Obstructive Sleep Apnea in Neuro-Ophthalmology

Background: Obstructive sleep apnea (OSA) is a common pulmonary disorder with many systemic sequelae. Its association with diseases seen in neuro-ophthalmology is being increasingly recognized. Treatment of OSA with continuous positive airway pressure (CPAP) may reverse the pathology in some eye diseases. Evidence acquisition: We conducted a search of the literature using the Ovid Medline database and Google Scholar, focusing on articles that explored the association between OSA and ophthalmic conditions. These included hypertensive retinopathy, diabetic retinopathy, central serous retinopathy (CSR), retinal vein occlusion (RVO), nonarteritic anterior ischemic optic neuropathy (NAION), glaucoma, idiopathic intracranial hypertension (IIH), papilledema, and stroke. Results: There is evidence of an independent association between OSA, and both hypertension and Type 2 diabetes mellitus, as well as the retinopathy associated with each disease. Evidence also suggests a link between OSA and CSR, NAION, and stroke. The evidence remains controversial or insufficient for convincing causative association with RVO, glaucoma, and IIH. However, in patients presenting with CSR, and IIH, underlying OSA is a common finding. CPAP reverses some pathological changes, but the evidence is limited. Conclusions: OSA is associated with many diseases seen in neuro-ophthalmology clinics. More studies are required to assess the real ability of CPAP to reverse pathological changes. Ophthalmologists can screen for undiagnosed OSA in patients presenting with certain eye diseases.

State-of-the-Art Review Section Editors: Fiona Costello, MD Sashank Prasad, MD Obstructive Sleep Apnea in Neuro-Ophthalmology Brendon Wong, MD, Clare L. Fraser, MMed, FRANZCO Background: Obstructive sleep apnea (OSA) is a common pulmonary disorder with many systemic sequelae. Its association with diseases seen in neuro-ophthalmology is being increasingly recognized. Treatment of OSA with continuous positive airway pressure (CPAP) may reverse the pathology in some eye diseases. Evidence Acquisition: We conducted a search of the literature using the Ovid Medline database and Google Scholar, focusing on articles that explored the association between OSA and ophthalmic conditions. These included hypertensive retinopathy, diabetic retinopathy, central serous retinopathy (CSR), retinal vein occlusion (RVO), nonarteritic anterior ischemic optic neuropathy (NAION), glaucoma, idiopathic intracranial hypertension (IIH), papilledema, and stroke. Results: There is evidence of an independent association between OSA, and both hypertension and Type 2 diabetes mellitus, as well as the retinopathy associated with each disease. Evidence also suggests a link between OSA and CSR, NAION, and stroke. The evidence remains controversial or insufficient for convincing causative association with RVO, glaucoma, and IIH. However, in patients presenting with CSR, and IIH, underlying OSA is a common finding. CPAP reverses some pathological changes, but the evidence is limited. Conclusions: OSA is associated with many diseases seen in neuro-ophthalmology clinics. More studies are required to assess the real ability of CPAP to reverse pathological changes. Ophthalmologists can screen for undiagnosed OSA in patients presenting with certain eye diseases. Journal of Neuro-Ophthalmology 2019;39:370-379 doi: 10.1097/WNO.0000000000000728 © 2018 by North American Neuro-Ophthalmology Society O bstructive sleep apnea (OSA) is a common condition characterized by repetitive episodes of partial or complete collapse of the pharynx during sleep. Its prevalence is approximately 3%-7% for men and 2%-5% for women Save Sight Institute, Discipline of Ophthalmology, Faculty of Medicine and Health Sciences, University of Sydney, Sydney, Australia; Department of Ophthalmology, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia. The authors report no conflicts of interest. Address correspondence to Clare L. Fraser, MMed, FRANZCO, Save Sight Institute, University of Sydney, 8 Macquarie Street, Sydney, NSW 2000, Australia; Email: [e-mail] 370 (1-4). Past studies have estimated that up to 82% of men and 93% of women with OSA remain undiagnosed (5,6) with certain population groups being at greater risk for under-recognition (cardiac, Type 2 diabetes, and obese patients) (7-9). However, more up-to-date systematic surveys to characterize sleep-disordered breathing in the general population still are not available (10). The health impacts of OSA have been widely studied, most notably in relation to systemic hypertension, cardiovascular disease, and disorders of glucose metabolism. The association between OSA and diseases seen in neuro-ophthalmology is being increasingly recognized. The in-laboratory polysomnogram (diagnostic polysomnography [dPSG]) is the "gold standard" investigation for OSA in detecting obstructive respiratory events during sleep. Apnea is defined as the complete cessation of airflow for at least 10 seconds. Hypopnea is a relative reduction in airflow accompanied by hypoxia or arousal from sleep (11,12). The number of events per hour constitutes the Apnea-Hypopnea Index (AHI). An AHI of 5-15 is mild, 15-30 is moderate, and .30 is severe OSA (13). Although dPSG remains the gold standard, there are issues with accessibility and cost. Several portable devices exist to perform "home polysomnography" with reduced costs (14). Studies show agreement between portable monitors and dPSG when AHI .5 is used to define OSA, with 95% sensitivity, 69% specificity, and 89% positive predictive value (15,16). Questionnaires including STOP-Bang, the Epworth Sleepiness Scale (ESS), and the Berlin Questionnaire are used for screening (17-19). The common features of these questionnaires are snoring, daytime sleepiness, observed apneas, and physiological measurements including body mass index, blood pressure (BP), and neck circumference. Questionnaires have moderate sensitivity and negative predictive value but poor specificity (18,20,21). The Berlin Questionnaire can be used in neuro-ophthalmology clinics to find which patients with idiopathic intracranial hypertension (IIH) are unlikely to have OSA (22). OSA requires a long-term, multidisciplinary approach to management. The 2 specific interventions that have been Wong and Fraser: J Neuro-Ophthalmol 2019; 39: 370-379 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review shown to improve outcomes are weight loss and continuous positive airway pressure (CPAP). Both reduce the number of AHI events during sleep (23-25). One study examined the effect of weight loss through diet and exercise on patients with OSA and obesity. After 12 weeks, there was an average of 9% reduction in bodyweight along with a reduction in AHI of 10 events per hour and improved nocturnal oxygen saturation from 94.9% to 95.2% (26). Additional improvements were seen in BP, metabolic profile, and subjective daytime sleepiness (27-29). For patients who have mild OSA or poor tolerance of CPAP, oral appliances are available to splint the upper airway by advancing the lower mandible or retaining the tongue. Although not as effective as CPAP, oral appliances are better tolerated and more effective than inactive control devices (30). Surgical procedures to open the upper airway are offered in specialized circumstances, that is, craniofacial abnormalities or discrete lesion causing airway obstruction (31). In patients who fail medical therapy, hypoglossal nerve stimulation has shown promising results in reducing AHI and ESS scores (32). In a subset of OSA patients, AHI events are confined mainly to rapid eye movement (REM) sleep, believed to be caused by decreased genioglossus muscle tone (33,34). Body position in sleep can have a marked impact on AHI events in these patients, and a lateral sleeping position is a potential conservative treatment option (35). Although the systemic consequences of OSA are incompletely understood, it is believed that hypoxemia and recurrent arousals result in sympathoactivation, release of oxidative species, and a systemic proinflammatory state (36-38). OSA causes nocturnal episodic increases in arterial BP and is an independent risk factor for daytime hypertension (39-41). These changes are potential contributing factors to the ophthalmic pathology associated with OSA. SYSTEMIC CHANGES AFFECTING THE EYE Hypertension OSA is an independent risk factor for hypertension (42,43), with OSA severity correlated with the degree of hypertension. Correa et al (44) reported that patients with AHI .15 had significantly higher systolic and diastolic BP than those with AHI $15 (122 vs 118 mm Hg, P = 0.014 and 78 vs 73 mm Hg, P = 0.008, respectively). The pathophysiology includes reflex activation of the sympathetic nervous system from repeated arousals and impaired endotheliumdependent vascular relaxation (36,41,45). Systemic hypertension is, in turn, associated with increased intraocular pressure (IOP), retinal microvascular changes, retinal vein occlusion (RVO), and diabetic retinopathy (DR) (46,47). There is strong evidence that the use of CPAP is associated with improved BP, although the effect size seems to be small. A meta-analysis of 31 randomized control trials (RCTs) comparing CPAP with other passive (sham CPAP, placebo Wong and Fraser: J Neuro-Ophthalmol 2019; 39: 370-379 medication, and conservative treatment) or active (oral appliance and antihypertensive drugs) treatments found a mean difference in systolic BP of 2.6 ± 0.6 mm Hg and diastolic BP of 2.0 ± 0.4 mm Hg in favor of CPAP (P , 0.001) (48). Another meta-analysis of 16 RCTs found CPAP-reduced systolic BP by 2.46 ± 1.84 mm Hg and diastolic BP by 1.83 ± 1.22 mm Hg compared with controls (49). Subgroup analysis has shown that certain populations may have greater BP reduction benefits from CPAP. A meta-analysis of OSA patients with resistant hypertension showed CPAP-reduced systolic and diastolic BPs by 5.40 ± 3.77 and 3.86 ± 2.56 mm Hg, respectively (50). Patients already being treated with antihypertensives at baseline also seemed to benefit more from CPAP with reductions in systolic and diastolic BPs of 2.73 ± 2.23 and 3.19 ± 1.40 mm Hg, respectively (51). A comparison RCT between CPAP and valsartan showed both interventions significantly reduced BP (22.1 mm Hg, P , 0.01 and 210.9 mm Hg, P , 0.001, respectively) (52). In patients receiving both interventions, the BP reduction seemed to be additive (53). A meta-analysis of oral OSA appliances in reducing BP found a mean reduction in systolic and diastolic BP of 2.7 ± 1.9 mm Hg (P = 0.04) and 2.7 ± 1.9 mm Hg (P = 0.004), respectively (54). A study examining retinal vascular changes in OSA found increased retinal arteriolar changes similar to hypertensive retinopathy in patients with severe OSA compared with mild OSA, independent of BP (55). OSA also is associated with attenuated vascular pulsation amplitude (56). Retinal vessels could be a surrogate biomarker of cerebral and systemic vascular risk in patients with OSA. Diabetes Mellitus Type 2 diabetes mellitus (T2DM) is common in OSA patients, yet discerning an independent link has been challenging because of the mutual relationship with obesity. Adjusting for this, OSA has been shown in several studies to be an independent risk factor for T2DM (57-60). A metaanalysis showed that moderate-severe OSA was associated with a greater risk of T2DM (rate ratio [RR] 1.63, 95% confidence interval [CI]: 1.09-2.45) (61). Higher AHI scores seem to be associated with poorer glycemic control in diabetic OSA patients, with the adjusted mean glycated hemoglobin (HbA1c) increased by 1.49% (P = 0.0028) in patients with mild OSA, 1.93% (P = 0.0033) in moderate OSA, and 3.69% (P , 0.0001) in severe OSA (60). The relationship between sleep and diabetes is complex, and it may be the fragmentation of sleep rather than OSA itself, which causes derangements in blood glucose control. A meta-analysis of prospective studies found a U-shaped dose- response relationship between sleep duration and risk of T2DM with the lowest risk at 7-8 hours of sleep per night (62). Another meta-analysis found short (,5-6 hours per night) and long (.8-9 hours per night) duration sleep, and 371 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review difficulty initiating sleep to all be associated with increased risk of T2DM. However, difficulty maintaining sleep conferred the greatest increased risk (RR 1.84, 95% CI: 1.39- 2.43, P , 0.0001) (63). The ability of CPAP to improve the metabolic profile of diabetics is still being investigated. One study of patients with both OSA and T2DM found that 6 months of CPAP reduced the HbA1c by 0.5% (95% CI: 0.09%-0.9%) compared patients not using CPAP (64). There is mixed evidence to suggest that DR is associated with OSA. Using the English National Screening Program method for scoring DR (65), West et al (66) found that retinopathy and maculopathy scores were significantly worse in patients with OSA (P , 0.0001). Multiple regression analysis showed only OSA (R2 = 0.19, P , 0.0001) and HbA1c (R2 = 0.04, P = 0.03) to be significant independent predictors of retinopathy (66). One meta-analysis found OSA was significantly associated with increased risk of DR (OR = 2.01, 95% CI: 1.49-2.72) (67), whereas another found no significant association (68). Central Serous Retinopathy Central serous retinopathy (CSR) is characterized by exudative detachment of the neurosensory retina. Endothelial dysfunction of the choroidal vessels has been implicated, as well as raised catecholamine levels, sympathetic activation, and elevated corticosteroid levels (both exogenous and endogenous) (69-72). There is evidence of these physiologic changes occurring in OSA (36,41,73). Population studies show a significant correlation between these 2 disease entities. Of 23 consecutive patients with CSR, 14 had OSA diagnosed with polysomnography (74). In another study, 14 of 56 consecutive patients with acute or chronic CSR had an ESS .10, of which 8 had OSA on polysomnography (75). In a retrospective case-control study, 58.6% of patients with CSR were at increased risk of OSA on the Berlin Questionnaire, compared with 31% of controls (76). Given the strength of this evidence, it is recommended to screen for OSA in patients presenting with CSR. Retinal Vein Occlusion RVO is the second most common retinal vascular disorder after DR. Its pathophysiology is believed to follow Virchow triad of endothelial damage, blood stasis, and hypercoagulability (77). OSA is known to cause endothelial damage and hemodynamic changes (41,78,79). It may also cause hypercoagulability through promotion of a proinflammatory state (78,80,81). Leroux les Jardins et al (82) were the first to suggest a possible association between RVO and OSA, reporting 3 cases of RVO who had OSA on further investigation. Two further studies showed 42% (8/19 patients) and 77% (23/30 patients) prevalence of OSA in RVO patients (47,83). In a retrospective matched-cohort study between 5,965 patients with OSA and 29,669 controls (84), patients 372 with OSA had a 1.94-fold (95% CI: 1.03-3.65) increased risk of RVO. More epidemiological studies are needed to confirm the association between RVO and OSA. OPTIC NERVE Nonarteritic Anterior Ischemic Optic Neuropathy Nonarteritic anterior ischemic optic neuropathy (NAION) is a microvascular infarction of the anterior portion of the optic nerve (85,86). Two prospective case-control studies using dPSG have reported a significantly higher prevalence of OSA in patients with NAION compared with matched controls (Table 1) (87,88). The prevalence of OSA ranged from 55.6% to 71% for NAION patients and 18% to 22.2% for controls. Another study found no significant difference in the prevalence of OSA in NAION patients and controls (85% and 65%, respectively, P . 0.05) (89). Nonetheless, it has been suggested that OSA is a contributing factor to NAION because of its effects on the vascular endothelium. Two cohort studies in NAION patients found the prevalence of OSA to be 75% (90) and 89% (91). Dysfunction of blood flow autoregulation of the posterior ciliary arteries supplying the anterior optic nerve has been hypothesized to contribute to NAION (85). Episodes of pronounced nocturnal hypotension, as may occur in OSA, could be a triggering event. Hayreh et al (92) found a high prevalence of patients (73.3%) presented with NAION on waking. However, the results of the Ischemic Optic Neuropathy Decompression Trial (93) found 42% of subjects reported onset of symptoms within 2 hours of awakening, whereas 41% reported that it did not; the remaining 17% could not recall. One study did find that 5/26 (19%) patients with sleep-disordered breathing had episodes of hypotension to 60 mm Hg or less (94). The reduced ability of the optic nerve microcirculation to autoregulate during these periods in OSA is believed to result from an imbalance between nitric oxide and endothelin (79,95,96). Blood vessel endothelial damage and dysfunction also may contribute to NAION. The repetitive episodes of hypoxia and reoxygenation lead to the production of oxygen species, activation of leucocytes, and production of cytokines, which directly damage vascular endothelium and accelerate atherogenesis (97-99). Decreased blood oxygen saturation during apneic events may also cause direct hypoxic damage to the optic nerve head (100). CPAP may reverse some pathological changes that trigger NAION. One study showed CPAP improved vascular reactivity and capacity for endothelial repair (78). Another report found CPAP improved baseline endothelial nitric oxide release and stimulated endothelium-dependent vasorelaxation leading to improved systemic vascular function (101). Nonadherence to CPAP in patients with severe OSA and NAION increased the risk of second eye Wong and Fraser: J Neuro-Ophthalmol 2019; 39: 370-379 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review TABLE 1. Studies evaluating the prevalence of OSA in patients with nonarteritic anterior ischemic optic neuropathy Prevalence of OSA Author (Reference) Number of Patients Method of Diagnosing OSA AHI Cutoff for OSA Cases Controls P value Aptel et al (90) Bilgin et al (87) Arda et al (89) Palombi et al (91) Mojon et al (88) 89 cases 27 cases, 27 controls 20 cases, 20 controls 27 cases 17 cases, 17 controls dPSG dPSG dPSG dPSG dPSG $15 $20 .5 .15 $10 67/89 (75%) 15/27 (55.6%) 17/20 (85%) 24/27 (89%) 12/17 (71%) - 6/27 (22.2%) 13/20 (65%) - 3/17 (18%) - ,0.05 .0.05 - =0.005 AHI, Apnea-Hypopnea Index; dPSG, diagnostic polysomnography; OSA, obstructive sleep apnea. involvement (hazard ratio 5.54; 95% CI: 1.13-27.11; P = 0.04) (90). However, in a prospective noncomparative case series of NAION, 3 of 108 patients developed NAION while being treated with CPAP for OSA (102). Glaucoma Both primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG) have been studied in relation to OSA, and the associations remain controversial (Table 2) (103). Several studies have documented a positive correlation (104-106). Ophthalmic examinations were performed on 114 patients consecutively referred for polysomnography, of which 69 were confirmed to have OSA (107). Five patients (7.2%) were found to have glaucoma, 2 with POAG and 3 with NTG, significantly higher than the population rate of 2% (P = 0.01). All these patients had OSA. Another study examined 100 moderate to severe OSA patients and found 27% had glaucoma (108). A population database study compared 1,012 patients with OSA with 6,072 matched subjects. Over a 5-year follow-up period, the incidence of glaucoma per 1,000 person-years was 11.2 (95% CI: 8.6- 4.4) and 6.76 (95% CI: 1.30-2.17) with and without OSA, respectively (109). However, other studies have found no correlation (110). A large multicentre prospective cohort study analyzed electronic records of 9,580 patients who had undergone polysomnography. Six thousand seven hundred fifty-four had OSA, and 330 had glaucoma (diagnosed by an ophthalmologist). Glaucoma prevalence was 3.55% in patients with OSA and 3.14% in patients without OSA (111). Another used hospital episode data to construct a cohort of 67,786 patients who were documented as having OSA. Comparing this with a reference cohort of 2,684,131, it was found that the risk of POAG was not elevated; RR 1.01 (95% CI: 0.85-1.19) (112). A meta-analysis showed a significantly increased risk of glaucoma in OSA patients with a pooled OR of 1.96 (95% CI: 1.37-2.80) across 6 case-control studies (113). Some studies have reported higher AHI scores are associated with increased IOP (105,107). Transient increases in BP and sympathetic activation are believed to be responsible. Wong and Fraser: J Neuro-Ophthalmol 2019; 39: 370-379 Interestingly, the use of CPAP has been known to cause additional increases in IOP at night (114). No current recommendations exist on the adjustment of CPAP pressure in patients with glaucoma. INTRACRANIAL Intracranial Hypertension OSA has been documented to cause raised intracranial pressure (ICP). Increased ICP was documented in 6 patients with severe OSA during apneic episodes, and morning ICP was higher than evening ICP (115). Purvin et al (116) report 4 patients with OSA and papilledema. All had normal cerebrospinal fluid opening pressures on lumbar puncture, but one patient had marked ICP elevation associated with apneas on 24-hour monitoring. The authors proposed that the intermittently raised ICP in OSA is enough to cause persistent papilledema (117). However, in a study using serial fundus photographs of 215 patients, of whom 127 had AHI .15, no patients had papilledema (55). Three studies have investigated the prevalence of OSA in IIH (Table 3). In one of 32 male IIH patients, 6 (19%) were found to have OSA (117). Another study using dPSG in 32 newly diagnosed IIH patients found 15 (47%) had OSA (22). Finally, 37 of 53 patients with IIH screened were identified as having a history of sleep disturbance. Of these, 14 underwent dPSG and 7 had OSA (118). In summary, large studies confirming increased prevalence of papilledema in OSA are lacking. There is a possible association between OSA and IIH, but the existing studies are small and noncomparative (119,120). Stroke OSA has been associated with hypertension, T2DM, and obesity, all risk factors for ischemic stroke. Several studies have attempted to investigate whether there is an independent correlation. An observational cohort study, involving 697 patients with dPSG-proven OSA where the combined endpoint was stroke or death from any cause, 373 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Author (Reference) Study Design Method of Diagnosing OSA AHI Cutoff for OSA Wong and Fraser: J Neuro-Ophthalmol 2019; 39: 370-379 Method of Diagnosing Glaucoma Number of Patients Prevalence of Glaucoma - Subsequent diagnosis of POAG documented on electronic medical record 67,786 OSA 2,684,131 controls $15 Diagnosis of glaucoma after examination by ophthalmologist recorded on database 6,754 OSA 2,826 controls Prospective examination by ophthalmologist Prospective examination by ophthalmologist Prospective examination by ophthalmologist Prospective examination by ophthalmologist Prospective examination by ophthalmologist Prospective examination by ophthalmologist 209 OSA 38 controls 100 OSA 145/67,786 (0.2%) 12,533/ 2,684,131 (0.4%) 3.55% (numbers not stated) 3.14% (numbers not stated) 12/209 (5.7%) 0/38 (0%) 27/100 (27%) 31 OSA 25 controls 51 OSA 40 controls 228 OSA 4/31 (12.9%) 0/25 (0%) 3/51 (5.9%) 0/40 (0%) 5/228 (2%) 69 OSA 5/69 (7.2%) Keenan et al (112) Case-control Documentation on electronic medical record Aptel et al (111) Case-control dPSG results recorded on electronic database Lin et al (109) Case-control dPSG $5 Bendel et al (108) Cross-sectional dPSG .15 Karakucuk et al (106) Case-control dPSG $5 Sergi et al (105) Case-control dPSG $10 Geyer et al (110) Cross-sectional dPSG .10 Mojon et al (107) Cross-sectional dPSG $10 Type of Glaucoma Significant Association POAG No Not specified No NTG Yes Not specified POAG Yes Yes NTG Yes OAG No POAG and NTG Yes AHI, Apnea-Hypopnea Index; dPSG, diagnostic polysomnography; NTG, normal tension glaucoma; OAG, open-angle glaucoma; OSA, obstructive sleep apnea; POAG, primary OAG. State-of-the-Art Review 374 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 2. Studies evaluating the prevalence of glaucoma in obstructed sleep apnea patients State-of-the-Art Review TABLE 3. Studies evaluating the prevalence of obstructive sleep apnea in patients with idiopathic intracranial hypertension Author (Reference) Number of Patients With IIH Thurtell et al (22) Lee et al (117) Marcus et al (118) 32 18 53 Method of Diagnosing OSA dPSG "Sleep study" History of sleep disturbance and then dPSG AHI Cutoff for OSA Prevalence of OSA $5 - $5 18/32 (56%) 6/18 (33%) 7/53 (13%)* *Thirty-seven of 53 patients had symptoms of sleep disturbance on history and were offered dPSG. Only 14 patients underwent dPSG and the rest declined. AHI, Apnea-Hypopnea Index; dPSG, diagnostic polysomnography; IIH, idiopathic intracranial hypertension; OSA, obstructive sleep apnea. found that OSA significantly increased the risk of stroke or death (hazard ratio 1.97, 95% CI: 1.12-3.48), even after adjustment for confounding factors including age, sex, body mass index, T2DM, and hypertension (121). A large cohort study as part of the Sleep Heart Health Study recruited 5,422 patients with untreated OSA. After adjusting for confounders, there was a significant association between OSA and ischemic stroke in men (P = 0.016). In those with AHI .19, adjusted hazard ratio was 2.86 (95% CI: 1.1-7.4). There also seemed to be correlation between the severity of OSA and the risk of stroke. An AHI .15 was 30% more common in stroke patients compared with controls. In mild-moderate OSA, each 1-unit increase in AHI was estimated to increase stroke risk by 6% (122). In another study, subjects with AHI $30 had a hazard ratio of 2.52 (95% CI: 1.04-6.01) for developing stroke after adjustment for confounding factors (123). Using an AHI cutoff $20, Arzt et al (124) reported an adjusted odds ratio of 4.33 (95% CI: 1.32- 14.24) for developing stroke. A higher than expected percentage of OSA patients experience stroke during sleep (125). This suggests that AHI events may precipitate ischemic stroke because of combination of 1) transient increases in ICP resulting in decreased cerebral perfusion, 2) increased sympathetic activity, and 3) REM sleep-induced paralysis that worsens OSA events (115,126-128). CONCLUSIONS OSA is common in the general population. Far from being a single system disorder, it is being increasingly recognized as having systemic sequelae, including the eye and central nervous system. Larger scale studies are needed to investigate the role of OSA as a risk factor for diseases seen in neuro-ophthalmology. The role of CPAP and the reversibility of pathology also require exploration. OSA is underrecognized, and ophthalmologists may be uniquely positioned to identify at-risk patients presenting with certain eye disorders. Wong and Fraser: J Neuro-Ophthalmol 2019; 39: 370-379 LITERATURE SEARCH STRATEGY The references for this review were found by conducting a systematic search of the Ovid MEDLINE databases for articles published before February 2018. We used the following search terms: "obstructive sleep apnea," "obstructive sleep apnea syndrome," "hypertension," "diabetes mellitus," "metabolic syndrome," "central serous retinopathy," "optic neuropathy," "non-arteritic anterior ischaemic optic neuropathy," "glaucoma," "papilloedema," "intracranial pressure," "stroke," and "retinal vein occlusion." Additional articles were found by searches of the above terms in Google Scholar and by hand searching relevant articles. They were first screened by reading the abstract. Irrelevant manuscripts, reviews, and duplicates were excluded. Full text versions were then downloaded for detailed analysis. STATEMENT OF AUTHORSHIP Category 1: a. conception and design: B. Wong and C. Fraser; b. acquisition of data: B. Wong and C. Fraser; c. analysis and interpretation of data: B. Wong and C. Fraser. Category 2: a. drafting the manuscript: B. Wong and C. Fraser; b. revising it for intellectual content: B. Wong and C. Fraser. Category 3: a. final approval of the completed manuscript: B. Wong and C. Fraser. REFERENCES 1. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328:1230-1235. 2. Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Rein J, VelaBueno A, Kales A. Prevalence of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med. 2001;163:608-613. 3. Bearpark H, Elliott L, Grunstein R, Cullen S, Schneider H, Althaus W, Sullivan C. 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