glaucomas. Except in very limited circumstances, it would be unethical to design a prospective study of untreated glaucomatous eyes. The Collaborative Normal Tension Glaucoma Study (CNTGS) and the Early Manifest Glaucoma Treatment Trial (EMGT) are both clinical trials that included an untreated cohort [4–6]. Although clinical trials are not optimal for studying the natural history of a chronic disease, information derived from EMGT and CNTGS supplement the information derived from the observational studies noted above (Olmsted County and St. Lucia) to provide a better­ understanding­ of the natural history of treated and untreated OAG.

The situation with ocular hypertension differs from that of OAG in that it is not considered a disease, but rather a risk factor for the disease. Additionally, because numerous studies to assess the benefit of treating ocular hypertension had yielded inclusive results, there existed no ethical barriers to designing a long-term clin­ ical trial of untreated vs. treated patients with elevated intraocular pressure (IOP). With the completion of the Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS), the natural history of untreated vs. treated ocular hypertension is now well established [7–9].

We will summarize the design and findings of these studies and explain how each contributes to our knowledge of the natural history of OAG and of ocular hypertension.

29.2  What Is the Natural History of Treated and Untreated Glaucoma?

29.2.1  Olmsted County, MN

In a retrospective community based incidence study, the Rochester Epidemiology Project database was used to access information on the 60,666 residents of Olmsted County, MN [1]. During the 16-year study interval, 114 patients were newly diagnosed with OAG. Eighty-nine percent (102/114) of patients with OAG had POAG. Annual incidence was noted to increase with age, ranging from 1.6/100,000 in the fourth decade of life to 94.3/100,000 in the eighth decade. While incidence rates peaked during the eighth decade, there was a notable decrease in incidence rates in the ninth and tenth decade of life. This downturn was attributed to either

the small number of patients in this age group or alternatively to the tendency of physicians not to treat existing POAG in these upper decades of life.

The overall gender and age-adjusted annual incidence rate was about 14.5 per 100,000, and gender was not noted to have a significant effect on incidence. Also of interest was the change in annual incidence rate of OAG in the last 2 years of the study (27.2 per 100,000) compared to earlier in the study (12.3 per 100,000). The authors suggested that this difference was due to the introduction of timolol in October of 1978. The existence of a relatively well tolerated and effective therapy may have made physicians more likely to diagnose OAG. Alternatively,­ the presence of a new therapy may have exposed physicians to new education about OAG and made them more likely to diagnose the disease.

In a 1998 report examining the Olmsted County retrospective data set, the probability of unilateral blindness was reported to be 27% and bilateral blindness was 9% after 20 years in the 295 patients classified as having classic glaucoma and ocular hypertension [10]. Blindness­ was defined as visual field constriction to within 20° of fixation or visual acuity of 20/200 or worse. In the “classic” glaucoma sub-group analysis, there was a 22% probability of bilateral blindness and 54% probability of unilateral blindness at 20 years. (Classic glaucoma was defined as meeting two of three of the following: IOP ³21 mmHg, optic nerve ­damage, and/or visual field defects. Of note, 89% of patients had IOP ³ 21 mmHg.) In the treated ocular hypertension group, cumulative probability for bilateral­ and unilateral blindness was 4 and 14%, respectively. It must be noted that during most of the time of this retrospective review, timolol and laser trabeculoplasty were not available treatment options.

The Olmsted County retrospective review clearly documented­ that the incidence of glaucoma increased with advancing age. The study is limited by its retrospective design, which did not allow for standardized treatments and data collection. Also, attempting to use data from this study to better understand the natural history of treated POAG today is ­limited due to the use of an entirely different group of medications. Beta blockers were not available for most of the study period, and selective alpha-agonists and prostaglandin analogs were years away from the marketplace. It could be argued that in comparison to currently available medications, these patients were sub-optimally

treated and may be more aptly classified as not treated. Another limitation of the data is that the population was almost exclusively Caucasian (98%) with considerable Scandinavian­ ancestry. The information obtained, while instructive, cannot probably be generalized to other racial/ethnic groups.

(30%), the percentage of black AGIS subjects with visual field progression at 10 years would be approximately 43% (assuming that the percentage increases linearly). In the St. Lucia follow-up study, a considerably larger percentage of untreated eyes progressed – 53%. Keep in mind that the AGIS and St. Lucia patients may not be equal in terms of baseline visual field loss.

29.2.2  St. Lucia Study

The initial St. Lucia Eye Study was conducted in 1986/1987 and documented the prevalence of POAG on the Caribbean island country [2]. This population-based survey included 1,679 subjects; 364 glaucoma subjects and glaucoma suspects were identified. Ten years later, a repeat examination was executed of the cohort of glaucoma subjects and glaucoma suspects who were still living and residing in St. Lucia, who had not undergone glaucoma surgery, and who were not being medically treated (n = 205) [3].

Humphrey 30-2 threshold visual fields were obtained at both the initial 1987 survey and the 1997 follow-up examination. Both sets of visual fields were converted to a format suitable for grading by criteria established and used by the Advanced Glaucoma Intervention Study (AGIS) and the Collaborative Initial Glaucoma Treatment Study (CIGTS). Studies comparing these two grading algorithms have found the AGIS algorithm to yield more conservative results than the CIGTS algorithm.

Using the AGIS criteria, 80 of 146 right eyes and 73 of 141 left eyes had progressed. Of the eyes that had progressed, 24 of the 80 right eyes (30%) and 21 of the 73 left eyes (29%) had progressed to end-stage glaucoma. Overall, the probability of reaching an “end-stage” visual field endpoint in at least one eye was 16% at 10 years.

The study population was exclusively black, and thus, generalizations from this study are limited. The best comparison of visual field progression in treated vs. untreated glaucomatous eyes is made by comparing the results of this study with a study that used the same definition of progression. Although the comparison is not ideal, the AGIS had subjects with varying levels of glaucoma severity, all the subjects were treated, the same visual field scoring algorithm was used, and the data allows comparison with black subjects only. Extrapolating from the percentage of black subjects with visual field loss progression at 7 years in AGIS

29.2.3  Collaborative Normal Tension

Glaucoma Study

The CNTGS was designed to measure the efficacy of a 30% IOP reduction on the rate of glaucoma progression in patients with pressures considered to be in the normal range (i.e., low or normal tension glaucoma) [4]. Eligible eyes had to manifest glaucomatous optic nerve excavation and a field defect consisting of a cluster of three non-edge points depressed by 5 dB, with one of the points also depressed by 10 dB (two of three baseline tests over 4 weeks had to agree). Progression was suspected if: (1) at least two contiguous points within or adjacent to a baseline defect showed a reduction in sensitivity from baseline of ³10 dB or if the reduction noted was three times the average baseline short-term fluctuation for that subject, (2) the sensitivity of each suspected point was outside the range of values observed during baseline testing, or (3) a defect occurred in a previously normal part of the field. Classification of a patient as “progressing” required agreement on four tests.

One hundred and forty eyes of 140 patients were used in this study (61 treatment and 79 control). Twentyeight (35%) of the control eyes and seven (12%) of the treated eyes reached either visual field or optic nerve end-points for progression. The mean time to progression was 2,688 ± 123 and 1,695 ± 143 days for the treated and control groups respectively (p < 0.0001). The authors concluded that IOP is part of the pathogenic process in normal-tension glaucoma. A follow-up report in 2001 focused specifically on 160 CNTGS patients who were untreated among a total enrollment of 260 [11]. Of these 160 patients, 49 were randomly assigned on enrollment to not receive therapy, 24 were followed without treatment until later being randomly assigned to treatment (due to progression by visual field testing or optic nerve examination), 31 were followed without treatment and were later randomly assigned to be followed for additional time without treatment, and