Citation: Kim EW, Park HS, Choi W, Lee K, Lee SY, Seong GJ, Kim CY, Bae HW. Progression patterns of normal-tension glaucoma groups classified by hierarchical cluster analysis. Eye (Lond) 2021 Feb; 35(2):536-543.
The authors did a retrospective cohort study to compare the differences in progression patterns in normal-tension glaucoma (NTG) patients classified into three clusters using hierarchical cluster analysis (HCA). The authors concluded that the pattern of progression differed by NTG groups, and that young myopic eyes showed a mixture of two patterns. HCA is an analytical method in which similar characteristics are identified and divided into clusters by an automated computer program. NTG is a multifactorial optic neuropathy with different progression rates for each patient. According to the Collaborative Normal-Tension Glaucoma Study (CNTGS), NTG in half of the untreated patients did not progress for 5–7 years. In this study, peripapillary retinal nerve fiber layer (RNFL) thickness was measured by Cirrus HD_optical coherence tomography (OCT) and progression rate was calculated by trend analysis (Guided Progression Analysis [GPA]). The visual field (VF) progression rate was evaluated by linear regression analysis of mean deviation (MD). Cluster 1 had small cupping with thick RNFL suggestive of early glaucoma patients. Cluster 2 exhibited moderate glaucoma findings. Cluster 3 had young, myopic patients. One-way analysis of variance (ANOVA) was used to analyze differences between clusters, and Bonferroni post-hoc test was performed to assess statistical significance between clusters. The progressive rate distribution of each cluster was represented by a histogram.
Cluster 1 exhibited the fastest progression rate on OCT, with a decrease in average RNFL thickness of −0.83 ± 0.89 μm/year. The progression rates for cluster 2 and 3 were −0.45 ± 0.76 μm/year and − 0.36 ± 0.79 μm/year, respectively (P < 0.011). There were no significant differences in the baseline intraocular pressure (IOP) among groups. The mean IOP and fluctuations during the follow-up period were not significantly different among clusters. The mean number of IOP lowering agents was significantly less in cluster 1.
Regarding the average RNFL thickness progression rate for each cluster, cluster 1 progressed the fastest and was skewed toward the negative progression rate section. Cluster 2 exhibited a normal distribution with many patients falling in the range of 0 to −1.0 μm. Cluster 3 displayed a double-peak distribution. Patients in cluster 3 were divided into two groups and their characteristics were compared.
Cluster 1 had the fastest visual field progression rate (−0.16 ± 0.61 dB/year), but clinically, there was no significant progression difference among the three clusters in VF tests. This is probably because most patients enrolled in this study were at an early to moderate stage, and because the structural abnormalities are typically detected in OCT before VF defects occur. Also, these patients were managed effectively with IOP lowering drugs.
IOP was decreased approximately 20% from baseline. Less number of medications were used in cluster 1, in contrast, patients were administered more topical drugs in cluster 2. This may explain why cluster 2 progressed less than cluster 1. There was no significant difference in progression rates between clusters 2 and 3 and it was further analyzed by a histogram. The distribution of progression in cluster 3 showed a double-peak pattern, unlike other clusters, suggesting that one group showed rapid progression like cluster 1, and the other group hardly progressed. Glaucomatous damage progressed in both the superior and inferior RNFL of those in the fast progression group.
There are widespread disputes regarding glaucoma progression in myopic patients. One opinion is that it progresses regardless of the degree of myopia or that it progresses less than other types of glaucoma without myopia. However, in this study, the progression of myopic glaucoma did not exhibit a single phenomenon, suggesting the presence of at least two patterns with different characteristics: “progress” and “non-progress.” In the progress group, myopia may have increased glaucoma susceptibility. Kim et al. reported that eyes with a particular posterior sclera structure are at increased risk for glaucoma progression in treated myopic NTG patients. Sohn et al. found out that myopia did not influence the progression rate of NTG after treatment. Limitations of this study include follow-up loss and reduction in sample size. The use of medications was not adjusted in this study.
Bae et al. predicted that inferotemporal RNFL thinning could be a risk factor for progression in NTG patients with myopia. In a study conducted by Han et al., younger age, presence of disc hemorrhage, more temporally tilted disc, and parapapillary atrophy were associated with progression. It also showed that NTG with myopia progressed very slowly even without antiglaucoma drugs. Only 10.3% and 24.8% of patients showed VF progression at 3 years and 5 years of follow-up in untreated NTG with myopia. Higher long-term fluctuation of IOP was associated with faster VF progression rates only in myopic NTG according to Lee et al. Jonas et al. also observed that structural changes of the sclera in myopia increase stress and strain on the lamina cribrosa, thereby increasing glaucoma susceptibility. Patients with NTG and superior field defects had significantly faster progression rates than patients with inferior field defects, and the difference in the progression rates was more observed in the central and nasal zones.
The complex etiology of NTG is not yet completely understood. In fact, early NTG is missed and not assessed appropriately since there is no severe damage, but early glaucoma with a low cup-to-disc ratio can progress faster. Therefore, those patients should be vigorously treated with proper follow-ups. In the young myopic eyes, two types of progression patterns were noted and, in such patients, only the progressive cases should be actively identified and treated. Although practically, control of IOP remains the mainstay of treating NTG patients, we should also evaluate other risk factors, especially those that may influence perfusion of the optic nerve head.
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