ARTICLE
`
`Efficacy of brimonidine tartrate 0.2% ophthalmic
`solution in reducing halos after laser in situ
`keratomileusis
`
`Ji Hoon Lee, MD, Yong Sung You, MD, Chul Myong Choe, MD, Eun Suk Lee, MD
`
`PURPOSE: To quantitatively evaluate the effect of brimonidine tartrate 0.2% (Alphagan) on halo and
`pupil size in patients who had symptomatic night-vision difficulties after laser in situ keratomileusis
`(LASIK).
`
`SETTING: Nune Eye Hospital, Seoul, Korea.
`
`METHODS: This study comprised 28 eyes of 14 patients with symptomatic night-vision difficulties
`after LASIK. Pupil diameter was measured with a Colvard pupillometer (Oasis Medical, Inc.). Quan-
`titative analysis of halos was performed by measuring the area using a new computerized method.
`Pupil size and halo size were evaluated under scotopic and normal room light conditions. Alphagan
`was administered, and the effect was measured after 30 minutes and 1, 6, 12, and 24 hours.
`RESULTS: There was a statistically significant correlation between pupil size and halo size (r Z
`0.527; P<.0001; slope Z 691.6 pixel/mm). Pupil size and halo size decreased significantly 30 min-
`utes after Alphagan instillation under both luminance conditions (all P<.0001). Under normal room
`light, the pupil and halo remained decreased until the last measurement at 24 hours. Under scotopic
`conditions, the pupil returned to its preinstillation size at 24 hours while the halo remained de-
`creased. The maximum effect on halos was observed after 6 hours, when the mean reduction
`over preinstillation size was 28.2% and 29.1% under normal room light conditions and scotopic
`conditions, respectively.
`
`CONCLUSION: Alphagan effectively reduced halo size and pupil size in postoperative LASIK patients
`with night-vision symptoms.
`
`J Cataract Refract Surg 2008; 34:963–967 Q 2008 ASCRS and ESCRS
`
`Night-vision difficulties such as glare and halos are
`major concerns after excimer laser refractive surgery.
`In the early postoperative period, patients with large
`pupils under scotopic conditions are at high risk for
`night-vision difficulties caused by corneal aberrations
`related to pupil size.1
`Brimonidine tartrate 0.2% ophthalmic solution is
`a highly selective a-2 adrenergic receptor agonist
`that has been shown to reduce intraocular pressure
`(IOP) in patients with glaucoma2 and to attenuate
`IOP elevation after anterior laser procedures with min-
`imal side effects and good systemic tolerance.3,4 It also
`decreases pupil size, especially under scotopic condi-
`tions. Although the reduction in pupil size under sco-
`topic conditions may result in decreased night-vision
`difficulties, to our knowledge no study in the literature
`has demonstrated quantitative improvement in night-
`vision difficulties with brimonidine tartrate.
`There are few methods to assess the degree of night
`glare disability,
`including the Brightness Acuity
`
`Q 2008 ASCRS and ESCRS
`
`Published by Elsevier Inc.
`
`Tester, psychometric questionnaires, and the Night
`Vision Recording Chart; however, no gold-standard
`clinical tests are currently available.5 Subjective obser-
`vations of halos and disturbances caused by them after
`LASIK are often evaluated using a questionnaire. We
`introduce a new computerized method to quantify
`the severity of halos.
`The purpose of our study was to evaluate the effect
`of brimonidine tartrate 0.2% (Alphagan) on pupil size
`and halos after laser in situ keratomileusis (LASIK) by
`quantitative analysis of halo size using a computerized
`method over a 24-hour period. We also evaluated the
`correlation between pupillometer-measured pupil
`size and computer-measured halo size.
`
`PATIENTS AND METHODS
`Of the 318 patients who had LASIK for myopia and astigma-
`tism from January 2004 to March 2004 at Nune Eye Hospital,
`Seoul, Korea, 14 (28 eyes) were enrolled in this study. Inclu-
`sion criteria were uneventful LASIK for myopia with or
`
`0886-3350/08/$dsee front matter
`doi:10.1016/j.jcrs.2008.01.028
`
`963
`
`Downloaded from http://journals.lww.com/jcrs by m7j+Lz0A3XtswKY/tv8RN1QKQlJP6/VVSYaAis4y17hfNBU9WW6eKJ+h7ScwrBbUbDOi8G3tRFyL4gIbL9xbarjUn23y66buvAJyGYQjZfsiAZxFU4Pv3KemJ1FqhbIhxjfgnqoR0OG6dENDmikQnSb5s1ca5SQF7Qhzk4Obbbc= on 12/22/2021
`
`

`

`964
`
`BRIMONIDINE TARTRATE TO REDUCE HALOS AFTER LASIK
`
`without astigmatism performed at least 6 months before
`study enrolment, best corrected visual acuity (BCVA) better
`than 0.7 (Snellen chart), no previous intraocular surgery or
`other ophthalmic disorders that could influence glare dis-
`ability or halo size, and history of stable night-vision distur-
`bance for at least 3 months. Patients were asked about optical
`symptoms of night-vision disturbance (halo, star burst, and
`night-driving difficulties) in each eye separately. Also ex-
`cluded were patients with ablations decentered by more
`than 1.0 mm, which was assessed by comparing the center
`of the optical zone between the preoperative and postopera-
`tive corneal topography.
`All LASIK procedures were performed by the same sur-
`geon (C.M.C.). The corneal flap was created with a Hansa-
`tome microkeratome (Bausch & Lomb Surgical) with a
`160 mm head. The ablation was performed using the S4 exci-
`mer laser (Visx). Data on preoperative refractive error, abla-
`tion depth, and the optical and transition zones were collected.
`A computer image-analysis program (Scion Corp.) was
`used to measure the size of the halo. The patients were seated
`50 cm from a 17-inch, 75 Hz TFT-LCD monitor (1184 pixels 
`864 pixels, Samsung) and asked to looked at a white circle
`(316 pixel unit) on the screen. The circle was a white light
`source with a luminance of 56.6 cd/m2 that appeared in
`the center of the video monitor against a background lumi-
`nance of 0.01 cd/m2. Monocular testing was performed after
`the refractive error was corrected with manifest refraction
`and a C2.00 diopter addition to prevent accommodative pu-
`pil miosis. Eyeglasses were always used. The patients traced
`the boundary of the halo with a graphic tablet (Figure 1, left);
`the size of the halo was calculated in pixels (Figure 1, right).
`The halo measurement was repeated 3 times in each eye, and
`the mean size calculated in pixels. Pupil size was measured
`with a Colvard pupillometer (Oasis Medical, Inc.) after pa-
`tients adapted to luminance conditions for 3 minutes. Pupil
`size and halo size were measured under 2 luminance condi-
`tions, scotopic (1 cd/m2) and normal room light (5 cd/m2).
`One drop of Alphagan was instilled in each eye. Halo size
`was measured after 30 minutes and 1, 6, 12, and 24 hours
`and pupil size, after 30 minutes and 1 and 24 hours.
`Statistical analyses comparing the change in halo size and
`pupil size were performed using a repeated-measures anal-
`ysis of variance (ANOVA). Post hoc multiple comparisons
`were performed when the difference was significant by re-
`peated-measures ANOVA. Pearson correlations (r) and
`
`Accepted for publication January 21, 2008.
`
`From the Yonsei Eye Clinic (J.H. Lee), Uijeongbu, Nune Eye Hospital
`(You, Choe), and Institute of Vision Research (E.S. Lee), Depart-
`ment of Ophthalmology, Yonsei University College of Medicine,
`Seoul, Korea.
`
`No author has a financial or proprietary interest in any material or
`method mentioned.
`
`Presented as a poster at the annual meeting of the Association for
`Research in Vision and Ophthalmology, Fort Lauderdale, Florida,
`USA, May 2002.
`
`Corresponding author: Eun Suk Lee, MD, Institute of Vision Re-
`search, Department of Ophthalmology, Yonsei University College
`of Medicine, CPO Box 8044, Seoul 120-752, Korea. E-mail:
`xmas365@gmail.com.
`
`linear regression were used to examine the association be-
`tween halo size and pupil size. The intraclass correlation co-
`efficient was estimated to assess intraexaminer repeatability
`using 1-way random-effects analysis of variance (ANOVA).
`Intraexaminer repeatability was determined using the ap-
`proach proposed by Bland and Altman,6 which includes cal-
`culation of the repeatability coefficients and 95% limits of
`agreement between first-session and second-session mea-
`surements. A P value of 0.05 or less was considered statisti-
`cally significant. All statistical calculations were performed
`using SPSS software (version 11.5, SPSS, Inc.).
`
`RESULTS
`The mean age of the 14 patients was 26.3 years G 5.2
`(SD) (range 22 to 35 years). Table 1 shows the patients’
`characteristics. Of the 28 eyes, 28 had subjective symp-
`toms of halo and 26 had star bursts; 3 patients reported
`night-driving difficulties. Table 2 shows the intraexa-
`miner repeatability for halo-size measurements.
`Pupil size and halo size decreased significantly after
`Alphagan instillation under normal room light and
`scotopic luminance conditions (all P!.0001,
`re-
`peated-measures ANOVA). Table 3 shows the effect
`of Alphagan on pupil size and halo size under both lu-
`minance conditions. There was a significant correla-
`tion between pupil size and halo size (r Z 0.527;
`P!.0001; slope Z 691.6 pixel/mm) (Figure 2).
`
`Normal Room Luminance
`Pupils were statistically significantly smaller at the
`first measurement 30 minutes after Alphagan instilla-
`tion. Pupil size decreased further 1 hour after instilla-
`tion, although the change was not
`statistically
`significant. At the next measurement at 24 hours, the
`pupil was larger than in previous measurements but
`was statistically significantly smaller than before Al-
`phagan was instilled (Figure 3). Halo size decreased
`significantly 30 minutes after instillation and remained
`stable through the measurement at 24 hours (Table 3
`and Figure 4). The halos were smallest (mean 28.2%
`of original size) 6 hours after instillation.
`In 21
`(87.5%) of 2 eyes, the halo was the smallest 6 or 12
`hours after Alphagan instillation.
`
`Scotopic Luminance
`Under scotopic conditions, pupil size decreased 30
`minutes and 1 hour after Alphagan instillation and re-
`turned to preinstillation size at 24 hours. Halo size con-
`tinued to decrease until 1 hour after instillation and
`remained decreased through the measurement at 24
`hours (Table 3). The maximum effect on halos was at
`6 hours, at which time halos were a mean of 29.1% of
`the size before instillation. In 20 (87.0%) of 23 eyes,
`the halo was smallest 6 or 12 hours after Alphagan in-
`stillation (Figure 4).
`
`J CATARACT REFRACT SURG - VOL 34, JUNE 2008
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`

`

`BRIMONIDINE TARTRATE TO REDUCE HALOS AFTER LASIK
`
`965
`
`Figure 1. Left: A halo displayed on
`a TFT-LCD monitor with a graphic
`tablet. Right: Halo size was deter-
`mined by measuring the area in
`pixels after the boundary of the
`halo was traced.
`
`DISCUSSION
`After refractive surgery, even patients with good
`BCVA can have night-vision disturbances. Factors
`known to increase the risks for such disturbances in-
`clude large pupils, small optical treatment zones,
`and higher-order aberrations. Some studies7–10 sug-
`gest that topical solutions such as brimonidine, dapi-
`prazole, and aceclidine can be used to temporarily
`resolve night-vision disturbances by contracting the
`pupil. Although the effectiveness of these drugs in de-
`creasing pupil size has been reported, no published
`study has directly evaluated their effect on night-vi-
`sion disturbances. In this study, we found a quantita-
`tive improvement in halos, one of the most serious
`symptoms causing night-vision disturbance, after ad-
`ministration of Alphagan, whose active ingredient,
`brimonidine tartrate, causes miosis with few side
`effects.9
`In our study, halo size under scotopic conditions re-
`mained decreased through 24 hours after Alphagan in-
`stillation; the maximum effect was at 1 hour and 12
`hours. This indicates one drop a day helps not only pa-
`tients who require short-term relief from halos but also
`those who may have the symptom for an entire night.
`Previous studies8-10 did not evaluate how long miosis
`lasted because the last measurement was between
`3 hours and 6 hours after administration.
`
`Table 1. Patient characteristics.
`
`Parameter
`
`Patients (n)
`Eyes (n)
`Mean age (y) G SD
`Sex (n)
`Male
`Female
`Mean preop refractive error (D) G SD
`Mean ablation depth (mm) G SD
`Mean optical zone (mm) G SD
`Mean transition zone (mm) G SD
`
`Value
`
`14
`28
`26.3 G 5.2
`
`3
`11
`6.49 G 2.17
`83.03 G 18.03
`5.25 G 0.34
`7.12 G 0.27
`
`Although not statistically significant, the mean halo
`size was smallest at 6 hours and the mean pupil size
`was smallest at 1 hour under both luminance condi-
`tions (normal room light and scotopic). As we mea-
`sured pupil size only 30 minutes, 1 hour, and 24
`hours after Alphagan instillation, it is possible that
`the pupil was the smallest between 6 hours and 24
`hours. Pupil size and halo size became statistically sig-
`nificantly stable 30 minutes after instillation under
`room light conditions and 1 hour after instillation un-
`der scotopic conditions. As the pupil is bigger under
`scotopic conditions,
`it is likely that more time is
`needed to reach Alphagan’s maximum effect on pupil
`and halos.
`Multiple comparisons with Bonferroni correction
`were performed to compare the measurements taken
`at different time points. The Bonferroni method is
`one of the most widely used corrections to minimize
`type I error (false positive when there is no real differ-
`ence) when interpreting significant variation between
`the means in 3 or more groups. However, its disadvan-
`tage is that it is conservative because although the F
`test in the ANOVA is significantly significant, no
`pair of means can be significantly different.11 In our
`study, mean pupil size under scotopic condition 24
`hours after Alphagan installation was not statistically
`significantly different from that before installation by
`multiple comparison with Bonferroni
`correction
`(P Z .162). However, when the means in the 2 groups
`were compared by paired t test, the difference was sta-
`tistically significant (P Z .027). Thus,
`it may be
`
`Table 2. Intraexaminer repeatability for patient’s tracings of
`halo size.
`
`Measure
`
`ICC (95% CI)
`Repeatability coefficient
`95% LoA (pixels)
`
`Result
`
`0.92 (0.90 to 0.93)
`678.6
`646.4 to 683.6
`
`CI Z confidence interval; ICC Z intraclass correlation coefficient; LoA Z
`limits of agreement
`
`J CATARACT REFRACT SURG - VOL 34, JUNE 2008
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`966
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`BRIMONIDINE TARTRATE TO REDUCE HALOS AFTER LASIK
`
`Table 3. Variations in pupil size and halo size after Alphagan instillation.
`
`Time After Instillation
`
`Condition/Measurement
`
`0 Min
`
`30 Min
`
`1 Hr
`
`5.2 G 0.6
`
`4.6 G 0.6†,z
`
`4.4 G 0.5†
`
`6 Hr
`
`NA
`
`12 Hr
`
`24 Hr
`
`P
`Value*
`
`NA
`
`4.7 G 0.7†,z !.0001
`
`Room light
`Mean pupil
`size (mm) G SD
`Mean halo size
`(pixels) G SD
`Scotopic
`Mean pupil
`size (mm) G SD
`Mean halo size
`(pixels) G SD
`
`1855.3 G 277.3
`
`885.6 G 118.3†,z 676.5 G 82.8†
`
`541.4 G 91.3†
`
`582.6 G 94.8†
`
`1124.9 G 195.6† !.0001
`
`6.4 G 0.7
`
`5.6 G 1.0†,z
`
`5.04 G 0.8†,z
`
`NA
`
`NA
`
`6.1 G 0.9z !.0001
`
`2626.8 G 373.0 1341.0 G 244.8†,z 963.1 G 153.2†,z 766.3 G 151.1† 782.4 G 133.2† 1976.2 G 423.6† !.0001
`
`NA Z not applicable
`*Repeated-measures analysis of variance
`†P%.05 compared with 0 min
`zP%.05 compared with previous time
`
`somewhat controversial to say the effect of Alphagan
`will last for 24 hours after instillation under scotopic
`conditions.
`Only one report12 has evaluated the reduction in
`halos after LASIK. However,
`the reduction was
`achieved using over-minused lenses, not an ophthal-
`mic solution, and used a subjective scale on which pa-
`tients approximated the percentage change from
`baseline. Few quantitative assessments of halos have
`been reported.13,14 Pieh et al.13 measured the halo
`size in subjects with multifocal intraocular lenses and
`Lackner et al.,14 in LASIK patients. Both studies were
`done at the same institute using the Glare & Halo
`computer program (Tomey AG). Except for the com-
`puter program used, the basic settings for halo mea-
`surements are similar between the 2 previous studies
`
`and our study. However, in the previous studies,
`based on the patient’s instructions, an operator used
`a cursor to distinguish the outer margin of the halo;
`in our study, the patients themselves traced the area
`of the halo using a graphic tablet.
`Our method of quantifying halo size did not involve
`equipment or software developed for halo measure-
`ments. However, ours is the first study to show that
`symptomatic halos can be decreased by pupil constric-
`tion and to describe the quantitative change in halo
`size after instillation of brimonidine tartrate 0.2%, in
`this case Alphagan.
`In conclusion, a single-drop instillation of Alphagan
`effectively decreased halos by contracting the pupil. Its
`effect began at 30 minutes, with the maximum effect 1
`hour after administration under scotopic conditions.
`
`Figure 2. Regression and correlation between pupil (diameter, mm)
`and halo size (area, pixel).
`
`Figure 3. Pupil size at different times after installation of Alphagan.
`
`J CATARACT REFRACT SURG - VOL 34, JUNE 2008
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`BRIMONIDINE TARTRATE TO REDUCE HALOS AFTER LASIK
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`967
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`elevations in intraocular pressure after laser trabeculoplasty.
`Ophthalmology 1993; 100:1083–1088
`4. Chevrier RL, Assalian A, Duperre´ J, Lesk MR. Apraclonidine
`0.5% versus brimonidine 0.2% for the control of intraocular pres-
`sure elevation after anterior segment laser procedures. Ophthal-
`mic Surg Laser 1999; 30:199–204
`5. Fan-Paul NI, Li J, Sullivan Miller J, Florakis GJ. Night vision dis-
`turbances after corneal refractive surgery. Surv Ophthalmol
`2002; 47:533–546
`6. Bland JM, Altman DG. Statistical methods for assessing agree-
`ment between two methods of clinical measurement. Lancet
`1986; 1:307–310
`7. Randazzo A, Nizzola F, Rossetti L, Orzalesi N, Vinciguerra P.
`Pharmacological management of night vision disturbances after
`refractive surgery; results of a randomized clinical trial. J Cata-
`ract Refract Surg 2005; 31:1764–1772
`8. Kesler A, Shemesh G, Rothkoff L, Lazar M. Effect of brimonidine
`tartrate 0.2% ophthalmic solution on pupil size. J Cataract Re-
`fract Surg 2004; 30:1707–1710
`9. McDonald JE II, El-Moatassem Kotb AM, Decker BB. Effect of
`brimonidine tartrate ophthalmic solution 0.2% on pupil size in
`normal eyes under different luminance conditions. J Cataract
`Refract Surg 2001; 27:560–564
`10. Marx-Gross S, Krummenauer F, Dick HB, Pfeiffer N. Brimoni-
`dine versus dapiprazole: influence on pupil size at various illumi-
`nation levels. J Cataract Refract Surg 2005; 31:1372–1376
`11. Altman DG. Practical Statistics for Medical Research. London,
`UK, Chapman and Hall, 1991; 211–212
`12. Boxer Wachler BS, Hiatt D, Chou B, Christie JP. Reduction of
`pupil size and halos with minus lenses after laser in situ kerato-
`mileusis. J Refract Surg 2004; 20:149–154
`13. Pieh S, Lackner B, Hanselmayer G, Zo¨ hrer R, Sticker M,
`Weghaupt H, Fercher A, Skorpik C. Halo size under distance
`and near conditions in refractive multifocal intraocular lenses.
`Br J Ophthalmol 2001; 85:816–821
`14. Lackner B, Pieh S, Schmidinger G, Hanselmayer G, Simader C,
`Reitner A, Skorpik C. Glare and halo phenomena after laser in
`situ keratomileusis. J Cataract Refract Surg 2003; 29:444–450
`
`Figure 4. Halo size at different times after installation of Alphagan.
`
`The halo size decreased from the preinstillation size by
`a mean of 71.8% and 70.9% under normal room light
`conditions and scotopic conditions, respectively. The
`action on halos lasted as long as 24 hours.
`
`REFERENCES
`1. Schallhorn SC, Kaupp SE, Tanzer DJ, Tidwell J, Laurent J,
`Bourque LB. Pupil size and quality of vision after LASIK. Oph-
`thalmology 2003; 110:1606–1614
`2. Katz LJ. Brimonidine tartrate 0.2% twice daily vs timolol 0.5%
`twice daily: 1-year results in glaucoma patients; the Brimonidine
`Study Group. Am J Ophthalmol 1999; 127:20–26
`3. Barnebey HS, Robin AL, Zimmerman TJ, Morrison JC,
`Hersh SB, Lewis RA, Coleman AL, Cinotti DJ, Walt J,
`Chen KS, Kelley EP. The efficacy of brimonidine in decreasing
`
`J CATARACT REFRACT SURG - VOL 34, JUNE 2008
`
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