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·
Clinical Research
·
Ecacy of topical dorzolamide 2% in diabetic cystoid
macular edema
Amani E Badawi, Tharwat H. Mokbel, Eman M Elhefney, Sherein M. Hagras, Ameera G
Abdelhameed
Department of Ophthalmology, Mansoura Ophthalmic Center,
Faculty of Medicine, Mansoura University, Mansoura 35516,
Egypt
Correspondence to: Ameera G Abdelhameed. Department
of Ophthalmology, Mansoura Ophthalmic Center, Faculty
of Medicine, Mansoura University, Mansoura 35516, Egypt.
amiragamal287@gmail.com
Received: 2020-10-06 Accepted: 2021-03-25
Abstract
● AIM:
To study the effect of topical dorzolamide 2% on
macular thickness reduction in diabetic cystoid macular
edema (CME).
● METHODS:
This was a prospective, non-randomized,
open study including eyes with diabetic macular edema
(DME). All eyes received topical dorzolamide 2% three times
daily for one month. Changes in best-corrected visual acuity
(BCVA), and central macular thickness (CMT) by optical
coherence tomography) were evaluated at 1wk, 1, and 3mo
post-treatment.
● RESULTS:
Ninety-three eyes (84 patients) were
included. Mean±SD (logMAR) BCVA improved significantly
from 1.08±0.26 pretreatment to 0.66±0.24 at 1mo
and 0.87±0.26 at 3mo post-treatment (P<0.001 both).
The mean±SD CMT was significantly reduced from
535.27±97.4 μm at baseline to 357.43±125.8 μm at 1mo
and 376.23±114.5 μm at 3mo post-treatment (P<0.001 both).
No signicant ocular or systemic side effects were recorded.
● CONCLUSION:
Topical dorzolamide 2% results in
significant improvement of mean BCVA and reduction of
mean CMT at 3mo post-treatment. It can be used as an
effective, affordable, and safe therapy for treatment of non-
refractory diabetic CME.
● KEYWORDS:
cystoid macular edema; diabetic
maculopathy; dorzolamide; retina
DOI:10.18240/ijo.2021.09.18
Citation: Badawi AE, Mokbel TH, Elhefney EM, Hagras SM,
Abdelhameed AG. Efficacy of topical dorzolamide 2% in diabetic
cystoid macular edema. Int J Ophthalmol 2021;14(9):1413-1418
INTRODUCTION
D
iabetic macular edema (DME) is among the most
prevalent causes of visual loss in diabetic retinopathy
[1]
,
whereas its global occurrence ratio is about 6.8% among
diabetic patients
[2]
. The exact pathophysiology of DME is still
unclear, but it is believed to be multifactorial and complicated,
caused mainly by blood-retinal barrier (BRB) disruption due
to functional damage and necrosis of retinal capillaries. This
disruption of BRB leads to abnormal leakage and accumulation
of intravascular fluid into the neurosensory retina and in the
intraretinal layers of the macula
[3]
. The resulting macular
thickening deforms photoreceptors, thus causing vision loss
[4]
.
Laser photocoagulation has been proved effective in
minimizing blindness from DME by at least 60%
[5]
. However,
it is usually associated with retinal necrosis resulting in a
reduction of pericentral-sensitivity
[6]
. That is why treatment
should also include drugs capable of reduction or elimination
of the edema without permanent destruction of the retinal
anatomy.
Earlier studies concluded the benefits of intravitreal
triamcinolone acetonide injection in the treatment of DME
either alone or versus laser therapy
[7]
. Despite these benefits,
the associated high incidences of cataracts and consistent
intraocular pressure (IOP) increase are considered major
drawbacks of intravitreal triamcinolone acetonide therapy
[8]
.
Currently, anti-vascular endothelial growth factor (anti-
VEGF) substances are widely used and have revolutionized
diabetic retinopathy treatment. They have been demonstrated
as effective alternatives to laser photocoagulation and have
replaced it as first-line therapy
[9]
. Although the results of
anti-VEGF agents in diabetic retinopathy are promising,
each intravitreal injection has the risk of post-injection
and/or drug-class-associated devastating adverse effects
as endophthalmitis
[10]
, intraocular inflammation
[11]
, IOP
elevation
[12]
, and systemic side events
[13]
.
Systemic carbonic anhydrase inhibitors (CAIs) have been
efficient in treating maculopathy present in retinal diseases
as uveitis
[14]
, retinitis pigmentosa
[15]
, or postoperatively after
cataract surgery
[16]
, as well as that associated with epiretinal
membranes
[17]
. However, the use of systemic CAIs is further
1414
limited by frequent and hazardous side effects
[18]
which are
thought to result from inhibition of intracellular carbonic
anhydrase (CA) isoenzymes
[19]
. Dorzolamide, a topical
CAIs, well-tolerated and effective as an ocular hypotensive
drug
[20]
, has been used for macular edema due to retinitis
pigmentosa
[21-22]
, retinoschisis
[23]
, and choroideremia
[24]
. It
has a comparable effect to acetazolamide in macular edema
due to retinitis pigmentosa
[25]
. In fact, few studies
[26-27]
have
investigated the efficacy of CAIs, especially the topical
dorzolamide, in resolving cystoid macular edema (CME) in
diabetic retinopathy. This study was carried out to study the
ecacy of topical dorzolamide 2% in the treatment of CME in
diabetes patients.
SUBJECTS AND METHODS
Ethical Approval The study protocol was reviewed and
approved by the Ethical Committee of Mansoura University,
Faculty of Medicine, and was performed in accordance with
the rules of the Helsinki Declaration (R/16.04.65). The study
was registered in UMIN clinical trial register system (ID
issued: UMIN 000022608 Receipt No: R000026059). Written
informed consent was obtained from all patients after a clear
explanation of the purpose of the study, the nature of the
procedure, conceivable benets, and possible risks.
This was a prospective, nonrandomized, open, and interventional
study carried out on diabetic patients with CME recruited
at Mansoura Ophthalmolic Center, Mansoura University in
Mansoura city, Egypt.
Patients’ Selection
Inclusion criteria The study included adult diabetic patients
(both type 1 and 2) recently diagnosed with diabetic CME
(of duration less than 3mo). CME was diagnosed by slit lamp
biomicroscopy with non-contact lens, uorescein angiography,
and optical coherence tomography (OCT; Topcon Corp, Tokyo,
Japan).
Exclusion criteria Patients were excluded from the study if
they had: 1) advanced diabetic retinopathy; 2) serous retinal
detachment; 3) vitreo-retinal traction syndrome; 4) Mixed
maculopathy (macular ischemia by angiography ); 5) prior
laser therapy or intravitreal injections (IVI); 6) additional
ocular diseases, including uveitis, glaucoma, or neoplasms; 7)
history of other medications with potential eect on the visual
acuity and/or retinal function.
Initial assessment All subjects underwent an ophthalmic
examination that included: 1) best-corrected Snellen
visual acuity (BCVA) measurement; 2) standard slit-lamp
biomicroscopy; 3) IOP measurement by Goldmann applanation
tonometry; 4) dilated fundus examination using non-contact
Volk 90 lens, and indirect ophthalmoscope; 5) the severity
and the level of diabetic retinopathy were evaluated through
the fundus examination and fluorescein angiography based
on the International Clinical Diabetic Retinopathy Disease
Severity Scale
[28]
; 6) OCT: 3D-OCT 2000 (Topcon Corp,
Tokyo, Japan) was used in this study for macular scanning.
It was performed at a resolution of 512×128 with six linear
scans oriented radially 30° apart and centered on the fovea.
Central macular and foveal thicknesses were measured within
a 6 mm diameter circle centered on the foveola and the
circular map was subdivided into 9 regions. The 6 mm ring
was divided into 3 rings, with the inner ring 1 mm in diameter,
the middle ring 2 mm and the outer ring 3 mm in diameter. It
was corresponding to the foveal, perifoveal, and parafoveal
areas respectively. Color-coded graphs and numerical maps
were used for quantitative evaluation. CME was diagnosed as
an absence of central foveal contour, diuse thickening of the
foveal/or perifoveal area more than 250 μm, and a presence of
intraretinal cysts. Scans with the image quality of 55 or more
were included for analysis; 7) all participant’s glycemic control
was ascertained pretreatment and at 3mo post-treatment
through glycosylated hemoglobin A1C (HbA1c) measurement.
Treatment protocol This comprised administration of topical
dorzolamide 2% eye drops (Trusopt 2% eye drops, Merck &
Co., Inc., NJ, USA) three times daily for 30d.
Post-treatment evaluation and follow-up schedule The rst
follow-up visit was at one week, then each patient was seen
after one month, and three months to evaluate the patient’s
response to treatment. At each follow-up visit, BCVA, IOP,
fundus biomicroscopy, and OCT images were obtained and
recorded.
Study outcomes and data analysis The main primary
outcome was the changes in macular morphology post-
treatment. OCT findings were evaluated by measuring the
changes in the central foveal zone (CFZ) thickness and then
all study participants were graded as responders or non-
responders. The non-responders to the topical dorzolamide 2%
were further classied as non-responders without worsening,
or non-responders with worsening.
Secondary outcomes measurements included changes in
BCVA, HbA1c variables, and IOP. Snellen visual acuity
measurements were converted into logMAR equivalents for
statistical analysis.
Statistical Analysis The baseline and the outcome data were
classified, scheduled, and then analyzed using the computer
program SPSS (Statistical package for social science) version
17.0 (SPSS Inc. Chicago, Illinois, USA). To compare the
mean values and changes from pretreatment values, the paired
Student’s t-test was used. The P value of less than 0.05 was
considered statistically significant. Independent t-test was
conducted to measure the dierence between mean values of
HbA1c variables among the responders and non-responders
and to assess its impact on the treatment outcomes.
Topical dorzolamide 2% for DME
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RESULTS
Ninety-three patients fullled the inclusion criteria; however, 9
patients were excluded from the study as they did not complete
the 3mo follow-up period. Accordingly, 84 patients (93 eyes)
were included in the study; with a mean age of 54.22±5.8y.
Patients’ demographic and basic clinical data are shown in
Table 1.
There was a statistically significant improvement in BCVA
mainly one month after treatment (Figure 1). The mean±SD
baseline logMAR BCVA was 1.08±0.26. It improved to
1.02±0.28 (P=0.116), 0.66±0.24 (P<0.001), and 0.87±0.26
(P<0.001) at 1wk, 1, and 3mo after treatment respectively
(Table 2). At the end of 3mo, sixty-four eyes (68.8%) had
a subjective improvement in the BCVA. Twenty-two eyes
(23.7%) had no change from the initial pretreatment BCVA,
while 7 eyes (7.5%) showed a decline in their BCVA (Table 3).
The mean±SD IOP changed from16.52±2.57 mm Hg at
baseline to15.42±1.37 mm Hg at 1wk, to 14.66±1.74 mm Hg
after 1mo and to 15.84±1.49 mm Hg at the end of 3mo. The
changes were statistically significant (P=0.002, <0.001,
<0.001) respectively (Table 4).
Detailed OCT images analysis showed that all post-treatment
central foveal thickness (CFT) values were significantly
decreased compared to baseline values (P<0.05; Figure 2).
The mean±SD baseline CFT was 535.27±97.4 μm, which
decreased at one week to 420.87±115.2 μm and further
decreased at one month to 357.43±125.8 μm, then slightly
increased to 376.23±114.5 μm at the end of 3mo, but remained
signicantly lower than the pretreatment value (Table 5).
OCT analysis revealed that, 56 eyes (60.02%) showed
improvement in response to topical dorzolamide 2% through
the follow-up period (3mo), 27 eyes (29.03%) did not show
any improvement and the macular thickness did not worsen,
while 10 eyes (10.57%) did not show any improvement but the
macular thickness worsened when compared to the baseline
thickness. The mean baseline and post-treatment HbA1c values
were significantly higher in non-responders as compared to
responders (P<0.001; Table 6).
All patients completed the follow-up period of at least 3mo
(mean±SD follow-up 3.95±1.3mo; range: 3-7mo). There were
no signicant ocular or systemic side eects observed during
the follow-up period.
DISCUSSION
The pathogenesis of DME seems to be attributable to
inammatory processes which play a main role in functional
and morphological changes of DME
[29]
. Several previous
studies have handled and evaluated the various methods for the
treatment of diabetic maculopathy
[3,5-9,30]
.
Lately, clinical interest has focused on the effect of
acetazolamide, a systemic CAI, on the macular edema from
various retinal disorders
[14-17]
. Unfortunately, acetazolamide
may lead to serious side eects
[18-19]
. That is why it cannot
be administered for a long time (3-5 days maximum).
Dorzolamide is a topical CAI that can be used as an alternative
prolonged therapy and can be administered to these patients
constantly to prevent their visual acuity impairment
[26-27]
.
It has been reported that the response to CAI therapy is better
in patients with diuse retinal pigment epithelial (RPE) disease
than in those with primary retinal vascular disease, such as
Table 1 Patients demographics
Items Data
Mean age (y) 54.22±5.8 (43-67)
Gender
Male 36
Female 48
Laterality
Unilateral 75
Bilateral 9
Severity distribution
a
Mild-moderate NPDR 26 eyes
Severe NPDR 55 eyes
Low risk PDR 12 eyes
a
International Clinical Diabetic Retinopathy Disease Severity Scale
[32]
.
NPDR: Non-proliferative diabetic retinopathy; PDR: Proliferative
diabetic retinopathy.
Table 2 The mean BCVA prior and after treatment
Time BCVA (logMAR), mean±SD (range) P
a
Baseline 1.08±0.26 (1.5-0.8)
1wk 1.02±0.28 (1.3-0.6) 0.116
1mo 0.66±0.24 (1.2-0.5) <0.001
3mo 0.87±0.26 (1.4-0.5) <0.001
a
Paired samples t-test vs baseline. BCVA: Best corrected visual acuity;
SD: Standard deviation, Min: Minimum, Max: Maximum.
Table 3 Change in BCVA of 93 eyes at the end of follow-up
BCVA change Number of eyes (%; n=93 eyes)
Worsening 7 (7.5)
No change 22 (23.7)
1 line improvement 35 (37.6)
≥2 lines improvement 29 (31.2)
BCVA: Best corrected visual acuity.
Table 4 The mean IOP
Time IOP, mean±SD (range), mm Hg P
a
Baseline 16.52±2.57 (12-22)
1wk 15.42±1.37 (12-16) 0.002
1mo 14.66±1.74 (11-14) <0.001
3mo 15.84±1.49 (12-17) <0.001
a
Paired samples t-test vs baseline. IOP: Intraocular pressure; SD:
Standard deviation.
1416
diabetes or retinal vein occlusion
[31]
. This was explained by
alteration of RPE membrane-bound CAIs, which may have
lost their polarized distribution due to accumulation of macular
edema, with resultant stimulation of ion and fluid-removal
across the RPE from the retina to the choroid
[32]
. However,
some reports suggested that CAIs affect the BRB as they
stimulate at least one ion-pump transport mechanism, resulting
in an increase in passive permeability and outward-active
transport across the BRB
[33]
. The exact mechanism for fluid
transport across broken-down BRB in diabetic retinopathy
remains obscure.
As the anti-inflammatory effect of dorzolamide had been
reported before
[34]
, the authors assumed that it would help
in endogenous intraretinal fluid absorption through RPE
and thus can improve the vision and prevente further retinal
photoreceptor loss and neurodegeneration. The purpose of the
current study was to evaluate the anatomical and functional
effects of topical dorzolamide 2%, on CME in diabetic
patients.
Based on analysis of the current series OCT, it was found that
56 eyes (60.2%) showed a signicant improvement in central
macular thickness (CMT) in response to topical dorzolamide,
29% did not show an improvement or worsening, and 10.8%
showed an increase in macular thickness compared with pre-
treatment values. The mean CFT was significantly lower at
all post-treatment time points with the best-recorded results
at one month and minimal deterioration at three months, but
still better than pre-treatment levels. So, it can be assumed that
sustained therapy may be required. Among the study cohort,
68.8% of eyes demonstrated a subjective improvement in the
BCVA, 23.7% did not show any change from the pre-treatment
BCVA value, while only 7.5% showed a decrease in their
BCVA.
Several prior studies have investigated the eect of HbA1c on
the treatment outcomes of diabetic edema with variable designs
and conclusions. Some reported a strong correlation between
the high HbA1c and the persistent macular edema
[35-36]
; by
contrast, others found there was no relation
[37]
. In the current
cohort, patients who had lower HbA1c levels either baseline
or post-treatment showed a better response to treatment,
suggesting that HbA1c is one of the sensitive variables to
predict nal treatment outcomes.
Lima-Gómez et al
[27]
studied the eect of topical dorzolamide,
in comparison to placebo on the reduction of retinal thickness
after focal laser photocoagulation in DME. They reported a
signicant reduction in CMT after topical dorzolamide, which
was absent in eyes that received a placebo. But the reduced
CMT was not followed by a signicant improvement in visual
acuity. In their study, topical dorzolamide was used three
times daily for only three weeks. Moreover, the duration of
CME was not specied; patients could have prolonged edema
which would have caused irreversible functional damage to
retinal photoreceptors, even if anatomical architecture has been
restored. In the current study, patients with recently diagnosed
diabetic edema were selected as the duration of DME, which
could aect the macular cells’ function either mechanically or
toxically with more photoreceptor damage during the evolution
of the disease.
One of the interesting questions here is the maintained response to
treatment at the end of three months in spite that patients were o-
treatment for two months. Understanding the pharmacokinetics
of topical dorzolamide can interpret this topic point and might
be a valuable guide. Following chronic topical application
of dorzolamide, the drug reaches the systemic circulation
and accumulates as well as its metabolite (N-desthyl) in red
Table 5 The mean central foveal thickness
Time
Foveal thickness,
mean±SD (range), µm
P
a
Decrease in
thickness (%)
Baseline 535.27±97.4 (320-653)
1wk 420.87±115.2 (260-586) <0.001 21.4
1mo 357.43±125.8 (177-554) <0.001 33.2
3mo 376.23±114.5 (195-620) <0.001 29.7
a
Paired samples t-test vs baseline. SD: Standard deviation.
Table 6 The mean HbA1c among the responders and non-responders
HbA1c
Responders
(n=56 eyes)
Non-responders
(n=37 eyes)
P
a
Baseline 7.32±0.35 8.72±0.76 <0.001
Posttreatment 7.16 ±0.35 8.69±0.74 <0.001
a
Independent t-test. HbA1c: Glycosylated hemoglobin A1c; SD:
Standard deviation.
Figure 1 Mean BCVA prior and after treatment with topical
dorzolamide 2% BCVA: Best corrected visual acuity.
Figure 2 Mean CFT prior and after treatment with topical
dorzolamide 2% CFT: Central foveal thickness.
Topical dorzolamide 2% for DME
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Tel: 8629-82245172 8629-82210956 Email: ijopress@163.com
blood cells (RBCs). After the cease of the drug, its RBCs
concentration initially shows a sudden decline followed by
slower nonlinear wash-out of RBCs resulting in a prolonged
half-life of the elimination phase up to four months
[38]
.
The prolonged effect of dorzolamide is mostly related to the
incomplete washout of the drug from the eye. Until now, there
is no consensus regarding the complete washout period of
topical anti-glaucomatous drops. According to the published
literature; it varies from 4 to 8wk
[39]
. In the current work, the
IOP decreased until the first month then started to increase
again in the third month.
The current study confirms a promising effect of topical
dorzolamide in visual improvement and CMT reduction within
three months. To the authors’ knowledge, there have not been
published trials of the ecacy of topical dorzolamide 2% as a
rst-line treatment for diabetic CME. Recent trials investigated
its additive role to the intravitreal anti-VEGFs and reported
promising effects
[40-41]
. This novel study also has attempted
to evaluate a less invasive approach than the intravitreal
one in non-refractory diabetic edema with fewer potential
complications. The absence of a randomized design and a
control group are the limitations of the present study. Further
randomized investigations of a larger number of cases with
longer follow-up will be needed.
In conclusion, the current study suggests that topical
dorzolamide 2% can be promising, effective, affordable, and
safe therapy in treating non-refractory diabetic CME. The poor
control of diabetes mellitus and elevated serum HbA1c might
contribute to unsatisfactory treatment outcomes.
ACKNOWLEDGEMENTS
The manuscript was accepted in part at 10
th
International
Conference on Clinical & Experimental Ophthalmology
(Dubai, UAE) as oral presentation and the abstract published
as a conference paper in J Clin Exp Ophthalmol. DOI:
10.4172/2155-9570.C1.048.
Conicts of Interest: Badawi AE, None; Mokbel TH, None;
Elhefney EM, None; Hagras SM, None; Abdelhameed AG,
None.
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