Anders Heijl

Early manifest glaucoma trial: Design and baseline data

OBJECTIVES The Early Manifest Glaucoma Trial (EMGT) will evaluate the effectiveness of reducing intraocular pressure (IOP) in early, previously untreated open-angle glaucoma. Its secondary aims are to explore factors related to glaucoma progression and to study the natural history of the disease. This article describes the EMGT design and presents baseline data. DESIGN Randomized, clinical trial. PARTICIPANTS Newly diagnosed patients 50 to 80 years of age with early glaucomatous visual field defects were mainly identified from a population-based screening of more than 44,000 residents of Malmö and Helsingborg, Sweden. Exclusion criteria were advanced visual field loss; mean IOP greater than 30 mmHg or any IOP greater than 35 mmHg; visual acuity less than 0.5; and inability to complete follow-up protocols. INTERVENTIONS After informed consent, patients were randomized to treatment or no initial treatment with close follow-up. Treated patients had laser trabeculoplasty and started receiving topical betaxolol twice daily in eligible eyes. Follow-up visits include computerized perimetry and tonometry every 3 months and fundus photography every 6 months. Decisions to change or begin treatment are made jointly with the patient when EMGT progression occurs and also later if clinically needed. MAIN OUTCOME MEASURES The EMGT progression is defined by sustained increases of visual field loss in three consecutive C30-2 Humphrey tests, as determined from computer-based analyses, or by optic disc changes, as determined from flicker chronoscopy and side-by-side comparisons of fundus photographs performed by masked, independent graders. RESULTS A total of 255 patients were randomized between 1993 and 1997 and will be followed for at least 4 years. All had generally good health status; mean age was 68.1 years, and 66% were women. At baseline, mean IOP was 20.6 mmHg and 80% of eyes had IOP less than 25 mmHg. CONCLUSIONS The Early Manifest Glaucoma Trial is the first large randomized, clinical trial to evaluate the role of immediate pressure reduction, as compared to no initial reduction, in patients with early glaucoma and normal or moderately elevated IOP. Its results will have implications for: (1) the clinical management of glaucoma; (2) understanding the role of IOP and the natural history of glaucoma; and (3) evaluating the rationale for glaucoma screening.

Test-Retest Variability in Glaucomatous Visual Fields

We measured test-retest variations in computerized visual fields from glaucomatous eyes. Fifty-one patients were tested four times within a four-week period; the severity of disease varied from incipient to advanced. We determined the dependence of threshold variability on defect depth and test point location. In areas of the visual field initially found to have moderate loss of sensitivity, variation in follow-up measurements ranged from normal sensitivity to absolute defect, with little dependence on distance from fixation. Conversely, large changes were considerably more unusual in locations initially showing normal or near-normal sensitivities, and variability was lowest in the most central portion of the field. Our findings suggest that differentiation between true progression and random variation will be facilitated if these factors are taken into account, as well as if comparisons are based on more than two tests. The complex nature of interest variation in glaucoma makes it natural to approach this problem with the help of computer-assisted analyses.

Practical recommendations for measuring rates of visual field change in glaucoma.

To date, there has been a lack of evidence-based guidance on the frequency of visual field examinations required to identify clinically meaningful rates of change in glaucoma. The objective of this perspective is to provide practical recommendations for this purpose. The primary emphasis is on the period of time and number of examinations required to measure various rates of change in mean deviation (MD) with adequate statistical power. Empirical data were used to obtain variability estimates of MD while statistical modelling techniques derived the required time periods to detect change with various degrees of visual field variability. We provide the frequency of examinations per year required to detect different amounts of change in 2, 3 and 5 years. For instance, three examinations per year are required to identify an overall change in MD of 4 dB over 2 years in a patient with average visual field variability. Recommendations on other issues such as examination type, strategy and quality are also made.

Natural History of Open-Angle Glaucoma

OBJECTIVE This article, based on the Early Manifest Glaucoma Trial (EMGT), provides prospective natural history data on progression of glaucomatous field defects in 3 of the most common glaucoma types. DESIGN Cohort of EMGT patients randomized to the untreated control group and followed up to the time of progression, when treatment could be initiated. PARTICIPANTS We evaluated 118 control patients: 46 with high-tension glaucoma (HTG), 57 with normal-tension glaucoma (NTG), and 15 with pseudoexfoliation glaucoma (PEXG). METHODS Visual fields were tested every 3 months with the Humphrey 30-2 Full Threshold test program. MAIN OUTCOME MEASURES Linear regression analyses of the perimetric mean deviation (MD) values were performed, and the rate of progression was defined as the regression coefficient in decibels per year. Percentages of progressed eyes and time to progression were determined using EMGT event-based predetermined progression criteria derived from Glaucoma Change Probability Maps. RESULTS The median and interquartile rates of visual function loss were -0.40 (1.05) dB/year overall and -0.46 (1.61) in HTG, -0.22 (0.65) in NTG, and -1.13 (6.13) in PEXG. Thus, interpatient variability was large. Mean rates were considerably higher than medians: -1.08 dB/year overall, -1.31 in HTG, -0.36 in NTG, and -3.13 in PEXG. Differences in median visual function progression rates among groups were statistically significant (NTG vs. HTG, P = 0.003; PEXG vs. non-PEXG, P<0.001). Progression was considerably and significantly faster in older than in younger patients (P = 0.002). By 6 years, 68% of patients had progressed overall, 74% of those with HTG, 56% of those with NTG, and 93% of those with PEXG (P = 0.012). Median time to progression also differed considerably among groups: 19.5 months in PEXG, 44.8 months in HTG, and particularly 61.1 months in NTG (P<0.0001). CONCLUSIONS In this 6-year follow-up study, the median untreated rate of progression corresponded to advancing from normal visual function to blindness in approximately 70 years, whereas on the basis of the mean rate, visual function would show the same deterioration in approximately 25 years. Large differences existed among patients and different glaucoma types, with PEXG progressing considerably faster than HTG, and NTG progressing at the lowest rate.

A package for the statistical analysis of visual fields

We have devised a package for the statistical analysis of computerized visual fields. It is based on a new mathematical model of the normal visual field and intended to facilitate interpretation of single fields and to illustrate changes over time in consecutive threshold fields. Single field analyses include maps showing pointwise total and pattern deviations from the age-corrected normal reference field. These maps are displayed both numerically, in dB, and as noninterpolated greyscaled probability maps illustrating the statistical significance of measured deviations. These probability maps help emphasize shallow, but significant, depressions in the paracentral field while frequently occurring false positive deviations occurring in the midperiphery are de-emphasized. Visual field indices, summarizing the deviations of height (Mean Deviation) and shape (Pattern Standard Deviation and Corrected Pattern Standard Deviation) of the measured field are weighted according to the normal variance among healthy individuals and printed out together with level of statistical significance. For follow-up the programme contains several different options. These range from an Overview format where threshold printouts and probability maps from several tests are printed in reduced size, but without any reduction of data, on a single sheet of paper, to a box plot format where the development of the field is shown with an intermediate degree of data reduction and a format employing a high degree of data reduction: graphs over visual field indices over time. If five or more tests are available a linear regression analysis of Mean Deviation is automatically performed. The programme will become available in the Humphrey Field Analyzer.

Diurnal IOP fluctuation: not an independent risk factor for glaucomatous visual field loss in high-risk ocular hypertension

PurposeTo establish whether intraocular pressure (IOP) fluctuations contribute to the risk of developing glaucoma in patients with high-risk ocular hypertension.MethodsNinety patients included in the Malmö Ocular Hypertension Study were examined every 3 months with office-hours diurnal tension curves and computerised perimetry. Patients were followed up prospectively for 10 years or until glaucomatous visual field loss could be demonstrated. Poststudy data were included in the analyses, extending maximum follow-up to 17 years.ResultsAfter 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<0.0001), i.e. IOP fluctuation was larger in eyes with higher IOP levels.ConclusionIOP fluctuations were not an independent risk factor for the incidence of glaucomatous visual field loss in subjects with ocular hypertension.

Factors for progression and glaucoma treatment: the Early Manifest Glaucoma Trial.

Purpose of review This review summarizes factors for progression in the Early Manifest Glaucoma Trial (EMGT), including the effect of treatment. EMGT randomized patients with early glaucoma either to argon laser trabeculoplasty plus betaxolol (n = 129) or to no immediate treatment (n = 126) and followed them every 3 months. Recent findings Treated patients had delayed progression, as compared with controls. In Cox regression, EMGT treatment halved the risk of progression (hazard ratio = 0.50; 95% confidence interval: 0.35, 0.71). Risk decreased about 10% with each millimeter mercury of intraocular pressure (IOP) reduction from baseline; the higher (or lower) the IOP at follow-up, the higher (or lower) the risk. Baseline factors increasing progression were higher IOP, exfoliation, bilateral disease, worse perimetric mean deviation and older age; frequent disc hemorrhages at follow-up also increased risk. Summary EMGT treatment reduced progression risk in half, demonstrating the value of IOP lowering in early glaucoma. Age and indicators of disease severity also predicted progression.

The effects of antiglaucoma and systemic medications on ocular blood flow

Based on the body of evidence implicating ocular blood flow disturbances in the pathogenesis of glaucoma, there is great interest in the investigation of the effects of antiglaucoma drugs and systemic medications on the various ocular vascular beds. The primary aim of this article was to review the current data available on the effects of antiglaucoma drugs and systemic medications on ocular blood flow. We performed a literature search in November 2002, which consisted of a textword search in MEDLINE for the years 1968-2002. The results of this review suggest that there is a severe lack of well-designed long-term studies investigating the effects of antiglaucoma and systemic medications on ocular blood flow in glaucomatous patients. However, among the 136 articles dealing with the effect of antiglaucoma drugs on ocular blood flow, only 36 (26.5%) investigated the effects of medications on glaucoma patients. Among these 36 articles, only 3 (8.3%) were long-term studies, and only 16 (44.4%) were double-masked, randomized, prospective trials. Among the 33 articles describing the effects of systemic medications on ocular blood flow, only 11 (33.3%) investigated glaucoma patients, of which only one (9.1%) was a double-masked, randomized, prospective trial. Based on this preliminary data, we would intimate that few antiglaucoma medications have the potential to directly improve ocular blood flow. Unoprostone appears to have a reproducible antiendothelin-1 effect, betaxolol may exert a calcium-channel blocker action, apraclonidine consistently leads to anterior segment vasoconstriction, and carbonic anhydrase inhibitors seem to accelerate the retinal circulation. Longitudinal, prospective, randomized trials are needed to investigate the effects of vasoactive substances with no hypotensive effect on the progression of glaucoma.

False-negative responses in glaucoma perimetry: indicators of patient performance or test reliability?

PURPOSE. To study whether false-negative answers in computerized glaucoma perimetry indicate the patients ability to perform perimetry or test result reliability. METHODS. A retrospective evaluation was performed of visual field test results obtained with a perimetry program (Humphrey 30-2 Sita Standard; Humphrey Instruments, San Leandro, CA) in 70 consecutive patients with unilateral glaucomatous field loss. Frequencies of false-negative answers were compared between the two eyes of each patient and related to amount of visual field damage in the glaucomatous eyes using linear regression analysis. RESULTS. Frequencies of false-negative answers were higher in eyes with field loss. The intrapatient intereye difference was 6.6% on average (P < 0.0001). In seven subjects with false-negative frequency of 5% or more in both eyes, the mean difference was 12.7% between eyes. The differences in false-negative answers depended significantly on the amount of field loss in the glaucomatous eyes (P = 0.0003). Larger differences were seen in patients with advanced field loss in the affected eye. CONCLUSIONS. The increased frequencies of false-negative answers in eyes with field loss were strongly associated with field status. The higher false-negative frequencies in eyes with glaucomatous field loss compared with unaffected eyes may be explained by the increased variability in threshold values typically found in such eyes. False-negative answers in patients with glaucoma therefore represent eye rather than patient status.

Prediction of glaucomatous visual field loss by extrapolation of linear trends.

OBJECTIVE To investigate how well short-term progression rates can predict long-term visual field outcomes in patients with glaucoma. METHODS We calculated visual field rates of progression using linear regression analysis of the Visual Field Index (VFI) for 100 consecutive patients with glaucoma having 10 or more Swedish Interactive Thresholding Algorithm standard field tests. Final VFI was predicted on the basis of linear extrapolation of the slope defined by the initial 5 field test results. Final VFI also was estimated using linear regression of all qualifying examination results for each patient. Primary outcome measures were the absolute difference and the correlation between predicted and estimated final VFI values. RESULTS Patient follow-up averaged 8.2 years and 11 field examinations. Median VFI progression rate was -1.1% per year both for the initial 5 test results and also for the complete series. Seventy percent of patients had a predicted final VFI within +/-10% of the estimated final VFI, and the 2 VFI calculations had a correlation coefficient of 0.84. CONCLUSION Linear extrapolation based on 5 initial visual field test results was a reliable predictor of future field loss in most patients. Patients in whom linear regression analysis suggests dangerously rapid rates of visual field progression may be candidates for significant alterations in therapy.