Diurnal IOP Fluctuation – Not an Independent Risk Factor for Glaucomatous Visual Field Loss in High Risk Ocular Hypertension Authors:
چکیده
Purpose: To study whether intraocular pressure (IOP) fluctuations contribute to the risk of developing glaucoma in patients with high-risk ocular hypertension. Methods: Ninety patients included in the Malmö Ocular Hypertension Study were examined every 3 months with office hour diurnal tension curves and computerised perimetry. Patients were followed prospectively for 10 years or until glaucomatous visual field loss could be demonstrated. Post-study data was included in the analyses, extending maximum follow-up to 17 years. Results: After 17 years 37 patients had developed glaucomatous visual field defects. When applying univariate Cox regression analyses, mean IOP of all measurements during the prospective part of the study was a significant risk factor for developing glaucoma (95% confidence interval (CI): 1.08 —1.39), while IOP fluctuations were almost significant (95% CI: 0.98—1.93). When separating effects of mean IOP level and mean IOP fluctuation using Cox multiple regression analysis, only IOP level came out as significant (95% CI: 1.09–1.38), and IOP fluctuations did not contribute to the risk (95% CI: 0.80—1.60). IOP fluctuation depended linearly on IOP level (p 5mmHg and another with such fluctuations ≤5 mmHg at a baseline tension curve. Thus, the importance of IOP level was not considered at all. Our univariate analysis also suggested that increased IOP fluctuations may be a risk factor, but when taking IOP level into account IOP fluctuations lost importance totally. Most studies have looked at IOP fluctuations as a risk factor for progression of glaucomatous visual field loss. Such progression may be more difficult to estimate than onset of glaucomatous damage because of the much larger perimetric test-retest variability in diseased eyes as compared to normal ones. Different criteria for field progression could then yield different study results. Thus, Ishida and co-workers found that increased IOP fluctuations was a risk for visual field progression when defining progression as pointwise deterioration of threshold values, but not when defining progression as deterioration of the global Mean Deviation values [16]. In our study all patients were tested with the threshold program of the computerized static Competer perimeter during the prospective phase. During the clinical follow-up the patients switched to the 30-2 Full Threshold program of the Humphrey Field Analyzer (Carl Zeiss Meditech Inc, Dublin, Calif). This means that the patients who developed glaucoma during the prospective part were diagnosed using a different instrument than those who developed Bengtsson & Heijl: IOP fluctuations and risk for GLVFL 12 reproducible field loss during the retrospective follow-up part. We do not believe, however, that there were any important differences between the two instruments in their ability to identify repeatable glaucomatous field loss. Some early studies reported similar sensitivities and specificities between the Competer and the Octopus perimeters (Haag-Streit AG Switzerland), and between the Octopus and Humphrey Field Analyzer perimeters [13,22]. Asrani et al found that IOP fluctuations, as measured with self tonometry at home, was a significant risk factor for progression independent of IOP level [2]. This report has often been cited as the proof for variability as a risk factor for glaucoma progression. Others have pointed out, however, that the Asrani study lacked well-defined criteria for visual field glaucoma progression, and also doubts have been raised about patients’ ability to perform the self tonometry making the significance of the results less reliable [26]. Further, the analysis was limited to patients with normal or only slightly increased IOP. More than 60% of the subjects originally included were excluded from the analysis because they showed IOP > 24mmHg once or more during the 5 year follow-up. The conclusions of Asrani and coworker’s study could therefore not be considered as relevant for the large majority of clinical glaucoma patients having increased IOP. The patients included in Asrani’s study were quite different from the ones included our study. We included patients with increased IOP only, while such patients were excluded from the analyses in Asrani’s study, hence, there is little similarity between patients analysed in the present study and their paper. In the study by Bergeå et al. also multivariate analyses including several different IOP parameters were performed [4]. Prior to the risk analyses they carried out principal component analysis to avoid multicollinearity, i.e to avoid highly inter-correlated explanatory variables in the same model. This resulted in a number of multivariate regression models Bengtsson & Heijl: IOP fluctuations and risk for GLVFL 13 including different IOP parameters. Two of them included IOP range, calculated in the same way as our “mean of daily range”. In these two regression models IOP range was combined with: untreated baseline IOP, and with IOP change, i.e. treatment effect calculated as the difference between untreated baseline IOP and mean of treated follow-up IOP. Effects of follow-up IOP level and follow-up IOP fluctuations were not simultaneously tested in the same model. Thus, this study neither showed, nor disapprove, that IOP fluctuations were a risk factor for glaucoma progression independent of IOP level. A recent paper by Nouri-Mahdavi and co-workers [23] reports that IOP fluctuations, calculated as the standard deviation of single IOP measurements measured at different days during the follow-up of the Advanced Glaucoma Intervention Study and analysed using multivariate technique, was a significant risk factor for visual field deterioration. Surprisingly, and in contrast with an earlier AGIS report [1], mean IOP did not increase risk for field worsening. While the apparent differences between our results and several studies discussed above, most likely depend on whether both IOP level and IOP variability have been independently analysed in a multivariate way. We should point out that we measured IOP during office hours only. More measurements outside office hours would of course improve estimates of fluctuations, but retention was also important. It is not likely that patients would have stayed for 10 years in the prospective part of the study if we had asked them to come for measurements more than three times per day every three months. Bergeå also measured office hour curves 3 times per day[4], while the patients included in Asrani and co-workers’ study [2] measured their own pressure 5 times a day, from early morning to bedtime. In this context it could be of interest to mention a more recent study by Liu and co-workers [20], where IOP Bengtsson & Heijl: IOP fluctuations and risk for GLVFL 14 was measured every 2 hours during a 24-hour period in patients with untreated glaucoma and in age-matched healthy subjects. They found that diurnal IOP was higher in the glaucoma eyes, but that the diurnal to nocturnal IOP range was larger in the healthy eyes. This result could be interpreted as high diurnal IOP is a risk for glaucoma, but not large IOP fluctuation. 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