Connection emerging between obstructive sleep apnea, ocular conditions
Obstructive sleep apnea is a common breathing-related sleep disorder, with a growing prevalence due to the aging population and the rise of obesity.
In 2019, a study by Benjafield and colleagues in The Lancet Respiratory Medicine estimated that nearly 1 billion adults between the ages of 30 and 69 years are affected by mild to severe obstructive sleep apnea (OSA). Nearly half the cases are moderate to severe, for which treatment is recommended.
Source: Wei-Chi Wu, MD, PhD
In 2021, Circulation published a statement from the American Heart Association that reported a prevalence of OSA of 34% in middle-aged men and 17% in middle-aged women and recommended screening for OSA in patients with risk factors for cardiovascular disease, as well as treatment for all patients with OSA (Yeghiazarians Y, et al.).
“OSA is often underrecognized and undertreated in cardiovascular practice,” the authors wrote.
Even more neglected and underestimated is OSA as a risk factor for a number of ocular sequelae, ranging from the retina and the optic nerve to the cornea and the adnexa.
“We need to raise awareness among ophthalmologists. OSA can affect multiple organs, and we should work together as a team with ENT, diabetes and metabolism specialists, cardiovascular specialists, pediatricians and general practitioners to evaluate the prevalence, impact and treatment strategies,” Wei-Chi Wu, MD, PhD, said.
The connection between specific ocular conditions and OSA is emerging, according to Nancy M. Holekamp, MD.
“It is difficult, though, because historically it was not taught in medical school, leading to underappreciation and underdiagnosis,” she said. “In particular, when it comes to ocular conditions, doctors are so focused on the eye itself that they fail to take a full history, ask the right questions, and make the connection between sleep apnea and what is going on in the eye.”
How OSA affects the eye
OSA is caused by closure of the airway during fully relaxed sleep, Holekamp said. Being overweight can cause excess fatty tissue in the soft palate that, when relaxed, collapses and obstructs the airway. The anatomy of the jaw can predispose to this: A large tongue, adenoids and tonsils and a short neck can be risk factors. Smoking, alcohol or drug use, sleeping position and genetics may also contribute.
“OSA is multifactorial. There are many different potential causes,” she said.
Ocular manifestations of OSA are related to two mechanisms, according to Matthew Santos, MD. The first one is vascular: Chronic intermittent hypoxia causes expression of inflammatory stress markers, leading to damage of the vascular tissue throughout the body, increased risk for heart attacks and strokes, hypertension and high cholesterol. This mechanism can also affect the eye.
“Most of the ocular manifestations of sleep apnea are related to that vascular injury, including age-related macular degeneration, nonarteritic anterior ischemic optic neuropathy, glaucoma and retinal vein occlusion,” Santos said.
The other component is the mechanical effect: Sleep apnea is related to abnormal looseness of the pharyngeal soft tissues due to obesity and increased neck thickness.
“Floppy eyelid syndrome (FES) is similarly related to weakness of the connective tissue that leaves the eyelid prone to eversion and malposition,” he said.
Multiple studies have confirmed this association, and a meta-analysis of more than 1,100 patients, published in Survey of Ophthalmology by Cheong and co-authors, showed that patients with OSA had twice the chance of developing FES.
OSA might even be a contributing factor to keratoconus, a similar connective tissue-based disorder.
“It’s the chicken or the egg, where there’s maybe some predisposition to connective tissue disease and then ongoing vascular damage to their tissues that further weakens them,” Santos said.
Interconnections may occur between sleep apnea, FES and keratoconus because irritated eyelids cause eye rubbing, which, in turn, is a known cause of ectasia.
A hit to homeostasis
Holekamp has had a career-long interest in oxygen and the eye, with a focus on the mechanisms the eye utilizes to keep intraocular tension low in the vitreous, lens and anterior chamber angle. These tissues are susceptible to oxidative damage and, at the same time, are just millimeters away from other ocular tissues such as the retina and choroid that have a high metabolic demand and need a high, continuous supply of oxygen.
“What I have learned is that to be in homeostasis, we all need to exist at 21% oxygen. No more, no less. The cyclical hypoxia of nighttime OSA is a huge ‘hit’ to our homeostasis,” she said.
OSA is “a double whammy” for any patient with diabetic retinopathy (DR), she said. The blood vessels are damaged so there is less blood and therefore less oxygen being delivered to the retinal tissues.
“Layer on top of that the hypoxia that occurs when a sleeping patient intermittently stops breathing. And it doesn’t stop there: In response to hypoxia, a sleeping patient with OSA will have spikes in blood pressure,” she said.
Moderate sleep apnea is when a patient stops breathing 15 to 30 times an hour. The resulting spikes in blood pressure lead to nerve fiber layer infarcts, also known as cotton wool spots (CWS), throughout the posterior pole.
“Many clinicians think these CWS are due to the diabetes, but they are due to hypertensive spikes in blood pressure and are classically located in a pattern around the optic nerve head. In my clinical practice, I could diagnose a diabetic patient with OSA simply by the presence of six or more peripapillary CWS in both eyes. Patients were amazed that I would look into their eyes and say, ‘Do you have sleep apnea?’” Holekamp said.
A risk factor for DR and DME
In a recent retrospective cohort study, Rahimy and colleagues found an increased rate of DR progression and systemic vascular events, including death, in 11,931 patients with nonproliferative diabetic retinopathy (NPDR) and OSA compared with an equal number of patients with NPDR without OSA.
Another retrospective cohort study by Chiang and colleagues, conducted in 14,152 patients, found that severe OSA is a risk factor for diabetic macular edema and is associated with having refractory DME. Wu was one of the authors of this study.
“We had a follow-up of about 7 years and found that OSA is the independent No. 1 risk factor associated with DME, with an odds ratio of 7.36, compared to other significant factors like hypertension or HbA1c. That means that if you have OSA, the likelihood of having DME will be seven times higher than the patient without OSA,” he said.
This study also compared for the first time severe vs. not severe OSA and found that severe OSA is associated with refractory DME with an odds ratio of 1.30.
“Those patients required more anti-VEGF injections and had less improvement anatomically and functionally,” Wu said.
The relationship between OSA and DME is still unclear. One theory is that hypoxia triggers the overactivation of sympathetic tone, which would result in reperfusion or resupply of oxygen, generating hypoxic-reperfusion injury. Another theory, Wu said, is that hypoxia could increase the production of VEGF in the eye.
“Overproduction of VEGF is associated with dysregulation of the epithelial functions that could result in the blood-retina barrier breakdown and leakage of the proteins from the vessel, causing DME,” he said. “Hypoxia also increases inflammation and oxidative stress. These are several possible mechanisms, but overall, the main reason is that you have less inhaled oxygen, less perfusion to the tissue, which triggers hypoxic ischemic injury and perhaps reperfusion later, leading to a vicious cycle of hypoxia reperfusion.”
Look for OSA in patients with neovascular AMD
The same mechanisms are likely to contribute to AMD onset and progression. A paper by Alshaikhsalama and colleagues studied a large population-based dataset and found a compelling connection of OSA to AMD.
“Their results showed an elevated risk of developing AMD and progression to later stages of the disease among individuals with diagnosed OSA. Affected patients also had a higher chance of requiring more anti-VEGF injections. This makes sense because hypoxia is a trigger for a pathological cascade that results in VEGF production and new blood vessel growth,” Holekamp said.
Nocturnal hypoxia may be an underappreciated important modifiable risk factor for neovascular AMD, according to Robyn Guymer, AM, MBBS, PhD.
“We really haven’t had a new modifiable risk factor for AMD for decades. We know about smoking, weight and lack of exercise, but we haven’t really advanced our ability to reduce risk. This is a very treatable risk factor, if indeed it is the case,” she said.
In a cross-sectional study conducted by Chaudhary and colleagues, with Guymer as the corresponding author, participants with AMD of all stages as well as normal controls were tested for sleep apnea by at-home overnight pulse oximetry.
“Subjects with the neovascular disease, where the new blood vessels are growing, presumably as a response to hypoxia, they were more likely to have obstructive sleep apnea,” Guymer said. “Our numbers were not large. They were just slightly over 200, so maybe we didn’t have enough data to find an association with AMD overall, but this particular destructive form of AMD seems to be clearly associated with OSA.”
Nighttime is crucial for the retina, when the oxygen consumption of the retina is enormous and larger than during the daytime, Guymer said.
“Just slightly less oxygen getting to your retina, when it particularly needs it at night, is likely to cause damage. We are not sure exactly of the mechanism, but presumably, hypoxia leads to inflammation, poor circulation and more VEGF expression,” she said.
There have been studies showing that people with OSA and neovascular AMD are harder to manage, need more injections and more often develop bilateral disease and earlier-onset disease. These findings offer new insights into disease mechanisms, potentially leading to new intervention strategies, she said.
“Given the risk of nAMD is sixfold higher if you have OSA, then it seems prudent to consider screening OSA in people with nAMD and potentially those with high-risk intermediate AMD. If you’re constantly having to inject anti-VEGF but the eye is making more VEGF because of hypoxia, then you know you’re defeating yourself,” Guymer said.
Increasing the odds of glaucoma and NAION
A strong association between OSA and glaucoma was found in a meta-analysis by Cheong and colleagues with a total study population of 4,566,984 patients.
“After adjusting for confounders, people with OSA had up to 40% higher odds of glaucoma,” said Tin Aung, MBBS, MMed, FRCS, FRCOphth, FAMS, PhD, co-author of the study.
An even higher risk rate was found in the normal-tension glaucoma subgroup, suggesting that other IOP-independent, hypoxia-related mechanisms might be involved, such as increased systemic inflammation, overactivation of the sympathetic nervous system, altered cerebral and ocular circulation, vasospasm, and direct damage to the optic nerve head, he said.
OSA-induced hyper-hypoxia is likely a mechanism that glaucomatous optic neuropathy has in common with nonarteritic anterior ischemic optic neuropathy (NAION).
“It depends on which part of the blood supply to the nerve is involved. If it is the optic nerve head, it could cause NAION, while if it is chronic ischemia, it could result in glaucoma,” Aung said.
A study by Aptel and co-authors found that out of 118 patients with NAION, 89 had OSA. Nonadherence to continuous positive airway pressure treatment led to a more than fivefold higher chance of developing NAION in the other eye.
Watch out for symptoms, refer for testing
Being involved in a study on this topic prompted Aung to pay more attention to OSA in the management of patients with glaucoma.
“Especially patients with normal-tension glaucoma, I will definitely ask about history and symptoms of sleep apnea. I also found that people with asymmetric glaucoma more often have sleep apnea, but we don’t know why,” Aung said.
In his hospital, many patients have been found to have combined glaucoma and sleep apnea, and they are regularly sent to the sleep clinic for further assessment and treatment.
“Those who respond well to the treatment report a marked improvement in their general well-being, a lot more energy, and stop feeling tired and sleepy. In terms of their glaucoma, we don’t have a prospective study to show the effects of treating sleep apnea, but we hope that it will definitely help to control it and slow down progression,” Aung said.
He emphasized that collaboration between sleep specialists and glaucoma specialists is important. Sleep specialists should be made aware that sleep apnea, besides all other systemic effects, can cause eye problems. Conversely, ophthalmologists should be aware that some eye diseases can be associated with sleep apnea.
Aung also noted that while in the West there is a clear association between sleep apnea and weight gain, the same is not found in his region.
“Many of our patients with OSA are thin, small sized and don’t have a large neck. Unlike in the West, we cannot ask them to lose weight as a first intervention,” he said.
Increasing awareness
In a review article published in the Journal of Clinical Sleep Medicine, Santos and Hoffmann include in their objectives the hope to increase awareness and stimulate cooperation.
“Knowledge of these ocular sequelae may facilitate triage between sleep specialists and ophthalmologists, thereby preventing ocular complications and vision loss in patients with OSA,” they wrote.
“Going through medical school, sleep apnea is probably the condition about which I gained the most respect. There’s even a nursery rhyme: ‘It’s raining, it’s pouring, the old man is snoring.’ It’s not really thought of as something dangerous, but then you learn that it is a risk factor even for heart attacks,” Santos said.
Physicians and patients alike need to be aware that it is not just “the old man is snoring” but a serious health hazard.
“A lot of patients, in my experience, don’t quite understand the gravity of it. I see patients who are not aware of snoring, but the partners say, ‘Oh yes, they snore.’ It’s said in a loving way but not necessarily knowing how serious it can be. It’s important to teach patients that if they have the CPAP at home, they should really try it, and if it doesn’t quite fit the way they want to, work with the provider to find a suitable alternative,” Santos said.
“As ophthalmologists, we need more education, more information on OSA and more studies,” Wu said.
Despite his specialization in pediatric retina, Wu admitted that before initiating a study specifically on OSA, he was not aware that this is a common disorder in children who were born prematurely or have craniofacial anomalies.
“Premature children are often reported to have attention deficit at school. When examined, almost 50% are found to have OSA, and after treatment with CPAP, their attention and performance at school improves significantly,” Wu said.
Patients with OSA snore frequently, and when he started asking the parents of premature children, surprisingly many of them said that they could often hear their children snoring.
“This is very uncommon in full-term children, so I realized that definitely sleep apnea is a condition we should watch for also in kids,” he said.
Working as a team
Patients, ophthalmologists, pediatricians and also general practitioners (GPs) need to work together and become educated to understand how to test for and treat sleep apnea, Guymer said.
“As ophthalmologists, we have to be aware that it may be associated with multiple eye disorders and then suggest to the patients’ GPs that they need screening. In some of our studies, we have incidentally picked up quite a number of severe cases of OSA, and with the support of the GP, they have been tested and treated,” she said.
High blood pressure, daytime sleepiness and frequent car accidents should be interpreted by GPs as signs that a patient might have sleep apnea and should be tested.
Access to polysomnography, however, is often limited by high cost and long waiting lists. Home sleep apnea tests may be an alternative, and pulse oximetry can be an initial inexpensive screening test, Guymer said.
As well as increased awareness, communication and collaboration between health professionals will be key in the future management of OSA and related consequences.
“Sleep medicine is a relatively new area of medicine. This field did not exist when I went to medical school. Fortunately, it does now, but these doctors are either hospital based or in private practices. Most ophthalmologists are office based. U.S. health care is fragmented in this sense, and the two specialties do not interact often,” Holekamp said. “I think the key to more collaboration and better patient care is twofold: increased awareness and shared system-wide electronic medical records. Happily, both of these changes are in motion, and I am optimistic about the future.”
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- For more information:
- Tin Aung, MBBS, MMed, FRCS, FRCOphth, FAMS, PhD, CEO of Singapore National Eye Centre, can be reached at aung.tin@singhealth.com.sg.
- Robyn Guymer, AM, MBBS, PhD, deputy director and head of macular research at the Centre for Eye Research Australia and professor of ophthalmology at Melbourne University, can be reached at rh.guymer@unimelb.edu.au.
- Nancy M. Holekamp, MD, principal global medical science leader at Roche Pharmaceuticals, can be reached at nholekamp@gmail.com.
- Matthew Santos, MD, assistant professor of clinical ophthalmology at the University of Pennsylvania, can be reached at matt.santos150@gmail.com.
- Wei-Chi Wu, MD, PhD, professor of ophthalmology at Chang Gung Memorial Hospital in Taipei, Taiwan, can be reached at weichi666@gmail.com.
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