|Year : 2018 | Volume
| Issue : 2 | Page : 134-139
Evaluation of topical α-2 agonist in the treatment of mixed diabetic maculopathy
Basem M Ibrahim, Haitham Y Al-Nashar
Departments of Ophthalmology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
|Date of Submission||02-Nov-2017|
|Date of Acceptance||02-Jan-2018|
|Date of Web Publication||7-Jun-2018|
Basem M Ibrahim
Department of Ophthalmology, Faculty of Medicine, Zagazig University, Zagazig 44519
Source of Support: None, Conflict of Interest: None
Purpose To evaluate the efficacy of topical α-2 agonist (brimonidine) in the treatment of mixed diabetic maculopathy (with edema and ischemia).
Design This is a prospective randomized case series.
Patients and methods Thirty eyes of 30 patients were included in this study. All eyes had mixed diabetic maculopathy as diagnosed by fluorescein angiography and spectral domain optical coherence tomography. The cases were divided into two groups: group I (15 eyes) was treated by intravitreal triamcinolone injection and topical brimonidine twice daily for 3 months, and group II (15 eyes) was treated only by intravitreal triamcinolone injection. Visual acuity, fluorescein angiography, and optical coherence tomography were done for all patients before the beginning of the treatment and every month for 3 months to detect the changes in logarithm of minimal angle of resolution (logMAR) visual acuity and the changes in the size of the foveal avascular zone and macular thickness.
Results The mean logMAR visual acuity improved from 0.9±0.012 to 0.4±0.1 in group I and from 0.8±0.1 to 0.5±0.02 in group II after 3 months of treatment, with a statistically significant difference between the two groups (P=0.01). The mean central macular thickness improved from 475±25 to 395±11 μm in group I and from 480±14 to 387±9 μm in group II after 3 months of treatment, with no statistically significant difference between the two groups (P=0.5). There was more improvement in the size of the foveal avascular zone with fewer disturbances of its edges in group I when compared with group II throughout the follow-up period. The mean intraocular pressure after 3 months of treatment was 11.5±0.1 mmHg in group I and 18.5±0.02 mmHg in group II, with a significant difference between the two groups (P=0.01).
Conclusion α-2 Agonist (brimonidine) has a role in the treatment of mixed diabetic maculopathy.
Keywords: α-agonist, brimonidine, diabetes, ischemic maculopathy, macular edema
|How to cite this article:|
Ibrahim BM, Al-Nashar HY. Evaluation of topical α-2 agonist in the treatment of mixed diabetic maculopathy. Delta J Ophthalmol 2018;19:134-9
|How to cite this URL:|
Ibrahim BM, Al-Nashar HY. Evaluation of topical α-2 agonist in the treatment of mixed diabetic maculopathy. Delta J Ophthalmol [serial online] 2018 [cited 2018 Aug 19];19:134-9. Available from: http://www.djo.eg.net/text.asp?2018/19/2/134/233937
| Introduction|| |
Diabetic maculopathy is one of the manifestations of diabetes in the eye. It is the main cause of visual impairment in diabetic patients, and it is a reflection of the advanced biochemical and pathophysiological processes on the level of retinal microcirculation .
The type of diabetic maculopathy whether edematous, ischemic, or mixed is determined according to the angiographic findings and clinical characteristics. Dominant ischemic maculopathy is the one where capillary ‘drop out’ on perifoveolar capillary net is present for more than 6 h . Mixed type of maculopathy has microaneurysms with diffuse leakage with one or more zones of ischemia .
Neuroprotection of retinal neuronal cells may inhibit apoptosis associated with ischemic maculopathy . Brimonidine is an α-2 adrenergic agonist that is 1000-fold more selective for the α-2 adrenoreceptors than the α-1 adrenoreceptors . α-2 Agonists prevent progressive retinal ganglion cell damage and enhance its resistance to stress. Brimonidine reduces intraocular pressure (IOP), increases ocular perfusion, and improves microcirculation of the retina, so it reduces the ischemia at the capillary level of the macula . Brimonidine also up-regulates the brain-derived neurotrophic factor in the retina, so it decreases the damage of retinal ganglion cells .
The aim of this work was to evaluate the efficacy of topical α-2 agonist (brimonidine) in the treatment of diabetic maculopathy with mixed edema and ischemia.
| Patients and methods|| |
This study was carried out between November 2016 and June 2017 in Al-Fat’h Eye Hospital, Zagazig City, Sharkia Governorate, Egypt. The study was approved by the Local Ethical Committee in Al-Fat’h Eye Hospital. Written consent was signed by all the patients and included an explanation of the study.
This is a randomized prospective study to investigate the value of topical α-2 agonist (brimonidine) in the treatment of mixed diabetic maculopathy.
Thirty eyes of 30 patients were involved in this study. Detailed history was taken from all patients, including age, sex, type, and duration of diabetes. Best-corrected visual acuity (BCVA) was tested for all patients before beginning of the treatment.
All eyes had mixed diabetic maculopathy as diagnosed by fluorescein angiography (FA) (Topcon fundus camera TRC 50DX; Topcon, Tokyo, Japan) and spectral domain optical coherence tomography (SD-OCT) (Spectralis HRA-OCT; Heidelberg Engineering, Inc., Germany) ([Figure 1]).
|Figure 1 Pretreatment fundus fluorescein angiography and optical coherence tomography examination showing mixed diabetic maculopathy (the red irregular line in fluorescein angiography represent the widened irregular foveal avascular zone).|
Click here to view
Cases were randomly distributed between two groups according to their order of presentation. Group I included 15 eyes that were treated by both intravitreal triamcinolone injection (Kenacort A 40 mg/1 ml; GSK-GlaxoSmithKline, Al Salam City, Cairo, Egypt) and topical brimonidine 0.15% eye drops twice daily (Alphagan P; Allergan, Waco, Texas, USA). Group II included 15 eyes that were treated by intravitreal injection of triamcinolone only. Triamcinolone (4 mg in 0.1 ml) was injected intravitreally by 27-G needle at a distance from the limbus of 4 mm in phakic eyes and 3.5 mm in aphakic and pseudophakic eyes.
BCVA, FA, and OCT were done for all patients before the beginning of the treatment and every month for 3 months. The changes in logarithm of minimal angle of resolution (logMAR) visual acuity, size of foveal avascular zone (FAZ), and the macular thickness were detected and recorded.
| Results|| |
This study included 30 eyes of 30 patients. They were divided into two groups: group I included 15 eyes of 15 patients with a mean age of 52±2.1 years (range: 42–67 years), and group II included 15 eyes of 15 patients with a mean age of 54±1.9 years (range: 49–66 years). Sixteen patients were females (nine in group I and seven in group II) and 14 were males (six in group I and eight in group II). The mean duration of diabetes was 11±1.3 years (range: 6–17 years) in group I and 10±1.1 years in group II.
The mean logMAR best-corrected visual acuity at the beginning of the treatment was 0.9±0.012 in group I (range from 1.00 to 0.7) and 0.8±0.10 in group II (range from 1.00 to 0.7), with no significant difference between the two groups (P=0.3).
The mean logMAR in group I improved to 0.6±0.03 at 1 month, 0.5±0.02 at 2 months, and 0.4±0.1 after 3 months. In group II, it improved to 0.7±0.1, 0.6±0.15 and 0.5±0.02 at 1, 2, and 3 months, respectively. The BCVA significantly improved more in group I in comparison with group II ([Table 1]).
The mean central macular thickness (CMT) was 475±25 μm in group I (range: 450–515 μm) and 480±14 μm in group II (range: 445–520 μm) at the beginning of the treatment, with no significant difference between the two groups (P=0.4). The mean CMT in group I improved to 415±18 μm at 1 month, 402±12 μm at 2 months, and 395±11 μm after 3 months. In group II, it improved to 409±14, 400±21, and 387±9 μm at 1, 2, and 3 months, respectively. There was no significant difference in CMT between the two groups in the whole period of follow-up ([Table 2] and [Figure 2]).
|Figure 2 Marked improvement of macular thickness after 1 month of intravitreal steroid injection.|
Click here to view
Repeated intravitreal steroid injections (4 mg in 0.1 ml) were needed in eyes that showed inadequate improvement in CMT (≥400 μm by OCT) or still had edema involving the center of the macula after 1 month from the first injection. Nine eyes (four in group I and five in group II) needed one or more additional injections. In group I, three eyes were re-injected once after the first month whereas one eye needed another two injections (at first and second month). In group II, three eyes were re-injected once after the first month whereas two eyes needed another two injections (at first and second month).
FA before treatment showed that the FAZ was widened than its normal size with a disturbance of its edges in both groups. After treatment, the size of the FAZ improved progressively with fewer disturbances of its edges when compared with the previous imaging, and this was much more evident in group I ([Figure 3]).
|Figure 3 Improvement of capillary drop out around the foveal avascular zone after 2 months of treatment with brimonidine eye drops in group I.|
Click here to view
The mean IOP at the beginning of treatment was 15.3±0.5 mmHg in group I (range: 12–21 mmHg) and 14.2±0.1 mmHg in group II (range: 13–19 mmHg), with no significant difference between the two groups (P=0.5). The mean IOP in group I was 12.1±0.3 mmHg at 1 month, 11.7±0.2 mmHg at 2 months, and 11.5±0.1 mmHg after 3 months. In group II, it was 18.7±0.1, 19.6±0.15, and 18.5±0.02 mmHg at 1, 2, and 3 months, respectively. The IOP was statistically significantly lower in group I in comparison with group II. No antiglaucomatous drugs were used in group II except in three cases that showed marked increase in IOP in which topical timolol with prostaglandin analogue was used ([Table 3]).
| Discussion|| |
Diabetic macular edema is characterized by the presence of retinal edema at the posterior pole of the retina between the temporal vascular arcades. It results from the accumulation of fluid and other plasma materials (lipids and lipoproteins) in the retina .
According to clinical manifestations and angiographic findings, there are several types of diabetic maculopathy. In the extensive analysis of diabetic lesions of the macula conducted by Bailey et al. , the exudative type of maculopathy prevailed and was found in ∼70% of the patients. Mixed type of maculopathy, which has been dominant, is a result of greater impairment of macular capillary net.
Changes that occur in the retina during the course of the diabetic disease are the result of continual chronic repetitive damages where one degree of the disease leads to another one, more advanced, which increases the risk of visual impairment .
Macular ischemia is a devastating condition that causes irreversible visual loss. It occurs more in type I diabetes. Pathogenesis of macular ischemia includes basement membrane thickening, increased viscosity of blood, and endothelial cell damage. This results in closure of perifoveal capillaries as evidenced by irregular widening of the FAZ and budding of capillaries into FAZ on fundus FA .
α-Adrenergic agonists (brimonidine) are used in the treatment of glaucoma by decreasing the production of aqueous fluid by the ciliary body of the eye and also by increasing the uveo-scleral outflow. It also has a neuroprotective effect on the retinal nerve fiber layer .
In this study, 30 eyes with mixed diabetic maculopathy (having both macular edema and ischemia) were treated by two modalities: 15 eyes with both intravitreal steroid and topical α-2 agonist and the other 15 eyes with intravitreal steroid only.In the present study, the macular edema and macular thickness improved in both groups, as expected, with intravitreal steroid injection. The macular ischemia improved in the eyes that received topical α-2 agonist treatment. This improvement was detected by significant visual acuity improvement in comparison with the other group which was not treated by α-2 agonist and by the area of macular ischemia that was detected by FA to be reduced with topical brimonidine treatment. This was in accordance with the results of Gupta et al.  who studied the effect of brimonidine drops, twice daily for 6 months, in the treatment of clinically significant macular edema in diabetic maculopathy with ischemic changes. They found that the FAZ area and radius were significantly improved in the study group when compared with a control group. There was improvement in visual acuity in both groups, but the difference was insignificant between the brimonidine group and the control group. They concluded that brimonidine may have a role in the treatment of ischemic macula in clinically significant macular edema .
Jyotirmoy et al.  investigated the effect of systemic brimonidine on retinal ischemia and retinal and choroidal neovascularization in a mouse model of retinopathy of prematurity and laser-treated rats. They concluded that brimonidine treatment significantly decreased vitreoretinal vascular endothelial growth factor concentrations, retinal and choroidal neovascularization, and retinal vascular leakage, in animal models of retinopathy of prematurity and choroidal neovascularization. Brimonidine may prevent underlying event(s) of ischemia responsible for the production of vascular endothelial growth factor and consequently reduces retinal-choroidal neovascularization and vascular leakage.
As topical α-2 agonist has a lowering effect on the IOP, a statistically significant difference was found between the two groups in IOP during the follow-up period. No antiglaucoma drugs were used in group II except for three cases with marked increase in IOP and in whom topical timolol with prostaglandin analogue was used.
The results obtained in this study suggest that the use of topical α-2 receptor agonist has an effect on the treatment of mixed maculopathy in combination with intravitreal steroid injection, as the topical α-2 agonist improved the ischemic element in mixed maculopathy.
| Conclusion|| |
α-2 Agonist (brimonidine) has a role in the treatment of macular ischemia in cases of mixed diabetic maculopathy. It improved the macular ischemia with increase in visual acuity.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bek T. Diabetic maculopathy caused by disturbances in retinal vasomotion. A new hypothesis. Acta Ophthalmol Scand 1999; 77:376–380.
Balasubramanyam M, Rema M, Premanand C. Biochemical and molecular mechanisms of diabetic retinopathy. Curr Sci 2002; 83:112–115.
Unoki N, Nishijima K, Sakamoto A. Retinal sensitivity loss and structural disturbance in areas of capillary non-perfusion of eyes with diabetic retinopathy. Am J Ophthalmol 2007; 144:755–760.
Jonas JB, Martus P, Degenring RF, Kreissig I, Akkoyun I. Predictive factors for visual acuity after intravitreal triamcinolone treatment for diabetic macular edema. Arch Ophthalmol 2005; 123:1338–1343.
Bailey CC, Sparrow JM, Grey RH, Cheng H. The national diabetic retinopathy laser treatment. Eye 1998; 12:69–76.
Brownlee M. The pathobiology of diabetic complications. A unifying mechanism. Diabetes 2005; 54:1615–1625.
Hamanaka T, Akabane N, Yajima T, Takahashi T, Tanabe A. Retinal ischemia and angle neovascularization in proliferative diabetic retinopathy. Am J Ophthalmol 2001; 132:648–658.
Conrath J, Giorgi R, Raccah D, Ridings B. Foveal avascular zone in diabetic retinopathy: quantitative versus qualitative assessment. Eye (Lond) 2005; 19:322–326.
Dubis AM, Hansen BR, Cooper RF, Beringer J, Dubra A, Carroll J. The relationship between the foveal avascular zone and foveal pit morphology. Invest Ophthalmol Vis Sci 2012; 53:1628–1636.
Hussain B, Saleh GM, Sivaprasad S, Hammond CJ. Changing from Snellen to LogMAR: debate or delay? Clin Exp Ophthalmol 2006; 34:6–8.
Cantor LB. Brimonidine in the treatment of glaucoma and ocular hypertension. Ther Clin Risk Manag 2006; 2:337–346.
Gupta PC, Sood S, Narang S, Ichhpujani P. Role of brimonidine in the treatment of clinically significant macular edema with ischemic changes in diabetic maculopathy. Int Ophthalmol 2014; 34:787–792.
Jyotirmoy K, Edwin P, Sheila Z, Yanyan B, Juanjuan W, Zhiming S et al.
Effect of brimonidine on retinal and choroidal neovascularization in a mouse model of retinopathy of prematurity and laser-treated rats. Invest Ophthalmol Vis Sci 2011; 52:5424–5431.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]