- Email: [email protected]
The eye and sleep apnea
ARTICLE IN PRESS Sleep Medicine Reviews (2007) 11, 269–276
www.elsevier.com/locate/smrv
CLINICAL REVIEW
The eye and sleep apnea Alan A. McNab Orbital Plastic and Lacrimal Clinic, Royal Victorian Eye and Ear Hospital, East Melbourne, 3002 Vic., Australia
KEYWORDS Obstructive sleep apnea; Floppy eyelid syndrome; Blindness; Eye diseases; Glaucoma; Non-arteritic anterior ischemic optic neuropathy; Papilledema; Idiopathic intracranial hypertension
Summary Several eye disorders have been found in association with obstructive sleep apnea (OSA). This paper reviews the current state of knowledge of eye disorders associated with OSA. OSA is associated with a number of eye disorders including floppy eyelid syndrome (FES), optic neuropathy, glaucoma, non-arteritic anterior ischemic optic neuropathy and papilledema secondary to raised intracranial pressure. FES patients have a very high incidence of OSA and a causal relationship may exist, but amongst patients with OSA, FES is uncommon but commoner than in the general population. Treatment of OSA may help floppy eyelid syndrome, halt progression of associated glaucoma or optic neuropathy, and reduce intracranial pressure in patients with associated papilledema. Sleep apnea patients should be asked about ocular symptoms and appropriately examined or referred for assessment as some of the associated eye disorders may permanently impair vision. Ophthalmologists should be aware of the association of sleep apnea with these eye disorders and consider referral to a sleep physician for investigation and possible treatment. & 2007 Published by Elsevier Ltd.
Introduction This paper reviews the subject of eye diseases associated with obstructive sleep apnea (OSA). Several eye disorders have been described in association with OSA and these are summarized in Table 1. Ophthalmologists should be alert to the possibility of sleep disorders in their patients, and sleep physicians should similarly be alert to Suite 12, Level 1, 59-61 Victoria Pde, Fitzroy, 3065 Vic.,
Australia. Tel.: +61 3 9417 0714; fax: +61 3 9417 0716. E-mail address: [email protected] 1087-0792/$ - see front matter & 2007 Published by Elsevier Ltd. doi:10.1016/j.smrv.2007.03.006
the possibility of eye disorders in their patients with OSA. One of the commonest disorders associated with OSA is floppy eyelid syndrome (FES), a disorder almost always associated with OSA and very rarely with other risk factors. Given the profound pathophysiological changes that can occur with OSA, it is not surprising that eye disorders may occur in association with OSA. These include non-arteritic anterior ischemic optic neuropathy (NAION), papilledema secondary to raised intracranial pressure (ICP), and an optic neuropathy with associated visual field defects that may mimic glaucoma.
ARTICLE IN PRESS 270
A.A. McNab
Table 1 Eye disorders associated with obstructive sleep apnea. Floppy eyelid syndrome (and associated corneal changes of superficial punctate keratopathy, ulceration, scarring, perforation, keratoconus) Primary open-angle glaucoma Normal-tension glaucoma Optic neuropathy Non-arteritic anterior ischemic optic neuropathy Papilledema with raised intracranial pressure
These eye conditions are associated with a number of other risk factors, but OSA is an important and treatable risk factor, which clearly should be thought about when evaluating such patients.
Floppy eyelid syndrome and obstructive sleep apnea In 1981, two ophthalmologists, Culbertson and Ostler, described for the first time an unusual entity characterised by ‘‘floppy’’ and redundant upper eyelids with marked papillary conjunctivitis in obese middle-aged and older men1 (Fig. 1). They coined the term ‘‘floppy eyelid syndrome’’. The affected eye corresponded to the side the patient preferentially slept on, and if both eyes were affected, the patient alternated sides they slept on, or they slept face down. Some were noted to sleep with the affected upper eyelid spontaneously everted and rubbing on the pillow, and many had associated corneal abnormalities, particularly widespread punctate keratopathy. The patients typically complained of symptoms of watering, stickiness, discomfort and blurred vision in the affected eye(s), and these symptoms were typically worse on waking. A number of scattered case reports followed, and some commented that the patient was Pickwickian or had been diagnosed with obstructive sleep apnea, but no firm conclusion was drawn about a causal link between FES and OSA.2–4 My own interest in patients with FES led to the first published attempt at a systematic evaluation of the possible association between FES and OSA, and also for the first time systematically examined a cohort of patients already diagnosed with OSA to see how frequent FES was amongst this population, and to look for other possible associated eye disorders. All patients that I diagnosed with FES were offered referral for sleep studies. Of the eight patients referred for sleep studies, all were found
Figure 1 (a) An older obese male with left floppy eyelid syndrome and sleep apnea. Note the mild left upper eyelid ptosis, the lashes point downwards compared to the right, and the left eye is reddened. (b) With upward traction applied to the upper eyelids, the left upper eyelid spontaneously everts revealing the conjunctival lining to be reddened and thickened (papillary conjunctivitis).
to have OSA, many of them with severe OSA.5 Additionally, a consecutive group of 20 patients with diagnosed OSA was selected randomly from the register of a sleep laboratory and had thorough eye examinations. One of the 20 was found with full-blown FES, and two further asymptomatic patients had early signs of FES.5 Since that time I have accumulated and published data on a total of 50 patients with FES.6 Forty-three were men (86%), 44 (88%) were obese (body mass index over 30) and 21 (42%) were on treatment for systemic hypertension. All were asked for symptoms suggestive of OSA, and 48 (96%) admitted to such symptoms (snoring, daytime somnolence, waking feeling unrefreshed, apneas during sleep observed by others and waking gasping for air during the night). Eleven of these 50 patients had already undergone sleep studies and had a diagnosis of OSA, and 33 were offered sleep studies. Sixteen declined personally or their family
ARTICLE IN PRESS The eye and sleep apnea physician elected not to refer them. Of the 17 referred who underwent sleep studies, 16 were found to have OSA. No referral was made in six because of factors such as age, social circumstances or geography. Therefore, in 27 patients with FES who had formal sleep studies, 26 were found to have OSA. Clearly, there is a very strong association between these two conditions, and any patient diagnosed with FES should be considered for sleep studies. Despite this, only a small proportion of patients with OSA have been found with the full constellation of symptoms and signs of FES in two reported series,5,7 where 2% and 5% of OSA patients were found with FES. One other study reported 14 of 44 (32%) patients with OSA had ‘‘floppy eyelids’’, but the authors did not specify whether these patients had the other symptoms and signs that constitute FES.8 Their patients had a very low incidence of corneal changes compared to other series, and no mention is made of papillary conjunctivitis which is part of FES. It is likely that their patients with ‘‘floppy eyelids’’ had eyelid laxity which might lead to the full-blown FES over time. It is unclear why only a small minority of patients (between 2% and 5%) with OSA have FES,5,7 and yet, a large majority of FES patients have OSA. We have analysed the data of 12 patients with FES in whom we had detailed sleep study results and compared them to a large group of patients previously diagnosed with OSA from a large Melbourne sleep laboratory (St. Vincent’s Hospital). The results are summarized in Table 2. The FES patients have the same gender distribution, but are younger (po0.001) and are more obese (po0.001). Their indices of severity for OSA (AHI and SpO2min, where AHI is the number of apneic or hypopneic episodes per hour, and SpO2min is the minimum saturation of arterial oxygen) are also statistically worse than the general OSA population. These data should be interpreted with caution, as the two populations have certain biases within them, however, it does appear that FES is often an indicator of severe OSA, and as FES patients tend to be younger than most OSA patients, there may be an even stronger reason to investigate and treat them for OSA. Continuous positive airway pressure (CPAP) treatment alone may help the symptoms and signs of FES. I have reported one patient whose symptoms and signs of FES disappeared with OSA treatment,9 although he had only moderately severe FES. I have observed several other patients with FES where symptoms and signs improved significantly with just treatment of the OSA. Conversely, patients with FES and OSA who do not have the OSA treated have been observed to develop recurrent signs of FES
271 Table 2 A comparison between a large population of obstructive sleep apnea patients and a group of floppy eyelid syndrome (FES) patients. St. Vincent’s Number Age (years) BMI
466 55 (8–88) 28.7 (13–117) Female (%) 25 AHI (events/h) 11 (0–110) SpO2min (%) 87 (21–98) Severity (%) Normal Mild Moderate Moderately severe Severe
FES
p-Value
12 44 (33–57) 39 (30–45)
po0.01 po0.001
27 42 17 6
28 NS 50 (12–130) po0.001 74.5 po0.01 (29–91) po0.001 0 33 8 17
8
42
Age, body mass index (BMI) apnoea/hypopnoea index (AHI, the number of apneic and hypopneic events per hour) and SpO2min (minimum arterial oxygen saturation during apneic/hyponpeic event) are shown as median and range. The comparative statistic is the Mann–Whitney U-test. Female gender and severity of apnea are expressed as percentages. The comparative statistic is Fisher’s Exact test. Severity of OSA is based on the AHI and SpO2min, adapted from the Stanford Sleep Centre, and classified as follows.
Normal Mild Moderate Moderately severe Severe
AHI
SpO2min
o10 10–20 20–40 40–60 460
490 485 480 470 o70
months or years after surgical tightening of their eyelids. FES patients should probably therefore have any OSA treated before they are offered corrective eyelid surgery. FES may be associated with a number of other ocular and peri-ocular changes.5 The commonest are corneal changes.10 These range from superficial punctate keratopathy, which is nearly always present and probably is the result of poor upper eyelid contact between the floppy upper eyelid and the cornea leading to poor ocular surface wetting, through frank ulceration, scarring and vascularization and rarely corneal perforation11. Corneal ectasia in the form of keratoconus has also been reported in association with FES,10,12 and keratoconus is known to develop in patients who are
ARTICLE IN PRESS 272 chronic ‘‘eye-rubbers’’, such as those with severe atopy. Other eyelid changes reported to occur with FES include lower eyelid ectropion, hyperkeratotic skin lesions of the lids and face, keratinisation of the conjunctival surface of the affected upper eyelid, upper eyelid ptosis and eyelash ptosis (downward sloping lashes) and loss of eyelash parallelism.5 Loss of elasticity, sagging and wrinkling of the facial skin on the same side as the FES is often seen and can be extreme, giving the patient the appearance of premature aging on one side of the face (Figs. 2 and 3). This presumably relates to loss of elastin in the skin as has been observed in the eyelids of patients with FES (see below). There has been considerable speculation about the pathogenesis of FES. There is a clear relationship to OSA, and the fact that the affected side corresponds to habitual sleeping posture suggests a strong link between what is happening during these patients’ disturbed sleep and their eyelid changes. Chronic eyelid rubbing and stretching might lead to the observed changes in the eyelids, and once the eyelid begins to spontaneously evert during sleep, these changes could accelerate. Histopathologically, the affected eyelids have been noted to have loss of normal elastin fibres.13 A recent study looked at changes in resected segments of eyelid from patients with FES, and in particular, immunohistochemically examined for the presence of specific matrix metalloproteinases (MMPs). These authors found an increased immunoreactivity for the elastolytic proteases, particularly MMP-7 and MMP-9, in areas with elastin depletion compared to controls, indicating an upregulation of these elastolytic enzymes.14 This would account for the loss of elasticity seen clinically in FES patients. The mechanism of upregulation of these MMPs is unclear, but other studies have shown that repeated minor trauma or mechanical stress in vitro can lead to similar changes in other tissues.15,16 An additional possible mechanism may involve ischemia–reperfusion injury, and this has also been reported to lead to upregulation of some MMPs in tissues such as brain, heart and lungs.17 This same loss of elasticity is likely to be found in the surrounding skin of the eyelids and face, and it would of interest to examine the tissues of the upper airways in patients with OSA to see if similar changes were occurring. The treatment of FES, other than treating the underlying OSA, involves measures to prevent the underlying presumed mechanical minor traumas and stretching that appear to lead to the condition, and surgically correcting eyelid laxity. Patients can gain some relief by wearing a firm shield over the
A.A. McNab
Figure 2 (a) A patient with left floppy eyelid syndrome. In addition to the upper eyelid ptosis and downward pointing lashes, the eyebrow hairs are also disturbed and the skin around the eye shows more aging changes compared to the right side. (b) The left upper eyelid spontaneously everts on upwards traction.
eye at night, although the shield itself may press into the surrounding tissues causing discomfort and poor compliance. Better results can be obtained with custom-made soft silicone masks that fit over the eyes comfortably and reduce symptoms. Hospital prosthetics laboratories can make these devices. For the non-ophthalmologist, diagnosing FES is not difficult in a patient with established changes. The symptoms as listed above give a clue to the diagnosis. External examination of the eyes will usually show that the affected eye has downward pointing eyelashes compared to the more normal side (lash ptosis), the lashes are often not parallel to each other, and there may be a degree of ptosis of the whole lid. If a thumb is placed on the upper lid skin near the eyelid margin, and traction is applied upwards, an eyelid with established FES will often evert spontaneously, exposing the conjunctival lining of the upper eyelid, which is typically redder than normal, with a velvety texture (papillary conjunctivitis) (Fig. 1b).
ARTICLE IN PRESS The eye and sleep apnea
273
Figure 3 (a) A younger obese male with right floppy eyelid syndrome and sleep apnea. Note the marked asymmetry in facial skin between the two sides with the right side showing marked wrinkling and laxity compared to the left side. (b and c) Semi-profile views to show the skin changes and differences between the two sides. (d and e) The right upper eyelid everts spontaneously compared to the left.
Surgically tightening the eyelids has been shown to reduce symptoms and signs of FES.18 The surgical tightening can involve full-thickness resections of the floppy eyelid or tightening and re-inforcing the canthal tendons.19 However, the eyelid laxity, floppiness and symptoms can recur within months or years if the underlying OSA is not satisfactorily treated. Most reports of surgical eyelid tightening give follow-up periods up to 18 months at most.5
Glaucoma and obstructive sleep apnea My own study of FES patients suggested a possible association between FES and glaucoma.5 Since that initial report, other reports have identified an increased prevalence of primary open angle glaucoma in patients with OSA20 and also a high
prevalence of sleep-disordered breathing in patients with primary open angle glaucoma.21 One study showed a correlation between the severity of the sleep disturbance and severity of the visual field loss.22 Others have reported an association between normal-tension glaucoma and OSA, particularly in older patients.23 A variety of visual field defects in OSA patients was also reported by Mojon et al. in nine patients, and in two patients treated with CPAP, the field defects stabilised.24 Another patient has also been reported with normal-tension glaucoma and progressive field loss despite pressure lowering by drops and surgery, whose field loss stabilised after diagnosis of OSA and treatment with CPAP.25 Against this background of reports, one conflicting study has shown the prevalence of glaucoma in a group of OSA patients to be the same as the general population26 but the weight of evidence does seem to favour the hypothesis that
ARTICLE IN PRESS 274 a type of optic neuropathy is commoner in OSA patients. The nocturnal intra-ocular pressure of patients with normal-tension glaucoma and OSA has been measured and found to be normal,27 so it seems more likely the optic neuropathy or ‘‘normaltension glaucoma’’ in OSA patients is related to ischemic insults, and is a different type of optic neuropathy to that which occurs in primary open angle glaucoma. It would seem prudent to ask for symptoms of OSA in patients with an optic neuropathy that could mimic primary open-angle glaucoma, especially those in whom there is no other identifiable risk factor, the principle one being an elevated intraocular pressure. Such patients are often labelled as normal-tension glaucoma, which should be a diagnosis of exclusion. A recent study from Hong Kong looked at the computerised visual fields and optic discs of patients with moderate to severe OSA who had normal intra-ocular pressure, and compared these to an age-matched non-OSA population.28 In 41 ethnic Chinese patients with moderate to severe OSA, they found significantly subnormal visual fields and optic disc changes similar to that seen in primary open angle glaucoma (optic cupping) at a rate four times that seen in the control group. Another interesting parallel between OSA and normal-tension glaucoma has been highlighted by an Australian study showing a significantly greater extent of cerebral infarcts and white matter loss in the corpus callosum in a group of normal-tension glaucoma patients compared to controls studied with MRI.29 Other studies have shown that OSA patients show areas of cerebral cortical loss (gray matter) on MRI, presumably due to ischemia.30
Non-arteritic ischemic optic neuropathy and sleep apnea Another type of optic nerve disorder reported to be associated with OSA is non-arteritic anterior ischemic optic neuropathy.31 This seems hardly surprising given the profound pathophysiological changes that occur in patients with OSA during sleep and it is well known that a high proportion of non-arteritic AION patients first report their visual loss on waking (73.3% of 544 cases in Hayreh’s et al. series32). Mojon et al.31 recruited 17 patients with NAION and compared them to 17 age- and sexmatched controls, and performed overnight polysomnography on each patient. Twelve of 17 (71%) of
A.A. McNab the NAION patients had sleep apnea, 4 with mild OSA, 4 moderate and 4 severe. This compared to 3 of 18 controls (18%) (po0.001). The likelihood of OSA being present in the NAION patients increased with increasing age. Another more recent study looked at the incidence of OSA in patients newly diagnosed with NAION.33 All newly diagnosed patients with NAION underwent polysomnography, and other more traditional risk factors such as hypertension, diabetes, hyperlipidemia and atheromatous carotid artery disease were also identified. In 27 consecutive NAION patients, 24 (89%) were diagnosed with OSA on testing with a mean respiratory disturbance index of 37.2/h (SD 18.3/h). OSA was 1.5–2-fold more frequent than the rate of other identified risk factors such as hypertension and diabetes. It might be hoped that treating any underlying OSA would prevent a patient with unilateral NAION from developing NAION in the other eye. A recent small case series questions this.34 Three cases of NAION were reported in patients with OSA who were being treated with nocturnal continuous positive airway pressure. However, larger comparative observational series would need to be performed to establish what benefit CPAP might confer in preventing the development of NAION.
Papilledema, raised intracranial pressure and sleep apnea A further association between OSA and optic nerve pathology has been long recognised. Patients with OSA often complain of headache on waking. The intracranial pressure of OSA patients has been measured overnight and found to be markedly elevated in an episodic fashion, paralleling apneic episodes.35 It has been suggested that hypercapnia leads to cerebral venous dilatation. Raised venous pressure due to forced expiration against a closed glottis may also play a role. A number of case reports and small case series of patients with papilledema and sleep apnea have been published.36–44 The typical patient with idiopathic intracranial hypertension (IIH) is a younger, overweight female. Older male patients with IIH and papilledema are particularly at risk of having OSA as a causative factor, and treatment with CPAP may reverse the disc swelling.42 Such patients often have normal or high normal intracranial pressure when it is measured during the day, and nocturnal measurements may be more useful in reaching a diagnosis. All patients with IIH should
ARTICLE IN PRESS The eye and sleep apnea have an appropriate sleep history taken, but those at greatest risk of having OSA as a possible causative factor are obese middle-aged or older males.
Practice points Eye disorders associated with sleep apnea include: 1. Floppy eyelid syndrome (FES) (almost unique to sleep apnea patients), which causes ocular surface symptoms such as watering, soreness and discharge, especially on waking, can lead to corneal scarring, and may be associated with keratoconus. 2. Optic neuropathy that can mimic chronic open angle glaucoma. 3. Non-arteritic anterior ischemic optic neuropathy (OSA is a major risk factor for this disorder). 4. Papilledema associated with raised intracranial pressure (rare amongst OSA patients, but chronic headache should alert physicians to this possibility). Many of these disorders may be halted or improved with appropriate treatment of OSA.
Research agenda Floppy eyelid syndrome (FES): 1. Further work on the pathophysiology of FES may lead to a better understanding of how this condition develops and why it develops in some patients with OSA and not others. 2. Work on upregulation of matrix metalloproteinases, especially elastases, in the eyelids of FES patients could be expanded to look at tissue changes in the upper airways of OSA sufferers. Other eye conditions: 1. It would be useful to be able to more clearly identify groups of OSA patients at risk of eye disorders, and similarly identify those patients with identified eye disorders more likely to suffer from OSA. 2. The effects of treatment of OSA on associated eye disorders should be more systematically studied.
275
Acknowledgment Dr. John Santamaria, Director, Intensive Care Unit and Sleep Unit, St. Vincent’s Hospital, Melbourne, Australia.
References *1. Culbertson WW, Ostler HB. The floppy eyelid syndrome. Am J Ophthalmol 1981;92:568–75. 2. Gonnering RS, Sonneland PR. Meibomian gland dysfunction in floppy eyelid syndrome. Ophthal Plast Reconstr Surg 1987;3:99–103. 3. Goldberg RA, Coden DJ, Hornblass A, Mitchell JP. Floppy eyelid syndrome with marked lower eyelid ectropion. Am J Ophthalmol 1989;108:610–2. 4. Woog JJ. Obstructive sleep apnea and floppy eyelid syndrome. Am J Ophthamol 1990;110:314–5. *5. McNab AA. Floppy eyelid syndrome and obstructive sleep apnea. Ophthalmol Plast Reconstr Surg 1997;13: 98–114. *6. McNab AA. The eye and sleep. Clin Exp Ophthalmol 2005;33:117–25. 7. Karger RA, White WA, Park W-C, et al. Prevalence of floppy eyelid syndrome in obstructive sleep apnea–hypopnea syndrome. Ophthalmology 2006;113:1669–74. 8. Mojon DS, Goldblum D, Fleischhauer J, et al. Eyelid, conjunctival, and corneal findings in sleep apnea syndrome. Ophthalmology 1999;106:1182–5. 9. McNab AA. Reversal of floppy eyelid syndrome with treatment of obstructive sleep apnoea. Clin Exp Ophthalmol 2000;28:125–6. 10. Culbertson WW, Tseng SC. Corneal disorders in floppy eyelid syndrome. Cornea 1994;13:33–42. 11. Imbert P, Williamson W, Leger F, Gauthier L, Lagoutte F. Bilateral corneal neovascularization and floppy eyelid syndrome. A case report. J Fr Ophtalmol 1990;13:223–5. 12. Donnenfeld ED, Perry HD, Gibraltar RP, Ingraham HJ, Udell IJ. Keratoconus associated with floppy eyelid syndrome. Ophthalmology 1991;98:1674–8. 13. Netland PA, Sugrue SP, Albert DM, Shore JW. Histopathologic features of floppy eyelid syndrome. Involvement of tarsal elastin. Ophthalmology 1994;101:174–81. *14. Scho ¨ltzer-Schrehardt U, Stojkovic M, Hofmann-Rummelt C, Cursiefen C, Kruse FE, Holbach LM. The pathogenesis of floppy eyelid syndrome. Involvement of matrix metalloproteinases in elastic fiber degradation. Ophthalmology 2005;112:694–704. 15. Swartz MA, Tschumperlin DJ, Kamm RD, DRazen JM. Mechanical stress is communicated between different cell types to elicit matrix remodelling. Proc Natl Acad Sci USA 2001;98:6180–5. 16. Prajapati RT, Eastwood M, Brown RA. Duration and orientation of mechanical loads determine fibroblast cyto-mechanical activation: monitored by protease release. Wound Repair Regen 2000;8:238–46. 17. Lindsey M, Wedin K, Brown MD, et al. Matrix-dependent mechanism of neutrophil-mediated release and activation of matrix metalloproteinase 9 in myocardial ischemia/ reperfusion. Circulation 2001;103:2181–7. 18. Schwartz LK, Gelender H, Forster RK. Chronic conjunctivitis associated with ‘‘floppy eyelids’’. Arch Ophthalmol 1983;101:1884–8. The most important references are denoted by an asterisk.
ARTICLE IN PRESS 276 19. Valenzuela AA, Sullivan TJ. Medial upper eyelid shortening to correct medial eyelid laxity in floppy eyelid syndrome: a new surgical approach. Ophthal Plast Reconstr Surg 2005; 21:259–63. 20. Mojon DS, Hess CW, Goldblum D, Fleischhauer J, Koerner F, Bassetti C, et al. High prevalence of glaucoma in patients with sleep apnea syndrome. Ophthalmology 1999;106: 1009–12. 21. Onen SH, Mouriaux F, Berramdane L, Dascotte JC, Kulik JF, Rouland JF. High prevalence of sleep-disordered breathing in patients with primary open-angle glaucoma. Acta Ophthalmol Scand 2000;78:638–41. *22. Batisse JL, Vix J, Swalduz B, Chave N, Mage F. Sleep-related breathing disorders and normal or high-tension glaucoma: 35 patients with polysomnographic records. J Fr Ophtalmol 2004;27:605–12. 23. Mojon DS, Hess CW, Goldblum D, et al. Normal-tension glaucoma is associated with sleep apnea syndrome. Ophthalmologica 2002;216:180–4. *24. Mojon DS, Mathis J, Zulauf M, Koerner F, Hess CW. Optic neuropathy associated with sleep apnea syndrome. Ophthalmology 1998;105:874–7. 25. Kremmer S, Selbach JM, Ayertey HD, Steuhl KP. Normal tension glaucoma, sleep apnea syndrome and nasal continuous positive airway pressure therapy—case report with a review of literature. Klin Monatsbl Augenheilkd 2001;218:262–8. 26. Geyer O, Cohen N, Segev E, et al. The prevalence of glaucoma in patients with sleep apnea syndrome: same as in the general population. Am J Ophthalmol 2003;136: 1093–6. 27. Goldblum D, Mathis J, Bohnke M, et al. Nocturnal measurements of intraocular pressure in patients with normal-tension glaucoma and sleep apnea syndrome. Klin Monatsbl Augenheilkd 2000;216:246–9. *28. Tsang CS, Chong SL, Ho CK, Li MF. Moderate to severe obstructive sleep apnea is associated with a higher incidence of visual field defect. Eye 2006;20:38–42. 29. Ong K, Farinelli A, Billson F, Houang M, Stern M. Comparative study of brain magnetic resonance imaging findings in patients with low-tension glaucoma and control subjects. Ophthalmology 1995;102:1632–8. 30. Macey PM, Henderson LA, Macey KE, et al. Brain morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med 2002;166:1382–7. *31. Mojon DS, Hedges 3rd TR, Ehrenberg B, et al. Association between sleep apnea syndrome and nonarteritic anterior ischemic optic neuropathy. Arch Ophthalmol 2002;120: 601–5. 32. Hayreh SS, Podhajsky PA, Zimmerman B. Nonarteritic anterior ischemic optic neuropathy: time of onset of visual loss. Am J Ophthalmol 1997;124:641–7. *33. Palombi K, Renard E, Levy P, et al. Non-arteritic anterior ischaemic optic neuropathy is nearly systematically associated with obstructive sleep apnea. Br J Ophthalmol 2006;90:879–82.
A.A. McNab 34. Behbehani R, Matthews MK, Sergott RC, Savino PJ. Nonarteritic anterior ischemic optic neuropathy in patients with sleep apnea while being treated with continuous positive airway pressure. Am J Ophthalmol 2005;139:518–21. 35. Sugita Y, Iijima S, Teshima Y, et al. Marked episodic elevation of cerebrospinal fluid pressure during nocturnal sleep in patients with sleep apnea hypersomnia syndrome. Electroencephalogr Clin Neurophysiol 1985;60:214–9. 36. Bloomfield RL, Felts JH, Burkart JM, Cashwell FL. Optic disc edema in a pickwickian man mimicking hypertensive crisis. J Clin Hypertens 1987;3:27–30. 37. Bucci Jr FA, Krohel GB. Optic nerve swelling secondary to the obstructive sleep apnea syndrome. Am J Ophthalmol 1988;105:428–30. 38. Jennum P, Borgesen SE. Intracranial pressure and obstructive sleep apnea. Chest 1989;95:279–83. 39. Pasterkamp H, Cardoso ER, Booth FA. Obstructive sleep apnea leading to increased intracranial pressure in a patient with hydrocephalus and syringomyelia. Chest 1989;95:1064–7. 40. Doyle KJ, Tami TA. Increased intracranial pressure and blindness associated with obstructive sleep apnea. Otolaryngol Head Neck Surg 1991;105:613–6. 41. Purvin VA, Kawasaki A, Yee RD. Papilledema and obstructive sleep apnea syndrome. Arch Ophthalmol 2000;118: 1626–30. *42. Lee AG, Golnik K, Kardon R, Wall M, Eggenberger E, Yedavally S. Sleep apnea and intracranial hypertension in men. Ophthalmology 2002;109:482–5. 43. Marcus DM, Lynn J, Miller JJ, Chaudhary O, Thomas D, Chaudhary B. Sleep disorders: a risk factor for pseudotumor cerebri? J Neuroophthalmol 2001;21:121–3. 44. Hanigan WC, Zallek SN. Headaches, shunts, and obstructive sleep apnea: report of two cases. Neurosurgery 2004;54: 764–8.
Glossary of terms Keratoconus: a corneal ectasia characterized by thinning, outward bowing and distortion of the corneal surface. Non-arteritic anterior ischemic optic neuropathy: a condition of sudden onset characterized by unilateral visual loss, often with an altitudinal visual field defect, where the optic nerve head is swollen and pale and has suffered an ischemic event (the arteritic form of the condition occurs in giant cell (temporal) arteritis). Normal-tension glaucoma: a form of glaucoma or optic neuropathy usually indistinguishable from chronic open angle glaucoma in which the main risk factor is raised intra-ocular pressure. Papillary conjunctivitis: a clinicopathological term describing a thickened, velvety reddened surface of the conjunctiva lining the tarsal plates. Punctate keratopathy: multiple superficial microscopic corneal epithelial ulcers, best seen under magnification using fluorescein staining.
www.elsevier.com/locate/smrv
CLINICAL REVIEW
The eye and sleep apnea Alan A. McNab Orbital Plastic and Lacrimal Clinic, Royal Victorian Eye and Ear Hospital, East Melbourne, 3002 Vic., Australia
KEYWORDS Obstructive sleep apnea; Floppy eyelid syndrome; Blindness; Eye diseases; Glaucoma; Non-arteritic anterior ischemic optic neuropathy; Papilledema; Idiopathic intracranial hypertension
Summary Several eye disorders have been found in association with obstructive sleep apnea (OSA). This paper reviews the current state of knowledge of eye disorders associated with OSA. OSA is associated with a number of eye disorders including floppy eyelid syndrome (FES), optic neuropathy, glaucoma, non-arteritic anterior ischemic optic neuropathy and papilledema secondary to raised intracranial pressure. FES patients have a very high incidence of OSA and a causal relationship may exist, but amongst patients with OSA, FES is uncommon but commoner than in the general population. Treatment of OSA may help floppy eyelid syndrome, halt progression of associated glaucoma or optic neuropathy, and reduce intracranial pressure in patients with associated papilledema. Sleep apnea patients should be asked about ocular symptoms and appropriately examined or referred for assessment as some of the associated eye disorders may permanently impair vision. Ophthalmologists should be aware of the association of sleep apnea with these eye disorders and consider referral to a sleep physician for investigation and possible treatment. & 2007 Published by Elsevier Ltd.
Introduction This paper reviews the subject of eye diseases associated with obstructive sleep apnea (OSA). Several eye disorders have been described in association with OSA and these are summarized in Table 1. Ophthalmologists should be alert to the possibility of sleep disorders in their patients, and sleep physicians should similarly be alert to Suite 12, Level 1, 59-61 Victoria Pde, Fitzroy, 3065 Vic.,
Australia. Tel.: +61 3 9417 0714; fax: +61 3 9417 0716. E-mail address: [email protected] 1087-0792/$ - see front matter & 2007 Published by Elsevier Ltd. doi:10.1016/j.smrv.2007.03.006
the possibility of eye disorders in their patients with OSA. One of the commonest disorders associated with OSA is floppy eyelid syndrome (FES), a disorder almost always associated with OSA and very rarely with other risk factors. Given the profound pathophysiological changes that can occur with OSA, it is not surprising that eye disorders may occur in association with OSA. These include non-arteritic anterior ischemic optic neuropathy (NAION), papilledema secondary to raised intracranial pressure (ICP), and an optic neuropathy with associated visual field defects that may mimic glaucoma.
ARTICLE IN PRESS 270
A.A. McNab
Table 1 Eye disorders associated with obstructive sleep apnea. Floppy eyelid syndrome (and associated corneal changes of superficial punctate keratopathy, ulceration, scarring, perforation, keratoconus) Primary open-angle glaucoma Normal-tension glaucoma Optic neuropathy Non-arteritic anterior ischemic optic neuropathy Papilledema with raised intracranial pressure
These eye conditions are associated with a number of other risk factors, but OSA is an important and treatable risk factor, which clearly should be thought about when evaluating such patients.
Floppy eyelid syndrome and obstructive sleep apnea In 1981, two ophthalmologists, Culbertson and Ostler, described for the first time an unusual entity characterised by ‘‘floppy’’ and redundant upper eyelids with marked papillary conjunctivitis in obese middle-aged and older men1 (Fig. 1). They coined the term ‘‘floppy eyelid syndrome’’. The affected eye corresponded to the side the patient preferentially slept on, and if both eyes were affected, the patient alternated sides they slept on, or they slept face down. Some were noted to sleep with the affected upper eyelid spontaneously everted and rubbing on the pillow, and many had associated corneal abnormalities, particularly widespread punctate keratopathy. The patients typically complained of symptoms of watering, stickiness, discomfort and blurred vision in the affected eye(s), and these symptoms were typically worse on waking. A number of scattered case reports followed, and some commented that the patient was Pickwickian or had been diagnosed with obstructive sleep apnea, but no firm conclusion was drawn about a causal link between FES and OSA.2–4 My own interest in patients with FES led to the first published attempt at a systematic evaluation of the possible association between FES and OSA, and also for the first time systematically examined a cohort of patients already diagnosed with OSA to see how frequent FES was amongst this population, and to look for other possible associated eye disorders. All patients that I diagnosed with FES were offered referral for sleep studies. Of the eight patients referred for sleep studies, all were found
Figure 1 (a) An older obese male with left floppy eyelid syndrome and sleep apnea. Note the mild left upper eyelid ptosis, the lashes point downwards compared to the right, and the left eye is reddened. (b) With upward traction applied to the upper eyelids, the left upper eyelid spontaneously everts revealing the conjunctival lining to be reddened and thickened (papillary conjunctivitis).
to have OSA, many of them with severe OSA.5 Additionally, a consecutive group of 20 patients with diagnosed OSA was selected randomly from the register of a sleep laboratory and had thorough eye examinations. One of the 20 was found with full-blown FES, and two further asymptomatic patients had early signs of FES.5 Since that time I have accumulated and published data on a total of 50 patients with FES.6 Forty-three were men (86%), 44 (88%) were obese (body mass index over 30) and 21 (42%) were on treatment for systemic hypertension. All were asked for symptoms suggestive of OSA, and 48 (96%) admitted to such symptoms (snoring, daytime somnolence, waking feeling unrefreshed, apneas during sleep observed by others and waking gasping for air during the night). Eleven of these 50 patients had already undergone sleep studies and had a diagnosis of OSA, and 33 were offered sleep studies. Sixteen declined personally or their family
ARTICLE IN PRESS The eye and sleep apnea physician elected not to refer them. Of the 17 referred who underwent sleep studies, 16 were found to have OSA. No referral was made in six because of factors such as age, social circumstances or geography. Therefore, in 27 patients with FES who had formal sleep studies, 26 were found to have OSA. Clearly, there is a very strong association between these two conditions, and any patient diagnosed with FES should be considered for sleep studies. Despite this, only a small proportion of patients with OSA have been found with the full constellation of symptoms and signs of FES in two reported series,5,7 where 2% and 5% of OSA patients were found with FES. One other study reported 14 of 44 (32%) patients with OSA had ‘‘floppy eyelids’’, but the authors did not specify whether these patients had the other symptoms and signs that constitute FES.8 Their patients had a very low incidence of corneal changes compared to other series, and no mention is made of papillary conjunctivitis which is part of FES. It is likely that their patients with ‘‘floppy eyelids’’ had eyelid laxity which might lead to the full-blown FES over time. It is unclear why only a small minority of patients (between 2% and 5%) with OSA have FES,5,7 and yet, a large majority of FES patients have OSA. We have analysed the data of 12 patients with FES in whom we had detailed sleep study results and compared them to a large group of patients previously diagnosed with OSA from a large Melbourne sleep laboratory (St. Vincent’s Hospital). The results are summarized in Table 2. The FES patients have the same gender distribution, but are younger (po0.001) and are more obese (po0.001). Their indices of severity for OSA (AHI and SpO2min, where AHI is the number of apneic or hypopneic episodes per hour, and SpO2min is the minimum saturation of arterial oxygen) are also statistically worse than the general OSA population. These data should be interpreted with caution, as the two populations have certain biases within them, however, it does appear that FES is often an indicator of severe OSA, and as FES patients tend to be younger than most OSA patients, there may be an even stronger reason to investigate and treat them for OSA. Continuous positive airway pressure (CPAP) treatment alone may help the symptoms and signs of FES. I have reported one patient whose symptoms and signs of FES disappeared with OSA treatment,9 although he had only moderately severe FES. I have observed several other patients with FES where symptoms and signs improved significantly with just treatment of the OSA. Conversely, patients with FES and OSA who do not have the OSA treated have been observed to develop recurrent signs of FES
271 Table 2 A comparison between a large population of obstructive sleep apnea patients and a group of floppy eyelid syndrome (FES) patients. St. Vincent’s Number Age (years) BMI
466 55 (8–88) 28.7 (13–117) Female (%) 25 AHI (events/h) 11 (0–110) SpO2min (%) 87 (21–98) Severity (%) Normal Mild Moderate Moderately severe Severe
FES
p-Value
12 44 (33–57) 39 (30–45)
po0.01 po0.001
27 42 17 6
28 NS 50 (12–130) po0.001 74.5 po0.01 (29–91) po0.001 0 33 8 17
8
42
Age, body mass index (BMI) apnoea/hypopnoea index (AHI, the number of apneic and hypopneic events per hour) and SpO2min (minimum arterial oxygen saturation during apneic/hyponpeic event) are shown as median and range. The comparative statistic is the Mann–Whitney U-test. Female gender and severity of apnea are expressed as percentages. The comparative statistic is Fisher’s Exact test. Severity of OSA is based on the AHI and SpO2min, adapted from the Stanford Sleep Centre, and classified as follows.
Normal Mild Moderate Moderately severe Severe
AHI
SpO2min
o10 10–20 20–40 40–60 460
490 485 480 470 o70
months or years after surgical tightening of their eyelids. FES patients should probably therefore have any OSA treated before they are offered corrective eyelid surgery. FES may be associated with a number of other ocular and peri-ocular changes.5 The commonest are corneal changes.10 These range from superficial punctate keratopathy, which is nearly always present and probably is the result of poor upper eyelid contact between the floppy upper eyelid and the cornea leading to poor ocular surface wetting, through frank ulceration, scarring and vascularization and rarely corneal perforation11. Corneal ectasia in the form of keratoconus has also been reported in association with FES,10,12 and keratoconus is known to develop in patients who are
ARTICLE IN PRESS 272 chronic ‘‘eye-rubbers’’, such as those with severe atopy. Other eyelid changes reported to occur with FES include lower eyelid ectropion, hyperkeratotic skin lesions of the lids and face, keratinisation of the conjunctival surface of the affected upper eyelid, upper eyelid ptosis and eyelash ptosis (downward sloping lashes) and loss of eyelash parallelism.5 Loss of elasticity, sagging and wrinkling of the facial skin on the same side as the FES is often seen and can be extreme, giving the patient the appearance of premature aging on one side of the face (Figs. 2 and 3). This presumably relates to loss of elastin in the skin as has been observed in the eyelids of patients with FES (see below). There has been considerable speculation about the pathogenesis of FES. There is a clear relationship to OSA, and the fact that the affected side corresponds to habitual sleeping posture suggests a strong link between what is happening during these patients’ disturbed sleep and their eyelid changes. Chronic eyelid rubbing and stretching might lead to the observed changes in the eyelids, and once the eyelid begins to spontaneously evert during sleep, these changes could accelerate. Histopathologically, the affected eyelids have been noted to have loss of normal elastin fibres.13 A recent study looked at changes in resected segments of eyelid from patients with FES, and in particular, immunohistochemically examined for the presence of specific matrix metalloproteinases (MMPs). These authors found an increased immunoreactivity for the elastolytic proteases, particularly MMP-7 and MMP-9, in areas with elastin depletion compared to controls, indicating an upregulation of these elastolytic enzymes.14 This would account for the loss of elasticity seen clinically in FES patients. The mechanism of upregulation of these MMPs is unclear, but other studies have shown that repeated minor trauma or mechanical stress in vitro can lead to similar changes in other tissues.15,16 An additional possible mechanism may involve ischemia–reperfusion injury, and this has also been reported to lead to upregulation of some MMPs in tissues such as brain, heart and lungs.17 This same loss of elasticity is likely to be found in the surrounding skin of the eyelids and face, and it would of interest to examine the tissues of the upper airways in patients with OSA to see if similar changes were occurring. The treatment of FES, other than treating the underlying OSA, involves measures to prevent the underlying presumed mechanical minor traumas and stretching that appear to lead to the condition, and surgically correcting eyelid laxity. Patients can gain some relief by wearing a firm shield over the
A.A. McNab
Figure 2 (a) A patient with left floppy eyelid syndrome. In addition to the upper eyelid ptosis and downward pointing lashes, the eyebrow hairs are also disturbed and the skin around the eye shows more aging changes compared to the right side. (b) The left upper eyelid spontaneously everts on upwards traction.
eye at night, although the shield itself may press into the surrounding tissues causing discomfort and poor compliance. Better results can be obtained with custom-made soft silicone masks that fit over the eyes comfortably and reduce symptoms. Hospital prosthetics laboratories can make these devices. For the non-ophthalmologist, diagnosing FES is not difficult in a patient with established changes. The symptoms as listed above give a clue to the diagnosis. External examination of the eyes will usually show that the affected eye has downward pointing eyelashes compared to the more normal side (lash ptosis), the lashes are often not parallel to each other, and there may be a degree of ptosis of the whole lid. If a thumb is placed on the upper lid skin near the eyelid margin, and traction is applied upwards, an eyelid with established FES will often evert spontaneously, exposing the conjunctival lining of the upper eyelid, which is typically redder than normal, with a velvety texture (papillary conjunctivitis) (Fig. 1b).
ARTICLE IN PRESS The eye and sleep apnea
273
Figure 3 (a) A younger obese male with right floppy eyelid syndrome and sleep apnea. Note the marked asymmetry in facial skin between the two sides with the right side showing marked wrinkling and laxity compared to the left side. (b and c) Semi-profile views to show the skin changes and differences between the two sides. (d and e) The right upper eyelid everts spontaneously compared to the left.
Surgically tightening the eyelids has been shown to reduce symptoms and signs of FES.18 The surgical tightening can involve full-thickness resections of the floppy eyelid or tightening and re-inforcing the canthal tendons.19 However, the eyelid laxity, floppiness and symptoms can recur within months or years if the underlying OSA is not satisfactorily treated. Most reports of surgical eyelid tightening give follow-up periods up to 18 months at most.5
Glaucoma and obstructive sleep apnea My own study of FES patients suggested a possible association between FES and glaucoma.5 Since that initial report, other reports have identified an increased prevalence of primary open angle glaucoma in patients with OSA20 and also a high
prevalence of sleep-disordered breathing in patients with primary open angle glaucoma.21 One study showed a correlation between the severity of the sleep disturbance and severity of the visual field loss.22 Others have reported an association between normal-tension glaucoma and OSA, particularly in older patients.23 A variety of visual field defects in OSA patients was also reported by Mojon et al. in nine patients, and in two patients treated with CPAP, the field defects stabilised.24 Another patient has also been reported with normal-tension glaucoma and progressive field loss despite pressure lowering by drops and surgery, whose field loss stabilised after diagnosis of OSA and treatment with CPAP.25 Against this background of reports, one conflicting study has shown the prevalence of glaucoma in a group of OSA patients to be the same as the general population26 but the weight of evidence does seem to favour the hypothesis that
ARTICLE IN PRESS 274 a type of optic neuropathy is commoner in OSA patients. The nocturnal intra-ocular pressure of patients with normal-tension glaucoma and OSA has been measured and found to be normal,27 so it seems more likely the optic neuropathy or ‘‘normaltension glaucoma’’ in OSA patients is related to ischemic insults, and is a different type of optic neuropathy to that which occurs in primary open angle glaucoma. It would seem prudent to ask for symptoms of OSA in patients with an optic neuropathy that could mimic primary open-angle glaucoma, especially those in whom there is no other identifiable risk factor, the principle one being an elevated intraocular pressure. Such patients are often labelled as normal-tension glaucoma, which should be a diagnosis of exclusion. A recent study from Hong Kong looked at the computerised visual fields and optic discs of patients with moderate to severe OSA who had normal intra-ocular pressure, and compared these to an age-matched non-OSA population.28 In 41 ethnic Chinese patients with moderate to severe OSA, they found significantly subnormal visual fields and optic disc changes similar to that seen in primary open angle glaucoma (optic cupping) at a rate four times that seen in the control group. Another interesting parallel between OSA and normal-tension glaucoma has been highlighted by an Australian study showing a significantly greater extent of cerebral infarcts and white matter loss in the corpus callosum in a group of normal-tension glaucoma patients compared to controls studied with MRI.29 Other studies have shown that OSA patients show areas of cerebral cortical loss (gray matter) on MRI, presumably due to ischemia.30
Non-arteritic ischemic optic neuropathy and sleep apnea Another type of optic nerve disorder reported to be associated with OSA is non-arteritic anterior ischemic optic neuropathy.31 This seems hardly surprising given the profound pathophysiological changes that occur in patients with OSA during sleep and it is well known that a high proportion of non-arteritic AION patients first report their visual loss on waking (73.3% of 544 cases in Hayreh’s et al. series32). Mojon et al.31 recruited 17 patients with NAION and compared them to 17 age- and sexmatched controls, and performed overnight polysomnography on each patient. Twelve of 17 (71%) of
A.A. McNab the NAION patients had sleep apnea, 4 with mild OSA, 4 moderate and 4 severe. This compared to 3 of 18 controls (18%) (po0.001). The likelihood of OSA being present in the NAION patients increased with increasing age. Another more recent study looked at the incidence of OSA in patients newly diagnosed with NAION.33 All newly diagnosed patients with NAION underwent polysomnography, and other more traditional risk factors such as hypertension, diabetes, hyperlipidemia and atheromatous carotid artery disease were also identified. In 27 consecutive NAION patients, 24 (89%) were diagnosed with OSA on testing with a mean respiratory disturbance index of 37.2/h (SD 18.3/h). OSA was 1.5–2-fold more frequent than the rate of other identified risk factors such as hypertension and diabetes. It might be hoped that treating any underlying OSA would prevent a patient with unilateral NAION from developing NAION in the other eye. A recent small case series questions this.34 Three cases of NAION were reported in patients with OSA who were being treated with nocturnal continuous positive airway pressure. However, larger comparative observational series would need to be performed to establish what benefit CPAP might confer in preventing the development of NAION.
Papilledema, raised intracranial pressure and sleep apnea A further association between OSA and optic nerve pathology has been long recognised. Patients with OSA often complain of headache on waking. The intracranial pressure of OSA patients has been measured overnight and found to be markedly elevated in an episodic fashion, paralleling apneic episodes.35 It has been suggested that hypercapnia leads to cerebral venous dilatation. Raised venous pressure due to forced expiration against a closed glottis may also play a role. A number of case reports and small case series of patients with papilledema and sleep apnea have been published.36–44 The typical patient with idiopathic intracranial hypertension (IIH) is a younger, overweight female. Older male patients with IIH and papilledema are particularly at risk of having OSA as a causative factor, and treatment with CPAP may reverse the disc swelling.42 Such patients often have normal or high normal intracranial pressure when it is measured during the day, and nocturnal measurements may be more useful in reaching a diagnosis. All patients with IIH should
ARTICLE IN PRESS The eye and sleep apnea have an appropriate sleep history taken, but those at greatest risk of having OSA as a possible causative factor are obese middle-aged or older males.
Practice points Eye disorders associated with sleep apnea include: 1. Floppy eyelid syndrome (FES) (almost unique to sleep apnea patients), which causes ocular surface symptoms such as watering, soreness and discharge, especially on waking, can lead to corneal scarring, and may be associated with keratoconus. 2. Optic neuropathy that can mimic chronic open angle glaucoma. 3. Non-arteritic anterior ischemic optic neuropathy (OSA is a major risk factor for this disorder). 4. Papilledema associated with raised intracranial pressure (rare amongst OSA patients, but chronic headache should alert physicians to this possibility). Many of these disorders may be halted or improved with appropriate treatment of OSA.
Research agenda Floppy eyelid syndrome (FES): 1. Further work on the pathophysiology of FES may lead to a better understanding of how this condition develops and why it develops in some patients with OSA and not others. 2. Work on upregulation of matrix metalloproteinases, especially elastases, in the eyelids of FES patients could be expanded to look at tissue changes in the upper airways of OSA sufferers. Other eye conditions: 1. It would be useful to be able to more clearly identify groups of OSA patients at risk of eye disorders, and similarly identify those patients with identified eye disorders more likely to suffer from OSA. 2. The effects of treatment of OSA on associated eye disorders should be more systematically studied.
275
Acknowledgment Dr. John Santamaria, Director, Intensive Care Unit and Sleep Unit, St. Vincent’s Hospital, Melbourne, Australia.
References *1. Culbertson WW, Ostler HB. The floppy eyelid syndrome. Am J Ophthalmol 1981;92:568–75. 2. Gonnering RS, Sonneland PR. Meibomian gland dysfunction in floppy eyelid syndrome. Ophthal Plast Reconstr Surg 1987;3:99–103. 3. Goldberg RA, Coden DJ, Hornblass A, Mitchell JP. Floppy eyelid syndrome with marked lower eyelid ectropion. Am J Ophthalmol 1989;108:610–2. 4. Woog JJ. Obstructive sleep apnea and floppy eyelid syndrome. Am J Ophthamol 1990;110:314–5. *5. McNab AA. Floppy eyelid syndrome and obstructive sleep apnea. Ophthalmol Plast Reconstr Surg 1997;13: 98–114. *6. McNab AA. The eye and sleep. Clin Exp Ophthalmol 2005;33:117–25. 7. Karger RA, White WA, Park W-C, et al. Prevalence of floppy eyelid syndrome in obstructive sleep apnea–hypopnea syndrome. Ophthalmology 2006;113:1669–74. 8. Mojon DS, Goldblum D, Fleischhauer J, et al. Eyelid, conjunctival, and corneal findings in sleep apnea syndrome. Ophthalmology 1999;106:1182–5. 9. McNab AA. Reversal of floppy eyelid syndrome with treatment of obstructive sleep apnoea. Clin Exp Ophthalmol 2000;28:125–6. 10. Culbertson WW, Tseng SC. Corneal disorders in floppy eyelid syndrome. Cornea 1994;13:33–42. 11. Imbert P, Williamson W, Leger F, Gauthier L, Lagoutte F. Bilateral corneal neovascularization and floppy eyelid syndrome. A case report. J Fr Ophtalmol 1990;13:223–5. 12. Donnenfeld ED, Perry HD, Gibraltar RP, Ingraham HJ, Udell IJ. Keratoconus associated with floppy eyelid syndrome. Ophthalmology 1991;98:1674–8. 13. Netland PA, Sugrue SP, Albert DM, Shore JW. Histopathologic features of floppy eyelid syndrome. Involvement of tarsal elastin. Ophthalmology 1994;101:174–81. *14. Scho ¨ltzer-Schrehardt U, Stojkovic M, Hofmann-Rummelt C, Cursiefen C, Kruse FE, Holbach LM. The pathogenesis of floppy eyelid syndrome. Involvement of matrix metalloproteinases in elastic fiber degradation. Ophthalmology 2005;112:694–704. 15. Swartz MA, Tschumperlin DJ, Kamm RD, DRazen JM. Mechanical stress is communicated between different cell types to elicit matrix remodelling. Proc Natl Acad Sci USA 2001;98:6180–5. 16. Prajapati RT, Eastwood M, Brown RA. Duration and orientation of mechanical loads determine fibroblast cyto-mechanical activation: monitored by protease release. Wound Repair Regen 2000;8:238–46. 17. Lindsey M, Wedin K, Brown MD, et al. Matrix-dependent mechanism of neutrophil-mediated release and activation of matrix metalloproteinase 9 in myocardial ischemia/ reperfusion. Circulation 2001;103:2181–7. 18. Schwartz LK, Gelender H, Forster RK. Chronic conjunctivitis associated with ‘‘floppy eyelids’’. Arch Ophthalmol 1983;101:1884–8. The most important references are denoted by an asterisk.
ARTICLE IN PRESS 276 19. Valenzuela AA, Sullivan TJ. Medial upper eyelid shortening to correct medial eyelid laxity in floppy eyelid syndrome: a new surgical approach. Ophthal Plast Reconstr Surg 2005; 21:259–63. 20. Mojon DS, Hess CW, Goldblum D, Fleischhauer J, Koerner F, Bassetti C, et al. High prevalence of glaucoma in patients with sleep apnea syndrome. Ophthalmology 1999;106: 1009–12. 21. Onen SH, Mouriaux F, Berramdane L, Dascotte JC, Kulik JF, Rouland JF. High prevalence of sleep-disordered breathing in patients with primary open-angle glaucoma. Acta Ophthalmol Scand 2000;78:638–41. *22. Batisse JL, Vix J, Swalduz B, Chave N, Mage F. Sleep-related breathing disorders and normal or high-tension glaucoma: 35 patients with polysomnographic records. J Fr Ophtalmol 2004;27:605–12. 23. Mojon DS, Hess CW, Goldblum D, et al. Normal-tension glaucoma is associated with sleep apnea syndrome. Ophthalmologica 2002;216:180–4. *24. Mojon DS, Mathis J, Zulauf M, Koerner F, Hess CW. Optic neuropathy associated with sleep apnea syndrome. Ophthalmology 1998;105:874–7. 25. Kremmer S, Selbach JM, Ayertey HD, Steuhl KP. Normal tension glaucoma, sleep apnea syndrome and nasal continuous positive airway pressure therapy—case report with a review of literature. Klin Monatsbl Augenheilkd 2001;218:262–8. 26. Geyer O, Cohen N, Segev E, et al. The prevalence of glaucoma in patients with sleep apnea syndrome: same as in the general population. Am J Ophthalmol 2003;136: 1093–6. 27. Goldblum D, Mathis J, Bohnke M, et al. Nocturnal measurements of intraocular pressure in patients with normal-tension glaucoma and sleep apnea syndrome. Klin Monatsbl Augenheilkd 2000;216:246–9. *28. Tsang CS, Chong SL, Ho CK, Li MF. Moderate to severe obstructive sleep apnea is associated with a higher incidence of visual field defect. Eye 2006;20:38–42. 29. Ong K, Farinelli A, Billson F, Houang M, Stern M. Comparative study of brain magnetic resonance imaging findings in patients with low-tension glaucoma and control subjects. Ophthalmology 1995;102:1632–8. 30. Macey PM, Henderson LA, Macey KE, et al. Brain morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med 2002;166:1382–7. *31. Mojon DS, Hedges 3rd TR, Ehrenberg B, et al. Association between sleep apnea syndrome and nonarteritic anterior ischemic optic neuropathy. Arch Ophthalmol 2002;120: 601–5. 32. Hayreh SS, Podhajsky PA, Zimmerman B. Nonarteritic anterior ischemic optic neuropathy: time of onset of visual loss. Am J Ophthalmol 1997;124:641–7. *33. Palombi K, Renard E, Levy P, et al. Non-arteritic anterior ischaemic optic neuropathy is nearly systematically associated with obstructive sleep apnea. Br J Ophthalmol 2006;90:879–82.
A.A. McNab 34. Behbehani R, Matthews MK, Sergott RC, Savino PJ. Nonarteritic anterior ischemic optic neuropathy in patients with sleep apnea while being treated with continuous positive airway pressure. Am J Ophthalmol 2005;139:518–21. 35. Sugita Y, Iijima S, Teshima Y, et al. Marked episodic elevation of cerebrospinal fluid pressure during nocturnal sleep in patients with sleep apnea hypersomnia syndrome. Electroencephalogr Clin Neurophysiol 1985;60:214–9. 36. Bloomfield RL, Felts JH, Burkart JM, Cashwell FL. Optic disc edema in a pickwickian man mimicking hypertensive crisis. J Clin Hypertens 1987;3:27–30. 37. Bucci Jr FA, Krohel GB. Optic nerve swelling secondary to the obstructive sleep apnea syndrome. Am J Ophthalmol 1988;105:428–30. 38. Jennum P, Borgesen SE. Intracranial pressure and obstructive sleep apnea. Chest 1989;95:279–83. 39. Pasterkamp H, Cardoso ER, Booth FA. Obstructive sleep apnea leading to increased intracranial pressure in a patient with hydrocephalus and syringomyelia. Chest 1989;95:1064–7. 40. Doyle KJ, Tami TA. Increased intracranial pressure and blindness associated with obstructive sleep apnea. Otolaryngol Head Neck Surg 1991;105:613–6. 41. Purvin VA, Kawasaki A, Yee RD. Papilledema and obstructive sleep apnea syndrome. Arch Ophthalmol 2000;118: 1626–30. *42. Lee AG, Golnik K, Kardon R, Wall M, Eggenberger E, Yedavally S. Sleep apnea and intracranial hypertension in men. Ophthalmology 2002;109:482–5. 43. Marcus DM, Lynn J, Miller JJ, Chaudhary O, Thomas D, Chaudhary B. Sleep disorders: a risk factor for pseudotumor cerebri? J Neuroophthalmol 2001;21:121–3. 44. Hanigan WC, Zallek SN. Headaches, shunts, and obstructive sleep apnea: report of two cases. Neurosurgery 2004;54: 764–8.
Glossary of terms Keratoconus: a corneal ectasia characterized by thinning, outward bowing and distortion of the corneal surface. Non-arteritic anterior ischemic optic neuropathy: a condition of sudden onset characterized by unilateral visual loss, often with an altitudinal visual field defect, where the optic nerve head is swollen and pale and has suffered an ischemic event (the arteritic form of the condition occurs in giant cell (temporal) arteritis). Normal-tension glaucoma: a form of glaucoma or optic neuropathy usually indistinguishable from chronic open angle glaucoma in which the main risk factor is raised intra-ocular pressure. Papillary conjunctivitis: a clinicopathological term describing a thickened, velvety reddened surface of the conjunctiva lining the tarsal plates. Punctate keratopathy: multiple superficial microscopic corneal epithelial ulcers, best seen under magnification using fluorescein staining.