Sleep apnoea syndrome and primary open-angle glaucoma

It has already been demonstrated that primary open-angle glaucoma (POAG) is associated with a large variety of dysfunctions of the autonomic nervous system (ANS) Ð the part of the nervous system which regulates individual organ functions and is not under voluntary control.
Sleep-related breathing disorders (SBD) are examples of such autonomic dysfunctions and the study of a possible relationship between them and circulatory parameters relevant to glaucoma pathogenesis has attracted many researchers.

Clinical background
Sleep apnoea represents a disorder characterised by recurrent interruption of normal breathing during sleep owing to upper airway obstruction.1 Sleep apnoea is generally classified as central, obstructive and mixed. Central sleep apnoea is a rare disorder and it occurs in patients with severe neurological problems such as encephalitis affecting the brainstem, neurodegenerative disorders, stroke, complications of surgery of the cervical spine and with primary hypoventilation syndrome.
Obstructive sleep apnoea (OSA) is, however, the most common form and occurs when tissues in the upper throat (or airway) collapse at intervals during sleep, thereby blocking the passage of air. This form of the disease will be discussed below.
Although many people with OSA, particularly women and children, are not overweight,2 OSA typically affects obese, middle-aged individuals.3 Patients present a history of loud snoring and excessive daytime somnolence (such as fatigue and sleep attacks). Cognitive impairment,4 systemic hypertension,5-7 and an increased risk of stroke3 have also been reported in patients with OSA.
Common systemic associations of OSA include systemic hypertension,5-7 stroke3, 8-10 chronic headache, and cognitive dysfunction.11 Although OSA has been associated with chronic hypertension,5-7 not all subjects with sleep-related breathing disorders are hypertensive.12,13
It has been shown that some elderly subjects develop nocturnal low blood pressure (BP) directly after an apnoeic attack.14 In addition, there are subjects referred for sleep studies who report orthostatic intolerance (OI) due to orthostatic hypotension.15 Moreover, it is estimated that approximately 25 per cent of subjects with upper airway resistance syndrome (UARS, characterised by frequent arousals and sleep fragmentation due to abnormal breathing) complain of both low BP with OI and cold extremities.15
Ocular diseases associated with OSA are floppy eyelid syndrome, keratoconus,16 papilloedema,17 and ischaemic optic neuropathy.18,19 The association between OSA and glaucoma was first reported in 1982 by Walsh and Montplaisir20 who found a combination of OSA and glaucoma in five members of two generations of a family.
Later, Robert et al21 and McNab et al22 reported that some patients with sleep disorders screened for floppy eyelid syndrome were also being treated for glaucoma. Other authors have also reported a significantly higher prevalence of SBD in POAG patients compared to controls.23-26 These reports have opened a new and interesting path in the study of POAG pathogenesis.

Pathogenic mechanisms
The underlying pathogenic mechanisms for the neurological and circulatory problems associated with OSA are still unclear. OSA is accompanied by decreased oxygen saturation and hypercapnia.27 Hypoxia causes arteriolar vasodilation by a direct mechanism. However, the stimulation of the hypoxic peripheral chemoreceptors also leads to changes in heart rate (HR) and peripheral sympathetic outflow.28
Hypoxia results in an increase in minute ventilation, sympathetic stimulation of the peripheral blood vessels and parasympathetic stimulation of the heart. The direct effect of these influences is the appearance of hyperventilation, peripheral vasoconstriction, bradycardia and cerebral vasodilation.29
In addition, intermittent hypoxia may cause sustained activation of the sympathetic nervous system and result in systemic hypertension.28
Sleeping position seems to have an impact on the occurrence of apneic events and the associated periods of oxygen desaturation. Episodes of apnoea tend to be less frequent while patients sleep on their side comparing to when they turn into a supine position.30
Hypoxia and acidosis, which are also associated with OSA, might result in extreme cardiac arrhythmias (as a result of the catecholamine surges upon termination of the apnoea) and nocturnal sudden death.29
Hypercapnia induces cerebral vasodilation and narrows the autoregulatory plateau in the cerebral vasculature.31 This phenomenon has been used as an indicator of the metabolic mechanism underlying cerebral blood flow autoregulation.
Often, hypoxia and hypercapnia act together. Morgan et al32 found that sustained hypoxia, when combined with hypercapnia, resulted in sympathetic activation that persisted for 20 minutes after exposure.
All of these findings are suggestive of the role of a chemoreceptor-induced sympathetic activation in OSA that contributes to the aetiology of systemic hypertension in patients suffering from this syndrome.33
In addition, patients with OSA may have an impairment of resistance-vessel endothelium-dependent vasodilation34 probably due to endothelial damage from apnoea-induced hypoxia.35
A hormonal mechanism involving an imbalance between vasoconstrictor and vasorelaxing factors has also been suggested.36These changes may precede the occurrence of cardiovascular and cerebrovascular diseases in OSA patients.
Decreased arterial blood oxygen saturation is compensated by increased cerebral blood flow (CBF) and consequently the oxygen supply to the brain normally remains unchanged.37 Hypercapnia leads to dilation of the cerebral arteries38, decreased cerebral resistance, and increased CBF.39 Changes in blood gas levels influence the retinal and optic nerve blood flow in a manner similar to that in the cerebral circulation.
In the eye, hypercapnia results in increased blood flow in the retina and optic nerve.40 Although one can expect that a high blood flow (as a result of hypercapnia) would improve the visual function, it has been demonstrated that contrast sensitivity may decrease in response to hypercapnia (studies performed on young normal subjects and on untreated early POAG patients). These findings could suggest that the vasodilation and consequent ocular blood flow improvement alone are not sufficient to dictate the visual function outcome during gas perturbations and that the harmful effect of acidosis could be more important than the beneficial contribution of the improved perfusion.
Moreover, in glaucoma patients with disturbed autoregulation, hypercapnia-induced vasodilation could potentially redirect blood flow away from the optic nerve head (ONH). It seems that the metabolic and vascular effects resulted from elevated blood levels of carbon dioxide together with endothelial damage from apnoea-induced hypoxia could play an important role in the pathogenesis of POAG associated with OSA.
It seems that the effects of the apnoeic episodes on IOP are somewhat less dramatic than those on ocular circulation. It also seems that there is no difference between the IOP measured at the end of prolonged apnoea and the values assessed during periods of normal respiration in patients suffering from both OSA and normal tension glaucoma.41 It can be hypothesised that in these patients, the optic nerve is likely to be damaged directly by repetitive periods of hypoxia, or by an impaired autoregulation of blood flow as a secondary response to repetitive prolonged apnoeas.

Conclusion
Symptoms of OSA should be recognised and patients at risk should be referred for more extensive examination. Signs and symptoms suggestive of OSA as well as diagnosis techniques are listed in Table 1. It is still unclear if in POAG patients suffering from OSA the occurrence or progression of glaucomatous optic neuropathy is due to the OSA per se, or to concurrent episodes of exaggerated nocturnal haemodynamic disturbances.
In these patients, however, the IOP-lowering therapy may be insufficient and additional specialised approach may have an invaluable contribution. General lifestyle advice, sleep hygiene and weight reduction are a few of the measures that could and should be promoted among susceptible patients.42 Appropriate management of conditions such as obesity and abnormal BP, together with an improvement in our understanding of their relationship to POAG might have a beneficial effect in developing new therapeutic strategies for this disease.

References
1 Guilleminault C, van den Hoed J, Mitler M: Clinical overview of the sleep apnea syndrome. In: Guilleminault C, Dement W eds. Sleep Apnoea Syndromes. New-York: Liss, 1978:1-12.
2 Guilleminault C: Clinical features and evaluation of obstructive sleep apnoea. In: Karger MH, Roth T, Dement WC eds. Principles and Practice of Sleep Medicine. London: Saunders, 1994:667-677.
3 Palomaki H, Partinen M, Erkinjuntti T. Snoring, sleep apnoea syndrome and stroke. Neurology, 1992;42 (Suppl 6):75-82.
4 Findley LJ, Barth JT, Powers DC, et al. Cognitive impairment in patients with obstructive sleep apnoea and associated hypoxemia. Chest, 1986;90:686-690.
5 Eisensehr I, Ehrenberg BL, Noachtar S, Korbett K, Byrne A, McAulley A, Palabrica T. Platelet activation, epinephrine, and blood pressure in obstructive sleep apnoea syndrome. Neurology, 1998;51:188-195.
6 Lavie P, Ben-Yosef R, Rubin AE. Prevalence of sleep apnoea syndrome among patients with essential hypertension. Am Heart J, 1984;108:373-376.
7 Hoffstein V, Mateika S, Rubinstein I, Slutsky AS. Determinants of blood pressure in snorers. Lancet, 1988;2:992-994.
8 Norton PG, Dunn EV. Snoring as a risk factor for disease: An epidemiological survey. BMJ, 1985;291:630-632.
9 Pertinen M, Palomaki H. Snoring and cerebral infarction. Lancet 1985;2:1325-1326.
10 Dyken ME, Somers VK, Yamada T, Ren ZY, Zimmerman MB. Investigating the relationship between stroke and obstructive sleep apnoea. Stroke, 1996;27:401-407.
11 Jennum P, Hein HO, Suadicani P, Gytelberg F. Headache and cognitive dysfunction in snorers: A cross-sectional study of 3,323 men aged 54 to 74 years: The Copenhagen Male Study. Arch Neurol, 1994;51:937-942.
12 Duchna HW, Guilleminault C, Stoohs RA, Faul JL, Moreno H, Hoffman BB, Blaschke TF. Vascular rectivity in obstructive sleep apnoea syndrome. Am J Respir Crit Care Med 2000;161:187-191.
13 Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med, 2000;342:1378-1384.
14 McGinty D, Beahm E, Stern N, Littner M, Sowers J, Reige W. Nocturnal hypotension in older men with sleep-related breathing disorders. Chest, 1988;94:305-311.
15 Guilleminault C, Faul JL, Stoohs R. Sleep-disordered breathing and hypotension. Am J Respir Crit Care Med, 2001;164:1242-1247.
16 Mojon DS, Goldblum D, Fleischhauer J, Chiou AGY, Frueh BE, Hess CW, Gugger M, Basseti C, Boehnke M, Mathis J. Eyelid, conjunctival, and corneal findings in sleep apnoea syndrome. Ophthalmology, 1999;106:1182-1185.
17 Purvin V, Kawasaki A, Yee RD. Papilledema and obstructive sleep apnoea syndrome. Arch Ophthalmol, 2000;118:1626-1630.
18 Mojon DS, Hedges TR, Ehrenberg B, Karam EZ, Goldblum D, Abou-Chebl A, Gugger M, Mathis J. Association between sleep apnoea syndrome and nonarteritic anterior ischemic optic neuropathy. Arch Ophthalmol 2002;120:601-605.
19 Lee AG. Three questions on the role of sleep apnoea syndrome in optic disc edema. Arch Ophthalmol, 2001;119:1225.
20 Walsh JT, Montplaisir J. Familial glaucoma with sleep apnoea: A new syndrome? Thorax, 1982;37:845-849.
21 Robert PY, Adenis JP, Tapie P, Melloni B. Eyelid hyperlaxity and obstructive sleep apnoea syndrome. Eur J Ophthalmol, 1997;7:211-215.
22 McNab AA. Floppy eyelid syndrome and obstructive sleep apnoea. Ophthalmic Plast Reconstr Surg, 1997;13:98-114.
23 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;78:638-641.
24 Mojon DS, Hess CW, Goldblum D, Bohnke M, Korner F, Mathis J. Primary open-angle glaucoma is associated with sleep apnoea syndrome. Ophthalmologica, 2000;214:115-118.
25 Marcus DM, Costarides AP, Gokhale P, Papastergiou G, Miller JJ, Johnson MH, Chaudhary BA. Sleep disorders: A risk factor for normal-tension glaucoma? J Glaucoma, 2001;10:177-183.
26 Mojon DS, Hess CW, Goldblum D, Boehnke M, Koerner F, Gugger M, Bassetti C, Mathis J. Normal-tension glaucoma is associated with sleep apnoea syndrome. Ophthalmologica, 2002;216:180-184.
27 Hajak G, Klingelhofer J, Schulz-Varszegi M, Sander D, Ruther E. Sleep apnoea syndrome and cerebral hemodynamics. Chest, 1996;110:670-679.
28 Fletcher EC, Lesske J, Behm R, Miller III CC, Stauss H, Unger T. Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea. J Appl Physiol, 1992;72:1978-1984.
29 Dart RA, Gregoire JR, Gutterman DD, Woolf SH. The association of hypertension and secondary cardiovascular disease with sleep-disordered breathing. Chest 2003;123:244-260.
30 Masood A, Phillips B: Sleep apnoea. Curr Opin Pulm Med, 2000;6:479-484.
31 Raichle ME, Stone HL. Cerebral blood flow autoregulation and graded hypercapnia. Eur Neurol, 1972;6:1-5.
32 Morgan BJ, Crabtree DC, Palta M, Skatrud JB. Combined hypoxia and hypercapnia evokes lasting sympathetic activation in humans. J Appl Physiol, 1995;79:205-213.
33 Remsburg S, Launois SH, Weiss JW. Patients with obstructive sleep apnoea have an abnormal peripheral vascular response to hypoxia. J Appl Physiol, 1999;87:1148-1153.
34 Kato M, Roberts-Thomson P, Phillips BG, Haynes WG, Winnicki M, Accurso V, Somers VK. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnoea. Circulation, 2000;102:2607-2610.
35 Dean RT, Wilcox I. Possible atherogenic effects of hypoxia during obstructive sleep apnoea. Sleep, 1993;16:S15-S22.
36 Moller DS, Lind P, Strunge B, Pedersen EB. Abnormal vasoactive hormones and 24-hour blood pressure in obstructive sleep apnoea. Am J Hypertens, 2003;16:274-280.
37 Hayakawa T, Terashima M, Kayukawa Y, Ohta T, Okada. Changes in cerebral oxygenation and hemodynamics during obstructive sleep apneas. Chest, 1996;109:916-921.
38 Wei EP, Kontos HA, Patterson JLJ. Dependence of pial arteriolar response to hypercapnia on vessel size. Am J Physiol, 1980;238:H697-703.
39 Kety SS, Schmidt CF. The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest, 1948;27:484-492.
40 Roff EJ, Harris A, Chung HS, Hosking SL, Morrison AM, Halter PJ, Kagemann L. Comprehensive assessment of retinal, choroidal and retrobulbar haemodynamics during blood gas perturbation. Graefe's Arch Clin Exp Ophthalmol, 1999;237:984-990.
41 Goldblum D, Mathis J, Bohnke M, Bassetti C, Hess CW, Gugger M. Nocturnal measurements of intraocular pressure in patients with normal-tension glaucoma and sleep apnoea syndrome. Klin Monatsbl Augenheilk, 2000;216:246-249.
42 McNicholas WT. Obstructive sleep apnoea syndrome: Who should be treated? Sleep, 2000;23 Suppl4:S187-190.
43 Davies RJ, Ali NJ, Stradling JR. Neck circumference and other clinical features in the diagnosis of the obstructive sleep apnoea syndrome. Thorax, 1992;47:101-105.
44 Malhotra A, White DP. Obstructive sleep apnoea. Lancet 2002;360:237-245.
45 Rechtschaffen A, Kales A. A manual of standardised terminology, techniques and scoring system for sleep stages of human subjects. Los Angeles: Brain Information/Brain Research Institute: UCLA, 1968.
46 Series F, Marc I, Cormier Y, LaForge J. Utility of nocturnal home oximetry for case finding patients with suspected sleep apnoea hypopnoea syndrome. Ann Intern Med, 1993;119:449-453.
47 Strollo P, Sanders M, Constantino J, Walsh S, Stiller R, Atwood C. Split-night studies for the diagnosis and treatment of sleep-disordered breathing. Sleep, 1996;19:255-259.
48 Ayappa I, Norman RG, Krieger AC, Rosen A, Om RL, Rapoport DM. Non-invasive detection of respitratory effort-related arousals (REras) by nasal cannula/pressure transducer system. Sleep, 2000;23:763-771.
49 Pittman SD, Tal N, Pillar G, et al. Automated detection of obstructive sleep disordered breathing events using peripheral arterial tonometry and oximetry. Comput Cardiol, 2000;27:485-488.

Doina Gherghel is lecturer in ophthalmology at the Neuroscience Research Institute, Aston UniversityIt has already been demonstrated that primary open-angle glaucoma (POAG) is associated with a large variety of dysfunctions of the autonomic nervous system (ANS) Ð the part of the nervous system which regulates individual organ functions and is not under voluntary control.
Sleep-related breathing disorders (SBD) are examples of such autonomic dysfunctions and the study of a possible relationship between them and circulatory parameters relevant to glaucoma pathogenesis has attracted many researchers.

Clinical background
Sleep apnoea represents a disorder characterised by recurrent interruption of normal breathing during sleep owing to upper airway obstruction.1 Sleep apnoea is generally classified as central, obstructive and mixed. Central sleep apnoea is a rare disorder and it occurs in patients with severe neurological problems such as encephalitis affecting the brainstem, neurodegenerative disorders, stroke, complications of surgery of the cervical spine and with primary hypoventilation syndrome.
Obstructive sleep apnoea (OSA) is, however, the most common form and occurs when tissues in the upper throat (or airway) collapse at intervals during sleep, thereby blocking the passage of air. This form of the disease will be discussed below.
Although many people with OSA, particularly women and children, are not overweight,2 OSA typically affects obese, middle-aged individuals.3 Patients present a history of loud snoring and excessive daytime somnolence (such as fatigue and sleep attacks). Cognitive impairment,4 systemic hypertension,5-7 and an increased risk of stroke3 have also been reported in patients with OSA.
Common systemic associations of OSA include systemic hypertension,5-7 stroke3, 8-10 chronic headache, and cognitive dysfunction.11 Although OSA has been associated with chronic hypertension,5-7 not all subjects with sleep-related breathing disorders are hypertensive.12,13
It has been shown that some elderly subjects develop nocturnal low blood pressure (BP) directly after an apnoeic attack.14 In addition, there are subjects referred for sleep studies who report orthostatic intolerance (OI) due to orthostatic hypotension.15 Moreover, it is estimated that approximately 25 per cent of subjects with upper airway resistance syndrome (UARS, characterised by frequent arousals and sleep fragmentation due to abnormal breathing) complain of both low BP with OI and cold extremities.15
Ocular diseases associated with OSA are floppy eyelid syndrome, keratoconus,16 papilloedema,17 and ischaemic optic neuropathy.18,19 The association between OSA and glaucoma was first reported in 1982 by Walsh and Montplaisir20 who found a combination of OSA and glaucoma in five members of two generations of a family.
Later, Robert et al21 and McNab et al22 reported that some patients with sleep disorders screened for floppy eyelid syndrome were also being treated for glaucoma. Other authors have also reported a significantly higher prevalence of SBD in POAG patients compared to controls.23-26 These reports have opened a new and interesting path in the study of POAG pathogenesis.

Pathogenic mechanisms
The underlying pathogenic mechanisms for the neurological and circulatory problems associated with OSA are still unclear. OSA is accompanied by decreased oxygen saturation and hypercapnia.27 Hypoxia causes arteriolar vasodilation by a direct mechanism. However, the stimulation of the hypoxic peripheral chemoreceptors also leads to changes in heart rate (HR) and peripheral sympathetic outflow.28
Hypoxia results in an increase in minute ventilation, sympathetic stimulation of the peripheral blood vessels and parasympathetic stimulation of the heart. The direct effect of these influences is the appearance of hyperventilation, peripheral vasoconstriction, bradycardia and cerebral vasodilation.29
In addition, intermittent hypoxia may cause sustained activation of the sympathetic nervous system and result in systemic hypertension.28
Sleeping position seems to have an impact on the occurrence of apneic events and the associated periods of oxygen desaturation. Episodes of apnoea tend to be less frequent while patients sleep on their side comparing to when they turn into a supine position.30
Hypoxia and acidosis, which are also associated with OSA, might result in extreme cardiac arrhythmias (as a result of the catecholamine surges upon termination of the apnoea) and nocturnal sudden death.29
Hypercapnia induces cerebral vasodilation and narrows the autoregulatory plateau in the cerebral vasculature.31 This phenomenon has been used as an indicator of the metabolic mechanism underlying cerebral blood flow autoregulation.
Often, hypoxia and hypercapnia act together. Morgan et al32 found that sustained hypoxia, when combined with hypercapnia, resulted in sympathetic activation that persisted for 20 minutes after exposure.
All of these findings are suggestive of the role of a chemoreceptor-induced sympathetic activation in OSA that contributes to the aetiology of systemic hypertension in patients suffering from this syndrome.33
In addition, patients with OSA may have an impairment of resistance-vessel endothelium-dependent vasodilation34 probably due to endothelial damage from apnoea-induced hypoxia.35
A hormonal mechanism involving an imbalance between vasoconstrictor and vasorelaxing factors has also been suggested.36These changes may precede the occurrence of cardiovascular and cerebrovascular diseases in OSA patients.
Decreased arterial blood oxygen saturation is compensated by increased cerebral blood flow (CBF) and consequently the oxygen supply to the brain normally remains unchanged.37 Hypercapnia leads to dilation of the cerebral arteries38, decreased cerebral resistance, and increased CBF.39 Changes in blood gas levels influence the retinal and optic nerve blood flow in a manner similar to that in the cerebral circulation.
In the eye, hypercapnia results in increased blood flow in the retina and optic nerve.40 Although one can expect that a high blood flow (as a result of hypercapnia) would improve the visual function, it has been demonstrated that contrast sensitivity may decrease in response to hypercapnia (studies performed on young normal subjects and on untreated early POAG patients). These findings could suggest that the vasodilation and consequent ocular blood flow improvement alone are not sufficient to dictate the visual function outcome during gas perturbations and that the harmful effect of acidosis could be more important than the beneficial contribution of the improved perfusion.
Moreover, in glaucoma patients with disturbed autoregulation, hypercapnia-induced vasodilation could potentially redirect blood flow away from the optic nerve head (ONH). It seems that the metabolic and vascular effects resulted from elevated blood levels of carbon dioxide together with endothelial damage from apnoea-induced hypoxia could play an important role in the pathogenesis of POAG associated with OSA.
It seems that the effects of the apnoeic episodes on IOP are somewhat less dramatic than those on ocular circulation. It also seems that there is no difference between the IOP measured at the end of prolonged apnoea and the values assessed during periods of normal respiration in patients suffering from both OSA and normal tension glaucoma.41 It can be hypothesised that in these patients, the optic nerve is likely to be damaged directly by repetitive periods of hypoxia, or by an impaired autoregulation of blood flow as a secondary response to repetitive prolonged apnoeas.

Conclusion
Symptoms of OSA should be recognised and patients at risk should be referred for more extensive examination. Signs and symptoms suggestive of OSA as well as diagnosis techniques are listed in Table 1. It is still unclear if in POAG patients suffering from OSA the occurrence or progression of glaucomatous optic neuropathy is due to the OSA per se, or to concurrent episodes of exaggerated nocturnal haemodynamic disturbances.
In these patients, however, the IOP-lowering therapy may be insufficient and additional specialised approach may have an invaluable contribution. General lifestyle advice, sleep hygiene and weight reduction are a few of the measures that could and should be promoted among susceptible patients.42 Appropriate management of conditions such as obesity and abnormal BP, together with an improvement in our understanding of their relationship to POAG might have a beneficial effect in developing new therapeutic strategies for this disease.

References
1 Guilleminault C, van den Hoed J, Mitler M: Clinical overview of the sleep apnea syndrome. In: Guilleminault C, Dement W eds. Sleep Apnoea Syndromes. New-York: Liss, 1978:1-12.
2 Guilleminault C: Clinical features and evaluation of obstructive sleep apnoea. In: Karger MH, Roth T, Dement WC eds. Principles and Practice of Sleep Medicine. London: Saunders, 1994:667-677.
3 Palomaki H, Partinen M, Erkinjuntti T. Snoring, sleep apnoea syndrome and stroke. Neurology, 1992;42 (Suppl 6):75-82.
4 Findley LJ, Barth JT, Powers DC, et al. Cognitive impairment in patients with obstructive sleep apnoea and associated hypoxemia. Chest, 1986;90:686-690.
5 Eisensehr I, Ehrenberg BL, Noachtar S, Korbett K, Byrne A, McAulley A, Palabrica T. Platelet activation, epinephrine, and blood pressure in obstructive sleep apnoea syndrome. Neurology, 1998;51:188-195.
6 Lavie P, Ben-Yosef R, Rubin AE. Prevalence of sleep apnoea syndrome among patients with essential hypertension. Am Heart J, 1984;108:373-376.
7 Hoffstein V, Mateika S, Rubinstein I, Slutsky AS. Determinants of blood pressure in snorers. Lancet, 1988;2:992-994.
8 Norton PG, Dunn EV. Snoring as a risk factor for disease: An epidemiological survey. BMJ, 1985;291:630-632.
9 Pertinen M, Palomaki H. Snoring and cerebral infarction. Lancet 1985;2:1325-1326.
10 Dyken ME, Somers VK, Yamada T, Ren ZY, Zimmerman MB. Investigating the relationship between stroke and obstructive sleep apnoea. Stroke, 1996;27:401-407.
11 Jennum P, Hein HO, Suadicani P, Gytelberg F. Headache and cognitive dysfunction in snorers: A cross-sectional study of 3,323 men aged 54 to 74 years: The Copenhagen Male Study. Arch Neurol, 1994;51:937-942.
12 Duchna HW, Guilleminault C, Stoohs RA, Faul JL, Moreno H, Hoffman BB, Blaschke TF. Vascular rectivity in obstructive sleep apnoea syndrome. Am J Respir Crit Care Med 2000;161:187-191.
13 Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med, 2000;342:1378-1384.
14 McGinty D, Beahm E, Stern N, Littner M, Sowers J, Reige W. Nocturnal hypotension in older men with sleep-related breathing disorders. Chest, 1988;94:305-311.
15 Guilleminault C, Faul JL, Stoohs R. Sleep-disordered breathing and hypotension. Am J Respir Crit Care Med, 2001;164:1242-1247.
16 Mojon DS, Goldblum D, Fleischhauer J, Chiou AGY, Frueh BE, Hess CW, Gugger M, Basseti C, Boehnke M, Mathis J. Eyelid, conjunctival, and corneal findings in sleep apnoea syndrome. Ophthalmology, 1999;106:1182-1185.
17 Purvin V, Kawasaki A, Yee RD. Papilledema and obstructive sleep apnoea syndrome. Arch Ophthalmol, 2000;118:1626-1630.
18 Mojon DS, Hedges TR, Ehrenberg B, Karam EZ, Goldblum D, Abou-Chebl A, Gugger M, Mathis J. Association between sleep apnoea syndrome and nonarteritic anterior ischemic optic neuropathy. Arch Ophthalmol 2002;120:601-605.
19 Lee AG. Three questions on the role of sleep apnoea syndrome in optic disc edema. Arch Ophthalmol, 2001;119:1225.
20 Walsh JT, Montplaisir J. Familial glaucoma with sleep apnoea: A new syndrome? Thorax, 1982;37:845-849.
21 Robert PY, Adenis JP, Tapie P, Melloni B. Eyelid hyperlaxity and obstructive sleep apnoea syndrome. Eur J Ophthalmol, 1997;7:211-215.
22 McNab AA. Floppy eyelid syndrome and obstructive sleep apnoea. Ophthalmic Plast Reconstr Surg, 1997;13:98-114.
23 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;78:638-641.
24 Mojon DS, Hess CW, Goldblum D, Bohnke M, Korner F, Mathis J. Primary open-angle glaucoma is associated with sleep apnoea syndrome. Ophthalmologica, 2000;214:115-118.
25 Marcus DM, Costarides AP, Gokhale P, Papastergiou G, Miller JJ, Johnson MH, Chaudhary BA. Sleep disorders: A risk factor for normal-tension glaucoma? J Glaucoma, 2001;10:177-183.
26 Mojon DS, Hess CW, Goldblum D, Boehnke M, Koerner F, Gugger M, Bassetti C, Mathis J. Normal-tension glaucoma is associated with sleep apnoea syndrome. Ophthalmologica, 2002;216:180-184.
27 Hajak G, Klingelhofer J, Schulz-Varszegi M, Sander D, Ruther E. Sleep apnoea syndrome and cerebral hemodynamics. Chest, 1996;110:670-679.
28 Fletcher EC, Lesske J, Behm R, Miller III CC, Stauss H, Unger T. Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea. J Appl Physiol, 1992;72:1978-1984.
29 Dart RA, Gregoire JR, Gutterman DD, Woolf SH. The association of hypertension and secondary cardiovascular disease with sleep-disordered breathing. Chest 2003;123:244-260.
30 Masood A, Phillips B: Sleep apnoea. Curr Opin Pulm Med, 2000;6:479-484.
31 Raichle ME, Stone HL. Cerebral blood flow autoregulation and graded hypercapnia. Eur Neurol, 1972;6:1-5.
32 Morgan BJ, Crabtree DC, Palta M, Skatrud JB. Combined hypoxia and hypercapnia evokes lasting sympathetic activation in humans. J Appl Physiol, 1995;79:205-213.
33 Remsburg S, Launois SH, Weiss JW. Patients with obstructive sleep apnoea have an abnormal peripheral vascular response to hypoxia. J Appl Physiol, 1999;87:1148-1153.
34 Kato M, Roberts-Thomson P, Phillips BG, Haynes WG, Winnicki M, Accurso V, Somers VK. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnoea. Circulation, 2000;102:2607-2610.
35 Dean RT, Wilcox I. Possible atherogenic effects of hypoxia during obstructive sleep apnoea. Sleep, 1993;16:S15-S22.
36 Moller DS, Lind P, Strunge B, Pedersen EB. Abnormal vasoactive hormones and 24-hour blood pressure in obstructive sleep apnoea. Am J Hypertens, 2003;16:274-280.
37 Hayakawa T, Terashima M, Kayukawa Y, Ohta T, Okada. Changes in cerebral oxygenation and hemodynamics during obstructive sleep apneas. Chest, 1996;109:916-921.
38 Wei EP, Kontos HA, Patterson JLJ. Dependence of pial arteriolar response to hypercapnia on vessel size. Am J Physiol, 1980;238:H697-703.
39 Kety SS, Schmidt CF. The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest, 1948;27:484-492.
40 Roff EJ, Harris A, Chung HS, Hosking SL, Morrison AM, Halter PJ, Kagemann L. Comprehensive assessment of retinal, choroidal and retrobulbar haemodynamics during blood gas perturbation. Graefe's Arch Clin Exp Ophthalmol, 1999;237:984-990.
41 Goldblum D, Mathis J, Bohnke M, Bassetti C, Hess CW, Gugger M. Nocturnal measurements of intraocular pressure in patients with normal-tension glaucoma and sleep apnoea syndrome. Klin Monatsbl Augenheilk, 2000;216:246-249.
42 McNicholas WT. Obstructive sleep apnoea syndrome: Who should be treated? Sleep, 2000;23 Suppl4:S187-190.
43 Davies RJ, Ali NJ, Stradling JR. Neck circumference and other clinical features in the diagnosis of the obstructive sleep apnoea syndrome. Thorax, 1992;47:101-105.
44 Malhotra A, White DP. Obstructive sleep apnoea. Lancet 2002;360:237-245.
45 Rechtschaffen A, Kales A. A manual of standardised terminology, techniques and scoring system for sleep stages of human subjects. Los Angeles: Brain Information/Brain Research Institute: UCLA, 1968.
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Doina Gherghel is lecturer in ophthalmology at the Neuroscience Research Institute, Aston University