Role of sleep-disordered breathing in age-related macular degeneration

Introduction

Age-related macular degeneration (AMD) is a complex genetic disease, affecting approximately 9% of people over 50 years of age and its prevalence is increasing, with an expected prevalence of 288 million worldwide by 2040.1 2 Apart from smoking cessation, dietary modifications, general lifestyle modification and nutritional supplementation, there has been limited progress in identifying additional modifiable risk factors that may prevent AMD or slow its progression to late vision threatening stages.3 Therefore, identifying new ways to reduce the incidence and progression of AMD, through identifying modifiable risk factors, is urgently needed.

While advances have been made in determining underlying genetic associations with AMD and several mechanistic pathways, such as those involving oxidative stress, lipid biology, chronic inflammation and extracellular matrix homoeostasis, the exact pathophysiology of AMD remains to be elucidated.4 Understanding the underlying pathological pathways is critical in advancing our ability to identify potentially modifiable risk factors that contribute to this disease. There is an increasing evidence to suggest that hypoxia may play a crucial role in the pathogenesis of AMD, with the retinal pigment epithelium (RPE) and photoreceptors being highly metabolically active and in high demand for oxygen and with the inner segments of the photoreceptors dominating retinal oxygen consumption.5 A lack of metabolic supply to the outer retina results in impaired health and function of the RPE and photoreceptors. There is evidence of oxidative stress and mitochondrial damage occurring in the RPE, which results in reduction of glucose supply to photoreceptors.6–8 Thus hypoxia-mediated RPE and photoreceptor injury may play a crucial role in AMD development and progression.

The choroid is the main source of oxygen and nutrient supply to the outer retina, with computational modelling of oxygen distribution in the outer retina suggesting that reduction in oxygen diffusion and transport from the choroid to the outer retina, due to the presence of drusen, could potentially link hypoxia to AMD progression.8 Even under normal conditions, oxygen tension in the outer retina, particularly at the photoreceptor inner segments, is reduced to a very low level in darkness, due to retinal oxygen consumption being highest in darkness. The retina requires 50% more oxygen in the dark than in the light, due in large part to the need to maintain the dark current.9–11 Thus, any additional factors that alter this tenuous metabolic supply and oxygen delivery to the outer retina, will likely increase hypoxia in the outer retina, creating an environment that predisposes to AMD and its progression.

A common group of disorders that cause nocturnal hypoxia are known as sleep-disordered breathing (SDB),12 13 and includes several disorders, the most common being obstructive sleep apnoea (OSA).14 15 Like AMD, the prevalence of SDB increases with age, with 24% of people over 65 thought to experience some degree of SDB.16 In SDB, repetitive episodes of upper airway collapse cause apnoeas and hypopneas during sleep, thereby resulting in a prolonged state of recurring nocturnal hypoxia. OSA has been associated with several ophthalmic conditions, such as glaucoma, diabetic retinopathy, nonarteritic anterior ischaemic optic neuropathy, retinal vein occlusion, central serous chorioretinopathy and floppy eye lid syndrome.17–21

There is no established consensus regarding the association between AMD and SDB, with only a small number of studies having explored this relationship. In a study of 5604 participants, Nau reported that those with sleep disorders were more than twice as likely to have AMD.22 In this study, the definition of sleep disorder encompassed a myriad of different conditions such as OSA, insomnia and snoring, some of which are not considered SDB and do not cause nocturnal hypoxia. In a prospective cohort study of more than 500 000 participants, Han et al found that people with OSA were significantly more likely to develop AMD compared with controls (HR=1.39, p<0.001).23 A record linkage study of approximately 45 000 individuals also observed that the risk of having a subsequent hospital record of AMD was higher for those with a hospital record of OSA than those that did not (rate ratio 1.44; 95% CI 1.32 to 1.57).24 A cross-sectional study also reported an increased prevalence of OSA across all AMD subtypes in comparison to estimated population norms (11–28% vs 3–7%). However, this study did not investigate the association using a model that adjusted for relevant confounders.25 Several studies have investigated an association between OSA and response to treatment with anti-VEGF therapy for neovascular AMD citing a poorer treatment response in those with OSA.26 27

Typically, studies investigating SDB use questionnaires to assess the risk of SDB. Two commonly used, validated, questionnaires are the Epworth Sleepiness Scale (ESS) and the STOP-Bang questionnaire (SBQ) which provide risk assessment for having SDB.28 29 Individuals in a high-risk category would usually be referred onto formal sleep studies with in-laboratory polysomnography to confirm the presence of nocturnal hypoxia.

The purpose of this study is to further investigate the association between the risk of moderate-to-severe OSA and AMD using validated questionnaires in a carefully phenotyped cohort. The role of nocturnal hypoxia in the AMD phenotype with reticular pseudodrusen (RPD) is also of particular interest given their association with poor rod function, where rod photoreceptors are dependent on the highly metabolically demanding nocturnal recycling of outer segments and visual pigment regeneration. Several studies have also reported increase in choriocapillaris flow deficits in those with RPD which could potentially compound any other cause of low oxygen to the outer retina.30 31 This could be further compromised by low retinal oxygen levels.32 33 If OSA-mediated nocturnal hypoxia is associated with a higher risk of AMD, a viable treatment option presents itself through devices delivering continuous positive airway pressure (CPAP) such as is used routinely to treat OSA.

Materials and methods

Results

A total of 351 participants were included in the study; where 211 (60.1%) had AMD and 140 (39.9%) were control participants with normal maculae. The mean age of the AMD group (75.6±8.1 years) was significantly older than that of the control group (71.3±7.9 years, p<0.001). Compared with the control group, the AMD group had a higher proportion of females (69.7% vs 54.3%, p=0.003), but there was no significant difference in the proportion of individuals who had a history of past or current smoking between the two groups (p=0.185). Within the AMD group, there were 102 participants (48.3%) with intermediate AMD (bilateral large drusen) and 109 participants (51.7%) with late AMD. Within this group of 211 AMD participants, 107 (50.7%) had coexisting RPD.

Discussion

This study investigated the possible association between clinically diagnosed OSA, treated OSA and OSA risk with the likelihood of having AMD, or the AMD subphenotype with RPD. We used two different risk scales based on validated sleep questionnaires (ESS and SBQ) to determine the risk of having moderate-to-severe OSA. After adjusting for age, gender and smoking history, a clinical diagnosis of OSA or being at higher risk of moderate-to-severe OSA, based on the validated questionnaires, was not associated with a higher likelihood of having AMD, nor with the presence of RPD coexistent with AMD. However, when considering individuals with a formal diagnosis of OSA, who were also receiving treatment using an assisted breathing device, while they were not more likely to have AMD, they were 3.7 times more likely to have RPD coexistent with AMD compared with those who were not receiving treatment for OSA.

The lack of association could be due to the fact that the sleep questionnaires are only screening tools for the diagnosis of OSA, since being at high risk of OSA does not necessarily mean that one has OSA or experiences hypoxic episodes at night and similarly not showing increased risk on the sleep questionnaire does not mean that they do not have OSA. Hence, the potential mismatch between those identified as being at high risk and those who actually experience hypoxia at night may have contributed to the lack of association.

Interestingly, participants with a formal diagnosis of OSA who were receiving treatment with an assisted breathing device, which we considered indicated a higher degree of nocturnal hypoxia, were more likely to have RPD coexistent with AMD, compared with those not undergoing this treatment for OSA. In the current analysis, those participants with a formal diagnosis of OSA and who were using an assisted breathing device were not included in the questionnaire analysis, as we felt the treatment would alter the responses. This, therefore, biases the questionnaire cohort towards those without OSA. When those with a formal diagnosis of OSA on treatment were arbitrarily assigned a maximum score, there was a significant association between the SBQ score and AMD with coexistent RPD. This adds weight to the possible association between OSA and the subphenotype of AMD with RPD. The AMD sub phenotype with RPD was hypothesised to be potentially more likely associated with OSA due to the possibility that rod dysfunction, known to be a hallmark of RPD, could result from the inability to meet the nocturnal metabolic demands required for rod photoreceptor recycling. If, in addition, there are deficits in choriocapillary flow in those with RPD, the hypoxic environment would be further aggravated.30

The gold standard for the diagnosis of OSA is in-laboratory polysomnography testing with a sleep specialist to interpret the recordings together with clinical and medical history.39 40 Indeed, several of the participants in this study who were assessed as being at high risk of OSA went on to have formal polysomnography testing and were diagnosed with OSA. However, home-based pulse oximetry can be used to monitor oxygen levels at night and could serve as a more accurate screening test than questionnaires for OSA. Home-based nocturnal oximetry may be a practical approach for further studies to directly measure oxygen levels at night to further address this important potential association. If nocturnal hypoxia could be validated as a risk factor for AMD, or only AMD cases with RPD, it raises the possibility of using an already available treatment such as CPAP therapy, to either reduce AMD incidence or its progression.

The strengths of our study were the extensive questionnaire-based risk assessment of OSA in individuals who also had extensive retinal imaging to assess AMD and RPD. The size of the cohort allowed us to consider the association of OSA with all AMD as well as AMD with and without the RPD phenotype. In addition, adjusting for confounders such as age, which have been strongly associated with AMD and OSA increased the validity of our results. The combined use of two validated sleep questionnaires and two different validated risk scoring algorithms provided complementary approaches for assessing the risk of OSA with different levels of sensitivities and specificities. However, the study may have been underpowered to find significant results as the trend in the results was consistent in showing an association and other studies with larger sample sizes were able to find a significant association.22 23 The finding of an increased likelihood of having the AMD subphenotype with RPD in those being treated for a formal diagnosis of OSA, when compared with those who were not receiving treatment for OSA, is limited by the small number of participants on treatment for OSA, which resulted in wide CIs for the estimates, but these findings were nonetheless statistically significant.

In summary, our study found that participants who are on treatment for previously diagnosed OSA, a type of SDB that is highly prevalent in our older community and a major cause of nocturnal hypoxia, have significantly higher risk of having RPD coexistent with AMD. However, having a higher risk of moderate-to-severe OSA based on sleep questionnaires was not associated with a significantly increased likelihood of AMD presence, nor with the presence of the RPD subphenotype coexistent with AMD. The preliminary findings confirm the need for further research exploring the role of nocturnal hypoxia as a risk factor in the development of AMD and its progression to late-stage disease, especially the links to AMD with RPD. Studies involving nocturnal pulse oximetry or formal polysomnography with appropriately experienced clinicians to interpret the results would be an ideal study design to further investigate a possible relationship between AMD and nocturnal hypoxia.