IOP: Fluctuation

Core Messages

››Both short-term and long-term intraocular pressure (IOP) fluctuation may impact the prognosis of glaucoma and glaucoma suspects.

››The existing literature on IOP fluctuation can be interpreted in many ways; the true impact of fluctuation remains unclear.

››For every patient treatment for glaucoma is a balance between expected risks of worsening and expected benefits of treatment.

––Inconsistent usage of medications may increase long-term IOP fluctuation.

––Surgery reduces both long-term and shortterm fluctuation.

13.1  Why is IOP Fluctuation a Topic of Interest?

Glaucoma is a leading cause of visual impairment and blindness in the United States [1, 2] and worldwide [3]. Lowering intraocular pressure (IOP) is the only proven means to slow or halt disease progression in those at higher risk of developing glaucoma (Ocular Hypertension­ Treatment Study [OHTS]) [4], in those with early to moderate glaucoma (Collaborative Initial Glaucoma­ Treatment Study [CIGTS] [5] and Early Manifest Glaucoma Trial [EMGT] [6, 7], in those with

M. B. Sultan ( )

New York Eye & Ear Infirmary, New York, NY, USA e-mail: mbsultan@pol.net

more advanced glaucoma (Collaborative Initial Normal-Tension Glaucoma Study [CNTGS] [8, 9] and Advanced Glaucoma Intervention Study [AGIS] [10]. Across all randomized, controlled trials, lowering IOP by at least 18% (mean) from baseline results in a 40% or greater reduction in glaucoma progression over 5 years [5–7, 9].

Past observations that glaucoma patients experience a wider range of IOP fluctuation than normal patients may indicate a greater propensity for glaucomatous worsening in eyes with greater IOP fluctuation. Indeed, several (but not all) recent publications have highlighted the likelihood of worsening glaucoma among those individuals with larger IOP swings within defined time periods [6, 10–13]. It is important to keep the concepts of short-term and long-term IOP fluctuation separate. For the purposes of this chapter, we use “short-term” fluctuation to represent IOP variation within a 24 h time period, while “long-term” fluctuation represents variation across different days.

Summary for the Clinician

››IOP fluctuation is a proposed risk factor for glaucoma development and progression.

››“Short-term” fluctuation represents IOP variation within a 24 h time period.

››“Long-term” fluctuation represents variation across different days.

››Different conclusions can be drawn from the literature concerning IOP fluctuation; however, there is a growing belief that larger longterm fluctuation is associated with progression of disease.

13.2  What Factors Should

Be Considered When

Measuring Short-Term

IOP Fluctuation?

Regardless of how IOP is measured, a single in-office IOP measurement will not capture an individual eye’s entire IOP range [14]. In normal individuals, IOP has been reported to fluctuate 2–6 mmHg over a 24 h period, while in an eye with glaucoma fluctuation it can be significantly greater than 6 mmHg [15]. In fact, it has been suggested that if fluctuation of 10 mmHg or more is seen within a 24 h period that glaucoma should be suspected [16]. Traditionally, peak IOP was believed to occur early in the morning, but recent research has indicated that some individuals peak in the afternoon or evening, and yet others have no reproducible pattern of IOP fluctuation [16]. In order to understand the extent of IOP change over a 24 h time period, IOP needs to be measured at various times during the day in each individual [17].

Some glaucoma specialists consider a sleep lab assessment of IOP over a 24 h time period with multiple measurements (every 2 h including the moment the patient wakes up) to be the gold standard evaluation of short-term IOP. However, virtually all agree that sleep lab assessment is impractical in the large majority of patients and has significant limitations (e.g., waking the patient, whether patient is supine or sitting).

Short-term IOP fluctuation is often assessed with office measurements, typically between 7 a.m. and 6 p.m. A few published papers include a late evening IOP measurement taken as late as midnight. However, one study [18] has noted that IOP measurement during routine office hours can miss up to 62% of IOP peaks found in testing outside of office hours [17] and up to 88% of IOP troughs [14, 17]. No study has specifically reported on the test–retest reliability of either sleep lab or in-office IOP measurements over a prolonged or 24 h time period.

Summary for the Clinician

››In order to understand the extent of IOP fluctuation in an individual over a 24 h time period, IOP needs to be measured at various times over the course of a day.

››IOP measurement during routine office hours can underestimate peak IOP and the range of fluctuation – it may miss up to 62% of IOP peaks found in testing outside of office hours as well 88% of IOP troughs.

››A sleep laboratory may provide the most controlled setting for measuring IOP over a 24 h time period but it has both practical and scientific limitations.

13.3  What is the Significance

of Short-Term IOP Fluctuation?

The primary question that clinicians and researchers have been asking is whether or not larger IOP fluctuations over a 24 h period confer greater risk of developing glaucoma and progressing to more advanced stages of disease. Several studies have assessed the relationship between short-term IOP fluctuation as measured in the office setting and the status of ocular hypertension and glaucoma patients [11, 13, 19–22]. Some of these studies indicate no association between shortterm fluctuation and the development or progression of glaucoma. However, there are two studies that do show an association between short-term fluctuation and increased likelihood of disease. Mean short-term IOP fluctuation (measured at 2 h intervals from 10 a.m. to 6 p.m.) was found to be 8.6 mmHg in an Indian ocular hypertensive population that progressed to POAG compared to 5.4 mmHg in the group that did not progress (relative risk of 9.1 (95% confidence interval [CI]: 2.2–163.4) [21]. In another study, Gonzalez et al. [19] demonstrated that 64% of ocular hypertensives with short-term IOP fluctuation greater than 5 mmHg (measured every 2 h beginning at 8 a.m. for a minimum of 12 h) developed glaucomatous visual field defects within 4 years compared to 18% with lower fluctuation (p < 0.05).

In summary, there are studies on both sides of the short-term fluctuation debate. Some support the notion that greater fluctuation increases the risk of glaucoma and its rate of worsening, while others do not. In the studies that do not show a relationship, weaknesses include the fact that IOPs were not assessed at time points shown to be potentially important (i.e., night-time IOP) [23–25] and patients were under treatment with

drug classes shown to reduce fluctuation as part of their treatment profile [13], therefore, it is difficult to say with confidence what is the true impact of short term fluctuation.

Summary for the Clinician

››There is conflicting data regarding the effect of short-term IOP fluctuation on glaucoma development and progression.

››Some studies indicate that short-term IOP fluctuation is associated with a greater risk or rate of worsening of status among patients with both ocular hypertension and glaucoma, while others show no effect.

13.4  What Factors Should Be

Considered in Measuring

Long-Term IOP Fluctuation?

Because long-term IOP fluctuation requires measurement of IOP over different days and visits, sleep lab assessments evaluating multiple 24 h periods and across different days have not been published. Thus, long-term IOP fluctuation has only been assessed with measurements taken in the office setting and, in one study by Asrani et al. [26], in the home setting. Unfortunately, many questions remain unanswered in terms of long-term fluctuation including: (1) what standard deviation or amount of visit to visit fluctuation is clinically significant, (2) which is more important – fluctuation of mean IOP or fluctuation of range of IOP, and (3) what is the effect of IOP fluctuation due to inconsistent use of medications.

Summary for the Clinician

››Long-term IOP fluctuation requires measurement of IOP over different days and visits.

››Settings for long-term IOP fluctuation measurements could include the laboratory, office setting, and home setting.

13.5  What is the Significance of Measures of Long-Term IOP Fluctuation?

Asrani et al. [26] trained patients to measure their own IOP at home using a specially designed device over a 5-day period to assess diurnal IOP fluctuation’s effect on glaucoma progression. After 8 years of follow up, they found that progression occurred in 88% of patients in the upper 25th percentile of IOP fluctuation (11.8 mmHg) and in 57% of patients in the lower 25th percentile of IOP fluctuation (7.7 mmHg) based on the single 5-day period of IOP monitoring, and it was independent of office IOP, age, race, gender, and visual field damage at baseline [26]. The hazard ratio for glaucoma progression was 5.69 (95% CI: 1.86–7.35; p < 0.0005 comparing those in the upper 25% with those in the lower 25%).

Aside from Asrani’s work, all other studies assessing IOP fluctuation and its relationship to glaucoma status used in-office measurements during routine office hours. No studies have assessed how many different office visits should be included in analyses and whether the time period for office visits should differ from visit to visit.

While EMGT confirmed that elevated IOP is a strong risk factor for glaucoma progression [6, 7, 12], with hazard ratio increasing by 11% for every 1 mmHg of increase in IOP, long-term IOP fluctuation was found not to be an independent factor in analyses. In contrast, using an associative analysis of the percent of visits where IOP was less than 18 mmHg [10], the AGIS investigators found that patients whose IOP measurements were always under 18 mmHg, and who therefore presumably had less IOP fluctuation (mean IOP 12.3 mmHg during the first 6 years), had almost no mean worsening of visual field defect scores from baseline to follow up over 6 years. In contrast, patients with IOP measurements both above and below 18 mmHg at visits experienced a one-unit loss of visual field (roughly, on a 20-point scale) at 5 years ( p-values between 0.01 and 0.06 for the three groups) and an additional two-unit loss at 7 years ( p-values between 0.001 and 0.03). Mean IOP was 20.2 mmHg for those with IOP below 18 mmHg at less than 50% of their visits, 16.9 mmHg for those with 50–74% of their visits below 18, and 14.7 mmHg for those between 75 and 99% of visits below 18 mmHg. In another analysis of AGIS data [27, 28], use of standard deviation as a

measure of variation was shown to be of value in understanding IOP fluctuation over time. Four variables were associated with a higher probability of visual field progression as assessed by pointwise linear regression: older age at the time of first intervention (p = 0.0012), greater IOP fluctuation, as measured by the standard deviation of IOPs from visit to visit (p = 0.0013), increasing number of glaucoma interventions (p = 0.0103), and longer follow-up (p = 0.0223) [27, 28]. The possible factors that might underlie the different findings with different studies include: (1) the AGIS analyses [27, 28] included postprogression IOP values, which might be biased toward larger fluctuations induced by more intensive treatment; (2) study population differences; and (3) significant differences in the baseline IOPs of the different studies, with the EMGT population having a much lower baseline IOP. The most recent analysis of the AGIS population, which removed posttreatment IOPs, maintains that long-term fluctuation in IOP was associated with visual field progression (26% of eyes) (p = 0.009). However, IOP fluctuation was only found to be associated with visual field progression in the low mean IOP group (p = 0.002) and not in the high mean IOP group (p = 0.2).

Additional studies from other sources also tend to support the importance of long-term IOP fluctuation. Analysis of the Olmsted County data [29] indicates that a greater range of IOP from visit to visit is associated with a greater risk of progression to blindness. Similarly, studies by Bergea et al. [12] and O’Brien et al. [29] suggest that understanding the range of IOP over time may be another simple but useful means to glaucoma progression.

Summary for the Clinician

››Several studies have demonstrated conflicting results with regards to the importance of assessing long-term IOP fluctuation. Studies following IOP over longer time intervals suggest an association between greater fluctuation and glaucoma progression. Newer analyses of data now suggest that fluctuation may be more important in patients starting off with lower levels of IOP.

››Different definitions of long-term fluctuation, analyses, study populations, treatment regimens, time periods of IOP measurement and baseline IOPs make direct comparison between the various studies examining IOP fluctuation difficult.

››Additional investigation is needed to better understand the best method for assessing longterm IOP fluctuation and the value of measuring long-term IOP fluctuation.

13.6  What is the Impact of Medication on Short-Term and Long-Term IOP Fluctuation?

Analysis of published studies suggests that prostaglandin analogs and combination beta-blockers/carbonic anhydrase inhibitors are most effective in reducing shortterm IOP fluctuation [30], while topical carbonic anhydrase inhibitors alone and possibly alpha-adrenergic agonists alone are superior to beta-adrenergic blockers alone. Few studies have specifically analyzed long-term IOP fluctuation. Additional analyses that report standard deviations for IOP would be helpful to better understand the differences, if any, among the medication classes in controlling long-term IOP fluctuation.

Patients who intermittently use their medication may be exaggerating both shortand long-term IOP fluctuation in their own eyes. Unlike patients enrolled in clinical trials, patients cared for in routine clinical environments do not benefit from the supportive infrastructure of a trial that helps them obtain and use medications as directed and to follow up at regular intervals. Indeed, even for patients enrolled in clinical trials, as in AGIS [10], significant fluctuations in IOP from visit to visit (long-term IOP fluctuation) can occur; to what degree this is due to the disease versus to poor adherence with prescribed medications cannot be determined. However, intermittent usage of medications over sufficiently long periods of time may result in greater levels of IOP fluctuation and long-term IOP fluctuation.

Summary for the Clinician

››Patients who consistently take medication as prescribed presumably have lower degrees of IOP fluctuation compared to untreated patients.

››Analysis of published studies suggests that prostaglandin analogs and combination betablockers and carbonic anhydrase inhibitors are most effective in reducing short-term IOP fluctuation. Few studies have specifically analyzed long-term IOP fluctuation.