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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 19  |  Issue : 1  |  Page : 58-64

Evaluation of early versus late intravitreal bevacizumab injection in the treatment of macular edema secondary to branch retinal vein occlusion


Department of Ophthalmology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Date of Submission17-May-2017
Date of Acceptance21-Sep-2017
Date of Web Publication1-Feb-2018

Correspondence Address:
Hesham A Enany
Department of Ophthalmology, Faculty of Medicine, Zagazig University, Zagazig 44519
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/DJO.DJO_38_17

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  Abstract 

Purpose
The aim of this study was to evaluate the efficacy and safety of early versus late use of bevacizumab (Avastin) as an intravitreal injection in cases with branch retinal vein occlusion (BRVO).
Patients and methods
Twenty patients with BRVO with macular edema were divided according to the time elapsed between presentation and the onset of the vascular event into two groups: group I included 10 patients presenting within 3 months of BRVO and group II included 10 patients with BRVO presenting after 3 months of the vascular event. Patients in both groups received three intravitreal injections of bevacizumab. The first injection was administered at presentation, and then monthly for two additional doses.
Results
Foveal thickness measured by optical coherence tomography in µm decreased significantly after the intravitreal bevacizumab injection in group I from 451.5±57.9 to 428.1±59.5 after 1 month, to 369.5±52.6 after 3 months, and to 342.4±41.1 after 6 months, whereas in group II, the foveal thickness was reduced from 440.3±75.5 to 437.3±70.3 after 1 month, to 419.1±63.1 after 3 months, and to 380.1+69.4 after 6 months, a statistically insignificant difference. Best-corrected visual acuity in log MAR at baseline in group I was 0.84+0.2 and improved to 0.74+0.19 at 1 month, 0.74+0.25 at 3 months, and 0.72+0.15 after 6 months, whereas in group II, BCVA in log Mar at baseline was 0.75+0.2 and improved after 1 month of intravitreal bevacizumab injection to 0.74±0.26, to 0.74±0.27 after 3 months, and to 0.70±0.27 after 6 months.
Conclusion
The study showed improved visual acuity following treatment of BRVO-associated macular edema with bevacizumab intravitreal injections. The benefit was greater in the patients who received the first injection early in the course of the disease and in patients in whom three injections were administered.

Keywords: bevacizumab, branch retinal vein occlusion, intravitreal, macular edema, retina


How to cite this article:
Enany HA. Evaluation of early versus late intravitreal bevacizumab injection in the treatment of macular edema secondary to branch retinal vein occlusion. Delta J Ophthalmol 2018;19:58-64

How to cite this URL:
Enany HA. Evaluation of early versus late intravitreal bevacizumab injection in the treatment of macular edema secondary to branch retinal vein occlusion. Delta J Ophthalmol [serial online] 2018 [cited 2018 Apr 19];19:58-64. Available from: http://www.djo.eg.net/text.asp?2018/19/1/58/224563


  Introduction Top


Retinal vein occlusions are the second most common severe vascular disorder. Branch retinal vein occlusion (BRVO) and central retinal occlusion (CRVO) are the two basic types of vein occlusion. BRVO is three times more common than CRVO and secondary to diabetic retinopathy as the most common retinal vascular cause of visual loss [1].

BRVO is the most common retinal disease encountered in clinical practice. It is usually a disease of the elderly, with 90% of patients being older than 50 years of age in a large series. Recognition of the disease is of paramount importance because its complications are a cause of significant visual morbidity [2].

BRVO induces variable functional deficits depending on the grade of vascular occlusion and its localization. BRVO may lead to significant reductions in central and paracentral retinal functions [3]. It causes a painless decrease in vision, resulting in misty or distorted vision. Its visual effects range from nil to severe visual loss. Multiple factors play a role in the pathogenesis of this visual loss, including macular edema (ME), macular hemorrhage, macular ischemia, and foveal hemorrhage, vitreous hemorrhage, epiretinal membrane, and retinal detachment [4].

The disruption of either the inner or the outer blood–retinal barrier is common in diseases associated with ME [5].

Treatment of any underlying systemic conditions is indicated. Although this only rarely reverses the vein occlusion, it might help to prevent the opposite eye from developing a vascular occlusion [6].

Treatment options for managing ME with BRVO include macular grid laser photocoagulation and intravitreal injections [7],[8],[9],[10],[11]. Laser therapy improves oxygenation to the treated area, causing constriction of the occluded vein and the adjacent arteriole, resulting in decreased edema [12]. Steroids such as triamcinolone and dexamethasone have anti-inflammatory and antiangiogenic properties that inhibit the expression of vascular endothelial growth factor (VEGF) and other proinflammatory cytokines. VEGF is known to promote edema [13].

A study comparing the efficacy of bevacizumab with grid laser photocoagulation reported that bevacizumab treatment resulted in better and faster visual recovery [14].

A number of studies have shown promising short-term effects of bevacizumab when used for ME with BRVO or CRVO. After an intravitreal bevacizumab injection (IVB), optical coherence tomography (OCT) shows an immediate reduction in foveal thickness and an improved visual acuity. In most reports, the morphologic effect of bevacizumab was studied on the basis of foveal thickness measured by OCT and visual function evaluated by visual acuity (VA) measurement [15].

For BRVO, spontaneous resolution usually occurs after a suitable waiting period. If BRVO does not resolve, therapy is initiated typically with anti-VEGF therapy, either ranibizumab or bevacizumab [16].

In patients with ME, an injection of bevacizumab (0.05 ml/1.25 mg) into the vitreous cavity through pars plana has been shown to be effective not only in resolving the edema but also in corresponding vision improvement. Injections of bevacizumab every 6 weeks for 6 months improve VA and significantly reduce edema compared with sham [17].

The aim of this study was to evaluate the efficacy and safety of an early versus a late bevacizumab (Avastin) intravitreal injection in cases of ME secondary to BRVO.


  Patients and methods Top


Twenty patients (15 men and five women) with a mean age of 55 years (ranging from 50 to 60 years) with BRVO were included in this study. These patients attended the Ophthalmic Outpatient Clinic, Zagazig University Hospitals, in the period from February 2014 to December 2015. All patients underwent a general examination; patients with uncontrolled hypertension or with a history of any other thromboembolic events or anticoagulant therapy were excluded.

Best-corrected visual acuity (BCVA) was measured with Snellen’s chart with log MAR equivalent. A complete slit-lamp examination, Goldmann applanation tonometery, and detailed fundus examination were performed for all patients.

Fluorescein angiography and OCT (using Spectralis Heidelberg Engineering, Heidelberg, Germany) were performed for all patients with BRVO to confirm ME and to measure macular thickness. ME secondary to BRVO was evidenced by diffuse leakage from perifoveal capillaries on fluorescein angiography and diffuse thickening of the macula on OCT with central macula thickness of more than 300 µm.

All patients in this study had BRVO with ME. Patients were divided into two groups according to the time interval from the onset of vascular event till seeking medical advice:
  1. Group I included 10 patients presenting within 3 months of BRVO.
  2. Group II included 10 patients presenting after 3 months of the vascular event.


Patients in both groups received three intravitreal injections of bevacizumab. The first injection was administered at presentation, and then monthly for two additional doses. Bevacizumab (1.25 mg in 0.05 ml) was injected intravitreally under complete aseptic conditions with adequate illumination.

VA and complications related to sterilization and the technique of intravitreal injection itself were carefully monitored and reported, including infection, noninfectious endophthalmitis, and iatrogenic injury of intraocular structures, retinal detachment, vitreous hemorrhage, or increase in intraocular pressure.

All data were collected and statically analyzed using SPSS 22.0 for Windows (SPSS Inc., Chicago, Illinois, USA)

Regular follow-up for all patients was performed on day 1, day 7, and the fourth week after each injection and then monthly for 3 months and at 6 months.

At each follow-up visit, a complete ophthalmological examination was performed including Goldmann applanation tonometry, slit-lamp, and fundus examination. OCT was performed 1, 3, and 6 months after the first injection.

The procedures followed were in accordance with the ethical standards of the Institutional Review Board and were approved by the board. A written consent was signed by all patients.


  Results Top


This study included 20 eyes of 20 patients with BRVO with ME ([Table 1]).
Table 1: Patients’ data

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In group I, foveal thickness decreased significantly from 451.5±57.9 µm at baseline to 428.1±59.5 µm at 1 month (P<0.05), 369+52.6 µm after 3 months (P<0.001), and 342.4±41.1 µm after 6 months (P<0.001) from the first injection ([Table 2] and [Figure 1],[Figure 2],[Figure 3]).
Table 2: Foveal thickness at baseline, 1 month, 3 months, and 6 months after intravitreal injection of bevacizumab

Click here to view
Figure 1: (a, b) Fluorescein angiogram of a case of branch retinal vein occlusion (group I) with macular edema after 1 month. (c) Optical coherence tomography (OCT) of the same case showing marked thickening of the macula (640 μm) with cystoid spaces within the inner retinal layers and neurosensory retinal detachment at the macula. (d) OCT after 6 months from the first injection of the three intravitreal bevacizumab injections, showing a marked decrease in foveal thickness (340 μm).

Click here to view
Figure 2: (a) Optical coherence tomography (OCT) of a case of branch retinal vein occlusion (group I) 1 month after onset showing marked cystoid edema with central macular thickness of 540 μm. (b) OCT after 6 months from the first injection of the three intravitreal bevacizumab injections, showing a marked decrease in foveal thickness (220 μm).

Click here to view
Figure 3: (a) Optical coherence tomography (OCT) of a case of branch retinal vein occlusion (group I) 1 month after onset, showing increased macular thickness (380 μm). (b) OCT after 6 months from the first injection of the three intravitreal bevacizumab injections, showing a marked decrease in foveal thickness (290 μm).

Click here to view


In group II, foveal thickness decreased from 440±75.5 µm at baseline to 437.3±70.3 µm at 1 month (P=0.41), 419±63.1 µm after 3 months (P=0.07), and 390.1±69.4 µm after 6 months (P=0.37) from the first injection. The reported change was statistically insignificant ([Table 2] and [Figure 4],[Figure 5],[Figure 6]). On comparison between P values in group I and group II, the difference was statistically significant.
Figure 4: (a) Colored photo of a case of branch retinal vein occlusion (group II) 5 months after onset, showing extensive macular edema. (b) Optical coherence tomography (OCT) of the same case showing marked thickening of the macula (570 μm) with cystoid spaces. (c, d) OCT after 6 months from the first injection of the three intravitreal bevacizumab injections, showing a mild decrease in foveal thickness (450 μm).

Click here to view
Figure 5: (a) Optical coherence tomography (OCT) of a case of branch retinal vein occlusion (group II) 4 months after onset, showing increased macular thickness (450 μm). (b) OCT after 6 months from the first injection of the three intravitreal bevacizumab injections showing a mild decrease in foveal thickness (390 μm).

Click here to view
Figure 6: (a) Optical coherence tomography (OCT) of a case of branch retinal vein occlusion (group II) 6 months after onset, showing increased central macular thickness (430 μm). (b) OCT after 6 months from the first injection of the three intravitreal bevacizumab injections, showing a mild decrease in foveal thickness (380 μm).

Click here to view


In group I, the mean BCVA improved significantly from 0.84±0.2 log MAR at baseline to 0.74±0.19 at 1 month (P<0.001), 0.74±0.25 log MAR (P<0.001) at 3 months, and 0.72±0.15 log MAR (P<0.001) at 6 months after the first injection. In group II, the mean BCVA changed from 0.75±0.2 LogMAR at baseline to 0.74±0.26 log MAR (P=0.26) at 1 month, 0.74±0.27 log MAR (P=0.3) at 3 months, and 0.70±0.27 log MAR (P= 0.15) at 6 months after the first injection. This change was statistically insignificant ([Table 3]). On comparison between P values in group I and group II, the difference was statistically significant.
Table 3: Best-corrected visual acuity in log MAR at baseline, 1, 3, and 6 months after intravitreal injection of bevacizumab

Click here to view


During the 6 months of follow-up, no intraocular or systemic adverse effects such as increased intraocular pressure, retinal tear, induced cataract formation, retinal detachment, inflammation, systemic hypertension, or thromboembolic events were recorded in the current study.

Conjunctival hyperemia was present in all patients and mild subconjunctival hemorrhage was found in five patients, but resolved within one week of injection.


  Discussion Top


BRVO is a frequent retinal vascular disease with an incidence of 2–14/1000/year in the population older than 40 years of age [18].

Intravitreal bevacizumab is an effective and long-lasting treatment for ME after BRVO [19]. In addition, bevacizumab treatment leads to improved visual function and decreased central retinal thickness in patients with BRVO with ME [20]. In one study, bevacizumab was used for the treatment of CRVO. VA, retinal thickness, and electroretinogram amplitudes were improved after bevacizumab treatment in patients with ME because of CRVO [21].

A phase III multicenter randomized study, comparing the efficacy and safety of ranibizumab injection compared with sham in patients with ME secondary to BRVO, showed that injections of ranibizumab provided rapid and effective treatment for BRVO [7].

The present study included 20 eyes of 20 patients with ME secondary to BRVO. Patients were divided into two groups according to the time elapsed from the onset of the vascular event to the first injection. All patients received an IVB at presentation and then monthly for two additional doses. The follow-up period was 6 months.

The duration of BRVO among cases in the present study ranged from 1 day to 3 months, with an average of 45.2±41.3 days in group I, and was more than 3 months, with an average 98.3±91.4 days in group II.

Rensch and colleagues studied 25 patients with shorter duration of 4.2±3.6 days from the onset of the vascular event to the first injection, but there was no comparative group of patients with late presentation. All patients received three IVB with an interval of 6 weeks between the injections. Rensch et al. [22] reported a significant increase in vision and a corresponding decrease in ME.

Pikkel and colleagues compared the effect of the protocol of three prescheduled bevacizumab injections starting within 1 month of a CRVO event with a single injection versus starting treatment after more than 3 months of the vascular event. The findings of this study indicated that the timing of treatment had a greater effect than the number of injections. Patients who received only one early bevacizumab injection 1 month after CRVO showed greater improvement in the final VA than patients who received three injections, the first of which was administered more than 2 months after a CRVO event [23]. The findings are in agreement with a published case series showing that bevacizumab treatment leads to improved visual function and decreased central retinal thickness (CRT) in patients with BRVO with ME. Although these studies showed beneficial effects of bevacizumab on both VA and CRT, they showed considerable variability in injection frequencies, follow-up duration, and treatment interval. Similarly, the study carried out by Kreutzer et al. on 27 patients is comparable to the present study. Kriechbaum and colleagues reported more dry macula patients after a single injection (80%), although 45% of the patients required more than one injection of bevacizumab. Three larger series published in 2008 arrived at similar conclusions; both prospective and retrospective analyses showed that repeated injections of bevacizumab are necessary for long-lasting results on VA and CRT [17],[18].

Kreutzer et al. [24] found that the mean retinal thickness at baseline decreased from 474 to 316 µm at sixth month after an intravitreal injection of 1.25 mg bevacizumab. Moreover, Cheng et al. [25] found that an IVB in BRVO improved VA and induced a significant decrease in ME on OCT examination. Furthermore, Wu et al. [26] showed that intravitreal bevacizumab in the treatment of BRVO reduced central macular thickness (CMT) in the 1.25 mg group from 453±140 to 244±125 µm versus 144±175 to 234±80 µm in the 2.5 mg group. In the present study, foveal thickness in µm decreased after an IVB in group I from 451.5±57.9 to 428.1±59.5 after 1 month, 369.5±52.6 after 3 months, and 342.4±41.1 after 6 months, whereas in group II, foveal thickness was reduced from 440.3±75.5 to 437.3±70.3 µm after 1 month, to 419.1±63.1 µm after 3 months, and to 380.1±69.4 µm after 6 months. It was noted that the difference between the two groups in the change in foveal thickness 1 month after the first injection was insignificant. However, it became significant at 3 and 6 months after the first injection. Similarly, Gunduz and Bakri [27] showed that the decrease in CMT between the baseline and 1 month, baseline and 6 months, and between baseline and the final follow-up was also statistically significant after the use of intravitreal bevacizumab for ME secondary to BRVO. Chen et al. [28] also found that in the IVB group, CMT decreased significantly from 457±98 µm at baseline to 299±83, 282±72, 316±84, and 323±86 µm at 4, 8, 12, and 24 weeks after treatment, respectively.

In the present study, BCVA in log MAR at baseline in group I was 0.84±0.2 and improved after 1 month of IVB injection to 0.74±0.19 and was 0.74±0.2 after 3 months and 0.72±0.15 after 6 months, whereas in group B, BCVA in log Mar at baseline was 0.75±0.2, and after 1 month of IVB injection, it was 0.74±0.26, after 3 months, it was 0.74±0.27, and after 6 months, it was 0.70±0.27. Gunduz and Bakri [27] reported that at a mean follow-up of 9–8 months (range: 6–17 months), the mean number of IVB injections administered was 4 (range: 1–6) and the differences in log MAR VA between baseline and 1 month, between baseline and 6 months, and between baseline and the final follow-up were significant.

Rush et al. [29] reported that early diagnosis and treatment of BRVO-associated ME was accompanied by reduced CMT. Moreover, the presenting BCVA was better in their study patients compared with the patients in the BRAVO trial.

In the current study, no intraocular or systemic adverse events were recorded during the 6 months of follow-up. Similarly, Chen et al. [28] reported that the intravitreal injections appeared to be well tolerated and patients did not experience immediate procedure-related complications or any obvious systemic adverse events following IVB injections.


  Conclusion Top


The findings of this study showed the efficacy of an early intravitreal injection of bevacizumab in the treatment of ME secondary to BRVO more than a late intravitreal injection of bevacizumab.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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