The Importance of Diurnal Variability
How valuable are monocular trials in open-angle glaucoma?

RICHARD MADONNA, O.D., M.A. F.A.A.O., New York

A62 year-old African-American man is referred to you for glaucoma evaluation. He has no significant history of eye problems, nor does he have a family history of glaucoma. He is not taking any systemic medications. Your examination reveals best-corrected visual acuity of 20/20 in each eye, normal anterior segments, open angles on gonioscopy without abnormality, equally reactive pupils without afferent defect and clear media in each eye. Intraocular pressure (IOP) with Goldmann applanation tonometry (GAT) taken at three visits, at different times of day, are 21mm-, 22mmand 20mm Hg O.D. and 24mm-, 24mm- and 25mm Hg O.S. His central corneal thickness measured with ultrasonic pachymetry is 540 microns O.D. and 543 microns O.S. Optic nerve examination reveals C/D ratio of 0.5/0.6 with questionable inferior rim thinning in the right eye and 0.5/0.8 with an inferior notch in the left eye. There is a nerve fiber layer wedge defect associated with the notch. All other fundus findings are within normal limits. Visual field exam with standard white-onwhite perimetry is within normal limits in the right eye, but shows a superior arcuate defect in the left.
Based on these exam findings, you diagnose primary open-angle glaucoma (POAG) and initiate treatment. After discussing the risks and benefits of treatment with the patient, you decide on treatment with a prostaglandin analog. Your target IOP is 16mm Hg in each eye. Based on the literature and recommendations, most O.D.s would begin with a monocular treatment trial. You prescribe q.d. prostaglandin therapy in the left eye and instruct the patient to return in three weeks. He returns and says he has been using the drop as instructed, had no problems with instillation, nor any adverse drug reactions. Your GAT readings are 18mm Hg O.D. and 21mm Hg O.S. How should you interpret the results of the trial?

Monocular trial rationale
We generally assume that, at least in disease-free eyes, the diurnal variation in intraocular pressure (IOP) is approximately symmetric in each eye of a given patient. There may be a difference between the two eyes at a given time of day (e.g. 14mm Hg O.D. and 12mm Hg O.S. at 5:00pm — a difference of 2mm Hg), but this difference is generally very similar in a 24-hour cycle (e.g. 18mm Hg O.D. and 16mm Hg O.S. at 8:00am). This assumption is the basis for the notion that, after a monocular treatment period long enough to achieve a steady-state effect (and assume no or minimal cross over effect), then the difference in IOP is a result of the medication and not another source of fluctuation, which, in theory, would affect both eyes equally. In essence, the untreated eye serves as a control for the treated eye. Several glaucoma textbooks recommend this approach, as well as the “Preferred Practice Patterns of the American Academy of Ophthalmology” and Clinical Practice Guidelines of the American Optometric Association. And, it was used in the Ocular Hypertensive Treatment Study (OHTS).^1-5
But is this assumption valid? Do we make other assumptions that also affect the validity of the trial? Most important, does the response to treatment of one eye accurately predict the response to treatment of the other?

Symmetrical IOP fluctuations
Maintaining IOP is a dynamic process with peaks and valleys in a 24-hour cycle. It has been assumed that the diurnal fluctuation in IOP occurs symmetrically between eyes. However, studies dating as far back as 1964 have shown that a significant number of glaucoma patients have asymmetrical diurnal curves between eyes.^6-8 One of these studies reported that up to one third of patients with POAG had asymmetrical diurnal curves with asynchronous peaks and troughs.⁷ In fact, relative asymmetry between eyes is fairly common, even in patients without glaucoma.⁸ It stands to reason then, that the normal (disease-free) cycle would be interrupted by diseaseinduced changes in outflow facility that would affect each eye in a somewhat different way. As such, we would expect intraocular variations in IOP to occur. Diurnal variations for glaucoma patients are generally between 6mm- and 11mm Hg, with variations greater than or equal to 3mm Hg occurring in more than 63% of glaucoma patients on stable medication regimens.^8-12

Additional assumptions
Another basic assumption of the monocular treatment trial is that both eyes will respond similarly to a given medication. Unfortunately, there is no clear-cut evidence to confirm or refute this assumption. Some reports have indicated that both eyes respond similarly to medications, while others have shown a significant difference in the second eye’s response in a monocular treatment trial.^13,14 Using the rationale developed earlier, this would explain why diseased eyes with abnormal outflow facility would respond differently to some medications, particularly those that enhance outflow facility.
The most recognized argument against the monocular treatment trial has been the socalled crossover effect of betablockers. One study showed that the IOP-lowering effect of a betablocker may be as much as 25% in the contralateral eye.¹⁵ This crossover effect would appear to obviate the use of a monocular treatment trial when prescribing beta-blockers. (This effect does not appear to be present for other medications.)
The final assumption involved in monocular treatment trials is that the patient is following your instructions. Anyone providing clinical care knows that assuming patient adherence to care is purely speculative. Although you may instruct your patient to use the drop in one eye, they may use it in this eye sporadically, not at all or use the drop in both eyes. Your evaluation of medication efficacy, including the results of a monocular treatment trial, should always include a healthy amount of skepticism regarding adherence to care and careful questioning of the patient regarding the appropriateness of their use of the medication.

Are monocular trials useful?
Although many of the perceived advantages of the monocular treatment trial have been shown to be misleading, one definite advantage is the control of the amount of drug that a patient will instill during the beginning of treatment. In the monocular treatment trial, only half of the intended amount of drug is instilled, allowing you to detect systemic or adverse drug reactions in sensitive individuals at a lower drug dosage. Additionally, you can use the untreated eye as a control for the detection of adverse reactions in the treated eye.
Whether you believe that medications should be started by using a monocular treatment trial or via bilateral treatment, you will not be able to determine the efficacy of an IOP-lowering medication until you have taken multiple pre-treatment and posttreatment IOP measurements, preferably at different times of the day. In this way, you can factor asynchronous diurnal curves into your final decision regarding the utility of a specific medication. This is especially true when the IOP-lowering effect of a medication is much less than would be expected for that medication.

Our patient
In the pretreatment period, our patient appeared to have relative symmetry between eyes, with IOPs of 21mm-, 22mmand 20mm Hg O.D. and 24mm-, 24mm- and 25mm Hg O.S. However, a monocular treatment trial O.S. found the IOP to be 18mm Hg O.D. and 21mm Hg O.S. You could conclude that the drop was ineffective, using the rationale that the untreated IOP O.D. was reduced by approximately 15% (21mm to 18mm) and the treated O.S. IOP was reduced by only about 12% (24mm to 21mm). You could draw this conclusion if you were sure the patient had synchronous diurnal curves between eyes.
However, a reasonable alternative is that a conclusion can’t be reached, as it is still possible that the drug was effective if the left eye was at an IOP peak and/or the right eye was at an IOP trough. Additionally, the patient may not have been using the drop as prescribed.
My experience is that many clinicians give up on a medication at this point and try another, or worse add a second medication. Keep in mind that most studies of the IOP-lowering effects of prostaglandins have shown extremely high responder rates, so some IOP-lowering effect is expected in the great majority of patients. In this case, we reinstructed the patient on appropriate use of the medication and asked him to schedule a follow- up IOP check. Upon return, the untreated IOP was 22mm Hg O.D., while the treated eye’s IOP (O.S.) measured 17mm Hg, nearly a 30% reduction in IOP. It would appear that the drug was efficacious, but if you were still skeptical that this could be an IOP peak O.D. and an IOP trough O.S., you could measure the IOP again at another time.
Whether you feel more comfortable starting your patients on monocular treatment trials or feel the evidence supports initializing treatment binocularly, it appears that in all cases, multiple pre- and post-treatment IOP measurements at different times of day will minimize the masking effect of asynchronous diurnal curves and allow a more realistic interpretation of medication efficacy. This will help eliminate inappropriate modification of medication regimens or over treatment with multiple medications.

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Dr. Madonna is associate professor of optometry at the SUNY State College of Optometry and recently received the State University of New York Chancellor’s Award for Excellence in Teaching.