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The eye in sleep apnea syndrome
Sleep Medicine 7 (2006) 107–115 www.elsevier.com/locate/sleep
Review article
The eye in sleep apnea syndrome Helen Abdala, Joseph J. Pizzimentia,*, Cheryl C. Purvisb b
a Health Professions Division, College of Optometry, Nova Southeastern University, 3200 South University Drive, Ft. Lauderdale, FL 33328-2018, USA Health Professions Division, College of Medical Sciences, Nova Southeastern University, 3200 South University Drive, Ft. Lauderdale, FL 33328-2018, USA
Received 15 March 2005; received in revised form 9 August 2005; accepted 12 August 2005
Abstract Sleep apnea syndrome (SAS) is a disease characterized by recurrent complete or partial upper airway obstructions during sleep. The majority of patients with SAS demonstrate this obstruction either at the nasopharynx or the oropharynx. Risk factors for SAS include obesity, male gender, upper airway abnormalities, alcohol use, snoring, and neck girth of more than 17 in. in men or 16 in. in women. Reported ophthalmic findings in patients with SAS include floppy eyelid syndrome (FES), glaucoma, and non-arteritic anterior ischemic optic neuropathy (NAION). q 2005 Elsevier B.V. All rights reserved. Keywords: Sleep apnea syndrome; Obstructive sleep apnea; Floppy eyelid syndrome; Open-angle glaucoma; Normal tension glaucoma; Non-arteritic anterior ischemic optic neuropathy; Keratitis
1. Introduction Sleep apnea syndrome (SAS) is characterized by cessation of breathing during sleep, known as periods of apnea [1]. Clinically, apnea is defined as complete cessation of breathing for more than 10 s in adults [2]. Normally, when an individual is awake, the upper airway remains patent, allowing airflow to the lungs, except for momentary closures during swallowing and speech [3]. In some individuals, however, the pharyngeal lumen may become obstructed during sleep [4]. Sleep apnea syndrome describes two major sleep-related clinical problems: central sleep apnea and obstructive sleep apnea (OSA). Central sleep apnea is caused by the loss of ventilatory effort controlled by the nervous system. OSA is caused by upper airway obstruction. However, the mechanisms underlying these different types of sleep apnea are likely to overlap [5]. The prevalence of sleep-disordered breathing is approximately 2% in women and 4% in men between 30 and 60 years of age [6]. The majority of patients with SAS are diagnosed with OSA, the most common form of sleep * Corresponding author. Tel.: C1 954 262 1474; fax: C1 954 262 1818. E-mail address: [email protected] (J.J. Pizzimenti).
1389-9457/$ - see front matter q 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2005.08.010
apnea. Physical obstruction of the airway can result from a variety or combination of anatomical factors [7] such as enlarged tonsils [8], enlarged uvula [9], increased tongue size [10] and abnormal craniofacial morphology [11]. Genetics have also been found to be a factor [12–14]. In individuals with OSA, numerous sleep-related obstructive breathing events can occur throughout the night. In mild cases, there can be 5–15 episodes per hour and in severe cases more than 30 episodes per hour [15]. These respiratory disturbances may lead to hypoxia and hypercapnia, which can trigger arousal from sleep by increasing ventilatory drive [16–18]. As a result of this sleep disruption, excessive daytime sleepiness is the most common presenting complaint [19]. Other symptoms of sleep apnea may include loud snoring, not feeling well-rested in the morning, chronic fatigue [20], falling asleep at inappropriate times of day, morning headaches, recent weight gain, limited attention span, memory loss, poor judgment, personality changes, and lethargy [21]. These symptoms can significantly decrease quality of life and increase the risk of accidents [22,23]. Unfortunately, sleep apnea may go undiagnosed for years [24,25]. This is most likely because the people themselves may not remember the episodes of apnea. For this reason, it is often the patient’s spouse, bed partner, roommate or family member who may witness the periods
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of apnea, alternating with arousals and accompanied by loud snoring [26,27]. However, it is important to note that although snoring is the most common complaint associated with sleep apnea, most patients who snore do not have sleep apnea [26,28]. Therefore, patients reporting symptoms of SAS should be referred to a sleep center for an overnight sleep study. SAS is usually diagnosed by overnight polysomnography, including simultaneous electroencephalography (EEG), electromyography (EMG), electrocardiography (ECG), an electro-oculogram (EOG), oximetry, airflow through the mouth and nose, and thoracic and abdominal respiration by plethysmography [29]. From the overnight sleep study, the number of obstructive breathing events per hour can be determined. This calculation is commonly called the respiratory disturbance index (RDI) or more specifically, the apnea-hyponea index (AHI), which represents the sum total of apneas, hypopneas and respiratory arousals per hour of sleep [30]. The RDI value is used to diagnose and grade the severity of the sleep apnea [15]. Risk factors for SAS include upper airway abnormalities [7], male gender [31–33], alcohol use [34–36], snoring [26], obesity [37] (especially of the upper body), and a neck circumference of more than 17 in. in men or 16 in. in women [38,39]. Sadly, in the United States, with the increased prevalence of obesity in children and adolescence [40], we are beginning to see symptoms of sleep apnea at an earlier age [41]. Treatment of SAS can range from conservative methods such as oral appliances [42], to moderate intervention such as continuous positive airway pressure (CPAP) [43], to more radical approaches, including surgical removal of anatomic obstructions [44]. Since SAS is treatable, early recognition of the symptoms of this sleep disorder is crucial. Recent evidence in the literature suggests that the eye may help us identify individuals who suffer from undiagnosed SAS. Reported ophthalmic findings in patients with SAS may include floppy eyelid syndrome [45], nonarteritic anterior ischemic optic neuropathy [46,47], and glaucoma [48–50]. Being on the frontline of health care, eye care practitioners are likely to be the first health care professionals to see the general public. For this reason, it is essential for eye care professionals to recognize patients with symptoms of sleep apnea and refer them to a sleep specialist. Similarly, sleep medicine specialists who treat SAS should refer their patients for appropriate ophthalmic evaluation. In this review article, we describe each of the reported ocular complications associated with SAS. It is our hope that an increased awareness of the possible connection between SAS and ocular disease will promote crossreferrals between ophthalmic clinicians and sleep medicine specialists, resulting in improved patient outcomes.
2. Changes in eyelid tissue 2.1. Floppy eyelid syndrome Floppy eyelid syndrome (FES) was first described in 1981 by Culbertson and Ostler [51]. It is an under-diagnosed disorder of unknown pathogenesis that is characterized by lax upper eyelids that readily evert on elevation, a soft and foldable tarsus, and a chronic papillary reaction (conjunctivitis) of the upper palpebral conjunctiva [51]. Papillary conjunctivitis is defined as inflammation of the conjunctiva that presents as raised, vascularized areas (papillae). (Fig. 1) [52]. Additional clinical findings may include eyelash ptosis [53], aponeurotic blepharoptosis [54] and chronic corneal lesions, such as punctate epithelial keratopathy and corneal ulceration [55–57]. In addition, a number of ocular and systemic diseases have been reported in association with FES, including keratoconus [58], blepharochalasis and dermatochalasis [59], tear film abnormalities and meibomian gland dysfunction [60], hyperglycemia [61], and mental retardation [62]. FES was originally seen in overweight males that presented with rubbery, easily everted upper eyelids; however, the condition has also been reported in females and non-obese patients. A growing body of literature suggests that FES may be associated with OSA [51,63–65]. 2.1.1. Pathophysiology The pathophysiology of FES centers on the elastin located within the tarsal plate of the upper eyelid [51]. Although the tarsal collagen appears normal in patients with FES, histopathologic studies using special stains, immunohistochemistry, and electron microscopy demonstrate a significant decrease in the amount of tarsal elastin [64,66]. Other theories about the pathogenesis of FES include tear film disorders [59,67,68], meibomian gland abnormality including cystic degeneration, squamous metaplasia of the orifice, and atrophy of acini [60].
Fig. 1. Conjunctival papillae presenting as raised, vascular areas.
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2.1.2. Signs and symptoms FES may present with symptoms of nonspecific irritation, foreign body sensation, mucoid discharge, dryness, redness, photosensitivity, and eyelid swelling [60]. Many of these symptoms seem to be worse in the morning; it is speculated that one pathogenic mechanism of FES is through contact between the palpebral conjunctiva and pillow during sleep. Some reports suggest that in patients with FES, the worse floppy eyelid corresponds to the side of the body upon which the patient lies during sleep, and that there is also a preference for sleeping on one’s stomach [53,55,60,66]. 2.1.3. Diagnosis Ophthalmic clinicians may employ several measures to diagnose FES, including gross examination, slit lamp biomicroscopy, and tear film/lacrimal testing. Direct external examination with palpation may uncover laxity of the lids. A loose upper eyelid is easily everted when pulled superiorly toward the eyebrow because the soft, rubbery tarsal plate can be folded upon itself. With chronic FES, the tarsal plate area may appear atrophic on biomicroscopy [69]. Under biomicroscopy, the pre-corneal tear film, which is composed of lipids, electrolytes, and protein containing aqueous fluid and mucins, can be evaluated [70]. The tear film serves several functions. In addition to its primary action of lubricating the ocular surface, it is used as a waste removal system, as well as a defense mechanism for the cornea. The tear layer also provides anti-microbial protection. Under normal circumstances, aqueous tears are secreted by the lacrimal gland, spread over the entire cornea by lid blinking, and then cleared from the eye into the nose through the nasolacrimal drainage system, which includes the superior and inferior puncta and canaliculi, the lacrimal sac, and nasolacrimal duct [71,72]. Dyes such as fluorescein, rose bengal and lissamine green are used to establish an aqueous tear deficiency. One common way of measuring tear clearance is to measure the tear break-up time (TBUT). Using fluorescein, the TBUT can be measured. It is evaluated by placing a drop of fluorescein into the inferior fornix, asking the patient to close his eyes, then to open them and keep them open. The examiner then measures the number of seconds (after opening) until the tear film breaks. Rose bengal and lissamine green dyes are also used to evaluate ocular surface integrity. These dyes stain mucus, degenerating cells, and dead cells of the corneal epithelium. In addition, a Schirmer test [73] can be performed. During this test, a bent piece of Whatman No. 41 filter paper is placed in the lower conjunctiva, and the amount of tearing on the filter paper is recorded in millimeters. A positive Schirmer result is less than 5 mm after 5 min, indicating a compromised tear layer.
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The differential diagnoses of FES include the vernal, atopic, superior limbal, and giant papillary keratoconjunctivitities, as well as nocturnal lagophthalmos [73]. A detailed history and proper ophthalmic workup can rule out these masqueraders. 2.1.4. Treatment The goal of treatment of FES is to protect the ocular surface during sleep. Topical management centers upon the frequent instillation of artificial tears and ocular lubricants. In the event of significant corneal or conjunctival compromise, such as superficial punctate keratitis, a broad-spectrum antibiotic ophthalmic ointment, such as erythromycin, can be prescribed [73]. Surgical intervention is usually reserved for those patients who do not benefit from topical treatment. Horizontal lid shortening is a surgical technique in which the loose lid is resected and shortened, thus preventing spontaneous eversion during sleep [74]. 2.1.5. FES and SAS Both FES and specifically OSA syndrome have similar patient profiles—middle aged, obese men. A common thread that may link FES to OSA is a defect in elastic tissue. In FES, tarsal elastin is affected; in OSA, palatine elastin is affected [65,74]. In a case series, Mojon et al. determined the prevalence of eyelid, conjunctival, and corneal findings in patients referred for polysomnography because of suspected SAS [45]. Seventy-two out of 80 patients received an ophthalmic examination, videokeratography, general neurologic and laboratory examinations, and sleep studies, which were interpreted and graded according to the RDI. In this study, the Spearman rank correlations between the RDI and tear film break-up time (distribution of an adequate tear film), eyelid distraction distance, presence or absence of blepharoptosis (a drooping eyelid), floppy eyelids, lacrimal (tear producing) gland prolapse, keratoconus (irregular protrusion of the cornea), and corneal endothelial dystrophy were calculated. The presence or absence of symptoms of ocular irritation was also correlated with the RDI. Each correlation was controlled for age and body mass index [45]. The authors concluded that SAS was significantly associated with reduced tear film break-up time, floppy eyelids, and lacrimal gland prolapse. According to the RDI, 61% (44 out of the 72) of the patients with these ocular findings had SAS. In addition, the RDI correlated positively with the eyelid distraction distance (PZ0.05), presence or absence of floppy eyelids (PZ0.01), and lacrimal gland prolapse (PZ0.01). However, the RDI correlated negatively with tear film break-up time (PZ0.02). Thus, the authors were unable to confirm previous studies that reported a high prevalence of corneal involvement in floppy eyelid syndrome [45]. In another study, Robert et al. set out to establish the frequency of FES or other palpebral and ocular
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abnormalities in patients with sleep disorders [65]. The sample consisted of 69 patients with sleep disorders, of which 46 had been diagnosed with OSA syndrome, 16 with untreated apneas and seven with heavy snoring without apneas. The control group consisted of 45 patients with neither SAS nor palpebral troubles. The authors found an association between upper eyelid hyperlaxity (chi-squared test PZ0.001) and OSA. They also identified one case of papillary conjunctivitis and two cases of punctate epithelial keratitis. In addition, the authors found an abnormal elasticity in patients with OSA syndrome, supporting the theory of a disorder of elastin fibers. However, this remains to be proven histologically [65]. Like Mojon et al. [45], the authors were not able to establish any significant prevalence of corneal involvement. Thus, they concluded that OSA was associated with upper eyelid hyperlaxity, but not FES.
(i.e. short posterior ciliary arteries) supplying the optic nerve at its exit from the eye. Only glial cells support the optic disc at this site, and it is the only site in which swelling can occur [80–82]. As an ischemic episode evolves, the swelling compromises circulation, with a spiral of ischemia resulting in further neuronal damage [81].
3. Changes in the optic nerve
3.1.3. Diagnosis Most of the time, a relative afferent pupillary defect (APD) is noted in the eye with NAION. Examining the pupillary responses with a bright light identifies a relative APD. In normal circumstances, when a light is shone in one eye, both pupils constrict briskly and to an equal extent. When a light is shone in the abnormal eye of a patient with a relative APD, both pupils will constrict equally, however, the constriction of both pupils will be less pronounced [84]. A unilateral or asymmetric bilateral NAION will produce a relative APD. This abnormal response signifies a reduced conduction of one optic nerve relative to the fellow nerve. Initially in NAION, the optic disc appears swollen and hyperemic, often in a generalized or diffuse manner. Sectoral disc edema and pallor, especially superiorly, usually develops shortly thereafter [80]. Visual field testing will typically reveal a corresponding inferior or superior altitudinal loss. One of the most important laboratory tests for any patient with NAION is the erythrocyte sedimentation rate (ESR). In NAION, the ESR is likely to be normal. It is essential to rule out the arteritic form of ischemic optic neuropathy (AION). Here, the etiology is giant cell arteritis (GCA), rather than ischemic vascular disease. Other blood tests, such as the C-reactive protein (CRP), have been useful in diagnosing GCA [83]. If GCA is suspected, a temporal artery biopsy may also be performed, although a normal biopsy does not completely exclude the possibility of GCA [84].
3.1. Non-arteritic anterior ischemic optic neuropathy Non-arteritic anterior ischemic optic neuropathy (NAION) is a disease characterized by a sudden, painless, irreversible, non-progressive visual loss of moderate degree, initially unilateral, though it may become bilateral [73]. Clinical signs include optic nerve fiber bundle field defects, a relative afferent pupillary defect, and optic disc edema (Fig. 2.). The prevalence of NAION increases with age and is associated with a small cup-to-disc ratio [75,76], hypertension [75,77], diabetes mellitus [75,77,78], arteriosclerosis [78], and hypercholesterolemia [78,79]. 3.1.1. Pathophysiology NAION is thought to be an ischemic process affecting the posterior circulation of the globe, principally vessels
Fig. 2. Optic disc edema as it presents in NAION. Note the elevated, blurred disc margins.
3.1.2. Signs and symptoms Visual loss is acute, unilateral, and painless in approximately 90% of patients with NAION [83]. Critical signs include a relative afferent pupillary defect, pale optic nerve head swelling involving only a segment of the disc, flameshaped hemorrhages, and normal erythrocyte sedimentation rate (ESR) [73,80,81]. The visual acuity and visual field loss is typically noticed upon awakening, perhaps due to nocturnal hypotension. NAION may also present in a progressive form, with the onset of symptoms occurring over a few days, rather than the acute-onset form.
3.1.4. Treatment Medical treatment for NAION has included anticoagulants and antiplatelet agents, vasodilators, diphenylhydantoin, intraocular pressure lowering agents (norepinephrine) to improve the gradient of nerve head perfusion pressure to intraocular pressure and oral corticosteroids [85]. None of these treatments have proven to be effective. Aspirin is often given to patients following the development of NAION, but there does not seem to be
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any beneficial effect of this treatment on the eventual visual outcome [86]. Some authors have suggested that aspirin may reduce the risk of NAION in the fellow eye [87]. If ischemic vascular disease is involved, this should be treated in consultation with the primary care physician. 3.1.5. NAION and SAS There are several theories about the link between NAION and SAS. Mojon et al. hypothesized that the damage may result from impaired optic nerve head blood flow autoregulation, secondary to repetitive prolonged apneas. Optic nerve vascular dysregulation may occur secondary to arteriosclerosis and arterial blood pressure variations (episodic nocturnal hypertension or hypotension) seen in SAS. This dysregulation may be due to the imbalance between nitric oxide (a vasodilator) and endothelin (a vasoconstrictor). Repetitive or prolonged episodes of hypoxia may cause direct damage to the optic nerve. Because of the large stores of carbon dioxide and excellent buffering capacity of the body, changes in PaCO2 and pH during apneas remain modest (in contrast to changes in PaO2). Therefore, PaCO2 variations are not considered to be especially harmful. Episodic increased intracranial pressure during apneic episodes may also have adverse effects on the optic nerve, either directly or indirectly by compromising the vascular supply [47]. Mojon et al. have correlated optic neuropathy with SAS [47]. In this case series study, visual field defects were correlated with the RDI values for suspected SAS patients. The results of this study showed that the RDI correlated positively with both the mean visual field defect (rsZ0.81, P!0.05) and the visual field loss variance (rsZ0.78, P!0.05). Thus, the investigators concluded that visual fields of patients with SAS showed defects consistent with an optic neuropathy. However, their data did not demonstrate a direct causal relationship between SAS and visual field defects. Mojon et al. have also examined the prevalence of SAS in patients with NAION [46]. In this case series study, the subjects consist of 17 patients diagnosed with NAION and 17 control patients diagnosed with restless leg syndrome and matched for age and sex. The authors found that twelve (71%) of their 17 patients with NAION had SAS. According to the respiratory disturbance index, 4 patients (24%) had mild, 4 patients (24%) had moderate, and 4 patients (24%) had severe SAS. Only 3 (18%) of 17 controls had SAS (PZ005) [46].
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unusually susceptible to damage, resulting in histopathological changes in this tissue [88]. 3.2.1. Pathophysiology The two proposed mechanisms for glaucoma pathogenesis are the mechanical theory and the vascular theory. The mechanical theory suggests that abnormally high intraocular pressure (IOP) ultimately causes direct damage to the optic nerve [88]. This IOP elevation may be due to overproduction of aqueous fluid or impaired aqueous outflow. The vascular theory postulates that there is insufficient blood supply to nourish the nerve fiber layer and/or optic nerve [88]. If a patient is vascularly compromised through either atherosclerosis or arteriosclerosis, then the short posterior ciliary arteries which feed the anterior optic nerve could be attenuated, leading to ischemia and loss of neural tissue [88]. The glaucomas are classified into several types. The two that have been associated with SAS are normal tension glaucoma (NTG) [48,89] and primary open-angle glaucoma (POAG) [49,50]. NTG is a type of open-angle glaucoma that is characterized by glaucomatous optic nerve head cupping, visual field defects, and open anterior chamber angles without elevated IOP [73]. Various risk factors are associated with NTG, but a cause-and-effect relationship has not been established for this optic neuropathy [48]. POAG has the same characteristics as NTG, with the exception that in POAG, the IOP is abnormally high for that individual. POAG is, by far, the most common form of glaucoma [73]. The exact cause of glaucomatous optic neuropathy is not known; however, many risk factors have been identified, including pre-existing family history, race, myopia, thin cornea as measured by pachymetry, and age (older than 40 years) [88]. 3.2.2. Signs and symptoms In the chronic glaucomas such as NTG and POAG, patients are usually asymptomatic [73]. These types of glaucoma occur gradually and are best diagnosed by an ophthalmic physician. By contrast, symptoms of ocular pain and decreased vision occur in acute forms of the disease such as acute angle-closure glaucoma [73]. A dilated fundus examination is required to accurately assess the health of the optic nerve and nerve fiber layer. Signs of typical glaucomatous optic nerve damage include a deepening and widening of the optic cup (Fig. 3), vertical elongation of the optic cup, peripapillary atrophy, optic disc hemorrhages, asymmetry between the two optic nerves; and nerve fiber layer loss/drop-out [88].
3.2. Glaucoma Glaucoma is not a single-disease entity, but rather a group of ocular diseases with various etiologies that ultimately result in a consistent optic neuropathy. Glaucoma results when intraocular pressure becomes ‘abnormal’ for a given individual or when the optic nerve head becomes
3.2.3. Diagnosis The diagnosis of glaucoma can be made by a careful history, in addition to thorough, non-invasive ophthalmic testing. Screening the general population for POAG is mandatory for every individual over 45 years of age, since no subjective sign will cause the patient to seek immediate
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[89]. The study included 23 patients with NTG, 14 NTG suspects, and 30 comparison patients without glaucoma. To be diagnosed with NTG, patients needed to have unilateral or bilateral optic disc abnormalities and visual field defects judged by the authors to be characteristic of glaucoma. In addition, they had to have had no recorded intraocular pressure readings greater than 24 mmHg with diurnal applanation tonometry testing. To be diagnosed as ‘NTG suspect’, patients needed to have the above optic disc abnormalities with normal diurnal intraocular pressure readings, in the absence of visual field defects. The sleep history obtained in this study consisted of the following questions:
Fig. 3. Glaucomatous optic nerve cupping.
consult. Diagnostic testing includes a dilated fundus examination, intra-ocular pressure (IOP) testing by applanation tonometry, and visual field testing by perimetry. For the specialized check-up of diagnosed glaucoma, pachymetry (corneal thickness), gonioscopy (anterior chamber angle assessment), and scanning laser techniques (such as optical coherence tomograpghy, polarimetry or nerve fiber analysis, and retinal tomography) may be warranted. At follow-up visits, an IOP check as well as a visual field and dilated fundus exam are performed. 3.2.4. Treatment Glaucoma may be treated medically, with laser surgery, or with incisional surgery. All of these treatments center on the lowering of intraocular pressure (IOP) [88]. The majority of POAG and NTG cases are effectively treated with topical medications. The main drug classes for medical treatment include prostaglandin analogs, alpha-agonists, beta-blockers, carbonic anhydrase inhibitors, and miotic agents. Each of these drug classes has a particular mechanism of action, but their goal is the same: to preserve the optic nerve and nerve fiber layer by means of IOP reduction. 3.2.5. Glaucoma and SAS The theories that link glaucoma to SAS are similar to those that link NAION and SAS. These theories include impaired optic nerve head blood flow autoregulation secondary to repetitive prolonged apneas, optic nerve vascular dysregulation secondary to arteriosclerosis and arterial blood pressure variations (episodic nocturnal hypertension or hypotension), and repetitive or prolonged episodes of hypoxia causing direct damage to the optic nerve. In a case series study conducted by Marcus et al., the authors sought to determine the prevalence of sleep-related symptoms and sleep-related breathing disorders by polysomnography, in patients with normal-tension glaucoma
(1) Do you have trouble sleeping at night? Why (heart failure, urination, other)? (2) Does someone sleep close enough to you to hear any nighttime noise, such as snoring? (3) Are you sleepy during the daytime or do you fall asleep at times when you should not? (4) Do you snore or have frequent awakenings? Why (heart failure, urination, and so forth)? (5) Do you have frequent headaches, especially in the morning after awakening? (6) Do you have a known sleep disorder or have you ever had a sleep study (polysomnography)? Prevalence of sleep disorders and a positive sleep history were the main outcome measures. A positive response to one or more of these questions corresponds with a positive sleep history, suggestive of a sleep disorder. The results of this study showed a significant correlation between glaucoma and sleep-disordered breathing. The authors found that 13 of the 23 (57%) patients with NTG, six of the 14 (43%) NTG suspects, and one of the 30 (3%) nonglaucoma comparison patients had a positive sleep history (PZ0.001). Nine of the 13 patients with NTG and four of the six NTG suspects with a positive sleep history chose to undergo polysomnography. Seven of the nine patients with NTG and all four NTG suspects that underwent polysomnography were diagnosed with a sleep disorder. Five patients with NTG had sleep apnea (defined as a cessation of airflow for more than 10 s) and two had sleep hypopnea (defined as a reduction in air flow for 10 s associated with oxygen desaturation). Two NTG suspects had sleep apnea, one had sleep hypopnea, and one had upper airway resistance syndrome. The one comparison patient with a positive sleep history was diagnosed with upper airway resistance syndrome by polysomnography. The authors concluded that sleep-disturbed breathing may be a risk factor for NTG. In addition, although their results did not provide evidence for a cause-and-effect relationship, various physiologic factors produced by sleepdisturbed breathing may play a significant role in the pathogenesis of NTG. The main risk factor among this
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group was hypoperfusion of the optic nerve head as a result of chronic progressive ischemia. In a recent study, Mojon et al. also found an association between NTG and SAS [48]. In this study, overnight polsomnography was performed on 16 consecutive Caucasian patients with NTG. The authors found the following prevelances of obstructive sleep apnea in NTG patients: none (0 of 2) for the group of patients younger than 45 years of age, 50% (3 of 6) for the age group 45–64 years old and 63% (5 of 8) for the group older than 64 years of age. Since 1999, Mojon et al. have sought to establish the incidence of both NTG and POAG in patients with SAS [49]. For the diagnosis of primary open-angle glaucoma, the following criteria were applied: typical glaucomatous optic nerve cupping, glaucomatous visual field defects, open and also otherwise normal anterior chamber angles, and untreated IOPs above 21 mmHg. For the diagnosis of NTG, the following criteria had to be met: typical glaucomatous optic nerve cupping, glaucomatous visual field defects, open and also otherwise normal anterior chamber angles, and untreated IOPs below 22 mmHg during at least one diurnal testing [49]. The authors found that 69 of the 114 (60.5%) patients in the study were diagnosed with SAS (RDIR10). Of these 69 patients, only 3 patients had POAG and 2 had NTG. In addition, the RDI correlated positively with IOP (PZ 0.025), visual field loss variance (PZ0.03), glaucomatous optic disc changes (PZ0.001), and diagnosis of glaucoma (PZ0.01). The authors concluded that SAS constitutes a high-risk population for glaucoma. In a subsequent case series study, Mojon et al. set out to determine the prevalence of SAS in POAG [50]. Overnight transcutaneous finger oximetry was performed in 30 consecutive patients having POAG. The authors concluded that SAS was more prevalent among POAG patients compared to normal historic controls of the same age and sex distribution (x2Z9.35, d.f. Z3, P!0.025). In addition, the oximetry disturbance index grade was significantly larger in the POAG group compared to normal controls (PZ 0.01). According to this index, an astounding 20% of POAG patients had an association with SAS.
4. Other associations 4.1. Marfan’s syndrome Marfan’s syndrome is a hereditary connective tissue disorder, manifested principally by changes in the skeleton, eyes and the cardiovascular system [90,91]. It is characterized by long extremities, ocular complications, and cardiovascular abnormalities [91,92]. Individuals with Marfan’s syndrome have also been shown to experience obstructive sleep apnea, which can be attributed to relaxed connective tissue, leading to upper airway collapsibility [93].
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Ocular complications of Marfan’s syndrome are usually manifested as ectopia lentis [90,92]. This is characterized by a decentered crystalline lens, secondary to disruption of the surrounding zonular fibers [92]. Patients with ectopia lentis are at an increased risk for retinal detachment [94]. Another reported ocular manifestation is keratoconus, an abnormal thinning and bulging of the cornea [95].
5. Conclusions As the importance of sleep becomes more apparent to the medical community [96], it is our responsibility as health care professionals to recognize signs and symptoms of disorders that are not directly related to our specialties, but affect the overall health of our patients. A growing body of literature in the fields of sleep medicine and ophthalmic disorders provides evidence that suggests an association between sleep apnea syndrome and ocular problems. Although the precise mechanisms linking SAS and ocular problems are poorly understood, the literature suggests that patients with SAS may have an increased incidence of normal tension glaucoma [48,89], open-angle glaucoma [49,50], non-arteritic anterior ischemic optic neuropathy [46], and floppy eyelid syndrome [45,47,65]. Since glaucoma and floppy eye syndrome are treatable, early detection of these conditions can significantly improve patient outcomes. Just as an increased knowledge of the effect of extended work shifts could result in better policies for truck drivers and medical interns [96], we hope an increased awareness of ocular problems associated with SAS will result in more cross-referrals between sleep specialists and ophthalmic clinicians. Specifically, in the future, it may become standard practice for ophthalmic clinicians to refer their patients with these ocular entities for a sleep study, particularly if the patient fits the demographic profile or complains of sleep disturbances. Similarly, sleep apnea specialists should recommend that all their patients have a thorough ocular health examination with routine testing for glaucoma and floppy eyelid syndrome. A dilated retinal and optic nerve evaluation should be performed as part of a comprehensive ophthalmic examination. Like the Yin-Yang symbol that was adopted by the American Academy of Sleep Disorders Association to represent the interlocking importance of sleep and wakefulness [97], it is our hope that this review article will unite sleep medicine specialists and ophthalmic clinicians to recognize the association between SAS and the eye.
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Review article
The eye in sleep apnea syndrome Helen Abdala, Joseph J. Pizzimentia,*, Cheryl C. Purvisb b
a Health Professions Division, College of Optometry, Nova Southeastern University, 3200 South University Drive, Ft. Lauderdale, FL 33328-2018, USA Health Professions Division, College of Medical Sciences, Nova Southeastern University, 3200 South University Drive, Ft. Lauderdale, FL 33328-2018, USA
Received 15 March 2005; received in revised form 9 August 2005; accepted 12 August 2005
Abstract Sleep apnea syndrome (SAS) is a disease characterized by recurrent complete or partial upper airway obstructions during sleep. The majority of patients with SAS demonstrate this obstruction either at the nasopharynx or the oropharynx. Risk factors for SAS include obesity, male gender, upper airway abnormalities, alcohol use, snoring, and neck girth of more than 17 in. in men or 16 in. in women. Reported ophthalmic findings in patients with SAS include floppy eyelid syndrome (FES), glaucoma, and non-arteritic anterior ischemic optic neuropathy (NAION). q 2005 Elsevier B.V. All rights reserved. Keywords: Sleep apnea syndrome; Obstructive sleep apnea; Floppy eyelid syndrome; Open-angle glaucoma; Normal tension glaucoma; Non-arteritic anterior ischemic optic neuropathy; Keratitis
1. Introduction Sleep apnea syndrome (SAS) is characterized by cessation of breathing during sleep, known as periods of apnea [1]. Clinically, apnea is defined as complete cessation of breathing for more than 10 s in adults [2]. Normally, when an individual is awake, the upper airway remains patent, allowing airflow to the lungs, except for momentary closures during swallowing and speech [3]. In some individuals, however, the pharyngeal lumen may become obstructed during sleep [4]. Sleep apnea syndrome describes two major sleep-related clinical problems: central sleep apnea and obstructive sleep apnea (OSA). Central sleep apnea is caused by the loss of ventilatory effort controlled by the nervous system. OSA is caused by upper airway obstruction. However, the mechanisms underlying these different types of sleep apnea are likely to overlap [5]. The prevalence of sleep-disordered breathing is approximately 2% in women and 4% in men between 30 and 60 years of age [6]. The majority of patients with SAS are diagnosed with OSA, the most common form of sleep * Corresponding author. Tel.: C1 954 262 1474; fax: C1 954 262 1818. E-mail address: [email protected] (J.J. Pizzimenti).
1389-9457/$ - see front matter q 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2005.08.010
apnea. Physical obstruction of the airway can result from a variety or combination of anatomical factors [7] such as enlarged tonsils [8], enlarged uvula [9], increased tongue size [10] and abnormal craniofacial morphology [11]. Genetics have also been found to be a factor [12–14]. In individuals with OSA, numerous sleep-related obstructive breathing events can occur throughout the night. In mild cases, there can be 5–15 episodes per hour and in severe cases more than 30 episodes per hour [15]. These respiratory disturbances may lead to hypoxia and hypercapnia, which can trigger arousal from sleep by increasing ventilatory drive [16–18]. As a result of this sleep disruption, excessive daytime sleepiness is the most common presenting complaint [19]. Other symptoms of sleep apnea may include loud snoring, not feeling well-rested in the morning, chronic fatigue [20], falling asleep at inappropriate times of day, morning headaches, recent weight gain, limited attention span, memory loss, poor judgment, personality changes, and lethargy [21]. These symptoms can significantly decrease quality of life and increase the risk of accidents [22,23]. Unfortunately, sleep apnea may go undiagnosed for years [24,25]. This is most likely because the people themselves may not remember the episodes of apnea. For this reason, it is often the patient’s spouse, bed partner, roommate or family member who may witness the periods
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of apnea, alternating with arousals and accompanied by loud snoring [26,27]. However, it is important to note that although snoring is the most common complaint associated with sleep apnea, most patients who snore do not have sleep apnea [26,28]. Therefore, patients reporting symptoms of SAS should be referred to a sleep center for an overnight sleep study. SAS is usually diagnosed by overnight polysomnography, including simultaneous electroencephalography (EEG), electromyography (EMG), electrocardiography (ECG), an electro-oculogram (EOG), oximetry, airflow through the mouth and nose, and thoracic and abdominal respiration by plethysmography [29]. From the overnight sleep study, the number of obstructive breathing events per hour can be determined. This calculation is commonly called the respiratory disturbance index (RDI) or more specifically, the apnea-hyponea index (AHI), which represents the sum total of apneas, hypopneas and respiratory arousals per hour of sleep [30]. The RDI value is used to diagnose and grade the severity of the sleep apnea [15]. Risk factors for SAS include upper airway abnormalities [7], male gender [31–33], alcohol use [34–36], snoring [26], obesity [37] (especially of the upper body), and a neck circumference of more than 17 in. in men or 16 in. in women [38,39]. Sadly, in the United States, with the increased prevalence of obesity in children and adolescence [40], we are beginning to see symptoms of sleep apnea at an earlier age [41]. Treatment of SAS can range from conservative methods such as oral appliances [42], to moderate intervention such as continuous positive airway pressure (CPAP) [43], to more radical approaches, including surgical removal of anatomic obstructions [44]. Since SAS is treatable, early recognition of the symptoms of this sleep disorder is crucial. Recent evidence in the literature suggests that the eye may help us identify individuals who suffer from undiagnosed SAS. Reported ophthalmic findings in patients with SAS may include floppy eyelid syndrome [45], nonarteritic anterior ischemic optic neuropathy [46,47], and glaucoma [48–50]. Being on the frontline of health care, eye care practitioners are likely to be the first health care professionals to see the general public. For this reason, it is essential for eye care professionals to recognize patients with symptoms of sleep apnea and refer them to a sleep specialist. Similarly, sleep medicine specialists who treat SAS should refer their patients for appropriate ophthalmic evaluation. In this review article, we describe each of the reported ocular complications associated with SAS. It is our hope that an increased awareness of the possible connection between SAS and ocular disease will promote crossreferrals between ophthalmic clinicians and sleep medicine specialists, resulting in improved patient outcomes.
2. Changes in eyelid tissue 2.1. Floppy eyelid syndrome Floppy eyelid syndrome (FES) was first described in 1981 by Culbertson and Ostler [51]. It is an under-diagnosed disorder of unknown pathogenesis that is characterized by lax upper eyelids that readily evert on elevation, a soft and foldable tarsus, and a chronic papillary reaction (conjunctivitis) of the upper palpebral conjunctiva [51]. Papillary conjunctivitis is defined as inflammation of the conjunctiva that presents as raised, vascularized areas (papillae). (Fig. 1) [52]. Additional clinical findings may include eyelash ptosis [53], aponeurotic blepharoptosis [54] and chronic corneal lesions, such as punctate epithelial keratopathy and corneal ulceration [55–57]. In addition, a number of ocular and systemic diseases have been reported in association with FES, including keratoconus [58], blepharochalasis and dermatochalasis [59], tear film abnormalities and meibomian gland dysfunction [60], hyperglycemia [61], and mental retardation [62]. FES was originally seen in overweight males that presented with rubbery, easily everted upper eyelids; however, the condition has also been reported in females and non-obese patients. A growing body of literature suggests that FES may be associated with OSA [51,63–65]. 2.1.1. Pathophysiology The pathophysiology of FES centers on the elastin located within the tarsal plate of the upper eyelid [51]. Although the tarsal collagen appears normal in patients with FES, histopathologic studies using special stains, immunohistochemistry, and electron microscopy demonstrate a significant decrease in the amount of tarsal elastin [64,66]. Other theories about the pathogenesis of FES include tear film disorders [59,67,68], meibomian gland abnormality including cystic degeneration, squamous metaplasia of the orifice, and atrophy of acini [60].
Fig. 1. Conjunctival papillae presenting as raised, vascular areas.
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2.1.2. Signs and symptoms FES may present with symptoms of nonspecific irritation, foreign body sensation, mucoid discharge, dryness, redness, photosensitivity, and eyelid swelling [60]. Many of these symptoms seem to be worse in the morning; it is speculated that one pathogenic mechanism of FES is through contact between the palpebral conjunctiva and pillow during sleep. Some reports suggest that in patients with FES, the worse floppy eyelid corresponds to the side of the body upon which the patient lies during sleep, and that there is also a preference for sleeping on one’s stomach [53,55,60,66]. 2.1.3. Diagnosis Ophthalmic clinicians may employ several measures to diagnose FES, including gross examination, slit lamp biomicroscopy, and tear film/lacrimal testing. Direct external examination with palpation may uncover laxity of the lids. A loose upper eyelid is easily everted when pulled superiorly toward the eyebrow because the soft, rubbery tarsal plate can be folded upon itself. With chronic FES, the tarsal plate area may appear atrophic on biomicroscopy [69]. Under biomicroscopy, the pre-corneal tear film, which is composed of lipids, electrolytes, and protein containing aqueous fluid and mucins, can be evaluated [70]. The tear film serves several functions. In addition to its primary action of lubricating the ocular surface, it is used as a waste removal system, as well as a defense mechanism for the cornea. The tear layer also provides anti-microbial protection. Under normal circumstances, aqueous tears are secreted by the lacrimal gland, spread over the entire cornea by lid blinking, and then cleared from the eye into the nose through the nasolacrimal drainage system, which includes the superior and inferior puncta and canaliculi, the lacrimal sac, and nasolacrimal duct [71,72]. Dyes such as fluorescein, rose bengal and lissamine green are used to establish an aqueous tear deficiency. One common way of measuring tear clearance is to measure the tear break-up time (TBUT). Using fluorescein, the TBUT can be measured. It is evaluated by placing a drop of fluorescein into the inferior fornix, asking the patient to close his eyes, then to open them and keep them open. The examiner then measures the number of seconds (after opening) until the tear film breaks. Rose bengal and lissamine green dyes are also used to evaluate ocular surface integrity. These dyes stain mucus, degenerating cells, and dead cells of the corneal epithelium. In addition, a Schirmer test [73] can be performed. During this test, a bent piece of Whatman No. 41 filter paper is placed in the lower conjunctiva, and the amount of tearing on the filter paper is recorded in millimeters. A positive Schirmer result is less than 5 mm after 5 min, indicating a compromised tear layer.
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The differential diagnoses of FES include the vernal, atopic, superior limbal, and giant papillary keratoconjunctivitities, as well as nocturnal lagophthalmos [73]. A detailed history and proper ophthalmic workup can rule out these masqueraders. 2.1.4. Treatment The goal of treatment of FES is to protect the ocular surface during sleep. Topical management centers upon the frequent instillation of artificial tears and ocular lubricants. In the event of significant corneal or conjunctival compromise, such as superficial punctate keratitis, a broad-spectrum antibiotic ophthalmic ointment, such as erythromycin, can be prescribed [73]. Surgical intervention is usually reserved for those patients who do not benefit from topical treatment. Horizontal lid shortening is a surgical technique in which the loose lid is resected and shortened, thus preventing spontaneous eversion during sleep [74]. 2.1.5. FES and SAS Both FES and specifically OSA syndrome have similar patient profiles—middle aged, obese men. A common thread that may link FES to OSA is a defect in elastic tissue. In FES, tarsal elastin is affected; in OSA, palatine elastin is affected [65,74]. In a case series, Mojon et al. determined the prevalence of eyelid, conjunctival, and corneal findings in patients referred for polysomnography because of suspected SAS [45]. Seventy-two out of 80 patients received an ophthalmic examination, videokeratography, general neurologic and laboratory examinations, and sleep studies, which were interpreted and graded according to the RDI. In this study, the Spearman rank correlations between the RDI and tear film break-up time (distribution of an adequate tear film), eyelid distraction distance, presence or absence of blepharoptosis (a drooping eyelid), floppy eyelids, lacrimal (tear producing) gland prolapse, keratoconus (irregular protrusion of the cornea), and corneal endothelial dystrophy were calculated. The presence or absence of symptoms of ocular irritation was also correlated with the RDI. Each correlation was controlled for age and body mass index [45]. The authors concluded that SAS was significantly associated with reduced tear film break-up time, floppy eyelids, and lacrimal gland prolapse. According to the RDI, 61% (44 out of the 72) of the patients with these ocular findings had SAS. In addition, the RDI correlated positively with the eyelid distraction distance (PZ0.05), presence or absence of floppy eyelids (PZ0.01), and lacrimal gland prolapse (PZ0.01). However, the RDI correlated negatively with tear film break-up time (PZ0.02). Thus, the authors were unable to confirm previous studies that reported a high prevalence of corneal involvement in floppy eyelid syndrome [45]. In another study, Robert et al. set out to establish the frequency of FES or other palpebral and ocular
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abnormalities in patients with sleep disorders [65]. The sample consisted of 69 patients with sleep disorders, of which 46 had been diagnosed with OSA syndrome, 16 with untreated apneas and seven with heavy snoring without apneas. The control group consisted of 45 patients with neither SAS nor palpebral troubles. The authors found an association between upper eyelid hyperlaxity (chi-squared test PZ0.001) and OSA. They also identified one case of papillary conjunctivitis and two cases of punctate epithelial keratitis. In addition, the authors found an abnormal elasticity in patients with OSA syndrome, supporting the theory of a disorder of elastin fibers. However, this remains to be proven histologically [65]. Like Mojon et al. [45], the authors were not able to establish any significant prevalence of corneal involvement. Thus, they concluded that OSA was associated with upper eyelid hyperlaxity, but not FES.
(i.e. short posterior ciliary arteries) supplying the optic nerve at its exit from the eye. Only glial cells support the optic disc at this site, and it is the only site in which swelling can occur [80–82]. As an ischemic episode evolves, the swelling compromises circulation, with a spiral of ischemia resulting in further neuronal damage [81].
3. Changes in the optic nerve
3.1.3. Diagnosis Most of the time, a relative afferent pupillary defect (APD) is noted in the eye with NAION. Examining the pupillary responses with a bright light identifies a relative APD. In normal circumstances, when a light is shone in one eye, both pupils constrict briskly and to an equal extent. When a light is shone in the abnormal eye of a patient with a relative APD, both pupils will constrict equally, however, the constriction of both pupils will be less pronounced [84]. A unilateral or asymmetric bilateral NAION will produce a relative APD. This abnormal response signifies a reduced conduction of one optic nerve relative to the fellow nerve. Initially in NAION, the optic disc appears swollen and hyperemic, often in a generalized or diffuse manner. Sectoral disc edema and pallor, especially superiorly, usually develops shortly thereafter [80]. Visual field testing will typically reveal a corresponding inferior or superior altitudinal loss. One of the most important laboratory tests for any patient with NAION is the erythrocyte sedimentation rate (ESR). In NAION, the ESR is likely to be normal. It is essential to rule out the arteritic form of ischemic optic neuropathy (AION). Here, the etiology is giant cell arteritis (GCA), rather than ischemic vascular disease. Other blood tests, such as the C-reactive protein (CRP), have been useful in diagnosing GCA [83]. If GCA is suspected, a temporal artery biopsy may also be performed, although a normal biopsy does not completely exclude the possibility of GCA [84].
3.1. Non-arteritic anterior ischemic optic neuropathy Non-arteritic anterior ischemic optic neuropathy (NAION) is a disease characterized by a sudden, painless, irreversible, non-progressive visual loss of moderate degree, initially unilateral, though it may become bilateral [73]. Clinical signs include optic nerve fiber bundle field defects, a relative afferent pupillary defect, and optic disc edema (Fig. 2.). The prevalence of NAION increases with age and is associated with a small cup-to-disc ratio [75,76], hypertension [75,77], diabetes mellitus [75,77,78], arteriosclerosis [78], and hypercholesterolemia [78,79]. 3.1.1. Pathophysiology NAION is thought to be an ischemic process affecting the posterior circulation of the globe, principally vessels
Fig. 2. Optic disc edema as it presents in NAION. Note the elevated, blurred disc margins.
3.1.2. Signs and symptoms Visual loss is acute, unilateral, and painless in approximately 90% of patients with NAION [83]. Critical signs include a relative afferent pupillary defect, pale optic nerve head swelling involving only a segment of the disc, flameshaped hemorrhages, and normal erythrocyte sedimentation rate (ESR) [73,80,81]. The visual acuity and visual field loss is typically noticed upon awakening, perhaps due to nocturnal hypotension. NAION may also present in a progressive form, with the onset of symptoms occurring over a few days, rather than the acute-onset form.
3.1.4. Treatment Medical treatment for NAION has included anticoagulants and antiplatelet agents, vasodilators, diphenylhydantoin, intraocular pressure lowering agents (norepinephrine) to improve the gradient of nerve head perfusion pressure to intraocular pressure and oral corticosteroids [85]. None of these treatments have proven to be effective. Aspirin is often given to patients following the development of NAION, but there does not seem to be
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any beneficial effect of this treatment on the eventual visual outcome [86]. Some authors have suggested that aspirin may reduce the risk of NAION in the fellow eye [87]. If ischemic vascular disease is involved, this should be treated in consultation with the primary care physician. 3.1.5. NAION and SAS There are several theories about the link between NAION and SAS. Mojon et al. hypothesized that the damage may result from impaired optic nerve head blood flow autoregulation, secondary to repetitive prolonged apneas. Optic nerve vascular dysregulation may occur secondary to arteriosclerosis and arterial blood pressure variations (episodic nocturnal hypertension or hypotension) seen in SAS. This dysregulation may be due to the imbalance between nitric oxide (a vasodilator) and endothelin (a vasoconstrictor). Repetitive or prolonged episodes of hypoxia may cause direct damage to the optic nerve. Because of the large stores of carbon dioxide and excellent buffering capacity of the body, changes in PaCO2 and pH during apneas remain modest (in contrast to changes in PaO2). Therefore, PaCO2 variations are not considered to be especially harmful. Episodic increased intracranial pressure during apneic episodes may also have adverse effects on the optic nerve, either directly or indirectly by compromising the vascular supply [47]. Mojon et al. have correlated optic neuropathy with SAS [47]. In this case series study, visual field defects were correlated with the RDI values for suspected SAS patients. The results of this study showed that the RDI correlated positively with both the mean visual field defect (rsZ0.81, P!0.05) and the visual field loss variance (rsZ0.78, P!0.05). Thus, the investigators concluded that visual fields of patients with SAS showed defects consistent with an optic neuropathy. However, their data did not demonstrate a direct causal relationship between SAS and visual field defects. Mojon et al. have also examined the prevalence of SAS in patients with NAION [46]. In this case series study, the subjects consist of 17 patients diagnosed with NAION and 17 control patients diagnosed with restless leg syndrome and matched for age and sex. The authors found that twelve (71%) of their 17 patients with NAION had SAS. According to the respiratory disturbance index, 4 patients (24%) had mild, 4 patients (24%) had moderate, and 4 patients (24%) had severe SAS. Only 3 (18%) of 17 controls had SAS (PZ005) [46].
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unusually susceptible to damage, resulting in histopathological changes in this tissue [88]. 3.2.1. Pathophysiology The two proposed mechanisms for glaucoma pathogenesis are the mechanical theory and the vascular theory. The mechanical theory suggests that abnormally high intraocular pressure (IOP) ultimately causes direct damage to the optic nerve [88]. This IOP elevation may be due to overproduction of aqueous fluid or impaired aqueous outflow. The vascular theory postulates that there is insufficient blood supply to nourish the nerve fiber layer and/or optic nerve [88]. If a patient is vascularly compromised through either atherosclerosis or arteriosclerosis, then the short posterior ciliary arteries which feed the anterior optic nerve could be attenuated, leading to ischemia and loss of neural tissue [88]. The glaucomas are classified into several types. The two that have been associated with SAS are normal tension glaucoma (NTG) [48,89] and primary open-angle glaucoma (POAG) [49,50]. NTG is a type of open-angle glaucoma that is characterized by glaucomatous optic nerve head cupping, visual field defects, and open anterior chamber angles without elevated IOP [73]. Various risk factors are associated with NTG, but a cause-and-effect relationship has not been established for this optic neuropathy [48]. POAG has the same characteristics as NTG, with the exception that in POAG, the IOP is abnormally high for that individual. POAG is, by far, the most common form of glaucoma [73]. The exact cause of glaucomatous optic neuropathy is not known; however, many risk factors have been identified, including pre-existing family history, race, myopia, thin cornea as measured by pachymetry, and age (older than 40 years) [88]. 3.2.2. Signs and symptoms In the chronic glaucomas such as NTG and POAG, patients are usually asymptomatic [73]. These types of glaucoma occur gradually and are best diagnosed by an ophthalmic physician. By contrast, symptoms of ocular pain and decreased vision occur in acute forms of the disease such as acute angle-closure glaucoma [73]. A dilated fundus examination is required to accurately assess the health of the optic nerve and nerve fiber layer. Signs of typical glaucomatous optic nerve damage include a deepening and widening of the optic cup (Fig. 3), vertical elongation of the optic cup, peripapillary atrophy, optic disc hemorrhages, asymmetry between the two optic nerves; and nerve fiber layer loss/drop-out [88].
3.2. Glaucoma Glaucoma is not a single-disease entity, but rather a group of ocular diseases with various etiologies that ultimately result in a consistent optic neuropathy. Glaucoma results when intraocular pressure becomes ‘abnormal’ for a given individual or when the optic nerve head becomes
3.2.3. Diagnosis The diagnosis of glaucoma can be made by a careful history, in addition to thorough, non-invasive ophthalmic testing. Screening the general population for POAG is mandatory for every individual over 45 years of age, since no subjective sign will cause the patient to seek immediate
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[89]. The study included 23 patients with NTG, 14 NTG suspects, and 30 comparison patients without glaucoma. To be diagnosed with NTG, patients needed to have unilateral or bilateral optic disc abnormalities and visual field defects judged by the authors to be characteristic of glaucoma. In addition, they had to have had no recorded intraocular pressure readings greater than 24 mmHg with diurnal applanation tonometry testing. To be diagnosed as ‘NTG suspect’, patients needed to have the above optic disc abnormalities with normal diurnal intraocular pressure readings, in the absence of visual field defects. The sleep history obtained in this study consisted of the following questions:
Fig. 3. Glaucomatous optic nerve cupping.
consult. Diagnostic testing includes a dilated fundus examination, intra-ocular pressure (IOP) testing by applanation tonometry, and visual field testing by perimetry. For the specialized check-up of diagnosed glaucoma, pachymetry (corneal thickness), gonioscopy (anterior chamber angle assessment), and scanning laser techniques (such as optical coherence tomograpghy, polarimetry or nerve fiber analysis, and retinal tomography) may be warranted. At follow-up visits, an IOP check as well as a visual field and dilated fundus exam are performed. 3.2.4. Treatment Glaucoma may be treated medically, with laser surgery, or with incisional surgery. All of these treatments center on the lowering of intraocular pressure (IOP) [88]. The majority of POAG and NTG cases are effectively treated with topical medications. The main drug classes for medical treatment include prostaglandin analogs, alpha-agonists, beta-blockers, carbonic anhydrase inhibitors, and miotic agents. Each of these drug classes has a particular mechanism of action, but their goal is the same: to preserve the optic nerve and nerve fiber layer by means of IOP reduction. 3.2.5. Glaucoma and SAS The theories that link glaucoma to SAS are similar to those that link NAION and SAS. These theories include impaired optic nerve head blood flow autoregulation secondary to repetitive prolonged apneas, optic nerve vascular dysregulation secondary to arteriosclerosis and arterial blood pressure variations (episodic nocturnal hypertension or hypotension), and repetitive or prolonged episodes of hypoxia causing direct damage to the optic nerve. In a case series study conducted by Marcus et al., the authors sought to determine the prevalence of sleep-related symptoms and sleep-related breathing disorders by polysomnography, in patients with normal-tension glaucoma
(1) Do you have trouble sleeping at night? Why (heart failure, urination, other)? (2) Does someone sleep close enough to you to hear any nighttime noise, such as snoring? (3) Are you sleepy during the daytime or do you fall asleep at times when you should not? (4) Do you snore or have frequent awakenings? Why (heart failure, urination, and so forth)? (5) Do you have frequent headaches, especially in the morning after awakening? (6) Do you have a known sleep disorder or have you ever had a sleep study (polysomnography)? Prevalence of sleep disorders and a positive sleep history were the main outcome measures. A positive response to one or more of these questions corresponds with a positive sleep history, suggestive of a sleep disorder. The results of this study showed a significant correlation between glaucoma and sleep-disordered breathing. The authors found that 13 of the 23 (57%) patients with NTG, six of the 14 (43%) NTG suspects, and one of the 30 (3%) nonglaucoma comparison patients had a positive sleep history (PZ0.001). Nine of the 13 patients with NTG and four of the six NTG suspects with a positive sleep history chose to undergo polysomnography. Seven of the nine patients with NTG and all four NTG suspects that underwent polysomnography were diagnosed with a sleep disorder. Five patients with NTG had sleep apnea (defined as a cessation of airflow for more than 10 s) and two had sleep hypopnea (defined as a reduction in air flow for 10 s associated with oxygen desaturation). Two NTG suspects had sleep apnea, one had sleep hypopnea, and one had upper airway resistance syndrome. The one comparison patient with a positive sleep history was diagnosed with upper airway resistance syndrome by polysomnography. The authors concluded that sleep-disturbed breathing may be a risk factor for NTG. In addition, although their results did not provide evidence for a cause-and-effect relationship, various physiologic factors produced by sleepdisturbed breathing may play a significant role in the pathogenesis of NTG. The main risk factor among this
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group was hypoperfusion of the optic nerve head as a result of chronic progressive ischemia. In a recent study, Mojon et al. also found an association between NTG and SAS [48]. In this study, overnight polsomnography was performed on 16 consecutive Caucasian patients with NTG. The authors found the following prevelances of obstructive sleep apnea in NTG patients: none (0 of 2) for the group of patients younger than 45 years of age, 50% (3 of 6) for the age group 45–64 years old and 63% (5 of 8) for the group older than 64 years of age. Since 1999, Mojon et al. have sought to establish the incidence of both NTG and POAG in patients with SAS [49]. For the diagnosis of primary open-angle glaucoma, the following criteria were applied: typical glaucomatous optic nerve cupping, glaucomatous visual field defects, open and also otherwise normal anterior chamber angles, and untreated IOPs above 21 mmHg. For the diagnosis of NTG, the following criteria had to be met: typical glaucomatous optic nerve cupping, glaucomatous visual field defects, open and also otherwise normal anterior chamber angles, and untreated IOPs below 22 mmHg during at least one diurnal testing [49]. The authors found that 69 of the 114 (60.5%) patients in the study were diagnosed with SAS (RDIR10). Of these 69 patients, only 3 patients had POAG and 2 had NTG. In addition, the RDI correlated positively with IOP (PZ 0.025), visual field loss variance (PZ0.03), glaucomatous optic disc changes (PZ0.001), and diagnosis of glaucoma (PZ0.01). The authors concluded that SAS constitutes a high-risk population for glaucoma. In a subsequent case series study, Mojon et al. set out to determine the prevalence of SAS in POAG [50]. Overnight transcutaneous finger oximetry was performed in 30 consecutive patients having POAG. The authors concluded that SAS was more prevalent among POAG patients compared to normal historic controls of the same age and sex distribution (x2Z9.35, d.f. Z3, P!0.025). In addition, the oximetry disturbance index grade was significantly larger in the POAG group compared to normal controls (PZ 0.01). According to this index, an astounding 20% of POAG patients had an association with SAS.
4. Other associations 4.1. Marfan’s syndrome Marfan’s syndrome is a hereditary connective tissue disorder, manifested principally by changes in the skeleton, eyes and the cardiovascular system [90,91]. It is characterized by long extremities, ocular complications, and cardiovascular abnormalities [91,92]. Individuals with Marfan’s syndrome have also been shown to experience obstructive sleep apnea, which can be attributed to relaxed connective tissue, leading to upper airway collapsibility [93].
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Ocular complications of Marfan’s syndrome are usually manifested as ectopia lentis [90,92]. This is characterized by a decentered crystalline lens, secondary to disruption of the surrounding zonular fibers [92]. Patients with ectopia lentis are at an increased risk for retinal detachment [94]. Another reported ocular manifestation is keratoconus, an abnormal thinning and bulging of the cornea [95].
5. Conclusions As the importance of sleep becomes more apparent to the medical community [96], it is our responsibility as health care professionals to recognize signs and symptoms of disorders that are not directly related to our specialties, but affect the overall health of our patients. A growing body of literature in the fields of sleep medicine and ophthalmic disorders provides evidence that suggests an association between sleep apnea syndrome and ocular problems. Although the precise mechanisms linking SAS and ocular problems are poorly understood, the literature suggests that patients with SAS may have an increased incidence of normal tension glaucoma [48,89], open-angle glaucoma [49,50], non-arteritic anterior ischemic optic neuropathy [46], and floppy eyelid syndrome [45,47,65]. Since glaucoma and floppy eye syndrome are treatable, early detection of these conditions can significantly improve patient outcomes. Just as an increased knowledge of the effect of extended work shifts could result in better policies for truck drivers and medical interns [96], we hope an increased awareness of ocular problems associated with SAS will result in more cross-referrals between sleep specialists and ophthalmic clinicians. Specifically, in the future, it may become standard practice for ophthalmic clinicians to refer their patients with these ocular entities for a sleep study, particularly if the patient fits the demographic profile or complains of sleep disturbances. Similarly, sleep apnea specialists should recommend that all their patients have a thorough ocular health examination with routine testing for glaucoma and floppy eyelid syndrome. A dilated retinal and optic nerve evaluation should be performed as part of a comprehensive ophthalmic examination. Like the Yin-Yang symbol that was adopted by the American Academy of Sleep Disorders Association to represent the interlocking importance of sleep and wakefulness [97], it is our hope that this review article will unite sleep medicine specialists and ophthalmic clinicians to recognize the association between SAS and the eye.
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