ORIGINAL PAPER

Role of brimonidine in the treatment of clinically significantmacular edema with ischemic changes in diabeticmaculopathy

Parul Chawla Gupta • Sunandan Sood •

Subina Narang • Parul Ichhpujani

Received: 25 July 2013 / Accepted: 13 October 2013

� Springer Science+Business Media Dordrecht 2013

Abstract To evaluate the role of brimonidine

(BMD), an alpha-2 agonist, in the management of

clinically significant macular edema (CSME) in

diabetic maculopathy with ischemic changes. A

prospective, randomized controlled trial including 30

eyes of 30 metabolically stable diabetic patients with

CSME showing fundus fluorescein angiography doc-

umented ischemic changes. Group I included 17 eyes

of patients who received topical BMD (0.2 %) twice

daily for 6 months while Group II included 13 eyes of

age-matched patients who were kept under observa-

tion and acted as controls. The mean change in

logMAR visual acuity and any change in the grade of

the foveal avascular zone (FAZ) size, outline, capil-

lary non-perfusion, or capillary dilatation was noted in

the two groups and compared at the end of 6 months.

The FAZ area and radius was significantly less in the

study group than the control group. However, no

significant difference in FAZ capillary outline, FAZ

capillary loss, FAZ capillary dilatation and overall

grade of ischemia between the two groups was seen.

There was improvement in visual acuity from baseline

to 6 months but it was comparable between the two

groups (p = 0.02). BMD may have a role in the

treatment of ischemic macula in CSME since the FAZ

area and radius were significantly less in the study

group. However, a larger sample size and a longer

follow-up are needed to further authenticate the results

of this pilot study.

Keywords Brimonidine � Clinically significant

macular edema � Diabetic retinopathy �Foveal avascular zone

Introduction

Diabetes mellitus is emerging as an important cause of

blindness in the world’s adult population, and it is

expected to reach epidemic proportions in the coming

years.

Microangiopathy in the capillary bed of the retina

of long-standing diabetes mellitus leads to retinal

ischemia and hypoxia [1]. Patients with diabetic

retinopathy show decreased density of the perifoveal

capillary network and an enlarged foveal avascular

zone (FAZ) [2]. In long-standing diabetic patients,

multiple foci of tissue hypoxia are prevalent and play a

major role in the pathogenesis of vascular and visual

dysfunction [3]. It has been well proven that an

enlarged FAZ and perifoveal intercapillary area (PIA)

indicate ischemia and correlate with visual acuity [4].

Recently, increased apoptotic markers have been seen

in diabetic retina which could be attributed to the

ischemic nature of the disease [5].

Neuroprotection is a therapy directed at neuronal

loss, by way of inhibiting apoptosis. Alpha-2 agonists

P. C. Gupta (&) � S. Sood � S. Narang � P. Ichhpujani

Department of Ophthalmology, Government Medical

College and Hospital, Sector 32, Chandigarh, India

e-mail: pcgpgi@gmail.com

123

Int Ophthalmol

DOI 10.1007/s10792-013-9871-y

prevent the progressive loss of retinal ganglion cells

by maintaining and enhancing their ability to resist

stress if given before or even after the stress, as seen in

experimental studies [6].

Brimonidine (BMD) reduces intraocular pressure,

increases ocular perfusion, improves microcirculation

of the retina and therefore reduces ischemia at the

capillary bed of retina. It also eliminates glutamate-

induced excitotoxicity of N-methyl-D-aspartate recep-

tors which cause large influxes of calcium ions and

resultant cell injury [7]. Inhibition of vitreoretinal

vascular endothelial growth factor elevation and

blood–retinal barrier breakdown has also been shown

by BMD in diabetic rats [8]. It also causes upregula-

tion of brain-derived neurotrophic factor in the retina

which prevents retinal ganglion cell death. The

neuroprotective effect of topically applied BMD

0.2 % in an endothelin-1-induced optic nerve ische-

mia model of rabbits has been studied [9]. The drug

has been found to be beneficial in the very early stages

of non-proliferative diabetic retinopathy (NPDR) [7];

however, the literature is scant and more trials are

needed to determine the efficacy of alpha-2 agonists in

diabetic eyes.

Hence, the present study was carried out to

investigate the role of topical BMD in the progression

of ischemic changes in diabetic retinopathy with

clinically significant macular edema (CSME).

Materials and methods

This study was a prospective, single institution-based

randomized control trial which included 30 eyes of 30

diabetic patients with CSME and ischemic changes

detected by fundus fluorescein angiography (FFA)

presenting to the retina services of a tertiary level

health care center. The enrolled subjects had a visual

acuity C 6/60 and good metabolic control of diabetes

mellitus. The Ethics Committee of the institute

approved the study. Each subject provided written

informed consent before inclusion in the study which

conformed to the tenets of the Declaration of Helsinki

(sixth revision, 2008).

Patient population

The study population included consecutive diabetic

patients of either gender who were randomized into

two groups using computer-generated random number

tables. Group I (17 eyes; 17 patients) received topical

BMD (0.2 %) twice daily throughout the 6-month

study period. Group II (13 eyes; 13 patients) were

given a tear supplement as placebo and served as

controls. The preservative used in both BMD and the

tear supplement was benzalkonium chloride 0.05 mg.

The metabolic control of diabetes (blood glucose

level, lipid profile and renal status) was confirmed

every 3 months in both groups in consultation with an

internist. According to the American Diabetes Asso-

ciation, good metabolic control implied glycosylated

hemoglobin (A1C) B 6.5 % or fasting plasma glu-

cose (FPG) B 126 mg/dL (7.0 mmol/L), fasting low-

density lipoprotein (LDL) cholesterol B 100 mg/dL,

triglycerides B 150 mg/dL, and B 300 mg/day of

urinary albumin excretion.

Patients with significant media opacities precluding

fundus photo, angiography and visual field assessment

were excluded. Patients with macular diseases other

than CSME such as macular scars, choroidal neovas-

cular membrane, preretinal bleeding or thick hard

exudates in the foveal region which would prevent

proper assessment of the FAZ were excluded. Patients

requiring posterior subtenon triamcinolone acetonide or

intravitreal bevacizumab were excluded. Patients with

any other condition precipitating ischemic changes

apart from diabetic retinopathy such as glaucoma, optic

atrophy, anterior ischemic optic neuropathy, or retinal

vein occlusions were also excluded. Patients with a

history of cataract surgery within 3 months of the study

or during the study, were allergic to fluorescein dye or

with previous hypersensitivity to BMD tartrate, or were

receiving monoamine oxidase therapy were also

excluded. Patients with psychiatric ailments, cerebral

and coronary insufficiency, Raynaud’s phenomenon,

orthostatic hypotension, uncontrolled hypertension and

pregnant females were also excluded.

Baseline evaluation

A detailed history was recorded of the demographic

profile including age, sex, duration, type and treatment

of diabetes mellitus. History regarding any other

diagnosed systemic ailments and treatment received,

time and pattern of previous laser photocoagulation

(if any) and prior intraocular surgery was also recorded.

Best-corrected visual acuity was recorded for all

patients by an independent examiner using the

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logMAR visual acuity chart. Detailed slit-lamp bio-

microscopy was performed. We especially looked for

iris neovascularization, pupillary reaction, intraocular

pressure and the presence of cataract. Diabetic

retinopathy was graded as mild, moderate, severe,

very severe non-proliferative diabetic retinopathy or

early and high-risk proliferative diabetic retinopathy

as per the Early Treatment Diabetic Retinopathy Study

(ETDRS), using standard photographs 2A and 8A

[10]. The extent of the CSME was documented as per

clinical examination using an area centralis fundus

contact lens and 7-field fundus photographs as per

modified Airlie House Classification [10].

FFA was performed for all eyes using a Zeiss

FF-450 IRU digital fundus camera with the VISUPAC

system 430; this was carried out especially to record

field 2F in the early- and mid-phase. Grading was

performed as per EDTRS report no. 11 for FAZ size,

outline, capillary dropout, and capillary bed dilatation

in standard field 2F on FFA. Two observers (PC, SN)

graded the severity of capillary abnormalities. The

patients were offered standard conventional treatment

for diabetic retinopathy and maculopathy depending

on optical coherence tomography and FFA findings

prior to recruitment. All patients were subjected to

systemic investigations including hemoglobin, gly-

cosylated hemoglobin (HbA1c), urine albumin and

sugar, fasting blood sugar, post-prandial blood sugar

and blood pressure. Diabetics were also subjected to

other tests such as 24-h urinary protein, renal function

tests and lipid profile. Only metabolically well-

controlled diabetics were enrolled and their metabolic

stability was confirmed every 3 months. These

patients were treatment-naive patients or had been

treated for CSME (lasered) more than 3 months before

enrolling in the study.

Follow-up

All patients were followed up at 3 months and again at

6 months. A detailed history was taken for possible

side-effects of BMD such as dry mouth and drowsi-

ness and the patients underwent a complete ocular

examination.

Main outcome measures

The mean change in logMAR visual acuity in the two

groups was compared. The logMAR equivalents of

Snellens visual acuity chart were used. Any change in

the grade of FAZ size, outline, capillary non-perfu-

sion, or capillary dilatation was noted in the two

groups and compared.

Statistical analysis

Statistical analysis was carried out using the Statistical

Package for Social Sciences (SPSS Inc., Chicago, IL,

USA, ver. 15.0 for Windows). All quantitative vari-

ables were estimated using measures of central

location (mean, median) and measures of dispersion

(standard deviation and standard error). Normality of

data was checked by measures of skewness and

Kolmogorov–Smirnov tests of normality. For nor-

mally distributed data, means were compared using

Student’s t test for two. For skewed data, the Mann–

Whitney test was applied. For time-related compari-

son, the paired t-test or Wilcoxon signed-rank test was

applied. Qualitative or categorical variables were

described as frequencies and proportions. Proportions

were compared using Chi squared or Fisher’s exact

test, whichever was applicable. Pre- and post-test

comparisons were performed using the McNemar–

Bowker test. All statistical tests were two sided and

performed at a significance level of p = 0.05.

Results

The demographic profile and the baseline variables of the

two groups are shown in Table 1. The mean values of

HbA1C, FPG, fasting LDL, triglycerides and 24-h

urinary albumin excretion in the study/control group

were 6.22 ± 0.24/6.28 ± 0.21 % (p = 0.114), 88.65 ±

8.78/89.85 ± 7.64 mg/dL (p = 0.549), 76.06 ± 20.42/

75.31 ± 18.83 mg/dL (p = 0.776), 123.24 ± 17.43/

129.54 ± 12.60 mg/dL (p = 0.206) and 222 ± 28/

226 ± 29 mg/day (p = 0.675), respectively. The mean

FAZ area and radius in each group are shown in Table 2.

A significant decrease was found in the FAZ area and

radius in Group I (p = 0.01, 0.01, respectively)

(Fig. 1a, b) whereas no significant decrease was found

in Group II (p = 0.66, 0.77, respectively) when the

first visit was compared with the 6-month visit

(Fig. 2a, b). This finding suggests that although the

FAZ area and radius have decreased in both groups,

they have decreased significantly in the group receiv-

ing topical BMD.

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However, on analysis of other FAZ parameters such

as FAZ grade, capillary outline, capillary loss and

capillary dilatation, no significant difference was seen

between and within the two groups at the first visit and

the 6-month visit.

On adding up all FAZ grades in the study as well

as the control group, i.e., FAZ grade, capillary

outline, capillary loss, capillary dilatation, the aver-

age grade of ischemia in the study group was 31 and

in the control group was 30.2 at the first visit. It was

30.1 and 31.1, respectively, at the 6-month visit. The

change in total grade of ischemia from baseline was

not significant (p = 0.39, 0.08). Furthermore, there

was no significant difference between the two

groups when compared to each other (p = 0.30,

0.14). Maximum ischemia in our study was found in

the inner zone of the study group as well as the

control group.

Table 1 Demographic

profile and baseline

characteristics of the two

groups

OHA oral hypoglycemic

agents, DD disc diameter,

NPDR proliferative diabetic

retinopathy, PDR

proliferative diabetic

retinopathy

Group I Group II p value

(n = 17) (n = 13)

Mean age ± SD (years) 60.82 ± 8.69 58.08 ± 9.07 0.45

Gender

Females 6 (35.3 %) 3 (23.1 %) 0.69

Males 11 (64.7 %) 10 (76.9 %)

Mean duration

of diabetes ± SD (years)

9.29 ± 3.74 8.38 ± 4.39 0.61

Medication

OHA 14 (82.4 %) 12 (92.3 %) 0.61

Insulin 3 (17.6 %) 1 (7.7 %)

Hypertension

Present 11 (64.70 %) 8 (61.53 %) 1

Absent 6 (35.30 %) 5 (38.46 %)

Lenticular status

Phakic 10 (58.8 %) 9 (69.2 %) 0.71

Pseudophakic 7 (41.2 %) 4 (30.8)

Classification

Mild NPDR 1 (5.9 %) 1 (7.7 %) 0.25

Moderate NPDR 3 (17.6 %) 4 (30.8 %)

Severe NPDR 7 (41.2 %) 3 (23.1 %)

Very severe NPDR 0 (0 %) 3 (23.1 %)

Early PDR 5 (29.4 %) 2 (15.4 %)

High-risk PDR 1 (5.9 %) 0 (0 %)

CSME

\2 DD 11 (64.7 %) 7 (53.8 %) 0.41

[2 DD 6 (35.3 %) 6 (46.2 %)

Table 2 Mean FAZ area and radius in the two groups at 6 months was significantly better in the treatment group than in the control

group (p \ 0.001)

Group FAZ area at

1st visit (mm2)

FAZ area at

6-month visit (mm2)

FAZ radius at

1st visit (lm)

FAZ radius at

6-month visit (lm)

I 2.05 ± 0.97 1.29 ± 0.71 760.59 ± 186.09 623.53 ± 158.58

II 2.04 ± 1.44 1.95 ± 0.70 769.23 ± 244.87 763.85 ± 145.32

P 0.66 0.01 0.77 0.01

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The mean logMAR visual acuity in each of the

groups is shown in Table 3. In the study group

(Group I), there was no significant improvement in

visual acuity in the third month (p = 0.07), whereas

there was significant improvement in visual acuity in

the sixth month (p = 0.02) as compared with the first

visit. In the control group (Group II), there was

significant improvement in the third month (p = 0.04)

and sixth month (p = 0.02) as compared with the first

visit. However, the visual acuity when compared

during all the follow-up visits, was comparable

between the two groups (p = 0.56, 0.65, 0.88,

respectively).

Discussion

A significant difference was found in the FAZ area and

radius at the 6-month visit when the two groups were

compared. No studies were available in literature to

compare and contrast this finding.

Animals possess three subtypes of alpha-2 recep-

tors—alpha-2a, alpha-2b, alpha-2c and human beings

have alpha-2b and alpha-2c. It appears that the animal

model success with the neuroprotective role of BMD

may possibly be translated to human beings as well.

In both groups, the significant improvement in

visual acuity at 6 months (p = 0.02) as compared with

the first visit was possibly because of the metabolically

stable diabetic status in the two groups as well as due

to laser treatment performed 3 months prior to inclu-

sion in the study. As the patients were under surveil-

lance and 3-monthly tests were carried out, the

patients could have been more stringent for metabolic

control than usual. Hence, the consistently stable

diabetic status contributed to the significant improve-

ment in visual acuity.

Fig. 1 a FFA arteriovenous

phase at baseline shows

microaneurysms, area of

capillary non-perfusion and

enlarged foveal avascular

zone. b Arteriovenous phase

of FFA at 6-month follow-

up shows an increase in

capillary non-perfusion and

leakage from

neovascularization in a

patient in the control group

Fig. 2 a FFA early arteriovenous phase shows enlarged foveal

avascular zone, microaneurysms and temporal capillary non-

perfusion. b 6-month follow-up angiogram shows a decrease in

the foveal avascular zone but persistence of temporal capillary

non-perfusion areas in a patient in the study group

Table 3 Mean logMAR visual acuity with comparison

between the two groups at 6 months

Group logMAR VA

at 1st visit

logMAR VA at

6-month visit

p value

I Mean 0.56 ± 0.27 0.43 ± 0.31 0.02

II Mean 0.62 ± 0.27 0.43 ± 0.29 0.02

p value 0.56 0.88

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Mondal et al. [7] showed in their study that no new

microaneurysm developed in 100 % of study group

patients who received topical BMD over 2 years

whereas an average of four new microaneurysms

developed in all patients in the control group. It was

further observed that visual acuity improved by one

line in 60 % of patients and remained unchanged in the

rest of the patients in the study group, whereas visual

acuity was reduced by one line in 80 % of patients and

by two lines in 20 % patients in the control group who

received placebo eye drops; furthermore, CSME

developed in these 20 % patients. Their results

correlated with the present study where no worsening

was noted with BMD and the FAZ area and radius was

significantly lower in the study group. Capillary

remodulation is a known phenomenon and this could

possibly explain the decrease in the FAZ area in the

study group.

There is no study in the available literature to

contrast and compare the findings of the FAZ area and

radius in the study group who received topical BMD.

However, the findings in the control group (Group II)

of an increase in the FAZ over a 6-month follow-up

period were consistent with the study by Oliver et al.

[2]. They reported PIA and FAZ to be significantly

enlarged in diabetics as compared with healthy

controls. They also concluded that an enlarged FAZ

and PIA indicate ischemia and this may help in

identifying the presence of ischemic diabetic macu-

lopathy. It appears that BMD, which has been reported

to be reaching the posterior segment of the eye in

therapeutic concentrations [11] on topical administra-

tion, might be improving microcirculation of the

macula and having a possible neuroprotective effect in

diabetic maculopathy.

Although topical BMD was found to significantly

reduce the FAZ radius and area in the study group it

did not seem to alter the other FAZ parameters. It

appears that a longer follow-up might show some

significant alterations in the aforementioned FAZ

parameters.

A limitation to our study is that we included

patients who had received laser treatment at least

3 months before enrollment; these patients should

have been excluded.

There were no major systemic adverse effects.

One patient receiving BMD developed red eye and

was excluded from the study two weeks after

enrollment.

Conclusion

BMD may have a role in the treatment of ischemic

macula in CSME since the FAZ area and radius were

significantly less in the study group. However, BMD

does not affect the overall progression of macular

ischemia and visual acuity after 6 months. A larger

sample size and a longer follow-up are needed to

further authenticate the results of this pilot study.

Conflict of interests The authors declared no conflicts of

interest with respect to the authorship and/or publication of this

article.

Funding The authors received no financial support for the

research and/or authorship of this article.

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