BRVO Etiopatho, Management with studies

1. MANAGEMENT OF B.R.V.O.
LITERATURE REVIEW AND CURRENT
TRENDS
MODERATOR- DR MANOJ SASWADE
PRESENTOR- DR VIVEK ADWE

2. • Common cause of retinal vascular disease, second only to DR,
• 4 times as common as CRVO
• One of the branches of main vein are blocked
–Superotemporal branch…66%
–Inferotemporal branch…22-43%
–Nasal branches…0.5-2.6%
–Macular branch…24%
• PATHOGENESIS
• -MULTIFACTORIAL -THREE MECHANISMS MAY BE INVOLVED
1. Compression of vein at arteriovenous (A/V) crossing
2. Degenerative changes of vessel wall
3. Abnormal hematological factors

3. 1. Koyanagi first described association btw A/V crossing & BRVO -Common adventitial sheath of
retinal artery & vein provides settings for occlusion -Arteriosclerosis further aggravates the risk
• Zhao et al studied 106 eyes with BRVO… -They found artery anterior to vein in 99% cases -However,
in approx60% of normal…artery crosses anterior to vein without causing BRVO
2. DEGENERATIVE CHANGES OF VESSEL WALL
• Jefferies et al showed that…Bending of vein into nerve fiber layer at this point without compression
• Histological findings of venous lumen at A/V crossing suggested thrombus formation as to be a cause
• Alteration of venous endothelium & intima media as root of pathogenesis of BRVO
3. ABNORMAL HEMATOLOGICAL FACTORS
• Relation btw BRVO and hyper-viscosity of blood and dysregulation of thrombosis-fibrinolysis balance
• Resistance to activated protein C
• Protein C or protein S deficiency
• Deficiency of Antithrombin III
• Genetic mutation in the prothrombin gene
• Anti-phospholipid antibodies
• Hyper-homocysteinemia
• Lupus erythematosus

5. • FUNDUS FINDINGS
• Acute BRVO
1. Dilated tortuous vein distal to occlusion
2. Flame shaped hemorrhages respecting horizontal raphe
3. Retinal edema
4. Macular hemorrhage…macular BRVO
5. Fluid leakage from distal vein
6. Occasionally…subhyaloid hemorrhage
7. Rarely…vitreous hemorrhage
8. Cotton-wool spots…ischemia

6. • Chronic BRVO
1. Loss of retinal transparency
2. Collaterals around area of occlusion
3. Arteriolar narrowing & sclerosis
4. Vascular sheathing
5. Hard exudates
6. CME & pigment clumps at macula
7. NVD or NVE…in 36% eyes with
nonperfusion > 5 DD
8. Retinal detachment…rare

7. • INVESTIGATIONS-
• SYSTEMIC
• Systemic assessment is aimed principally at reducing the risk of future vascular occlusive events, both
ocular and systemic.
• All patients • Blood pressure (BP).
• Erythrocyte sedimentation rate (ESR)
• Full blood count (FBC).
• Blood glucose.
• Random total and high-density lipoprotein (HDL) cholesterol.

8. Urea, electrolytes creatinine –chronic renal failure is also a rare cause of RVO.
Thyroid function testing.
Electrocardiography (ECG). Left ventricular hypertrophy is associated with hypertension.
Selected patients according to clinical indication
In patients under age of 50, in bilateral RVO, patients with previous thrombosis or family
history of thrombosis, and some patients in whom investigation for common associations is negative.
Chest X-ray. Sarcoidosis, tuberculosis, left ventricular hypertrophy in hypertension.
C-reactive protein (CRP). Sensitive indicator of inflammation.
Plasma homocysteine level. To exclude hyperhomocysteinaemia, for which there is reasonable
evidence of an increased RVO risk.

9. ‘Thrombophilia screen’. Thrombin time,
prothrombin time and activated partial thromboplastin time,
antithrombin functional assay, protein C, protein S, activated protein C
resistance, factor Leiden mutation,
lupus anticoagulant and anticardiolipin antibody (IgG and IgM); the last may
be the most important of these.
Autoantibodies. Rheumatoid factor,
antinuclear antibody (ANA),
anti-DNA antibody, antineutrophil cytoplasmic antibody (ANCA).
Serum angiotensin-converting enzyme (ACE)-Sarcoidosis.
Treponemal serology
Carotid duplex imaging to exclude mimicking ocular ischaemic syndrome.

10. • OCULAR INVESTIGATIONS
• A complete ophthalmic examination should be performed, paying particular attention to history of
glaucoma and signs of intraocular inflammation.
• Careful examination of iris and angle should be performed in appropriate cases to monitor for early
signs of rubeosis or neovascular glaucoma.
• FLUORESCEIN ANGIOGRAPHY-
• Verify the diagnosis and evaluate for complications,
• Delineate retinal vascular characteristics that may have prognostic significance: macular leakage and
edema, macular ischemia, and large segments of capillary nonperfusion
• It is advisable to obtain FA only after the intraretinal hemorrhages have cleared significantly from the
macula.
• Findings - Delayed filling of occluded retinal vein.
capillary nonperfusion,
blockage from intraretinal hemorrhages,
telangiectatic collateral vessels, dye extravasation from macular edema or NVEs

11. In chronic cases, when hges have resolved, microvascular changes on FA may provide the only clues of
a previous BRVO.
When FA demonstrates macular leakage and edema with cystoid involvement of the fovea, but no
capillary nonperfusion, it is presumed that the macular edema is the cause of vision loss. Under these
circumstances, about one-third of patients will spontaneously regain some vision.
• When macular edema is present ophthalmoscopically within the first 6 months after a BRVO and
there is little or no leakage on FA, macular ischemia may be the cause of the macular edema. In such
circumstances, the edema almost always spontaneously resorbs in the first year after the occlusion, often
with return of vision.
• OCT
Noninvasive and rapid method of quantitatively measuring macular edema.
Used to monitor the response to treatment of macular edema .
Intraretinal hemorrhages have minimal effect on the interpretation of OCT.

12. • FINDINGS –
• cystoid edema
• intraretinal hyper reflectivity from hemorrhages,
• shadowing from edema and hemorrhages, and
• occasionally subretinal fluid .
• In chronic cases, photoreceptor inner-segment–outer-segment junction
abnormalities from long-standing macular ischemia and macular edema may
also be seen .

13. • MANAGEMENT-
• The treatment for BRVO is aimed at treatment/prevention of the complications that cause vision loss
including macular edema, macular ischemia and neovascularization. The systemic risk factors should
be optimized in consultation the primary care doctor. Macular edema is the most common cause of
vision loss in BRVO.
• Treatment options for managing macular edema with BRVO include macular grid laser
photocoagulation and intravitreal injections.
• Laser therapy improves oxygenation to the treated area causing constriction of the occluded vein and
the adjacent arteriole resulting decreased edema.
• Steroids such as triamcinolone and dexamethasone have antiinflammatory and antiangiogenic
properties that inhibit the expression of vascular endothelial growth factor (VEGF) and other
proinflammatory cytokines. VEGF is known to promote edema.

14. • Laser Photocoagulation
• Prior to the advent of anti-vascular endothelial growth factor (VEGF) agents, laser photocoagulation
was considered the gold standard for the treatment of BRVO as established by the BVOS Group.
• BVOS Group – 1984 and 1986
• Goal to assess if photocoagulation can: (1) prevent neovascularization,
(2) prevent vitreous hemorrhage, and
(3) improve vision in eyes with macular edema with ≤ 20/40 from BRVO.
• Total patients: 319+ 82+139 ; Duration: mean of 3.1 years
• Groups
• Eyes with ≥ 5 disk diameters of nonperfusion without NV treated with either scatter laser or no
laser
• Eyes with NV treated with either scatter laser or no laser
• Eyes with BRVO and macular edema and visual acuity of ≤ 20/40 randomized to grid laser or no
laser

15. • Results
• 319 eyes recruited. 12% in treated eyes developed NV and 22% in non-treated eyes developed
NV. However, no change in visual acuity from baseline. 36% of non-treated eyes developed NV
• 82 eyes recruited. 29% of treated eyes developed VH and 61% of non-treated eyes developed VH.
12% of eyes that developed VH had vision loss.
• 139 eyes recruited. 65% of treated eyes gained two or more lines from baseline, compared with
17% of non-treated eyes. Overall, treated eyes gained 1.33 lines compared to non-treated eyes
gained 0.23 lines of vision.
• Conclusion
• Eyes randomized to grid laser had visual acuity gain.
• According to results, patients with BRVO and > 5 disc diameters of retinal capillary nonperfusion
should undergo scattered laser photocoagulation only once neovascularization has developed as scatter
photocoagulation after neovascularization develops is as effective as before neovascularization in
preventing vitreous hemorrhage.
• BVOS group recommended use of grid laser for BRVO with macular edema and VA ≤ 20/40. It also
recommended following nonperfused eyes at 4 months intervals and use of scattered laser once NV
develops.

16. • Photocoagulation can be considered in patients with perfused macular edema with VA ≤ 20/40
without improvement in visual acuity for at least 3 months. Before application of laser
photocoagulation, an FA of the macula is obtained to demonstrate the absence of a large area of
capillary nonperfusion adjacent to the capillary free zone that could explain the vision loss.
• The recommended parameters for GRID LASER - Duration of 0.1 seconds, 100 µm diameter spot
- power to produce a medium white burn.
• Applied in a grid pattern throughout a leaking area, but not involving the edge of FAZ. FA is repeated
in 2-4 months to assess the need for additional laser and resolution of macular edema.
• The recommended parameters for SCATTER LASER - duration of 0.2 seconds, 200-500 µm spot
- Power to produce a medium white burn.
Applied in the area of capillary nonperfusion as defined by FA, with laser applied peripherally at least
to the equator and no closer than 2DD from the center of the fovea.

17. • Steroid Treatment
• The SCORE-BRVO study is the largest trial that evaluated the safety and efficacy of intravitreal
triamcinolone compared to grid laser in the treatment of macular edema.
• SCORE-BRVO – 2009
• Total patients: 411 patient with macular edema due to BRVO - Duration: 12 months
• Objective: compare efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal
triamcinolone with standard care (grid laser)
• Randomized to 1mg, or 4mg preservative-free intravitreal triamcinolone or macular grid laser
• Results: all three groups had equivalent percentage of patients with gain of ≥ 15 letters from baseline at
12 months. The rate of elevated intraocular pressure and cataracts were significantly higher in the 4-mg
group. Volume of all injections was 0.05 mL
• Summary: There is no difference in visual acuity gained at 12 months but grid laser and triamcinolone;
however, there is higher rates of cataracts and elevation of intraocular pressure with the use of
triamcinolone 4-mg
• Three year results showed a significant increase in vision in the laser group compared to the intravitreal
triamcinolone groups. From the results of this study, intravitreal triamcinolone is not recommended as a
first-line therapy for macular edema due to BRVO. It is utilized as an adjunct to laser or anti-VEGF
agents or as second line agent.

18. • GENEVA – 2010
• Total patients: 830 patients with BRVO and macular edema for 6 weeks to 12 months, and 437 patients
with CRVO and macular edema for 6 weeks to 9 months.
• Duration: 6 months
• Objective: evaluate efficacy and safety of dexamethasone intravitreal implant (DEX implant,
OZURDEX) in CRVO and BRVO with macular edema.
• Randomized to sham procedure, 0.35mg DEX implant, or 0.7mg DEX implant
• Results -BRVO and CRVO analyzed as a single group.
• At 30 to 90 days DEX implant groups had a higher percentage of eyes with BCVA gain ≥ 15 letters
• A lower percentage of eyes had a loss ≥ 15 letters in DEX implant groups compared to sham group
at all time points
A repeat injection of 0.7 mg at the end of 6 months also yielded similar results.
Eyes treated with sham initially and Ozurdex® after 6 months had an improvement in visual acuity and
retinal thickness but the gains were lower than eyes treated since baseline.

19. • The incidence of cataract was 29.8% of phakic eyes (90/302) in 0.7/0.7 mg group, 19.8% (56/283) in
the 0.35/0.7 mg group, and 10.5% (31/296) in the delayed treatment group (P < 0.001).
• The incidence of increased IOP of atleast 10 mmHg maximized 60 days after the implant. The
incidence of increased IOP was 12.6% after the first implant and 15.4% after the second implant in the
retreated group (0.7 mg/0.7 mg). The cumulative incidence of increased IOP of 10 mmHg or higher at
some point in the 1st year in the retreated group was 32.8%.
• Summary: DEX implants can improve the speed of visual improvement in eyes with macular edema
due to BRVO or CRVO.
The study was limited by the absence of rescue laser for treatment of the sham group.

20. AntiVEGFs

21. • BERVOLT Study – 2015
• Total patients: 87 eyes with BRVO ; Duration: mean follow up of 24.4 months
• Retrospective, non-comparative case series of BRVO of patients who received ≥ 1 intravitreal injection
of bevacizumab
• Results: there was significant improvement of visual acuity with mean change of BCVA of 0.25
logMAR (13 letters) at 2 years with an average of 7.6 injections.
• Summary: bevacizumab is an alternative to other anti-VEGF therapies for BRVO with macular edema.
The letter gain equivalent is around 15, which is similar to findings in BRAVO/HORIZON studies.
However, the study is limited by the retrospective protocol, lack of randomization, 14 month delay
between diagnosis and treatment, and variable protocolled use of bevacizumab.
• Russo et al - 30 eyes - either grid laser or intravitreal bevacizumab. Bevacizumab was given at 1, 3, 6
and 12 months. Grid laser was applied at baseline and reassessed at 3 months for possible retreatment.
At 12 months the mean gain in BCVA was 0.31 logMAR (15 letters) in the bevacizumab group
compared with 0.20 logMAR (10 letters) in the grid laser group. Result similar to mean gains in the
BRAVO/HORIZON and VIBRANT studies.
Russo V, et al. Bevacizumab compared with macular laser grid photocoagulation for macular edema in
branch retinal vein occlusions. Retina 2009; 29: 511–515.

22. • Wu et al - 2.5mg and 1.25mg doses of bevacizumab were compared retrospectively on BCVA gain and
central subfield thickness.
• The mean BCVA gain at 6 months was 5.1 lines and 4.5 lines in the 1.25mg group and 2.5mg group,
respectively. There was no statistically significant difference between the two doses on BCVA and
central subfield thickness.
Wu L, et al. Comparison of two doses of intravitreal bevacizumab (Avastin) for treatment of macular edema secondary to
branch retinal vein occlusion: results from the Pan-American Collaborative Retina Study Group at 6 months of follow-up. Retina.
2008 Feb;28(2):212-9.
Hikichi et al studied efficacy of bevacizumab as a PRN treatment.
Eligible patients were followed up every 3 months or earlier with no fixed follow-up protocol and
underwent reinjection if the foveal thickness was >250 µ or there was persistent or recurrent macular
edema affecting visual acuity.
They found that gains in visual acuity and foveal thickness with this therapy. Patients required an
average of 3.8 ± 1.5 injections over 2 years with a provision for rescue laser at the end of 3 months. The
authors suggested that the decreased frequency of injections might be related to greater intravitreal halflife
of bevacizumab as noted in the animal models
Hikichi T, Higuchi M, Matsushita T, Kosaka S, Matsushita R, Takami K, et al. Two-year outcomes of intravitreal bevacizumab
therapy for macular oedema secondary to branch retinal vein occlusion. Br J Ophthalmol. 2014;98:195–9.

23. • Bevacizumab was also efficacious with a treat and extend regime.
Patients were given 3 loading dose of the injection followed by a repeat monthly injections until the
macula was dry.There was a gradual 2 weeks increment in follow-up injections until it reached 3
months. The gap between injections was reduced by 2 weeks if the fluid reappeared.
Visual acuity gains and number of injections required at the end of 1 year was similar to BRAVO study.
Number of hospital visits was much lower and resulting in fewer investigations. This outcome coupled
with the lower cost of bevacizumab compared to ranibizumab provided annual savings of $16,663.50 per
patient.
Rush RB, Simunovic MP, Aragon AV, 2nd, Ysasaga JE. Treat-and-extend intravitreal bevacizumab for branch retinal vein
occlusion. Ophthalmic Surg Lasers Imaging Retina. 2014;45:212–6.
• A comparitive study found that Ozurdex® treatment resulted in better recovery of BCVA and greater
reduction in foveal thickness at 1-month follow-up compared to bevacizumab. However, these
differences disappered by 3 months onward with both the treatments providing similar results. After the
initial loading dose, the reinjection rate was higher with Ozurdex® compared to bevacizumab.
Guignier B, Subilia-Guignier A, Fournier I, Ballonzoli L, Speeg-Schatz C, Gaucher D. Prospective pilot study: Efficacy of
intravitreal dexamethasone and bevacizumab injections in the treatment of macular oedema associated with branch retinal vein
occlusion. Ophthalmologica. 2013;230:43–9.

24. • A comparison of the efficacy of bevacizumab to grid laser reported that bevacizumab treatment resulted
in better and faster visual recovery.
• Leitritz MA, Gelisken F, Ziemssen F, Szurman P, Bartz-Schmidt KU, Jaissle GB. Grid laser photocoagulation for macular
oedema due to branch retinal vein occlusion in the age of bevacizumab? Results of a prospective study with crossover
design. Br J Ophthalmol. 2013;97:215–9.
• Systematic reviews have shown that eyes which are treated with anti-VEGF agents from the beginning
fare better than eyes which are either observed or treated with other modalities but crossover to anti-
VEGF treatment after 6 months of the disease onset. Nonresponders who crossed over after 12 months
of treatment fared better suggesting alternative treatment modalities in nonresponders. Major limitation
of studies involving grid laser is a lack of uniformity of laser treatment and absence of objectivity due
to lack of evaluation of the grid by a reading center.
• Pielen A, Feltgen N, Isserstedt C, Callizo J, Junker B, Schmucker C. Efficacy and safety of intravitreal therapy in macular
edema due to branch and central retinal vein occlusion: A systematic review. PLoS One. 2013;8:e78538.
• The vision gained in eyes treated with anti-VEGF agents from the beginning was 18.3 letters at the end
of 12 months compared to 12.1 letters when the patient was initially treated with sham and crossed over
to anti-VEGF agents at the end of 6 months. This observation indicates that early anti-VEGF treatment
provides better results than natural history.
• Brown DM, Campochiaro PA, Bhisitkul RB, Ho AC, Gray S, Saroj N, et al. Sustained benefits from ranibizumab for macular
edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology. 2011;118:1594–602.

25. • RANIBIZUMAB
• BRAVO STUDY-
• Patients with best corrected visual acuity (BCVA) between 20/40 and 20/400, diagnosed with macular
edema secondary to BRVO in the last 12 months with no history of treatment and central foveal
thickness (CFT) more than 250 µ
• Subdivided into three treatment groups (sham, 0.3 mg ranibizumab, and 0.5 mg ranibizumab).
• Treated with monthly injections for 6 months with a provision for rescue laser after 3 months if visual
acuity did not improve more than 5 letters with CFT being >250 µ with <50 micron reduction in
thickness despite 3 injections.
• At the end of 6 months, there was a statistically significant improvement in visual acuity in the
ranibizumab group (0.3 and 0.5 mg) compared to the sham group. The patients noted improved visual
functions over a wide field of activities as early as 1 month after the first injection of ranibizumab.
• The BRAVO study showed that ranibizumab is superior to traditional grid laser for macular edema
from BRVO. The study also showed that PRN treatment was able to maintain gains in vision after 5
monthly injections. However, the study did not evaluate when to switch to PRN schedule.
• Varma R, Bressler NM, Suñer I, Lee P, Dolan CM, Ward J, et al. Improved vision-related function after ranibizumab for macular
edema after retinal vein occlusion: Results from the BRAVO and CRUISE trials. Ophthalmology. 2012;119:2108–18.

26. • HORIZON trial was a 12 month extension of BRAVO and CRUISE trials and followed patients
every 3 months for 12 months.
• Patients were given PRN ranibizumab 0.5mg based on the criteria in the BRAVO study.
HORIZON concluded that PRN use of ranibizumab after an intensive year of treatment was able to
maintain visual acuity gains.
Heier JS, et al. Ranibizumab for Macular Edema Due to Retinal Vein Occlusions Long-term Follow-up in the HORIZON Trial.
Ophthalmology 2012; 119:802-809
MARVEL study evaluated the efficacy of bevacizumab compared to ranibizumab on a PRN basis for
the management of BRVO with macular edema.
Study found that PRN administration of either bevacizumab or ranibizumab was effective in reducing
macular edema with improvement in visual acuity with 2.53 letters difference between two drugs
(ranibizumab 18.08 letters; bevacizumab 15.55 letters). Both treatments also resulted in rapid restoration
of anatomy and function which was sustained by PRN treatment with rescue laser therapy in 12/75 (16%)
eyes.
Narayanan R, Panchal B, Das T, Chhablani J, Jalali S, Ali MH MARVEL study group. A randomised, double-masked,
controlled study of the efficacy and safety of intravitreal bevacizumab versus ranibizumab in the treatment of macular oedema
due to branch retinal vein occlusion: MARVEL Report No 1. Br J Ophthalmol. 2015;99:954–9.

27. • VEGF-TRAP/ AFLIBERCEPT
• VIBRANT study
• double-masked, multicenter trial to assess the efficacy of aflibercept compared to macular laser in eyes
with macular edema secondary to BRVO.
• Arm one received 6 injections of 2 mg aflibercept, second received baseline laser. Sham laser or
injections were also given in order to ensure masking. Rescue laser therapy occurred as needed after 12
weeks.
• At 6 months, eyes treated with aflibercept had more favorable outcomes in terms of reduced edema
(aflibercept 280.5 µ/laser 128 µ) or visual recovery (aflibercepept 17 letters/laser 6.9 letters).
• At 52 weeks - aflibercept injections at 8 weeks interval after the first 6 months helped maintain vision
and foveal thickness in the aflibercept arm of the study. Similarly, rescue aflibercept for the patients in
the laser arm from 24 weeks onward resulted in substantial improvement in vision and foveal thickness
at the end of 52 weeks. Rescue laser in the aflibercept arm was given at 36 weeks in 10.6% of the eys
while rescue injection of aflibercept was given between 24 and 48 weeks of the study in 80.7% eyes in
the laser arm. This was the first study to directly compare the efficacy of an anti-VEGF agent to laser
therapy and show that anti-VEGF was superior.
• Clark WL, Boyer DS, Heier JS, Brown DM, Haller JA, Vitti R, et al. Intravitreal aflibercept for macular edema following
branch retinal vein occlusion: 52-week results of the VIBRANT study. Ophthalmology. 2015 pii: S0161-642001113-6.

28. • A network meta-analysis of eight randomized control studies comprised approved treatment modalities
(laser, ranibizumab, Ozurdex®, and aflibercept) was performed.
• The authors reported that the probability of being the most efficacious treatment was 54% for
ranibizumab and 30% for aflibercept.
• Probability of gaining more than 15 letters was 39% for aflibercept and 35% for ranibizumab.
• There was no statistically significant difference in the visual outcomes between ranibizumab and
aflibercept. These modalities were also reported to be superior to laser and Ozurdex®.
Regnier SA, Larsen M, Bezlyak V, Allen F. Comparative efficacy and safety of approved treatments for macular oedema
secondary to branch retinal vein occlusion: A network meta-analysis. BMJ Open. 2015;5:e007527.

29. • Is combination therapy better?
• Tomomatsu et al. assessed the efficacy of bevacizumab combined with targeted retinal
photocoagulation (TRP) compared to bevacizumab alone.TRP was performed when an area of
nonperfusion was >5DD .Laser was performed with the posterior extent being 3000 µ away from the
fovea. Bevacizumab injection was performed 2 weeks after TRP. The authors concluded that the
combination therapy help reduce recurrence of macular edema.
Tomomatsu Y, Tomomatsu T, Takamura Y, Gozawa M, Arimura S, Takihara Y, et al. Comparative study of combined
bevacizumab/targeted photocoagulation vs bevacizumab alone for macular oedema in ischaemic branch retinal vein
occlusions. Acta Ophthalmol. 2015 Epub ahead of print.
• RELATE trial evaluated the combination of grid and scatter photocoagulation 24 weeks after
randomization into the ranibizumab group. Found no additional benefits of laser in terms of
improvement in vision, resolution of macular edema, or reduced number of intravitreal injections.
• Campochiaro PA, Hafiz G, Mir TA, Scott AW, Solomon S, Zimmer-Galler I, et al. Scatter photocoagulation does not reduce
macular edema or treatment burden in patients with retinal vein occlusion: The RELATE
Trial. Ophthalmology. 2015;122:1426–37.

30. • A Cochrane database review reported that there is no benefit in performing early (before 3 months) or
late laser (after 6 months) in eyes with macular edema secondary to BRVO.
• Lam FC, Chia SN, Lee RM. Macular grid laser photocoagulation for branch retinal vein occlusion. Cochrane Database Syst
Rev. 2015;5:CD008732.
• A separate review also found uncertain benefits of adjunctive laser in cases of BRVO with macular
edema.
• Glanville J, Patterson J, McCool R, Ferreira A, Gairy K, Pearce I. Efficacy and safety of widely used treatments for macular
oedema secondary to retinal vein occlusion: A systematic review. BMC Ophthalmol. 2014;14:7.
• The European Vitreoretinal Society (EVRS) also found that for medical management, monotherapy
with anti-VEGF agents were superior to any form of combination therapy.
• Adelman RA, Parnes AJ, Bopp S, Saad Othman I, Ducournau D. Strategy for the management of macular edema in retinal
vein occlusion: The European VitreoRetinal Society macular edema study. Biomed Res Int 2015. 2015 870987.

31. • Adverse events
• Cataract, retinal tear with detachment, endophthalmitis. Incidence was lower and may be related to the
procedure rather than the drug itself. Hemorrhagic stroke and myocardial infarction.
• The RETAIN trial was conducted to determine the long-term outcomes of patients with ranibiziumab
treated for retinal vein occlusions. The trial found serious systemic adverse events in 12/66 (18.18%)
cases. The role of ranibizumab could not be proven in any of these cases.
Campochiaro PA, Sophie R, Pearlman J, Brown DM, Boyer DS, Heier JS, et al. Long-term outcomes in patients with retinal
vein occlusion treated with ranibizumab: The RETAIN study. Ophthalmology. 2014;121:209–19.
• Compared to this, the reported incidence of systemic serious adverse events for patients with age-
related macular degeneration (ARMD) in the CATT trial was 31.1% for ranibizumab and 39.9% for
bevacizumab. There was no difference between the two drugs for the development of cardiac or
neurological disorders.
Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Martin DF, Maguire MG,
Fine SL, Ying GS, Jaffe GJ, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular
degeneration: Two-year results. Ophthalmology. 2012;119:1388–98.
• A Cochrane database review of all the nonindustry-sponsored randomized controlled trials for ARMD
found the risk of developing serious systemic adverse events with ranibizumab was 222/1000 and
240/1000 with bevacizumab (relative risk 1.08; confidence interval: 0.90–1.31). Deaths reported in
these trials were unlikely to be the effect of the choice of drug that was injected.
Moja L, Lucenteforte E, Kwag KH, Bertele V, Campomori A, Chakravarthy U, et al. Systemic safety of bevacizumab
versus ranibizumab for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2014;9:CD011230.

32. • Current practice in the management of branch retinal vein occlusion in Japan: Survey results of
retina specialists in Japan. Ogura Y1, Kondo M2 et al.
• Purpose: To elucidate the current clinical practice patterns of BRVO management by retina specialists
in Japan in the era of anti-VEGF therapy.
• Study design: A voting survey using an answer pad system.
• Methods: On May 28, 2017, forty-one retina specialists were surveyed on the pathology and clinical
practice of BRVO management.
• Results:77.5% specialists use fundus examination and optical coherence tomography (OCT) for
diagnosis of macular edema (ME) secondary to BRVO. All assess the condition of the ellipsoid zone
(EZ) and external limiting membrane (ELM) and consider this a visual prognostic factor. For ME
secondary to BRVO, anti-VEGF therapy is the first choice, and most specialists (82.4%) select initial
injection followed by a pro re nata (PRN) regimen. For switching to other treatment options for
persistent cases, combination therapy of anti-VEGF injections and laser therapy is the most common
choice (35.9%), whereas 25.6% select vitreous surgery and 15.4% select adding steroid injections.
• Conclusions: Our survey presents the current opinions on the diagnosis and treatment of BRVO by
retina specialists in Japan, and reveals the common views about damage to the EZ/ELM as a factor of
poor prognosis and anti-VEGF therapy as the first line treatment, highlighting various opinions on
initiation and switching of therapy

33. • Future directions
• The role of autologous plasmin enzyme
• Plasmin is a serine protease and has a proteolytic effect on fibrin, laminin, and fibronectin.
• Laminin and fibronectin are the components of internal limiting membrane (ILM) which help in its
adhesion to the collagen fibers of the posterior vitreous cortex. By breaking these adhesions, plasmin
induces posterior vitreous detachment (PVD) thereby relieving any traction which might be present.
They are also known to increase the oxygen levels in vitreous.
• A study evaluated the outcomes of an injection of 0.2 ml of plasmin and reported improvements in
BCVA and foveal thickness which persisted for 6 months. PVD and pharmacological vitreolysis
induced by the plasmin may be equivalent to the effect of PPV without complications of the surgery
• Udaondo P, Díaz-Llopis M, García-Delpech S, Salom D, Romero FJ. Intravitreal plasmin without vitrectomy for macular
edema secondary to branch retinal vein occlusion. Arch Ophthalmol. 2011;129:283–7.
• Sakuma et al. used intravitreal autologous plasmin in the management of macular edema due to BRVO
in 26 eyes.31 PVD was induced after injection in 23 of these eyes whereas the rest had no PVD. BCVA
improved irrespective of the induction of PVD suggesting that mechanisms other than vitreolysis might
be in play. Electroretinograms of these eyes did not show any signs of retinal toxicity.
• Sakuma T, Mizota A, Inoue J, Tanaka M. Intravitreal injection of autologous plasmin enzyme for macular edema associated
with branch retinal vein occlusion. Am J Ophthalmol. 2010;150:876–82.

34. • Pars plana vitrectomy with ILM peeling-
The rationale for this treatment includes relief of traction, improved oxygenation of vitreous and retina thereby
preventing photoreceptor loss, removal of inflammatory, and permeability factors such as VEGF and upregulation
of epidermal growth factors which help the healing process. EVRS found vitrectomy with ILM peeling was the
most effective management reporting visual gains that were almost twice as high as anti-VEGF agents at 24 months
postoperatively.
Adelman RA, Parnes AJ, Bopp S, Saad Othman I, Ducournau D. Strategy for the management of macular edema in retinal vein
occlusion: The European VitreoRetinal Society macular edema study. Biomed Res Int 2015. 2015 870987
• Okunuki et al. found that patients who had high vitreal levels of VEGF and interleukin-8 before vitrectomy had
greater macular edema preoperatively and had a significant decrease on foveal thickness at 6 months
postoperatively. They also found that high intraocular levels of monokine induced by γ interferon were associated
with reduced foveal thickness at 6 months postoperatively.
Okunuki Y, Usui Y, Katai N, Kezuka T, Takeuchi M, Goto H, et al. Relation of intraocular concentrations of inflammatory
factors and improvement of macular edema after vitrectomy in branch retinal vein occlusion. Am J Ophthalmol. 2011;151:610–
6.e1.
• The comparative efficacy of vitrectomy, tissue plasminogen activator (tPA), and bevacizumab-
• At 12 months follow-up, the visual outcomes in all the three groups were similar. However, some of the eyes
treated with tPA and bevacizumab required additional vitrectomy due to sequelae such as epiretinal membrane
and vitreous hemorrhage. While the results of vitrectomy with ILM peeling are promising, further studies are
required to validate the efficacy of this approach.
Kumagai K, Ogino N, Furukawa M, Larson E. Three treatments for macular edema because of branch retinal vein occlusion:
Intravitreous bevacizumab or tissue plasminogen activator, and vitrectomy. Retina. 2012;32:520–9.

35. • In summary,
 Laser for macular edema in BRVO has been the gold standard of management for more than two
decades. However, its limitation includes slow and uncertain visual recovery which has prompted a
search for other options.
 Steroids show promising results but are associated with increased IOP and cataract formation.
 Intravitreal anti-VEGF has resulted in the best outcomes to date with little direct evidence of ocular
or systemic side effects. However, long-term data from the RETAIN study indicate that 50% of the
patients require at least three injections even after 4 years of therapy to maintain the visual gains.
 Most of the studies seem to suggest that anti-VEGF monotherapy continues to be the best
management of macular edema secondary to BRVO. Various treatment regimens have been tested
ranging from the loading dose model in the BRAVO study to the PRN dosing in the MARVEL study.
While the former runs the risk of too many injections, the latter could result in undertreatment.
 Overall, anti-VEGF agents have become the mainstay of management with every patient needing
personalized management.
While plasmin and vitrectomy seem to show promising results, they require further validation before
being accepted as a routine management modality.