Gaurav K. Shah
BASICS
DESCRIPTION
• An obstruction of blood flow through the central retinal vein. It commonly presents with a variable level of decreased or blurred vision.
– Can be classified as one of two clinical subtypes, i.e. ischemic or nonischemic, which differ in their presentation, clinical course, and prognosis (1)[C]
Geriatric Considerations
The overwhelming majority of central retinal vein occlusions (CRVOs) occur in older individuals, with over 90% of patients >50 years of age.
Pediatric Considerations
Pediatric cases of CRVO are rare. Most cases of CRVO in patients younger than 30 years have a definable underlying etiology such as a hypercoagulable state; however, CRVOs have been reported in otherwise healthy children.
Pregnancy Considerations
Venous occlusive disease in the setting of uncomplicated pregnancy and the absence of a hypercoagulable state is rare but has been described, typically as a papillophlebitis that resolves spontaneously. Recent studies have shown higher rates of spontaneous miscarriages in women with a history of CRVO (28%), compared to the general US population (15%). CRVO has also been described in the setting of pre-eclampsia, a disorder seen in up to 5% of pregnancies.
EPIDEMIOLOGY
Incidence
• Second to diabetic retinopathy, retinal vein occlusions are the most frequently encountered retinal vascular disorder. Branch retinal vein occlusions (BRVO, see a separate chapter on this) are more common than CRVOs.
– Occurs in 2–8 per 1000 persons
– The 15-year cumulative incidence is 0.5% as per the Beaver Dam Eye Study
– Most commonly encountered in the 60- to 70-year-old age group, but can occur at all ages
– Males and females are equally affected
– There is a 5–10% risk of the fellow eye becoming involved in 5 years
Prevalence
• Affects an estimated 2.5 million people worldwide.
– Prevalence is approximately 0.8 per 1000 persons.
RISK FACTORS
• CRVO has been associated with primary open angle glaucoma, systemic hypertension, diabetes mellitus, oral contraceptive use, vasculitis, blood dyscrasias, clotting disorders, autoimmune disorders, and trauma.
• Increasing levels of physical activity, moderate alcohol consumption, and exogenous estrogens (in women) have been shown to be protective.
PATHOPHYSIOLOGY
• The exact mechanism of pathogenesis is unknown.
• The occlusion is thought to occur at the level of the lamina cribrosa of the optic nerve secondary to a thrombotic event, though this has been questioned (2)[C].
• Factors predisposing to this location include the close approximation of the central retinal vein and artery which share a common adventitial sheath, and hemodynamic changes secondary to atherosclerosis of the central retinal artery.
• Stagnant blood flow results in hypoxia and damage to the capillary endothelium causing leakage of blood constituents.
• The veno-occlusive event causes an increase in levels of vascular endothelial growth factor (VEGF).
• Vision loss can be due to secondary macular edema, macular ischemia, or neovascularization and its sequelae.
ETIOLOGY
• Most age-related CRVOs are associated with hypertensive or diabetic vasculopathy or increased intraocular pressure.
• Vein occlusion in a younger patient necessitates further workup for a hypercoagulable state or other less common etiology.
COMMONLY ASSOCIATED CONDITIONS
• Systemic vasculopathy is often a comorbidity.
– Diabetes is present in 5–10%
– Hypertension is seen in >50% of patients
DIAGNOSIS
HISTORY
• A targeted history should be elicited from the patient, specifically inquiring about the risk factors listed above.
– Symptoms vary on presentation, and mild cases may be asymptomatic. However, most will present with gradual or sudden vision loss, blurring of vision, and photophobia. Those presenting after development of neovascular disease may complain of pain, redness, and epiphora.
PHYSICAL EXAM
• A complete ocular examination including gonioscopy and dilated funduscopy at the initial and follow-up visits should be performed in all patients suspected of having CRVO.
– Clinically, this condition presents with diffuse flame-shaped intraretinal hemorrhages in all four quadrants of the retina (“Blood and Thunder” appearance). Dilated and tortuous retinal vessels may be present, as well as disk edema, cotton wool spots, and retinal edema. Optociliary shunt vessels, optic atrophy, and macular retinal pigment epithelial changes may occur late in the course of the disease.
• Occasionally CRVO will present after the development of neovascularization, which manifests itself as vitreous hemorrhage, rubeosis (anterior segment neovascularization), or neovascular glaucoma.
• Signs of an ischemic CRVO include poor visual acuity (<20/200), a diminished B-wave on ERG, >10 disk areas of nonperfusion on fluorescein angiography, and the presence of an afferent papillary defect.
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Laboratory testing is not needed to make the diagnosis.
• No further workup is necessary in older (>50 years) individuals with known vascular disease.
• All individuals under the age of 50 without a preexisting underlying etiology require a workup for a systemic cause.
– This may initially include CBC, chemistry profile, fasting glucose and/or glucose tolerance testing, hemoglobin A1c, and lipid profile.
– In addition, testing for a hypercoagulable state may include homocysteine, protein C, protein S, antithrombin III, anticardiolipin antibodies, antiphospholipid antibodies, lupus anticoagulant (DRVVT), ANA, SPEP, activated protein C resistance, factor VIIIc, factor V leiden, and prothrombin variant 20210A.
Imaging
• Fluorescein angiography shows a delayed arterio–venous transit time as well as diffuse capillary leakage. Ischemic CRVOs will show >10 disk areas of retinal capillary nonperfusion.
• Optical coherence tomography (OCT) is useful in assessing the presence of macular edema.
Diagnostic Procedures/Other
• Electroretinography shows a decreased B-wave (negative ERG), decreased bright flash, more pronounced in the ischemic variant.
• Perimetry can also be useful in determining the ischemic subtype of the vein occlusion.
Pathological Findings
• Early CRVOs may demonstrate intraretinal edema, retinal hemorrhages, disk swelling, and cystoid macular edema.
• Old CRVOs may show disorganization of the retinal layers (especially inner), retinal hemosiderin deposits, and preretinal fibrosis and neovascular membranes.
DIFFERENTIAL DIAGNOSIS
• Ocular ischemic syndrome
• Diabetic retinopathy
• Hypertensive retinopathy
• Hyperviscosity syndrome
• Anterior ischemic optic neuropathy
• Papilledema
• Retinal vasculitis
• Radiation retinopathy
TREATMENT
MEDICATION
First Line
• Management of retinal vein occlusion typically involves treatment of neovascular complications and macular edema resulting from the initial event.
• Historically, medical management of CRVO has been limited and primary therapy was panretinal laser photocoagulation (PRP) for neovascular complications (see the Surgery section below) (3)[A].
• Recent studies have demonstrated efficacy of intravitreally administered drugs in improving macular edema and improving and/or stabilizing visual acuity in patients with CRVO.
– Avastin (bevacizumab) is a humanized monoclonal antibody against VEGF that is injected into the vitreous cavity. It has been FDA approved for intravenous use in the management of certain cancers; however, it has been successfully utilized intravitreally for CRVO.
– Lucentis (ranibizumab) is also an anti-VEGF antibody approved for ophthalmic use that is injected into the vitreous cavity. Recent studies including the CRUISE trial have shown its efficacy for CRVO (4)[A].
– Kenalog (triamcinolone) is a steroid suspension that can be injected intravitreally or into the subtenon’s space. Though not approved for ophthalmic use, its efficacy in improving macular edema has been demonstrated in the SCORE trial (5)[A].
– Ozurdex (dexamethasone, 0.7 mg) is a slow release implant that is injected into the vitreous cavity.
Second Line
• Other medications are presently under investigation for use in vein occlusions.
– VEGF-trap is a fusion protein which binds to the VEGF-A and placental growth factor. Clinical trials are presently underway to determine its efficacy in vein occlusions.
– Combination treatments of the above medical therapies and surgical therapies (see below) are also being studied.
ADDITIONAL TREATMENT
Issues for Referral
Coordination of care with the patient’s primary physician is important for optimization of the patient’s comorbid systemic medical conditions such as hypertension.
SURGERY/OTHER PROCEDURES
• PRP remains the mainstay of treatment for neovascular disease resulting from CRVO, as per the results of the central vein occlusion study (CVOS). It should be noted that prophylactic PRP has not shown to be of benefit in preventing neovascularization.
– If neovascular glaucoma is present a combination of treatments with anti-VEGF agents and panretinal photocoagulation may be of benefit (6)[C].
• Pars plana vitrectomy with or without internal limiting membrane peeling, endovascular administration of tissue plasminogen activator, radial optic neurotomy, and laser-induced chorioretinal anastomoses, are all surgical procedures that have shown mixed results in terms of efficacy, but are sometimes utilized in refractory cases of CRVO.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
• After the initial event, patients should be followed monthly for the first 3 months, then every 3 months for the first year.
– A dilated fundus examination and gonioscopy should be performed at each follow-up visit.
Patient Monitoring
OCT, visual fields, and fluorescein angiography may be useful adjunctive tests to follow this condition.
PROGNOSIS
• As shown in the CVOS, initial visual acuity is strongly correlated with final visual outcome.
• Many nonischemic CRVOs will spontaneously resolve and have lower rates of vision loss.
– 10% of patients eventually develop neovascularization.
• The overall prognosis is worse in patients with an ischemic CRVO.
– <15% will have a visual acuity better than 20/400 after 1 year
– 40% of patients eventually develop neovascularization
COMPLICATIONS
• Vision loss due to a variety of reasons:
– Macular ischemia
– Macular edema
– Neovascular disease, including glaucoma
• Complications secondary to comorbid systemic vascular disease or a hypercoagulable state
REFERENCES
1. Haymore JG, Mejico LJ. Retinal vascular occlusion syndromes. Int Ophthalmol Clin 2009;49(3):63–78.
2. Hayreh SS. Pathogenesis of occlusion of the central retinal vessels. Am J Ophthalmol 1971;72(5):998–1011.
3. The Central Vein Occlusion Study Group. Natural history and clinical management of central retinal vein occlusion. Arch Ophthalmol 1997;115(4):486–491.
4. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion six-month primary end point results of a phase III study. The CRUISE investigators. Ophthalmology 2010, in press.
5. Ip MS, Scott IU, Vanveldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: The standard care vs corticosteroid for retinal vein occlusion (score) study report 5. Arch Ophthalmology 2009;127(9):1101–1114.
6. Gheith M, Siam G, de Barros D, Garg SJ, Moster M. Role of intravitreal bevacizumab (Avastin®) in neovascular glaucoma. J Ocul Pharmacol Ther 2007;23(5):487–491.
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