Randomized Clinical Trial of Topical
Betaxolol for Persistent Macular Edema After
Vitrectomy and Epiretinal Membrane Removal
HIROSHI KOBAYASHI, MD, PHD, KAORI KOBAYASHI, MD, PHD,
AND SATOSHI OKINAMI, MD, PHD
● PURPOSE: To report the efficacy and safety of topical
betaxolol for treatment of persistent macular edema.
● DESIGN: Randomized clinical trial.
● METHODS: Thirty-seven eyes (37 patients) with best-
corrected visual acuity between 20/200 and 20/50 and
macular edema that remained for 3 months after vitrec-
tomy and removal of epiretinal membrane were prospec-
tively, randomly assigned to receive betaxolol or placebo.
Nineteen eyes of 19 patients received betaxolol twice
daily, and 18 eyes of 18 patients received placebo as a
randomized comparison group. The patients were fol-
lowed up for 6 months. This study evaluated the effect of
betaxolol on best-corrected visual acuity and area of
macular edema, which was digitally measured on serial
fluorescein angiogram. Calculations of mean best-cor-
rected visual acuity were based on logarithm of the
minimal angle of resolution (logMAR). To assess
B
changes in area of edema, the initial (pretreatment) size
of the edema was set to 100%, and all posttreatment
measurements were normalized relative to the initial size.
● RESULTS: Mean best-corrected visual acuity at baseline
was 0.216 (20 of 92.6) and 0.244 (20 of 82.0) in the
treatment and control group, respectively. Mean area of
macular edema was 2.271 ⴞ 1.629 mm2 and 2.273 ⴞ
1.209 mm2 in the treatment and control group; there was
no significant difference. The visual acuity at 6 months
after the start of the follow-up was 0.471 (20 of 42.5) in
the treatment group and 0.236 (20 of 84.7) in the
control group. Mean changes in logMAR of visual acuity
for 3- and 6-month follow-up were ⴚ0.282 ⴞ 0.191 and
ⴚ0.337 ⴞ 0.197 in the treatment group, and ⴚ0.016 ⴞ
0.186 and ⴙ0.015 ⴞ 0.267 in the control group; a
significant difference was found (P <.0001; P <.0001).
Areas of macular edema at 6 months after the start of the
Accepted for publication Jan 23, 2003.
InternetAdvance publication at ajo.com Feb 27, 2003.
From the Department of Ophthalmology, Saga Medical School, Saga,
Japan.
Inquiries to Hiroshi Kobayashi, MD, PhD, Department of Ophthal-
mology, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan;
fax: (⫹81) 952-33-3696); e-mail: kobayas3@post.saga-med.ac.jp
244 © 2003 BY ELSEVIER INC. ALL
follow-up were 1.492 ⴞ 1.357 mm2 in the treatment
group and 2.125 ⴞ 1.434 mm2in the control group.
Mean change in area of the edema for 6 months were
76.5% ⴞ 24.1% and 63.4% ⴞ 28.3% in the treatment
group and 92.9% ⴞ 15.4% and 87.4% ⴞ 25.6% in the
control group; treated patients showed a significantly
larger reduction than untreated patients at each exami-
nation (P ⴝ .0193; P ⴝ .0102). No complication
associated with treatment or placebo was found.
● CONCLUSIONS: Topical betaxolol appeared to have a
favorable treatment effect in eyes with macular edema
that remained after vitrectomy and removal of epiretinal
membrane. Further investigation of more cases and
longer follow-up are needed. (Am J Ophthalmol 2003;
136:244 –251. © 2003 by Elsevier Inc. All rights
reserved.)
ETAXOLOL, A ␤1-SELECTIVE ADRENOCEPTOR ANTAG-
onist, is widely used in the treatment of glaucoma. In
addition to its ocular hypotensive effects, betaxolol
has may act as a retinal neuroprotective agent1– 6 and
vasodilator,7–12 acting by Ca2⫹channel blockade.
Macular edema results from breakdown of the blood-
retinal barrier, leading to accumulation of intracellular
fluid as well as extracellular fluid.13–19 Macular edema
occurs in a variety of pathologic conditions, including
diabetic retinopathy, central and branch retinal vein
occlusions, hypertensive retinopathy, uveitis, retinitis pig-
mentosa, and other nutritional and metabolic diseases, as
well as after cataract surgery, retinal detachment surgery,
vitrectomy, and glaucoma procedures.
The first step in managing macular edema is treating the
primary disease. Various other treatments have been tried
with very limited success. These include treatment with
corticosteroid,20 carbonic anhydrase inhibitor,21,22 photo-
coagulation,23–25 hyperbaric oxygen,26,27 and vitrec-
tomy.28,29
The pathogenesis of macular edema is frequently multi-
factorial background. To study the efficacy of a drug for
macular edema, an ideal subject should be macular edema
RIGHTS RESERVED. 0002-9394/03/$30.00
doi:10.1016/S0002-9394(03)00151-X
that results from a single cause, and the cause should be
removed. In this study, we chose patients who underwent
vitrectomy and removal of epiretinal membrane and had
edema showing no tendency to resolve 3 months after
surgery. The purpose of this study is to determine the
efficacy and safety of topical bexolol for treating macular
edema.
DESIGN
THIS IS A RANDOMIZED CLINICAL STUDY.
METHODS
THIRTY-SEVEN PATIENTS WITH MACULAR EDEMA AFTER
removal of epiretinal membrane who fulfilled the criteria
for this study were enrolled. Indications for were (1)
undergoing vitrectomy and removal of epiretinal mem-
brane for treatment of epiretinal membrane and macular
edema, (2) the presence of macular edema, which was
worse or unchanged 3 months postoperatively compared
with immediately after surgery, and (3) visual acuity of
20/200 to 20/50. Vitrectomy and epiretinal membrane
removal essentially was the same in all eyes. Any patients
with preexisting ocular disease (that is, glaucoma, high
myopia, chronic inflammatory, or neoplastic disorders)
were excluded as were those with systemic disorders
(diabetes, uncontrolled hypertension) or a known life-
threatening disease at enrollment into the study. The study
was approved by an Institutional Review Board. Patients
were informed of the purpose of our study and provided
their signed consent to participate. Thirty-seven patients
were prospectively randomly assigned to receive betaxolol
or placebo. The patients were randomized using computer-
generated numbers: 0 is to receive topical betaxolol, and 1
is to receive placebo. The patients’ randomization state
was masked to the treating doctor. Within a week after
random assignments, treatment was to begin.
To evaluate the effects and safeaty of treatment, all
recruited patients underwent a detailed ophthalmic exam-
ination, including slit-lamp biomicroscopy and confocal
scanning laser tomography. Best-corrected visual acuity
was measured using the Early Treatment Diabetic Retinop-
athy Study (ETDRS) chart, and the log of the minimal
angle of resolution (logMAR) was calculated and used for
all statistical analysis. A pretreatment fluorescein angio-
gram was obtained within 1 week of commencing treat-
ment. After the start of follow-up, the patients were
reviewed at 0.5, 1, 2, 3, 4, 5, and 6 months and then every
2 months. Visual function was assessed at every visit, and
angiography scheduled for the visits at 1, 2, 3, 4, 5, 6, 9, 12,
18, and 24 months. An increase or decrease in visual acuity
was defined as a change of greater than 0.2 of logMAR
visual acuity. Goldmann tonometry was used to determine
VOL. 136, NO. 2 BETAXOLOL FOR
intraocular pressure (IOP). Three measurements were
recorded in each eye, and the mean of the three was used
in the calculations. The IOP was measured at 10:00 AM and
at 5:00 PM at baseline and 6-month visits, and IOP
measurements were performed at 10:00 AM at the other
visits. Safety was evaluated by determining the incidence
of treatment-related complications and adverse reactions
for both treatment and control groups. The patients were
regularly questioned and examined for side effects. Assess-
ment of outcomes, including visual acuity, angiographic
interpretation, assessment of complications and adverse
events, was performed in a masked fashion.
Area of macular edema is defined as the area of hyper-
fluorescence on the angiogram. Fundus angiograms were
obtained using a high-resolution digital fundus imaging
system based on a Canon UVi fundus camera (Canon,
Tokyo, Japan). In each angiogram, one picture was se-
lected to show the extent of the macular edema and the
optic disk. The image was analyzed with UTHSCSA
Image Tool 32-bit image analysis program (developed at
the University of Texas Health Science Center at San
Antonio).30 After applying sharpening and contrast-en-
hancing image filters, the outline of the edema was drawn
on the image manually and the membrane surface was
calculated. The outline of the optic disk was simulta-
neously drawn and saved. To calculate for magnification
errors, the disk/edema ratio was calculated for each image.
The initial (pretreatment) size of the macular edema was
set to 100%, and all posttreatment measurements were
normalized relative to the initial size. Measurements were
repeated five times. When repeated measurement was done
on the same picture, statistical analysis of the reproduc-
ibility of this measuring method showed a high correlation
coefficient of 0.995. A change of less than 20% was
considered as unchanged.
All patients underwent phacoemulsification and poly-
acrylic intraocular lens implantation (MA60BM; Alcon,
Fort Worth, Texas, USA). A standard three-port pars
plana vitrectomy was performed in all patients. We
achieved a complete posterior vitreous detachment during
pars plana vitrectomy using a soft-tipped needle and
removed basal vitreous as much as possible with indenta-
tion. Epiretinal membranes were removed with a slightly
bent microvitreoretinal blade and microforceps; their ab-
sence was then verified. No internal limiting membrane
removal or gas tamponade was employed.
For statistical analysis, if the difference in the percent of
patients who have a significant improvement between the
treatment and control groups is 33%, each group needs 18
patients, as the power is 80% (␣ ⫽ 0.05). Values are
presented as the mean ⫾ SD and as the range, or the
frequencies. For all two-by-two comparisons, the Fisher
exact test was used. Other comparisons of frequency
distributions were performed using the ␹2 test for indepen-
dence. Unless otherwise specified, data were analyzed by
MACULAR EDEMA 245
FIGURE 1. (A, B) Fluorescein angiographs of a 67-year-old woman before and 3 months after vitrectomy and removal of epiretinal
membrane (before the start of betaxolol treatment). (C, D) Three and 6 months after the start of betaxolol treatment.
unpaired two-sided t tests. A level of P ⬍.05 was accepted
as statistically significant.
For the pairing of both groups, age, sex, visual acuity,
area of macular edema and area, volume at baseline, and
duration from the surgery to the start of follow-up were
used for matching. We studied a correlation between the
paired observations. If these observations were correlated,
the F-test was used to study two population variances.
CASE REPORT
A 64-YEAR-OLD WOMAN HAD DECREASED VISION IN HER
left eye for 6 months. Ocular history was unremarkable.
Results of examination showed best-corrected visual acuity
of 20/20 in the right eye and 20/100 in the left eye. Fundus
examination showed the presence of epiretinal membrane
246 AMERICAN JOURNAL
over the macular region in the left eye. Fluorescein
angiography showed macular edema and leakage from
vessels in the macular region (Figure 1). A pars plana
vitrectomy and removal of epiretinal membrane was per-
formed. After 1 month, best-corrected visual acuity im-
proved to 20/50. Macular edema showed a gradual
aggravation. Three months after the surgery, visual acuity
decreased to 20/200 and the area of the macular edema was
4.188 mm2. The patient was randomly assigned and began
treatment. The edema gradually resolved. Three months
later, visual acuity improved to 20/40 and the area of the
macular edema decreased to 0.523 mm2. The macular
edema showed a further resolution. Six months after the
start of treatment, visual acuity was 20/25 and the area of
the edema was 0.273 mm2. After completion of the
6-month follow-up, the code was broken and it was learned
that the patient had received topical betaxolol.
OF OPHTHALMOLOGY AUGUST 2003
 TABLE 1. Demographics of Patient Groups

Treatment Group Control Group

Number of subjects enrolled 19 18

Men 8 (43.5%) 7 (40.4%)
Women 11 (56.5%) 12 (59.6%)
OD 11 (52.2%) 9 (50.0%)
OS 8 (47.8%) 9 (50.0%)
Age (years) 64.5 ⫾ 10.8 (46–85) 63.3 ⫾ 9.8 (48–79)
Interval from surgery to the start 12.9 ⫾ 1.0 (12–15) 12.8 ⫾ 1.0 (12–15)
of follow-up (weeks)
Area of edema (mm2) 6.097 ⫾ 6.283 (0.778–25.124) 6.604 ⫾ 6.908 (0.887–25.442)
Best-corrected visual 0.176 (20/113.6) 0.154 (20/129.9)
acuity (range) (0.1–0.5) (0.1–0.5)
LogMAR visual acuity 0.612 ⫾ 0.272 0.576 ⫾ 0.259

Log MAR ⫽ logarithm of the minimal angle of resolution; OD ⫽ right eye; OS ⫽ left eye.

TABLE 2. Change in Area of Macular Edema

Treatment Group Control Group P Value

Number of patients 19 18
Area of macular edema (mm2)
Baseline 2.271 ⫾ 1.629 (0.543–6.123) 2.273 ⫾ 1.209 (1.023–5.354) NS
1 month 2.064 ⫾ 1.579 (0.437–6.033) 2.194 ⫾ 1.278 (1.030–5.289) NS
3 months 1.818 ⫾ 1.551 (0–5.328) 2.178 ⫾ 1.326 (0.732–5.553) NS
6 months 1.492 ⫾ 1.357 (0–5.078) 2.125 ⫾ 1.434 (0.432–5.218) NS
Change in area of macular
edema (%)
1 month 88.6 ⫾ 21.8 (53.6–117.6) 98.4 ⫾ 11.3 (77.5–113.2) NS
3 months 76.5 ⫾ 24.1 (0–103.6) 92.9 ⫾ 15.4 (66.5–110.5) .0193
6 months 63.4 ⫾ 28.3 (0–98.7) 87.4 ⫾ 25.6 (32.7–125.4) .0102
Number of eyes with change in
area of macular edema for
6 months (%)
⬍60% 8 (42.1%) 4 (22.2%) .0402
60% to 79% 6 (31.6%) 2 (11.1%)
81% to 120% 5 (26.3%) 11 (61.1%)
121% to 140% 0 (0.0%) 1 (5.6%)
⬎141% 0 (0.0%) 0 (0.0%)

NS ⫽ not significant.

RESULTS 92.6) and 0.244 (20/82.0) in the treatment and control

BASELINE DATA ARE SUMMARIZED IN TABLE 1. NINETEEN
eyes of 19 patients and 18 eyes of 18 patients were enrolled
and followed up for 6 months in the treatment group and
control group, respectively. The duration between the
surgery and the start of the follow-up was 12.9 ⫾ 1.0 weeks
in the treatment group and 12.8 ⫾ 1.0 weeks in the control
group; there was no difference between the two groups. At
baseline mean best-corrected visual acuity was 0.216 (20/
group, respectively (Table 1). Baseline best-corrected vi-
sual acuity was slightly poorer in the treatment group
compared with the control group, but the difference of
logMAR best-corrected visual acuity was not statistically
significant. Mean area of macular edema at baseline was
2.271 ⫾ 1.629 mm2 in the treatment group and 2.273 ⫾
1.209 mm2in the control group (Table 1).
The mean area of macular edema at 6 months after the
start of follow-up was 1.492 ⫾ 1.357 mm2 and 2.125 ⫾

VOL. 136, NO. 2 BETAXOLOL FOR MACULAR EDEMA 247

 TABLE 3. Change in Best-corrected Visual Acuity

Treatment Group Control Group P Value

Number of patients 19 18
Best-corrected visual acuity (BCVA)
Baseline BCVA 0.216 (0.1–0.5) 0.244 (0.1–0.5)
LogMAR BCVA 0.664 ⫾ 0.279 0.612 ⫾ 0.272 NS
1-month BCVA 0.283 (0.1–0.8) 0.239 (0.1–0.7)
LogMAR BCVA 0.548 ⫾ 0.241 0.621 ⫾ 0.269 NS
3-month BCVA 0.415 (0.15–0.8) 0.254 (0.05–0.8)
LogMAR BCVA 0.382 ⫾ 0.187 0.596 ⫾ 0.312 .0154
6-month BCVA 0.471 (0.02–1.0) 0.236 (0.04–0.8)
LogMAR BCVA 0.327 ⫾ 0.197 0.627 ⫾ 0.311 .0012
Change in LogMAR
best-corrected visual acuity
1 month ⫺0.116 ⫾ 0.143 (⫺0.477–⫹0.176) ⫹0.010 ⫾ 0.152 (⫺0.368–⫹0.222) .0136
3 months ⫺0.282 ⫾ 0.191 (⫺0.602–0) ⫺0.016 ⫾ 0.186 (⫺0.426–⫹0.477) .0001
6 months ⫺0.337 ⫾ 0.197 (⫺0.699–0) ⫹0.015 ⫾ 0.267 (⫺0.477–⫹0.574) ⬍.0001
Number of eyes with change in
LogMAR best-corrected visual
acuity for 6 months
⬍⫺0.6 3 (15.8%) 0 (0.0%) .0003
⫺0.401 to ⫺0.6 5 (26.3%) 2 (11.1%)
⫺0.201 to ⫺0.4 8 (42.1%) 1 (5.6%)
⫺0.2 to ⫹0.2 3 (15.8%) 11 (61.1%)
⫹0.201 to ⫹0.4 0 (0.0%) 3 (16.7%)
⫹0.401 to ⫹0.6 0 (0.0%) 1 (5.6%)
Number of eyes with best-corrected
visual acuity at 6 months
⬎0.5 (20/40) 11 (57.9%) 3 (16.7%) .0002
0.3 to 0.4 (20/66.7 to 20/50) 6 (31.6%) 4 (22.2%)
0.1 to 0.2 (20/200 to 20/100) 2 (10.5%) 10 (55.5%)
0.06 to 0.09 (20/333.3 to 20/222.2) 0 (0.0%) 0 (0.0%)
0.01 to 0.05 (20/2000 to 20/400) 0 (0.0%) 1 (5.6%)

LogMAR ⫽ logarithm of the minimal angle of resolution; BCVA ⫽ best-corrected visual acuity; NS ⫽ not significant.

1.434 mm2in the treatment and control groups, respec-
tively (Table 2). Mean changes of area of the edema for 3
and 6 months were 76.5% ⫾ 24.1% and 63.4% ⫾ 28.3%
in the treatment group and 92.9% ⫾ 15.4% and 87.4% ⫾
25.6% in the control group. The reduction in the size of
macular edema for 3 and 6 months in the treatment group
was significantly larger than in the control group (P ⫽
.0193; P ⫽ .0102).
In the treatment group, 14 patients (74%) showed a
significant resolution of macular edema, and five (26%)
showed stable fluorescein angiographic appearance at 6
months after the start of follow-up (Table 2). In the
control group, six patients (33%) showed a significant
resolution of macular edema.
In the treated eyes, mean best-corrected visual acuity
before and 3 and 6 months after the start of treatment was
0.216 (20/92.6), 0.415 (20/48.2), and 0.471 (20/42.5),
respectively (Table 3); there was a significant improve-
ment in best-corrected visual acuity for 3 and 6 months (P
⫽ .0008; P ⫽ .0001). In the control eyes, best-corrected
visual acuity before and 3 and 6 months after the start of
follow-up was 0.244 (20/82.0), 0.254 (20/78.7), and 0.236
(20/84.7); no significant change in visual acuity was found
for any follow-up duration. A change in logMAR visual
acuity for 3 and 6 months was ⫺0.282 ⫾ 0.191 and
⫺0.337 ⫾ 0.197 in the treatment group and ⫺0.016 ⫾
0.186 and ⫹0.015 ⫾ 0.267 in the control group. A
significant difference was found for a follow-up of 3 and 6
months (P ⫽ .0001; P ⬍.0001).
In treated patients, 13 patients (68%) showed a signif-
icant improvement of best-corrected visual acuity, and the
remaining six patients (32%) showed unchanged visual
acuity for 6 months. In the control group, three patients
(17%) showed a significant improvement, 11 patients
(61%) unchanged visual acuity, and four patients (22%) a
significant deterioration (Table 3).
Throughout the study, patients were monitored for any
possible adverse side effects that could be attributed to the

248 AMERICAN JOURNAL OF OPHTHALMOLOGY AUGUST 2003

 TABLE 4. Change of Intraocular Pressure, Heart Rate, and Blood Pressure

Treatment Group Control Group P Value

Number of patients 19 18
Intraocular pressure (mm Hg)
Baseline 15.5 ⫾ 2.3 (12–20) 15.4 ⫾ 3.0 (11–21) .9098
6 months 13.9 ⫾ 2.2 (11–18) 15.3 ⫾ 2.7 (11–21) .0918
Change in intraocular pressure
(mm Hg)
6 months ⫺1.6 ⫾ 0.8 (⫺3–0) ⫹0.2 ⫾ 2.2 (⫺2–⫹4) .0020
Heart rate (beats/min)
Baseline 70.9 ⫾ 9.8 (56–88) 72.6 ⫾ 11.8 (52–88) .6358
6 months 68.1 ⫾ 8.8 (58–86) 72.4 ⫾ 9.1 (60–86) .1529
Change in heart rate (beats/min)
6 months ⫺2.8 ⫾ 4.8 (⫺13–⫹5) ⫺0.1 ⫾ 5.7 (⫺8–⫹10) .1274
Systolic pressure (mm Hg)
Baseline 132.3 ⫾ 13.1 (110–152) 132.9 ⫾ 10.2 (114–148) .8778
6 months 127.5 ⫾ 13.4 (104–148) 132.2 ⫾ 10.9 (110–150) .3647
Change in systolic pressure
(mm Hg)
6 months ⫺4.8 ⫾ 4.5 (⫺16–⫹6) ⫺0.6 ⫾ 5.7 (⫺8–⫹8) .0656
Diastolic pressure (mm Hg)
Baseline 76.5 ⫾ 7.9 (64–92) 75.4 ⫾ 6.1 (66–88) .6398
6 months 76.0 ⫾ 7.1 (66–88) 75.7 ⫾ 6.2 (64–86) .8921
Change in diastolic pressure
(mm Hg)
6 months ⫺0.5 ⫾ 2.6 (⫺4–⫹4) ⫹0.2 ⫾ 2.5 (⫺4–⫹6) .4100

drugs. There were no significant systemic and ocular
complications and adverse events.
Mean intraocular pressure at baseline and at 6 months
after the start of follow-up was 15.5 ⫾ 2.3 mm Hg and 13.9
⫾ 2.2 mm Hg in the treatment group and 15.4 ⫾ 3.0 mm
Hg and 15.3 ⫾ 2.7 mm Hg in the control group (Table 4).
The treatment group showed a significant reduction in IOP
after administration of topical betaxolol (P ⫽ .0350). At
baseline and at 6 months after the start of follow-up, mean
heart rate was 72.3 ⫾ 8.6 beats per minute and 68.1 ⫾ 8.8
beats per minute; and mean systolic pressure was 132.3 ⫾
13.1 mm Hg and 127.5 ⫾ 13. 4 mm Hg. The betaxolol
group showed a decrease in heart rate and systolic pressure;
this was not statistically significant.
DISCUSSION
THIS STUDY EVALUATED THE EFFICACY OF BETAXOLOL FOR
macular edema that remained after vitrectomy and re-
moval of epiretinal membrane. Betaxolol significantly
improved visual acuity compared with untreated eyes.
Patients with topical betaxolol showed a significant reduc-
tion in macular edema, whereas no such effect was ob-
served in untreated eyes. Betaxolol appeared to have a
favorable effect in reducing macular edema. Therefore,
topical betaxolol may promote resolution of macular
edema and restore function.
Topically applied betaxolol was observed to reach the
retina in maximal amounts within 60 minutes in rabbits.6
Some of the substance was also found in the contralateral
retina of the untreated eye, suggesting that the agent
reaches the retina by local systemic and retinal circulation.
Betaxolol penetrates the conjunctive and accumulate in
the Tenon capsule.31 In patients under long-term therapy,
the periocular tissue can accumulate a greater quantity of
the ␤-antagonist than is present in a daily dosage of
applied eyedrops, manyfold higher than the maximal
intraocular concentration.31 Therefore, topically applied
betaxolol may reach the posterior segment of the eye and
improve metabolism and microcirculation of the macular
region.
The vasodilating effects of betaxolol on ocular vessels
have recently been demonstrated in vivo and in vitro studies
acting via a Ca2⫹ channel blocking activity.7–12,32–37 Changes
in ocular blood flow velocity by topically applied betaxolol
have been measured using various methods, including
color Doppler imaging method, laser Doppler velocimetry,
scanning laser fluorescein angiography, fundus pulsation
amplitudes measurement, and laser-speckle tissue blood
flow analysis.32–37 Retinal blood flow increases as a long-
term effect of betaxolol.
The effects of betaxolol have been studied in isolated
porcine posterior ciliary artery and bovine retinal arteries
with the use of ring segment preparation.7–12 Betaxolol
induced a dose-dependent dilation with a threshold as low

VOL. 136, NO. 2 BETAXOLOL FOR MACULAR EDEMA 249

as 10⫺12 M. Therefore, betaxolol may play a role in
relaxing the retinal microarteries to improve the ocular
circulation, resolve macular edema, and restore function.
Several studies have demonstrated that betaxolol can
protect retinal neurons from ischemia.1– 6 Topical betaxo-
lol can blunt the effects of ischemia/perfusion to the
retina.4,6 Betaxolol can reduce influx of both sodium and
calcium into neurons through interaction at neurotoxin
site 2 of the sodium channel and the L-type calcium
channel, respectively. Betaxolol has been reported to raise
levels of mRNA for brain derived neurotrophic factor,6
suggesting that betaxolol can induce changes in expression
of factors that are known themselves to provide neuropro-
tection to retinal neurons. Injury to neurons, including
macular edema, has been proposed to cause cellular death
and idling neurons, whose functions reach a standstill.38 In
addition to improvement of microcirculation and brain
derived neurotrophic factor upregulation, the ability of
betaxolol to interact with sodium channel and L-type
calcium channel may have a role in its therapeutic effects
in restoring functions of idling neurons and glia. There is
a possibility that betaxolol may protect retinal neuron and
glia from macular edema and restore function.
Although the sample size in each group was small, the
current study demonstrated that betaxolol may have a
favorable effect for treating macular edema. Future study of
a large population is needed to verify this observation. As
macular edema results from a variety of diseases and
pathologic conditions, we need to study the kind of
pathologic condition resulting in macular edema for which
betaxolol is effective. This information may be clinically
valuable when treating macular edema.
REFERENCES
1. Osborne NN, Cazevieille C, Carvalho AL, Larsen AK,
DeSantis L. In vivo and in vitro experiments show that
betaxolol is a retinal neuroprotective agent. Brain Res
1997;751:113–123.
2. Chidlow G, Melena J, Osborne NN. Betaxolol, a beta(1)-
adrenoceptor antagonist, reduces Na(⫹) influx into cortical
synaptosomes by direct interaction with Na(⫹) channels:
comparison with other beta-adrenoceptor antagonists. Br J
Pharmacol 2000;130:759 –766.
3. Hirooka K, Kelly ME, Baldridge WH, Barnes S. Suppressive
actions of betaxolol on ionic currents in retinal ganglion cells
may explain its neuroprotective effects. Exp Eye Res 2000;
70:611–621.
4. Wood JP, DeSantis L, Chao HM, Osborne NN. Topically
applied betaxolol attenuates ischaemia-induced effects to the
rat retina and stimulates BDNF mRNA. Exp Eye Res
2001;72:79 –86.
5. Melena J, Wood JP, Osborne NN. Betaxolol, a beta1-
adrenoceptor antagonist, has an affinity for L-type Ca2⫹
channels. Eur J Pharmacol 1999;378:317–322.
6. Osborne NN, DeSantis L, Bae JH, et al. Topically applied
betaxolol attenuates NMDA-induced toxicity to ganglion
250 AMERICAN JOURNAL
cells and the effects of ischaemia to the retina. Exp Eye Res
1999;69:331–342.
7. Hoste AM, Boels PJ, Andries Lj, Brutsaert DL, Laey JJ.
Effects of beta-antagonists on contraction of bovine retinal
microarteries in vitro. Invest Ophthalmol Vis Sci 1990;31:
1231–1237.
8. Hester RK, Chen Z, Becker EJ, Mclaughlin M, Desantis L.
The direct vascular relaxing action of betaxolol, carteolol
and timolol in porcine long ciliary artery. Surv Ophthalmol
1994;38(Suppl):S125–S134.
9. Yu DY, Su EN, Cringle Sj, et al. Intra- and extra-luminal
betaxolol dilates potassium-contracted perfused porcine ret-
inal arteries and branches. Invest Ophthalmol Vis Sci 1996;
37:S844.
10. Hoste AM, Sys SU. Ca2⫹ channel-blocking activity of
propranolol and betaxolol in isolated bovine retinal micro-
artery. J Cardiovasc Pharmacol 1998;32:390 –396.
11. Yu DY, Su EN, Cringle SJ, Alder VA, Yu PK, DeSantis L.
Systemic and ocular vascular roles of the antiglaucoma
agents beta-adrenergic antagonists and Ca2⫹ entry blockers.
Surv Ophthalmol 1999;43(Suppl 1):S214 –S222.
12. Hoste AM. In vitro studies of the effects of beta-adrenergic
drugs on retinal and posterior ciliary microarteries. Surv
Ophthalmol 1999;43(Suppl 1):S183–S190.
13. Fine S, Brucker AJ. Macular edema and cystoid macular
edema. Am J Ophthalmol 1981;92:466 –481.
14. Yanoff M, Fine S, Brucker AJ, Eagle RC Jr. Pathology of
human cystoid macular edema. Surv Ophthalmol 1984;
28(Suppl):505–511.
15. Gass JMD, Anderson DR, Davis EB. A clinical, fluorescein
angiographic, and electron microscopic correlation of cystoid
macular edema. Am J Ophthalmol 1985;100:82–85.
16. Bresnick GH. Diabetic maculopathy. A critical review high-
lighting diffuse macular edema. Ophthalmology 1983;90:
1301–1317.
17. Bird AC. Retinal edema. Introduction to the first interna-
tional cystoid macular edema symposium. Surv Ophthalmol
1984;28(Suppl):433–436.
18. Tso MOM. Pathology of cystoid macular edema. Ophthal-
mology 1982;89:902–915.
19. Schepens CL, Avila MP, Jalkh AE, Trempe CL. Role of the
vitreous in cystoid macular edema. Surv Ophthalmol 1984;
28(Suppl):499 –504.
20. Monin C, Lepvrier-Guibal N, Guillot de Suduiraut C,
Dobler O, Bey Boumezrag A, Haut J. Treatment of diabetic
macular edema with neuroepithelium detachment combin-
ing high-dose corticotherapy and photocoagulation. J Fr
Ophthalmol 1994;17:585–590.
21. Whitcup SM, Csaky KG, Podgor MJ, Chew EY, Perry CH,
Nussenblatt RB. A randomized, masked crossover trial of
acetazolamide for cystoid macular edema in patients with
uveitis. Ophthamology 1996;103:1054 –1063.
22. Grover S, Fishman GA, Fiscella RG, Adelman AE. Efficacy
of dorzolamide hydrochloride in the management of chronic
cystoid macular edema in patients with retinitis pigmentosa.
Retina 1997;17:222–231.
23. Early Treatment Diabetic Retinopathy Study Research
Group. Photocoagulation for diabetic macular edema: Early
Treatment Diabetic Retinopathy Study report number 1.
Arch Ophthalmol 1985;103:1796 –1806.
24. Early Treatment Diabetic Retinopathy Study Research
Group. Focal photocoagulation treatment of diabetic macu-
lar edema. Relationship of treatment effect to fluorescein
angiographic and other retinal characteristics at baseline:
ETDRS No.19. Arch Ophthalmol 1995;114:1144 –1155.
25. Branch Vein Occlusion Study Group. Argon laser photoco-
OF OPHTHALMOLOGY AUGUST 2003
 agulation for macular edema in branch vein occlusion. Am J
Ophthalmol 1984;98:271–282.
26. Ogura Y, Takahashi M, Ueno S, Honda Y. Hyperbaric
oxygen treatment for chronic cystoid macular edema after
branch vein occlusion. Am J Ophthalmol 1987;104:301–
302.
27. Proff DS, Thom SR. Preliminary report on the effect of
hyperbaric oxygen on cystoid macular edema. J Cataract
Refract Surg 1987;13:136 –140.
28. Lewis H, Abrams GW, Blumenkranz MS, Campo RV.
Vitrectomy for diabetic macular traction and edema associ-
ated with posterior hyaloid traction. Ophthalmology 1992;
99:753–759.
29. Tachi N, Ogino N. Vitrectomy for diffuse macular edema in
cases of diabetic retinopathy. Am J Ophthalmol 1996;122:
258 –260.
30. Stalmans P, Leys A, Van Limbergen E. External beam
radiotherapy (20 Gy, 2 Gy fractions) fails to control the
growth of choroidal neovascularization in age-related macu-
lar degeneration. Retina 1997;17:481–492.
31. Sponsel WE, Terry S, Khuu HD, Lam WK, Frenzel H.
Periocular accumulation of timolol and betaxolol in glau-
coma patients under long-term therapy. Surv Ophthalmol
1999;43(Suppl 1):210 –213.
VOL. 136, NO. 2 BETAXOLOL FOR
32. Schmetterer L, Strenn K, Findl O, et al. Effects of antiglau-
coma drugs on ocular hemodynamics in healthy volunteers.
Clin Pharmacol Ther 1997;61:583–595.
33. Tamaki Y, Araie M, Tomita K, Nagahara M. Effect of topical
betaxolol on tissue circulation in the human optic nerve
head. J Ocul Pharmacol Ther 1999;15:313–312.
34. Yoshida A, Ogasawara H, Fujio N, et al. Comparison of
short- and long-term effects of betaxolol and timolol on
human retinal circulation. Eye. 199 8;12:848 – 853.
35. Araie M. In vivo measurement of ocular circulation with the
laser speckle method-development of apparatus and applica-
tion in ophthalmological research. Nippon Ganka Gakkai
Zasshi 1999;103:871–909.
36. Harris A, Arend O, Chung HS, Kagemann L. A comparative
study of betaxolol and dorzolamide effect on ocular circula-
tion in normal-tension glaucoma patients. Ophthalmology
2000;107:430 – 434.
37. Altan-Yaycioglu R, Turker G, Akdol S, Acunas G, Izgi B.
The effects of beta-blockers on ocular blood flow in patients
with primary open angle glaucoma: a color Doppler imaging
study. Eur J Ophthalmol 2001;11:37–46.
38. Neubauer RA, Gottlieb SF, Kagan RT. Enhancing “idling”
neurons. Lancet 1990;335:542.
MACULAR EDEMA 251