Introduction: other anti-VEGFs in the treatment of CRVO.

Introduction:

Central retinal vein occlusion (CRVO) is one of the most common retinal vascular disorders with potential risk of profound and permanent visual loss. The visual prognosis of the eyes of CRVO often depends on the type of retinal vein occlusion, time of presentation, the severity of retinal ischemia and macular edema (ME). ME is a major risk factor for visual loss. ME  associated predominantly with cystoid changes or chronicity (>8 months), often can lead to  permanent vision loss mainly due to the insult to the visual components at microscopic levels .(1)

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Macular edema secondary to retinal vein occlusion is thought to be caused by vasculogenic or inflammatory mechanism or both. (2) After Rosenfeld et al (3) reported that Bevacizumab can successfully resolve macular edema due to retinal vein occlusion, it has gained popularity and has been widely used as an off-label treatment for this pathology. It still remains a mainstay of treatment in many countries  around the world.(4)

 

There have been numerous reports regarding both the benefits and disadvantages of the use of Bevacizumab and other anti-VEGFs in the treatment of CRVO.  Recently, a rather surprising complication- formation of macular holes in the eye in cases treated with Bevacizumab for ME secondary to CRVO  has started being documented in cases around the world.(5–7)

 

 Georgalas et al(5) have reported the development of a full thickness macular hole (FTMH) in a 44-year-old patient with cystoid macular edema secondary to central retinal vein occlusion after treatment with an intravitreal injection of Bevacizumab. Similarly, Nagpal et al(6) have also reported another case where the full-thickness macular hole was noticed one month after intravitreal bevacizumab for macular edema secondary to hemi-central retinal vein occlusion.In another report,  Muramatsu et al(7) report the formation of a full thickness macular hole in a 63-year-old just after nine days after injection of Ranibizumab for treatment of ME due to CRVO.

 

With growing evidence suggesting the possibility of formation of macular hole with use of an anti-VEGFs while being used for the treatment of CRVO, we analyzed major literature review by Ghasemi Falavarjani et al (8) and a report by George J Manayath et al (4) on long-term analysis of eyes treated with Bevacizumab for CME secondary to CRVO .We found no mentioning on such association. To our knowledge, no study has evaluated the association of macular hole following anti-VEGF treatment in patients with macular edema secondary to CRVO. Accordingly, the purpose of this study was to evaluate a possible relation and incidence of ME secondary to CRVO after use of bevacizumab , to determine whether the patients profile, existing systemic pathologies such as hypertension or Diabete ,’ baseline central macular thickness, the nature of the edema, status of the vitreous and subsequent response pose a risk for macular hole formation in cases of CRVO.

 

 

 

 

 

Methods

This is a prospective analytical study.We analyzed the treatment outcomes following intravitreal bevacizumab for macular edema secondary to central retinal vein occlusion.

This study was conducted at tertiary eye care center in Nepal – B.P Koirala Lions Centre for Ophthalmic Studies, Institute of Medicine and during the reporting period from May 2016 to Feb 2017, Thirty-four cases with CRVO were included. The diagnosis of CRVO was based on the fundus examination and Fundus Fluorescence angiography (FFA). The macular edema was classified as cystoid and non-cystoid. Criteria to label cystoid macular edema was adopted from the American Academy of Ophthalmology Preferred Practice Patterns-which defines Cystoid Macular Edema (CME) as retinal thickening of the macula due to a disruption of the normal blood-retinal barrier and accumulation of fluid within the intracellular spaces of the retina, primarily in the outer plexiform layer.(9)

The inclusion criteria for this study consisted newly diagnosed cases with macular edema due to CRVO and were treated initially with monthly anti-VEGF injections for 3 months.Patients were followed-up till 3 months.

Patients who had any of the following therapy in the study eye either prior to or during the initial 3 anti-VEGF injections were excluded: focal/grid laser photocoagulation, pan-retinal photocoagulation (PRP) or peri/ intravitreal injections (e.g. intravitreal or sub-Tenon’s injections of corticosteroids). Patients were also excluded if they had any of the following concomitant ocular diseases: diabetic macular edema, age-related macular degeneration, prior ocular surgery (except cataract surgery) and choroidal neovascularization. The results were analyzed using SPSS software (Ver 20.0)

All patients included in the study received central macular scan using the Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany) platform using the automated software in the 31-line raster scan pattern.Central macular thickness was measured at baseline and in subsequent follow-ups after each dose of bevacizumab using the built-in caliper.All scans were interpreted by two experienced vitreoretinal surgeons.

The clinical details reported from each case included laterality, number of treatment(s) utilized and the pre- and posttreatment central macular thickness (CMT) using Heidelberg Engineering Spectralis optical coherence tomography (OCT). Cases were observed for the response to anti-VEGF following each dose. During each follow-up, final central macular thickness and possible indicators for the development of macular holes in the case were evaluated.

 

RESULTS:

A total of 34 eyes from  34 patients diagnosed with CRVO were included in this study. 20 (58.8%) were male and 14(41.2%) were female. The mean time of presentation after symptoms developed was 4.1 days ± 1.6 days.

 

 Baseline characteristics of the patients are reported in table 1. Mean CMT for eyes diagnosed with CRVO at baseline was 645± 202 microns.

 

There were eighteen eyes with predominantly cystoid edema (52.9%) and sixteen (47.1%) with minimal cystoid changes. The CMT for eyes with predominantly cystoid edema was 706± 66microns and for minimally cystoid was 509± 54 microns.

 

Response to Bevacizumab and outcome

Eight (23.5%) of the CRVO eyes treated with anti-VEGF injections developed full thickness macular hole(FTMH) .The mean duration of formation of macular hole was 42.9 days with mean dose of 1.7 injection . (Figure 1) The mean age of patients with macular holes was 64.9 ± 11.3 years in contrast to patients not developing macular hole who had mean age of 56.6 ± 8.9 years( P=0.030)by the end of the study . 6(75%) of the patients who developed macular hole were female. Similarly, 5 out of the 8 patients developing macular hole had both hypertension and diabetes. 4 (50%) of the patients with macular hole were pseudophakic.(Table 1)

 

The eyes with predominately cystoid edema at baseline were found to have greater risk of developing macular hole following treatment. (OR 9.54, CI  95%  1.02 , 89.2 , p = 0.025)(Table 2) 7 out of 18 (38%) of eyes with CME developed macular hole while 7 out of  8 eye (87.5%) eye developing macular hole were predominately cystoid in nature at presentation. The eyes developing FTMH had mean baseline CMT baseline of 665 ± 82 microns  , which was significantly higher than eyes with  non-cystoid edema 536± 38 (p<0.05). The mean age of the patients who had predominantly cystoid macular edema was 66.2±7.1 years.   12 eyes (35.1%) of the eyes treated  developed evident vitreous detachment(VD) or Vitreomacular traction(VMT) in the course of the pathology after receiving Bevacizumab. (Figure 2) All of them had predominantely cystoid macular edema at baseline with mean CMT 701± 28 microns  None of the eyes when initially evaluated before treatment had VMT or VD. The peculiarity of this finding was that the average response after a single dose of bevacizumab in this group was 379.8± 42microns compared to other eyes which had an average response of 118.3±47microns. The average duration to treatment and detection of VD or VMT was 32.3 days This duration could however be misleading as most patients only followed up prior to their next injection – usually scheduled at 4 weeks after the previous injection.   Five out of these 12 eyes (35%)  developing VMT or VD developed macular hole. 4 of the eyes with vitreo-retinal abnormality had developed a FTMH by the time of their 2nd treatment schedule (mean duration – 34.4 days).(Figure 2) One eye which had no VMT/VD during the 1st follow-up presented with macular hole with VMT after 2nd injection of Bevacizumab on 51st day. The most common complaint  of the patients presenting with macular holes was sudden onset of shadow in the central visual field.     Discussion: Bevacizumab is widely accepted as an initial treatment for ME seconday to CRVO. The benefit of using anti-vegfs for treatment of this pathology needs no further description and has been reported in various studies. ( ). Many of the adverse effects have also been documented and reported in various studies. But very few literatures can be found regarding the formation of full thickness macular holes in eyes treated for ME due to CRVO.   We found that Age was an important factor – patients with age of 64.9 ± 11.3  were likely to develeop macular hole( P=0.030.) Age more than 65 years is a well established risk factor for development of spontaneous macular hole and an additive pathology such as ME secondary to CRVO may act as an catalyst to a predisposed risk. (ref)   The mean duration of formation of macular hole was 42.9 days with mean dose of 1.7 injection.23.5% of the CRVO eyes treated with bevacizumab developed macular hole.   7 out of  8 eyes (87.5%) eye developing macular hole were predominately cystoid in nature( OR 9.54, CI  95%  1.02 , 89.2 , p = 0.025)(Table 2) at baseline with CMT of 665 ± 82  compared to mean CMT eyes not develeoping macular hole 536± 38 (p<0.05). .The mean age of the patients who had predominantly cystoid macular edema was 66.2±7.1 years.   We also observed that following a single dose of bevacizumab, a mean decrease of CMT of 379.8± 42microns  could impose a risk of VMT or VD and macular hole in the later stages. 12 eyes (35.1%) of the eyes treated showed similar response and all developed VD or VMT after receiving Bevacizumab. VMT and VD are a known risk after injection of anti-vegfs(10) Although weak, the posterior vitreous has a very good adhesion around the foveolar and the parafoveolar region(11,12). Wong et al have described about better anatomical results in cases where spontaneous release of the VMT occurred.(13) None of our cases developed a spontaneous VMT release. 5( 41.6%) of these eyes developed full thickness macular hole.     Conclusion: Anti-vegf agents have been widely accepted as the first line of choice for treatment of ME secondary to CRVO. Our study highlights that macular hole formation may be associated with treatment with anti-vegf in certain groups of patients who demonstrate key pre-treatment and post treatment features.Age of 64.9 ± 11.3  ,patients with predominantly CME at presentation with baseline of 665 ± 82 microns and CMT decrease by over 379.8± 42microns  following a single dose of bevacizumab with production of VMT or VD are the risk factors that could indicate a possibility of FTMH formation later on the course. In such cases, initial treatment with alternative agents such as intravitreal steroids / implants may be considered.The results of these agents however should also be monitored and assessed and opens new doors for research in treatment of CRVO.    

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