Retinal Vein Occlusion
Author: Ameen Marashi, MD
Documenting the visual loss is essential, which includes the location and duration along with detailed ocular history including associated ophthalmic diseases such as glaucoma, cataract, amblyopia, etc.. with precise previous ocular treatments such as topical medications, surgical interventions (cataract, refractive, etc.) laser, injections (intravitreal, sub-tenon, etc.) and medication such as Anti-VEGF, steroids or other.
Medical history of diabetes mellitus, systemic hypertension, especially in patients older than 50 years, and hyperlipidemia in patients less than 50 years, along with cardiovascular diseases, sleep apnea, coagulopathies, thrombotic disorders, etc.. are documented.
A list of ocular examination should set
1) Best-corrected visual acuity (BCVA), this is an essential step which can be performed by a trained optometrist or certified ophthalmologist to document the visual impairment. This will help in the follow-up visits to assess the efficacy of the treatment. The lower BCVA at baseline, the worse the prognosis in terms of proliferative changes, especially in cases of central vein occlusion (CRVO)  .
2) Pupillary reaction evolution is important as large areas of retinal ischemia may induce relative afferent defect as this may hold prognostic factor of developing neovascularization on the iris.
3) A slit-lamp examination done with a thorough exam of clarity and regularity of the cornea and to rule out any conjunctival abnormality such injection of conjunctival vessels should be documented. Any other inflammations of the conjunctiva or eyelids is documented and managed before any treatment decision. Meticulous iris exam to rule out neovascularization is crucial and crystalline lens exam to rule out cataract or intraocular lens (IOL) to document the position and clarity of the posterior capsule.
4) Intra Ocular Pressure (IOP) documentation is essential as high IOP is associated with neovascular glaucoma, iris, or/and angle neovascularization or patient with glaucoma history. IOP rise can occur in the 1st 100 days of RVO .
Note when high IOP spotted a corrected IOP documented after central corneal thickness measurement.
5) Gonioscopy before dilated eye exam is essential to document anterior chamber angle status (open or closed) and to rule out neovascularization on the angle, blood in Schlemm’s canal, and fibrovascular tissue, especially in cases of a relative pupillary defect, high IOP and ischemic retinal changes .
Gonioscopy can be scheduled after the dilated fundus exam (if not done in the initial ocular examination) when ischemic changes are confirmed.
6) Bilateral dilated fundus exam is an essential and detailed examination of the optic disc, macula, posterior pole, a mid-peripheral and peripheral retinal exam with specialized indirect wide-field lenses using slit-lamp biomicroscopy or indirect ophthalmoscopy :
Dilated and tortuous retinal veins with attenuation of the retinal artery along with intraretinal and flame-shaped hemorrhages and presence of cotton wool spots
Macular edema secondary to RVO documented clinically and by using OCT.
Macular pigmentary changes are due to long standing edema.
Signs of ischemia such as neovascularization (on the optic disc or/and elsewhere), severe hemorrhages, cotton wool spots, collateral vessels, and venous beadings documented.
Prepapillary vascular looping which can be mistaken as NVD.
Presence of Vitreous or pre-retinal hemorrhage documented as well.
Fundus images are essential for documenting the severity of retinal vein occlusion which will show dilated and tortuous retinal veins with attenuation of the retinal artery along with intraretinal and flamed shaped hemorrhages and presence of cotton wool spots, optic disc edema, retinal vascular changes (beading or ischemic changes), neovascularization of the disc, or/and elsewhere; pre-retinal or vitreous hemorrhages, and it can be used for follow up after treatment or the natural course of the disease to document improvement or worsening .
It is rare for CRVO to be caused by arteriovenous anastomoses, which are direct connections between veins and arteries. Three types exist.
Type 1: arteriolar or abnormal capillary plexus between artery and vein.
Type 2: direct arteriovenous communication.
Type 3: widespread retinal arteriovenouses that are large in calibre with convoluted vessels or cirsoid.
Can be presented with or without central nervous system arteriovenous malformations (Wyburn Mason Syndrome).
Optical Coherence Tomography (OCT)
OCT is an essential tool to determine the presence of macular edema related to retinal vein occlusion.
Which has unique characteristics such as increased macular thickness along with hyperreflectivity of inner retinal tissues with empty cystic changes and can combine with subretinal fluids.
In cases of ischemic retinal vein occlusion, the OCT scan may show thinning of inner retinal layers; however, FFA or OCTa are required to diagnose the area of ischemia.
OCT is essential to rule out vitreomacular abnormalities such as an epiretinal membrane or vitreomacular traction, PRE changes, or other macular pathology .
OCT can assess treatment efficacy based on macular thickness changes determined by OCT. Physicians can decide if treatment needs to stop or changed, along with visual acuity changes. Please note that central macular thickness is not correlated to visual acuity .
OCT can show the boundaries between inner retinal layers and the status of the ellipsoid zone The disrupted integrity of the ellipsoid zone in acute phases of the disease doesn't always mean a bad visual prognosis; in contrast, the ellipsoid zone post-treatment disruption may affect visual prognosis.The same applies for persisted DRIL post-treatment, which is correlated to the magnitude of nonperfusion on FFA .
The presence of hyperreflective foci may hold poor visual prognosis as it can be associated with ellipsoid zone disruption; however, hyperreflective foci at the outer retinal layer may predict a good response to AntiVEGF therapy.
OCT angiography is a useful tool to determine the perfusion status of the macula with a precise location, depth, and maximum ischemic changes without the need to inject fluorescein dye, which is utilized in cases when fluorescein contraindicated . As the deep capillary plexus is more vulnerable to ischemic changes than superficial capillary plexus. OCTa can show areas of non-perfusion in the periphery in cases of BRVO  .
Fundus Fluorescein Angiography (FFA)
The main features of retinal vein occlusion in FFA is delayed venous filling along with hypofluorescence due to intraretinal hemorrhages and hypoperfusion (in cases of ischemic changes) and hyperfluorescence due to microvascular leakage in late phases in certain cases.
FFA is a useful tool to check the perfusion status of the macula (ischemic or non-ischemic edema) and retinal periphery .
FFA shows capillary dropout and leak, which was useful when grid laser utilized. Due to the superiority of Anti-VEGF and steroids treatment in terms of efficacy, the laser becomes less used .
However, intraretinal and flamed shaped hemorrhages appear as blocked fluorescence and may mask underlying retina, while FFA is a great tool to identify collateral vessels.
FFA useful tool in showing ischemic changes identified as more than five discs diameters area in branch retinal vein occlusion (BRVO)  wherein CRVO 10-75 or more discs diameters area of non-perfusion . The increased area of nonperfusion, the higher risk of developing iris or angle neovascularization, or other proliferative changes in the area of nonperfusion, FFA may show perivascular staining of major retinal vessels.
FFA may show early leak from subtle neovascularization, which is useful to differentiate it from optociliary shunts.
FFA assesses the efficacy of laser treatment, especially when there are areas of untreated nonperfusion in the presence of persistent neovascularization post-laser treatment.
Note that the physician should obtain signed consent explaining the rare complications of FFA, including death 1/200000, and FFA facility should have an emergency plan in situ .
B-scan echography is essential in cases of non-clear media due to vitreous hemorrhage or other media opacity to rule out retinal detachment.
Also, there are no definitive guidelines, cardiovascular consultation along with ECG, CBC, prothrombin, and bleeding time ordered in patients under 50 years old, high-risk patients, bilateral retinal vein occlusion cases . Systemic workup should rule out hypercoagulopathy, inflammatory, or infectious causes . Including factor V Leiden thrombophilia, Waldenström’s macroglobulinemia, myeloproliferative disorders, disturbance of the protein S and C pathways, anti-thrombin 3 deficiency, and oral contraceptives. Systemic inflammatory disorders that cause retinal vasculitis, including polyarteritis nodosa, sarcoidosis, Behçet’s disease, Goodpasture’s syndrome and granulomatosis with polyangiitis (Wegener’s), may induce RVO.
It is vital to check blood pressure and glucose and systemic evaluation for cardiovascular risk factors in young patients and older patients who don't have any systemic diseases as RVO patients are more likely to experience stroke or acute myocardial infarction.
Managing patients with retinal vein occlusion
There are three medical treatment options, which are:
VEGF Blockade agents
VEGF Blockade agents are the most popular and proved both safety and efficacy.
The commercially available VEGF blockade agents are Anti-VEGF such as Bevacizumab, which used off label & Ranibizumab and VEGF trap agents such as Aflibercept and Conbercept (Available in China).
1)A solution such as Triamcinolone acetonide (4 mg/0.1 ml)
2)Biodegradable inserts such as Dexamethasone intravitreal implant with efficacy for up to 4 months.
Although studies have demonstrated the effectiveness of intravitreal steroids for macular edema, there is a risk of cataract development and an increase of intraocular pressure .
Another fluocinolone acetonide non-biodegradable intravitreal implant is available but not FDA approved for the treatment of macular edema related to retinal vein occlusion, which may offer efficacy up to 36 months but with increased risk of inducing elevated IOP and cataract. 
Steroids can be used as first-line therapy when there are major cardiovascular events. Patients are unwilling to comply with monthly office visits but keep in mind that IOP should be checked every 2 to 8 weeks post-injection.
Laser used to be the treatment of choice for cystoid macular edema related to BRVO with reduced vision.
It has been replaced with intravitreal VEGF blockade agents and become a second-line therapy .
The laser may cause damage to perifoveal capillaries and lead to a lack of visual recovery .
However, scatter laser photocoagulation to areas of non-perfusion remains the treatment of choice to treat wide ischemic areas presented with proliferative changes and it complications related to retinal vein occlusions such as vitreous hemorrhage, neovascularization or rubeosis iridis [9,11].
Scatter laser to peripheral areas of nonperfusion won’t decrease macular edema, as shown in the RELATE study. 
In a nutshell, scatter laser application recommended in proliferative changes, as vitreous hemorrhage, neovascularization on disc (NVD), or elsewhere (NVE).
However, it is recommended to use Pan Retinal Photocoagulation (PRP) for iris/ angle neovascularization (NVI/NVA) or neovascular glaucoma (NVG).
Other treatment options
Subthreshold microsecond laser may offer a safe method for laser delivery to treat persistent macular edema without causing retinal scars when comparing it with traditional grid laser .
Suprachoroidal injection of triamcinolone acetonide is an effective method to treat cystoid macular edema when it is resistant to VEGF blockade agents.
Suprachoroidal injection induces fewer compilations when comparing it to intravitreal steroids injections [20,21].
Studies showed that it does not reduce the frequency of needed intravitreal injections.
Posterior sub-tenon injection of triamcinolone acetonide small studies showed that this procedure could be effective and safe in the treatment of macular edema .
Pars plana vitrectomy indicated in situations of non-clearing vitreous hemorrhage and tractional maculopathy.
The injection should be carried out in sterile conditions where the injection site is prepared by disinfecting the skin using povidone-iodine 10%.
After installing topical anesthesia, and the conjunctiva disinfected using povidone-iodine 4%.
The injection is carried out after placing sterile drape and lid speculum isolating eyelashes in the superior temporal quadrant.
Injection site measured with calipers 4.00 mm for phakic and 3.5 mm from limbus for pseudophakic or aphakic, a 30 gauge half-inch needle is used to inject triamcinolone or VEGF blockade agents. In contrast, the dexamethasone implant comes with a 23 gauge injector that needs to be inserted obliquely after conjunctival displacement, then inserted vertically and then injected after that a cotton tip applicator is placed over the injection site to prevent reflux of fluid.
Laser photocoagulation technique
For scatter laser: Laser burns with medium white intensity spaced one burn apart, using 200 to 500 µm and 0.2s duration to all nonperfusion areas defined by fluorescein angiogram applying 1200 to 1500 burns. Laser burn shouldn't extend more than two disc diameters from the fovea. Laser application should avoid intraretinal hemorrhage as blood may uptake the photocoagulation damaging the retinal nerve fiber layer and preventing the wanted application of the retinal pigment epithelium.
For Grid laser: Laser burn with medium white intensity using 100 µm and 0.1 s. Laser applied in a grid fashion to the leaking areas defined by fluorescein angiogram avoiding the application of the foveal avascular zone.
For Microsecond subthreshold laser: Low-intensity high-density protocol with spot size 100-200 µm with duration 0.2s. Power adjusted (on the non-edematous nasal retina) using the titration method with a 5 % duty cycle, the power used is 50 % off from power used to achieve tissue reaction using microsecond laser with 5% duty cycle, laser applied in painting fashion on the edematous area defined by OCT.
Recommendations for central macular edema treatment in de-novo or Naïve eyes
-Intravitreal injection of VEGF blockade agents such as Aflibercept 2.0 mg (0.05ml), Ranibizumab 0.5 mg (0.05ml), or Bevacizumab 1.25 mg (0.05ml) every four weeks for three consecutive injections .
-OCT should be done four weeks after the third injection for macular edema assessment and how it responds to treatment .
-Treatment with the same agent is continued with a monthly injection if there is an improvement of the central macular thickness or/and improved vision .
-Treatment withheld when BCVA reaches 20/20 or/and central macular thickness is 250 µm or less.
Recommendations for central macular edema treatment in partial responder to previous therapy in the last 12 weeks based on OCT/ BCVA
-Intravitreal injection of VEGF blockade agents such as Aflibercept 2.0 mg, Ranibizumab 0.5 mg, and Bevacizumab 1.25 mg every four weeks for more three consecutive injections .
-OCT should be repeated four weeks after the third injection for macular edema assessment and how it responds to treatment.
-Treatment withheld when BCVA reaches 20/20 and-or central macular thickness is 250 µm or less .
Recommendations for central macular edema treatment in non-responders to previous therapy in the last 12 weeks based on OCT/ BCVA
- If the edema didn't respond to the initial loading dose of Anti-VEGF agents such as Ranibizumab 0.5mg or Bevacizumab 1.25 mg, then switch to VEGF trap agents such as Aflibercept 2.0 mg for another three consecutive injections  which may offer anatomical improvement with a modest gain in visual acuity.
-Intravitreal steroids such as dexamethasone implant or intravitreal triamcinolone 1 mg administered if the edema failed to respond after three injections of VEGF trap agents or Anti-VEGF  especially in pseudophakic patients with no history of glaucoma.
-Intravitreal steroids may increase intraocular pressure there for a close monitor of intraocular pressure is warranted, along with increased cataract formation or progression .
-Some cases may need a combination of intravitreal steroids and Anti-VEGF in recalcitrant cystoid macular edema related to retinal vein occlusion .
-Grid or Subthreshold laser added in refractory macular edema cases related to BRVO as a second or even third-line therapy in combination with other treatments .
-OCT should repeat every four weeks for macular edema assessment and how it responds to treatment.
-Treatment withheld when BCVA reaches 20/20 or/and central macular thickness is 250 µm.
Recommendations for substantial ischemia based on FFA or/and signs of proliferation based on fundus examination /imaging and-or FFA
-Intravitreal injection of VEGF blockade agents such as Aflibercept 2.0 mg, Ranibizumab 0.5 mg, and Bevacizumab 1.25 mg every four weeks for three consecutive injections in the presence of macular edema .
-OCT should be done four weeks after the third injection for macular edema assessment and how it responds to treatment .
- The development of proliferative changes increases when an area of non-perfusion (ischemia) for more than five discs diameters in BRVO  while 10-75 or more in CRVO defined by fluorescein angiogram.
Scatter laser photocoagulation applied in the area of non-perfusion in cases of retinal or disc neovascularization or/and vitreous hemorrhage, avoiding areas of retinal hemorrhage.
Pan-retinal laser photocoagulation applied in cases of angle or iris neovascularization, or sometimes in high-risk cases such as extensive retinal non-perfusion and short duration of CRVO.
- Treatment withheld when BCVA reaches 20/20 or/and central macular thickness is 250 µm or less retreat only in cases of worsening of proliferative signs or macular edema .
Recommendations for Rubeosis iridis due to retinal vein occlusion
-In eyes with clear media and beneficial vision but without an increase in IOP nor angle neovascularization or synechia, Panretinal laser photocoagulation should be applied  as soon as possible for at least 1500 burns in the 1st session. Intravitreal VEGF blockade agents  can speed up neovascular regression, but keep in mind that Anti-VEGF effect is only for the short term.
-In eyes with non-clear media and beneficial vision but without an increase in IOP nor angle neovascularization or synechia, Intravitreal VEGF blockade agents can speed up neovascular regression. Anti VEGF effect is only for the short term. If cataract or vitreous hemorrhage is preventing laser application, they managed, then pan-retinal laser photocoagulation applied for at least 1500 burns in the 1st session .
-In eyes with clear media and beneficial vision but with an increase in IOP, angle neovascularization, or/and synechia, Pan retinal laser photocoagulation should be applied a soon as possible for at least 1500 burns in the 1st session. High IOP managed topically with steroids, cycloplegic, and antihypertensive eye drops. In the case of high IOP refractory to topical treatment, then glaucoma drainage surgery indicated +/- VEGF blockade agents .
- In eyes with non-clear media and beneficial vision but with an increase in IOP, angle neovascularization, or/and synechia. In case cataract or vitreous hemorrhage is preventing laser application, they managed after IOP stabilization, then pan-retinal laser photocoagulation applied for at least 1500 burns in the 1st session. If High IOP causes corneal edema, then topical treatment with steroids, cycloplegic, and antihypertensive eye drops are used. In the case of high IOP refractory to topical therapy, then glaucoma drainage surgery indicated +/- VEGF blockade agents . Pan-retinal laser photocoagulation applied as soon as retinal view permits.
- In painful eyes with non-beneficial vision, a diode laser transscleral cyclo photocoagulation to the ciliary body recommended,  which may induce phthisis bulbi, other treatment options include retrobulbar alcohol or sometimes enucleation.
Pars Plana vitrectomy
Vitrectomy with or without sheathotomy in cases of BRVO studies and reports confirmed the efficacy of this procedure to improve vision and anatomical outcomes .
Other reports reported otherwise, and due to the difficulty of the technique , sheathotomy shouldn't be considered as 1st line therapy. Other reports concluded that ILM peeling over arterial-vein crossing other reports showed that posterior vitreous detachment induction might improve vision and anatomical outcomes .
Vitrectomy only recommended when medical treatment fails .
Vitrectomy with radial optic neurotomy for CRVO showed some efficacy in clinical trials  but failed to show in other studies .
Due to the high risk of complications such as visual field defect, globe perforation, laceration of central retinal vessels, etc., is abandoned.
Vitrectomy is considered when there is a complication of proliferative changes such as non-clearing vitreous hemorrhage  or tractional retinal detachment.
Another indication of vitrectomy is tractional maculopathy inducing moderate visual loss .
Flow chart summarizes the approach and management of macular edema related to retinal vein occlusion.
Flow chart summarizes the approach and management of ischemic retinal changes related to retinal vein occlusion.
Follow up and prognosis
- It is imperative to know that the follow-up of patients suffering from retinal vein occlusion is at least 24 months  and up to five years  . As a persistent or recurrent cystoid macular edema can occur later in the course of follow up despite the resolution of other retinal findings such as intraretinal hemorrhages, venous tortuosity, etc...
- In the follow-up, check visual acuity changes and pupillary reaction; inspect iris, and angle (using gonioscopy) for neovascularization before pupil dilatation along with IOP, then dilated fundus exam documenting any clinical retinal changes, while OCT or FFA is done when appropriate.
- When treatment withheld after BCVA reaches 20/20 or/and central macular thickness is 250 µm or less, retreatment and follow-up can be carried out following one of two protocols:
1. PRO RE NATA (PRN): when patients achieve good visual acuity (20/25 or better) or dry macula (250 µm or less) after several intravitreal injections. The patient followed up monthly for evaluation of worsening in visual acuity and central macular thickness; if any, then monthly injection until the patient regains dry macula or good visual acuity again, then a monthly follow up is recommended .
2. Treat and Extend (T&E): when patients achieve good visual acuity (20/25 or better) or dry macula (250 µm or less) after one month after the last VEGF blockade intravitreal injection. The patient receives additional intravitreal injection after two weeks and re-evaluated after eight weeks. If there is no sign of edema, proliferation, nor changes in visual acuity, a further injection added. Then patient evaluation and treatment extended for more than two weeks, but the extension shouldn't exceed 12 weeks. During the T&E follow up if a worsening based on OCT or/and BCVA is noticed, then a switch to monthly injection for two consecutive injections and follow up extended again .
- Clinical trials didn't show a significant difference between T&E and PRN in terms of visual acuity, although T&E requires more injections, there is less burden for the patient .
-Despite the critical role of intravitreal VEGF blockade agents in the treatment of retinal vein occlusion, they don't eliminate the risk of developing neovascularization. It may only delay it, especially in cases of CRVO. As studies showed that neovascularization might appear up to 7.8%, in these cases, an application of scatter or pan-retinal photocoagulation recommended .
- In cases of re proliferation after successful laser application, an additional laser applied to regress neovascularization.
-Cooperating with an internist to find the systemic vascular risk factor is essential to control any underlying disease such as diabetes mellitus, systemic hypertension, etc.
-When RVO patients are treated with anti-VEGF intravitreal injections and then loss follow-up, those patients will suffer from BCVA reduction that won't reach the same BCVA before the loss of follow-up even if there is an improvement in central macular thickness after retreatment.
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These guidelines were reviewed and updated in December 2022