis J. Do optic nerve head and visual 58. Sun MH, Lee CY, Liao YJ, Sun CC. Nonarteritic anterior ischae- field parameters in patients with obstructive sleep apnea syndrome mic optic neuropathy and its association with obstructive sleep differ from those in control individuals? Klin Monatsbl apnoea: a health insurance database study. Acta Ophthalmol. Augenheilkd. 2014;231(4):340–3. https://doi.org/10.1055/s- 2019;97(1):e64–70. https://doi.org/10.1111/aos.13832. 0034-1368260. 59. Behbehani R, Mathews MK, Sergott RC, Savino PJ. Nonarteritic 44. Wozniak D, Bourne R, Peretz G, Kean J, Willshire C, Harun S, et al. anterior ischemic optic neuropathy in patients with sleep apnea Obstructive sleep apnea in patients with primary-open angle glauco- while being treated with continuous positive airway pressure. ma: no role for a screening program. J Glaucoma. 2019;28(8):668–75. Am J Ophthalmol. 2005;139(3):518–21. https://doi.org/10.1016/ https://doi.org/10.1097/IJG.0000000000001296. j.ajo.2004.11.004. 45. Keenan TD, Goldacre R, Goldacre MJ. Associations between ob- 60. Altaf QA, Dodson P, Ali A, Raymond NT, Wharton H, Fellows structive sleep apnoea, primary open angle glaucoma and age- H, et al. Obstructive sleep apnea and retinopathy in patients with related macular degeneration: record linkage study. Br J type 2 diabetes. A Longitudinal Study. Am J Respir Crit Care Ophthalmol. 2017;101(2):155–9. https://doi.org/10.1136/ Med. 2017;196(7):892–900. https://doi.org/10.1164/rccm. bjophthalmol-2015-308278. 201701-0175OC. 46. Himori N, Ogawa H, Ichinose M, Nakazawa T. CPAP therapy 61. Chang AC, Fox TP, Wang S, Wu AY. Relationship between ob- reduces oxidative stress in patients with glaucoma and OSAS structive sleep apnea and the presence and severity of diabetic and improves the visual field. Graefes Arch Clin Exp retinopathy. Retina. 2018;38(11):2197–206. https://doi.org/10. Ophthalmol. 2020;258(4):939–41. https://doi.org/10.1007/ 1097/IAE.0000000000001848. s00417-019-04483-z. 62. Chew M, Tan NYQ, Lamoureux E, Cheng CY, Wong TY, 47. Lin PW, Friedman M, Lin HC, Chang HW, Wilson M, Lin MC. Sabanayagam C. The associations of objectively measured sleep Normal tension glaucoma in patients with obstructive sleep apnea/ duration and sleep disturbances with diabetic retinopathy. hypopnea syndrome. J Glaucoma. 2011;20(9):553–8. https://doi. Diabetes Res Clin Pract. 2020;159:107967. https://doi.org/10. org/10.1097/IJG.0b013e3181f3eb81. 1016/j.diabres.2019.107967. 48. Sergi M, Salerno DE, Rizzi M, Blini M, Andreoli A, Messenio D, 63. Du C, He C, Dong L, Zheng S, Wang W, Zheng C, et al. Associations et al. Prevalence of normal tension glaucoma in obstructive sleep of apnea hypopnea index and educational attainments with microvas- apnea syndrome patients. J Glaucoma. 2007;16(1):42–6. https:// cular complications in patients with T2DM. Endocrine. 2020;67(2): doi.org/10.1097/01.ijg.0000243472.51461.24. 363–73. https://doi.org/10.1007/s12020-020-02192-w. 49. Bilgin G. Normal-tension glaucoma and obstructive sleep apnea 64. Zhang R, Zhang P, Zhao F, Han X, Ji L. Association of diabetic syndrome: a prospective study. BMC Ophthalmol. 2014;14:27. microvascular complications and parameters of obstructive sleep https://doi.org/10.1186/1471-2415-14-27. apnea in patients with type 2 diabetes. Diabetes Technol Ther. 2016;18(7):415–20. https://doi.org/10.1089/dia.2015.0433. 50. Kremmer S, Selbach JM, Ayertey HD, Steuhl KP. Normal tension glaucoma, sleep apnea syndrome and nasal continuous positive 65. Zhu Z, Zhang F, Liu Y, Yang S, Li C, Niu Q, et al. Relationship of airway pressure therapy–case report with a review of literature. obstructive sleep apnoea with diabetic retinopathy: a meta-analy- Klin Monatsbl Augenheilkd. 2001;218(4):263–8. https://doi.org/ sis. Biomed Res Int. 2017;2017:4737064. https://doi.org/10.1155/ 10.1055/s-2001-14923. 2017/4737064. 51. Aptel F, Khayi H, Pepin JL, Tamisier R, Levy P, Romanet JP, et al. 66. Vie AL, Kodjikian L, Agard E, Voirin N, El Chehab H, Denis P, Association of nonarteritic ischemic optic neuropathy with obstructive et al. Evaluation of obstructive sleep apnea syndrome as a risk sleep apnea syndrome: consequences for obstructive sleep apnea factor for diabetic macular edema in patients with type II diabetes. screening and treatment. JAMA Ophthalmol. 2015;133(7):797–804. Retina. 2019;39(2):274–80. https://doi.org/10.1097/IAE. https://doi.org/10.1001/jamaophthalmol.2015.0893. 0000000000001954. 52. Berry S, Lin WV, Sadaka A, Lee AG. Nonarteritic anterior ische- 67. Smith JP, Cyr LG, Dowd LK, Duchin KS, Lenihan PA, Sprague J. mic optic neuropathy: cause, effect, and management. Eye Brain. The Veterans Affairs continuous positive airway pressure use and 2017;9:23–8. https://doi.org/10.2147/EB.S125311. diabetic retinopathy study. Optom Vis Sci. 2019;96(11):874–8. https://doi.org/10.1097/OPX.0000000000001446. 53. Bilgin G, Koban Y, Arnold AC. Nonarteritic anterior ischemic optic neuropathy and obstructive sleep apnea. J 68. Shiba T, Takahashi M, Matsumoto T, Hori Y. Sleep-disordered Neuroophthalmol. 2013;33(3):232–4. https://doi.org/10.1097/ breathing is a stronger risk factor for proliferative diabetic retinop- WNO.0b013e31828eecbd. athy than metabolic syndrome and the number of its individual components. Semin Ophthalmol. 2019;34(2):59–65. https://doi. 54. Chang MY, Keltner JL. Risk factors for fellow eye involvement in org/10.1080/08820538.2019.1569074. nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol. 2019;39(2):147–52. https://doi.org/10.1097/ 69. Tan NYQ, Chew M, Tham YC, Nguyen QD, Yasuda M, Cheng WNO.0000000000000715. CY, et al. Associations between sleep duration, sleep quality and 76 Curr Sleep Medicine Rep (2021) 7:65–79 diabetic retinopathy. PLoS One. 2018;13(5):e0196399. https:// 85. West SD, Prudon B, Hughes J, Gupta R, Mohammed SB, Gerry S, et al. Continuous positive airway pressure effect on visual acuity doi.org/10.1371/journal.pone.0196399. 70. Leong WB, Jadhakhan F, Taheri S, Chen YF, Adab P, Thomas in patients with type 2 diabetes and obstructive sleep apnoea: a multicentre randomised controlled trial. Eur Respir J. 2018;52(4). GN. Effect of obstructive sleep apnoea on diabetic retinopathy and maculopathy: a systematic review and meta-analysis. Diabet Med. https://doi.org/10.1183/13993003.01177-2018. 2016;33(2):158–68. https://doi.org/10.1111/dme.12817. 86. Agard E, El Chehab H, Vie AL, Voirin N, Coste O, Dot C. Retinal 71. He M, Huang W. The role of choroidal thickness in diabetic reti- vein occlusion and obstructive sleep apnea: a series of 114 pa- nopathy and obstructive sleep apnea syndrome. Sleep Breath. tients. Acta Ophthalmol. 2018;96(8):e919–e25. https://doi.org/ 2016;20(3):1009–10. https://doi.org/10.1007/s11325-016-1343-y. 10.1111/aos.13798. 72. Baba A, Zbiba W, Bouayed E, Korbi M, Ghrairi H. Obstructive 87. Govetto A, Dominguez R, Rojas L, Pereiro M, Lorente R. Bilateral sleep apnea syndrome. Is it a risk factor for diabetic retinopathy? J and simultaneous central retinal vein occlusion in a patient with ob- Fr Ophtalmol. 2016;39(2):139–42. https://doi.org/10.1016/j.jfo. structive sleep apnea syndrome. Case Rep Ophthalmol. 2014;5(2): 2015.08.014. 150–6. https://doi.org/10.1159/000363132. 73. Nishimura A, Kasai T, Tamura H, Yamato A, Yasuda D, 88. Turati M, Velez-Montoya R, Gonzalez-Mijares CC, Perez- Nagasawa K, et al. Relationship between sleep disordered breath- Montesinos A, Quiroz-Mercado H, Garcia-Aguirre G. Bilateral ing and diabetic retinopathy: analysis of 136 patients with diabe- central retina vein occlusion associated with obesity- tes. Diabetes Res Clin Pract. 2015;109(2):306–11. https://doi.org/ hypoventilation syndrome (pickwickian syndrome). Retin Cases 10.1016/j.diabres.2015.05.015. Brief Rep. 2009;3(2):140–3. https://doi.org/10.1097/ICB. 74. Banerjee D, Leong WB, Arora T, Nolen M, Punamiya V, 0b013e31815e9919. Grunstein R, et al. The potential association between obstructive 89. Kwon HJ, Kang EC, Lee J, Han J, Song WK. Obstructive sleep sleep apnea and diabetic retinopathy in severe obesity-the role of apnea in patients with branch retinal vein occlusion: a preliminary hypoxemia. PLoS One. 2013;8(11):e79521. https://doi.org/10. study. Korean J Ophthalmol. 2016;30(2):121–6. https://doi.org/ 1371/journal.pone.0079521. 10.3341/kjo.2016.30.2.121. 75. Rudrappa S, Warren G, Idris I. Obstructive sleep apnoea is asso- 90. Kanai H, Shiba T, Hori Y, Saishin Y, Maeno T, Takahashi M. ciated with the development and progression of diabetic retinopa- Prevalence of sleep-disordered breathing in patients with retinal thy, independent of conventional risk factors and novel bio- vein occlusion. Nippon Ganka Gakkai Zasshi. 2012;116(2):81–5. markers for diabetic retinopathy. Br J Ophthalmol. 2012;96(12): 91. Chou KT, Huang CC, Tsai DC, Chen YM, Perng DW, Shiao GM, 1535. https://doi.org/10.1136/bjophthalmol-2012-301991. et al. Sleep apnea and risk of retinal vein occlusion: a nationwide 76. Mason RH, West SD, Kiire CA, Groves DC, Lipinski HJ, Jaycock population-based study of Taiwanese. Am J Ophthalmol. A, et al. High prevalence of sleep disordered breathing in patients 2012;154(1):200–5e1. https://doi.org/10.1016/j.ajo.2012.01.011. with diabetic macular edema. Retina. 2012;32(9):1791–8. https:// 92. Glacet-Bernard A. Leroux les Jardins G, Lasry S, Coscas G, doi.org/10.1097/IAE.0b013e318259568b. Soubrane G, Souied E et al. Obstructive sleep apnea among patients 77. Shiba T, Takahashi M, Hori Y, Saishin Y, Sato Y, Maeno T. with retinal vein occlusion. Arch Ophthalmol. 2010;128(12):1533– Relationship between sleep-disordered breathing and iris and/or 8. https://doi.org/10.1001/archophthalmol.2010.272. angle neovascularization in proliferative diabetic retinopathy 93. Leroux les Jardins G, Glacet Bernard A, Lasry S, Housset B, cases. Am J Ophthalmol. 2011;151(4):604–9. https://doi.org/10. Coscas G, Soubrane G. Retinal vein occlusion and obstructive 1016/j.ajo.2010.10.002. sleep apnea syndrome. J Fr Ophtalmol. 2009;32(6):420–4. 78. Shiba T, Takahashi M, Hori Y, Saishin Y, Sato Y, Maeno T. https://doi.org/10.1016/j.jfo.2009.04.012. Evaluation of the relationship between background factors and 94. Wu CY, Riangwiwat T, Rattanawong P, Nesmith BLW, sleep-disordered breathing in patients with proliferative diabetic Deobhakta A. Association of obstructive sleep apnea with central retinopathy. Jpn J Ophthalmol. 2011;55(6):638–42. https://doi. serous chorioretinopathy and choroidal thickness: a systematic org/10.1007/s10384-011-0076-5. review and meta-analysis. Retina. 2018;38(9):1642–51. https:// 79. West SD, Groves DC, Lipinski HJ, Nicoll DJ, Mason RH, doi.org/10.1097/IAE.0000000000002117. Scanlon PH, et al. The prevalence of retinopathy in men with type 95. Brodie FL, Charlson ES, Aleman TS, Salvo RT, Gewaily DY, Lau 2 diabetes and obstructive sleep apnoea. Diabet Med. 2010;27(4): MK, et al. Obstructive sleep apnea and central serous 423–30. https://doi.org/10.1111/j.1464-5491.2010.02962.x. chorioretinopathy. Retina. 2015;35(2):238–43. https://doi.org/10. 80. Shiba T, Maeno T, Saishin Y, Hori Y, Takahashi M. Nocturnal 1097/IAE.0000000000000326. intermittent serious hypoxia and reoxygenation in proliferative 96. Chang YS, Weng SF, Wang JJ, Jan RL. Increased risk of central diabetic retinopathy cases. Am J Ophthalmol. 2010;149(6):959– serous chorioretinopathy following end-stage renal disease: a nation- 63. https://doi.org/10.1016/j.ajo.2010.01.006. wide population-based study. Medicine (Baltimore). 2019;98(11): 81. Kosseifi S, Bailey B, Price R, Roy TM, Byrd RP Jr, Peiris AN. The e14859. https://doi.org/10.1097/MD.0000000000014859. association between obstructive sleep apnea syndrome and microvas- 97. Chatziralli I, Kabanarou SA, Parikakis E, Chatzirallis A, Xirou T, cular complications in well-controlled diabetic patients. Mil Med. Mitropoulos P. Risk factors for central serous chorioretinopathy: mul- 2010;175(11):913–6. https://doi.org/10.7205/milmed-d-10-00131. tivariate approach in a case-control study. Curr Eye Res. 2017;42(7): 82. Shiba T, Sato Y, Takahashi M. Relationship between diabetic 1069–73. https://doi.org/10.1080/02713683.2016.1276196. retinopathy and sleep-disordered breathing. Am J Ophthalmol. 98. Kloos P, Laube I, Thoelen A. Obstructive sleep apnea in patients 2009;147(6):1017–21. https://doi.org/10.1016/j.ajo.2008.12.027. with central serous chorioretinopathy. Graefes Arch Clin Exp 83. Mason RH, Kiire CA, Groves DC, Lipinski HJ, Jaycock A, Winter Ophthalmol. 2008;246(9):1225–8. https://doi.org/10.1007/ BC, et al. Visual improvement following continuous positive airway s00417-008-0837-0. pressure therapy in diabetic subjects with clinically significant macular 99. Leveque TK, Yu L, Musch DC, Chervin RD, Zacks DN. Central oedema and obstructive sleep apnoea: proof of principle study. Respiration. 2012;84(4):275–82. https://doi.org/10.1159/000334090. serous chorioretinopathy and risk for obstructive sleep apnea. Sleep Breath. 2007;11(4):253–7. https://doi.org/10.1007/s11325- 84. Raman R, Verma A, Srinivasan S, Bhojwani D. Partial reversal of 007-0112-3. color vision impairment in type 2 diabetes associated with obstruc- tive sleep apnea. GMS Ophthalmol Cases. 2018;8:Doc05. https:// 100. Yavas GF, Kusbeci T, Kasikci M, Gunay E, Dogan M, Unlu M, doi.org/10.3205/oc000087. et al. Obstructive sleep apnea in patients with central serous Curr Sleep Medicine Rep (2021) 7:65–79 77 chorioretinopathy. Curr Eye Res. 2014;39(1):88–92. https://doi. syndrome. Eye Contact Lens. 2018;44(Suppl 2):S361–S4. org/10.3109/02713683.2013.824986. https://doi.org/10.1097/ICL.0000000000000489. 101. Nesmith BL, Ihnen M, Schaal S. Poor responders to bevacizumab 118. Huseyinoglu N, Ekinci M, Ozben S, Buyukuysal C, Kale MY, pharmacotherapy in age-related macular degeneration and in dia- Sanivar HS. Optic disc and retinal nerve fiber layer parameters betic macular edema demonstrate increased risk for obstructive as indicators of neurodegenerative brain changes in patients with sleep apnea. Retina. 2014;34(12):2423–30. https://doi.org/10. obstructive sleep apnea syndrome. Sleep Breath. 2014;18(1):95– 1097/IAE.0000000000000247. 102. https://doi.org/10.1007/s11325-013-0854-z. 102. Schaal S, Sherman MP, Nesmith B, Barak Y. Untreated obstruc- 119.� Yang HK, Park SJ, Byun SJ, Park KH, Kim JW, Hwang JM. tive sleep apnea hinders response to bevacizumab in age-related Obstructive sleep apnoea and increased risk of non-arteritic ante- macular degeneration. Retina. 2016;36(4):791–7. https://doi.org/ rior ischaemic optic neuropathy. Br J Ophthalmol. 2019;103(8): 10.1097/IAE.0000000000000981. 1123–8. https://doi.org/10.1136/bjophthalmol-2018-312910 A 103. Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP. nationwide population-based, retrospective cohort study Pathophysiology of sleep apnea. Physiol Rev. 2010;90(1):47– showing increased risk of NAION in the OSA group. 112. https://doi.org/10.1152/physrev.00043.2008. 120.� SSY L, McArdle N, Sanfilippo PG, Yazar S, Eastwood PR, Hewitt AW, et al. Associations between optic disc measures and obstruc- 104. Veasey SC, Rosen IM. Obstructive sleep apnea in adults. N Engl J tive sleep apnea in young adults. Ophthalmology. 2019;126(10): Med. 2019;380(15):1442–9. https://doi.org/10.1056/ 1372–84. https://doi.org/10.1016/j.ophtha.2019.04.041 NEJMcp1816152. Preclinical peripapillary RNFL thinning was present in 105. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive young adults with obstructive sleep apnea suggesting possible sleep apnea: a population health perspective. Am J Respir Crit increased glaucoma risk in these patients. Care Med. 2002;165(9):1217–39. https://doi.org/10.1164/rccm. 2109080. 121. Shiba T, Takahashi M, Sato Y, Onoda Y, Hori Y, Sugiyama T, et al. Relationship between severity of obstructive sleep apnea 106. Bostanci A, Bozkurt S, Turhan M. Impact of age on intermittent syndrome and retinal nerve fiber layer thickness. Am J hypoxia in obstructive sleep apnea: a propensity-matched analysis. Ophthalmol. 2014;157(6):1202–8. https://doi.org/10.1016/j.ajo. Sleep Breath. 2018;22(2):317–22. https://doi.org/10.1007/ 2014.01.028. s11325-017-1560-z. 122. Wang W, He M, Huang W. Changes of retinal nerve fiber layer 107. Clark RA, Suh SY, Caprioli J, Giaconi JA, Nouri-Mahdavi K, Law thickness in obstructive sleep apnea syndrome: a systematic re- SK, et al. Adduction-induced strain on the optic nerve in primary open view and meta-analysis. Curr Eye Res. 2017;42(5):796–802. angle glaucoma at normal intraocular pressure. Curr Eye Res. 2020:1– https://doi.org/10.1080/02713683.2016.1238942. 11. https://doi.org/10.1080/02713683.2020.1817491. 123. Yu JG, Mei ZM, Ye T, Feng YF, Zhao F, Jia J, et al. Changes in 108. Li Y, Wei Q, Le A, Gawargious BA, Demer JL. Rectus retinal nerve fiber layer thickness in obstructive sleep apnea/ extraocular muscle paths and staphylomata in high myopia. Am hypopnea syndrome: a meta-analysis. Ophthalmic Res. J Ophthalmol. 2019;201:37–45. https://doi.org/10.1016/j.ajo. 2016;56(2):57–67. https://doi.org/10.1159/000444301. 2019.01.029. 124. Friedman DI, Jacobson DM. Diagnostic criteria for idiopathic in- 109. Netland PA, Sugrue SP, Albert DM, Shore JW. Histopathologic tracranial hypertension. Neurology. 2002;59(10):1492–5. https:// features of the floppy eyelid syndrome. involvement of tarsal elas- doi.org/10.1212/01.wnl.0000029570.69134.1b. tin. Ophthalmology. 1994;101(1):174–81. https://doi.org/10. 1016/s0161-6420(94)31368-6. 125. Wall M, Purvin V. Idiopathic intracranial hypertension in men and 110. Schlotzer-Schrehardt U, Stojkovic M, Hofmann-Rummelt C, the relationship to sleep apnea. Neurology. 2009;72(4):300–1. Cursiefen C, Kruse FE, Holbach LM. The pathogenesis of floppy https://doi.org/10.1212/01.wnl.0000336338.97703.fb. eyelid syndrome: involvement of matrix metalloproteinases in 126. Lee AG, Golnik K, Kardon R, Wall M, Eggenberger E, Yedavally elastic fiber degradation. Ophthalmology. 2005;112(4):694–704. S. Sleep apnea and intracranial hypertension in men. https://doi.org/10.1016/j.ophtha.2004.11.031. Ophthalmology. 2002;109(3):482–5. https://doi.org/10.1016/ s0161-6420(01)00987-3. 111. Series F, Chakir J, Boivin D. Influence of weight and sleep apnea status on immunologic and structural features of the uvula. Am J 127. Sugita Y, Iijima S, Teshima Y, Shimizu T, Nishimura N, Tsutsumi Respir Crit Care Med. 2004;170(10):1114–9. https://doi.org/10. T, et al. Marked episodic elevation of cerebrospinal fluid pressure 1164/rccm.200404-458OC. during nocturnal sleep in patients with sleep apnea hypersomnia syndrome. Electroencephalogr Clin Neurophysiol. 1985;60(3): 112. Acar M, Firat H, Acar U, Ardic S. Ocular surface assessment in patients with obstructive sleep apnea-hypopnea syndrome. Sleep 214–9. https://doi.org/10.1016/0013-4694(85)90033-1. Breath. 2013;17(2):583–8. https://doi.org/10.1007/s11325-012- 128. Purvin VA, Kawasaki A, Yee RD. Papilledema and obstructive 0724-0. sleep apnea syndrome. Arch Ophthalmol. 2000;118(12):1626–30. 113. du Toit R, Vega JA, Fonn D, Simpson T. Diurnal variation of https://doi.org/10.1001/archopht.118.12.1626. corneal sensitivity and thickness. Cornea. 2003;22(3):205–9. 129. Onder H, Aksoy M. Resolution of idiopathic intracranial hyper- https://doi.org/10.1097/00003226-200304000-00004. tension symptoms by surgery for obstructive sleep apnea in a pediatric patient. J Pediatr Neurosci. 2019;14(2):110–2. https:// 114. Polse KA, Mandell RB. Critical oxygen tension at the corneal doi.org/10.4103/jpn.JPN_30_19. surface. Arch Ophthalmol. 1970;84(4):505–8. https://doi.org/10. 1001/archopht.1970.00990040507021. 130. Lacharme T, Almanjoumi A, Aptel F, Khayi H, Pepin JL, Baguet 115. Gelir E, Budak MT, Ardic S. The relationship between CPAP JP, et al. Twenty-four-hour rhythm of ocular perfusion pressure in usage and corneal thickness. PLoS One. 2014;9(1):e87274. non-arteritic anterior ischaemic optic neuropathy. Acta https://doi.org/10.1371/journal.pone.0087274. Ophthalmol. 2014;92(5):e346–52. https://doi.org/10.1111/aos. 116. Koseoglu HI, Kanbay A, Ortak H, Karadag R, Demir O, Demir S, et al. Effect of obstructive sleep apnea syndrome on corneal thick- 131. Hayreh SS. Blood flow in the optic nerve head and factors that ness. Int Ophthalmol. 2016;36(3):327–33. https://doi.org/10. may influence it. Prog Retin Eye Res. 2001;20(5):595–624. 1007/s10792-015-0122-2. https://doi.org/10.1016/s1350-9462(01)00005-2. 132. Hayreh SS, Podhajsky PA, Zimmerman B. Nonarteritic anterior 117. Dikkaya F, Yildirim R, Erdur SK, Benbir G, Aydin R, Karadeniz ischemic optic neuropathy: time of onset of visual loss. Am J D. Corneal biomechanical properties in obstructive sleep apnea 78 Curr Sleep Medicine Rep (2021) 7:65–79 Ophthalmol. 1997;124(5):641–7. https://doi.org/10.1016/s0002- chorioretinopathy: a review. Med Hypothesis Discov Innov Ophthalmol. 2017;6(4):118–24. 9394(14)70902-x. 133. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL. 149. Tsai CC, Kuo TY, Hong ZW, Yeh YC, Shih KS, Du SY, et al. Nocturnal arterial hypotension and its role in optic nerve head Helicobacter pylori neutrophil-activating protein induces release and ocular ischemic disorders. Am J Ophthalmol. 1994;117(5): of histamine and interleukin-6 through G protein-mediated 603–24. https://doi.org/10.1016/s0002-9394(14)70067-4. MAPKs and PI3K/Akt pathways in HMC-1 cells. Virulence. 134. Phillips BG, Narkiewicz K, Pesek CA, Haynes WG, Dyken ME, 2015;6(8):755–65. https://doi.org/10.1080/21505594.2015. Somers VK. Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens. 1999;17(1):61–6. https://doi. 150. Caruso RA, Parisi A, Crisafulli C, Bonanno A, Lucian R, Branca org/10.1097/00004872-199917010-00010. G, et al. Intraepithelial infiltration by mast cells in human 135. Hayreh SS. Ischemic optic neuropathy. Prog Retin Eye Res. Helicobacter pylori active gastritis. Ultrastruct Pathol. 2009;28(1):34–62. https://doi.org/10.1016/j.preteyeres.2008.11. 2011;35(6):251–5. https://doi.org/10.3109/01913123.2011. 136. Palombi K, Renard E, Levy P, Chiquet C, Deschaux C, Romanet 151. Nakajima S, Bamba N, Hattori T. Histological aspects and role of JP, et al. Non-arteritic anterior ischaemic optic neuropathy is near- mast cells in Helicobacter pylori-infected gastritis. Aliment ly systematically associated with obstructive sleep apnoea. Br J Pharmacol Ther. 2004;20(Suppl 1):165–70. https://doi.org/10. Ophthalmol. 2006;90(7):879–82. https://doi.org/10.1136/bjo. 1111/j.1365-2036.2004.01974.x. 2005.087452. 152. Yamamoto J, Watanabe S, Hirose M, Osada T, Ra C, Sato N. Role 137. Nickla DL, Wallman J. The multifunctional choroid. Prog Retin of mast cells as a trigger of inflammation in Helicobacter pylori Eye Res. 2010;29(2):144–68. https://doi.org/10.1016/j.preteyeres. infection. J Physiol Pharmacol. 1999;50(1):17–23. 2009.12.002. 153. Nakajima S, Krishnan B, Ota H, Segura AM, Hattori T, Graham 138. Tonini M, Khayi H, Pepin JL, Renard E, Baguet JP, Levy P, et al. DY, et al. Mast cell involvement in gastritis with or without Choroidal blood-flow responses to hyperoxia and hypercapnia in Helicobacter pylori infection. Gastroenterology. 1997;113(3): men with obstructive sleep apnea. Sleep. 2010;33(6):811–8. 746–54. https://doi.org/10.1016/s0016-5085(97)70167-7. https://doi.org/10.1093/sleep/33.6.811. 154. Kurose I, Granger DN, Evans DJ Jr, Evans DG, Graham DY, 139. Xin C, Wang J, Zhang W, Wang L, Peng X. Retinal and choroidal Miyasaka M, et al. Helicobacter pylori-induced microvascular thickness evaluation by SD-OCT in adults with obstructive sleep protein leakage in rats: role of neutrophils, mast cells, and plate- apnea-hypopnea syndrome (OSAS). Eye (Lond). 2014;28(4): lets. Gastroenterology. 1994;107(1):70–9. https://doi.org/10. 415–21. https://doi.org/10.1038/eye.2013.307. 1016/0016-5085(94)90062-0. 140. Karaca EE, Ekici F, Yalcin NG, Ciftci TU, Ozdek S. Macular 155. Kountouras C, Polyzos SA, Stergiopoulos C, Katsinelos P, choroidal thickness measurements in patients with obstructive Tzivras D, Zavos C, et al. A potential impact of Helicobacter sleep apnea syndrome. Sleep Breath. 2015;19(1):335–41. https:// pylori infection on both obstructive sleep apnea and atrial doi.org/10.1007/s11325-014-1025-6. fibrillation-related stroke. Sleep Med. 2017;34:256. https://doi. 141. He M, Han X, Wu H, Huang W. Choroidal thickness changes in org/10.1016/j.sleep.2017.03.010. obstructive sleep apnea syndrome: a systematic review and meta- 156. Banawan LAH, Daabis RGA, Elsheikh WH, Tolba MM, Youssef analysis. Sleep Breath. 2016;20(1):369–78. https://doi.org/10. AM. The prevalence of Helicobacter pylori infection in patients 1007/s11325-015-1306-8. with obstructive sleep apnea having metabolic syndrome and its 142. Zengin MO, Oz T, Baysak A, Cinar E, Kucukerdonmez C. relation to both disorders. Egyptian Journal of Bronchology. Changes in choroidal thickness in patients with obstructive sleep 2017;11(3):268–75. https://doi.org/10.4103/ejb.ejb_54_16. apnea syndrome. Ophthalmic Surg Lasers Imaging Retina. 157. Wasilewska J, Klukowski M, Debkowska K, Kilon J, Citko D, 2014;45(4):298–304. https://doi.org/10.3928/23258160- Flisiak M, et al. Helicobacter pylori seroprevalence in children 20140624-02. with sleep-disordered breathing. Int J Pediatr Otorhinolaryngol. 143. Karalezli A, Eroglu FC, Kivanc T, Dogan R. Evaluation of cho- 2016;87:208–12. https://doi.org/10.1016/j.ijporl.2016.06.024. roidal thickness using spectral-domain optical coherence tomog- 158. Kountouras J, Polyzos SA, Deretzi G. Helicobacter pylori associ- raphy in patients with severe obstructive sleep apnea syndrome: a ated with obstructive sleep apnea might contribute to sleep, cog- comparative study. Int J Ophthalmol. 2014;7(6):1030–4. https:// nition, and driving performance disturbances in patients with cir- doi.org/10.3980/j.issn.2222-3959.2014.06.22. rhosis. Clin Gastroenterol Hepatol. 2015;13(8):1547. https://doi. 144. Uslu H, Kanra AY, Cetintas G, Tatar MG. Effect of therapy on org/10.1016/j.cgh.2015.02.009. choroidal thickness in patients with obstructive sleep apnea syn- 159. Nartova E, Kraus J, Pavlik E, Lukes P, Katra R, Plzak J, et al. drome. Ophthalmic Surg Lasers Imaging Retina. 2018;49(11): Presence of different genotypes of Helicobacter pylori in patients 846–51. https://doi.org/10.3928/23258160-20181101-05. with chronic tonsillitis and sleep apnoea syndrome. Eur Arch 145. Cakabay T, Ustun Bezgin S, Bayramoglu SE, Sayin N, Kocyigit Otorhinolaryngol. 2014;271(3):607–13. https://doi.org/10.1007/ M. Evaluation of choroidal thickness in children with adenoid s00405-013-2607-9. hypertrophy. Eur Arch Otorhinolaryngol. 2018;275(2):439–42. 160. Stergiopoulos C, Kountouras J, Daskalopoulou-Vlachoyianni E, https://doi.org/10.1007/s00405-017-4846-7. Polyzos SA, Zavos C, Vlachoyiannis E, et al. Helicobacter pylori 146. Ghimire-Aryal P, Schwartz S, Sebastião YV, Anderson WM, may play a role in both obstructive sleep apnea and metabolic Foul is PR. 0914 Association between obstructive sleep apnea, syndrome. Sleep Med. 2012;13(2):212–3. https://doi.org/10. nightmare disorder and incident herpes zoster. Sleep. 1016/j.sleep.2011.04.016. 2018;41(suppl_1):A339–A40. https://doi.org/10.1093/sleep/ zsy061.913. 161. Ye XW, Xiao J, Qiu T, Tang YJ, Feng YL, Wang K, et al. Helicobacter pylori seroprevalence in patients with obstructive 147. Chung WS, Lin HH, Cheng NC. The incidence and risk of herpes zoster in patients with sleep disorders: a population-based cohort sleep apnea syndrome among a Chinese population. Saudi Med J. 2009;30(5):693–7. study. Medicine (Baltimore). 2016;95(11):e2195. https://doi.org/ 10.1097/MD.0000000000002195. 162. Unal M, Ozturk L, Ozturk C, Kabal A. The seroprevalence of 148. Bagheri M, Rashe Z, Ahoor MH, Somi MH. Prevalence of Helicobacter pylori infection in patients with obstructive sleep Helicobacter pylori infection in patients with central serous apnoea: a preliminary study. Clin Otolaryngol Allied Sci. Curr Sleep Medicine Rep (2021) 7:65–79 79 2003;28(2):100–2. https://doi.org/10.1046/j.1365-2273.2003. meta-analysis. PLoS One. 2014;9(1):e85718. https://doi.org/10. 1371/journal.pone.0085718. 00672.x. 163. Bousquet E, Zhao M, Thillaye-Goldenberg B, Lorena V, 178. Lee JY, Ahn J, Oh S, Shin JY, Kim YK, Nam H, et al. Retina Castaneda B, Naud MC, et al. Choroidal mast cells in retinal thickness as a marker of neurodegeneration in prodromal lewy pathology: a potential target for intervention. Am J Pathol. body disease. Mov Disord. 2020;35(2):349–54. https://doi.org/ 2015;185(8):2083–95. https://doi.org/10.1016/j.ajpath.2015.04. 10.1002/mds.27914. 179. Chrysou A, Jansonius NM, van Laar T. Retinal layers in 164. Casas P, Ascaso FJ, Vicente E, Tejero-Garces G, Adiego MI, Parkinson’s disease: a meta-analysis of spectral-domain optical Cristobal JA. Visual field defects and retinal nerve fiber imaging coherence tomography studies. Parkinsonism Relat Disord. in patients with obstructive sleep apnea syndrome and in healthy 2019;64:40–9. https://doi.org/10.1016/j.parkreldis.2019.04.023. controls. BMC Ophthalmol. 2018;18(1):66. https://doi.org/10. 180. Yang ZJ, Wei J, Mao CJ, Zhang JR, Chen J, Ji XY, et al. Retinal 1186/s12886-018-0728-z. nerve fiber layer thinning: a window into rapid eye movement 165. Yazgan S, Erboy F, Celik HU, Ornek T, Ugurbas SH, Kokturk F, sleep behavior disorders in Parkinson’s disease. Sleep Breath. et al. Peripapillary choroidal thickness and retinal nerve fiber layer 2016;20(4):1285–92. https://doi.org/10.1007/s11325-016-1366- in untreated patients with obstructive sleep apnea-hypopnea syn- drome: a case-control study. Curr Eye Res. 2017;42(11):1552–60. 181. Ahn J, Lee JY, Kim TW, Yoon EJ, Oh S, Kim YK, et al. Retinal https://doi.org/10.1080/02713683.2016.1266661. thinning associates with nigral dopaminergic loss in de novo 166. Zhao XJ, Yang CC, Zhang JC, Zheng H, Liu PP, Li Q. Parkinson disease. Neurology. 2018;91(11):e1003–e12. https:// Obstructive sleep apnea and retinal nerve fiber layer thickness: a doi.org/10.1212/WNL.0000000000006157. meta-analysis. J Glaucoma. 2016;25(4):e413–8. https://doi.org/ 182. Lax P, Ortuno-Lizaran I, Maneu V, Vidal-Sanz M, Cuenca N. 10.1097/IJG.0000000000000349. Photosensitive melanopsin-containing retinal ganglion cells in 167. Sun CL, Zhou LX, Dang Y, Huo YP, Shi L, Chang YJ. Decreased health and disease: implications for circadian rhythms. Int J Mol retinal nerve fiber layer thickness in patients with obstructive sleep Sci. 2019;20(13). https://doi.org/10.3390/ijms20133164. apnea syndrome: a meta-analysis. Medicine (Baltimore). 183. Do MTH. Melanopsin and the intrinsically photosensitive retinal 2016;95(32):e4499. https://doi.org/10.1097/MD. ganglion cells: biophysics to behavior. Neuron. 2019;104(2):205– 26. https://doi.org/10.1016/j.neuron.2019.07.016. 168. Ferrandez B, Ferreras A, Calvo P, Abadia B, Marin JM, Pajarin 184. Ortuno-Lizaran I, Esquiva G, Beach TG, Serrano GE, Adler CH, AB. Assessment of the retinal nerve fiber layer in individuals with Lax P, et al. Degeneration of human photosensitive retinal gangli- obstructive sleep apnea. BMC Ophthalmol. 2016;16:40. https:// on cells may explain sleep and circadian rhythms disorders in doi.org/10.1186/s12886-016-0216-2. Parkinson’s disease. Acta Neuropathol Commun. 2018;6(1):90. 169. Cinici E, Tatar A. Thickness alterations of retinal nerve fiber layer https://doi.org/10.1186/s40478-018-0596-z. in children with sleep-disordered breathing due to adenotonsillar 185. Ryan S, Taylor CT, McNicholas WT. Selective activation of in- hypertrophy. Int J Pediatr Otorhinolaryngol. 2015;79(8):1218–23. flammatory pathways by intermittent hypoxia in obstructive sleep https://doi.org/10.1016/j.ijporl.2015.05.017. apnea syndrome. Circulation. 2005;112(17):2660–7. https://doi. 170. Moghimi S, Ahmadraji A, Sotoodeh H, Sadeghniat K, org/10.1161/CIRCULATIONAHA.105.556746. Maghsoudipour M, Fakhraie G, et al. Retinal nerve fiber thick- 186. Fletcher EC. Sympathetic over activity in the etiology of hyper- ness is reduced in sleep apnea syndrome. Sleep Med. 2013;14(1): tension of obstructive sleep apnea. Sleep. 2003;26(1):15–9. 53–7. https://doi.org/10.1016/j.sleep.2012.07.004. https://doi.org/10.1093/sleep/26.1.15. 171. Adam M, Okka M, Yosunkaya S, Bozkurt B, Kerimoglu H, Turan 187. Kaczmarek E, Bakker JP, Clarke DN, Csizmadia E, Kocher O, M. The evaluation of retinal nerve fiber layer thickness in patients Veves A, et al. Molecular biomarkers of vascular dysfunction in with obstructive sleep apnea syndrome. J Ophthalmol. 2013;2013: obstructive sleep apnea. PLoS One. 2013;8(7):e70559. https://doi. 292158. https://doi.org/10.1155/2013/292158. org/10.1371/journal.pone.0070559. 172. Lin PW, Friedman M, Lin HC, Chang HW, Pulver TM, Chin CH. 188. Li Q, Verma A, Han PY, Nakagawa T, Johnson RJ, Grant MB, Decreased retinal nerve fiber layer thickness in patients with ob- et al. Diabetic eNOS-knockout mice develop accelerated retinop- structive sleep apnea/hypopnea syndrome. Graefes Arch Clin Exp athy. Invest Ophthalmol Vis Sci. 2010;51(10):5240–6. https://doi. Ophthalmol. 2011;249(4):585–93. https://doi.org/10.1007/ org/10.1167/iovs.09-5147. s00417-010-1544-1. 189. Kida T, Flammer J, Oku H, Konieczka K, Morishita S, Horie T, 173. Kargi SH, Altin R, Koksal M, Kart L, Cinar F, Ugurbas SH, et al. et al. Vasoactivity of retinal veins: a potential involvement of Retinal nerve fibre layer measurements are reduced in patients endothelin-1 (ET-1) in the pathogenesis of retinal vein occlusion with obstructive sleep apnoea syndrome. Eye (Lond). (RVO). Exp Eye Res. 2018;176:207–9. https://doi.org/10.1016/j. 2005;19(5):575–9. https://doi.org/10.1038/sj.eye.6701582. exer.2018.07.016. 174. Wang JS, Xie HT, Jia Y, Zhang MC. Retinal nerve fiber layer 190. Totan Y, Koca C, Erdurmus M, Keskin U, Yigitoglu R. thickness changes in obstructive sleep apnea syndrome: a system- Endothelin-1 and Nitric oxide levels in exudative age-related atic review and meta-analysis. Int J Ophthalmol. 2016;9(11): macular degeneration. J Ophthalmic Vis Res. 2015;10(2):151–4. 1651–6. https://doi.org/10.18240/ijo.2016.11.19. https://doi.org/10.4103/2008-322X.163765. 175. Comella CL. Sleep disorders in Parkinson’sdisease: anoverview. 191. Mentek M, Morand J, Baldazza M, Faury G, Aptel F, Pepin JL, Mov Disord. 2007;22(Suppl 17):S367–73. https://doi.org/10. et al. Chronic intermittent hypoxia alters rat ophthalmic artery 1002/mds.21682. reactivity through oxidative stress, endothelin and endothelium- 176. Nomura T, Inoue Y, Kagimura T, Nakashima K. Clinical signifi- derived hyperpolarizing pathways. Invest Ophthalmol Vis Sci. cance of REM sleep behavior disorder in Parkinson’s disease. 2018;59(12):5256–65. https://doi.org/10.1167/iovs.18-25151. Sleep Med. 2013;14(2):131–5. https://doi.org/10.1016/j.sleep. 2012.10.011. 177. Yu JG, Feng YF, Xiang Y, Huang JH, Savini G, Parisi V, et al. Publisher’sNote Springer Nature remains neutral with regard to jurisdic- Retinal nerve fiber layer thickness changes in Parkinson disease: a tional claims in published maps and institutional affiliations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Current Sleep Medicine Reports Springer Journals

The Associations of Obstructive Sleep Apnea and Eye Disorders: Potential Insights into Pathogenesis and Treatment

Loading next page...
 
/lp/springer-journals/the-associations-of-obstructive-sleep-apnea-and-eye-disorders-XdSdlb0ISr
Publisher
Springer Journals
Copyright
Copyright © The Author(s) 2021
eISSN
2198-6401
DOI
10.1007/s40675-021-00215-0
Publisher site
See Article on Publisher Site

Abstract

Purpose of Review Obstructive sleep apnea (OSA) patients are at significantly increased risks for cardiovascular and cerebro- vascular morbidities. Recently, there has been heightened interest in the association of OSA with numerous ocular diseases and possible improvement of these conditions with the initiation of OSA treatment. We reviewed the current evidence with an emphasis on the overlapping pathogeneses of both diseases. Recent Findings Currently available literature points to a substantial association of OSA with ocular diseases, ranging from those involving the eyelid to optic neuropathies and retinal vascular diseases. Since the retina is one of the highest oxygen-consuming tissues in the body, the intermittent hypoxia and hypercapnia ensuing in OSA can have deleterious effects on ocular function and health. Tissue hypoxia, autonomic dysfunction, microvascular dysfunction, and inflammation all play important roles in the pathogenesis of both OSA and ocular diseases. Whether OSA treatment is capable of reversing the course of associated ocular diseases remains to be determined. It is anticipated that future therapeutic approaches will target the common underlying pathophysiologic mechanisms and promote favorable effects on the treatment of known associated ocular diseases. Summary Emerging evidence supports the association of ocular diseases with untreated OSA. Future studies focusing on whether therapeutic approaches targeting the common pathophysiologic mechanisms will be beneficial for the course of both diseases are warranted. . . . Keywords Obstructive sleep apnea Floppy eyelid syndrome Optic neuropathy Nonarteritic anterior ischemic optic neuropathy (NAION) Retinal vascular disease Introduction in the eye that may shed light on the pathogenesis of ocular disorders in the context of OSA. As we better understand the Within the past 5 years, there have been several excellent metabolic, immune, and biological attributes of OSA, it is published reviews addressing the relationship of obstructive worthwhile to revisit these associations in order to better un- sleep apnea (OSA) and ocular disorders [1, 2�� , 3]. During this derstand potential models for the pathogeneses of these ocular period, there has also been an intensification of the relation- conditions and to potentially identify therapeutic interven- ship of OSA with ocular disorders that has been inspired by tions that might impact their management. This review will new imaging technologies that can identify structural changes attempt to summarize the evidence for the associations of OSA and ocular disorders, the newer structural and func- tional parameters of eye disorders and vision that may be This article is part of the Topical Collection on Sleep and Health linked to OSA, and attempt to consider the underlying met- Disparities abolic, genetic, and structural mechanisms that may inform our understanding of both OSA and ocular conditions * Michael B. Gorin gorin@jsei.ucla.edu (Table 1). In some instances, we will consider shared etiol- ogies and risk factors, while for others, we will consider Department of Ophthalmology, Seoul National University College of how the alterations caused by OSA may directly influence Medicine and Seoul Metropolitan Government Seoul National ocular function and disease. This third segment of the pa- University Boramae Medical Center, Seoul, Korea per, based on peer-reviewed publications, is ultimately UCLA Stein Eye Institute, Division of Retinal Disorders and speculative but gives us some hints for future research di- Ophthalmic Genetics, Department of Ophthalmology, David Geffen rections and potential therapies. School of Medicine, UCLA, Los Angeles, CA, USA 66 Curr Sleep Medicine Rep (2021) 7:65–79 Table 1 Evidence for, or a lack Association with OSA Response to OSA of, associations with various therapy ocular diseases and obstructive sleep apnea (OSA) and responses Yes No Yes No to OSA therapy External and surface eye disease Floppy eyelid [4–15][16][17–19] Keratoconus [20, 21� , 22–25][26] Dry eyes [11, 27, 28][11][29][30] Optic neuropathy Primary open-angle glaucoma [31–40][5, 41–45][46][32] Normal-tension glaucoma [35–38, 40, 42, 47–50][39][50] Non-arteritic ischemic optic neuropathy [51–58][59] Retinal vascular disease Diabetic retinopathy [60–82][74][60, 67, 83–85][85] Retinal vein occlusion [86–93] Central serous chorioretinopathy [94–100] Age-related macular degeneration [45, 101][102] Definition of OSA, Age-Dependent common disturbance in tissue perfusion and oxygenation as well Differences, and Implications for Eye as potential metabolic derangements that promote coagulation Disorders disorders. One can make a case that similar processes could underlie the association of OSA with both primary open-angle Obstructive sleep apnea (OSA) is a subset of sleep-disordered glaucoma and normal-tension glaucoma. However, it is certain- breathing that is characterized by episodic sleep state– ly possible that structural changes in connective tissue that con- dependent upper airway collapse, resulting in periodic reduc- tribute to the intermittent loss of airway integrity could act as a tions or cessations in ventilation, with subsequent hypoxia, hy- shared risk factor for floppy eyelid syndrome (FES), and also percapnia, or arousals from sleep [103]. Risk factors for OSA result in increased optic nerve vulnerability to damage from are conditions that reduce the size of the resting pharynx or elevated intraocular pressures or compression in high myopes increase airway collapsibility such as obesity, male sex, persons [107, 108]. These mechanisms do not seem to offer a clear with hypothyroidism or acromegaly, increased tonsillar and explanation for the associations of OSA with central serous adenoid tissue, and certain craniofacial abnormalities [104]. chorioretinopathy (CSR). While CSR is also intimately related In terms of OSA prevalence and age, although there is a to abnormalities of the choroidal circulation and closely associ- gradual increase, prevalence tends to level off after 65 years ated with choroidal thickening (known as pachychoroid), the [105]. Geriatric patients exhibit more severe and deeper noctur- distinct clinical features of CSR, the focal or multifocal character nal intermittent hypoxia compared to young adults, indepen- with considerable ocular asymmetry, its intermittent acute flares dent of OSA severity which could be reflective of the already and spontaneous remissions, and associations with endogenous present chronic hypoxemic conditions, due to the physiologic cortisol or exogenous steroid exposure seem to be outside of aging process [106]. When we consider the association of OSA known OSA risk factors. Yet, the association of OSA with with ocular conditions, we have to consider if these relation- CSR is so clearly established that some clinicians have even ships are due to pleiotropic effects of shared risk factors (such as suggested that every patient with CSR undergo testing for anatomic features and common physiologic pathways) and/or if OSA regardless of clinical symptoms [94]. the metabolic and systemic effects of the OSA itself contributes There is one study that indicates that the clinical response as a risk factor for these conditions, as illustrated in Fig. 1. to anti-vascular endothelial growth factor (VEGF) injections for treating exudative age-related macular degeneration (AMD) is impacted by whether or not an OSA patient is treat- Association of OSA with Specific Ocular ed with continuous positive airway pressure (CPAP) [101]. If such a finding were to be replicated, it would suggest a very Conditions dynamic relationship between the physiologic changes during sleep and potential exacerbations of retinal hypoxia and The association of OSA with microvascular eye diseases, in- cluding non-arteritic ischemic neuropathy, retinal vein occlu- secondary elevations of VEGF in the retina/choroid. Given our lack of therapies to prevent or slow the progression of sion, and diabetic retinopathy, seems to be strengthened by a Curr Sleep Medicine Rep (2021) 7:65–79 67 Obstructive Sleep Apnea Ocular Disease Shared etiologies Disorders of airway Disorders of ocular adnexa basement membrane and connective tissue integrity, inflammation structure and ocular structures Tissue Laxity FES � vasodilation Mast cell disease Dry Eye � vasoconstriction POAG � dysregulation of ocular perfusion pressure acute events Disorders of ocular blood flow Consequences of PCA Recurrent PCA NAION OSA on local and hypopnea/apnea RAO RVO systemic circulation DR POAG CRV CRA chronic events Optic nerve Disorders of ocular metabolism and immune system Metabolic/Immune CSR Shared etiologies Derangements AMD mast cells, inflammatory cytokines, POAG circadian dysfunction Fig. 1 The pleiotropic effects of shared etiologies on both obstructive CRV, central retinal vein; CRA, central retinal artery; NAION, non- sleep apnea (OSA) and ocular diseases, and the acute/chronic effects of arteritic ischemic optic neuropathy; RAO, retinal artery occlusion; OSA on ocular blood flow. FES, floppy eyelid syndrome; POAG, RVO, retinal vein occlusion; DR, diabetic retinopathy; CSR, central primary open-angle glaucoma; PR, prelaminar region; LC, lamina serous chorioretinopathy; AMD, age-related macular degeneration cribrosa; R, retina; C, choroid; S, sclera; PCA, posterior ciliary artery; nonexudative AMD and the relatively high percentage of pa- applied to the pretarsal skin in a vertical direction and found a tients with exudative AMD who demonstrate only a partial vertical lidpullof15 to 25mmfor FESpatients, 7to16mmfor response to anti-VEGF therapies, it would be invaluable to OSA,and5to10mmfor age- andgender-matchedcontrols explore the potential impact of OSA treatment on this [10]. Robert et al. found increased eyelid hyperlaxity in OSA condition. patients, and Mojon et al. found positive correlation between Figure 2 summarizes the effects of OSA on various ocular respiratory disturbance index (RDI) and eyelid distraction dis- structures and associated ocular diseases. tance [11, 13]. However, Fox et al. recently performed a cross- sectional observational study with individuals referred for over- night polysomnography and found no association between the The Association of OSA with Structural presence of OSA and eyelid laxity [16]. The authors enrolled a large number of patients (201 individuals, 402 eyes) and and Functional Changes of the Eye and Vision attempted to employ validated quantitative measurements to objectively determine the presence of eyelid laxity. The lack Eyelid and Ocular Surface Morphology of a gold standard for assessing and the relatively subjective Ever since Gonnering and Sonneland first reported a patient methods with which previous studies investigated structural with both obstructive sleep apnea (OSA) and floppy eyelid eyelid change are all possible reasons for the discrepancy in syndrome (FES) in 1987 [7], there have been numerous papers these study results. Age and body mass index (BMI) are both looking at the association between the two diseases [4, 8–12, important factors associated with increased eyelid laxity and 14, 16](Fig. 3). Lid laxity quantification is important in deter- OSA and may possibly act as a confounding factor, but previ- mining the presence or absence of structural eyelid change and ous studies controlling for these factors nonetheless found an there have been several methods suggested, such as measuring association between FES and OSA [8, 10, 11]. The number of elastin fibers has been found to be markedly the “vertical lid pull,”“vertical hyperlaxity of the lid,” or simply “horizontal eyelid distraction distance” [10, 11, 13]. McNab decreased in FES patients with increased expression of matrix metalloproteinases implicated as a possible cause [109, 110]. measured the excursion of the upper lid margin from traction 68 Curr Sleep Medicine Rep (2021) 7:65–79 FES DR RVO elasn fiber AMD disorganizaon OSA hypercapnia Mast Cell Fig. 3 A patient with floppy eyelid syndrome. There is significant lid Dysfuncon hypoxemia eversion (white arrow) with mild upward traction demonstrating extensive lid laxity. (Image credit: Dr. Robert A. Goldberg, UCLA oxidave Stein Eye Institute) stress features of OSA, can impact FES directly. This may also be autonomic due to inflammatory factors that appear to improve with OSA dysfuncon therapy and may contribute to the OSA severity, as well as to the severity of the lid swelling and laxity. Ocular Structural Changes Ocular surface changes have also been studied in conjunc- Opc disc Choroid Cornea RNFL tion with eyelid laxity in OSA patients. One study found that choroidal choroidal Surface drying RNFL thinning although 52% of OSA patients had abnormal eye findings and thinning thickening RDI correlated negatively with tear film break-up time (TBUT), corneal abnormalities were found in only 4.5%, with symptoms of ocular irritation being rare [11]. Another study NAION DED CSR NTG conducted a more comprehensive study focusing specifically POAG on ocular surface changes occurring in OSA patients and found that moderate and severe OSA is associated with lower Fig. 2 Summary of the effects of OSA on various ocular structures and Schirmer and TBUT, high scores on the ocular surface disease associated ocular diseases. Hypercapnia, hypoxemia, oxidative stress, index questionnaire, and corneal staining pattern stage [112]. and autonomic dysfunction, as a result of OSA, contribute to the pathogeneses of various retinal vascular diseases such as diabetic retinopathy, retinal vein occlusion, and age-related macular Corneal Hysteresis degeneration. Ocular structural changes arising in association with OSA result in various ocular diseases according to the different tissues affected. OSA, obstructive sleep apnea; DR, diabetic retinopathy; RVO, retinal Normal human corneal thickness is about 500 μm and diurnal vein occlusion; AMD, age-related macular degeneration; FES, floppy variation is present with overnight swelling and resolution by eyelid syndrome; RNFL, retinal nerve fiber layer; DED, dry eye early afternoon, possibly arising from hypoxia created by lid disease; NAION, non-arteritic ischemic optic neuropathy; NTG, normal-tension glaucoma; POAG, primary open-angle glaucoma; CSR, closure [113]. Both hypoxic and hypercapnic environments central serous chorioretinopathy are known to affect corneal thickness with 7% swelling per hour observed in the normal human cornea [114]. One study Interestingly, elastin fiber network disorganization in the distal analyzed changes in corneal thickness with/without CPAP uvula was found to be associated with the apnea-hypopnea application in OSA patients using an ultrasonic pachymeter index (AHI) [111] and such pathologic tissue changes may be and found a significant corneal thickness increase in only the the common pathophysiology underlying both FES and OSA. without-CPAP group [115]. Another study looked at central Therapeutic approaches that could mitigate these structural corneal thickness (CCT), TBUT, and Schirmer’stest in OSA changes to the tissues would potentially benefit patients with patients according to severity defined by AHI scores [116]. either FES or OSA. However, a more functional interrelation- CCT was significantly decreased in OSA patients compared to ship between these two conditions has been suggested by sev- that in the control group, and as OSA severity increased, CCT eral studies that reported that FES improved in a group of OSA decreased in a stepwise manner (mean CCT 570 mm, 561 patients with successful use of CPAP [18, 19]. The not-so- mm, and 534 mm in mild, moderate, and severe OSA, respec- clear-cut effects of CPAP therapy and OSA-related surgery tively, p < 0.05). There were no significant differences in on FES suggest that both shared factors related to the structural TBUT or Schirmer’s test results among different OSA sever- integrity of the palate and lid tissues, as well as dynamic ity groups. Dikkaya et al. used an ocular response analyzer to Curr Sleep Medicine Rep (2021) 7:65–79 69 study corneal biochemical properties in OSA patients and Optic Nerve Vasculature: Non-arteritic Ischemic Optic showed significantly lower corneal hysteresis and resistance Neuropathy in the severe OSA group, which implies possible corneal bio- chemical changes in OSA, especially in the severe type [117]. The perfusion of the retina by the central retinal artery and its branches is crucial for the maintenance of the inner retinal neu- Optic Disc rons. The outer retinal layers, specifically the photoreceptor layer, derive their vascular and metabolic support from the Retinal ganglion cells (RGCs) are responsible for conveying choroidal circulation. Effective blood flow and oxygenation synaptic input initiated by a visual stimulus to the visual cortex are achieved by having sufficient perfusion pressure of the within the brain. Ganglion cell axons converge at the optic disc retinal vasculature to overcome the resistance caused by the and exit through the lamina cribrosa to form the optic nerve. intraocular pressure. Reductions in nocturnal blood pressure, Optic nerve examination, as well as examination of the in conjunction with the impairment of central retinal artery peripapillary retinal nerve fiber layers (RNFL), consisting of blood flow and/or elevated intraocular pressures, can lead to ganglion cell axons, is useful for investigating the presence of acute ischemic events such as NAION (Fig. 4) and, more rare- neuroaxonal degeneration, either anterograde or retrograde. ly, central retinal artery occlusions (CRAO) [130, 131]. Among OSA has been reported to be associated with various optic nerve 925 episodes of NAION, 73% of patients first reported visual diseases, such as non-arteritic anterior ischemic optic neuropa- symptoms after waking from sleep, and nocturnal arterial hy- thy (NAION), primary open-angle glaucoma, normal-tension potension showed a significant correlation with progressive glaucoma, and papilledema [118, 119� , 120� , 121–123]. visual field deterioration in NAION, altogether implying that Huseyinoglu et al. looked specifically at changes in optic nocturnal blood pressure depression may precipitate NAION disc parameters in OSA patients, such as optic disc area, cup development in patients having additional risk factors [132, area, cup volume, cup/disc area ratio, and nerve head volume, 133]. In OSA, the imbalance between nitric oxide and using OCT to obtain 12 radial scans and 13 concentric rings, endothelin results in reduced autoregulatory ability of the optic centered on the disc, but were unable to detect any significant nerve microcirculation to compensate for fluctuations in blood differences [118]. pressure and decreased blood oxygen saturation during apnea Studies related to optic neuropathy/glaucoma and OSA have may cause direct injury to the optic nerve head [134, 135]. Such suggested that the negative effects of OSA on RNFL and nerve structural and functional changes occurring in OSA could act as oxygenation may be reversed by CPAP. However, to date, IOP the additional risk factor tipping the fine balance of perfusion control is the only proven treatment for glaucoma and there is towards ischemia for patients at risk for NAION. Prospective yet no evidence that IOP can be altered by CPAP therapy. studies also reported the prevalence of OSA in NAION patients Oxidative stress and lower oxygenation could also be contrib- to be 55.6~89% in comparison to that of 18~22% in the general uting factors for ischemic optic neuropathy, which also has population or a control group, while a 12-year nationwide implications for diabetic retinopathy (which also seems to re- population-based retrospective cohort study found an increased spond to CPAP therapy but not always consistently) [83], as risk of developing NAION in the OSA group compared to the well as complications of retinal vein occlusion (RVO). non-OSA group (HR 3.80; 95% CI 1.46 to 9.90) even after Idiopathic intracranial hypertension (IIH), a syndrome of adjusting for demographics, comorbidities, and co- increased intracranial pressure (ICP) with unknown etiology, medications [136, 57, 53, 105, 119]. Hence, individuals who hasalsobeenreported tobeassociated withOSA [124–126]. have experienced an episode of NAION or a CRAO should be Intermittent ICP elevation is not infrequently observed in carefully questioned regarding a history of OSA-related symp- OSA, and Sugita et al. hypothesized this to be due to a com- toms and a formal sleep study should be considered, even if bination of factors such as increased central venous pressure other OSA comorbidities are not present. There is no evidence and subsequent cerebrovascular volume increase, systemic at this time that suggests that treatment of OSA will alter the arterial hypertension with secondary increased cerebral perfu- recovery of the eye from one of these acute ischemic events sion pressure and cerebral vasodilation due to hypoxia and [59] although nonadherence to CPAP treatment in patients with hypercapnia, and resulting intracranial blood volume increase both OSA and unilateral NAION was found to increase the risk [127, 128]. Since IIH and OSA share a common risk factor of of fellow eye involvement [51]. obesity, it remains to be determined whether OSA itself is a comorbidity or an independent risk factor for IIH. There was a Choroidal Layer report of IIH symptom resolution after surgery for OSA in a pediatric patient and optic disc swelling resolution was ob- Choroidal circulation has autonomic regulation, sharing regu- served after CPAP, but as with the association between OSA latory properties as that of cerebral blood flow [137]. and IIH, there is no consensus at this time as to whether OSA Alternating hypoxia and arousal occurring in OSA is thought treatment affects IIH [126, 128, 129]. to stimulate the sympathetic nervous system leading to an 70 Curr Sleep Medicine Rep (2021) 7:65–79 Fig. 4 A 66-year-old male non-arteritic ischemic optic neuropathy patient (b). Humphrey visual field testing showed inferior visual field defect presenting with vision blurring in the right eye. Disc photograph of the (black arrows) in the right eye (c) corresponding to the area of optic right eye (a) showed blurring (white arrowheads) of the superotemporal disc swelling, while the left eye showed normal visual field (d) optic disc margin compared to a normal-looking optic disc in the left eye increase in choroidal blood flow following hypercapnia and in vessel permeability, and choroidal thinning. One study used expression of hypoxia-inducible factor and vascular growth choroidal laser Doppler flowmetry to study choroidal vascular factors, resulting in vascular endothelium damage, changes reactivity in OSA men with a mean age of 50.9 years, having Curr Sleep Medicine Rep (2021) 7:65–79 71 no cardiovascular comorbidities, and found no impairments, role in CSR, the activation and degranulation of mast cells that i.e., hypercapnia-induced blood flow increase and stable cho- are resident within the choriocapillaris may be a reasonable roidal blood flow in hyperoxia, suggesting long-term adaptive connection with other known associations of CSR such as mechanisms coming into play in the ocular microcirculation stress or low-dose (not high-dose) steroid exposure and [138]. As with RNFL, numerous studies have found thinner OSA, which can also modulate the immune system and trigger choroidal thickness while others have found no difference in mast cell degranulation. This hypothesis that CSR may be OSA patients compared to controls, although a meta-analysis driven and triggered by mast cell accumulation and degranu- was able to confirm significant choroidal thickness reduction, lation, as well as local inflammation, would also be consistent especially in severe OSA [94, 139–143]. In terms of reversal with the purported role of mast cell accumulation and activa- of choroidal thickness changes after treatment, one study re- tion in floppy eyelid syndrome [163]. ported significant increases in choroidal thickness after 12 months of CPAP institution with possible improvements in Retinal Nerve Fiber Layer and Ganglion Cell Layer choroidal function [144]. Different modalities and analysis techniques used to assess choroidal blood flow may be one Numerous studies have reported significant reduction, while oth- of the underlying reasons for varied results in previous studies. er studies have found no difference in RNFL thickness in OSA The biological basis between CSR, in which a thickened patients compared to normal controls [118, 121–123, 164–173]. choroid is the most distinct characteristic, and OSA is perhaps Recently, numerous meta-analyses have been published, in the most complicated and unclear (Fig. 5). CSR does not appear which all found a significant reduction of average RNFL thick- to be triggered by topical, periocular, or intravitreal exposures ness in OSA patients [122, 123, 166, 167, 174]. Recurrent ob- to steroids, even though there are multiple reports of activation struction of airflow occurring in OSA, leading to repeated hyp- associated with systemic steroids, as well as from intra-articu- oxemia, hypercapnia, and reduced perfusion in the optic nerve, lar, intranasal, and inhalant exposures. This paradox highlights would most likely result in retinal ganglion cell apoptosis and the fact that the underlying mechanism of CSR is poorly un- subsequent retinal nerve fiber layer reduction [118, 121]. derstood. The relationship of CSR and OSA becomes an even Sleep disturbance is one of the most prevalent non-motor more intriguing target for study. There is no evidence that the symptoms in Parkinson’sdisease (PD) [175]. Rapid eye move- choriocapillaris is thicker in OSA patients, suggesting that this ment sleep behavior disorder (RBD), characterized by the loss of “pachychoroid” feature is relatively independent of OSA. It is normal atonia during rapid eye movement (REM) sleep, has been possible that the association of OSA and CSR is not with the implicated as a precursor to α-synucleinopathies such as demen- underlying pathology that is required to develop CSR but may tiawithLewybody(DLB) andPD[176]. Peripapillary RNFL be related to factors that cause acute activation and/or persis- thickness, as well as inner retinal thickness in the macular area, tence of active CSR [94, 139, 141, 145]. has been reported to be reduced in both PD and RBD [177–181]. The initial activation and recurrences of CSR have sug- Melanopsin-containing retinal ganglion cells (mRGCs) are a sub- gested the possibility of an infectious and/or inflammatory set of RGCs that also participate in non-image-forming functions etiology for this condition. There is an association of OSA such as circadian rhythm regulation or pupillary light reflex acti- with activation of herpes zoster in patients which has been vation [182, 183]. Their degeneration and impairment are one of suggested to be due to modulation of the immune system the pathways in which sleep disturbance is hypothesized to occur [146, 147]. An infectious etiology for CSR has been proposed in PD [184]. Neither PD nor RBD has any overlapping patho- with an association of Helicobacter pylori [148], though the genic mechanisms with OSA; however, both neurodegenerative natural history of recurrent episodes would require either re- diseases result in sleep disturbance and have ocular manifesta- activation of infection or sensitization of the choroid with tions both functionally and anatomically, as in OSA, and are inflammatory cells that continue to reside in the choroid, and examples of a sleep-associated disease, such as OSA, in which which are vulnerable to sporadic activation. Other studies ophthalmic examination may reveal more than meets the eye. have shown that H. pylori can both promote the accumulation and degranulation of mast cells in different tissues [149–154]. There are even several studies that have focused on the asso- Metabolic, Structural, Genetic Correlates that ciation of H. pylori itself with OSA. Whether such infectious May Underlie the Association of OSA etiologies play an important role in the pathophysiology of with Ocular Disorders OSA and its comorbidities is a topic that requires further in- vestigations [155–162]. Hypoxia Some investigators have suggested that CSR activation may be due to the degranulation of mast cells that are resident In vitro model of intermittent hypoxia (IH)/reoxygenation in the choriocapillaris, and this could certainly be triggered by shows activation of the pro-inflammatory transcription factor low-dose steroid exposure. Whether or not H. pylori plays a NFκB. Circulating tumor necrosis factor-α levels which were 72 Curr Sleep Medicine Rep (2021) 7:65–79 Fig. 5 A patient with central serous chorioretinopathy. Subretinal fluid (arrowheads) is evident on fundus photograph (a) of the right eye and horizontal optical coherence tomography scan (b) shows subretinal fluid with elevated retina and thickened choroid (double head arrows) significantly higher in OSA patients normalized after CPAP chorioretinopathy, and age-related macular degeneration. therapy, demonstrating that selective activation of inflamma- However, treatments that would alter these autonomic states tory pathways as a result of intermittent hypoxia in OSA may have not been explored as potential treatments for these ocular be one of the molecular pathways underlying macro/ conditions as of yet. microvascular diseases associated with OSA [185]. The pro- 1)Elevated catecholamines and muscle sympathetic nerve inflammatory nature of OSA could potentially play important activity during apnea as while awake roles in the pathophysiology of floppy eyelids, dry eyes, dia- 2)Activation of the renin-angiotensin-aldosterone system betic retinopathy, and age-related macular degeneration. 3)Differing vascular reactivity between OSA and controls 4)Changes in sympathetic and vascular reactivity with OSA treatment Autonomic Dysfunction 5)Animals exposed to intermittent hypoxia or apnea show the above observations. High sympathetic tone, increase in baseline heart rate, and elevated muscle sympathetic nerve activity are all commonly observed in OSA patients [186]. The following phenomena all Microvascular Changes come into play in OSA patients, and such changes may affect the choroidal vascular supply, which is mainly controlled by One study used OSA patient skin biopsies to identify molec- the autonomic nervous system, pathologic changes in which ular biomarkers involved in the vascular dysfunction of OSA could have an impact on diabetic retinopathy, central serous and found endothelial nitric oxide synthase (eNOS), tumor Curr Sleep Medicine Rep (2021) 7:65–79 73 necrosis factor-α–induced protein 3, hypoxia-inducible factor therapeutic interventions for OSA and the impact of those treat- 1 α, and vascular cell adhesion molecule 1 (VCAM-1) expres- ments on ocular anatomy and metabolic states can help us better sions to be significantly upregulated [187]. All of these factors understand how the amelioration of OSA in patients with these have also been implicated in the pathogenesis of diabetic ret- ocular conditions may offer an adjunct to our current therapies. inopathy, retinal vascular occlusive disease, and exudative forms of age-related macular degeneration [188–190]. However, there is yet no study that has considered the role Compliance with Ethical Standards of these factors in the combined context of OSA patients with Conflict of Interest The authors report no conflicts of interest. any of these retinal diseases. Human and Animal Rights and Informed Consent This article does not Oxidative Stress contain any studies with human or animal subjects performed by any of the authors. When rats were exposed to 14 days of IH, superoxide ion Open Access This article is licensed under a Creative Commons expression in the ophthalmic artery (OA) wall and OA con- Attribution 4.0 International License, which permits use, sharing, adap- tractile response to endothelin-1 both increased, and nitric tation, distribution and reproduction in any medium or format, as long as oxide–mediated relaxation was significantly delayed [191]. you give appropriate credit to the original author(s) and the source, pro- vide a link to the Creative Commons licence, and indicate if changes were This shows the induction of oxidative stress in rat OA by made. The images or other third party material in this article are included chronic IH, combined with endothelial cell and nitric oxide in the article's Creative Commons licence, unless indicated otherwise in a synthase dysfunction. Given the known vulnerabilities of the credit line to the material. If material is not included in the article's optic nerve, as well as the retina, to damage from oxidative Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain stress for many of the conditions that we know are associated permission directly from the copyright holder. To view a copy of this with OSA, we need to consider if agents that reduce oxidative licence, visit http://creativecommons.org/licenses/by/4.0/. stress might be potentially useful in a subset of OSA patients and have a clinical impact on the ocular conditions in these individuals. References Conclusions and Future Directions Papers of particular interest, published recently, have been We can see that the ocular associations with OSA likely involve highlighted as: both structural comorbidities such as collagen mutations that � Of importance affect the structural integrity of the airways and the eyelids, as �� Of major importance well as the activation of mast cells that place a role in the atopic aspects of many cases of floppy eyelid syndrome as well as dry 1. West SD, Turnbull C. Obstructive sleep apnoea. Eye (Lond). 2018;32(5):889–903. https://doi.org/10.1038/s41433-017-0006-y. eye manifestations. At the same time, this modulation of mast 2.�� Mentek M, Aptel F, Godin-Ribuot D, Tamisier R, Pepin JL, cells and/or cortisol in patients with OSA may contribute to the Chiquet C. Diseases of the retina and the optic nerve associated risk of activation of CSR. Elevated inflammatory factors that with obstructive sleep apnea. Sleep Med Rev. 2018;38:113–30. have been reported in OSA may contribute to both AMD and https://doi.org/10.1016/j.smrv.2017.05.003 Comprehensive diabetic retinopathy. Microvascular changes may also play a role review of the effect of obstructive sleep apnea on specifically the retina and optic disc. in the severity and progression of diabetic retinopathy. The 3. Grover DP. Obstructive sleep apnea and ocular disorders. Curr chronic, intermittent hypoxia of untreated OSA may play a role Opin Ophthalmol. 2010;21(6):454–8. https://doi.org/10.1097/ in patients’ visual dysfunction and may offer a potential means of ICU.0b013e32833f00dc. functionally monitoring these patients both before and in re- 4. Chambe J, Laib S, Hubbard J, Erhardt C, Ruppert E, Schroder C, et al. sponse to treatment. Central serous chorioretinopathy appears Floppy eyelid syndrome is associated with obstructive sleep apnoea: a prospective study on 127 patients. J Sleep Res. 2012;21(3):308–15. to be ameliorated by the treatment of OSA and may be related https://doi.org/10.1111/j.1365-2869.2011.00968.x. to either cortisol modulation and/or mast cell activation. These 5. Kadyan A, Asghar J, Dowson L, Sandramouli S. Ocular findings in hypothetical connections offer new opportunities to better under- sleep apnoea patients using continuous positive airway pressure. Eye stand both OSA and the ocular conditions that are influenced by (Lond). 2010;24(5):843–50. https://doi.org/10.1038/eye.2009.212. 6. Ezra DG, Beaconsfield M, Sira M, Bunce C, Wormald R, Collin this disorder. They offer potential, testable interventions to limit R. The associations of floppy eyelid syndrome: a case control the damage from a number of these eye conditions by either study. Ophthalmology. 2010;117(4):831–8. https://doi.org/10. treating the underlying OSA or the shared pathways that may 1016/j.ophtha.2009.09.029. be contributory (even in individuals without clinical evidence of 7. Gonnering RS, Sonneland PR. Meibomian gland dysfunction in floppy eyelid syndrome. Ophthalmic Plast Reconstr Surg. OSA). Using ocular imaging and visual function to assess 74 Curr Sleep Medicine Rep (2021) 7:65–79 1987;3(2):99–103. https://doi.org/10.1097/00002341- 24. Pihlblad MS, Schaefer DP. Eyelid laxity, obesity, and obstructive sleep apnea in keratoconus. Cornea. 2013;32(9):1232–6. https:// 198703020-00009. doi.org/10.1097/ICO.0b013e318281e755. 8. Karger RA, White WA, Park WC, Rosales AG, McLaren JW, Olson EJ, et al. Prevalence of floppy eyelid syndrome in obstructive sleep 25. Saidel MA, Paik JY, Garcia C, Russo P, Cao D, Bouchard C. apnea-hypopnea syndrome. Ophthalmology. 2006;113(9):1669–74. Prevalence of sleep apnea syndrome and high-risk characteristics https://doi.org/10.1016/j.ophtha.2006.02.053. among keratoconus patients. Cornea. 2012;31(6):600–3. https:// doi.org/10.1097/ICO.0b013e318243e446. 9. Leibovitch I, Selva D. Floppy eyelid syndrome: clinical features and the association with obstructive sleep apnea. Sleep Med. 26. Gencer B, Ozgurhan EB, Kara S, Tufan HA, Arikan S, Bozkurt E, 2006;7(2):117–22. https://doi.org/10.1016/j.sleep.2005.07.001. et al. Obesity and obstructive sleep apnea in patients with 10. McNab AA. Floppy eyelid syndrome and obstructive sleep apnea. keratoconus in a Turkish population. Cornea. 2014;33(2):137– Ophthalmic Plast Reconstr Surg. 1997;13(2):98–114. https://doi. 40. https://doi.org/10.1097/ICO.0000000000000024. org/10.1097/00002341-199706000-00005. 27. Galor A, Feuer W, Lee DJ, Florez H, Carter D, Pouyeh B, et al. Prevalence and risk factors of dry eye syndrome in a United States 11. Mojon DS, Goldblum D, Fleischhauer J, Chiou AG, Frueh BE, veterans affairs population. Am J Ophthalmol. 2011;152(3):377– Hess CW, et al. Eyelid, conjunctival, and corneal findings in sleep 84 e2. https://doi.org/10.1016/j.ajo.2011.02.026. apnea syndrome. Ophthalmology. 1999;106(6):1182–5. https:// doi.org/10.1016/S0161-6420(99)90256-7. 28. Lim EWL, Chee ML, Sabanayagam C, Majithia S, Tao Y, Wong TY, et al. Relationship between sleep and symptoms of tear dys- 12. Muniesa MJ, Huerva V, Sanchez-de-la-Torre M, Martinez M, Jurjo function in Singapore Malays and Indians. Invest Ophthalmol Vis C, Barbe F. The relationship between floppy eyelid syndrome and Sci. 2019;60(6):1889–97. https://doi.org/10.1167/iovs.19-26810. obstructive sleep apnoea. Br J Ophthalmol. 2013;97(11):1387–90. https://doi.org/10.1136/bjophthalmol-2012-303051. 29. Acar M, Firat H, Yuceege M, Ardic S. Long-term effects of PAP 13. Robert PY, Adenis JP, Tapie P, Melloni B. Eyelid hyperlaxity and on ocular surface in obstructive sleep apnea syndrome. Can J obstructive sleep apnea (O.S.A.) syndrome. Eur J Ophthalmol. Ophthalmol. 2014;49(2):217–21. https://doi.org/10.1016/j.jcjo. 1997;7(3):211–5. 2013.11.010. 30. Hayirci E, Yagci A, Palamar M, Basoglu OK, Veral A. The effect 14. Woog JJ. Obstructive sleep apnea and the floppy eyelid syndrome. of continuous positive airway pressure treatment for obstructive Am J Ophthalmol. 1990;110(3):314–5. https://doi.org/10.1016/ sleep apnea syndrome on the ocular surface. Cornea. 2012;31(6): s0002-9394(14)76357-3. 604–8. https://doi.org/10.1097/ICO.0b013e31824a2040. 15. Wang P, Yu DJ, Feng G, Long ZH, Liu CJ, Li H, et al. Is floppy 31. Muniesa M, Sanchez-de-la-Torre M, Huerva V, Lumbierres M, eyelid syndrome more prevalent in obstructive sleep apnea syn- Barbe F. Floppy eyelid syndrome as an indicator of the presence drome patients? J Ophthalmol. 2016;2016:6980281. https://doi. org/10.1155/2016/6980281. of glaucoma in patients with obstructive sleep apnea. J Glaucoma. 2014;23(1):e81 –5. https://doi.org/10.1097/IJG. 16. Fox TP, Schwartz JA, Chang AC, Parvin-Nejad FP, Yim CK, 0b013e31829da19f. Feinsilver SH, et al. Association between eyelid laxity and ob- structive sleep apnea. JAMA Ophthalmol. 2017;135(10):1055– 32. Cohen Y, Ben-Mair E, Rosenzweig E, Shechter-Amir D, Solomon 61. https://doi.org/10.1001/jamaophthalmol.2017.3263. AS. The effect of nocturnal CPAP therapy on the intraocular pres- sure of patients with sleep apnea syndrome. Graefes Arch Clin 17. Bayir O, Acar M, Yuksel E, Yuceege M, Saylam G, Tatar EC, Exp Ophthalmol. 2015;253(12):2263–71. https://doi.org/10. et al. The effects of anterior palatoplasty on floppy eyelid syn- 1007/s00417-015-3153-5. drome patients with obstructive sleep apnea. Laryngoscope. 33. Fan YY, Su WW, Liu CH, Chen HS, Wu SC, Chang SHL, et al. 2016;126(9):2171–5. https://doi.org/10.1002/lary.25905. Correlation between structural progression in glaucoma and ob- 18. McNab AA. Reversal of floppy eyelid syndrome with treatment of structive sleep apnea. Eye (Lond). 2019;33(9):1459–65. https:// obstructive sleep apnoea. Clin Exp Ophthalmol. 2000;28(2):125– doi.org/10.1038/s41433-019-0430-2. 6. https://doi.org/10.1046/j.1442-9071.2000.00278.x. 34. Chen HY, Chang YC, Lin CC, Sung FC, Chen WC. Obstructive 19. Vieira MJ, Silva MJ, Lopes N, Moreira C, Carvalheira F, Sousa sleep apnea patients having surgery are less associated with glau- JP. Prospective evaluation of floppy eyelid syndrome at baseline coma. J Ophthalmol. 2014;2014:838912. https://doi.org/10.1155/ and after CPAP therapy. Curr Eye Res. 2020:1–4. https://doi.org/ 2014/838912. 10.1080/02713683.2020.1776332. 35. Aptel F, Chiquet C, Tamisier R, Sapene M, Martin F, Stach B, 20. Gupta PK, Stinnett SS, Carlson AN. Prevalence of sleep apnea in et al. Association between glaucoma and sleep apnea in a large patients with keratoconus. Cornea. 2012;31(6):595–9. https://doi. French multicenter prospective cohort. Sleep Med. 2014;15(5): org/10.1097/ICO.0b013e31823f8acd. 576–81. https://doi.org/10.1016/j.sleep.2013.11.790. 21.� Arriola-Villalobos P, Benito-Pascual B, Peraza-Nieves J, Perucho- Gonzalez L, Sastre-Ibanez M, Dupre-Pelaez MG, et al. Corneal 36. Bendel RE, Kaplan J, Heckman M, Fredrickson PA, Lin SC. Prevalence of glaucoma in patients with obstructive sleep topographic, anatomic, and biomechanical properties in severe obstructive sleep apnea-hypopnea syndrome. Cornea. apnoea–a cross-sectional case-series. Eye (Lond). 2008;22(9): 2020;39(1):88 –91. https://doi.org/10.1097/ICO. 1105–9. https://doi.org/10.1038/sj.eye.6702846. 0000000000002102 Comprehensive analysis of the corneal 37. Hashim SP, Al Mansouri FA, Farouk M, Al Hashemi AA, Singh topographic, anatomic, and biomechanical properties in R. Prevalence of glaucoma in patients with moderate to severe severe obstructive sleep apnea patients. obstructive sleep apnea: ocular morbidity and outcomes in a 3 year follow-up study. Eye (Lond). 2014;28(11):1304–9. https://doi. 22. Pedrotti E, Demasi CL, Fasolo A, Bonacci E, Brighenti T, Gennaro org/10.1038/eye.2014.195. N, et al. Obstructive sleep apnea assessed by overnight polysomnography in patients with keratoconus. Cornea. 2018;37(4): 38. Lin CC, Hu CC, Ho JD, Chiu HW, Lin HC. Obstructive sleep 470–3. https://doi.org/10.1097/ICO.0000000000001509. apnea and increased risk of glaucoma: a population-based matched-cohort study. Ophthalmology. 2013;120(8):1559–64. 23. Naderan M, Rezagholizadeh F, Zolfaghari M, Naderan M, Rajabi https://doi.org/10.1016/j.ophtha.2013.01.006. MT, Kamaleddin MA. Association between the prevalence of obstructive sleep apnoea and the severity of keratoconus. Br J 39. Wu X, Liu H. Obstructive sleep apnea/hypopnea syndrome in- Ophthalmol. 2015;99(12):1675–9. https://doi.org/10.1136/ creases glaucoma risk: evidence from a meta-analysis. Int J Clin bjophthalmol-2015-306665. Exp Med. 2015;8(1):297–303. Curr Sleep Medicine Rep (2021) 7:65–79 75 40. Perez-Rico C, Gutierrez-Diaz E, Mencia-Gutierrez E, Diaz-de- 55. Wu Y, Zhou LM, Lou H, Cheng JW, Wei RL. The association between obstructive sleep apnea and nonarteritic anterior ischemic Atauri MJ, Blanco R. Obstructive sleep apnea-hypopnea syn- drome (OSAHS) and glaucomatous optic neuropathy. Graefes optic neuropathy: a systematic review and meta-Analysis. Curr Arch Clin Exp Ophthalmol. 2014;252(9):1345–57. https://doi. Eye Res. 2016;41(7):987–92. https://doi.org/10.3109/02713683. org/10.1007/s00417-014-2669-4. 2015.1075221. 41. Cabrera M, Benavides AM, Hallaji NAE, Chung SA, Shapiro 56. Stein JD,Kim DS,Mundy KM,Talwar N,Nan B,ChervinRD, et al. CM, Trope GE, et al. Risk of obstructive sleep apnea in open- The association between glaucomatous and other causes of optic neu- angle glaucoma versus controls using the STOP-Bang question- ropathy and sleep apnea. Am J Ophthalmol. 2011;152(6):989–98 e3. naire. Can J Ophthalmol. 2018;53(1):76–80. https://doi.org/10. https://doi.org/10.1016/j.ajo.2011.04.030. 1016/j.jcjo.2017.07.008. 57. Mojon DS, Hedges TR 3rd, Ehrenberg B, Karam EZ, Goldblum 42. Bagabas N, Ghazali W, Mukhtar M, AlQassas I, Merdad R, D, Abou-Chebl A, et al. Association between sleep apnea syn- Maniyar A, et al. Prevalence of glaucoma in patients with obstruc- drome and nonarteritic anterior ischemic optic neuropathy. Arch tive sleep apnea. J Epidemiol Glob Health. 2019;9(3):198–203. Ophthalmol. 2002;120(5):601–5. https://doi.org/10.1001/ https://doi.org/10.2991/jegh.k.190816.001. archopht.120.5.601. 43. Salzgeber R, Iliev ME, Mathis J. Do optic nerve head and visual 58. Sun MH, Lee CY, Liao YJ, Sun CC. Nonarteritic anterior ischae- field parameters in patients with obstructive sleep apnea syndrome mic optic neuropathy and its association with obstructive sleep differ from those in control individuals? Klin Monatsbl apnoea: a health insurance database study. Acta Ophthalmol. Augenheilkd. 2014;231(4):340–3. https://doi.org/10.1055/s- 2019;97(1):e64–70. https://doi.org/10.1111/aos.13832. 0034-1368260. 59. Behbehani R, Mathews MK, Sergott RC, Savino PJ. Nonarteritic 44. Wozniak D, Bourne R, Peretz G, Kean J, Willshire C, Harun S, et al. anterior ischemic optic neuropathy in patients with sleep apnea Obstructive sleep apnea in patients with primary-open angle glauco- while being treated with continuous positive airway pressure. ma: no role for a screening program. J Glaucoma. 2019;28(8):668–75. Am J Ophthalmol. 2005;139(3):518–21. https://doi.org/10.1016/ https://doi.org/10.1097/IJG.0000000000001296. j.ajo.2004.11.004. 45. Keenan TD, Goldacre R, Goldacre MJ. Associations between ob- 60. Altaf QA, Dodson P, Ali A, Raymond NT, Wharton H, Fellows structive sleep apnoea, primary open angle glaucoma and age- H, et al. Obstructive sleep apnea and retinopathy in patients with related macular degeneration: record linkage study. Br J type 2 diabetes. A Longitudinal Study. Am J Respir Crit Care Ophthalmol. 2017;101(2):155–9. https://doi.org/10.1136/ Med. 2017;196(7):892–900. https://doi.org/10.1164/rccm. bjophthalmol-2015-308278. 201701-0175OC. 46. Himori N, Ogawa H, Ichinose M, Nakazawa T. CPAP therapy 61. Chang AC, Fox TP, Wang S, Wu AY. Relationship between ob- reduces oxidative stress in patients with glaucoma and OSAS structive sleep apnea and the presence and severity of diabetic and improves the visual field. Graefes Arch Clin Exp retinopathy. Retina. 2018;38(11):2197–206. https://doi.org/10. Ophthalmol. 2020;258(4):939–41. https://doi.org/10.1007/ 1097/IAE.0000000000001848. s00417-019-04483-z. 62. Chew M, Tan NYQ, Lamoureux E, Cheng CY, Wong TY, 47. Lin PW, Friedman M, Lin HC, Chang HW, Wilson M, Lin MC. Sabanayagam C. The associations of objectively measured sleep Normal tension glaucoma in patients with obstructive sleep apnea/ duration and sleep disturbances with diabetic retinopathy. hypopnea syndrome. J Glaucoma. 2011;20(9):553–8. https://doi. Diabetes Res Clin Pract. 2020;159:107967. https://doi.org/10. org/10.1097/IJG.0b013e3181f3eb81. 1016/j.diabres.2019.107967. 48. Sergi M, Salerno DE, Rizzi M, Blini M, Andreoli A, Messenio D, 63. Du C, He C, Dong L, Zheng S, Wang W, Zheng C, et al. Associations et al. Prevalence of normal tension glaucoma in obstructive sleep of apnea hypopnea index and educational attainments with microvas- apnea syndrome patients. J Glaucoma. 2007;16(1):42–6. https:// cular complications in patients with T2DM. Endocrine. 2020;67(2): doi.org/10.1097/01.ijg.0000243472.51461.24. 363–73. https://doi.org/10.1007/s12020-020-02192-w. 49. Bilgin G. Normal-tension glaucoma and obstructive sleep apnea 64. Zhang R, Zhang P, Zhao F, Han X, Ji L. Association of diabetic syndrome: a prospective study. BMC Ophthalmol. 2014;14:27. microvascular complications and parameters of obstructive sleep https://doi.org/10.1186/1471-2415-14-27. apnea in patients with type 2 diabetes. Diabetes Technol Ther. 2016;18(7):415–20. https://doi.org/10.1089/dia.2015.0433. 50. Kremmer S, Selbach JM, Ayertey HD, Steuhl KP. Normal tension glaucoma, sleep apnea syndrome and nasal continuous positive 65. Zhu Z, Zhang F, Liu Y, Yang S, Li C, Niu Q, et al. Relationship of airway pressure therapy–case report with a review of literature. obstructive sleep apnoea with diabetic retinopathy: a meta-analy- Klin Monatsbl Augenheilkd. 2001;218(4):263–8. https://doi.org/ sis. Biomed Res Int. 2017;2017:4737064. https://doi.org/10.1155/ 10.1055/s-2001-14923. 2017/4737064. 51. Aptel F, Khayi H, Pepin JL, Tamisier R, Levy P, Romanet JP, et al. 66. Vie AL, Kodjikian L, Agard E, Voirin N, El Chehab H, Denis P, Association of nonarteritic ischemic optic neuropathy with obstructive et al. Evaluation of obstructive sleep apnea syndrome as a risk sleep apnea syndrome: consequences for obstructive sleep apnea factor for diabetic macular edema in patients with type II diabetes. screening and treatment. JAMA Ophthalmol. 2015;133(7):797–804. Retina. 2019;39(2):274–80. https://doi.org/10.1097/IAE. https://doi.org/10.1001/jamaophthalmol.2015.0893. 0000000000001954. 52. Berry S, Lin WV, Sadaka A, Lee AG. Nonarteritic anterior ische- 67. Smith JP, Cyr LG, Dowd LK, Duchin KS, Lenihan PA, Sprague J. mic optic neuropathy: cause, effect, and management. Eye Brain. The Veterans Affairs continuous positive airway pressure use and 2017;9:23–8. https://doi.org/10.2147/EB.S125311. diabetic retinopathy study. Optom Vis Sci. 2019;96(11):874–8. https://doi.org/10.1097/OPX.0000000000001446. 53. Bilgin G, Koban Y, Arnold AC. Nonarteritic anterior ischemic optic neuropathy and obstructive sleep apnea. J 68. Shiba T, Takahashi M, Matsumoto T, Hori Y. Sleep-disordered Neuroophthalmol. 2013;33(3):232–4. https://doi.org/10.1097/ breathing is a stronger risk factor for proliferative diabetic retinop- WNO.0b013e31828eecbd. athy than metabolic syndrome and the number of its individual components. Semin Ophthalmol. 2019;34(2):59–65. https://doi. 54. Chang MY, Keltner JL. Risk factors for fellow eye involvement in org/10.1080/08820538.2019.1569074. nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol. 2019;39(2):147–52. https://doi.org/10.1097/ 69. Tan NYQ, Chew M, Tham YC, Nguyen QD, Yasuda M, Cheng WNO.0000000000000715. CY, et al. Associations between sleep duration, sleep quality and 76 Curr Sleep Medicine Rep (2021) 7:65–79 diabetic retinopathy. PLoS One. 2018;13(5):e0196399. https:// 85. West SD, Prudon B, Hughes J, Gupta R, Mohammed SB, Gerry S, et al. Continuous positive airway pressure effect on visual acuity doi.org/10.1371/journal.pone.0196399. 70. Leong WB, Jadhakhan F, Taheri S, Chen YF, Adab P, Thomas in patients with type 2 diabetes and obstructive sleep apnoea: a multicentre randomised controlled trial. Eur Respir J. 2018;52(4). GN. Effect of obstructive sleep apnoea on diabetic retinopathy and maculopathy: a systematic review and meta-analysis. Diabet Med. https://doi.org/10.1183/13993003.01177-2018. 2016;33(2):158–68. https://doi.org/10.1111/dme.12817. 86. Agard E, El Chehab H, Vie AL, Voirin N, Coste O, Dot C. Retinal 71. He M, Huang W. The role of choroidal thickness in diabetic reti- vein occlusion and obstructive sleep apnea: a series of 114 pa- nopathy and obstructive sleep apnea syndrome. Sleep Breath. tients. Acta Ophthalmol. 2018;96(8):e919–e25. https://doi.org/ 2016;20(3):1009–10. https://doi.org/10.1007/s11325-016-1343-y. 10.1111/aos.13798. 72. Baba A, Zbiba W, Bouayed E, Korbi M, Ghrairi H. Obstructive 87. Govetto A, Dominguez R, Rojas L, Pereiro M, Lorente R. Bilateral sleep apnea syndrome. Is it a risk factor for diabetic retinopathy? J and simultaneous central retinal vein occlusion in a patient with ob- Fr Ophtalmol. 2016;39(2):139–42. https://doi.org/10.1016/j.jfo. structive sleep apnea syndrome. Case Rep Ophthalmol. 2014;5(2): 2015.08.014. 150–6. https://doi.org/10.1159/000363132. 73. Nishimura A, Kasai T, Tamura H, Yamato A, Yasuda D, 88. Turati M, Velez-Montoya R, Gonzalez-Mijares CC, Perez- Nagasawa K, et al. Relationship between sleep disordered breath- Montesinos A, Quiroz-Mercado H, Garcia-Aguirre G. Bilateral ing and diabetic retinopathy: analysis of 136 patients with diabe- central retina vein occlusion associated with obesity- tes. Diabetes Res Clin Pract. 2015;109(2):306–11. https://doi.org/ hypoventilation syndrome (pickwickian syndrome). Retin Cases 10.1016/j.diabres.2015.05.015. Brief Rep. 2009;3(2):140–3. https://doi.org/10.1097/ICB. 74. Banerjee D, Leong WB, Arora T, Nolen M, Punamiya V, 0b013e31815e9919. Grunstein R, et al. The potential association between obstructive 89. Kwon HJ, Kang EC, Lee J, Han J, Song WK. Obstructive sleep sleep apnea and diabetic retinopathy in severe obesity-the role of apnea in patients with branch retinal vein occlusion: a preliminary hypoxemia. PLoS One. 2013;8(11):e79521. https://doi.org/10. study. Korean J Ophthalmol. 2016;30(2):121–6. https://doi.org/ 1371/journal.pone.0079521. 10.3341/kjo.2016.30.2.121. 75. Rudrappa S, Warren G, Idris I. Obstructive sleep apnoea is asso- 90. Kanai H, Shiba T, Hori Y, Saishin Y, Maeno T, Takahashi M. ciated with the development and progression of diabetic retinopa- Prevalence of sleep-disordered breathing in patients with retinal thy, independent of conventional risk factors and novel bio- vein occlusion. Nippon Ganka Gakkai Zasshi. 2012;116(2):81–5. markers for diabetic retinopathy. Br J Ophthalmol. 2012;96(12): 91. Chou KT, Huang CC, Tsai DC, Chen YM, Perng DW, Shiao GM, 1535. https://doi.org/10.1136/bjophthalmol-2012-301991. et al. Sleep apnea and risk of retinal vein occlusion: a nationwide 76. Mason RH, West SD, Kiire CA, Groves DC, Lipinski HJ, Jaycock population-based study of Taiwanese. Am J Ophthalmol. A, et al. High prevalence of sleep disordered breathing in patients 2012;154(1):200–5e1. https://doi.org/10.1016/j.ajo.2012.01.011. with diabetic macular edema. Retina. 2012;32(9):1791–8. https:// 92. Glacet-Bernard A. Leroux les Jardins G, Lasry S, Coscas G, doi.org/10.1097/IAE.0b013e318259568b. Soubrane G, Souied E et al. Obstructive sleep apnea among patients 77. Shiba T, Takahashi M, Hori Y, Saishin Y, Sato Y, Maeno T. with retinal vein occlusion. Arch Ophthalmol. 2010;128(12):1533– Relationship between sleep-disordered breathing and iris and/or 8. https://doi.org/10.1001/archophthalmol.2010.272. angle neovascularization in proliferative diabetic retinopathy 93. Leroux les Jardins G, Glacet Bernard A, Lasry S, Housset B, cases. Am J Ophthalmol. 2011;151(4):604–9. https://doi.org/10. Coscas G, Soubrane G. Retinal vein occlusion and obstructive 1016/j.ajo.2010.10.002. sleep apnea syndrome. J Fr Ophtalmol. 2009;32(6):420–4. 78. Shiba T, Takahashi M, Hori Y, Saishin Y, Sato Y, Maeno T. https://doi.org/10.1016/j.jfo.2009.04.012. Evaluation of the relationship between background factors and 94. Wu CY, Riangwiwat T, Rattanawong P, Nesmith BLW, sleep-disordered breathing in patients with proliferative diabetic Deobhakta A. Association of obstructive sleep apnea with central retinopathy. Jpn J Ophthalmol. 2011;55(6):638–42. https://doi. serous chorioretinopathy and choroidal thickness: a systematic org/10.1007/s10384-011-0076-5. review and meta-analysis. Retina. 2018;38(9):1642–51. https:// 79. West SD, Groves DC, Lipinski HJ, Nicoll DJ, Mason RH, doi.org/10.1097/IAE.0000000000002117. Scanlon PH, et al. The prevalence of retinopathy in men with type 95. Brodie FL, Charlson ES, Aleman TS, Salvo RT, Gewaily DY, Lau 2 diabetes and obstructive sleep apnoea. Diabet Med. 2010;27(4): MK, et al. Obstructive sleep apnea and central serous 423–30. https://doi.org/10.1111/j.1464-5491.2010.02962.x. chorioretinopathy. Retina. 2015;35(2):238–43. https://doi.org/10. 80. Shiba T, Maeno T, Saishin Y, Hori Y, Takahashi M. Nocturnal 1097/IAE.0000000000000326. intermittent serious hypoxia and reoxygenation in proliferative 96. Chang YS, Weng SF, Wang JJ, Jan RL. Increased risk of central diabetic retinopathy cases. Am J Ophthalmol. 2010;149(6):959– serous chorioretinopathy following end-stage renal disease: a nation- 63. https://doi.org/10.1016/j.ajo.2010.01.006. wide population-based study. Medicine (Baltimore). 2019;98(11): 81. Kosseifi S, Bailey B, Price R, Roy TM, Byrd RP Jr, Peiris AN. The e14859. https://doi.org/10.1097/MD.0000000000014859. association between obstructive sleep apnea syndrome and microvas- 97. Chatziralli I, Kabanarou SA, Parikakis E, Chatzirallis A, Xirou T, cular complications in well-controlled diabetic patients. Mil Med. Mitropoulos P. Risk factors for central serous chorioretinopathy: mul- 2010;175(11):913–6. https://doi.org/10.7205/milmed-d-10-00131. tivariate approach in a case-control study. Curr Eye Res. 2017;42(7): 82. Shiba T, Sato Y, Takahashi M. Relationship between diabetic 1069–73. https://doi.org/10.1080/02713683.2016.1276196. retinopathy and sleep-disordered breathing. Am J Ophthalmol. 98. Kloos P, Laube I, Thoelen A. Obstructive sleep apnea in patients 2009;147(6):1017–21. https://doi.org/10.1016/j.ajo.2008.12.027. with central serous chorioretinopathy. Graefes Arch Clin Exp 83. Mason RH, Kiire CA, Groves DC, Lipinski HJ, Jaycock A, Winter Ophthalmol. 2008;246(9):1225–8. https://doi.org/10.1007/ BC, et al. Visual improvement following continuous positive airway s00417-008-0837-0. pressure therapy in diabetic subjects with clinically significant macular 99. Leveque TK, Yu L, Musch DC, Chervin RD, Zacks DN. Central oedema and obstructive sleep apnoea: proof of principle study. Respiration. 2012;84(4):275–82. https://doi.org/10.1159/000334090. serous chorioretinopathy and risk for obstructive sleep apnea. Sleep Breath. 2007;11(4):253–7. https://doi.org/10.1007/s11325- 84. Raman R, Verma A, Srinivasan S, Bhojwani D. Partial reversal of 007-0112-3. color vision impairment in type 2 diabetes associated with obstruc- tive sleep apnea. GMS Ophthalmol Cases. 2018;8:Doc05. https:// 100. Yavas GF, Kusbeci T, Kasikci M, Gunay E, Dogan M, Unlu M, doi.org/10.3205/oc000087. et al. Obstructive sleep apnea in patients with central serous Curr Sleep Medicine Rep (2021) 7:65–79 77 chorioretinopathy. Curr Eye Res. 2014;39(1):88–92. https://doi. syndrome. Eye Contact Lens. 2018;44(Suppl 2):S361–S4. org/10.3109/02713683.2013.824986. https://doi.org/10.1097/ICL.0000000000000489. 101. Nesmith BL, Ihnen M, Schaal S. Poor responders to bevacizumab 118. Huseyinoglu N, Ekinci M, Ozben S, Buyukuysal C, Kale MY, pharmacotherapy in age-related macular degeneration and in dia- Sanivar HS. Optic disc and retinal nerve fiber layer parameters betic macular edema demonstrate increased risk for obstructive as indicators of neurodegenerative brain changes in patients with sleep apnea. Retina. 2014;34(12):2423–30. https://doi.org/10. obstructive sleep apnea syndrome. Sleep Breath. 2014;18(1):95– 1097/IAE.0000000000000247. 102. https://doi.org/10.1007/s11325-013-0854-z. 102. Schaal S, Sherman MP, Nesmith B, Barak Y. Untreated obstruc- 119.� Yang HK, Park SJ, Byun SJ, Park KH, Kim JW, Hwang JM. tive sleep apnea hinders response to bevacizumab in age-related Obstructive sleep apnoea and increased risk of non-arteritic ante- macular degeneration. Retina. 2016;36(4):791–7. https://doi.org/ rior ischaemic optic neuropathy. Br J Ophthalmol. 2019;103(8): 10.1097/IAE.0000000000000981. 1123–8. https://doi.org/10.1136/bjophthalmol-2018-312910 A 103. Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP. nationwide population-based, retrospective cohort study Pathophysiology of sleep apnea. Physiol Rev. 2010;90(1):47– showing increased risk of NAION in the OSA group. 112. https://doi.org/10.1152/physrev.00043.2008. 120.� SSY L, McArdle N, Sanfilippo PG, Yazar S, Eastwood PR, Hewitt AW, et al. Associations between optic disc measures and obstruc- 104. Veasey SC, Rosen IM. Obstructive sleep apnea in adults. N Engl J tive sleep apnea in young adults. Ophthalmology. 2019;126(10): Med. 2019;380(15):1442–9. https://doi.org/10.1056/ 1372–84. https://doi.org/10.1016/j.ophtha.2019.04.041 NEJMcp1816152. Preclinical peripapillary RNFL thinning was present in 105. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive young adults with obstructive sleep apnea suggesting possible sleep apnea: a population health perspective. Am J Respir Crit increased glaucoma risk in these patients. Care Med. 2002;165(9):1217–39. https://doi.org/10.1164/rccm. 2109080. 121. Shiba T, Takahashi M, Sato Y, Onoda Y, Hori Y, Sugiyama T, et al. Relationship between severity of obstructive sleep apnea 106. Bostanci A, Bozkurt S, Turhan M. Impact of age on intermittent syndrome and retinal nerve fiber layer thickness. Am J hypoxia in obstructive sleep apnea: a propensity-matched analysis. Ophthalmol. 2014;157(6):1202–8. https://doi.org/10.1016/j.ajo. Sleep Breath. 2018;22(2):317–22. https://doi.org/10.1007/ 2014.01.028. s11325-017-1560-z. 122. Wang W, He M, Huang W. Changes of retinal nerve fiber layer 107. Clark RA, Suh SY, Caprioli J, Giaconi JA, Nouri-Mahdavi K, Law thickness in obstructive sleep apnea syndrome: a systematic re- SK, et al. Adduction-induced strain on the optic nerve in primary open view and meta-analysis. Curr Eye Res. 2017;42(5):796–802. angle glaucoma at normal intraocular pressure. Curr Eye Res. 2020:1– https://doi.org/10.1080/02713683.2016.1238942. 11. https://doi.org/10.1080/02713683.2020.1817491. 123. Yu JG, Mei ZM, Ye T, Feng YF, Zhao F, Jia J, et al. Changes in 108. Li Y, Wei Q, Le A, Gawargious BA, Demer JL. Rectus retinal nerve fiber layer thickness in obstructive sleep apnea/ extraocular muscle paths and staphylomata in high myopia. Am hypopnea syndrome: a meta-analysis. Ophthalmic Res. J Ophthalmol. 2019;201:37–45. https://doi.org/10.1016/j.ajo. 2016;56(2):57–67. https://doi.org/10.1159/000444301. 2019.01.029. 124. Friedman DI, Jacobson DM. Diagnostic criteria for idiopathic in- 109. Netland PA, Sugrue SP, Albert DM, Shore JW. Histopathologic tracranial hypertension. Neurology. 2002;59(10):1492–5. https:// features of the floppy eyelid syndrome. involvement of tarsal elas- doi.org/10.1212/01.wnl.0000029570.69134.1b. tin. Ophthalmology. 1994;101(1):174–81. https://doi.org/10. 1016/s0161-6420(94)31368-6. 125. Wall M, Purvin V. Idiopathic intracranial hypertension in men and 110. Schlotzer-Schrehardt U, Stojkovic M, Hofmann-Rummelt C, the relationship to sleep apnea. Neurology. 2009;72(4):300–1. Cursiefen C, Kruse FE, Holbach LM. The pathogenesis of floppy https://doi.org/10.1212/01.wnl.0000336338.97703.fb. eyelid syndrome: involvement of matrix metalloproteinases in 126. Lee AG, Golnik K, Kardon R, Wall M, Eggenberger E, Yedavally elastic fiber degradation. Ophthalmology. 2005;112(4):694–704. S. Sleep apnea and intracranial hypertension in men. https://doi.org/10.1016/j.ophtha.2004.11.031. Ophthalmology. 2002;109(3):482–5. https://doi.org/10.1016/ s0161-6420(01)00987-3. 111. Series F, Chakir J, Boivin D. Influence of weight and sleep apnea status on immunologic and structural features of the uvula. Am J 127. Sugita Y, Iijima S, Teshima Y, Shimizu T, Nishimura N, Tsutsumi Respir Crit Care Med. 2004;170(10):1114–9. https://doi.org/10. T, et al. Marked episodic elevation of cerebrospinal fluid pressure 1164/rccm.200404-458OC. during nocturnal sleep in patients with sleep apnea hypersomnia syndrome. Electroencephalogr Clin Neurophysiol. 1985;60(3): 112. Acar M, Firat H, Acar U, Ardic S. Ocular surface assessment in patients with obstructive sleep apnea-hypopnea syndrome. Sleep 214–9. https://doi.org/10.1016/0013-4694(85)90033-1. Breath. 2013;17(2):583–8. https://doi.org/10.1007/s11325-012- 128. Purvin VA, Kawasaki A, Yee RD. Papilledema and obstructive 0724-0. sleep apnea syndrome. Arch Ophthalmol. 2000;118(12):1626–30. 113. du Toit R, Vega JA, Fonn D, Simpson T. Diurnal variation of https://doi.org/10.1001/archopht.118.12.1626. corneal sensitivity and thickness. Cornea. 2003;22(3):205–9. 129. Onder H, Aksoy M. Resolution of idiopathic intracranial hyper- https://doi.org/10.1097/00003226-200304000-00004. tension symptoms by surgery for obstructive sleep apnea in a pediatric patient. J Pediatr Neurosci. 2019;14(2):110–2. https:// 114. Polse KA, Mandell RB. Critical oxygen tension at the corneal doi.org/10.4103/jpn.JPN_30_19. surface. Arch Ophthalmol. 1970;84(4):505–8. https://doi.org/10. 1001/archopht.1970.00990040507021. 130. Lacharme T, Almanjoumi A, Aptel F, Khayi H, Pepin JL, Baguet 115. Gelir E, Budak MT, Ardic S. The relationship between CPAP JP, et al. Twenty-four-hour rhythm of ocular perfusion pressure in usage and corneal thickness. PLoS One. 2014;9(1):e87274. non-arteritic anterior ischaemic optic neuropathy. Acta https://doi.org/10.1371/journal.pone.0087274. Ophthalmol. 2014;92(5):e346–52. https://doi.org/10.1111/aos. 116. Koseoglu HI, Kanbay A, Ortak H, Karadag R, Demir O, Demir S, et al. Effect of obstructive sleep apnea syndrome on corneal thick- 131. Hayreh SS. Blood flow in the optic nerve head and factors that ness. Int Ophthalmol. 2016;36(3):327–33. https://doi.org/10. may influence it. Prog Retin Eye Res. 2001;20(5):595–624. 1007/s10792-015-0122-2. https://doi.org/10.1016/s1350-9462(01)00005-2. 132. Hayreh SS, Podhajsky PA, Zimmerman B. Nonarteritic anterior 117. Dikkaya F, Yildirim R, Erdur SK, Benbir G, Aydin R, Karadeniz ischemic optic neuropathy: time of onset of visual loss. Am J D. Corneal biomechanical properties in obstructive sleep apnea 78 Curr Sleep Medicine Rep (2021) 7:65–79 Ophthalmol. 1997;124(5):641–7. https://doi.org/10.1016/s0002- chorioretinopathy: a review. Med Hypothesis Discov Innov Ophthalmol. 2017;6(4):118–24. 9394(14)70902-x. 133. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL. 149. Tsai CC, Kuo TY, Hong ZW, Yeh YC, Shih KS, Du SY, et al. Nocturnal arterial hypotension and its role in optic nerve head Helicobacter pylori neutrophil-activating protein induces release and ocular ischemic disorders. Am J Ophthalmol. 1994;117(5): of histamine and interleukin-6 through G protein-mediated 603–24. https://doi.org/10.1016/s0002-9394(14)70067-4. MAPKs and PI3K/Akt pathways in HMC-1 cells. Virulence. 134. Phillips BG, Narkiewicz K, Pesek CA, Haynes WG, Dyken ME, 2015;6(8):755–65. https://doi.org/10.1080/21505594.2015. Somers VK. Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens. 1999;17(1):61–6. https://doi. 150. Caruso RA, Parisi A, Crisafulli C, Bonanno A, Lucian R, Branca org/10.1097/00004872-199917010-00010. G, et al. Intraepithelial infiltration by mast cells in human 135. Hayreh SS. Ischemic optic neuropathy. Prog Retin Eye Res. Helicobacter pylori active gastritis. Ultrastruct Pathol. 2009;28(1):34–62. https://doi.org/10.1016/j.preteyeres.2008.11. 2011;35(6):251–5. https://doi.org/10.3109/01913123.2011. 136. Palombi K, Renard E, Levy P, Chiquet C, Deschaux C, Romanet 151. Nakajima S, Bamba N, Hattori T. Histological aspects and role of JP, et al. Non-arteritic anterior ischaemic optic neuropathy is near- mast cells in Helicobacter pylori-infected gastritis. Aliment ly systematically associated with obstructive sleep apnoea. Br J Pharmacol Ther. 2004;20(Suppl 1):165–70. https://doi.org/10. Ophthalmol. 2006;90(7):879–82. https://doi.org/10.1136/bjo. 1111/j.1365-2036.2004.01974.x. 2005.087452. 152. Yamamoto J, Watanabe S, Hirose M, Osada T, Ra C, Sato N. Role 137. Nickla DL, Wallman J. The multifunctional choroid. Prog Retin of mast cells as a trigger of inflammation in Helicobacter pylori Eye Res. 2010;29(2):144–68. https://doi.org/10.1016/j.preteyeres. infection. J Physiol Pharmacol. 1999;50(1):17–23. 2009.12.002. 153. Nakajima S, Krishnan B, Ota H, Segura AM, Hattori T, Graham 138. Tonini M, Khayi H, Pepin JL, Renard E, Baguet JP, Levy P, et al. DY, et al. Mast cell involvement in gastritis with or without Choroidal blood-flow responses to hyperoxia and hypercapnia in Helicobacter pylori infection. Gastroenterology. 1997;113(3): men with obstructive sleep apnea. Sleep. 2010;33(6):811–8. 746–54. https://doi.org/10.1016/s0016-5085(97)70167-7. https://doi.org/10.1093/sleep/33.6.811. 154. Kurose I, Granger DN, Evans DJ Jr, Evans DG, Graham DY, 139. Xin C, Wang J, Zhang W, Wang L, Peng X. Retinal and choroidal Miyasaka M, et al. Helicobacter pylori-induced microvascular thickness evaluation by SD-OCT in adults with obstructive sleep protein leakage in rats: role of neutrophils, mast cells, and plate- apnea-hypopnea syndrome (OSAS). Eye (Lond). 2014;28(4): lets. Gastroenterology. 1994;107(1):70–9. https://doi.org/10. 415–21. https://doi.org/10.1038/eye.2013.307. 1016/0016-5085(94)90062-0. 140. Karaca EE, Ekici F, Yalcin NG, Ciftci TU, Ozdek S. Macular 155. Kountouras C, Polyzos SA, Stergiopoulos C, Katsinelos P, choroidal thickness measurements in patients with obstructive Tzivras D, Zavos C, et al. A potential impact of Helicobacter sleep apnea syndrome. Sleep Breath. 2015;19(1):335–41. https:// pylori infection on both obstructive sleep apnea and atrial doi.org/10.1007/s11325-014-1025-6. fibrillation-related stroke. Sleep Med. 2017;34:256. https://doi. 141. He M, Han X, Wu H, Huang W. Choroidal thickness changes in org/10.1016/j.sleep.2017.03.010. obstructive sleep apnea syndrome: a systematic review and meta- 156. Banawan LAH, Daabis RGA, Elsheikh WH, Tolba MM, Youssef analysis. Sleep Breath. 2016;20(1):369–78. https://doi.org/10. AM. The prevalence of Helicobacter pylori infection in patients 1007/s11325-015-1306-8. with obstructive sleep apnea having metabolic syndrome and its 142. Zengin MO, Oz T, Baysak A, Cinar E, Kucukerdonmez C. relation to both disorders. Egyptian Journal of Bronchology. Changes in choroidal thickness in patients with obstructive sleep 2017;11(3):268–75. https://doi.org/10.4103/ejb.ejb_54_16. apnea syndrome. Ophthalmic Surg Lasers Imaging Retina. 157. Wasilewska J, Klukowski M, Debkowska K, Kilon J, Citko D, 2014;45(4):298–304. https://doi.org/10.3928/23258160- Flisiak M, et al. Helicobacter pylori seroprevalence in children 20140624-02. with sleep-disordered breathing. Int J Pediatr Otorhinolaryngol. 143. Karalezli A, Eroglu FC, Kivanc T, Dogan R. Evaluation of cho- 2016;87:208–12. https://doi.org/10.1016/j.ijporl.2016.06.024. roidal thickness using spectral-domain optical coherence tomog- 158. Kountouras J, Polyzos SA, Deretzi G. Helicobacter pylori associ- raphy in patients with severe obstructive sleep apnea syndrome: a ated with obstructive sleep apnea might contribute to sleep, cog- comparative study. Int J Ophthalmol. 2014;7(6):1030–4. https:// nition, and driving performance disturbances in patients with cir- doi.org/10.3980/j.issn.2222-3959.2014.06.22. rhosis. Clin Gastroenterol Hepatol. 2015;13(8):1547. https://doi. 144. Uslu H, Kanra AY, Cetintas G, Tatar MG. Effect of therapy on org/10.1016/j.cgh.2015.02.009. choroidal thickness in patients with obstructive sleep apnea syn- 159. Nartova E, Kraus J, Pavlik E, Lukes P, Katra R, Plzak J, et al. drome. Ophthalmic Surg Lasers Imaging Retina. 2018;49(11): Presence of different genotypes of Helicobacter pylori in patients 846–51. https://doi.org/10.3928/23258160-20181101-05. with chronic tonsillitis and sleep apnoea syndrome. Eur Arch 145. Cakabay T, Ustun Bezgin S, Bayramoglu SE, Sayin N, Kocyigit Otorhinolaryngol. 2014;271(3):607–13. https://doi.org/10.1007/ M. Evaluation of choroidal thickness in children with adenoid s00405-013-2607-9. hypertrophy. Eur Arch Otorhinolaryngol. 2018;275(2):439–42. 160. Stergiopoulos C, Kountouras J, Daskalopoulou-Vlachoyianni E, https://doi.org/10.1007/s00405-017-4846-7. Polyzos SA, Zavos C, Vlachoyiannis E, et al. Helicobacter pylori 146. Ghimire-Aryal P, Schwartz S, Sebastião YV, Anderson WM, may play a role in both obstructive sleep apnea and metabolic Foul is PR. 0914 Association between obstructive sleep apnea, syndrome. Sleep Med. 2012;13(2):212–3. https://doi.org/10. nightmare disorder and incident herpes zoster. Sleep. 1016/j.sleep.2011.04.016. 2018;41(suppl_1):A339–A40. https://doi.org/10.1093/sleep/ zsy061.913. 161. Ye XW, Xiao J, Qiu T, Tang YJ, Feng YL, Wang K, et al. Helicobacter pylori seroprevalence in patients with obstructive 147. Chung WS, Lin HH, Cheng NC. The incidence and risk of herpes zoster in patients with sleep disorders: a population-based cohort sleep apnea syndrome among a Chinese population. Saudi Med J. 2009;30(5):693–7. study. Medicine (Baltimore). 2016;95(11):e2195. https://doi.org/ 10.1097/MD.0000000000002195. 162. Unal M, Ozturk L, Ozturk C, Kabal A. The seroprevalence of 148. Bagheri M, Rashe Z, Ahoor MH, Somi MH. Prevalence of Helicobacter pylori infection in patients with obstructive sleep Helicobacter pylori infection in patients with central serous apnoea: a preliminary study. Clin Otolaryngol Allied Sci. Curr Sleep Medicine Rep (2021) 7:65–79 79 2003;28(2):100–2. https://doi.org/10.1046/j.1365-2273.2003. meta-analysis. PLoS One. 2014;9(1):e85718. https://doi.org/10. 1371/journal.pone.0085718. 00672.x. 163. Bousquet E, Zhao M, Thillaye-Goldenberg B, Lorena V, 178. Lee JY, Ahn J, Oh S, Shin JY, Kim YK, Nam H, et al. Retina Castaneda B, Naud MC, et al. Choroidal mast cells in retinal thickness as a marker of neurodegeneration in prodromal lewy pathology: a potential target for intervention. Am J Pathol. body disease. Mov Disord. 2020;35(2):349–54. https://doi.org/ 2015;185(8):2083–95. https://doi.org/10.1016/j.ajpath.2015.04. 10.1002/mds.27914. 179. Chrysou A, Jansonius NM, van Laar T. Retinal layers in 164. Casas P, Ascaso FJ, Vicente E, Tejero-Garces G, Adiego MI, Parkinson’s disease: a meta-analysis of spectral-domain optical Cristobal JA. Visual field defects and retinal nerve fiber imaging coherence tomography studies. Parkinsonism Relat Disord. in patients with obstructive sleep apnea syndrome and in healthy 2019;64:40–9. https://doi.org/10.1016/j.parkreldis.2019.04.023. controls. BMC Ophthalmol. 2018;18(1):66. https://doi.org/10. 180. Yang ZJ, Wei J, Mao CJ, Zhang JR, Chen J, Ji XY, et al. Retinal 1186/s12886-018-0728-z. nerve fiber layer thinning: a window into rapid eye movement 165. Yazgan S, Erboy F, Celik HU, Ornek T, Ugurbas SH, Kokturk F, sleep behavior disorders in Parkinson’s disease. Sleep Breath. et al. Peripapillary choroidal thickness and retinal nerve fiber layer 2016;20(4):1285–92. https://doi.org/10.1007/s11325-016-1366- in untreated patients with obstructive sleep apnea-hypopnea syn- drome: a case-control study. Curr Eye Res. 2017;42(11):1552–60. 181. Ahn J, Lee JY, Kim TW, Yoon EJ, Oh S, Kim YK, et al. Retinal https://doi.org/10.1080/02713683.2016.1266661. thinning associates with nigral dopaminergic loss in de novo 166. Zhao XJ, Yang CC, Zhang JC, Zheng H, Liu PP, Li Q. Parkinson disease. Neurology. 2018;91(11):e1003–e12. https:// Obstructive sleep apnea and retinal nerve fiber layer thickness: a doi.org/10.1212/WNL.0000000000006157. meta-analysis. J Glaucoma. 2016;25(4):e413–8. https://doi.org/ 182. Lax P, Ortuno-Lizaran I, Maneu V, Vidal-Sanz M, Cuenca N. 10.1097/IJG.0000000000000349. Photosensitive melanopsin-containing retinal ganglion cells in 167. Sun CL, Zhou LX, Dang Y, Huo YP, Shi L, Chang YJ. Decreased health and disease: implications for circadian rhythms. Int J Mol retinal nerve fiber layer thickness in patients with obstructive sleep Sci. 2019;20(13). https://doi.org/10.3390/ijms20133164. apnea syndrome: a meta-analysis. Medicine (Baltimore). 183. Do MTH. Melanopsin and the intrinsically photosensitive retinal 2016;95(32):e4499. https://doi.org/10.1097/MD. ganglion cells: biophysics to behavior. Neuron. 2019;104(2):205– 26. https://doi.org/10.1016/j.neuron.2019.07.016. 168. Ferrandez B, Ferreras A, Calvo P, Abadia B, Marin JM, Pajarin 184. Ortuno-Lizaran I, Esquiva G, Beach TG, Serrano GE, Adler CH, AB. Assessment of the retinal nerve fiber layer in individuals with Lax P, et al. Degeneration of human photosensitive retinal gangli- obstructive sleep apnea. BMC Ophthalmol. 2016;16:40. https:// on cells may explain sleep and circadian rhythms disorders in doi.org/10.1186/s12886-016-0216-2. Parkinson’s disease. Acta Neuropathol Commun. 2018;6(1):90. 169. Cinici E, Tatar A. Thickness alterations of retinal nerve fiber layer https://doi.org/10.1186/s40478-018-0596-z. in children with sleep-disordered breathing due to adenotonsillar 185. Ryan S, Taylor CT, McNicholas WT. Selective activation of in- hypertrophy. Int J Pediatr Otorhinolaryngol. 2015;79(8):1218–23. flammatory pathways by intermittent hypoxia in obstructive sleep https://doi.org/10.1016/j.ijporl.2015.05.017. apnea syndrome. Circulation. 2005;112(17):2660–7. https://doi. 170. Moghimi S, Ahmadraji A, Sotoodeh H, Sadeghniat K, org/10.1161/CIRCULATIONAHA.105.556746. Maghsoudipour M, Fakhraie G, et al. Retinal nerve fiber thick- 186. Fletcher EC. Sympathetic over activity in the etiology of hyper- ness is reduced in sleep apnea syndrome. Sleep Med. 2013;14(1): tension of obstructive sleep apnea. Sleep. 2003;26(1):15–9. 53–7. https://doi.org/10.1016/j.sleep.2012.07.004. https://doi.org/10.1093/sleep/26.1.15. 171. Adam M, Okka M, Yosunkaya S, Bozkurt B, Kerimoglu H, Turan 187. Kaczmarek E, Bakker JP, Clarke DN, Csizmadia E, Kocher O, M. The evaluation of retinal nerve fiber layer thickness in patients Veves A, et al. Molecular biomarkers of vascular dysfunction in with obstructive sleep apnea syndrome. J Ophthalmol. 2013;2013: obstructive sleep apnea. PLoS One. 2013;8(7):e70559. https://doi. 292158. https://doi.org/10.1155/2013/292158. org/10.1371/journal.pone.0070559. 172. Lin PW, Friedman M, Lin HC, Chang HW, Pulver TM, Chin CH. 188. Li Q, Verma A, Han PY, Nakagawa T, Johnson RJ, Grant MB, Decreased retinal nerve fiber layer thickness in patients with ob- et al. Diabetic eNOS-knockout mice develop accelerated retinop- structive sleep apnea/hypopnea syndrome. Graefes Arch Clin Exp athy. Invest Ophthalmol Vis Sci. 2010;51(10):5240–6. https://doi. Ophthalmol. 2011;249(4):585–93. https://doi.org/10.1007/ org/10.1167/iovs.09-5147. s00417-010-1544-1. 189. Kida T, Flammer J, Oku H, Konieczka K, Morishita S, Horie T, 173. Kargi SH, Altin R, Koksal M, Kart L, Cinar F, Ugurbas SH, et al. et al. Vasoactivity of retinal veins: a potential involvement of Retinal nerve fibre layer measurements are reduced in patients endothelin-1 (ET-1) in the pathogenesis of retinal vein occlusion with obstructive sleep apnoea syndrome. Eye (Lond). (RVO). Exp Eye Res. 2018;176:207–9. https://doi.org/10.1016/j. 2005;19(5):575–9. https://doi.org/10.1038/sj.eye.6701582. exer.2018.07.016. 174. Wang JS, Xie HT, Jia Y, Zhang MC. Retinal nerve fiber layer 190. Totan Y, Koca C, Erdurmus M, Keskin U, Yigitoglu R. thickness changes in obstructive sleep apnea syndrome: a system- Endothelin-1 and Nitric oxide levels in exudative age-related atic review and meta-analysis. Int J Ophthalmol. 2016;9(11): macular degeneration. J Ophthalmic Vis Res. 2015;10(2):151–4. 1651–6. https://doi.org/10.18240/ijo.2016.11.19. https://doi.org/10.4103/2008-322X.163765. 175. Comella CL. Sleep disorders in Parkinson’sdisease: anoverview. 191. Mentek M, Morand J, Baldazza M, Faury G, Aptel F, Pepin JL, Mov Disord. 2007;22(Suppl 17):S367–73. https://doi.org/10. et al. Chronic intermittent hypoxia alters rat ophthalmic artery 1002/mds.21682. reactivity through oxidative stress, endothelin and endothelium- 176. Nomura T, Inoue Y, Kagimura T, Nakashima K. Clinical signifi- derived hyperpolarizing pathways. Invest Ophthalmol Vis Sci. cance of REM sleep behavior disorder in Parkinson’s disease. 2018;59(12):5256–65. https://doi.org/10.1167/iovs.18-25151. Sleep Med. 2013;14(2):131–5. https://doi.org/10.1016/j.sleep. 2012.10.011. 177. Yu JG, Feng YF, Xiang Y, Huang JH, Savini G, Parisi V, et al. Publisher’sNote Springer Nature remains neutral with regard to jurisdic- Retinal nerve fiber layer thickness changes in Parkinson disease: a tional claims in published maps and institutional affiliations.

Journal

Current Sleep Medicine ReportsSpringer Journals

Published: Sep 1, 2021

Keywords: Obstructive sleep apnea; Floppy eyelid syndrome; Optic neuropathy; Nonarteritic anterior ischemic optic neuropathy (NAION); Retinal vascular disease

References