Effects of Antiglaucoma Drugs on Refractive Outcomes in Eyes with Myopic Regression after Laser In Situ Keratomileusis

1. Effects of Antiglaucoma Drugs on Refractive Outcomes in Eyes with Myopic Regression after Laser In Situ Keratomileusis Kazutaka Kamiya, MD, PhD1), Daisuke Aizawa1), Akihito Igarashi2), Mari Komatsu2), and Kimiya Shimizu1) Department of Ophthalmology, Kitasato University, JAPAN1) Department of Ophthalmology, Sanno Hospital, JAPAN2)

2. Purpose • Forward shift of the cornea can be one of the factors responsible for regression after excimer laser surgery.1,2) • There have been case reports of transient keratectasia associated with marked elevation of IOP.3,4) • The preoperative IOP was significantly higher in regressive eyes than in non-regressive eyes after LASIK.5) • These results indicated that lowering the IOP might be an effective treatment for myopic regression after keratorefractive surgery. • The purpose of the study is prospectively to investigate the effects of the antiglaucoma drugs on the correction of regression in relation to corneal geometry and refractive power after LASIK.

3. Patients • 27 eyes of 17 patients (male, 7; female, 20 eyes) with regression (changes from the first postoperative month) -1.26 ± 0.48 (SD) D(-0.50 to -2.25 D) after LASIK (VISX STAR S2) • Age; 37.3 ± 9.6 years (23 to 57 years) • Preoperative manifest refraction; -6.31 ± 2.51 D (-3.0 to -11.0 D) • Topical administration of antiglaucoma drugs (2.5% nipradilol, Kowa, Japan) was consecutively applied twice a day. • Postoperative periods; 9.4 ± 2.8 months (6 to 13 months) • Informed consent was obtained from all patients. The study adhered to the tenets of the Declaration of Helsinki.

4. Methods • Before and 3 months after application • log MAR UCVA, log MAR BSCVA • manifest and cycloplegic refraction • IOP with a Goldmann applanation tonometer • central corneal pachymetry (DGH-500, DGH Tech) • corneal geometry6) measured with scanning-slit corneal topography (Orbscan, Bausch & Lomb) • total corneal refractive power within a central zone 3 mm in diameter measured with scanning-slit corneal topography

5. Results • Log MAR UCVA was significantly improved (p<0.001, Fig 1). • Log MAR BSCVA was not significantly changed (p=0.22, Fig 2). • Manifest and cycloplegic refraction was significantly improved (p<0.001, Fig 3). • Twenty-three (85%), 16 (59%) of 27 eyes showed refraction improvement of over 0.25 and 0.5D, respectively. • Manifest and cycloplegic astigmatism was not significantly changed (p=0.23, p=0.15, Fig 4). • IOP was significantly decreased from 11.4 ± 2.4 to 9.4 ± 1.3 mmHg (p<0.001). CCT was not significantly changed from 505.2 ± 39.3 to 503.6 ± 38.7 μm (p=0.61). • The posterior surface was shifted posteriorly by 9.1 ± 8.2 μm. • Refractive power of the total cornea within a 3-mm zone was significantly decreased from 38.4 ± 2.0 to 37.7 ± 2.0 D (p<0.001). • No serious complications occurred throughout follow-up periods.

6. Fig 2. Log MAR BSCVA Fig 1. Log MAR UCVA N.S. 0.25 -0.17 -0.18 *** -0.02 -0.26 *** Fig 3. Spherical Equivalent Fig 4. Astigmatism *** -0.44 -0.87 -0.43 N.S. -0.48 N.S. -1.02 -0.49 -0.55

7. Discussion • Topical application of the IOP-lowering drug was effective in reducing the refractive regression, especially of the spherical errors after LASIK. • Until now, enhancement ablation has been the sole treatment for the correction of residual refractive error after excimer surgery. • The current approach is unique in simply taking IOP-lowering eye drops, and thus it is clinically applicable to regressive eyes after refractive surgery. • Moreover, it has advantages over enhancement ablation because it appeared to be less invasive and to cause fewer side effects (e.g., keratectasia). • We could first attempt this new treatment before considering enhancement surgery, especially when the amount of myopic regression is not very large (approximately 0.5 D).

8. Nipradilol • Nipradilol, a nonselective alpha-1 beta adrenergic antagonist, is widely used in Japan as a safe and useful long-term antihypertensive drug which lowers IOP by decreasing the aqueous flow rate, and by increasing uveoscleral outflow.7,8) • If the refractive effects depend on the degree of IOP reduction, stronger IOP-lowering drugs such as prostaglandin derivatives may be more effective for the reduction of regression. • Nipradilol has been reported to inhibit corneal epithelial migration and proliferation.9,10) However, it did not induce a significant change in CCT and pupil diameter. • Although we cannot refute the possibility that the long-term use of nipradilol may affect corneal epithelium or tear film function, it was seen that nipradilol did not induce in the ocular surface a significant change capable of influencing refraction.

9. Mechanism • 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 morphological properties of the cornea are easily affected by subtle changes in IOP and atmospheric pressure when corneal rigidity is impaired by flap manipulation and laser ablation. • In our preliminarily data, refraction improvement was more prominent in eyes with thinner preoperative CCT or high myopic eyes requiring greater correction, suggesting that this treatment may be effective especially for biomechanically weakened eyes. • There were non-significant changes in CCT, indicating that corneal hydration might not play an important role in regression in these eyes. • Epithelial hyperplasia, development of new stromal collagen, and nuclear sclerosis might play a significant role in regression, but many cases may be unexpectedly caused by corneal geometric changes.

10. Limitation • The limitation of this study is that sample data are comparatively small in amount and follow-up time is short, and that the study is unmasked and has no placebo group. • A double-masked study with a control group receiving placebo might be appropriate for confirming the authenticity of the results. • 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 could be required to use the antiglaucoma drugs continuously. • We are currently conducting a further study to clarify whether this effect is maintained after long-term cessation of the medication.

11. Conclusions • The preliminary data show that antiglaucoma drugs are effective for the reduction of the refractive regression, especially of the spherical errors, after LASIK. • It is suggested that backward movement of the cornea may occur, possibly flattening the corneal curvature by lowering the IOP. • Although we accepted that there were some non-effective cases, this new approach to regression may be capable of improving refractive outcomes after keratorefractive surgery.

12. References • Miyata K, Kamiya K, Takahashi T, et al. Time course of changes in corneal forward shift after excimer laser photorefractive keratectomy. Arch Ophthalmol 2002;120:896-900. • Kamiya K, Oshika T. Corneal forward shift after excimer laser keratorefractive surgery. Semin Ophthalmol 2003;18:17-22. • Toshino A, Uno T, Ohashi Y, et al. Transient keratectasia caused by intraocular pressure elevation after laser in situ keratomileusis. J Cataract Refract Surg 2005;31:202-204. • Hiatt JA, Wachler BS, Grant C. Reversal of laser in situ keratomileusis-induced ectasia with intraocular pressure reduction. J Cataract Refract Surg 2005;31:1652-1655. • Qi H, Hao Y, Xia Y, et al. Regression-related factors before and after laser in situ keratomileusis. Ophthalmologica 2006;220:272-276. • Wang Z, Chen J, Yang B. Posterior corneal surface topographic changes after laser in situ keratomileusis are related to residual corneal bed thickness. Ophthalmology 1999;106:406-410. • Haneda T, Ogawa Y, Akaishi T, et al. Efficacy of long-term treatment with nipradilol, a nitroester-containingbeta-blocker, in patients with mild-to-moderate essential hypertension. Clin Ther 1995;17:667-679. • Kanno M, Araie M, Koibuchi H, et al. Effects of topical nipradilol, a beta blocking agent with alpha blocking and nitroglycerin-like activities, on intraocular pressure and aqueous dynamics in humans. Br J Ophthalmol 2000;84:293-299. • Aoyama Y, Motoki M, Hashimoto M. Effect of various anti-glaucoma eyedrops on human corneal epithelial cells Nippon Ganka Gakkai Zasshi 2004;108:75-83. • Hirano S, Sagara T, Suzuki K, et al. Inhibitory effects of anti-glaucoma drugs on corneal epithelial migration in a rabbit organ culture system. J Glaucoma 2004;13:196-199.