Evaluation of the role of timolol 0.1% gel in myopic regression after laser in situ keratomileusis☆
Article Outline
- Abstract
- 1. Introduction
- 2. Subjects and methods
- 3. Follow-up
- 4. Results
- 5. Discussion
- Conflict of Interest
- Declarations
- Acknowledgement
- References
- Copyright
Abstract
Purpose
To evaluate the efficacy of the concomitant administration of antiglaucoma medications namely timolol 0.1% gel in cases with myopic regression after myopic laser in situ keratomileusis (LASIK).
Design
Prospective observational clinical trial.
Subjects and methods
Ninty five eyes of 75 patients were included in this study prospectively. The mean myopic regression was −1.29
±0.83 diopters (range −0.5 to −4.62) after myopic LASIK. The eyes were divided into two groups: 50 eyes administrated timolol 0.1% gel once daily for 12months (treated group), and 45 eyes were age matched (control group). We assessed the amounts of myopic regression in terms of changes in the refraction (spherical equivalent and astigmatism), intraocular pressure (IOP), pachymetry and the refractive power of the cornea measurements for all participants.
Results
The refractive error and visual acuity were similar between the two groups at baseline. The treated group had an improvement in spherical equivalent significantly from −1.29±0.83 to −0.94±1.07 diopters (P=0.012). Astigmatism was changed from −0.94±0.53 to −0.86±0.60 diopters but this change was not statistically significant (P=0.20). The IOP was decreased significantly from 12.6±1.9 to 9.0±1.1mmHg (P<0.001). Central corneal thickness was changed from 425.6±19.86 to 429±18.1μm but not statistically significant (P=0.56). The central corneal power decreased significantly from 37.2±1.8 to 36.4±1.3 diopters (P<0.05).
Conclusion
Timolol 0.1% gel was effective for reduction and improvement of myopic regression especially the spherical errors after myopic LASIK.
Keywords: Timolol 0.1% gel, Myopic regression, Myopic LASIK
1. Introduction
Excimer laser surgery is widely accepted as a predictable and effective refractive surgical procedure for the correction of myopia. However, myopic regression of the initial surgical effect can affect the predictability, efficiency, and long-term stability of refractive surgery, leading to deterioration in visual performance. It is widely known that some regression does occur not only after photorefractive keratectomy (PRK) but also after laser in situ keratomileusis (LASIK) (Lohmann and Guell, 1998, Magallanes et al., 2001).
Nevertheless, the mechanism for myopic regression is complicated and is not fully understood. Some authors found that there was a significant correlation between forward shift of the cornea and the amount of myopic regression in a study of 65 eyes undergoing PRK, indicating that forward shift of the cornea can be one of the factors responsible for regression after excimer laser surgery (Miyata et al., 2002, Kamiya and Oshika, 2003). In addition, there had been case reports of transient keratectasia associated with marked elevation of intraocular pressure (IOP), suggesting that increases in the internal pressure may have expanded and distended the cornea, leading to anterior protrusion (Toshino et al., 2005, Hiatt et al., 2005).
In the last few years, it has also been reported that the pre-operative IOP was significantly higher in regressive eyes than in non-regressive eyes, whereas there was no significant difference of central corneal thickness between regressive and non-regressive eyes after LASIK (Qi et al., 2006). These results indicated that lowering the IOP may be an effective treatment for refractive regression after keratorefractive surgery.
Timolol 0.1% eye gel (Nyolol gel, Novartis Ophthalmic, Switzerland) is a non-selective B-blocker with carbomer and polyvinyl alcohol. It provides ocular comfort and lubrication also increased retinal and optic nerve perfusion. Its muco-adhesive hydrogel leads to longer precorneal retention time hence its use once daily. It reduces IOP by decreasing aqueous humor production. The purpose of the current study was to investigate the efficacy of timolol 0.1% gel on the correction of myopic regression after myopic LASIK.
2. Subjects and methods
This prospective study was conducted on 95 eyes of 75 patients (40 male and 35 female). The mean age of included patients was 29.16±4.7years (range 19–40years) with myopic regression of −1.29±0.83 (range −0.5 to −4.62 diopters) after myopic LASIK. Twenty patients had bilateral and 55 had unilateral LASIK. Informed consents were obtained from all patients after explaining the nature and possible outcomes of the study. The study protocol was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki.
The eyes were divided into two groups: 50 eyes administrated timolol 0.1% gel once daily for 12months (treated group), and 45 eyes were age matched (control group).
Inclusion criteria for LASIK were: age of patients 19years or more, patients not wearing contact lens 4weeks before the surgery, normal peripheral retina, no glaucoma, and stable refractive error at least 12months before surgery. Exclusion criteria were: eyes with central islands, active inflammation, Schirmer test less than 5.0mm, presence of corneal pathology (evidence of keratoconus or keratoconus suspect as evidenced by corneal topography), calculated post-operative corneal residual stromal bed thickness less than 250μm, and history of ocular trauma.
LASIK was performed with the Schwind Esiris excimer laser system using an average fluency of 650mJ/cm2 with a repetition rate of 200Hz and pulse duration of 8ns. Moria M2 single use Microkeratome (Moria, Georgres Besse, Antony, France) was used for creating a hinged corneal flap of 120μm in thickness. In all eyes, the pre-operative manifest spherical equivalent refraction was selected as the target myopic correction.
All patients involved in the study subjected to the following ophthalmic examinations: uncorrected distant visual acuity (UDVA), corrected distant visual acuity (CDVA), IOP measurement with a handheld applanation tonometer (Perkins, Edinbrugh, Scotland), Schirmer test, central corneal pachymetry (Nidek Up-1000, Japan), and corneal topography (Optikon Keratron, Scout, Germany). The refractive power of the total cornea was averaged within a central zone of 3mm diameter. All the measurements were performed at the same time of day to decrease the effect of the diurnal curve.
Patient satisfaction and optical symptoms surveys were obtained to document glare, halos, double vision, ghosting, and disturbance of night vision. These surveys were recorded at each follow-up visits. The patients’ comments divided into three categories: satisfied, moderate satisfied, and dissatisfied. Dissatisfied patients were those who reported comments of no improvement, blurring of vision, and or reporting optical symptoms.
3. Follow-up
Treated and control patients were examined at the pre-operative and pos-operative visits (first day, first week, first month, 3months, 6months, and 12months), patients were reviewed with assessment of uncorrected and corrected distant visual acuity, intraocular pressure measurement, Schirmer test, corneal topography, and corneal pachymetry.
3.1. Statistical analysis
Statistical analysis was performed using SPSS version 15. Values were presented as mean±standard deviation (SD). The student t-test and one way analysis of variance were used to evaluate the significance of difference. The Wilcoxon single-rank test was used to compare the pre-treatment and post-treatment. P-value less than 0.05 was considered to be statistically significant.
4. Results
All 95 eyes were followed for 12months. Table 1 summarizes the demographic and clinical profiles of the patients. Average age of patients was 29.16±4.7years (range 19–40years). The mean spherical equivalent (SE) before LASIK was −12.52±3.37 diopters, the mean astigmatism before LASIK was −2.11±1.5 diopters, and the mean corneal thickness before LASIK was 551.48±20.1 diopters.
Table 1. Demographic data and clinical parameters of the studied patients.
| No. of patients | 75 |
| No. of eyes | 95 |
| Male/female ratio | 40/35 |
| Mean age (years) | 29.16±4.7 |
| Mean pre-LASIK spherical equivalent (diopters) | −12.52±3.37 |
| Pre-LASIK astigmatism (diopters) | −2.11±1.15 |
| Pre-LASIK corneal thickness (μm) | 551.48±20.1 |
Table 2 shows the visual and refractive outcomes in the treated and control groups. The mean UDVA was improved significantly from 0.31±0.11 before treatment to 0.44±0.21 after treatment (P<0.001) (Fig. 1). Mean CDVA did not change significantly from 0.65±0.11 before treatment to 0.66±0.08 after treatment (P=0.39) (Fig. 2).
Table 2. Visual and refractive outcomes in the studied eyes.
| Outcomes | Group | Baseline | 12Months |
|---|---|---|---|
| Mean uncorrected distant V.A.±SD (decimal scale) | Treated group | 0.31±0.11 | 0.44±0.2 |
| Control group | 0.63±0.09 | 0.42±0.8 | |
| Mean corrected distant V.A.±SD (decimal scale) | Treated group | 0.65±0.11 | 0.66±0.08 |
| Control group | 0.63±0.09 | 0.65±0.07 | |
| Mean spherical equivalent±SD (D) | Treated group | −1.29±0.83 | −0.94±1.07 |
| Control group | −1.23±0.91 | 1.87±0.35 | |
| Mean astigmatism±SD (D) | Treated group | −0.94±0.53 | −0.86±0.60 |
| Control group | −0.86±0.66 | −0.85±0.74 | |
| Mean intraocular pressure±SD (mmHg) | Treated group | 12.6±1.9 | 9.0±1.1 |
| Control group | 13.2±1.8 | 12.6±1.7 | |
| Mean corneal thickness±SD (μm) | Treated group | 425.6±19.8 | 429.6±18.1 |
| Control group | 435.2±17.6 | 432.3±22.2 | |
| Mean corneal diopters±SD (D) | Treated group | 37.2±2.0 | 36.4±1.4 |
| Control group | 36.9±1.6 | 35.1±1.8 |
Figure 1.
UDVA before and 12
months after treatment.
Figure 2.
CDVA before and 12
months after treatment.
The mean spherical equivalent improved significantly from −1.29±0.83 to −0.94±1.07 diopters 12months after treatment (P=0.012) (Fig. 3). Forty five (47.3%) and 25 (26.3%) of 95 eyes showed improved of more than 0.5 and 0.25 diopters, respectively.
Figure 3.
Spherical equivalent before and 12
months after treatment.
However, the mean astigmatism was changed from −0.94±0.53 to −0.86±0.60 diopters but the difference was not significant (P=0.204) (Fig. 4). The mean IOP decreased significantly from 12.6±1.9 to 9.0±1.1mmHg (P<0.001) (Fig. 5). Mean corneal thickness did not change significantly from 425.6±19.8 to 429.6±18.1μm (P=0.73) (Fig. 6).
Figure 4.
Astigmatism before and 12
months after treatment.
Figure 5.
IOP before and 12
months after treatment.
Figure 6.
Corneal thickness before and 12
months after treatment.
The mean refractive corneal power within 3mm central zone in diameter decreased significantly from 37.2±2.0 to 36.4±1.4 diopters after 12months treatment (P<0.001) (Fig. 7). No vision threatening complications were seen throughout follow-up period.
Figure 7.
Corneal power before and 12
months after treatment.
At last follow-up, treated eyes with timolol 0.1% gel for 12months reported 40 (80%) satisfied, 7 (14%) moderate satisfied, and 3 (6%) dissatisfied. While, control eyes reported 30 (67%) satisfied, 10 (22%) moderate satisfied, and 5 (11%). Dissatisfied patients in treated group complained of blurring of vision (two eyes), and night glare (one eye).
Regarding the optical symptoms (glare, halos, double vision, and ghosting), treated eyes with timolol 0.1% gel for 12months reported an improvement from 8 (16%) to 2 (4%) eyes, but no improvement reported in control eyes.
5. Discussion
Although the exact mechanism for refractive regression remains unclear, one of possible explanations for regression is forward shift of the cornea. Steepening in the posterior surface means an increase in the negative power of that surface. In contrast, steepening in the anterior surface means an increase in the positive refractive power. Considering that both surfaces should bulge out equally, the anterior surface exerts far greater absolute refractive changes than does the posterior surface, because the former faces the air and the latter is in contact with the aqueous humor.
Accordingly, the forward shift of both surfaces counteracts the refractive effects of surgery, implying that it can be one of the factors responsible for refractive instability after excimer laser surgery (Miyata et al., 2002). This is important when enhancement ablation is required for myopic regression after surgery. If corneal tissue is subtracted excessively from the residual cornea, structural integrity of the cornea is compromised further, resulting in greater forward shift and further myopic regression (Kamiya and Oshika, 2003).
The once-daily application of timolol 0.1% gel in the morning would be optimal for patient compliance, also have another advantage since this would be expected to be associated with a lower plasma concentration of timolol at night. The lower plasma concentration of timolol after timolol 0.1% gel administration means diminished nocturnal arterial hypotension which in turn can lead to transient ischemia in the optic nerve head, and demonstrated better systemic tolerance and safety with longer treatment period (Rouland et al., 2002).
We demonstrated topical application of the timolol 0.1% gel drug was effective in reducing the refractive regression, especially of the spherical errors after LASIK. We also demonstrated that eyes that gained the improvement of manifest retraction of more than 0.25 and 0.5 diopters were 25 (26.3%) and 45 (47.3%) of 95 eyes, respectively. However, in 20 (21%) of 95 eyes, timolol 0.1% gel administration was not effective, although there was some lowering effect of the IOP in all eyes. Timolol 0.1% gel is a hydrogel formulation which slowly liquefies on ocular instillation and improving subjective symptoms of dry eye.
Pan et al. (2004) demonstrated that regressive eyes and non-regressive eyes exhibited similar time courses in central corneal pachymetry, whereas they differed in the corneal shifting movements after LASIK. These findings suggested that myopic regression may be caused mainly by corneal protrusion rather than by central corneal thickness, which is in good agreement with the Gullatrand principle that changes in corneal thickness play a subtle role in the total refraction of the eye. We found that there were non-significant changes in corneal thickness before and after treatment, indicating that corneal hydration may not play an important role in the refractive changes in these eyes.
Baek et al. (2001) reported in a study of 196 eyes undergoing LASIK that the higher IOP, the more it predisposes the cornea to an anterior shift. Toshino et al. (2005) presented a case of transient keratectasia in relation to marked elevation of 1OP after LASIK. In addition, Hiatt et al. (2005) described a similar case of corneal ectasia that was reversed with 1OP reduction. These previous findings indicate that a higher 1OP may be one of the main causative factors for structurally compromised corneas after LASIK. Hence, we assumed that it may be highly effective for regression mainly caused by corneal geometrical changes.
Many cases of myopic regression may be caused unexpectedly by forward movement of the cornea, other factors such as epithelial hyperplasia, development of new stromal collagen, and nuclear sclerosis of the lens may play a significant role in myopic regression (Lohmann et al., 1999, Moller-Pedersen et al., 2000).
We found that 1OP after 12months of treatment with timolol 0.1% gel was significantly lower than the IOP before treatment, as its ocular hypotensive efficacy was approximately 7mmHg or a 26% reduction from a baseline. The mean refractive power of the total cornea also decreased significantly after treatment. These results indicate that IOP reduction may have induced a backward shift of the cornea and reduction of corneal refractive power, resulting in refractive improvement in post-LASIK eyes. It may be that the morphologic properties of the cornea are affected easily by subtle changes in IOP and atmospheric pressure when corneal rigidity is impaired by flap manipulation and laser ablation such as LASIK.
From a biomechanical point of view, Hiatt et al. (2005) continued to use topical application of lOP-lowering eye drops for 7months when the cornea was believed to have stabilized, but the recurrence occurred on topography at 10months after treatment, indicating that biomechanical remodeling of the cornea had not been completed even 10months after application. However, Toshino et al. (2005) reported that corneal ectasia did not recur on topography after the normalization of IOP during a 12-month follow-up. Because it is unclear when the biomechanical properties of the cornea have stabilized, it is also unknown how long this treatment needs to be continued. If the refractive effects depend simply on the degree of IOP reduction, the patients may be required to use the antiglaucoma drugs continuously. Long-term results after cessation of the medication would help to strengthen the case for the use of antiglaucoma medication in these patients.
Until now, enhancement ablation has been the sole treatment for the correction of residual refractive error after excimer laser surgery. The current approach is unique in simply taking lOP-lowering eye drops, and thus it is clinically applicable to regressive eyes after refractive surgery. Moreover, it has advantages over enhancement ablation because it seems to be less invasive and to cause fewer side effects (e.g., keratectasia) in light of the biomechanical stability of the cornea. Although the refractive effect of this treatment is mild (approximately 0.5 diopters), we first could attempt this new treatment before considering enhancement surgery, especially when the amount of myopic regression is not very large.
In conclusion, we demonstrated that topical application of the lOP lowering drug is effective for the correction of the refractive regression that presumably results from the backward movement of the cornea and the flattening of its curvature after LASIK. This new approach to regression may be capable of improving refractive outcomes after keratorefractive surgery.
Conflict of Interest
None declared.
Declarations
No financial or proprietary interest in any aspect of this study.
Acknowledgement
The authors thank Taha Baker for his care and diligence during writing the paper.
References
- . Factors affecting the forward shift of posterior corneal surface after laser in situ keratomileuses. Ophthalmology. 2001;108:317–320
- . Reversal of laser in situ keratomileusis-induced ectasia with intraocular pressure reduction. J Cataract Refract Surg. 2005;31:1652–1655
- . Corneal forward shift alter excimer laser keratorefractive surgery. Semin Ophthalmol. 2003;18:17–22
- . Regression after LASIK for the treatment of myopia: the role of the corneal epithelium. Semin Ophthalmol. 1998;13:79–82
- . Regression and epithelial hyperplasia after myopic photorefractive keratectomy in a human cornea. J Cataract Refract Surg. 1999;25:712–715
- Stability after laser in situ keratomileusis in moderately and extremely myopic eyes. J Cataract Refract Surg. 2001;27:1007–1012
- Time course of changes in corneal forward shift after excimer laser photorefractive keratectomy. Arch Ophthalmol. 2002;120:896–900
- . Stromnal wound healing explains refractive instability and haze development after photorefractive keratectomy: a one year confocal microscopic study. Ophthalmology. 2000;107:1235–1245
- Differences between regressive eyes and non-regressive eyes after LASIK for myopia in the time course of corneal changes assessed with the Orbscan. Ophthalmologica. 2004;218:96–101
- . Regression-related factors before and after laser in situ keratomileusis. Ophthalmologica. 2006;220:272–276
- Timolol 0.1% gel (Nyolol gel 0.1%) once daily versus conventional timolol 0.5% solution twice daily: A comparison of efficacy and safety. Ophthalmologica. 2002;216:449–454
- . Transient keratectasia caused by intraocular pressure elevation after laser in situ keratomileusis. J Cataract Refract Surg. 2005;31:202–204
☆ The study was performed with informed consent and followed the guidelines required by the Institutional Review Board or Ethics Committee of the Institution.
PII: S1319-4534(10)00044-5
doi:10.1016/j.sjopt.2010.03.001
© 2010 Published by Elsevier Inc.
