We read with interest the article by Etminan and associates exploring possible links between topiramate (TPM) and glaucoma. In a part of our recent review article about effects of TPM on vision, we collected available data from 49 TPM-induced angle-closure glaucoma (TiACG) cases from published observational reports. In this regard, we would like to comment on the findings of the authors.

Along with all the strengths of this study, for example, novelty, large sample size, and rigorous case-control design, some unevaluated aspects are noteworthy. Yet, first and foremost, we bring an example. Six years ago, Rhee and associates introduced a very interesting female patient who consumed TPM 25 mg/day for approximately 60 days without any complications. Then, advised by her physician, she increased the dose from 25 mg every day to twice daily. After taking the third dose, she developed TiACG. According to the results of our literature review, in at least 5 other patients with safe frequent use of TPM, TiACG developed only after taking the doubled dose. Moreover, in another retrospective case series, 5 patients were identified with a similar condition. Given the design of Etminan and associates’ study, such cases, regardless of dose alterations, are classified as prevalent current users, whereas in our opinion, these cases are exposed to higher risks than ordinary consumers with a constant dose. In the Methods, the authors stated that “the prescription drug database captures information on drug dose, day supply, and quantity.” However, in the Results, there is no mention of dose-related analyses. We believe that the increase in TPM dose should have been considered in the classification of the study groups. As far as we understand from the article, the authors classified the current users into 2 categories: (1) first-time users who were shown to be at the highest risk of glaucoma (rate ratio, 1.54); and, (2) prevalent-current users who were at a significantly increased risk (rate ratio, 1.19). It would have been interesting if further subanalyses were performed to divide the prevalent-current users into 2 groups: with and without increasing dose. If so, one would expect an excessive risk among those with increased drug dose similar to that of the first-time users.

In their literature review, the authors cited a study by Fraunfelder and associates. They identified “a report describing 83 cases of acute-onset glaucoma associated with topiramate.” Indeed, in the above-mentioned study that included 86 cases, some outstanding points should be addressed: the onset of TiACG was reported to be acute, with a mean of 7 days from the therapy and 85% of cases occurred in the first 2 weeks of the treatment. Similarly, in our own review, the median and mean ± standard deviation of the duration from therapy to the onset of TiACG was calculated as 10 days and 12.38 ± 10.80 days, respectively. Furthermore, in 83% of the cases, symptoms occurred within the first 2 weeks. Surprisingly, the authors reported, “The median onset from the start of a topiramate prescription to the diagnosis of glaucoma was 28 days,” which is not consistent with previous case-based evidence. Also, it is unclear whether 28 days is for the entire group or a subgroup of patients, for example, first-time users. We wonder whether the authors could explain it to the readership.