Some researchers, fundamentally thinking that they were acting in the control of accommodation, continued to use atropine for the control of myopia during the early 20th century, which had already begun to be used in myopic patients 4 or 5 decades earlier. Pollock approximately between 1910 and 1915, was the first to use it for long periods of time for the treatment of myopia (for a duration of several months to almost a year). The therapy also required myopic schoolchildren to avoid near work (reading and writing), with the difficulties that this entailed in education . In the following four decades of the 20th century, the pharmacological treatment of myopia was practically abandoned to a large extent, or at least that is what the scarcity of publications on the matter in that period of time suggests [19, 20]. In the 1960s there appeared to be a resurgence of interest in the subject [21–24], but despite the evidence of the effectiveness of atropine treatment, even until the late 20th century this alternative was not popular among ophthalmologists in the Western Hemisphere and it had notable detractors [25–27]. Finally, a compelling body of evidence has emerged over the past 20 years, including very well-designed studies, conducted primarily in Asia, demonstrating the efficacy and safety of the use of topical atropine in the management of myopia in children, which has been proven in various meta-analysis, being in general more effective, however, atropine used at higher concentrations (0.5 or 1.0% daily), but which has the disadvantage of tolerance due to the effects on the pupil and blockage. of accommodation [2, 18, 28–35]. Both the concentration and the frequency of atropine have been modified in several studies in order to minimize the side effects, while trying to preserve the beneficial effects. As early as 1999 it had been suggested that because daily drops between 0.05% and 0.25% atropine were well tolerated, these concentrations could be used initially to control the progression of myopia in certain children . In 2012, the results of the Atropine for the Treatment of Myopia 2 (ATOM 2) study indicated that the efficacy of an atropine at an extremely low concentration (0.01%) applied once daily at night for the control of the progression of the myopia, had minimal side effects and after 2 years of treatment and 1 year of suspension, the most diluted atropine turned out to be the most effective, basically because it had a lower rebound effect, than the higher concentrations . However, as noted by Galvis et al., when in the ATOM 2 study considered children who received 0.1% atropine or 0.01% atropine compared to those who received the highest concentration (0.5% atropine), there were significant differences in progression during the first year of treatment, since a slower progression was observed in the 0.5% atropine group . The ATOM 2 study did not include the direct comparison of a dilute atropine group versus a control group, so Yam et al. designed the LAMP study (Low-concentration Atropine for Myopia Progression) whose initial results were published in 2019. They found that atropine diluted to 0.01% decreased axial length growth by only 12%, compared to the placebo group, and this difference did not reach statistical significance. The authors of the LAMP study suggested that 0.05% atropine was the most effective among the dilutions studied, in controlling the progression of myopia and elongation of axial length during 1 year of treatment, and was maintained as well tolerated . The authors of the LAMP study recently reported the results at 2 years of follow-up. The efficacy of atropine at 0.05% observed with this observation period was double that observed with atropine at 0.01%, and it remained the optimal concentration among the concentrations of diluted atropine studied in the slowing of the progression of the disease. myopia [34–35]. While Yam et al. found all low-concentration atropine (0.05%, 0.025%, and 0.01%) were well tolerated , recently Joachimsen et al. in a small group of Caucasian children found more frequent and severe symptoms than in a previous study by the same authors with 0.01% atropine [37, 38].
A different approach has been not to reduce the concentration of atropine, but its frequency of application, taking into account the long half-life of atropine, and inter-daily, weekly and even, recently, monthly doses have been reported [14, 29, 39]. In 2012, Galvis et al. suggested that applying a 1.0% drop of atropine each week, rather than a daily dose, would facilitate adherence in young patients. In their study, they used atropine together with progressive multifocal glasses with a photochromic filter and also hypotensive eye drops. Treatment tolerance was good and treatment was very effective in stopping the progression of myopia in a preliminary study with a group of 33 patients with one year of follow-up . Hypotensive drugs have been used by some researchers for decades in the control of myopia, with the idea that lowering intraocular pressure decreases a stimulus for the growing of axial length [11–13]. However, the evidence for this effect in humans is very poor, and in fact in a study published in 1991 including 142 children, the results did not favor the use of timolol to control the progression of myopia. After two years, myopia increased by -0.59 D/year in the timolol group, compared with − 0.57 D/year in the control group .
However, in experimental studies in guinea pigs, an ocular hypotensive (latanoprost) was recently found to significantly slow the progression of myopia [15, 16]. Furthermore, brimonidine has also shown an effect in the experimental inhibition of form-deprivation myopia . It is not yet clear what are the mechanisms of action in its anti-myopia effect.
In the patients included in the present study, hypotensive drugs were used either alone (dorzolamide + timolol every 12 hours) or combined with 1% atropine one drop weekly. To perform the analysis of the results, as already explained, the observation periods of at least 6 months for each eye were considered as the CMCV units of analysis. The percentages of CMCV units of analysis classified as “completely controlled myopia” were higher, with a statistically significant difference, in the eyes that during the periods analyzed received 1% atropine one drop per week plus ocular hypotensives every 12 hours, versus the other two groups. analyzed, that is, those eyes that did not receive any pharmacological treatment during the analyzed period (“non-adherent” group) and those that only received dorzolamide + timolol (“hypotensives” group). The hazard ratios reached very important values: when comparing the “atropine” group versus the “non-adherent” group it was 4.00 (95% CI 2.38–7.72) and when comparing it with the “hypotensives” group it was 3.05 (95% CI 2.13–4.39). This can be interpreted as that in a given period, an eye within the “atropine” group was 4 times more likely to have complete control of progression, compared to an eye within the “non-adherent” group, and approximately 3 times more likely than one in the "hypotensives" group. Analyzing the behavior of the CMCV units of analysis in each classification of myopia progression, and considering that there were no significant differences between the three groups (“non-adherent”, “atropine” and “hypotensives”) in the classification of "mild progression" of myopia, but a significant difference did appear in that of "moderate progression", the percentage of this last classification being lower in the group of "atropine", it would seem then that a large percentage of these eyes with "moderate progression" were those that presented minor progressions, eventually increasing the percentage of eyes with “completely controlled myopia”.
On the other hand, the percentages of CMCV units of analysis classified according to the progression of myopia did not reach significant differences between the “non-adherent” and “hypotensives” groups, which does not reinforce that the use of dorzolamide + timolol alone, have any significant effect in controlling the progression of myopia.
A statistically significant difference was also found between the progression rate of the CMCV units of analysis in periods in which the eyes were treated with 1% atropine weekly plus ocular hypotensives (-0.13 ± 0.41 D/year) versus the others two groups (“non-adherent” group = -0.59 ± 0.57 D/year and “hypotensives” group = -0.41 ± 0.54 D/year). This reinforces the possibility that the “atropine” group ultimately had greater control of myopia progression.
The methodology given to the analysis of the cases in the present study, in which the change in the magnitude of myopia in a given eye between two consecutive visits (CMCV) was considered as the unit of analysis, does not allow a direct comparison with the findings of other studies in which continuous follow-up periods of the patients were analyzed. This latter approach was not considered adequate in the present study because almost all the patients (89%) presented a change in medication or periods in which they reported non-adherence to treatment, during the time of follow-up. However, a rough comparison can be made with some of the results reported by other groups.
In the Atropine for the Treatment of Childhood Myopia (ATOM1) study, in the evaluation after one year, the mean progression of myopia in the eyes treated with placebo was − 0.76 ± 0.44 D, while in the group of children who received treatment with 1% atropine every night, there was a reduction in myopia by 0.03 ± 0.50 D . On the other hand, in the ATOM2 study, the average progression after one year of treatment with 0.5% daily atropine was − 0.17 ± 0.47 D . As a comparison in the LAMP study after 1 year of follow-up, the mean progression was − 0.27 ± 0.61 D in children who received atropine diluted 0.05% daily . Taking into account the limitations of the direct comparison, as explained above, in any case the data of the mean progression found in the present study in the eyes that received atropine at 1% weekly plus ocular hypotensives (-0.13 ± 0.41 D/year) would seem to be located between what was achieved with the use of 1% daily atropine in the ATOM1 study and that achieved with 0.5% daily atropine in the ATOM2 study, and it seems to be clearly better than the annual progression in the LAMP study with atropine daily at 0.05%.
Additionally, according to the data and the graph published in the ATOM1 and ATOM2 studies, it can be calculated that approximately 88.3% of the eyes of the children who received 1% atropine every night progressed < 0.50 D in one year. In the present study, 88.8% of the analysis units (that is, the change in the magnitude of myopia in a given eye between two consecutive visits, CMCV) in the eyes that during those periods received atropine 1% weekly + ocular hypotensives, progressed < 0.50 D in one year, a percentage slightly higher than that mentioned in the ATOM1 study, a clinical trial in which a much more frequent dose of 1% atropine was used (one drop every night). On the other hand, when comparing it with the percentages of eyes with progression < 0.50 D in one year using more diluted atropine, in the ATOM2 study, we found that these were much lower: the percentages of eyes that progressed less than 0.5 diopters in the first year were 50%, 58%, and 63% in the 0.01%, 0.1%, and 0.5% atropine groups, respectively .
In the LAMP study after one year of treatment, the percentages of eyes that progressed less than 0.5 D receiving diluted atropine at different concentrations were also lower (69.6%, 51.6% and 43.8% in the groups that received atropine at 0.05%, 0.025% and 0.01 %, respectively) .
In other words, the control of the progression of myopia achieved with the combination of atropine at 1% weekly and the use of ocular hypotensives, seems to be very similar to that achieved with atropine at 1% daily, and superior to that achieved with daily atropine in lower concentrations [18, 30, 33]. This leads us to wonder whether the concomitant use of ocular hypotensives (and specifically dorzolamide + timolol) has a possible synergistic effect on the effect of atropine in the control of myopia.
A weakness of the present study is that the axial length data could not be analyzed, since this measurement was performed only in a small percentage of the control visits. With all the recent evidence, this data has been indicated as very important in the follow-up of myopic patients in treatment [40–42]. Some investigators have suggested that the axial length of an eye can be calculated based on refraction and keratometry data , but such estimates have been shown to be inaccurate . It is therefore essential to carry out the measurement with a biometer, preferably optical, of which there are multiple models available for clinical use today, which have been shown to be quite comparable . Close monitoring of axial length is now included in our current protocol, at least once a year.
In conclusion, in a group of myopic children and adolescents in Colombia, it was found that during the periods of time in which they received 1% atropine, one dose a week, in combination with dorzolamide + timolol, every 12 hours, they presented better control of the progression of myopia, than in the time periods in which they received only ocular hypotensives or were not adherent to pharmacological treatment. Further studies are required to confirm if this beneficial effect is related only to the use of 1% atropine weekly, or if hypotensive substances add some efficacy to the effect of atropine.