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Change in Visual Acuity in Relation to Central Macular Thickness after Intravitreal Bevacizumab in Diabetic Macular Edema

Purpose: To evaluate the change in visual acuity (Log MAR) in relation to decrease in central macular thickness, after a single dose of intravitreal Bevacizumab injection. Study Design: Quasi experimental study. Place and Duration of Study: Rahbar Medical & Dental College, Punjab Rangers Teaching Hospital, Lahore, from January 2019 to June 2019. Material and Methods: 70 eyes of 70 patients diagnosed with diabetic macular edema were included in the study. Patients having high refractive errors (spherical equivalent of > ± 7.5D) and visual acuity worse than +1.2 or better than +0.2 on log MAR were excluded. Patients with ocular diseases other than diabetic macular edema were also excluded. Central macular edema was measured in μm on OCT and visual acuity was documented using Log MAR chart. These values were documented before and at 01 month after injection with intravitreal Bevacizumab (1.25 mg in 0.05 ml). Wilcoxon Signed rank test was used to evaluate the difference in VA before and after the anti-VEGF injection. Difference in visual acuity and macular edema (central) was observed, analyzed and represented in p value. P value was considered statistically significant if it was less than 0.01%. Results: Mean age of patients was 52.61 ± 1.3. Vision improved from 0.90 ± 0.02 to 0.84 ± 0.02 on log MAR chart. The change was statistically significant with p value < 0.001. Central macular thickness reduced from 328 ± 14 to 283 ± 10.6 μm on OCT after intravitreal anti-VEGF, with significant p value < 0.001. Conclusion: A 45 μm reduction in central macular thickness was associated with 0.1 Log MAR unit improvement in visual acuity after intravitreal Bevacizumab in diabetic macular edema.


INTRODUCTION
Diabetic macular edema results in increased central retinal thickness at macula which is a sight threatening condition. This increased thickness leads to reduction in visual acuity. Currently, intravitreal anti-VEGF drugs are recommended for management of diabetic macular edema 1 . These drugs are safe, decrease macular edema and restore vision. Amongst the various anti-VEGF agents available, Bevacizumab (1.25 mg in 0.05 ml) has revolutionized the management of diabetic macular edema in recent years. It is used off label in the developing world 2,3 . It is a humanized monoclonal antibody that swathes with all isoforms of vascular endothelial growth factors-A, with a molecular mass of 149 kDa that effectively binds and inhibits all the isoforms of VEGF 4,5 . Significant decrease in leakage from vessels has also been observed in proliferative diabetic retinopathy treated with single dose of intravitreal Bevacizumab (1.25 mg) 6 . It results in improved visual acuity (VA) with reduction in macular thickness 7 . Anti-VEGF or implantable dexamethasone with or without retinal laser are considered to be the treatment of choice in DME 8 . Improvement in diabetic macular edema is gauged by repeatedly measuring central retinal thickness, before and after the start of treatment using high resolution OCT (optical coherence tomography), a diagnostic tool for management of retinal diseases 9,10 .
The aim of this prospective study was to correlate the improvement in visual acuity with the corresponding reduction in central macular thickness after a single dose of intravitreal Bevacizumab therapy in patients with diabetic macular edema.

MATERIAL AND METHODS
The study was conducted at the Department of Ophthalmology Rahbar Medical & Dental College, Punjab Rangers Teaching Hospital, Lahore after approval from the ethical committee. In this Quasi experimental study, 70 eyes with diabetic macular edema were enrolled, having a clear media for OCT with minimum of 3 mm pupil diameter and best corrected visual acuity (BCVA) of +0.2 to +1.2 on log MAR with snellen equivalent of 6/12 to 6/120.
The patients having high refractive errors (spherical equivalent of > ± 7.5D) and visual acuity worse than +1.2 or better than +0.2 on log MAR were excluded. Any other ocular condition in which after treatment, the improvement in vision was not significant (e.g. ocular degenerative/dystrophic changes) and patients having any media opacity that could affect the visual acuity and OCT measurements were also excluded.
In the selected patients, prior to intravitreal injection of anti-VEGF, LogMAR distance visual acuity was recorded and a full ophthalmological examination including evaluation of refractive status, slit lamp examination for anterior and posterior segments was performed. Based on the clinical findings diabetic macular edema was diagnosed and the central macular thicknesswas measured in micron meter (µm) on OCT (NIDEK RS-3000 Advance). In selected patients, single dose of intravitreal anti-VEGF was injected by senior consultant ophthalmologist. Distance visual acuity and OCT parameters were re-evaluated one month after the intravitreal anti-VEGF therapy.
Data was analyzed using SPSS version 22. Quantitative data was represented as mean ± S.D. and S.E. while the qualitative data was represented in the form of pie chart.

RESULTS
A total of 70 eyes of 70 patients, 40 (57%) males and 30 (43%) females were enrolled in this research by convenient sampling technique. Mean age of the patients was 52.61 ± 1.3 with minimum age of 22 years and maximum 74 years (Table 1). Normality   Wilcoxon Signed rank test was used to evaluate the difference in VA before and after the anti-VEGF injection. It improved from 0.90 ± 0.02 to 0.84 ± 0.02 on log MAR chart. The change was statistically significant with p value < 0.001. Central macular thickness reduced from 328 ± 14 to 283 ± 10.6 µm on OCT after intravitreal anti-VEGF, with significant p value < 0.001 (Table 4).

DISCUSSION
Clinical evidence has established that increase in central macular thickness in diabetic macular edema results in corresponding decrease in visual acuity, and the treatment which reduces the retinal thickening improves vision. OCT can detect macular edema that is not clinically evident, and several OCT-derived biomarkers are useful predictors of its progression, severity, and visual outcome 11 . In this study, we documented the correlational change after a single injection of intravitreal bevacizumab injection between visual acuity and central macular thickness on OCT.
At any given central macular thickness, there was a corresponding significant change in visual acuity. Many eyes with significant macular edema had very good visual acuity and eyes with mild edema exhibited a profound decrease in vision. It is also reported that there is inconsistence increase in thickness of central macular point with the increase in visual acuity as well as incongruous decrease in thickness of central retina with the decrease in visual acuity is not common. 2 According to this, OCT measurement can be a good surrogate for visual acuity in macular edema related to diabetes.
Diabetic macular edema is the major clinical factor affecting visual acuity in diabetic retinopathy and is quantified for assessment and response to treatment by the central retinal thickness measured by OCT. Visual acuity is inversely related to the retinal thickness to some extent. In this study we found a strong correlation of visual acuity with OCT measurements of macular thickness (r 2 = -0.46). After the intravitreal bevacizumab therapy, the visual acuity improved with the reduction in retinal thickness. This study has shown that after a single dose of Bevacizumab therapy the central retinal thickness on OCT improved from 328 ± 14 to 283 ± 10.6 µm with a corresponding improvement in the mean visual acuity from 0.9 ± 0.02 to 0.84 ± 0.02 with significant p value ˂0.01.
Recent studies have suggested that anti-VEGF drugs are safe, cost effective, and easily admissible in clinical settings, well tolerated by the patients and remarkably well suited for treating macular edema secondary to diabetes. The efficacy of bevacizumab (1.25 mg) has been demonstrated in a study conducted on patients having diabetic macular edema. There was significant decrease in area of leaking vessels in proliferative diabetic retinopathy when treated with single dose of intravitreal bevacizumab (1.25 mg). There was a significant improvement in mean visual acuity associated with it 8 . These studies reported that often in bilateral DME, Bevacizumab effects reduction in macular thickness in un-injected fellow eye and improvement in visual acuity was seen in 40% eyes injected with Bevacizumab 12 .
According to previous studies, significant improvement of visual acuity was appreciated in diabetic macular edema with Bevacizumab when combined with dexamethasone, as compared to Bevacizumab monotherapy 13 . In this study, efficacy of treating diabetic macular with Anti-VEGF injection bevacizumab in diabetic patients was documented. Visual Acuity on Log MAR chart and central retinal thickness on OCT were the efficacy markers that were documented.
The mean BCVA on Log MAR chart at the start of the treatment was 0.42+/-0.14 Log MAR units. There was a significant improvement from baseline to 0.34+/-0.13, 0.25+/-0.12 and 0.17+/-0.12 Log MAR units at 1 monthly intervals after the three injections. At final visit at 6 months, the visual acuity was 0.16+/-0.14 Log Mar units. With a P value of P > 0.0001, the difference was statistically significant. The mean central retinal thickness of central 1 mm area improved from 452.9 +/-143.1 microns at base linento 279.8 +/-65.2 microns (P < 0.0001) on the final visit. 14 Another study also suggested that Bevacizumab is helpful in significant macular edema reduction and visual acuity improvement in wet age related Macular Degeneration. 15 In their study Santos et al. described the factors affecting response to intravitreal anti-VEGF injections in patients of diabetic macular edema. They found that BCVA improved from 4.78 and 5.52 letters, and a central retinal thickness decreased from 80.25 and 106.12 microns after 3 and 6 months of treatment. They concluded that optimal responders to anti-VEGF therapy could be identified based on their response to decrease in central retinal thickness and hence, could be a predictor of BCVA improvement after the treatment 16 .
Mansourian et al determined the efficacy of a single anti-VEGF injection of bevacizumab as primary treatment for diabetic macular edema. They compared the response to treatment using bevacizumab alone, in combination with intravitreal triamcinolone acetonide and compared the response to macular laser photocoagulation. The result showed no significant difference between these two treatments in reducing the central macular thickness with improvement in visual acuity 17 .
Yang et al compared the visual acuity, central retinal thickness and retinal sensitivity in different types of macular edema. He found that there was positive correlation between central foveal thickness and log MAR BCVA in patients with focal, diffuse and ischemic diabetic macular edema (r = 0.56, -0.62; P < 0.01). 18 Recent studies showed that visual outcome improves significantly if anti-VEGF therapy is started earlier in the course of disease. Patients presenting earlier with a shorter history of symptoms had better improvement in visual acuity and sustained decrease in central retinal thickness, 6 months after treatment. However patients with a prolonged disease history, the central retinal thickness and visual acuity at 3 months and 6 months post treatment would not be significantly different from baseline values at the start of treatment 19 . Thus, based on these results early treatment of macular edema is indicated for better and sustained anatomical and visual results. Thus earlier detection of reduced visual acuity is significantly important for the treatment of recurring macular edema. Another study highlighted the correlation between central subfield thickness and baseline visual acuity after treatment with Bevacizumab 20 .
Consistent with other studies, younger age of patients with diabetic macular edema was associated with significantly improved visual acuity s and reduced central retinal thickness after every 6 weeks of treatment. However, if the treatment is delayed by more than 6 weeks, repetition of intravitreal bevacizumab would not result in significant visual improvement 22 .
Limitation of our study was the small sample size. We did not study the association of vascular patterns of macula on OCTA with decreased visual acuity, which is also a contributory factor in decreased visual acuity.

CONCLUSION
Thus based on our study results, 45µm reduction in central macular thickness is associated with 0.1 LogMAR unit improvement in visual acuity in patients with Diabetic Macular edema after a single dose of Intravitreal Bevacizumab (1.25 mg).

Ethical Approval
The study was approved by the Institutional review board/Ethical review board.