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  • Comprehensive Ophthalmology, Glaucoma

    Variations in intraocular pressure (IOP) have long been known, but the 24-hour pattern of IOP measured in the normal physiologic positions (upright during waking hours and supine during sleeping hours) has been described only in the last decade. Circadian IOP is highest during sleeping hours and lower during the waking hours for both normal controls and untreated glaucoma patients.1, 2 The reason for this pattern is unclear, but it may have a significant impact on the pathogenesis and management of glaucoma.

    Body position undoubtedly plays a role in the circadian IOP pattern since most of the nocturnal elevation of IOP is eliminated if the pressure is measured in the supine position throughout the 24-hour period.1, 2 For normal subjects, peak supine pressure occurs at night, but for untreated glaucoma patients peak supine pressure occurs during the day. However, the circadian variations in IOP, when measured in the supine-only position are modest. These findings appear paradoxical since numerous studies on aqueous humor flow indicate that aqueous humor production in the nocturnal period drops by at least 50% in normal and glaucomatous eyes.3 If all other factors remain equal, there should be a significant decline in nocturnal IOP, which is not seen in either the supine or physiologic positions.

    A recent study examining the circadian variations in aqueous humor dynamics investigated other factors that could produce the observed circadian IOP pattern.4 Aqueous humor outflow facility measured with tonography did not decrease sufficiently at night to compensate for the decrease in aqueous production. Mathematical modeling of aqueous humor outflow dynamics suggested that the most likely factor responsible for the nocturnal IOP pattern was a change in episcleral venous pressure. However, other factors may be contributing as well, including changes in uveoscleral flow. This work is ongoing and the mechanisms responsible for the 24-hour IOP pattern remain to be elucidated.

    At this time, no clinical trial has examined 24-hour variations in IOP as an independent risk factor. However, there are good reasons to suspect that 24-hour IOP variations, and the nocturnal rise in IOP in particular, may contribute to glaucoma pathogenesis. Systemic blood pressure is known to decrease during sleep in most individuals. It is possible that the combination of increased nocturnal IOP and decreased nocturnal blood pressure may combine to compromise optic nerve head perfusion in susceptible patients. Evidence for this comes from the work of Graham et al.,5 who showed that glaucoma patients with apparently well-controlled IOP were more likely to progress if they had exaggerated nocturnal drops in blood pressure compared with smaller nocturnal blood pressure drops. More recent evidence from the Early Manifest Glaucoma Trial has also highlighted ocular perfusion pressure as a consistent risk factor for glaucomatous progression.6

    The potential effect of the nocturnal IOP rise on glaucoma progression is exacerbated by the fact not all glaucoma therapies have equivalent efficacy throughout the 24-hour period. Some medications, such as beta-blockers, have little or no IOP lowering effect during the nocturnal period despite good IOP lowering effect during the day.7, 8 In contrast, the prostaglandin analogues appear to have good IOP lowering effect throughout the 24-hour period, although somewhat less during the night than during the day.7 Similarly, carbonic anhydrase inhibitors have good efficacy throughout the 24-hour period.8 Based on current research, the prostaglandins appear to have the best 24-hour coverage, followed by the carbonic anhydrase inhibitors, then the alpha-agonists, and finally the beta-blockers. No information is available about the 24-hour efficacy of miotics. Some combinations of medications, such as the fixed combination of timolol and dorzolamide, appear to have 24-hour IOP efficacy equivalent to prostaglandins.9 However, for advanced glaucoma patients, surgical therapy appears to have superior 24-hour IOP control compared with medical therapy alone.10

    Given the likely importance of circadian IOP variations in general, and the nocturnal rise in IOP in particular, attention should be paid to maintaining consistent 24-hour IOP control in glaucoma patients. Current medications can reduce IOP over the entire 24-hour period, but with variable efficacy depending on the class of medication. Therefore, appropriate selection of medical and surgical therapies is necessary to optimize IOP control. As always, care must be taken to balance potential risks with any potential benefits of advancing treatment. Future glaucoma management will likely involve assessment of the 24-hour IOP pattern, but suitable technology to allow this to be performed on a routine clinical basis remains to be developed.


    1. Liu JH, Kripke DF, Twa MD, et al. Twenty-four-hour pattern of intraocular pressure in the aging population. Invest Ophthalmol Vis Sci. 1999;40(12):2912-2917.
    2. Liu JH, Zhang X, Kripke DF, Weinreb RN. Twenty-four-hour intraocular pressure pattern associated with early glaucomatous changes. Invest Ophthalmol Vis Sci. 2003;44(4):1586-1590.
    3. Brubaker RF. Flow of aqueous humor in humans [The Friedenwald Lecture]. Invest Ophthalmol Vis Sci. 1991;32(13):3145-3166.
    4. Sit AJ, Nau CB, McLaren JW, et al. Circadian variation of aqueous dynamics in young healthy adults. Invest Ophthalmol Vis Sci. 2008;49(4):1473-1479.
    5. Graham SL, Drance SM, Wijsman K, et al. Ambulatory blood pressure monitoring in glaucoma. The nocturnal dip. Ophthalmology. 1995;102(1):61-69.
    6. Leske MC, Heijl A, Hyman L, et al. Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology. 2007;114(11):1965-1972.
    7. Liu JH, Kripke DF, Weinreb RN. Comparison of the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure. Am J Ophthalmol. 2004;138(3):389-395.
    8. Orzalesi N, Rossetti L, Invernizzi T, Bottoli A, Autelitano A.. Effect of timolol, latanoprost, and dorzolamide on circadian IOP in glaucoma or ocular hypertension. Invest Ophthalmol Vis Sci. 2000;41(9):2566-2573.
    9. Orzalesi N, Rossetti L, Bottoli A, Fumagalli E, Fogagnolo P. The effect of latanoprost, brimonidine, and a fixed combination of timolol and dorzolamide on circadian intraocular pressure in patients with glaucoma or ocular hypertension. Arch Ophthalmol. 2003;121(4):453-457.
    10. Konstas AG, Topouzis F, Leliopoulou O, et al. 24-hour intraocular pressure control with maximum medical therapy compared with surgery in patients with advanced open-angle glaucoma. Ophthalmology. 2006;113(5):761-765 e1.

    Author Disclosure

    Dr. Sit has been a consultant for Pfizer and Alcon.