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Comment by Carol Toris & Shan Fan & Vikas Gulati on:

46409 Aqueous humor dynamics during the day and night in volunteers with ocular hypertension, Fan S; Hejkal JJ; Gulati V et al., Archives of Ophthalmology, 2011; 129: 1162-1166

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We appreciate the opportunity to reply to the comments from four leading experts in the field of aqueous humor dynamics. All their comments raise issues we too consider important. The issue of what is truly ocular hypertension is a complex one. As we have learned from the OHTS trial, IOPs of 90% of the ocular hypertensive subjects behaved no differently from ocular normotensive patients over the ensuing five years. It is difficult if not impossible to predict with any degree of certainty which 10% are 'different' from an ocular normotensive population. Nevertheless, we felt it was worthwhile to study the aqueous humor dynamics in a cohort that runs pressures more than 5 mmHg higher than a cohort of healthy volunteers. There are several reasons for the baseline IOP in our study subjects being close to 21 mmHg. Firstly, the treating physicians were concerned about allowing their patients to run high pressures during the washout periods and were not willing to offer enrollment to patients with relatively higher pressures before washout. Secondly, all enrolled subjects had prior documented IOPs of 21 mmHg or more (including on the screening visit or after washout), but these pressures may have dropped below 21 on the study visit. IOP being lower on study day compared to screening day is often found in clinical studies of IOPs. The control group in the EGPS study (inclusion IOP 22-29 mmHg) showed a 10-20% drop in IOP during follow up. A study of patients with glaucoma (with optic nerve and/or field damage) instead of ocular hypertension is clinically more relevant if not for the ethical issue of withholding IOP-lowering medications for many weeks. Such a study would likely enroll a population similar to the EMGT study (which had a baseline IOP of 20.6 mmHg) and make an artificial distinction on the basis of IOP unnecessary.

Another issue of importance in our study is episcleral venous pressure. Accurate assessment of this parameter is indeed difficult to obtain. In the absence of available means (to us) for measuring supine episcleral venous pressure, we used published data from investigators who had such instrumentation available to them. The published data were used to estimate supine nocturnal episcleral venous pres-sure in our study subjects. Using this published information to apply to our subjects is similar to using Dr. Friedenwald's pressure-volume data to apply to the eyes of any subjects being evaluated by tonography. Of course it would be preferable to make one's own measurements rather than utilize data from other investigators.

Calculated uveoscleral outflow is certainly a moving target and difficult to pinpoint in absolute terms. However, if treated as a relative number much useful information can be derived from calculated values. As shown in Table 3 in our paper, the 'change in uveoscleral outflow' varies little with changes in episcleral venous pressure, as long as the measurement methods remain consistent.

It is obvious that the techniques for measuring aqueous humor dynamics are limited. Some methods do not work at night. Others are difficult to perform and interpret. Still others are indirect with a high degree of variability. Accurate, non-invasive and consistent measurement techniques to assess aqueous humor dynamics through a closed eyelid of a sleeping patient depend on techniques yet to be developed. Until then, the methods currently available to us do pro-vide useful information on the physiology and pathology of aqueous humor dynamics. For example, our recently completed, but not yet published, studies of day and night effects of four IOP-lowering medications found that some drugs are ineffective at night because they cannot overcome the normal nighttime fluctuations in aqueous humor dynamics.

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