Pressure matters. Though IOP is no longer part of the formal definition of glaucoma, a recent string of large clinical trials have shown that it’s still the only modifiable risk factor. “Lowering pressure,” said Jacob T. Wilensky, MD, “is still the sine qua non of glaucoma therapy.”

Now a group of researchers is saying that we can’t know when to lower pressure unless we know true IOP in the first place. And that, they say, varies throughout the day. So questions arise. Does a swing in pressure matter? What bearing, if any, does the range of pressure throughout a 24-hour period have on disease progression? What happens to IOP while people are sleeping? Does body position affect IOP? They are even questioning the effect of seasonal changes on IOP.

“Nobody knows whether average IOP, peak IOP or 24-hour fluctuation is the most important predictor of which glaucoma patients are going to get worse,” said Kuldev Singh, MD, professor of ophthalmology and director of the glaucoma service, Stanford University. “Most likely all of the above are important. For now, all we can assume is that all other things being equal, lower is better.” Further studies, particularly those looking at the importance of nocturnal IOP, are needed, he said.

The Fluctuation Factor
Interest in pressure fluctuation is nothing new. More than 40 years ago, Stephen M. Drance, MD, checked the pressures of Canadian patients and found that pressure in normal subjects varied 3.7 mmHg, compared with an 11 mmHg or greater variation in glaucoma patients.¹

Interest was rekindled when Sanjay G. Asrani, MD, and colleagues reported that fluctuation in home diurnal IOP is a significant risk factor, independent of office IOP.²  “Drug companies jumped on the [Asrani] paper because they had a drug,” said Dr. Wilensky, professor of ophthalmology, University of Illinois at Chicago.

Large concern, or not? More recently, in a reanalysis of data from the Advanced Glaucoma Intervention Study, Kouros Nouri-Mahdavi, MD, and colleagues found greater IOP fluctuation to be an important risk factor for progression of visual field, second only to older age at the time of first intervention.³

Fluctuation proved much more important than the mean pressure, said co-author Joseph Caprioli, MD, professor of ophthalmology, and chief of the glaucoma division at University of California, Los Angeles. “In the last couple of years, there has been a realization that pressure variability, or long-term pressure fluctuation—fluctuation over many visits, over a period of months to years—has been shown pretty convincingly to be damaging.”

In yet another study, John H. K. Liu, MD, and colleagues measured IOP in a sleep lab for 24 hours, and found that mean IOP was significantly higher in the dark period than in the light/wake period.⁴ (See “While You Were Sleeping.”)

On the other hand, a study by Boel Bengtsson, PhD, and Anders Heijl, MD, PhD, found that while IOP level was significant, IOP fluctuations were not an independent risk factor for the incidence of visual field loss in patients with ocular hypertension.⁵  
 
Is there a way to reconcile the conflicting results? “It’s hard to sort out in studies whether it’s the upper level of fluctuation that’s bad, or something inherent about fluctuating IOP itself,” said Donald L. Budenz, MD, associate professor of ophthalmology, epidemiology and public health, Bascom Palmer Eye Institute. “That may be what accounts for some of the conflicting information out there. There’s a lot of room for more investigation.”

Time for Intervention
While noting that existing studies don’t offer much help with regards to clinical practice, Dr. Singh said it makes sense to minimize spikes in IOP.

Dr. Budenz agrees. “If it turns out that diurnal fluctuations are important, even in the normal range, then drugs that minimize fluctuation, like prostaglandins, should be prescribed,” he said. Some patients can’t tolerate prostaglandins, “but if you have a choice, they lower pressure better than beta-blockers, have fewer side effects, work during sleep and flatten pressure fluctuation.” Beta-blockers, which have been a first-line therapy since 1978, don’t work at night, he said, and he would avoid twice-daily topical carbonic anhydrase inhibitors because of the peaks and troughs, which put patients at risk of spending four to eight hours a day back at baseline.

To beta or not to beta. On the other hand, Dr. Wilensky conducted a study in which beta-blockers were administered once a day in the morning or at night and found no differences in effect. “Beta-blockers are a long duration drug,” he said, adding that “they can only work when there is beta stimulation of the ciliary body and beta tone is reduced at night so there is less aqueous production, but also lower IOP.”

No More Target Pressure?
The fluctuation studies have prompted some researchers to question the need for setting target pressures. “We used to think [target pressure] was tailored to each patient. But there is no evidence to support that notion,” said Dr. Caprioli, who helped write the Academy’s Preferred Practice Pattern on primary open-angle glaucoma.

“Maybe target pressure for most patients with primary open-angle glaucoma should just be low—maybe 10 to 12,” he said. “We want to keep the pressure constant, and perhaps the majority of our patients just need low pressure. To individualize may not be that important.”  Dr. Caprioli’s advice: “At least keep an eye on fluctuation.” 

Good-bye, single number. Dr. Singh agrees. “More than anything else, this de-emphasizes the concept of target IOP,” he said. If pressure varies as much as suspected throughout 24 hours, and doctors only get a few measurements during the daytime hours, they don’t have a good idea of what the true pressure is, he said. “If you don’t have a good idea of what the IOP is over 24 hours, how can you set an arbitrary target below which it should be? It is meaningless to fixate on a single number.”

Hello, hourly monitor. Dr. Singh noted that the large clinical trials that have shown the benefit of IOP lowering didn’t measure nocturnal IOPs, so it would be difficult to evaluate the significance of such data. That could change. “In the not-too-distant future, we will have a continuous 24-hour IOP monitor, allowing better evaluation of therapy in some, and perhaps many, patients,” he said.

For now, there are many more questions than there are answers. “The jury is still out on diurnal fluctuation,” said Dr. Budenz. “The bottom line: Stay tuned. We think there’s a story here, but it’s not fully known yet.”

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1 Arch Ophthalmol 1960;64:494–501.
2 J Glaucoma 2000;9:134–142.
3 Ophthalmology 2004;111(9):1627–1635.
4 Invest Ophthalmol Vis Sci 1999;40:2912–2917.
5 Graefes Arch Clin Exp Ophthalmol 2005; 243:513–518.

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Dr. Budenz has served as a consultant for Alcon and Pfizer, and served on the speaking bureaus for Alcon, Pfizer, Lumenis and Carl Zeiss Meditec. Dr. Caprioli has served as a consultant for Allergan, Merck and Pfizer, and served on the speakers’ bureaus for Allergan, Alcon and Pfizer. He has received grants from Allergan and Alcon. Drs. Mori and Singh have no financial interests. Dr. Wilensky has served as a consultant for Alcon, Vistakon, Ista and Bausch & Lomb and has received research support from Allergan.

While You Were Sleeping

“IOP is a variable variable. It fluctuates all the time,” said Dr. Wilensky. “That’s been known for a long, long time.” But when does it fluctuate? Do pressures change when the clock strikes a particular hour? In one study, by Dr. Liu and colleagues, IOP measurements were taken on 21 healthy volunteers who were housed in a sleep lab for 24 hours.1 Pressure was measured in the supine position during the dark period. Both sitting and supine readings were taken during the light/wake period. The study found that mean IOP in the dark period was significantly higher than in the light/wake period. “The main factor in the nocturnal IOP elevation appeared to be the shift from daytime upright posture to supine posture at night,” the authors report. Wake up, spike. Dr. Wilensky, who conducted his own sleep studies, disagreed, saying “I am very skeptical of a lot of the reputed sleep literature.” In one of his studies, he checked middle-of-the night IOP on both glaucoma and healthy patients. In both groups, a pressure spike, lasting only a couple of minutes, occurred upon waking. “We believe that what you’re measuring is the waking spike,” he said. Lie down, spike. “While it’s true you have to wake people up to measure their eye pressure, you don’t have to sit them up,” said Dr. Budenz. “I think the pressure really is up at night because people are lying down. So it’s a positional effect.” Dr. Wilensky acknowledged that possibility. “There are some postural differences. There’s no question.”  ______________________________ 1 Invest Ophthalmol Vis Sci 1999;40:2912–2917.

A Winter High-Pressure System

Seasonal changes may account for IOP fluctuation in certain types of glaucoma, including steroid-induced ocular hypertension. An observational control study by Kazuhiko Mori, MD, PhD, involving more than 43,000 cumulative patients at a glaucoma clinic in Kyoto found mean IOP becomes higher in winter and lower in summer. “The causes of the seasonal variation are still unclear,” Dr. Mori reported, but one theory holds that IOP spikes result from vascular changes in the eyes brought on by prolonged darkness or cold temperatures. Patients who suffer atopic dermatitis and use more steroids in winter should be more closely observed, added Dr. Mori, assistant professor of ophthalmology at Kyoto Prefectural University of Medicine. “We have experienced that those patients develop steroid-induced glaucoma in winter.” Physicians might consider adjusting medications for the winter-related high pressure or ensuring ophthalomogist visits over the winter season.