Pharmacological management of night vision disturbances after refractive surgery

Transcription

1 J CATARACT REFRACT SURG - VOL 31, SEPTEMBER 25 Pharmacological management of night vision disturbances after refractive surgery Results of a randomized clinical trial Alessandro Randazzo, MD, Francesco Nizzola, MD, Luca Rossetti, MD, Nicola Orzalesi, MD, Paolo Vinciguerra, MD PURPOSE: To evaluate the efficacy and safety of diluted aceclidine eyedrops in reducing night vision disturbances after refractive surgery. SETTING: Department of Ophthalmology, Istituto Clinico Humanitas, Rozzano-Milano, Italy. METHODS: This double-masked randomized clinical trial included 3 patients (6 eyes) with chronic night vision disturbance after refractive surgery. Patients were randomly allocated to receive (1) placebo, (2) aceclidine.16%, or (3) aceclidine.32%. Drugs were administered once or twice daily. Anterior segment, haze, uncorrected visual acuity, best corrected visual acuity, intraocular pressure, corneal maps, and scotopic pupil size were determined at baseline and at follow-up examinations (15 and 3 days after inclusion). Halos and double vision 4-step scales were built to determine subjective grading of night vision disturbance, and the root mean square (RMS) was calculated to determine objective changes in night vision disturbance. RESULTS: The effect of diluted aceclidine started about 15 minutes after instillation and lasted for about ours. No difference between the 2 dilutions could be found. Thirty-nine of 4 treated eyes showed a reduction in night vision disturbance. The mean reduction in halos and double vision grading was 1.42 G.5 (SD) and 1.14 G.4, respectively. A mean decrease in pupil size of 2.5 mm was measured. Thirty minutes after the instillation of diluted aceclidine, the topography-derived wavefront error showed a statistically significant reduction in RMS values (total, spherical, astigmatic, coma, and higher order), which was maintained for ours. A transitory conjunctival hyperemia was the only side effect reported. CONCLUSION: Diluted aceclidine seemed to be an effective and safe treatment for night vision disturbance following refractive surgery. J Cataract Refract Surg 25; 31: Q 25 ASCRS and ESCRS Every year, the number of patients having refractive surgery is increasing, and, as of today, only about 1 million surgeries have been performed in Italy. Despite high-quality laser technologies, an important percentage of patients report night vision disturbances after refractive surgery. 1 4 A direct association between pupil size in mesopic conditions and incidence of halos has been postulated. Schallorn et al. 5 showed that in the first postoperative year glare was significantly increased when pupils were mydriatic. Hersh et al. 6 found that after photorefractive keratectomy (PRK), glare worsened in 29.7% of patients while halos did in 5.9%. A metaanalysis of randomized clinical trials of results and complications of refractive surgery by Rossetti and coauthors 7 described a percentage of halos in 15.8% of patients after PRK and in 33% after laser in situ keratomileusis (LASIK). Pop and Payette 8 confirmed these percentages in a retrospective study. In a recent prospective study by Helgesen and coauthors, 9 large pupil size measured preoperatively was found to be correlated with an increased frequency of subjectively experienced post-lasik visual disturbances during scotopic conditions. On the other hand, Lee and coauthors 1 found no association between pupil size and night vision disturbance in post-lasik patients with pupil size up to 7. mm when a 6.5 mm optical zone (OZ) was used. Schallorn et al. 11 confirmed that patients with larger pupils (O6. mm) had more quality of vision problems in the early postoperative period, but no association was observed 6 months after surgery. Q 25 ASCRS and ESCRS Published by Elsevier Inc /5/$-see front matter doi:1.116/j.jcrs

2 Pop and Payette 12 related night vision disturbance to age, size of OZ, degree of spherical correction, and operative spherical equivalent, but not to pupil size. However, in the past few years, a careful surgical planning based on evaluation of OZ, transition zone, and pupil size has become increasingly mandatory. In particular, the preoperative evaluation of pupil diameter is today considered an important variable that can deeply influence the optical aberrations and, as a consequence, the quality of vision. In fact, it has been recently observed by Vinciguerra and coauthors 13 that the root mean square (RMS) total wavefront error generally increases in eyes with greater pupil diameters and this occurs both in healthy patients and after refractive surgery. It has been hypothesized that pharmacological reduction in pupil diameter might improve nocturnal vision after refractive surgery. It is possible to reduce pupil size in 2 ways: (1) by blocking the sympathetic system (with adrenergic agonists), and (2) by stimulating the parasympathetic system (with miotics). McDonald and coauthors 14 used brimonidine tartrate ophthalmic solution.2% (Alphagan), an a 2 adrenergic agonist, to evaluate the effect on pupil size in normal eyes. No relevant study of reduction in nocturnal discomfort after refractive surgery was found for miotics, probably due to the well-known side effects associated with these drugs. Among miotics, pilocarpine, carbachol, and aceclidine are the most widely used in ophthalmology. Their miotic effect is obtained through a direct action on iris sphinter muscle. Due to better tolerability and reduced side effects (less accommodative effects, with a reduction in peripheral retinal tractions), aceclidine was preferred to other miotics; moreover, the important action of aceclidine on pupil size reduction made it our first-choice drug to be tested in this clinical trial. The aim of this pilot study was to evaluate the efficacy and safety of 2 different dilutions of aceclidine in the management of nocturnal halos and double vision after refractive surgery. Accepted for publication February 18, 25. From the Department of Ophthalmology (Randazzo, Vinciguerra), Istituto Clinico Humanita Rozzano, the Oftalmologia e Futuro (Nizzola), Modena, and the University of Milan at San Paolo Hospital (Rossetti, Orzalesi), Milan, Italy. Presented at Refr@ctive On-line, Milan, Italy, September 22, and at the 8th Annual Nidek International Excimer Laser Symposium, Shanghai, China, December 22. No author has a financial or proprietary interest in any material or method mentioned. Patent pending. Reprint requests to Alessandro Randazzo, MD, Via Veneto 9/7, 268 Peschiera Borromeo, Milano, Italy. a.randazzo@ virgilio.it. PATIENTS AND METHODS Thirty patients (6 eyes) were enrolled in this randomized double-masked clinical trial. Inclusion criteria were the following: patients that had uneventful refractive surgery (PRK or LASIK) at least 6 months before study entry for myopia or hyperopia with or without astigmatism; best corrected visual acuity (BCVA) O.7 (Snellen chart); haze grading!1.5; no anterior segment or retinal diseases; no ocular hypertension (untreated intraocular pressure [IOP]!21 mm Hg); patients with stable night vision disturbance for at least 3 months. Patients with decentered ablations were excluded. Patients were recruited and examined at the Department of Ophthalmology of Istituto Clinico Humanitas and at the Oftalmologia e Futuro Clinic. Patients were randomized to 3 treatment groups: placebo (2 eyes); aceclidine.16% (2 eyes); aceclidine.32% (2 eyes). Patients were also randomly allocated to 2 therapeutic schemes: once daily (7 PM) versus twice daily (8 AM and 7 PM). Randomization was obtained through a list of random numbers. The drug was prepared by a nurse (masked to treatment assignment) according to the following scheme: for first dilution, 4 IU of aceclidine 2% were injected into 5 ml of artificial tears (hyaluronic acid.2 g/1 ml; Hyalistil) with a final concentration of.16%; for the second dilution, 8 IU of aceclidine 2% were injected into 5 ml of artificial tears (hyaluronic acid.2 g/1 ml; Hyalistil) with a final concentration of.32%; placebo contained 5 ml of hyaluronic acid (.2 g/1 ml; Hyalistil) alone. Drugs were given to the patients in unmarked bottles. Both the patient and evaluator were masked to treatment assignment. An informed consent was obtained from all patients. The trial lasted 1 month. Enrolled patients had a complete ophthalmic evaluation at each visit (baseline, at 2 weeks, and at 1 month) that included anterior segment examination (with haze grading), uncorrected visual acuity and BCVA (Snellen chart), intraocular pressure (IOP) measurement, corneal topography, and assessment of baseline (untreated) pupil size by means of an infrared pupillometer (CSO) in scotopic and photopic conditions (.4 lux and 5. lux, respectively; Figure 1). The pupil size was measured at time and then at 3 minutes and 1, 2, 3, 4, 5, and ours after drug instillation (Figure 2). Optical aberrations (total aberrations, astigmatism, spherical aberration, coma, and high order) due to the corneal surface were derived from the corneal topography for the different pupil diameters. Data on surgical technique (PRK or LASIK), OZ, and preoperative refractive defect were collected. Halos and double vision were graded using 2 scales ranging from 1 to 4; scales were built with images obtained from a web site and drawn up with Adobe Photoshop software 6. (Figures 3 and 4). Before randomization and at each follow-up visit, patients were asked to choose the scale image that best fit their subjective perception. During the last visit, patients also filled in a questionnaire regarding efficacy and duration of treatment, length of latent period after instillation, changes in visual function, and side effects. The main study outcome was the subjective improvement of night vision quality with a reduction in halos and double vision grading. To evaluate whether subjective improvement was associated with objective improvement of optical aberrations, topography-derived wavefront was calculated for the different pupil size of each subjective assessment. The study sample size was calculated assuming a reduction in night vision disturbance of 5% in treated groups. With an alpha error of.5 and a power of 8%, about 15 patients per study arm were needed. Due to the small sample size of this pilot study, nonparametric J CATARACT REFRACT SURG - VOL 31, SEPTEMBER

3 Photopic Scotopic Baseline 4.17 mm 6.98 mm NO PUPILLOPLEGIA Figure 1. An example of infrared pupil size measurements by CSO pupillometer (photopic and scotopic conditions) at baseline, after 3 minutes, and after ours with diluted aceclidine instillation. 3 min 1.25 mm 3.23 mm NO PUPILLOPLEGIA 3.46 mm 5.9 mm statistical tests (Mann-Whitney, Kruskall-Wallis) were used for comparisons. The Fisher exact test was used for analysis of proportions. All analyses were performed with SPSS software (6. version for Macintosh). RESULTS Thirty patients (6 eyes) were included in the trial: 1 (2 eyes) were randomized to receive the.16% solution, 1 (2 eyes) received the.32% solution, and 1 (2 eyes) were treated with placebo. Patient demographics and main characteristics are reported in Table 1. As presented in Figure 1, the drug was effective in reducing pupil diameter starting 3 minutes after instillation, but without inducing pupilloplegia or considerable miosis. As presented in Figure 2, pupil size showed a mean reduction of about 2.5 mm G 1.8 (SD) within the first 3 minutes; after 5 to ours, both concentrations progressively lost efficacy and pupil size was comparable to time. The mean baseline grading of halos and double vision was, respectively, 3.1 G.9 and 3. G.9 in the.16% solution group, 2.8 G.8 and 2.6 G.8 in the.32% Figure 2. Pupil size (mm) measurements at different times after instillation of 2 dilutions of aceclidine. A: At.16% dilution. B: At.32% dilution J CATARACT REFRACT SURG - VOL 31, SEPTEMBER 25

4 Figure 3. Halo grading. Figure 4. Double vision grading. solution group, and 2.9 G.8 and 2.4 G.7 in the placebo group. There was no significant difference in mean age, BCVA, preoperative refractive error, IOP, treated OZ, baseline grade of haze, halos, double vision, and pupil size between study groups. Most eyes (7%) had a PRK procedure, while only 13% had a LASIK surgery. Tables 2 and 3 show the refractive and clinical results at 15 days and at 1 month, respectively. At 2 weeks examination, the mean grading of halos and double vision was, respectively, 1.6 G.6 and 2. G.7 in the.16% solution group, 1.55 G.5 and 1.5 G.5 in the.32% solution group, and 2.8 G.8 and 2. G.7 in the placebo group. At the 1-month visit, grading of halos and double vision was respectively 1.5 G.5 and 1.8 G.7 in the.16% solution group, 1.4 G.4 and 1.4 G.4 in the.32% solution group, and 2.8 G.8 and 2. G.7 in the placebo group. Grade of halos and double vision was significantly reduced in the groups receiving an active treatment as compared with placebo, both at 15 days and at 1 month (P Z.3 and P Z.4, respectively). No significant difference between.16% and.32% solutions was found. No difference in mean pupil size, IOP, BCVA, and grade of haze was found among groups. Analysis of the questionnaire indicated that 6% of patients in the.16% solution group and 77% in the.32% solution group experienced a conjunctival hyperaemia that, on average, lasted 17 minutes (range 15 to 2 minutes) and J CATARACT REFRACT SURG - VOL 31, SEPTEMBER

5 Table 1. Patients epidemiologic and clinical data. Aceclidine Parameter.16%.32% Placebo Number of eyes Age, y (mean) Sex 2M/8F 6M/4F 4M/6F BCVA (mean) Mean preop refractive error, D (eyes) ÿ7.5 (16) ÿ6.2 (18) ÿ7.3 (16) C4.5 (4) C3.5 (2) C2.5 (4) IOP, mm Hg (mean) OZ, mm (mean) TZ, mm (mean) Haze grading (1 to 4) Duration of night vision disturbances, months (mean) Pupil size, mm (mean) Halos (mean) Double vision (mean) Surgery PRK LASIK BCVA Z best corrected visual acuity; IOP Z intraocular pressure; LASIK Z laser in situ keratomileusis; OZ Z optical zone; PRK Z photorefractive keratectomy; TZ Z transition zone 22 minutes (range 15 to 3 minutes), respectively. A mild burning at instillation was reported by 2% of patients in the.16% solution group, by 3% of the patients in.32% solution group, and by 1 patient receiving the placebo (1%). The effect of the drug on any night vision disturbance was evident starting from 12 to 15 minutes from instillation with both solutions and lasted for a mean of ours (range 4 to ours). Only 1 patient in the placebo group reported a reduction in night vision disturbance. All patients experiencing a change in night vision quality reported an improvement of vision, and in no case a worsening was mentioned. An association between the reduction in grade of halos and double vision and the reduction in the optical aberrations could be shown. Aberrometric analyses (total, astigmatic, spherical, coma, and high order) by means of corneal topography after drug instillation showed a progressive reduction in RMS as the pupil diameter decreased (Figures 5 and 6 and Tables 4 and 5). Starting at 3 minutes, a statistically significant (P!.5) reduction in RMS (total, astigmatic, spherical, coma, and high order) as compared with time could be evidenced only in aceclidine-treated groups. The decrease in RMS (found for all parameters) lasted for about ours, while ours after the instillation, it was not significantly different from baseline. The total RMS was reduced from 3.87 G 1.1 at time to.66 G.13 at 3 minutes in the.16% dilution group; after ours, the total RMS was 2.53 G.61, not significantly different from baseline. A similar finding was observed with the.32% dilution, while in placebo group, no significant change in RMS could be evidenced (Table 6). Spherical Table 2. Results at 15-day follow-up visit. Aceclidine Treatment Group.16%.32% Placebo Halos (mean) Double vision (mean) IOP, mm Hg (mean) Pupil size (without drop) Haze grading (1 to 4) BCVA BCVA Z best corrected visual acuity; IOP Z intraocular pressure Table 3. Results at 3-day follow-up visit. Aceclidine Treatment Group.16%.32% Placebo Halos (mean) Double vision (mean) IOP, mm Hg (mean) Pupil size (without drop) Haze grading (1 to 4) BVCA BCVA Z best corrected visual acuity; IOP Z intraocular pressure 1768 J CATARACT REFRACT SURG - VOL 31, SEPTEMBER 25

6 RMS (micron) Figure 5. Variations of RMS (total, astigmatic, spherical, coma, and high-order aberrations) after diluted aceclidine (.16%) instillation (time) min 3 min 3 min 3 min 3 min Total Ab Astigmatism Spherical Ab Coma HO and coma were the aberrations showing a more marked reduction after drug instillation (Tables 4 and 5). Patients in treated groups reported a reduction in subjective night vision disturbance starting from 15 minutes after drug instillation. Moreover, with bigger pupils, a greater standard deviation was observed; consequently, only small amounts of variation in pupil diameter were able to induce a considerable increase in optical aberrations. The data indicated that a subjective improvement was reported when the total RMS was less than 1.5 mm RMS (micron) Figure 6. Variations of RMS (total, astigmatic, spherical, coma, and high-order aberrations) after diluted aceclidine (.32%) instillation (time) min 3 min 3 min 3 min 3 min Total Ab Astigmatism SphericalAb Coma HO J CATARACT REFRACT SURG - VOL 31, SEPTEMBER

7 Table 4. Variations in RMS (total, astigmatic, spherical, coma, and high-order aberrations) after diluted aceclidine (.16%) instillation (time). Hours Parameter 3 Minutes G G.13*.57 G.12*.85 G.18* 1.32 G.29* 1.18 G.25* 1.82 G.42* 2.53 G.61 total G SD 1.49 G G.1*.25 G.9*.38 G.12*.61 G.21*.55 G.18*.83 G.28* 1.1 G.37 astigmatic G SD 2.8 G G.17*.25 G.16*.38 G.22*.68 G.33*.59 G.3* 1.6 G.48* 1.63 G.67 spherical G SD 2.99 G G.15*.3 G.17*.49 G.17*.82 G.29*.71 G.25* 1.3 G.46* 1.94 G.68 coma G SD high order G SD 1.4 G G.16*.32 G.12*.44 G.2*.57 G.24*.53 G.23*.69 G G.4 RMS Z root mean square *P!.5 compared with time DISCUSSION After refractive surgery, a number of patients, even those with a good BCVA, complain about a worsening of their quality of vision, particularly during the night hours. This is a common clinical finding and has often been reported in literature. In a recent prospective study 9 of 46 patients who had a LASIK procedure, a significant correlation between a large pupil diameter as evaluated preoperatively and an increased frequency of postoperative night vision disturbance during scotopic conditions was described, despite good BCVA. However, the possible role of pupil diameter in the occurrence of night vision disturbance after refractive surgery is still debated. One important issue is probably the method used to measure pupil diameter in clinical studies. In fact, a number of different tools have been described in the literature, and data about their validity and reproducibility are often lacking. An increase in spherical aberration and coma is 1 of the main causes of night vision disturbance after refractive surgery. Postoperative spherical aberration is influenced by a number of variables including preoperative shape of the cornea, targeted correction, some features of the laser algorhythm, and pupil diameter, while the increase in coma is mainly related to a decentered ablation The curvature of the corneal midperiphery is responsible for most of the optical aberrations. Thus, when the pupil is dilated (ie, at night), the corneal periphery is involved in the vision processes with a consequent increase in aberrations of the light rays. Excimer laser surgery, in fact, causes a shift of the corneal profile from a normal prolate shape to an oblate one and a significant change in the power of the cornea that, in its periphery, can exceed 2 diopters measured in tangential power maps. The increase in the aberrations observed after refractive surgery can induce a considerable change in the Table 5. Variations in RMS (total, astigmatic, spherical, coma, and high-order aberrations) after diluted aceclidine (.32%) instillation (time). Hours Parameter 3 Minutes G G.25* 1.2 G.21* 1.18 G.25* 2.4 G.57* 2.13 G.5* 2.73 G.63* 4.34 G 1.3 total G SD 2. G G.17*.51 G.15*.58 G.17* 1.7 G.34*.97 G.31* 1.18 G G.6 astigmatic G SD 4.34 G G.3*.48 G.26*.59 G.3* 1.53 G.64* 1.28 G.56*, * 1.82 G.72* 3.31 G 1.9 spherical G SD 2.46 G G.13*.47 G.11*.56 G.13* 1.23 G.53* 1.11 G.43* 1.39 G.64* 2.1 G 1.25 coma G SD high order G SD 1.31 G G.23*.49 G.22*.53 G.23*.81 G G G G.52 RMS Z root mean square *P!.5 compared with time 177 J CATARACT REFRACT SURG - VOL 31, SEPTEMBER 25

8 Table 6. Variations in RMS (total, astigmatic, spherical, coma, and high-order aberrations) after placebo instillation (time). Hours Parameter 3 Minutes G G G G G G G G 1.5 total G SD 1.49 G G G G G G G G.51 astigmatic G SD 2.75 G G G G G G G G.98 spherical G SD 2.22 G G G G G G G G.91 coma G SD high order G SD 1.7 G G.4.98 G G G G G G.51 RMS Z root mean square wavefront of the eye. Therefore, wavefront analysis represents the best tool to assess and quantify the optical aberrations following surgery. The improvement in knowledge and technologies has led to better ablation profiles and consequently to a reduced occurrence of night vision disturbance. However, in case of night vision disturbance, the only parameter that can be modified to reduce postoperative halos and double vision is pupil size. The aim of this pilot study was to evaluate how pupil size changes obtained through pharmacologic treatment could influence the quality of scotopic vision and the optical aberrations after refractive surgery. We found a statistically significant subjective reduction in night vision disturbance using diluted aceclidine. This finding was confirmed by the statistically significant reduction in the optical aberrations that was evident starting 3 minutes after drug instillation and lasting about ours. Six hours after drug instillation, a reduction in RMS parameters (total, astigmatic, spherical, coma, and high order), although not significant, was still observed. In the control group, no significant decrease in aberrations was shown at any time. An association between corneal RMS (total, astigmatic, spherical, coma, and high order) error and subjective visual disturbances was shown: The smaller the RMS, the better the quality of vision. In the future, ad hoc software, working on calculation of topography-derived RMS and pupil diameters, will be able to predict which patients will benefit from this miotic treatment. The drug seemed to be safe and well tolerated, allowing a good treatment compliance. The main advantage of diluted aceclidine is the ability to obtain a mild reduction in pupil diameter without pupilloplegia. This allows the patient to maintain acceptable nocturnal vision and a normal visual field and, at the same time, to avoid relevant changes in aqueous humor flow and the possibility of posterior synechias (Figure 1). Even with a reduction in its width, pupillary kinetic seems to be preserved. Among miotics, aceclidine seems to be preferable mainly for the reduced occurrence of side effects. Pilocarpine, in fact, is well known to cause accommodative problems, ocular pain, myopia, posterior synechias, and tractions on peripheral retina with a particular risk for retinal tears in myopic patients These kinds of side effects can be avoided with adrenergic drugs such as brimonidine. The main problem related to chronic use of brimonidine is ocular allergy, which may occur in 1% to 2% of cases All these side effects are not reported to be associated with the use of aceclidine. A significant difference between the 2 drug concentrations could not be evidenced in terms of clinical efficacy. Although the limited sample size did not allow for subgroup analyses, our findings seem to suggest that even a low concentration (within.3%) would be clinically useful. In our judgment, these pilot study results are encouraging and may provide a new tool to practicing ophthalmologists to reduce the disturbances related to optical aberrations of the periphery of the cornea in patients reporting night vision discomforts after refractive surgery. REFERENCES 1. Kim H-M, Jung HR. Laser assisted in situ keratomileusis for high myopia. Ophthalmic Surg Lasers 1996; 27:S58 S Gartry DS, Larkin DFP, Hill AR, et al. Retreatment for significant regression after excimer laser photorefractive keratectomy; a prospective, randomized, masked trial. Ophthalmology 1998; 15: O Brart DPS, Corbett MC, Lohmann CP, et al. The effects of ablation diameter on the outcome of excimer laser photorefractive keratectomy; a prospective, randomized, double-blind study. Arch Ophthalmol 1995; 113: Stephenson CG, Gartry DS, O Brart DPS, et al. Photorefractive keratectomy; a 6-year follow-up study. Ophthalmology 1998; 15: Schallhorn SC, Blanton CL, Kaupp SE, et al. Preliminary results of photorefractive keratectomy in active-duty United States Navy personnel. Ophthalmology 1996; 13:5 21; discussion by LJ Maguire, J CATARACT REFRACT SURG - VOL 31, SEPTEMBER

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