Ophthalmic Diseases in Patients With Obstructive Sleep Apnea

Floppy Eyelid Syndrome

A condition where the upper eyelid becomes highly elastic and is easily everted or folded upward (Figure 1), FES is often accompanied by papillary conjunctivitis, eyelid edema, and ocular discomfort. The prevalence of OSA in patients with FES may be as high as 96%.⁵ However, the prevalence of FES in patients with OSA has been reported to be anywhere between 2% and 33%.^5,6 Thus, most patients with FES have OSA, but fewer patients with OSA have FES. Of patients with FES, approximately 86% are male and 88% are obese.⁶ Although OSA is the most frequent systemic disease associated with FES, it is unclear if the relationship is causative.⁵ Floppy eyelid syndrome is also associated with diabetes, hypertension, hyperlipidemia, and ischemic heart disease.^5,6 All of these systemic diseases are frequently associated with obesity, making it complicated to determine the causative factor.^5,6

Figure 1.

Highly elastic and easily everted upper eyelid as seen in floppy eyelid syndrome.

Some of the ocular manifestations of FES are the result of the cornea being exposed at night, leading to punctate epithelial erosions, dry eyes, exposure keratopathy, corneal scarring, and neovascularization or ulceration, which may, rarely, lead to a microbial infection or corneal perforation.^5-7 Keratoconus, a progressive condition involving corneal thinning and irregular astigmatism, has been associated with FES.^5,7 Eyelid disorders have also been associated with FES, including eyelid edema, dermatochalasis (droopy upper eyelids with redundant skin), blepharitis, meibomianitis (inflammation of the eyelid margins and meibomian glands), ectropion (lower eyelid turns outwards away from the eyeball), eyelash ptosis (eyelashes point down instead of curling upward (Figure 2), and trichiasis (eyelashes point toward the eye and cause mechanical irritation).^5-7 Chronic papillary conjunctivitis is often present in patients with FES, and other types of conjunctivitis may occur.⁵

Figure 2.

Eyelash ptosis: eyelashes point down instead of curling upward.

Obstructive sleep apnea is the most frequent systemic disease that is associated with FES.

The upper eyelid in FES is easily everted. Whereas a normal eyelid stays relatively apposed to the globe when pulled upward, a floppy eyelid will evert, exposing the conjunctival inner lining of the eyelid. This sign has been reported to have been seen by sleep partners while the patient is asleep, and sometimes the patient notices it upon waking.⁷ Upper eyelid laxity can be quantified by measuring the vertical eyelid pull. This method involves measuring the difference between the eyelid at resting position and at maximal manual displacement superiorly. Normal eyelids measure approximately 5 to 10 mm; in FES, the eyelids measure 15 to 25 mm.⁷

Several possible mechanisms for FES have been proposed. The mechanical theory suggests that mechanical trauma caused by the eyelids rubbing against the pillows at night causes floppy eyelids and the associated papillary conjunctivitis.^5,7 This theory is supported by the evidence that FES occurs on the side the patient prefers to sleep on or occurs bilaterally if the patient alternates sleeping sides.^5,7 However, this correlation is not perfect. Eye rubbing, another form of mechanical trauma, is thought to be associated with FES and has also been implicated in keratoconus.⁵ Another theory suggests that in patients with OSA, the upper eyelid becomes ischemic while the patient is laying on his or her side. In this theory, sudden reperfusion as the patient awakens causes damage to the tarsal plate and triggers a papillary reaction.^5,7 However, to our knowledge, no clear evidence exists to support this idea. Other theories include poor eyelid-to-globe apposition, inflammation of the meibomian glands in the eyelid, Demodex eyelid infestation, or a genetic disease.⁵

The eyelid edema seen in patients with FES results from tissue fluid and plasma protein accumulation secondary to inflammation, mechanical trauma, and system dysfunction, causing an imbalance in the lymphaticovenous homeostasis.⁸ When venous or lymphatic congestion is involved, osteopathic manipulative treatment techniques that promote venous and lymphatic drainage from the head and neck may offer symptomatic relief. Superficial lymphatic drainage techniques such as effleurage to the face are directed at lymphatic flow as it leaves the eyelids and enters the lymphatics of the skin.⁸ The management of cervical and thoracic somatic dysfunctions can address restrictions that prevent proper lymphatic drainage from the head and neck, which may decrease periorbital edema.⁹ Additional conservative treatments include wearing a plastic or metal shield at night and using ocular lubricants or artificial tears.^5,7 However, FES is often resistant to topical treatment.^6,7 Patients with FES often show improvement with treatments for patients with OSA.⁷ Various surgical techniques have been described for tightening the upper eyelid, which are successful for most patients.⁵

Glaucoma

The mechanism for glaucoma is unknown; theories generally involve mechanical damage due to increased pressure or decreased vascular perfusion to the optic nerve. Glaucoma is a disease characterized by progressive thinning of the nerve fibers of the optic nerve that can lead to vision loss. Often there is an increase in intraocular pressure (IOP), but if the IOP is normal, the condition is termed normal-tension glaucoma. If the anterior chamber angle is narrow, decreasing aqueous outflow and increasing IOP, the condition is termed narrow-angle glaucoma. If the anterior chamber is not narrow, the condition is termed open-angle glaucoma. Glaucoma is asymptomatic until late in the disease process; thus, it is important for patients to be screened regularly by an eye care professional. Currently, no cure for glaucoma exists, and treatment involves lowering the IOP, which may help to slow progression of the disease.

Many studies have found a link between open-angle glaucoma and OSA,^10,11 although some of these studies failed to find a statistically significant relationship.^12,13 These studies^12,13 showed that glaucoma is more prevalent in patients with OSA, particularly in severe cases of OSA. The reverse has also been shown. Patients with glaucoma, particularly normal-tension glaucoma, have a higher prevalence of OSA than the general population.¹² The reported prevalence of glaucoma in patients with OSA ranges from 2% to 27%, whereas the presence of glaucoma in the general population is approximately 2% to 3%.¹² One study¹⁴ found that patients with FES may be more likely to have glaucoma.

Glaucoma is a sight-threatening disease; thus, it is imperative that patients with risk factors for glaucoma are monitored regularly.

Patients with OSA were found to be more likely than the general population to have many of the diagnostic criteria for glaucoma, including increased IOP, decreased thickness of the retinal nerve fiber layer, glaucomatous optic nerve changes, and abnormal visual field indices (Figure 3).¹² This study¹² found no statistically significant difference in ocular blood flow as measured by orbital Doppler ultrasonography between patients with OSA and the general population. Obstructive sleep apnea has been shown to cause a decrease in IOP at night, and continuous positive airway pressure (CPAP) machine use has been shown to increase IOP at night.¹⁵ Normally, IOP is highest during slow-wave sleep and lowest during rapid eye movement sleep.¹⁵ Obstructive sleep apnea tends to decrease the amount of time spent in slow-wave sleep, theoretically producing a lower IOP. Restoration of normal breathing patterns with CPAP therapy elevated IOP to a normal pattern in 12 patients.¹⁵ Pepin et al¹⁵ reported reestablishment of normal IOP and blood pressure rhythm with CPAP, citing a likely positive effect of glaucoma treatment due to improvements in underlying vascular variables.

Figure 3.

Fundus photograph of glaucomatous optic nerve showing increased cupping as a result of retinal nerve fiber loss.

The pathogenesis of glaucoma in patients with OSA is likely a combination of mechanical and vascular factors. Mechanical factors include increased IOP at night due to a supine sleeping position or an increase in episcleral venous pressure in obese patients.¹⁶ Vascular factors include periods of hypoxia followed by oxidative stress during reperfusion.¹² This combination of mechanical and vascular stress may lead to damage to the optic nerve and subsequent glaucoma diagnosis.

Glaucoma is a sight-threatening disease; thus, it is imperative that patients with risk factors for glaucoma be monitored regularly. Although the relationship between OSA and glaucoma is not yet fully understood, it is generally accepted that there is an association between the 2, especially in patients with severe OSA. Glaucoma management may include topical drops to lower IOP or various laser or surgical techniques also aimed at lowering IOP.

Nonarteritic Anterior Ischemic Optic Neuropathy

An ischemic injury to the optic nerve not related to arteritis, NAION occurs when hypoperfusion to the optic nerve causes sudden painless vision loss in one eye, edema of the optic disc, and a relative afferent pupillary defect (Figure 4).¹⁷ Often a defect exists in the visual field of the affected eye. The loss of vision may occur when a patient wakes in the morning.¹⁸ Patients with systemic diseases that can affect perfusion to the optic nerve, such as diabetes, hypertension, atherosclerosis, and OSA, may have a higher risk of NAION.¹⁷ A small optic nerve with a small optic cup is also a risk factor for NAION. This characteristic is often observed in the unaffected eye but presumed to be present in both eyes.¹⁷ Visual acuity may improve with time but remains poor in approximately two-thirds of patients.¹⁷

Figure 4.

Fundus photograph of localized optic disc swelling in a patient with nonarteritic anterior ischemic optic neuropathy.

Patients with OSA have been shown to have a greater prevalence of NAION than the general population.¹⁸ The presence of OSA in patients with NAION may be as high as 71% to 89%,^18,19 and NAION is 16% more likely to develop in patients with OSA than in patients without OSA.¹⁴ Several theories exist as to why OSA may cause patients to be susceptible to NAION. One theory suggests that nocturnal hypoxia in OSA directly causes nerve damage.¹⁸ Another theory predicts that OSA causes vascular dysregulation of the nerve due to oxidative stress and other factors.¹⁸ A different theory suggests that damage to the optic nerve is caused by an increase in intracranial pressure (ICP) during apneas.¹⁸ The pathophysiologic mechanism of NAION in OSA may be due to a combination of factors described in these theories.

Nonarteritic anterior ischemic optic neuropathy is more prevalent in patients with OSA than in the general population.

Nonarteritic anterior ischemic optic neuropathy is a serious condition that causes permanent vision loss and can occur in the fellow eye. Use of CPAP machines may decrease the risk of NAION developing in the fellow eye.¹⁹ Management of NAION involves controlling risk factors for recurrence, including management of any systemic disease involved. Orbital decompression surgery and intravitreal injections of steroids or anti-VEGF agents have not been shown to be effective treatment modalities.^18,20

Papilledema

The relationship between papilledema and OSA has not been as extensively researched as have FES, glaucoma, and NAION. Conflicting findings have been reported. Some case reports have demonstrated a positive correlation,¹⁷ and other studies have not.^21,22 Papilledema is bilateral swelling of the optic disc (Figure 5). When the disc edema is caused by an increase in ICP and not by any other mechanism, it is termed pseudotumor cerebri, or idiopathic intracranial hypertension (IIH). Patients with IIH are often obese, as are patients with OSA.

Figure 5.

Fundus photograph of papilledema.

During sleep, patients with OSA have been shown to have increases in their ICP that correspond to their episodes of apnea.²³ For some patients, these increases can cause papilledema.²¹ Owing to the lack of oxygen in the blood during apnea episodes, patients with OSA may be more at risk for vision loss than patients with IIH and without OSA.²¹ Multiple mechanisms are likely involved with papilledema in patients with OSA. Increased resistance in the jugular veins, leading to increased ICP, may be caused by a combination of mouth breathing, head posture, and obesity.²³ Intracranial edema in patients with OSA may be caused by neuroexcitotoxicity, disruption of the blood-brain barrier, or hypercoaguability.²³

Usually, IIH improves or resolves with weight loss. Complete resolution has been shown with a weight loss of just 6%.²⁴ An additional management method for IIH is diuretic prescription to decrease ICP (oral acetazolamide or another diuretic). Sometimes surgical methods are indicated, such as a lumboperitoneal shunt or optic nerve sheath fenestration. Patients with OSA and papilledema may have resolution of the papilledema with management of the OSA, including CPAP machine use or tracheostomy.^21,25

Keratoconus

In patients with keratoconus, the central cornea protrudes outward, forming the appearance of a cone. Keratoconus is a bilateral condition characterized by progressive thinning of the cornea and high irregular astigmatism. Studies have shown that patients with keratoconus are more likely to have OSA than the general population.²⁶ Approximately 18% to 20% of patients with keratoconus have OSA, and many more patients with keratoconus may be at risk for OSA.^27,28 Male patients with keratoconus who have a high body mass index (24.5-43.22) or a family history of OSA are more likely to have OSA.²⁸ Additionally, FES is more common in patients with keratoconus than in the general population.²⁹ When obesity was eliminated as a confounding factor, nonobese patients with keratoconus had no increased incidence of OSA than the general population.²⁵

The mechanism for keratoconus in patients with OSA is not well understood. Obesity may have a role in both conditions. A common theory is that eye rubbing or manipulation during sleep causes mechanical damage to the cornea.²⁶ The mechanical theory of FES suggests that rubbing of the eyelid and cornea against the pillow at night by OSA patients causes FES and its associated corneal conditions, including keratoconus. Sleeping position in patients with OSA may contribute to the development of keratoconus, but it has not been well researched.²⁷ Another theory speculates that an inflammatory process resulting from increased matrix metalloproteinases may be involved in the pathogenesis of both OSA and keratoconus.^27,29

Keratoconus is a progressive ophthalmic condition that can result in vision loss and severe corneal edema in extreme cases. The condition is treated in a variety of ways depending on patient characteristics. Refractive error is often better corrected with contact lenses, including scleral contact lenses, rigid gas permeable contact lenses, or hybrid hard lenses with a peripheral soft lens skirt. Surgical options include corneal transplant, implantable plastic rings, or corneal collagen crosslinking.

Central Serous Chorioretinopathy

Also called central serous retinopathy, CSCR is a condition in which a serous detachment of the neurosensory retina develops at the macula (Figure 6). Patients with CSCR may report distorted vision or have decreased visual acuity in the 20/30 to 20/60 range.³⁰ It may be caused by increased permeability in the choriocapillaris, a vascular layer of the choroid, and subsequent damage to the retinal pigment epithelium.³⁰ Central serous chorioretinopathy has been associated with increased endogenous or exogenous cortisol, which occurs with Cushing syndrome, corticosteroid therapy, pregnancy, and stress, as well as in patients with a “type A” personality.³⁰ This condition is more common in men.³⁰

Figure 6.

Fundus photograph of serous detachment of the neurosensory retina of the macula (arrows) seen in central serous chorioretinopathy.

Approximately two-thirds of patients with CSCR have OSA.³¹ One study found that when controlling for obesity, no statistically significant difference was found in the prevalence of OSA in patients with CSCR than in the general population.³² Thus, there seems to be a strong link between CSCR and OSA, but this correlation may result from the common factor of obesity.

One possible mechanism for the increased prevalence of CSCR in patients with OSA is increased oxidative stress. Oxidative stress can cause endothelial cell damage and vasoconstriction, both of which may be related to the pathogenesis of CSCR.³¹ Ischemia may cause increased permeability of the choriocapillaris.³¹ Another theory involves abnormalities of blood coagulation.³¹

Although usually self-limiting, CSCR recurs in up to 50% of patients.³⁰ If chronic, CSCR can lead to vision loss over time. Treatment for CSCR usually involves monitoring and decreasing risk factors. In chronic or recurrent cases, therapy may include laser treatment, intravitreal anti-VEGF agents, or systemic medications, such as aldosterone antagonists, β blockers, and carbonic anhydrase inhibitors.³⁰

Diabetic Macular Edema, Neovascular Age-Related Macular Degeneration, and Anti-VEGF

In patients with diabetes, retinal thickening and fluid accumulation at the macula is called diabetic macular edema (DME) (Figure 7). One study found an increase in the prevalence of DME in patients with OSA.³³ This association may be a result of periodic increases in blood pressure in patients with OSA, causing fluid leakage at the macula.³³ Focal laser treatment may be used, but DME is more commonly managed with anti-VEGF agents.

Figure 7.

Fundus photograph of diabetic macular edema. Note microaneurysms (A) and hard exudates (B).

More recently, a link has been found between the poor response to anti-VEGF therapy for DME or neovascular age-related macular degeneration (ARMD) in the presence of OSA.^34,35 Vascular endothelial growth factor is involved in the pathogenesis of both DME and neovascular ARMD, causing growth of new blood vessels, increased vascular permeability, and subsequent vessel leakage.³⁴ Intravitreal injections of anti-VEGF agents are the primary treatment used for patients with DME and neovascular ARMD. Resistance to anti-VEGF treatment in patients with OSA may be due to increased VEGF secretion during episodes of hypoxia.³⁴ Oxidative stress, inflammation, and endothelial cell dysfunction all cause increased VEGF secretion.³⁴ Management of OSA with CPAP therapy has been found to promote a positive response to anti-VEGF treatment, with a decrease in central retinal thickness and subretinal fluid and a need for fewer anti-VEGF injections.³⁵

Conclusion

The various ophthalmic diseases associated with OSA may cause patient discomfort or vision loss over time. To provide the highest level of care and improve patient quality of life, physicians should be aware of these associations and should refer patients with OSA for ophthalmic care. Management of OSA and its associated conditions should involve the patients’ primary care physician as well as ophthalmologists and other specialists, when applicable. Management should focus on improving ocular comfort and decreasing the risk of vision loss.