• Glaucoma

    Although elevated intraocular pressure (IOP) has been well recognized as a major risk factor for glaucoma, and IOP reduction is an effective treatment to prevent or slow its progression, recent evidence suggests that addressing fluctuations in IOP is critical in the management of glaucoma and may be even more important than modifying peak or mean IOP. Measuring these fluctuations, however, is a challenging task that must take into account the circadian cycle of IOP, the effect of posture, and the varying effects of pharmacologic or surgical therapy.

    Fluctuation’s Significance

    The importance of IOP fluctuation was punctuated by the pointwise, linear regression analysis of the Advanced Glaucoma Intervention Study (AGIS) patients reported by Nouri-Mahdavi et al (Ophthalmology. 2004;111:1627-1635). Greater intervisit IOP fluctuation and older age at the initial intervention were the most consistent predictors of visual field (VF) progression. Eyes with IOP fluctuations of = 3 mm Hg had significant VF progression over follow-up (Figure 1). The authors also found that each 1-mm Hg increase in IOP fluctuation equated to an approximately 30% increase in the risk of VF progression. Interestingly, they found no relationship between mean IOP and VF progression and only a weak correlation between mean IOP and IOP fluctuation (r=0.22).

    Ophthalmology. 2004
    Figure 1. Change in AGIS score over follow-up in eyes with IOP fluctuation.

    Meanwhile, Lee et al reported similar findings at the 16th Annual Meeting of the American Glaucoma Society (AGS) through a retrospective analysis of the clinical practices of 12 glaucoma specialists. The researchers found that each unit increase in an individual patient’s standard deviation of IOP, representing fluctuation of serial IOP measurements, yielded a 3.2 times higher rate of glaucoma progression over > 5 years of follow-up. These reports suggest that IOP fluctuation may be an independent and more critical target in the successful treatment of glaucoma.

    Treating Peak IOP

    Historically, peak IOP was believed to occur in the early morning hours for most patients with glaucoma. The report by Mosaed et al challenges this conception by demonstrating that the subjects evaluated in the sleep laboratory often experienced peak IOP during the nocturnal period (Am J Ophthalmol. 2005;139:320-324). The study also reemphasized the effect of posture, as supine IOP was consistently higher than sitting IOP at all time periods. How can a practicing clinician without ready access to a sleep laboratory measure nocturnal IOP and the accompanying circadian IOP fluctuation?

    According to the study, measuring IOP in a patient who has been placed in a supine position for several minutes during office hours may provide an estimate of the peak nocturnal IOP. This may be superior to relying solely on diurnal IOP measurements, which may provide an underestimation of the degree of IOP fluctuation for a given patient. Interest in the water provocation test may also be renewed, as clinicians seek ways to determine a patient’s peak IOP through a variety of different measurements. Finally, small subsets of patients with advanced damage or progression that is inconsistent with their IOP measurements may require actual 24-hour IOP monitoring after a hospital admission.

    IOP that peaks during nocturnal periods may potentially be better treated by specific pharmacologic therapy, which is relatively more efficacious during this period. Various reports have demonstrated that topical beta-blockers have minimal effects on the production of aqueous humor during the nocturnal period. By evaluating patients in a sleep laboratory, Liu et al confirmed that timolol fails to reduce IOP during nocturnal hours, but significant IOP lowering was achieved by a prostaglandin analog (Am J Ophthalmol. 2004;138:389-395).

    Additionally, Orzalesi et al’s crossover study comparing 3 prostaglandin analogs found no significant difference among the 3 agents in their ability to lower IOP during the 24-hour circadian cycle (Ophthalmology. 2006;113:239-246). Other crossover studies have reported conflicting findings, however. Although it is unclear if one of the prostaglandin analogs is superior to the others in its ability to dampen IOP fluctuation, the prostaglandin analog as a class appears to provide significant IOP reduction throughout the 24-hour circadian cycle.

    Surgery versus Medication

    Patients with advanced glaucoma whose condition appears to be controlled with multiple medications may still have wide fluctuations in IOP. In comparing glaucoma patients who were successfully treated with either trabeculectomy or multiple medical therapy, Konstas et al found a greater 24-hour IOP range for the medical group (4.8 ± 2.3 mm Hg versus 2.3 ± 0.8 mm Hg for the surgical group) (Ophthalmology. 2006;113:761-765). More than one-third of the patients in the medical group also had peak IOP = 18 mm Hg compared to none in the trabeculectomy group. Interestingly, nearly all of these peaks occurred during non-office hours.

    Therefore, patients with very advanced glaucoma may still benefit from a trabeculectomy, despite their apparently well-controlled IOP, especially if subjective or objective progression of glaucoma is suspected. This may explain why trabeculectomy can help to stabilize normal-tension glaucoma despite minimally lowered preoperative IOP pressures; the surgery appears to reduce IOP fluctuations as well as the mean IOP.

    The ophthalmic community is just beginning to understand the importance of IOP fluctuation and its effect on glaucoma progression. Rather than shooting for a single number for target IOP reduction, setting a target range seems more appropriate. Not only should physicians concentrate on achieving IOP reduction, but they should also focus on reducing long-term IOP fluctuations. Consequently, appropriate selection of therapy, pharmacologic or surgical, should be predicated upon each treatment’s effect on these fluctuations. To understand each individual patient’s baseline IOP fluctuation range, it may be necessary to discourage many clinicians’ tendency to initiate treatment after a single, elevated reading, because this practice might otherwise eliminate the opportunity to discover the range of patients’ IOP fluctuations and its contribution, if any, to the pathophysiology of their particular optic neuropathy.


    1. Nouri-Mahdavi K, Hoffman D, Coleman AL, et al. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study.Ophthalmology. 2004;111:1627-1635.
    2. Lee PP, Walt JG, Doyle JJ, et al. Association between IOP fluctuation and glaucoma progression. Paper presented at: Annual Meeting of the American Glaucoma Society (AGS); March 2-5 2006; Charleston, SC.
    3. Mosaed S, Liu JH, Weinreb RN. Correlation between office and peak nocturnal intraocular pressures in healthy subjects and glaucoma patients.Am J Ophthalmol. 2005;139:320-324.
    4. Liu JH, Kripke DF, Weinreb RN. Comparison of the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure.Am J Ophthalmol. 2004;138:389-395.
    5. Orzalesi N, Rossetti L, Bottoli A, Fogagnolo P. Comparison of the effects of latanoprost, travoprost, and bimatoprost on circadian intraocular pressure in patients with glaucoma or ocular hypertension.Ophthalmology. 2006;113:239-246.
    6. Konstas AG, Topouzis F, Leliopolou O, et al. 24-hour intraocular pressure control with maximum medical therapy compared with surgery in patients with advanced open-angle glaucoma.Ophthalmology. 2006;113:761-765.

    Author Disclosure

    Dr. Chang states that he has received honoraria from his service on the speakers’ bureau for Pfizer, Inc. & Alcon Laboratories, Inc. He has no proprietary interest in any of the products or developments discussed in this article.