Approach

Prompt and appropriate referral to an ophthalmologist is required when patients present with:[29]

  • Failure to achieve normal visual acuity in either eye, unless the case of the impairment has been medically confirmed by prior examination and visual acuity is stabilised

  • Symptoms of flashes of light, recent onset of floaters, halos, transient dimming, distortion of vision, obscured vision or loss of vision

  • Transient or sustained loss of any part of the visual field, or clinical suspicion or documentation of such field loss.

The management of a retinal vein occlusion depends on the location of the occlusion and the presence or absence of complications. Treatment is focused on vision-threatening complications such as macular oedema and neovascularisation. Potential management options include observation, management of underlying risk factors, vascular endothelial growth factor (VEGF) inhibitors given intravitreally, intravitreal corticosteroids, panretinal photocoagulation (PRP), control of intraocular pressure, pars plana vitrectomy, grid laser photocoagulation, and scatter laser photocoagulation.[1][3]​ There is no strong evidence that medical treatment can have a beneficial impact on the course of the retinal vein occlusion itself.[1]

Uncomplicated central retinal vein occlusion (CRVO)

The main goal of treatment of an uncomplicated CRVO, whether it is ischaemic or non-ischaemic, is observation and management of underlying risk factors. Concomitant medical conditions such as hypertension, atherosclerosis, hyperlipidaemia, diabetes mellitus, glaucoma, vasculitis, or hypercoagulable states should be treated if present. The patient should be closely monitored to detect complications such as macular oedema and neovascularisation. Patients with ischaemic CRVO should be followed more frequently than those with non-ischaemic CRVO.

CRVO with macular oedema

Concomitant medical conditions such as hypertension, atherosclerosis, hyperlipidaemia, diabetes mellitus, glaucoma, vasculitis, or hypercoagulable states should be treated if present.

Several randomised controlled trials have demonstrated effective treatment of macular oedema secondary to CRVO using intravitreal injection of VEGF inhibitors such as ranibizumab and aflibercept.[30][31][32] Bevacizumab, another VEGF inhibitor, is frequently used in a similar manner to ranibizumab, although its efficacy has not been studied as rigorously.[4][33][34][35][36][37][38] Clinical trials have also investgated intravitreal corticosteroids such as triamcinolone acetonide and dexamethasone (implant), with less significant results reported when used alone.[39][40][41][42][43][44][45][46][47] [ Cochrane Clinical Answers logo ]

A common approach is to initiate treatment with a VEGF inhibitor. Optical coherence tomography (OCT) can be used to evaluate response to treatment. If there is a good response to treatment after several monthly injections, then the injection interval may be increased.[48] If macular oedema persists after several monthly injections, an intravitreal corticosteroid may then be considered, usually to complement anti-VEGF therapy initially (rather than corticosteroid monotherapy). [ Cochrane Clinical Answers logo ]

Only ranibizumab, aflibercept, and dexamethasone implant are approved for the treatment of RVO-associated macular oedema. One systematic review reported clinically meaningful improvement in visual acuity and central retinal thickness for up to 5 years in patients treated with VEGF inhibitors or dexamethasone.[49]​ A subsequent systematic review found that VEGF inhibitors are recommended over intravitreal corticosteroids due to fewer adverse effects and better visual outcomes when corticosteroids are given 6-monthly.[50]

Factors to consider when deciding between VEGF inhibitors and intravitreal corticosteroids include duration of action (e.g., depot or implanted corticosteroids may have longer-lasting effects than VEGF inhibitors) and adverse effects (e.g., corticosteroids are associated with cataract progression and IOP elevation, whereas most of the adverse effects of VEGF inhibitors are associated with the intravitreal injection procedure). The long-term adverse effects of VEGF inhibition are not known. A systematic review comparing these two drug classes demonstrated that while dexamethasone required fewer injections, it was less efficacious in treating macular oedema than VEGF inhibitors.[51] Intravitreal triamcinolone is preferable to a dexamethasone implant when a patient is aphakic or has an anterior chamber intraocular lens. Migration of the implant into the anterior chamber can lead to corneal oedema which requires prompt surgical intervention.

Intravitreal injection with any agent can be complicated by endophthalmitis, retinal detachment, cataract, intraocular pressure elevation, and vitreous haemorrhage.

The Central Vein Occlusion Study (CVOS), a prospective, randomised controlled trial, demonstrated that grid laser photocoagulation did not improve visual acuity in patients with perfused macular oedema associated with CRVO.[52]

CRVO with neovascularisation

Concomitant medical conditions such as hypertension, atherosclerosis, hyperlipidaemia, diabetes mellitus, glaucoma, vasculitis, or hypercoagulable states should be treated if present.

Panretinal photocoagulation (PRP) is the application of laser energy to the retinal periphery for 360°. Results from the CVOS suggest that pan-retinal photocoagulation (PRP) should not be used until the appearance of retinal or anterior segment neovascularisation.[53] In other words, prophylactic PRP in the setting of CRVO is not necessary. The goal of PRP is to prevent further vision loss and to prevent the onset of neovascular glaucoma.

If neovascular glaucoma occurs, then control of intra-ocular pressure (IOP) should be initiated. IOP can be controlled with ophthalmic beta-blockers, alpha-2 agonists, carbonic anhydrase inhibitors, prostaglandin analogs, or glaucoma surgery.

Other complications of neovascularisation, such as vitreous haemorrhage or tractional retinal detachment, should be managed surgically with vitrectomy. A pars plana vitrectomy involves the surgical placement of a vitreous cutter, an infusion cannula, and a third instrument into the vitreous cavity through 3 sclera incisions located in the pars plana. The primary objective is removal of the vitreous humor.

The use of bevacizumab in the setting of neovascular glaucoma secondary to CRVO has been investigated, and rapid resolution of iris neovascularisation following treatment has been reported.[54][55][56][57] However, this resolution has not been shown to be sustained over time without the addition of PRP or endolaser.

Uncomplicated branch retinal vein occlusion (BRVO)

As with CRVO, the main goal of treatment of an uncomplicated BRVO, whether ischaemic or non-ischaemic, is observation and management of underlying risk factors. Concomitant medical conditions such as hypertension, atherosclerosis, hyperlipidaemia, diabetes mellitus, glaucoma, vasculitis, or hypercoagulable states should be treated if present. The patient should be closely monitored to detect complications such as macular oedema and neovascularisation. Patients with ischaemic BRVO should be followed more frequently than those with non-ischaemic BRVO.

BRVO with macular oedema

First-line treatment of macular oedema secondary to BRVO is intravitreal injection of a VEGF inhibitor or an intravitreal corticosteroid. For patients with macular oedema persisting for >3 months, despite intravitreal therapy, or for those patients who cannot receive corticosteroids (e.g., because of advanced or uncontrolled glaucoma), grid laser photocoagulation can be considered.[3]

Concomitant medical conditions such as hypertension, atherosclerosis, hyperlipidaemia, diabetes mellitus, glaucoma, vasculitis, or hypercoagulable states should be treated if present.

Several randomised controlled trials have demonstrated effective treatment of macular oedema secondary to BRVO using intravitreal injection of VEGF inhibitors such as ranibizumab and aflibercept.[58]​​[59][60][61]

Bevacizumab, another VEGF inhibitor, is frequently used in a similar manner to ranibizumab, although its efficacy has not been studied as rigorously.[4][37][62][63][64][65][66] Clinical trials have also investigated intravitreal corticosteroids such as triamcinolone acetonide and dexamethasone implant, with less significant results reported when used alone.[47][67]​​

A common approach is to initiate treatment with a VEGF inhibitor. Optical coherence tomography (OCT) can be used to evaluate response to treatment. If there is a good response to treatment after several monthly injections, then the injection interval may be increased.[48] If macular oedema persists after several monthly injections, an intravitreal corticosteroid may then be considered, usually to complement anti-VEGF therapy initially (rather than corticosteroid monotherapy).

Only ranibizumab, aflibercept, and dexamethasone are approved for the treatment of RVO-associated macular oedema.[4]

Factors to consider when deciding between VEGF inhibitors and intravitreal corticosteroids include duration of action (e.g., depot or implanted corticosteroids may have longer-lasting effects than VEGF inhibitors) and adverse effects (e.g., corticosteroids are associated with cataract progression and IOP elevation, whereas most of the adverse effects of VEGF inhibitors are associated with the intravitreal injection procedure). The long-term adverse effects of VEGF inhibition are not known. A systematic review comparing these two drug classes demonstrated that while dexamethasone required fewer injections, it was less efficacious in treating macular oedema than VEGF inhibitors.[51] Intravitreal triamcinolone is preferable to a dexamethasone implant when a patient is aphakic or has an anterior chamber intraocular lens. Migration of the implant into the anterior chamber can lead to corneal oedema which requires prompt surgical intervention.

Intravitreal injection with any agent can be complicated by endophthalmitis, retinal detachment, cataract, intraocular pressure elevation, and vitreous haemorrhage.

For patients with macular oedema persisting for >3 months, despite intravitreal therapy, or for those patients who cannot receive corticosteroids (e.g., because of advanced or uncontrolled glaucoma), grid laser photocoagulation can be considered. Grid laser photocoagulation involves the application of laser energy in a grid configuration in areas of leakage (as seen on fluorescein angiography) in the macula.

The Branch Vein Occlusion Study (BVOS) classified eligibility for laser treatment as follows: visual acuity worse than 20/40, <5 disk areas of non-perfusion on fluorescein angiography, no haemorrhage in the foveal center, and duration of disease of at least 3 months.[68] [ Cochrane Clinical Answers logo ] Patients in the BRAVO study were eligible to receive grid laser photocoagulation if needed.[60] Eligibility for laser treatment was as follows: visual acuity ≤20/40 or central subfield thickening ≥250 micrometers and <5 letters or <50 micrometer improvement compared with the visit 3 months prior. Additionally, macular haemorrhage had to have resolved.

The BVOS found that eyes treated with grid laser photocoagulation had improved vision and less macular oedema than untreated eyes at 3 years' follow-up.[69]

The utilisation of grid laser alone or in combination with ranibizumab has been investigated, and grid laser was not shown either to improve eventual visual function or to prolong time between anti-VEGF injections (i.e., reduce treatment burden).[70] [ Cochrane Clinical Answers logo ]

BRVO with neovascularisation

Concomitant medical conditions such as hypertension, atherosclerosis, hyperlipidaemia, diabetes mellitus, glaucoma, vasculitis, or hypercoagulable states should be treated if present.

The BVOS Group reported that scatter laser photocoagulation, applied directly to areas of non-perfusion, reduces the incidence of retinal neovascularisation in patients with non-perfused (5 disc areas of non-perfusion on fluorescein angiography) branch retinal vein occlusion (BRVO) by 50%, from 40% of affected patients to 20% of affected patients.[68] Scatter laser also reduces the number of patients who develop vitreous haemorrhage.[68] Nonetheless, scatter laser should only be performed once neovascularisation has developed, because a large percentage of patients with non-perfused BRVO never develop neovascularisation.[68]

Hemiretinal vein occlusion (HRVO)

Because there are no randomised controlled trials specific to HRVO, the treatment approach is frequently identical to that of BRVO. Treatment with intravitreal triamcinolone acetonide has been shown to have efficacy similar to that seen in BRVO and better efficacy than in CRVO.[71]

Drugs used in RVO

The main drug classes used in RVO are VEGF inhibitors and intravitreal corticosteroids.

VEGF inhibitors

Includes ranibizumab, bevacizumab, and aflibercept. Two systematic reviews have confirmed that VEGF inhibition is an efficacious approach to the treatment of RVO-associated macular oedema.[58][72]​​

Ranibizumab

  • Developed specifically for ophthalmic use, ranibizumab is recommended (and approved in some countries) for the treatment of neovascular age-related macular degeneration (AMD), diabetic retinopathy, myopic choroidal neovascularisation, and RVO-associated macular oedema.

  • In the CRUISE study, ranibizumab significantly improved visual acuity and reduced macular thickening in patients with CRVO and macular oedema, compared with sham injection followed by as-needed treatment.[31]

  • The BRAVO study reported similar findings. In patients with BRVO and BRVO-associated macular oedema, ranibizumab significantly improved visual acuity and reduced macular thickening compared with sham injection followed by as-needed treatment.[60]

  • Patients treated with ranibizumab in both the CRUISE and BRAVO studies had improved vision-related function.[73]

  • Long-term monthly monitoring is necessary to maintain the reduction in oedema and improvement in vision.[61]

Bevacizumab

  • Developed as a chemotherapeutic agent, bevacizumab is generally not approved for ophthalmic use; however, it is frequently used off-label. Several studies have reported promising, but inconsistent, results for the efficacy of bevacizumab in CRVO- and BRVO-associated macular oedema.[34][35][36][37]​​[62]​​[64][65][66][74]

  • The SCORE-2 randomised controlled trial found that bevacizumab is non-inferior to aflibercept for the treatment of macular oedema due to CRVO or HRVO, with respect to visual acuity after 6 months of treatment.[38]

  • A 5-year outcome analysis suggests that bevacizumab significantly improved long-term visual acuity in patients with CRVO-associated macular oedema.[75]

  • Bevacizumab appeared to be relatively well tolerated in open label studies of patients with neovascular ocular disease.[76]

Several studies suggest that the clinical efficacies of bevacizumab and ranibizumab may be equivalent in patients with AMD.[77][78][79][80] One study suggests that ranibizumab is superior.[81] No large, randomised controlled trial has compared bevacizumab with ranibizumab in patients with RVO. Nonetheless, clinicians frequently use results from AMD studies to inform drug interchangeability in the setting of RVO. One meta-analysis comparing VEGF inhibitors demonstrated that bevacizumab could be a reasonable alternative to ranibizumab and aflibercept in patients with retinal conditions, including RVO-associated macular oedema.[72]

Aflibercept

  • A fusion protein specifically designed for intravitreal use in neovascular age-related macular degeneration, diabetic retinopathy, and RVO-associated macular oedema; it binds both VEGF and placental growth factor.

  • In the COPERNICUS study, aflibercept significantly improved visual acuity and reduced macular oedema in patients with CRVO-associated macular oedema.[30]

  • The VIBRANT study reported similar findings for BRVO-associated macular oedema.[82] No adverse events significantly related to treatment were observed.

  • The LEAVO non-inferiority trial showed aflibercept to be non-inferior to ranibizumab in improving visual acuity at 100 weeks.[83]

  • ​A 5-year outcome analysis suggests that aflibercept significantly improved long-term visual acuity in patients with CRVO-associated macular oedema.[75]

Intravitreal injection with any agent can be complicated by endophthalmitis, retinal detachment, cataract, IOP elevation, and vitreous haemorrhage.

Intravitreal corticosteroids

Includes triamcinolone acetonide and dexamethasone.

Triamcinolone acetonide

  • The exact mechanism of action in the setting of macular oedema is not known. However, some investigators have reported case series of patients with CRVO who had some degree of visual and anatomical improvement.[39][40][41][42][43][44][45] One systematic review up to November 2014 included one RCT that compared two doses (1 mg and 4 mg) of triamcinolone with observation.[84] The RCT reported that both doses of triamcinolone were associated with greater improvements in visual acuity at 24 months.

  • The SCORE randomised controlled trial in patients with CRVO- and BRVO-associated macular oedema compared intravitreal triamcinolone acetonide with standard care (observation in CRVO and grid laser photocoagulation in BRVO).​[46][67][85]​ It found that 27% of triamcinolone-treated patients had at least 3 lines' improvement in visual acuity and a mean change in visual acuity of -1.2 letters. The change in macular thickness of -196 micrometres was similar between groups. In patients with BRVO, the results did not differ significantly between the two treatment arms.

  • Among those treated with triamcinolone acetonide, 20% required medication to control IOP and 26% had progression of cataract.

Dexamethasone

  • Delivered by an injectable intravitreal implant drug-delivery system that releases the dose of dexamethasone over a 6-month period.

  • In a randomised controlled trial evaluating the efficacy of dexamethasone in CRVO and BRVO, patients received either one or two treatments with a dexamethasone intravitreal implant.[47] An improvement in visual acuity at 2 months following implantation was reported; a gain of at least 15 letters was achieved in 30% to 32% of all treated subjects.[47] At 12 months, a gain of 3 lines of vision was reported in 24% of eyes treated with two dexamethasone implants compared with 21% of eyes treated with only one dexamethasone implant.

  • Results from this study suggest that prompt treatment for retinal vein occlusion, partcularly BRVO, may be associated with improved clinical outcomes.

Intravitreal injection with any agent can be complicated by endophthalmitis, retinal detachment, cataract, IOP elevation, and vitreous haemorrhage.

VEGF inhibitors versus intravitreal corticosteroids

Factors to consider when deciding between VEGF inhibitors and intravitreal corticosteroids include:

  • Duration of action (e.g., depot or implanted corticosteroids may have longer-lasting effects than VEGF inhibitors).

  • Adverse effects (e.g., corticosteroids are associated with cataract progression and IOP elevation, whereas most of the adverse effects of VEGF inhibitors are associated with the intravitreal injection procedure rather than with the injected agent). The long-term adverse effects of VEGF inhibition are not known.

Of all the intravitreal injections available, ranibizumab, aflibercept, and dexamethasone are usually the only ones approved for the treatment of RVO-associated macular oedema. All three agents have been studied in patients with BRVO-associated macular oedema of <3 months' duration. A systematic review comparing these two drug classes demonstrated that while dexamethasone required fewer injections, it was less efficacious in treating macular oedema than VEGF inhibitors.[51] Intravitreal triamcinolone is preferable to a dexamethasone implant when a patient is aphakic or has an anterior chamber intraocular lens. Migration of the implant into the anterior chamber can lead to corneal oedema which requires prompt surgical intervention.

Intravitreal injection with any agent can be complicated by endophthalmitis, retinal detachment, cataract, IOP elevation, and vitreous haemorrhage.

Biosimilars

Biosimilars for some biological agents used in ophthalmology are starting to become available. These are agents highly similar to the originator biological agent that can be prescribed at reduced cost. The American Academy of Ophthalmology has published a clinical statement about the use of biosimilars in ophthalmic practice.[86]

Other treatment options

Options such as laser chorioretinal venous anastomosis, radial optic neurotomy and tissue plasminogen activator (t-PA) have been investigated, but outcomes have not been encouraging and there is no compelling evidence to consider their use.[87][88][89][90][91][92][93][94][95][96][97]

  • Chorioretinal venous anastomosis can be complicated by vitreous haemorrhage, pre-retinal fibrosis with tractional retinal detachment, choroidal neovascularisation, and choroidovitreal neovascularisation.

  • Radical optic neurotomy has been associated with vitreal haemorrhage, visual field defects, retinal neovascularisation and retinal detachment.

  • Results of intravascular t-PA administration (retinal endovascular surgery), with or without intravitreal triamcinolone acetonide, vary greatly among surgeons, from highly successful and uncomplicated to unsuccessful and complicated.​[94][95][96][98]​ Adverse effects of t-PA given intravitreally or through direct venous cannulation include cataract, retinal neovascularisation, and retinal detachment.

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