Branch retinal vein occlusion: treatment modalities: an update of the literature.

Seminars in Ophthalmology, 2014; 29(2): 85–107 ! Informa Healthcare USA, Inc. ISSN: 0882-0538 print / 1744-5205 online DOI: 10.3109/08820538.2013.833271

Branch Retinal Vein Occlusion: Treatment Modalities: An Update of the Literature Irini P. Chatziralli1,2, Adil Jaulim3, Vasileios G. Peponis2, Panagiotis G. Mitropoulos2, and Marilita M. Moschos4 Department of Ophthalmology, Barts and the London NHS Trust, London, UK, 2Second Eye Clinic, Specialized Eye Hospital ‘‘Ophthalmiatrion Athinon,’’ Athens, Greece, 3Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK, and 4 First Department of Ophthalmology, University of Athens, Athens, Greece

ABSTRACT Background: Retinal vein occlusion is the second most common retinal vascular disorder after diabetic retinopathy and is considered to be an important cause of visual loss. In this review, our purpose is to update the literature about the treatment alternatives for branch retinal vein occlusion. Methods: Eligible papers were identified by a comprehensive literature search of PubMed, using the terms ‘‘branch retinal vein occlusion,’’ ‘‘therapy,’’ ‘‘intervention,’’ ‘‘treatment,’’ ‘‘vitrectomy,’’ ‘‘sheathotomy,’’ ‘‘laser,’’ ‘‘anti-VEGF,’’ ‘‘pegaptanib,’’ ‘‘bevacizumab,’’ ‘‘ranibizumab,’’ ‘‘triamcinolone,’’ ‘‘dexamethasone,’’ ‘‘corticosteroids,’’ ‘‘non-steroids,’’ ‘‘diclofenac,’’ ‘‘hemodilution,’’ ‘‘fibrinolysis,’’ ‘‘tPA,’’ and ‘‘BRVO.’’ Additional papers were also selected from reference lists of papers identified by the electronic database search. Results: Treatment modalities were analyzed. Conclusions: There are several treatment modalities for branch retinal vein occlusion and specifically for its complications, such as macular edema, vitreous hemorrhage, retinal neovascularization, and retinal detachment, including anti-aggregative therapy and fibrinolysis, isovolemic hemodilution, vitrectomy with or without sheathotomy, peripheral scatter and macular grid retinal laser therapy, non-steroid agents, intravitreal steroids, and intravitreal anti-vascular endothelial growth factors (anti-VEGFs). Keywords: Anti-VEGF, BRVO, dexamethasone, laser photocoagulation, surgical, triamcinolone

INTRODUCTION

scatter and macular grid retinal laser therapy, non-steroid agents, intravitreal steroids, and intravitreal anti-vascular endothelial growth factors (antiVEGFs).3,4 The aforementioned treatment modalities are widely used for the management of BRVO complications, such as macular edema, vitreous hemorrhage, retinal neovascularization, and retinal detachment. The existing literature on BRVO treatment is elusive, as several studies of BRVO also include cases of CRVO or HRVO, although they have different natural courses and visual prognoses. In addition, patients are commonly recruited at different stages of the disease, making the comparison inaccurate. In this review, our purpose is to update the literature on the treatment modalities against BRVO.

Retinal vein occlusion (RVO) is the second most common retinal vascular disorder after diabetic retinopathy and is considered to be an important cause of visual loss.1,2 RVOs are divided into central (CRVO), hemi-retinal (HRVO), and branch retinal vein occlusions (BRVO).3,4 CRVO is an obstruction occurring within the central retinal vein, which is virtually the sole venous drainage source of the retina, while BRVO can be thought of as venous occlusion that occurs in any of the branches of the central retinal vein.3 There have been a great variety of treatment modalities for BRVO, including anti-aggregative therapy and fibrinolysis, isovolemic hemodilution, vitrectomy with or without sheathotomy, peripheral

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1

Received 27 July 2013; accepted 6 August 2013; published online 10 October 2013 Correspondence: Irini P. Chatziralli MD, MSc, 28, Papanastasiou Street, Agios Dimitrios, 17342, Athens, Greece. E-mail: [email protected]

85

86 I. P. Chatziralli et al. Eligible papers were identified by a comprehensive literature search of MEDLINE (PubMed), using the terms ‘‘branch retinal vein occlusion,’’ ‘‘therapy,’’ ‘‘intervention,’’ ‘‘treatment,’’ ‘‘vitrectomy,’’ ‘‘sheathotomy,’’ ‘‘laser,’’ ‘‘anti-VEGF,’’ ‘‘pegaptanib,’’ ‘‘bevacizumab,’’ ‘‘ranibizumab,’’ ‘‘triamcinolone,’’ ‘‘dexamethasone,’’ ‘‘corticosteroids,’’ ‘‘non-steroids,’’ ‘‘diclofenac,’’ ‘‘hemodilution,’’ ‘‘fibrinolysis,’’ ‘‘tPA,’’ and ‘‘BRVO.’’ Additional papers were also selected from reference lists of papers identified by the electronic database search. There were no language restrictions.


Anti-Aggregative Therapy and Fibrinolysis Antithrombotic and fibrinolytic factors have been used since the middle of the last century to limit the retinal damage during the acute phase and prevent possible complications, supporting the thrombotic hypothesis in the pathogenesis of BRVO.5 Houtsmuller et al., in a double-masked study, compared the effect of ticlopidine, an anti-platelet aggregative factor, versus placebo in 54 patients with BRVO (29 and 25 patients in each group, respectively) less than three weeks from the beginning of symptoms.6 They found a significant improvement in visual acuity in 69% BRVO patients of ticlopidine group versus 52% of the placebo group in a six-month follow-up, suggesting that ticlopidine was effective for BRVO treatment.6 Accordingly, Glacet-Bernard et al., in their double-blind randomized study, examined the effectiveness of troxerutin, an antierythrocyte and anti-platelet aggregative drug, versus placebo in 26 patients with BRVO less than five months from the onset of symptoms.7 In a two-year follow-up (only four months masked), there was a significant improvement in visual acuity, as well as in macular edema, in patients treated with troxerutin compared to those treated with placebo.7 In addition, there was less progression to ischemia in patients treated with troxerutin.7 However, this study had a small sample size and did not separate the results for patients with BRVO and CRVO.7 Thrombolysis using administration of tissue plasminogen activator (tPA) intravitreally or directly into the retinal vein is another medical treatment option for RVO.8–15 Steinkamp et al. found an improvement in visual acuity and retinal perfusion in eight of nine patients with BRVO treated with tPA in combination with heparin, in accordance with Hattenbach et al., who also found an improvement in visual acuity, as well as decrease of areas of capillary non-perfusion, in two of three patients with BRVO treated with lowdose recombinant tPA.9,11 The same group, presenting the results of the prospective, randomized, controlled ROLF study 10 years later, compared the effectiveness of low-dose recombinant tPA versus hemodilution

therapy in 11 patients with BRVO.12 They found no significant difference in BCVA between the two groups at the one-year follow-up, concluding that there was no evidence to support the use of thrombolysis for the management of BRVO.12 Specifically, they supported that thrombolysis was not associated with a lower risk of ocular neovascularization.12 On the contrary, Murakami et al., in a retrospective interventional case series of 17 eyes with macular edema due to BRVO treated with tPA, found a significant improvement in visual acuity and foveal thickness at the six-month follow-up, suggesting that tPA was an effective treatment for macular edema due to BRVO.13 Kumagai et al. provided the most recent evidence of the effectiveness of tPA in a retrospective study of 71 BRVO eyes treated with tPA, supporting that intravitreal tPA led to improvement of visual acuity and reduction of foveal thickness in BRVO eyes with macular edema in the one-year follow-up, in line with Tagami et al., who also showed that intravitreal tPA seemed to be safe and effective for the treatment of macular edema secondary to RVO.14,15 Low-molecular-weight heparins (LMWHs) have been also used and are considered to be effective for the treatment of RVO, supporting the hypothesis that RVO is a venous thrombotic disorder.16 Steigerwalt et al., in a small case series, reported improvement in visual acuity and absorbing of retinal edema and hemorrhage in patients with BRVO treated with subcutaneous enoxaparin.17 Farahvash et al. compared dalteparin and aspirin, finding in the sixmonth follow-up no significant difference between the two groups in terms of visual acuity improvement.5,18 On the contrary, Ageno et al., in a multicenter, randomized, double blind, controlled trial, compared parnaparin versus aspirin and found a superiority of parnaparin in preventing functional worsening in patients with RVO in the six-month follow-up, as 42.1% of patients with BRVO treated with parnaparin presented visual and functional improvement versus 11.1% in the aspirin group.19

Isovolaemic Hemodilution There are three randomized controlled trials, evaluating hemodilution treatment in BRVO.20–23 Poupard et al., in their randomized trial of 25 BRVO patients, examined three treatment modalities; i.e., hemodilution with dextran for 21 days (n = 10), hemodilution with heparin for 21 days (n = 10), and heparin followed by anti-vitamin K drugs for 30 days (n = 5).21 They found a significant improvement in visual acuity in patients treated either with hemodilution/dextran or with hemodilution/heparin, while those receiving heparin and anti-vitamin K drugs presented a worsening in visual acuity during the first 30 days and returned to baseline values 60 days after Seminars in Ophthalmology


Treatment of BRVO 87 the beginning of treatment.21 Accordingly, Hansen et al. compared 18 BRVO patients randomized to receive hemodilution versus 17 BRVO patients who did not receive hemodilution, suggesting that 85% of patients receiving hemodilution exhibited an increase of four lines in visual acuity compared to 33% of patients not receiving hemodilution in the one-year follow-up.22 Furthermore, Chen et al. examined the efficacy of isovolaemic hemodilution in 34 patients with BRVO less than three months from onset of symptoms and hematocrit more than 38%, reporting a significant improvement of approximately four lines in visual acuity in BRVO eyes treated with hemodilution compared to the control group at the one-year follow-up, without reporting any major side-effects.23 Today, hemodilution is not generally accepted as a treatment option for BRVO, mainly due to its complications. Further prospective, randomized, with a long-term follow-up, trials are needed to assess the efficacy and safety of hemodilution in BRVO treatment.

Sheathotomy and Vitrectomy Vascular surgery targets restoring blood flow.2,24 Surgical sheathotomy consists of a pars plana vitrectomy, separation of the retinal vein from the retinal artery using the creation of an incision in the adventitial sheath adjacent to the arteriovenous crossing, and then separation of the adhesions.2 Osterloh and Charles were the first to report an improvement in visual acuity in patients with BRVO after surgical sheathotomy.24 There are several studies or case series having used sheathotomy for the treatment of BRVO whose results are presented in Table 1.24–58 All, except Le Rouic et al., found an improvement in visual acuity, resolution in macular edema, and increase in retinal perfusion, after sheathotomy.24–58 Additionally, vitrectomy was found to have promising results regarding macular edema and other complications of BRVO.59–66 Interestingly enough, Harino et al., in a recent prospective multicenter study, found that pars plana vitrectomy had a slight advantage over photocoagulation and per os medication for the treatment of macular edema due to BRVO, although there was no statistically significant difference of BCVA improvement in any group.64 Additionally, Sato et al. suggested that 25G vitrectomy and intravitreal bevacizumab had similar effects in improving the BCVA and central macular thickness in eyes with macular edema secondary to BRVO at the one-year follow-up.65 In accordance with this study, Noma et al. examined 18 patients with macular edema due to BRVO who underwent vitrectomy, and found that pars plana vitrectomy can improve both structural and functional changes and that morphological improvement in the remporal outer subfield after !

2014 Informa Healthcare USA, Inc.

vitrectomy might influence the functional prognosis of these patients.66 Vitrectomy and removal of the posterior hyaloid with peeling of the internal limiting membrane (ILM) seem to improve retinal oxygenation and lead to visual improvement.67–72 Furthermore, vitrectomy was combined with intravitreal triamcinolone, plasminogen, or anti-VEGFs, providing additional encouraging results.73–76

Laser Photocoagulation Laser photocoagulation has been considered to be the gold standard for the treatment of BRVO for many years. There are two possible mechanisms of laser photocoagulation action to prevent macular damage. First, the production of a scar between the fovea and the adjacent involver area provides a mechanical barrier, preventing progression of edema. Second, the destruction of the capillary bed reduces the input of arterial blood supply, allowing the remaining intact capillary bed to drain into the adjacent, lesscongested, intact capillary bed near the intercapillary communicating vessels.77 Weitzig et al., as well as Shilling and Jones, found that there was no difference in BRVO natural course in patients receiving laser photocoagulation or not, pointing out that it is difficult to evaluate the efficacy of each treatment modality in individual cases, as each case is unique.77,78 Additionally, Gutman et al. reported that chronic macular edema is a risk factor for poor visual prognosis, in line with Jalkh et al., and that 75% of cases presented remission in macular edema when treated with laser photocoagulation, although only 20% managed to achieve visual acuity (VA) more than 20/40.79,80 The Branch Vein Occlusion Study (BVOS) was the largest multicenter, randomized, controlled clinical trial designed to answer several questions regarding the management of complications of branch vein occlusion, evaluating the efficacy of grid-pattern laser photocoagulation for the treatment of macular edema due to BRVO.81–83 In this study, only eyes with recent BRVO, perfused macular edema, resolved foveal hemorrhage, VA 20/40 or worse, and no other ocular comorbidities were included. After a threeyear follow-up period, 65% of treated eyes gained improvement of two or more lines from baseline, as opposed to 37% of untreated eyes. Although the BVOS provided pivotal evidence regarding the efficacy of grid laser photocoagulation in the treatment of macular edema, there were some limitations. No patient was eligible for entry into the study in the first three months after the development of BRVO, excluding acute BRVO cases. In addition, patients with BRVO and foveal hemorrhage were excluded and the study was not designed to assess

Retrospective interventional case series

Case report

Prospective non-randomized comparative interventional study with control group

Prospective non-randomized interventional case series Prospective interventional nonrandomized

Lu (2003)34

Fujii (2003)35

Mason (2004)36

Lerche (2004)37

Prospective non-randomized interventional case series Retrospective interventional comparative case series

Prospective interventional nonrandomized study

Charbonnel (2004)39 Yamamoto (2004)40

Garcia-Arumi (2004)41

Asensio Sanchez (2004)38

Retrospective interventional case series Retrospective interventional case series

Retrospective non-controlled case series Prospective non-randomized interventional case series

15 eyes – sheathotomy

Prospective interventional case series Retrospective interventional case series Retrospective interventional case series Retrospective interventional case series Prospective interventional non randomized case-control

40 eyes – vitrectomy, sheathotomy, and injection of 25 mg tPA

20 eyes – sheathotomy 16 control eyes

13 months

12 months

7 months

12 months

13 eyes – sheathotomy 5 eyes – additionally ILM peeling 13 eyes – sheathotomy


14 months (sheathotomy) 19 months (controls) 3 months

6 months

20 months

10.5 months

6 months

6 months

12 months

6 weeks

12 months

10 months

6.5 years

6.5 years

8 months

Follow-up

20 eyes – sheathotomy 20 control eyes

1 eye – sheathotomy

20 eyes – PPV and dissection of AV crossing without separation of vessels 6 eyes – sheathotomy

6 eyes (sheathotomy þ ILM peeling) versus 6 controls (ILM peeling) 17 eyes – sheathotomy

43 eyes – sheathotomy 16 eyes additionally þ ILM peeling 25 control eyes 27 eyes – sheathotomy




1 eye – sheathotomy

Participants

Case report

Study type

Martinez-Soroa (2003)32 Han (2003)33

Becquet (2003)31

Cahill (2003)30

Mester (2002)29

Dotrelova (2001)28

Le Rouic (2001)27

Shah (2000)26

Osterloh and Charles (1988)24 Opremcak (1999)25

Author (Year)

TABLE 1. Sheathotomy for the treatment of branch retinal vein occlusion. Outcomes

of of of of

VA from 0.26 to 0.40 VA by more than 4 lines in 53% of patients VA by more than 2 lines in 16 eyes (80%). VA was 0.44 0.14 logMAR

Improvement of VA in both groups No significantly difference in VA and foveal thickness improvement between the two groups Improvement of VA from 20/100 to 20/40 Thrombus release in 11 eyes

Improvement of VA by more than 2 ETDRS liens in 9 eyes (69%)

Improvement of VA in 12 eyes (92%), but better results in ILM peeling group

Improvement of VA from 0.74 to 0.56 logMAR

Improvement of VA by more than 4 lines in 5 eyes Resolution of intraretinal hemorrhage and reduction of non-perfusion area in all patients Improvement of VA from 20/400 to 20/30 Improvement of foveal thickness from 450 mm to 161 mm Improvement of VA from 20/250 to 20/63 (sheathotomy group) Improvement of VA from 20/180 to 20/125 (control group)

Improvement Improvement Improvement Improvement

Improvement of VA and resolution of ME in 8 patients (29.6%), reduction of ME in 14 (51.8%), and persistence in 5 (18.5%) Significant improvement of VA in both groups No difference in VA or foveal thickness between the groups

Improvement of VA by more than 2 lines in 26 patients (60%) Better result in ILM peeling group ME and intratetinal hemorrhage resorbed in all patients

Improvement of VA in 2 patients and stabilization of VA in one patient

No significant improvement in VA

Improvement of VA by 4 lines in 10 patients Resolution of ME in 3 patients, but no improvement in VA Improvement of VA in 4 eyes from 20/30 to 20/70

Improvement of VA from 20/200 to 20/25


88 I. P. Chatziralli et al.

Seminars in Ophthalmology

!


Retrospective case series

Prospective randomized case series

Prospective case series

Prospective interventional case series Retrospective case series

Prospective interventional case series


Oh (2008)52

Chung (2008)53

Shimura (2008)54

Stoffelns (2009)55

Muqit (2010)57

Skevas (2011)58

36 eyes – sheathotomy þ ILM peeling 4 eyes – sheathotomy þ IV triamcinolone 5 eyes – sheathotomy 3 eyes – sheathotomy þ IV triamcinolone 17 eyes- sheathotomy


8 eyes – sheathotomy 8 control eyes 20 eyes – sheathotomy 20 eyes- IV triamcinolone

12 months

48 months

12 months

26.4 months

6 months

6 months

36 months

6 months

20 months

31 months

9 months

3 months

1 year

6 months 59 months

49.9 weeks

12 months

Improvement of VA from 0.84 to 0.36 logMAR in sheathotomy group, significant differed from grid laser group (1.06 to 0.82 logMAR) Improvement of VA from 0.52 to 0.08 logMAR, not significantly differing from control group (0.53 to 0.014 logMAR) Improvement of VA in 9 eyes (75%) Stabilization of VA in 1 eye (8.3%) Deterioration of VA in 2 eyes (16.7%) Improvement of VA from 20/50 to 20/40 Improvement of P1 amplitude from 39.90 10.86 nV/deg2 to 50.71 15.58 nV/deg2 in electroretinogram Improvement of VA from 1.10 0.34 to 0.80 0.36, but no difference with control group (1.15 0.43 to 0.43 0.39 logMAR) Improvement of VA from 20/80 to 20/40 in both groups Improvement in foveal thickness from 395 115.8 mm to 244.8 121.2 mm in sheathotomy group, not differing significantly from IV triamcinolone group (454 158.1 mm to 281.4 132.4 mm) Improvement of VA from 0.71 0.16 to 0.25 0.16 logMAR Improvement of foveal thickness from 586.4 84.7 mm to 288.7 63.9 mm Reduction of macular edema in all eyes Improvement of VA in 24/36 eyes – Stabilization of VA in 8/36 eyes Improvement of VA from 20/124 to 20/44 Improvement of ME Improvement of VA from 0.8 0.17 logMAR to 0.6 0.44, not differing between the two groups Increased retinal perfusion to 4 over 5 eyes in sheathotomy group Improvement of VA from 0.6 logMAR to 0.4 VA improvement in 13 patients and deterioration in 4 Improvement of macular edema in 7 patients, stabilization in 6 and deterioration in 4

Improvement in VA from 0.82 0.05 logMAR to 0.55 0.07 4 patients presented retinal detachment and 19 needed cataract surgery Improvement of VA from 0.79 0.29 to 0.57 0.33 logMAR

Improvement in retinal blood flow and decrease in macular thickness Improvement of VA from 0.3 to 1.0 (decimal) – No recurrence

Improvement of VA in both groups, with no significant difference in between absorption of ME in both groups Improvement of VA from 1.00 0.32 to 0.56 0.28

VA: visual acuity; ME: macular edema; ILM: internal limiting membrane; PPV: pars plana vitrectomy; AV: arteriovenous; IV: intravitreal.

Hwang (2010)56


Retrospective interventional case series Retrospective interventional comparative case series Prospective, randomized, comparative interventional study Retrospective interventional case series 15 eyes – sheathotomy

35 eyes- arterovenous dissection and vitrectomy after isovolaemic hemodilution 22 eyes – sheathotomy þ ILM peeling 11 eyes – sheathotomy 10 control eyes – grid laser 18 eyes – sheathotomy 18 control eyes 12 eyes – sheathotomy

Retrospective intrerventional case series

Interventional case series Case report

38 eyes- sheathotomy 45 control eyes 12 eyes – 25G transvitreal limited arteriovenous crossing manipulation without vitrectomy 7 eyes – sheathotomy 1 eye – sheathotomy

Prospective non-randomized comparative case series Retrospective interventional case series

Chung (2008)51

Crafoord (2007)50

Kumagai (2007)49

Avci (2007)48

Sohn (2006)47

Horio (2005)44 Wrigstad and Algvere (2005)45 Feltgen (2005)46

Lakhanpal (2005)43

Fujimoto (2004)42


Treatment of BRVO 89


90 I. P. Chatziralli et al. how long after the onset of BRVO a patient should be treated.81–83 Similar to the BVOS, several studies concluded that a grid laser could be useful in BRVO-associated macular edema treatment, in patients with the same eligibility criteria, but did not significantly improve the visual acuity.84–86 Battaglia Parodi et al. published two randomized controlled studies in which no significant benefit of grid laser photocoagulation on visual acuity was found, and suggested that sudden ischemic damage to central photoreceptors rather than the macular edema is the main factor for permanent visual acuity reduction.87,88 Thus, a grid laser was recommended as a treatment of macular edema due to BRVO after a period of three to six months after onset.87,88 Recently, a new prospective, double-masked randomized trial, the SCORE (Standard care versus COrticosteroid in REtinal vein Occlusion) study, recommended that grid photocoagulation should remain the treatment of choice for eyes with vision loss associated with macular edema secondary to BRVO, finding no difference in visual acuity at the one-year follow-up between the standard care group (grid laser photocoagulation) and the triamcinolone group.89,90 As far as scatter laser photocoagulation is concerned, the BVOS concluded that peripheral scatter laser photocoagulation significantly reduced the development of retinal neovascularization and vitreous hemorrhage and was recommended to be applied in ischemic BRVO after the development of neovascularization rather than before the development of neovascularization, in accordance with Hayreh et al.81–83,91 This study also demonstrated that, if all eyes with large retinal nonperfusion were treated, 64% of these patients would never develop neovascularization.81–83 Interestingly, Pitcher et al. suggested that shortduration pattern scanning laser (PASCAL) macular photocoagulation appears to be a safe treatment option that results in significant anatomical improvement in macular edema related to BRVO. In this study, although visual acuity was not significantly changed, the number of patients with vision better than 20/40 doubled following treatment, and central retinal thickness was reduced by an average of 110 mm. Additionally, no laser-related ocular complications were observed.92

Non-Steroid Anti-Inflammatory Drugs (NSAIDs) NSAIDs have been used to reduce the occurrence and severity of macular edema after cataract surgery, without causing elevation of intraocular pressure (IOP). Soheilian et al., in their pilot study about the

use of diclofenac in macular edema of various causes, included a 51-year-old female patient with old BRVO. The patient was treated with 500 mm/0.1 ml intravitreal diclofenac and, eight weeks after the injections, presented an improvement in visual acuity from 20/120 to 20/80, but central foveal thickness in optical coherence tomography remained relatively the same, from 433 to 429 mm.93 Further studies with large sample size are needed so as to reach a safe conclusion about the use of NSAIDS in BRVO treatment armamentarium.

Steroids Triamcinolone In several nonrandomized studies, intravitreal corticosteroids were successfully used for the treatment of BRVO, but limited randomized trials have been published.94,95 Corticosteroids inhibit VEGF and various proinflammatory mediators, which contribute to the pathogenesis of RVO. The results of various doses of intravitreal triamcinolone (IVT) against BRVO are shown in Table 2.96–120 Due to the limited duration of the intraocular availability of triamcinolone, it seems that the response in IVT lasts for a shorter time and more than one injection is needed. Moreover, the efficacy was better after the first injection and in nonischemic forms than after the next ones and in ischemic forms.94,95 In addition, the risks of steroid intake should be taken into account, such as raised intraocular pressure, infection, cataract formation, or retinal detachment. The largest multicenter clinical trial was the SCORE study, which compared the efficacy and safety of 1 mg and 4 mg IVT with grid laser photocoagulation (standard care) in eyes without dense macular hemorrhage vision loss secondary to BRVOassociated macular edema. Eyes with dense macular hemorrhage were deferred for photocoagulation. Of note, the drug used in this trial was prepared as a sterile, preservative-free, single-use intravitreal injection in a volume of 0.05 ml (TRIVARIS). According to this study, there was no difference in VA and retinal thickness at the one-year follow-up in the standard care group compared with the IVT group. Nevertheless, after 12 months and through month 36, the mean improvement in visual acuity as well as retinal thickness was better in the laser group. Rates of adverse effects were higher in the 4 mg group. Another interesting finding was that the duration of the edema should be considered. Subgroup analysis showed that patients with a disease duration of more than three months showed greater benefit with standard care. However, those with a macular edema for 1–3 months showed better results in the IVT group than in the photocoagulation group. Seminars in Ophthalmology

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Prospective, interventional non-controlled case series

Prospective interventional noncontrolled case series Retrospective non-controlled case series

Wakabayashi (2004)97

Chen (2004)98

Retrospective, interventional case series Retrospective, non-controlled case series Randomized clinical trial

Retrospective interventional comparative case series

Prospective non-randomized comparative study

Prospective interventional noncontrolled case series

Prospective interventional noncontrolled case series

Retrospective non-controlled case series

Prospective, randomized, interventional, clinical trial

Salinas-Alaman (2005)101

Ozkiris (2005)104

Jonas (2005)105

Tsujikawa (2005)106

Karacorlu (2005)107

Cecik (2005)108

Avitabile (2005)109

Hayashi (2005)103

Lee (2005)102

Case report

Chen (2005)100

Yepremyan (2005)99

Case report

Study type

Degenring (2003)96

Author (Year)

TABLE 2. Triamcinolone for branch retinal vein occlusion.

ME due to BRVO, CRVO or diabetic retinopathy – 22 IVT, 21 grid laser and 20 IVTþgrid

8 eyes with serous macular detachment due to BRVO4 mg IVT 13 BRVO eyes – 4 mg IVT

17 BRVO eyes-10 mg IVT þPPV

10 BRVO eyes treated with 20– 25 mg IVT and 18 control eyes

15 eyes – 8 mg IVT/0.2 ml 19 eyes grid laser photocoagulation

27 BRVO eyes – 4 mg IVT 25 BRVO eyes – 40 mg retrobulbar

6 BRVO eyes – 4 mg IVT

38-year-old man with ME due to BRVO-4 mg IVT 5 BRVO eyes – 4 mg IVT



75-year-old woman with macular edema due to BRVO – IVT 25 mg 11 BRVO eyes – 20 mg triamcinolone sub-tenon

Participants

9 months

13 months

6 months

IVT patients: 10.1 months Controls: 6 months 12.1 months

6.3 months

3 months

149.5 days

6 months

3 months

15.3 months

9 months

7 months

5 weeks

Follow-up

Outcomes

(continued )

Improvement in VA from 0.74 0.40 logMAR to 0.40 0.34 12 eyes with recurrent ME received subtenon triamcinolone Improvement in VA in 7 eyes (87.5%), recurrence in 2 eyes (25%), regression of ME and serous macular detachment in all eyes Improvement of VA in 7 eyes, stability in 4 eyes, and worsening in 2 eyes. Foveolar thickness decreased in 56% of patients Improvement of VA in IVT group versus laser, but the study also included other diseases except BRVO

Improvement of VA in 4 eyes. One eye needed reinjection due to recurrent ME. Improvement in VA 42 lines in 5 eyes (83.3%), VA from 20/166 to 20/106 Improvement in VA from 0.598 0.375 logMAR to 0.312 0.315 in group 1 and from 0.433 0.285 to 0.341 0.186 in group 2. No statistically significant difference between the two groups Improvement in VA from 0.98 0.19 logMAR to 0.24 0.24 in group 1 and from 1.02 0.22 to 0.5 0.28 in group 2. Improvement in group 1 was significantly higher than in group 2 Improvement in VA from 0.27 0.11 to 0.45 0.27, while in control group VA decreased

Improvement of VA from 0.25 to 0.5 (decimal). Improvement of macular thickness from 400 mm to 210 mm Improvement of VA from 0.37 to 0.48. No significant improvement of ME 2 patients needed additional injection on month 3 and 6 without improvement of macular edema. Improvement in VA from 0.81 0.36 logMAR to 0.65 0.3 logMAR Improvement in VA from 0.88 logMAR to 0.49 at the last follow-up. Improvement in VA 43 lines in 50% of eyes after 1 months and in 42% of eyes at last follow-up. Improvement in ME from 589 to 235 mm, 8 eyes developed recurrent ME at 5.5 months Improvement in VA from counting fingers to 20/80



Retrospective non-controlled case series

Prospective non-randomized interventional comparative study

Retrospective, interventional case series

Prospective study

Prospective, interventional case series

Retrospective study

Randomized controlled clinical trial

Ozkiris (2006)112

Cheng (2006)113

Oh (2007)114

Cakir (2008)115

Patel (2008)116

Ozdek (2008)117

Ramezani (2011)118


Noma (2012)120

30 BRVO eyes with duration of disease 510 weeks randomized in 4 mg IVT (16 eyes) and controls (14 eyes) 60-year-old woman with BRVO and vitreomacular traction – 4 mg IVT 20 BRVO eyes with macular edema – IVT 4 mg

20 BRVO eyes-posterior subtenon triamcinolone (group 1) 35 BRVO eyes-4 mg IVT (group 2) 24 BRVO eyes – grid laser photocoagulation (group 3)

50 BRVO eyes – 20 mg transtenon triamcinolone 8 BRVO eyes – 4 mg IVT

20 eyes with ME with disease duration 5(10 eyes) or 43 months (10 eyes) – IVT 4 mg

16 eyes (4 mg IVT) 11 controls

19 BRVO eyes-8 mg IVT/0.2 ml


9 eyes – 4 mg IVT

Participants

6 months

NA

4 months

6 months

12 months

12 months

103 days in TAgroup 94.5 days in controls 6 months

6.2 1.0 months

9 months

6 months

Follow-up

Mean BCVA significantly improved 6 months after IVTA. Mean retinal sensitivity, retinal thickness, and retinal volume significantly improved after 6 months.

Resolution of symptoms (metamorphopsia), but VA did not improve

In Group 53 months: VA improved from 1.07 to 0.63 logMAR in 1 month and to 0.34 in 6 months. In Group 43 months: VA improved from 0.80 to 0.47 in month 1 and to 0.6 in month 6. Foveal thickness was significantly reduced in 3 months. VA improved by 0.20 logMAR. Improvement in VA from 0.92 logMAR pre injection to 0.44 logMAR post-injection, but not maintained in the one-year follow-up (0.99 logMAR). Improvement in VA and CFT from 0.23 0.23 and 413.2 143.5 mm to 0.23 0.18 and 358.7 109.2 mm at the 3rd month, respectively, in group 1. Improvement in VA from 0.14 0.15 to 0.33 0.26 and in CFT from 518.2 145 to 292.9 121 mm in IVT group. Improvement in VA from 0.29 0.25 to 0.47 0.32 (p = 0.001) and in CFT from 397.3 105.9 to 307.1 88.4 mm in group 3. VA increase was significantly greater in the IVT group than in the PSTT group. Decrease in CFT was the highest in the IVT group. Significant improvement in VA and CFT was remarked in group 1 in 4 months. The two groups did not differ as far as VA and CFT were concerned at any time point.

No significant improvement in VA, no significant reduction in ME Improvement of VA from 1.24 0.5 logMAR to 0.59 0.3 logMAR in the 3-month follow-up. Decrease of ME from 458.4 149 mm to 182 50 mm. 33% recurrence in 9 months after injection. Improvement in VA from 1.01 0.16 logMAR to 0.62 0.22. The VA improved in 17 eyes and remained unchanged in 2 eyes. Improvement if VA from 0.77 0.43 logMAR to 0.44 0.43. No significant change of VA in controls

Outcomes

VA: visual acuity; BRVO: branch retinal vein occlusion; ME: macular edema; IVT: intravitreal triamcinolone; BCVA: best-corrected visual acuity; CFT: central foveal thickness.

Case report

Seymenog˘lu (2012)119

Tewari (2005)111

Prospective interventional noncontrolled case series Prospective, nonrandomized, clinical interventional study

Study type

Krepler (2005)110

Author (Year)

TABLE 2. Continued





Treatment of BRVO 93 Apart from IVT, periocular application of triamcinolone acetonide has also been used. Kawaji et al. evaluated the effectiveness and safety of trans-tenon retrobulbar injection of 40 mg of triamcinolone in 20 patients with macular edema secondary to BRVO after vitrectomy.121 Forteen eyes (70%) showed improvement in visual acuity.121 Additionally, Hayashi et al. compared the effect of IVT versus retrobulbar triamcinolone for the treatment of macular edema due to BRVO and found that improvement in visual acuity was better in the IVT group and that the need for re-injection was greater in the retrobulbar group.103 Furthermore, combined therapies may be a good alternative in BRVO treatment. The combination of IVT with grid laser photocoagulation has gained positive outcomes,122–124 while the combination of IVT with intravitreal bevacizumab was found to provide improvement more in structural outcomes than functional ones at the six-month follow-up.125

associated with a significantly lower likelihood of achieving clinically meaningful improvement in visual acuity or central retinal thickness at the oneyear follow-up.131 As a result, prompt treatment may be associated with improved clinical outcomes.131 As in triamcinolone use, combinations of treatment modalities were used with dexamethasone as well. Mayer et al. compared the combination of intravitreal bevacizumab and dexamethasone implant versus dexamethasone implant monotherapy in CRVO and BRVO patients, concluding that dexamethasone implant monotherapy was associated with better functional outcome in the treatment of macular edema due to BRVO, contrary to Singer et al., who found that the combination of intravitreal bevacizumab with dexamethasone implant had a synergistic action and provided better results, increasing visual acuity and prolonging the time between injections compared to each medication alone.132,133

Dexamethasone Dexamethasone has been considered to decrease inflammatory mediators implicated in macular edema.126 As intravitreal injections of dexamethasone have a short half-life, an intravitreal dexamethasone implant (Ozurdex , Allergan, Irvine, CA, USA) was developed. It is a prefilled, single-use, biodegradable, sustained-release intravitreal drug delivery system containing 0.7 mg dexamethasone, used in a multicenter, randomized controlled clinical trial for macular edema secondary to RVO, the Ozurdex GENEVA study.127 Indeed, this study included two identical, six-month, phase III, multicenter clinical trials, evaluating the efficacy and safety of intravitreal dexamethasone implant (0.7 mg and 0.35 mg) in macular edema due to BRVO or CRVO. Specifically, 830 BRVO patients were randomized in three groups: sham (n = 279), DEX 0.35 mg (n = 260), and DEX 0.7 mg (n = 291). The results of this study suggested that, after a single administration, improvement in visual acuity was achieved better and in less time in both dexamethasone groups than in the sham group. At day 180, 23% of patients treated with 0.7 mg DEX exhibited415 EDTRS letters improvement versus 20% of patients treated with sham. As far as the complications are concerned, Ozurdex was well-tolerated and only a transient IOP increase was remarked with a peak at day 60 and did not differ from sham at day 180.127,128 In line with this large study, other studies, providing long-term results, have also found that Ozurdex was effective and safe in the treatment of macular edema secondary to BRVO.129,130 Interestingly, Yeh et al., in their study about the impact of the duration of macular edema on clinical outcomes in RVO, found that longer macular edema duration at the time of first treatment with the dexamethasone intravitreal implant (0.7 mg) was

Intravitreal Anti-VEGF

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Pegaptanib Pegaptanib sodium (Macugen) is a selective antiVEGF, not well studied in RVO. There are studies suggesting that intravitreal injection of pegaptanib sodium can be effective in the treatment of ocular diseases; i.e., neovascular age-related macular degeneration, diabetic macular edema, and proliferative diabetic retinopathy.134–137 Pegaptanib has been also considered to offer significant improvement of VA in CRVO patients.138 As a result, it is hypothesized that pegaptanib sodium could be effective in BRVO as well. Wroblewski et al., in their small, prospective, uncontrolled study, randomized 20 patients with BRVO 3:1 to pegaptanib 0.3 mg or 1 mg and examined at baseline, six, and 12 weeks thereafter with subsequent injections at six-week intervals at the investigator discretion until week 48. They found improvement in VA and macular thickness at the 54-week followup.138,139 Nevertheless, in this study the authors didn’t define an observational window and included patients who also underwent grid laser for macular edema, having confounding bias.140 Accordingly, Gallengo et al. compared six patients with macular edema due to BRVO receiving intravitreal pegaptanib sodium with six patients receiving intravitreal ranibizumab, suggesting that there was no significant difference concerning improvement of VA, reduction of macular thickness, and the number of injections needed.141 On the other hand, Udaondo et al. reported a small case series of five eyes with BRVO treated before with either intravitreal triamcinolone of intravitreal bevacizumab with no improvement, but presented improvement in VA more than two Snellen lines and reduction of macular edema confirmed by optical coherence tomography (OCT) and fluorescein



angiography (FA) when treated with two injections of 0.3 mg intravitreal pegaptanib sodium.142 Bevacizumab There have been several studies concerning bevacizumab (Avastin) in macular edema due to BRVO, suggesting improvement in VA and reduction in macular thickness, as is shown on Table 3.143–177 The most common dosages were 1.25 and 2.5 mg and it is worth mentioning that the Pan-American Collaborative Retina Study found that there was no statistically significant difference between the two doses at the 24-month follow-up.143 However, there are case reports and small case series reporting that rebound in macular edema could occur after treatment with bevacizumab and therefore suggesting that frequent injections are needed to prevent the recurrence of macular edema, especially if treatment is initiated before macular edema reaches the maximum level.178–182 As a result, multiple injections are necessary for intravitreal anti-VEGF treatment and this is a significant drawback.164,168 Intravitreal bevacizumab (IVB) has been combined with grid laser photocoagulation. Hayashi et al. suggested that additional grid laser photocoagulation for recurrent macular edema after IVB maintained VA, but had no effect on the further recurrence of macular edema, consistent with Donati et al., Ogino et al., and Salinas-Alaman et al., who also found that grid laser photocoagulation provided good results in maintenance of VA when combined with IVB, resulting in a reduced number of injections if compared with monotherapy.183–186 As mentioned above, Ehrlich et al. combined 2 mg IVT and 1,25 mg IVB in eight BRVO eyes and found an improvement in VA from 1.025 0.58 to 0.66 0.34 and improvement in macular edema from 456 203 to 325 124 in the six-month follow-up.125 Furthermore, there are studies comparing intravitreal bevacizumab with other treatment modalities. Specifically, Russo et al., in their prospective randomized study, compared 15 BRVO eyes treated with 1.25 mg IVB and 15 BRVO eyes treated with grid laser photocoagulation and found that there was an improvement in VA and central foveal thickness (CFT) in both groups, although IVB exhibited better results in the 12-month follow-up, in line with Parveen et al. and Leitritz et al., who also suggested that even if grid laser photocoagulation reduced macular thickness in BRVO patients, IVB had better results in VA.187–189 As far as IVB comparison with tPA, Kumagai et al. reported that the two treatment modalities had similar results in VA and CFT.14 Additionally, there are several studies comparing IVB with IVT, whose results are depicted in Table 4.190–199 The majority of these studies reported that IVB had better results than IVT as far as VA and CFT are concerned. Nevertheless, there are also

studies suggesting that the two treatment modalities had no difference in their effect on BRVO treatment. Of note, a significant adverse effect of IVT is the IOP increase, as well as the cataract formation in patients treated with IVT. Ranibizumab Ranibizumab (Lucentis) is another anti-VEGF agent, which is used for the treatment of macular edema due to BRVO. There are several studies using ranibizumab for BRVO treatment, whose results are shown in Table 5, but the largest one was the BRAVO study.200–210 The BRAVO trial was a multicenter, randomized, double-masked, sham injectioncontrolled phase III study of 397 patients with macular edema due to BRVO. Patients were randomized into three groups: standard care with grid laser treatment, intravitreal injection of 0.3 or 0.5 mg ranibizumab, and both grid laser and intravitreal injection of 0.3 or 0.5 mg ranibizumab. The patients received monthly intravitreal injections during the first six months, and between month 6 and month 12, evaluations were carried out to determine whether retreatment was needed. In both studies, the preliminary results at six months showed that the treated groups had better visual recovery than the control groups. In this study, at six months, 55% of the patients who received 0.3 mg of Lucentis and 61% who received 0.5 mg of Lucentis had their vision improved by 15 letters or more compared to 29% of patients receiving sham injections and grid laser treatment. At six months, with an average of 5.7 injections in the first six months, the mean visual gain was 16.6 and 18.3 letters (0.3 and 0.5 mg), compared with 7.3 letters in the sham group. From months 6 to 12, the patients were treated in an open-label fashion pro re nata. Visual benefit was maintained with an additional mean number of injections of 2.7 in the second six months. Patients in the sham group also showed a benefit, although the amount of visual gain did not reach that of the patients who had been treated from baseline. As stated above, more than half of the patients in the BRAVO trial had macular edema of a short duration (51.5–53.8%).203,206 Additionally, patients with macular edema from BRVO, treated with monthly ranibizumab, reported greater improvements in vision-related function (measured by means of the 25-item National Eye Institute Visual Function Questionnaire - NEI VFQ-25) compared with shamtreated patients through six months.211 According to other studies as well, ranibizumab seems to be effective in the treatment of macular edema due to BRVO, presenting improvement in VA and reduction in macular thickness. Nevertheless, Karagiannis et al., in their study examining 22 BRVO patients treated with intravitreal ranibizumab for one year, found that recurrence of macular edema occurred in 13 patients (59%) with a mean time Seminars in Ophthalmology

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Case report

Prospective, nonrandomized, interventional case series Prospective study

Jaissle (2006)145

Spandau (2007)146

Pai (2007)147

Retrospective

Prospective, non-comparative, interventional case series Prospective, uncontrolled study

Retrospective, interventional case series

Retrospective, uncontrolled, interventional study

Case report


Retrospective study

Rabena (2007)150

Kreutzer (2008)151

Gunduz (2008)153

Wu (2008)154

Chalam (2008)155

Abegg (2008)156

Chung (2008)157

Kriechbaum (2008)152


Stahl (2007)149

Schaal (2007)148

Case report

Study type

Ahmadieh (2005)144

Author (Year)

50 eyes with BRVO and BCVA520/40, macular edema and recent FA

50-year-old female with macular edema due to BRVO – 1.25 mg IVB 32 eyes with BRVO – 1.25 mg IVB

24 eyes with macular edema due to BRVO – 1.25 mg IVB 21 eyes with macular edema due to BRVO – 2.5 mg IVB

3 months

6 weeks

1 week

35.2 weeks (at least 6 months)

9.8 months (at least 6 months)

6 months

21 BRVO patients – 1.25 IVB

12 eyes with macular edema due to BRVO – 1.25 mg IVB

6 months

3–8 months

9 weeks

23 13 weeks

12 weeks

1 month

3 months

1 month

Follow-up

34 patients with BRVO – 1.25 mg IVB on day 1 and 4 weeks thereafter

27 BRVO patients with macular edema- 1.25 IVB

7 BRVO patients – 1.25 mg IVB

22 BRVO patients with macular edema – 2.5 mg IVB

60-year-old female patient with macular edema due to BRVO1.5 mg IVB 12 BRVO patients – 1.25 mg IVB

60-year-old female patient with neovascularization due to BRVO1.25 mg IVB (previous 2 sessions of scatter laser photocoagulation) 3 BRVO patients – 1.0 mg IVB

Participants

TABLE 3. Intravitreal bevacizumab for the treatment of branch retinal vein occlusion. Outcomes

(continued )

Improvement in VA from 1.22 0.58 to 0.8 0.45 and reduction in macular thickness from 672.8 375.14 mm to 372.4 121.96 mm at 12-week follow-up Improvement in VA more than 3 ETDRS lines in 31.3% of patients in one week and 76.5% at the end of the follow-up. Reduction in macular thickness from 678 221 mm to 236 78 mm at the end of the follow-up Improvement in VA from 0.5 0.26 LogMAR to 0.37 0.27 LogMAR. Reduction in macular thickness from 408.3 95.7 mm to 377.7 97.1 mm at the 9-week follow-up Improvement in VA from 20/200 to 20/100 at the end of followup, Reduction in macular edema from 478 mm to 332 mm at the end of follow-up Improvement in VA from 0.79 0.39 LogMAR to 0.51 0.34 LogMAR. Reduction in macular thickness from 474 120 mm to 316 41 mm at the 6-month follow-up Improvement in VA from 20/80 to 20/40 and reduction in macular thickness from 574 mm to 349 mm with an average of 5.5 injections at the 6-month follow-up Improvement in VA from 0.91 LogMAR to 0.58 at 6 months and 0.48 at the end of follow-up. Reduction in macular thickness from 506.6 mm to 321.8 mm at 6 months and 267.5 mm at the end of the follow-up Improvement in VA from 1.1 LogMAR to 0.59 LogMAR and reduction in macular thickness from 461 211 to 277 114 mm with an average of 1.5 injections. Improvement in VA from 1.07 to 0.62LogMAR and reduction in macular thickness from 385 168 to 240 93 mm with an average of 2 injections at 6-month follow-up Improvement in VA from 20/40 to 20/20 and recovery of macular edema in OCT in one week after treatment Improvement of VA from 0.7 0.3 to 0.5 0.35 LogMAR and reduction in macular thickness from 454 117 to 305 119 mm at 6 weeks Improvement of VA of 45 EDTRS letters in 56% Improvement in macular thickness, which was not sustained in the ischemic group

Improvement in VA and central macular thickness, but not sustained with only one injection Improvement in VA from 20/200 to 20/60 Reduction in macular thickness from 605 mm to 205 mm

Improvement in VA from 20/70 to 20/60 Decrease of leakage in FA Stability in one-month follow-up




Prospective study

Retrospective study

Retrospective study

Case series

Prospective study

Prospective, non-comparative, interventional case series Prospective study

Jaissle (2009)159

Prager (2009)160

Ahmadi (2009)161

Gregori (2009)162

Yamauchi (2009)163

Hoh (2009)164

Gutierrez (2009)165

Retrospective, interventiona.l comparative study

Prospective, non-randomized, interventional case series

Wu (2009)143

Figueroa (2010)167

Kondo (2009)166

Prospective study

Study type

Rensch (2009)158

Author (Year)

TABLE 3. Continued

28 eyes with BRVO – 1.25 mg IVB

38 eyes with macular edema due to BRVO – 1.25 mg IVB 25 eyes with macular edema due to BRVO – 2.5 mg IVB

50 eyes with macular edema due to BRVO – 1.25 mg IVB

12 patients with BRVO – 1.25 mg IVB

6 eyes of 5 patients with BRVO treated previously with laser photocoagulation of IVT – 1.25 mg IVB 34 eyes with BRVO – 2.5 mg IVB

21 eyes with BRVO – 3 monthly injections of 1 mg IVB 42 patients with non-ischemic BRVO2.4 injections average of 1.25 mg IVB 52 BRVO patients – 1.25 mg IVB

23 eyes with perfused macular edema due to BRVO – 1.25 mg IVB

21 eyes with non-ischemic BRVO – 3 injections of 1.5 mg IVB

Participants

6 months

24 months

12 months

6 months

60 29 weeks

1 month

12 months

12 months

1 year

1 year

6.2 1.2 months

Follow-up

Outcomes

Improvement in VA by 1.8 2.6 lines and reduction in macular thickness from 602 207 to 386 178 mm at the end of the follow-up with an average of 4.9 2.9 injections Improvement in VA from 1.32 0.24 to 0.8 0.15 LogMAR and reduction in macular thickness from 615.5 116.29 to 420 72.53 mm at the 6-month follow-up Improvement in VA from 0.53 to 0.26 LogMAR and reduction in macular thickness from 523 to 305 mm at the 12-month follow-up Improvement in VA from 0.91 0.57to 0.54 0.54 at the first group and from 1.21 0.74 to 0.56 0.48 LogMAR at the 2nd group and reduction in macular thickness from 453 140 to 244 125 mm for the 1st group and 444 175 to 234 80 mm for the 2nd group Improvement in VA from 0.8 0.38 to 0.44 0.34 LogMAR and reduction in macular thickness from 486.9 138.5 to 268.2 62.5 mm at the 6-month follow-up

Improvement of VA from 0.81 0.53 to 0.55 0.49 Log MAR and reduction in macular thickness from 492 113 to 316 117 mm at 6-month follow-up Improvement of VA from 0.50 to 0.2 LogMAR at 6-month follow-up and reduction in macular thickness from 395 to 255 mm at the 48th week of the follow-up Improvement of VA from 20/80 to 20/32 and reduction in macular thickness by 241 mm at the one-year follow-up Improvement in VA from 1.15 0.11 to 0.94 0.14 LogMAR at the 8th follow-up visit (356 days) and reduction in macular thickness from 451 61.3 to 400 mm at 6-month follow-up Improvement in VA from 20/200 to 20/50 or 15 letters improvement in 12-months and decrease in macular thickness by 205 mm in 12-month follow-up Significant improvement in VA and foveal thickness at onemonth follow-up




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Prospective, interventional case series Retrospective study

Retospective study

Retrospective study


Prospective interventional study

Retrospective study

Retrospective study

Prospective study

Lim (2011)169

Ehlers (2011)170

Demir (2011)171

Yunoki (2012)172

Thapa (2012)173

Preti (2012)174

Siegel (2012)175

Kang (2012)176

Park (2012)177 19 BRVO naı¨ve eyes – 3 injections of 1.25 mg IVB at 6-week intervals

45 BRVO eyes with macular edema1.25 mg IVB in 3 monthly loading doses. If edema persisted after 4–6 injections, patients received grid laser 59 BRVO naı¨ve patients (CFT4300 mm) – 1.25 IVB

17 BRVO eyes (VA520/40, CFT4300, no treatment for 3 months) – one injection of 1.25 IVB

63 BRVO eyes- 1.25 mg IVB until macular edema subsidued

37 eyes of 37 patients – 2groups (a: one injection of 1.25 mg IVB and b) multiple injections)

33 eyes of 31 patients with BRVO – 1.25 mg IVB

46 eyes with macular edema due to BRVO – 1.25 mg IVB 53 eyes with BRVO – 1.25 mg IVB

91 eyes of 91 patients with BRVO1.25 mg IVB

18 weeks

12 months

18.8 months 8.3

3 months

12 months

24 weeks

12 months

9 months

12 months

12 weeks

Improvement in VA from 0.25 to 0.45 (decimal) and reduction in macular thickness from 610.8 to 368.7 mm at the 12-week follow-up. Recurrence in 26/47 eyes Significant improvement in VA and macular thickness at the 12-month follow-up Improvement in VA by 1.6 lines and reduction in macular thickness from 425 to 289 mm at the 9-month follow-up Improvement in VA from 0.66 0.20 to 0.22 0.13 LogMAR and reduction in macular thickness from 494.15 104.16 to 261.79 45.36 mm at the 12-month follow-up with an average of 5.3 injections Improvement in VA in both groups from 0.54 0.42 to 0.08 0.25 LogMAR and 0.48 0.27 to 0.24 0.24 LogMAR, respectively, and reduction in macular thickness from 401.1 117.7 to 194.1 23.6 mm and from 400.0 107.5 to 307.4 135.2 mm, respectively, at the 24-week follow-up Improvement in VA from 0.82 0.54 to 0.40 0.25 logMAR and decrease in macular edema from 515.3 189.4 to 233.6 101.5 mm. Recurrence of edema in 30.2% Improvement in VA from 0.772 to 0.613 in 1 month, but no statistically significant improvement in 3 months and decrease of macular edema from 552.47 150.36 322 127 in one month and to 439 179 in 3 months Improvement in VA from 20/140 to 20/70 and improvement of CFT from 382.2 155.6 to 320.5 172.8 33% laser before and 51% laser after. No difference between eyes that received laser before and not. Injection number: 8.8 3.8 Improvement of VA from 0.81 0.55 to 0.55 0.61 and decrease of macular edema from 604.53 183.19 to 346.76 164.61 mm. Number of injections: 2.47 1.22 Improvement in VA from 0.8 0.4 to 0.2 0.2 and improvement of CFT from 492.1 134.4 to 274.7 54.1

BRVO: branch retinal vein occlusion; VA: visual acuity; CFT: central foveal thickness; IVB: intravitreal bevacizumab; FA: fluorescein angiography.

Prospective study

Hara (2010)168



Retrospective study

Retrospective, comparative, interventional study

Retrospective interventional consecutive case series

Retrospective, nonrandomized, interventional study

Retrospective study

Retrospective comparative series

Prospective, interventional study

Prospective, comparative, randomized, interventional clinical trial

Randomized clinical trial

Kim (2009)191

Hou (2009)192

Cheng (2009)193

Chen (2010)194

Guthoff (2010)195

Byun (2010)196

Cekic (2010)197

Higashiyama (2011)198

Ramezani (2012)199

86 eyes with recent onset (512 weeks) of BRVO randomized in Group 1 (43 eyes) treated with 1.25 mg IVB 3 monthly and Group 2 (43 eyes) treated with 2 injections of 2 mg IVT with 2 month interval

17 patients with BRVO treated with 4 mg IVT, 14 patietns treated with 1.25 IVB and 21 patients treated with 2 mg IVT and 1.25 mg IVB 36 eyes with BRVO randomized in Group 1 (18 eyes) treated with 4 mg IVT and Group 2 (18 eyes) treated with 1.25 mg IVB

87 eyes with BRVO treated with IVT versus 47 eyes with BRVO treated with IVB

10 eyes with macular edema due to BRVO treated with IVT and 10 eyes with macular edema due to BRVO treated with IVB

83 eyes with BRVO randomized in Group 1 (25 eyes) treated with IVT, Group 2(24 eyes) treated with 1.25 mg IVB and Group 3 (34 eyes) controls

16 eyes with BRVO treated with 4 mg IVT and 13 eyes with BRVO treated with 1.25 mg IVB

34 eyes with BRVO treated with 1.25 mg IVB (group 1) and 34 eyes with BRVO treated with 4 mg IVT (group 2)

8 p with 4 mg IVT and 10 p with 1.25 mg IVB – Non-ischemic BRVO with macular edema 50 eyes with BRVO randomized to Group 1 (22 eyes) treated with 1.25 mg IVB and Group 2 (28 eyes) treated with 4 mg IVT

Participants

6 months

12 months

6 months

12 months

13 months

24 months

6 months

12 months

24 weeks

3 months

Follow-up

Outcomes

Improvement in VA from 0.58 0.27 to 0.46 0.33 LogMAR in Group 1 and from 0.58 0.19 to 0.25 0.29 LOgMAR in Group 2. There was a significant difference in favor of IVB. Reduction in macular thickness from 520 154 to 216 36 mm in Group 1 and 553 106 to 282 70 mm in Group 2. Improvement in VA from 0.68 0.25 to 0.31 0.21 LogMAR in Group 1 and from 0.67 0.27 to 0.46 0.31 LogMAR in Group 2. Reduction in macular thickness from 370 133 to 260 82 mm in Group 1 and from 372 99 to 298 101 mm in Group 2. There were statistical significant differences between the two groups in favor of IVB group.

Improvement in VA from 0.60 0.41 to 0.50 0.29 LogMAR in Group 1 and from 0.67 0.28 to 0.64 0.31 LogMAR in Group 2, reduction in macular thickness from 399.64 128.32 to 297.32 86.56 mm in Group 1 and from 466.39 121.29 to 356.68 106.06 mm in Group 2. Improvement in VA by 0.14 0.16 in group 1 and by 0.33 0.27 in group 2. Reduction in macular thickness from 506.9 182.8 to 228.0 104.85 mm in group 1 and from 525.18 192.12 to 188.2 48.87 mm in group 2 Improvement in VA from 0.77 0.45 to 0.39 0.42 LogMAR in group 1 and from 0.99 0.48 to 0.35 0.32 LogMAR in group 2. Reduction in macular thickness from 533.63 163.75 to 254 80.06 mm in group 1 and from 538.85 189.8 to 222.0 36.38 mm in group 2. No significant difference between the two groups Improvement in VA from 0.967 0.347, 0.959 0.319 and 0.956 0.473 LogMAR to 0.844 0.361, 0.833 0.310 and 0.997 0.472 LogMAR. respectively. Reduction in macular thickness from 450 92, 457 98, and 430 96 mm to 343 90, 323 86, and 359 93 mm, respectively. IVB seems to be safer as far as adverse effects (cataract, IOP increase) Improvement in VA by 0.6 0.35 lines in IVT group and by 2.8 4 lines in IVB group. Reduction in macular thickness from 492 102 to 238 118 mm in the IVB group and from 517 88 to 195 243 mm in the IVT group at the 13-month follow-up Improvement in VA from 0.87 0.14 to 0.49 0.33 LogMAR in Group 2 and from 0.91 0.13 to 0.45 0.36 LogMAR in Group 2. Reduction in macular thickness from 491 to 255.8 mm in group 1 and from 477.4 to 219.9 mm in group 2 in the 12-month follow-up Best results bevacizumab, similar therapeutic effect of the three treatment arms

Better results IVT

BRVO: branch retinal vein occlusion; IVB: intravitreal bevacizumab; IVT: intravitreal triamcinolone; VA: visual acuity.

Retrospective study

Study type

Kelkar (2009)190

Author (Year)

TABLE 4. Comparison between intravitreal triamcinolone and intravitreal bevacizumab for branch retinal vein occlusion.




!

2014 Informa Healthcare USA, Inc. 20 BRVO patients- 0.5 mg ranibizumab- only 17 completed the two-year follow-up 397 BRVO patients with macular edema randomized to receive 0.3 mg or 0.5 mg ranibizumab or sham injections

Prospective study

Campochiaro (2010)202 Campochiaro (2010)203


Prospective study

Prospective, randomized, sham injection-controlled, double-masked, multicenter trial.

Prospective study

Rouvas (2010)204

Pece (2010)205

Brown (2011)206

Azad (2012)207

30 eyes with BRVO randomized into three groups: Group 1 received grid laser treatment alone, Group 2 received an intravitreal injection of 0.5 mg ranibizumab and grid laser treatment on 7th day following injection, while Group 3 received three loading doses of intravitreal ranibizumab at monthly interval (i.e. 0, 1, & 2 months) þ standard laser treatment 7 days after the 1st injection.

397 BRVO patients with macular edema randomized to receive 0.3 mg or 0.5 mg ranibizumab or sham injections

8 BRVO patients- 0.5 mg ranibizumab

28 BRVO patients- 0.5 mg ranibizumab

12 BRVO patients randomized to intravitreal pegaptanib (n = 6) or ranibizumab (n = 6)- one injection and 6 weeks therafter, only in macular edema persists

Prospective study

Gallengo-Pinazo (2009)201

Prospective, randomized, doublemasked clinical trial.

20 BRVO patients ramdomized to 0.3 mg or 0.5 mg ranibizumab

Participants

Prospective study

Study type

Campochiaro (2008)200

Author (Year)

TABLE 5. Intravitreal ranibizumab in branch retinal vein occlusion.

6 months

12 months

12 months

9 months

6 months

24 months

30 weeks

6 months

Follow-up

Outcomes

(continued )

Improvement in VA 10 letters in the 0.3 mg group and 18 letters in the 0.5 mg group. Improvement in macular edema in about 85% in both groups Improvement in VA from 0.617 0.17 to 0.367 0.10 logMAR in pegaptanib group and from 0.717 0.19 to 0.351 0.21 in ranibizumab group. Improvement of macular edema from 498.83 86.37 to 266.33 20.70 in group 1 and from 545.67 87.66 to 260.67 31.76 in group 2. There was no difference between the two groups as far as VA or CFT is concerned. Number of injections 3.3 in group 1 and 2.3 in group 2 Improvement in VA 17.8 letters and improvement of macular edema from 481.5 to 245.8 mm in the two-year follow-up Mean change from baseline BCVA letter score at month 6 was 16.6 and 18.3 in the 0.3 mg and 0.5 mg ranibizumab groups and 7.3 in the sham group (p50.0001). At month 6, significantly more ranibizumab-treated patients (0.3 mg, 67.9%; 0.5 mg, 64.9%) had BCVA of 4 or =20/40 compared with sham patients (41.7%; p50.0001); and CFT had decreased by a mean of 337 microm (0.3 mg) and 345 microm (0.5 mg) in the ranibizumab groups and 158 microm in the sham group (p50.0001). More patients in the sham group (54.5%) received rescue grid laser compared with the 0.3 mg (18.7%) and 0.5 mg (19.8%) ranibizumab groups. Improvement in VA from 0.74 0.28 to 0.49 0.3. Improvement in central macular thickness from 349 112 at baseline to 229 44 at the end of follow-up. A mean of six injections was performed during the follow-up period. Improvement in VA from 20/126 to 20/50. Improvement in macular thickness from 533 to 278 mm. Number of injections 3.6 Mean (95% confidence interval) change from baseline VA letter score at month 12 was 16.4 (14.5–18.4) and 18.3 (15.8–20.9) in the 0.3 mg and 0.5 mg groups, respectively, and 12.1 (9.6–14.6) in the sham/ 0.5 mg group (p50.01, each ranibizumab group versus sham/ 0.5 mg). On average, there was a marked reduction in CFT after the first as-needed injection of 0.5 mg ranibizumab in the sham/0.5 mg group, which was sustained through month 12. Improvement in VA of 12 letters, 17.5 letters and 19 letters in groups 1, 2, and 3, respectively, with the decrease in CFT being 208.7 mm, 312.9 mm, and 326.8 mm, respectively, in these groups.



CONCLUSION

BRVO: branch retinal vein occlusion; CFT: central foveal thickness; VA: visual acuity.

Prospective study Heier (2012)210

Prospective study Kim (2012)209

interval of the recurrence 2.4 months from last injection.212

12 months

12 months

Improvement in VA from 20/160 to 20/80 after 1st injection Significant improvement in macular thickness Improvement in VA from 0.76 0.37 to 0.19 0.18 with an average injection number of 4.4 1.2 injections Improvement in VA of 15.6, 14.9 and 17.5 letters, respectively Improvement in macular edema with a reduction of 291.4, 330.6, and 304.2 mm, respectively 7 months

19 BRVO patients received 0.5 mg intravitreal ranibizumab 29 BRVO patients received 3 injections of 0.5 mg intravitreal renibizumab in monthly intervals 304 patients with BRVO from BRAVO study, randomized in sham, 0.3 mg ranibizumab and 0.5md ranibizumab. Reinjection if CFT4250 mm, or if macular edema persists or occurs again and affects patient’s VA Retrospective study Puche (2012)208

Author (Year)

TABLE 5. Continued

Study type

Participants

Follow-up


Outcomes


In conclusion, there are several treatment modalities for BRVO and specifically for its complications, such as macular edema, vitreous hemorrhage, retinal neovascularization, and retinal detachment. In BRVO, the patient should also be evaluated for known risk factors. The general physician must be notified of the occurrence of the retinal vascular occlusion and the need for diagnosis and control of arteriosclerotic risk factors. Contributing factors, such as hypertension, cardiovascular disease, and diabetes mellitus, should be identified and treated if needed. The patient was examined by VA assessment, biomicroscopy, IOP measurement, and OCT. It is also very important to know about the perfusion of the macula and periphery in all cases; therefore, FA should be performed in BRVO cases. Fluorescein angiography should be considered to identify the location of occlusion and areas of nonperfusion. The existence of macular edema and/or neovascularization (of the disk, retina, iris, and angle) should also be determined. If macula and periphery are perfused, VA plays an important role for therapy options. If VA is normal, there is a trend to make a close follow-up to the patient with biomicroscopy, OCT, and FA, even monthly, so as to assess for macular edema and evaluate potential complications. If VA is decreased and macular edema exists, in the era of anti-VEGF treatment, one can choose among intravitreal antiVEGF agents. Another option could be intravitreal corticosteroids, either IVT or dexamethasone implant. Laser photocoagulation should also be considered if there is no improvement with anti-VEGF treatment. On the other hand, if macula is not perfused and periphery suffers from ischemia as well, one should assess for macular edema and treat with either anti-VEGF or intravitreal corticosteroids, but laser treatment of the peripheral areas of nonperfusion can be considered if the area of periphery ischemia is very extensive. Another important point to rule out is peripheral neovascularization. In these cases, intravitreal therapy should be initiated, followed by scatter laser aimed at the non-perfused area.

DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Seminars in Ophthalmology



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Area of peripheral retinal nonperfusion and treatment response in branch and central retinal vein occlusion.

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Anatomy of arteriovenous crossings in branch retinal vein occlusion.

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Does Glaucoma Share Common Pathogenesis with Branch Retinal Vein Occlusion?

Bevacizumab for acute branch retinal vein occlusion with subretinal hemorrhage.

Visual field changes in branch retinal 'vein' occlusion.

Induced chorioretinal venous anastomosis in experimental retinal branch vein occlusion.

The treatment of acute branch vein occlusion by photocoagulation.

Pharmacotherapy for treatment of retinal vein occlusion.

Pharmacotherapy for treatment of retinal vein occlusion.

Bevacizumab treatment for acute branch retinal vein occlusion accompanied by subretinal hemorrhage.

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Dye-Free Porcine Model of Experimental Branch Retinal Vein Occlusion: A Suitable Approach for Retinal Proteomics.