Abnormal fluctuation in intraocular pressure has long been associated with glaucoma. Over the course of a 24-hour period, IOP normally varies by 2 to 6 mmHg as a result of imperfect synchronization of aqueous secretion and drainage. However, practitioners recognized decades ago that, unlike normal patients, glaucoma patients could have fluctuations greater than 10 mmHg. In fact, having a large amount of circadian variation can actually be one of the early signs of glaucoma.

However, it's not clear whether the presence of IOP fluctuation indicates a greater likelihood of glaucoma progression. This remains controversial for a number of reasons, including confusion caused by terms being used interchangeably and conflicting results from reliable studies.

In the past, the phrase "diurnal fluctuation," has been used to describe almost any kind of IOP fluctuation. The word diurnal means "around the day," so diurnal fluctuation really should refer to the circadian rhythm of IOP within a 24-hour period. However, some studies have used the phrase to refer to intervisit IOP fluctuation, which is potentially a different phenomenon. It's important to be able to differentiate between short-term (i.e., circadian) and long-term (intervisit) IOP fluctuation, as they may have different effects.

Clearly, it's helpful to specify which type of fluctuation a study is evaluating. When investigators examine IOP between separate visits, that data should be referred to as "intervisit IOP fluctuation."


A Closer Look at the Literature

Of the studies examining diurnal fluctuation, few have actually measured circadian IOP—i.e., IOP variation during a single 24-hour period. In two of the studies that did measure this, subjects used a self-tonometer to check their own pressures throughout the day. Both studies found that if you had a high amount of circadian fluctuation you were at a much greater risk of progressing.1,2

Other investigations have shown that intervisit IOP fluctuation leads to a poorer outcome—more visual field loss or optic nerve progression. However, it's difficult to know exactly what intervisit fluctuation represents. Is the effect purely attributable to circadian IOP variation, or is it the result of factors such as patient compliance or treatment failure? Also, some of the studies that have reported on IOP fluctuation were not primarily designed to examine that clinical question; many were examining the effectiveness of a surgical treatment for glaucoma such as trabeculectomy. They might observe, for example, that patients who had greater variability in their pressure measurements did worse in terms of outcome measurements such as visual fields and optic nerve changes. Was the observed effect caused by excessive fluctuation in circadian pressure rhythm? Maybe, but the effect could have been the result of the success or failure of the surgery, or a selection bias with progressing patients showing greater fluctuations of IOP due to medical or surgical treatment.

Further complicating matters, another study that measured circadian IOP fluctuation found that it was not a factor in converting from ocular hypertension to glaucoma.3
Admittedly, this study was looking at subjects who were much earlier in the disease process—and in this study, patients were removed from further analysis after they received treatments that could cause greater IOP fluctuation—but it suggests that if there is a connection between increased diurnal fluctuation and progression of glaucoma, it is not clear-cut at all stages of the disease.

Studies examining the potential connection between intervisit fluctuation and glaucoma progression are not uniformly consistent in their conclusions. At least two multicenter studies—the European Glaucoma Prevention Study and the Early Manifest Glaucoma Treatment Study—have found no connection.4,5 Data from studies such as these can't be easily dismissed. Given that the studies mentioned earlier that came to the opposite conclusion about the impact of intervisit fluctuation are also considered reliable, it should be no surprise that this debate is far from settled.


Why Are There So Few Studies?

One reason so few studies on circadian IOP and glaucoma have been performed is that this type of study is very difficult to conduct. First, in order to get a disease-modifying outcome, in terms of visual fields or the optic nerve, patients have to be followed for three, five, 10 or 15 years. That makes a study like this time-consuming and expensive. Second, no one has yet come up with a reliable way to measure IOP throughout the day (e.g., continuous IOP monitoring). Third, even if you monitor the pressure over the course of one day and then look at the progression of the disease over five years, can you assume that what happened on that one day accounts for what happened over the five years?

A better methodology would be to check IOP around the clock every day for five years and see how much fluctuation occurred on average. Once we have the technology to do that, it's certain that there will be an explosion of papers looking at this exact issue. But for now, that's not an option.


Is the Danger Real?

It seems like common sense that higher than average fluctuation in IOP could potentially cause damage to the optic nerve or retinal nerve fiber layer. After all, fluctuations are most likely going to reflect increases in pressure rather than decreases, and increased pressure certainly has the potential to cause damage.

However, one can make a reasonable argument that the eye is designed to withstand such fluctuations. After all, our eyes sustain huge fluctuations in IOP every time we blink, sit, bend over or do anything that causes a Valsalva maneuver. Studies back in the 1960s found that the act of blinking alone raises IOP to nearly 40 mmHg. The reality is that these fluctuations are present every day throughout life from the moment we're born, so our bodies are likely to have compensatory mechanisms for such short-term increases in pressure.

The counterpoint to this argument is that there's a difference between a physiologic blink, which is episodic, and circadian rhythms. Imagine IOP graphed over the course of 24 hours. Such a graph would probably show a sinusoidal wave with long ups and downs, but superimposed on that wave would be episodic spikes representing moments when we blink, sit down, and so forth. It's not hard to conceive that a longer-lasting, slow increase in intraocular pressure might have a different impact on tissues than brief episodic pressure spikes.


The Jury is Still Out, But ...

Given that the debate remains unresolved, is it worth being concerned about the degree of IOP fluctuation your patient is undergoing? My personal feeling is that this is a factor in glaucoma progression, and any pathology that leads to greater fluctuation could become a problem. However, at this point we're hard pressed to determine a patient's level of circadian fluctuation, and the evidence regarding the danger of greater fluctuation—cir-cadian or intervisit—is still unresolved. So for the foreseeable future I believe the basis for intervention will remain the traditional factors: the condition of the optic nerve, the status of visual fields, whether the pressure falls within the target range, and so forth. But if you detect an abnormally high level of fluctuation, it certainly could be considered incriminating evidence, worthy of further investigation.


Dr. Rhee is an assistant professor of ophthalmology at Harvard Medical School in Boston, and on staff at the Massachusetts Eye and Ear Infirmary.


1. Wilensky JT, Gieser DK, Dietsche ML, Mori MT, Zeimer R. Individual variability in the diurnal intraocular pressure curve. Ophthalmology 1993; 100:6:940-4.

2. Asrani S, Zeimer R, Wilensky J, Gieser D, Vitale S, Lindenmuth K. Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J Glaucoma 2000;9:2:


3. Bengtsson B, Heijl A. Diurnal IOP fluctuation: Not an independent risk factor for glaucomatous visual field loss in high-risk ocular hypertension. Graefes Arch Clin Exp Ophthalmol 2005;243:6:513-8.

4. Bengtsson B, Leske MC, Hyman L, et al. Fluctuation of intraocular pressure and glaucoma progression in the Early Manifest Glaucoma Trial. Ophthalmology 2007;114:2:205-209.

5. Ocular Hypertension Treatment Study Group; European Glaucoma Prevention Study Group; Gordon MO, et al. Validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension. Ophthalmology 2007;114:1:10-19.