Central Retinal Vein Occlusion
|Central Retinal Vein Occlusion|
|Classification and external resources|
Various terms have been used to describe the severity of retinopathy associated with central retinal venous obstruction. None is completely satisfactory. The clinical terms used to describe the ocular fundus reflect the degree of obstruction of the entire venous outflow from the retina (central retinal vein plus collateral vessels) and not just the central retinal vein alone. A patient may have complete anatomic obstruction of the central retinal vein at the level of the lamina cribrosa, with well-developed collateral venous channels, and manifest only minimal fundoscopic changes of venous occlusion.
- 1 Disease Entity
- 2 Diagnosis
- 3 Management
- 3.1 Follow-up
- 3.2 General treatment
- 3.3 Complications
- 3.3.1 Macular Edema
- 22.214.171.124 Macular Grid Laser
- 126.96.36.199 Intravitreal Therapy
- 188.8.131.52.1 Standard Care Versus Corticosteroid for Retinal Vein Occlusion (SCORE)
- 184.108.40.206.2 Ranibizumab for the Treatment of Macular Edema After Central Retinal Vein OcclusIon Study (CRUISE)
- 220.127.116.11.3 Ozurdex GENEVA study group
- 18.104.22.168.4 Controlled Phase III evaluation of repeated intravitreal administration of VEGF Trap-Eye in CRVO: utility & safety AND General assessment-limiting infiltration of exudates in CRVO with VEGF Trap-Eye
- 3.3.2 Neovascularization
- 3.3.3 Vitreous Hemorrhage
- 3.3.1 Macular Edema
- 3.4 Prognosis
- 4 References
International Classification of Disease (ICD)
- 362.35 Central retinal vein occlusion
Retinal vein occlusion (RVO) is a common cause of vision loss in older individuals, and the second most common retinal vascular disease after diabetic retinopathy1. There are two distinct types, classified according to the site of occlusion: in central RVO (CRVO), the occlusion is at or proximal to the lamina cribrosa of the optic nerve, where the central retinal vein exits the eye2. CRVO is further divided into the categories of perfused (nonischemic) and nonperfused (ischemic), each of which has implications for prognosis and treatment3.
The pathogenesis of CRVO is believed to follow the principles of Virchow’s triad for thrombogenesis, involving vessel damage, stasis and hypercoagulability4. The central retinal vein and artery share a common adventitial sheath at arterovenous crossings posterior to the lamina cribrosa so that atherosclerotic changes of the artery may compress the vein and precipitate CRVO5. Damage to the retinal vessel wall from atherosclerosis and compression alters rheologic properties in the adjacent central vein, contributing to stasis, thrombosis, and thus occlusion6.
Age is the most important factor, since over 90% of cases occur in patients over the age of 55 years.
A high blood pressure is present in up to 73% of CRVO patients over the age of 50 years and in 25% of younger patients. Inadequate control of hypertension may also predispose to recurrence of CRVO in the same or fellow eye.
A total cholesterol >6.5 mmol/l is present in 35% of patients with CRVO, irrespective of age.
Hyperglycemia is present in about 10% of cases over the age of 50 years but is uncommon in younger patients. This may be due to an associated higher prevalence of other cardiovascular risk factors such as hypertension which is present in 70% of type 2 diabetics.
Oral contraceptive pill
In younger females the contraceptive pill is the most common underlying association, and should not be taken following retinal vein occlusion. The risk may be exacerbated by thrombophilia.
Raised intraocular pressure
A high IOP increases the risk of CRVO, particularly when the site of obstruction is at the edge of the optic cup.
Current smoking may be associated with an increased incidence of CRVO, though studies have shown inconsistent results.
Other uncommon predispositions
- Abnormal plasma proteins (e.g. myeloma, Waldenström macroglobulinaemia).
Acquired hypercoagulable states
- Lupus anticoagulant and antiphospholipid antibodies
Inherited hypercoagulable states
- Activated protein C resistance (factor V Leiden mutation)
- Protein C deficiency
- Protein S deficiency
- Antithrombin deficiency
- Prothrombin gene mutation
- Factor Xll deficiency.
Inflammatory disease associated with occlusive periphlebitis
- Behçet syndrome
- Wegener granulomatosis
- Goodpasture syndrome.
- Chronic renal failure
- Causes of secondary hypertension (e.g. Cushing syndrome) or hyperlipidaemia (e.g. hypothyroidism)
- Orbital disease
- Dehydration may be significant, particularly in younger patients and in hot countries
Presentation is with sudden, unilateral blurred vision; in impending CRVO, the blurring is mild and characteristically worse on waking and improves during the day. In ischemic CRVO, visual impairment is sudden and severe7,8.
Impending (partial) CRVO is a relatively poorly-defined condition of patients who are either asymptomatic or who may complain of mild, often transient episodes of blurring of vision characteristically worse on waking and improves during the day. Their fundi demonstrate mild venous dilation and tortuosity, a few widely scattered flame-shaped retinal hemorrhages.
This condition may resolve or progress to complete obstruction, therefore treatment is aimed at preventing progression to complete occlusion by correcting any predisposing systemic conditions, avoiding dehydration, and lowering intraocular pressure (e.g. systemic carbonic anhydrase inhibitors) to improve perfusion. Antiplatelet agents may be of benefit, and in some circumstances such as monocularity in an otherwise healthy patient it may be appropriate to consider other options such as anticoagulants, fibrinolytics or hemodilution3,5.
Non-ischemic CRVO is the most common type, accounting for about 75%. Presentation is with sudden, unilateral blurred vision. Mild to moderate loss of acuity, usually 20/200 or better, and an absent or mild relative afferent pupillary defect (RAPD), characterize these patients. Fundoscopy shows tortuosity and dilatation of all branches of the central retinal vein, dot/blot and flame-shaped hemorrhages, throughout all four quadrants and most numerous in the periphery, and optic disc and macular edema. Blood levels are often seen within the large retinal cysts in the foveolar area. Some cotton-wool patches, particularly in hypertensive patients, may be present. Transient retinal vessel wall sheathing may occur3.5.
The acute signs resolve over 6-12 months, with disc collaterals and pigmentary changes at the macula as residual findings. In a clearly non-ischemic occlusion, initial follow-up should take place after 3 months. Conversion to ischemic CRVO occurs in 15% of cases within 4 months and 34% within 3 years. The patient should be instructed to make contact if the vision deteriorates as this may indicate the development of significant ischaemia. In cases that do not subsequently become ischaemic, the prognosis is reasonably good with return of vision to normal or near normal in about 50%.
Ischemic CRVO is characterized by rapid onset venous obstruction resulting in decreased retinal perfusion, capillary closure and retinal hypoxia. Patients with severe central retinal vein obstruction typically have severe visual loss, usually less than 20/200; a marked afferent pupillary defect; severe tortuosity and engorgement of all branches of the central retinal vein, extensive deep blot and flame-shaped hemorrhages involving the peripheral retina and posterior pole, severe disc edema and hyperemia.
This may lead to profound vascular leakage, rubeosis iridis and raised intraocular pressure. The prognosis is extremely poor due to macular ischemia. Rubeosis iridis develops in about 50% of eyes, usually between 2 and 4 months (100-day glaucoma), and there is a high risk of neovascular glaucoma. Retinal neovascularization occurs in about 5% of eyes. Where possible, patients with ischemic CRVO should be seen monthly for 6 months to detect the onset of anterior segment neovascularization. Subsequent review should usually be for up to 2 years to detect significant ischemia and macular oedema3,5.
In impending CRVO, fluorescein angiography (FA) will reveal a mild increase in retinal circulation time. In non-ischemic CRVO, FA shows marked delay in arteriovenous transit time, which is longer than 20 seconds, masking by retinal haemorrhages, and vessel wall staining. Late staining along the large retinal veins is a characteristic finding in moderate and severe degrees of central retinal vein obstruction. The ischemic form has extensive areas of capillary non- perfusion. Greater than 10 disc areas of retinal capillary non-perfusion is associated with an increased risk of neovascularization.
A timed fluorescein angiographic study, preferably using a wide-angle fundus camera, can document the degree of obstruction, the severity of the capillary permeability alterations, and after partial resolution of the intraretinal hemorrhages the extent of the retinal capillary nonperfusion. It is important to include views of the peripheral fundus and the posterior pole, since capillary nonperfusion is most likely to occur in these areas. In the presence of widespread confluent hemorrhages, it may not be possible to determine angiographically the extent of capillary closure.
Optical Coherence Tomography
Optical coherence tomography (OCT) is useful in the assessment of macular edema, and particularly in monitoring its course, especially with treatment of the edema. In patients with recent-onset CRVO, OCT can detect areas of presumed ischemic edema in the plexiform layer due to ischemia of intermediary neurons within the inner nuclear and inner plexiform layers9.
Fundus autofluorescence can detect, in patients with recent-onset CRVO, a perivenular hypoautofluorescence with a fern-like appearance.
This appearance is due to the masking of the normal autofluorescence from ischemic edema. In the retina tissue transparency is a clinical index of tissue oxygenation. With CRVO, the most sensitive tissue for manifesting decreased oxygenation will be perivenular, and especially in the posterior pole, where oxygen use is higher than in the retinal periphery. The perivenular location of ischemic edema is due to decreased arterial flow that leads to preferential oxygenation of the periarterial retina, which uptakes the available oxygen and subsequently desaturates hemoglobin before it can reach the perivenular space. This will manifest as patchy ischemic retinal whitening, located preferentially in a perivenular distribution near the macula9.
- Blood pressure
- Erythrocyte sedimentation rate (ESR)
- Full blood count (FBC)
- Random blood glucose
- Random total and HDL cholesterol
- Plasma protein electrophoresis (dysproteinemias such as multiple mieloma)
- Urea, electrolytes and creatinine (renal disease in association with hypertension)
- Thyroid function tests (associated with dyslipidemia)
- ECG (left ventricular hypertrophy secondary to hypertension).
Additional tests in patients under the age of 50, with bilateral RVO, a history of previous thromboses or a family history of thrombosis.
- Chest X-ray (sarcoidosis, tuberculosis)
- C-reactive protein (CRP)
- "Thrombophilia screen" (thrombin time, prothrombin time and activated partial thromboplastin time, antithrombin functional assay, protein C, protein S, activated protein C resistance, factor V Leiden mutation, prothrombin G20210A mutation; anticardiolipin antibody, lupus anticoagulant)
- Autoantibodies (rheumatoid factor, anti-nuclear antibody, anti-DNA antibody)
- Serum angiotensin-converting enzyme (ACE)
- Fasting plasma homocysteine level
- Treponemal serology
- Carotid duplex imaging (exclude ocular ischaemic syndrome).
Follow-up of CRVO is tailored to fit the different enthities and to prevent complications. For example in impending CRVO, management is aimed at preventing progression to complete occlusion by correcting any predisposing systemic conditions, avoiding dehydration, and lowering intraocular pressure (e.g. systemic carbonic anhydrase inhibitors) to improve perfusion. In a clearly non-ischaemic CRVO, initial follow-up should take place after 3 months. The patient should be instructed to make contact if the vision deteriorates as this may indicate the development of significant ischaemia. Subsequent review is dependent on the clinical picture, with discharge from follow-up usually at 18–24 months. Where possible, patients with ischaemic CRVO should be seen monthly for 6 months to detect the onset of anterior segment neovascularization. Routine gonioscopy of eyes at risk should therefore be performed and the pupillary margin should be examined prior to mydriasis. Subsequent review should usually be for up to 2 years to detect significant ischaemia and macular oedema.
There is no convincing evidence of medical treatment favorably altering the natural course of central retinal vein occlusion. Pilot studies have suggested that oral inhibitor of platelet and erythrocyte aggregation, and hemodilution treatment to lower blood viscosity may be of some benefit. Intravenous administration of streptokinase appeared to reduce the morbidity but has never gained favor because of the risk of intravitreal hemorrhage.
The hypoxic retinal tissue in CRVO may release vascular endothelial growth factor (VEGF) and inflammatory mediators, thereby inducing the complications of macular edema, vitreous hemorrhage and neovascular glaucoma.
Macular Grid Laser
Macular grid laser is not recommended, since it may reduce angiographically the macular leakage but without benefit on the visual acuity. The CVOS showed no benefit in terms of visual acuity in older patients, although a trend towards better acuity was seen in younger patients10.
Standard Care Versus Corticosteroid for Retinal Vein Occlusion (SCORE)
Between November 2004 and February 2008, 271 patients with CRVO were enrolled in the SCORE study, which was designed to compare 1 mg and 4 mg IVTA with standard-care treatment for vision loss associated with macu¬lar edema secondary to RVO. In patients with CRVO (the SCORE–CRVO trial), standard care was observation. In the SCORE–CRVO trial, the primary outcome – that is, the percentage of participants with a gain in visual acuity letter score of 15 or more from baseline to month 12 – was 6.8, 26.5 and 25.6% for the observation, 1-mg, and 4-mg groups, respectively. In contrast to the visual acuity results, there was no difference in retinal thickness between groups at 12 months11. With respect to optical coherence tomography (OCT)- measured central retinal thickness (CRT), all three groups showed a decrease from baseline to month 12. Analogous to the visual acuity results, only at month 4 did the 4-mg triamcinolone group demonstrate a greater treatment effect on center-point thickness than the 1-mg and standard-care groups. The rate of adverse events was higher in the 4-mg triamcinolone group. There was a dose-dependent higher frequency of initiating IOP-lowering medications in the triamcinolone groups (41% in the 4-mg group and 7% in the 1-mg group) compared with the standard-care group (2%). The proportion of eyes that were phakic at baseline and had new-onset lens opacity or progression of an exist¬ing opacity through 12 months was greater in the two triamcinolone groups (25–35%)12-14.
Ranibizumab for the Treatment of Macular Edema After Central Retinal Vein OcclusIon Study (CRUISE)
Between July 2007 and December 2008, 392 patients diagnosed with CRVO were randomized to monthly intraocular injections of 0.3 mg or 0.5 mg ranibizumab, or sham injections, for 6 months, with a further 6 months follow-up. Mean study eye baseline best-corrected visual acuity (BCVA) was 20/100, and mean baseline CRT was 685.2 μm. The primary efficacy outcome was mean change from baseline BCVA at 6 months; at month 6, patients in the 0.3- and 0.5-mg ranibizumab treatment groups had gained a mean of 12.7 and 14.9 letters, respectively, compared with 0.8 letters in the sham group. The improvement in BCVA letter score after injection of ranibizumab was rapid, with patients having gained an average of 9 letters 7 days after the first injection. Among the secondary outcomes, at month 6, 46.2 and 47.7% of patients in the 0.3- and 0.5-mg ranibizumab groups, respectively, had gained ≥15 letters from baseline BCVA, compared with 16.9% of patients in the sham group. Concomitant with the rapid improvement in BCVA, there was a rapid reduction in central foveal thickness after treatment with ranibizumab: at day 7, the mean reduction from baseline CRT was >250 μm in both ranibizumab groups, compared with no reduction in the sham group. There were no events of endophthalmitis, retinal tear or retinal detachment during the 6-month treatment period15-17.
Ozurdex GENEVA study group
Dexamethasone is a potent, water-soluble corticosteroid that can be delivered to the vitreous cavity by the dexamethasone intravitreal implant (DEX implant; Ozurdex). A DEX implant is composed of a biodegradable copolymer of lactic acid and glycolic acid-containing micronized dexamethasone.
The drug–copolymer complex gradually releases the total dose of dexamethasone over a series of months after insertion into the eye through a small pars plana puncture using a customized applicator system.
A total of 1267 patients (DEX implant 0.7 mg: n = 427; DEX implant 0.35 mg: n = 414; sham: n = 426) were recruited into the study between November 2004 and March 2008. At baseline, mean visual acuity was approximately 20/80 in all groups, and mean CRT was approximately 550 μm. Eyes receiv¬ing DEX implant 0.7 or 0.35 mg achieved a 15-letter improve¬ment in BCVA significantly faster than the eyes receiving sham treatment; furthermore, the response rates in the DEX implant 0.7-mg group were often numerically higher than those in the DEX implant 0.35-mg group. The greater improvements in visual acuity with the DEX implant were accompanied by a greater decrease in OCT-measured CRT than were seen with sham treatment.
The improvements in visual acuity outcomes persisted longer than the reduction in retinal thickness as measured by OCT, which suggests that factors in addition to changes in CRT may be affecting visual acuity in RVO eyes treated with the DEX implant. The adverse events that occurred at a significantly higher rate in the DEX implant treatment group than in the sham group were eye pain, ocular hypertension and anterior chamber cells; there was no statistically significant difference in the rate of cataract among the treatment groups, but 180 days may not be a long enough study period to detect an effect of treatment on cataract formation. The majority of patients treated with DEX implant did not experience a substantial increase in IOP; at peak (day 60), less than 16% of all eyes had an increase in IOP to ≥25 mmHg. Increase in IOP was typically transient and nearly all cases of elevated IOP were managed with observation or topical medications alone18,19.
Controlled Phase III evaluation of repeated intravitreal administration of VEGF Trap-Eye in CRVO: utility & safety AND General assessment-limiting infiltration of exudates in CRVO with VEGF Trap-Eye
Patients diagnosed with CRVO in the Controlled Phase 3 Evaluation of Repeated Intravitreal Administration of VEGF Trap-Eye in Central Retinal Vein Occlusion: Utility and Safety (COPERNICUS) and the almost identical General Assessment Limiting Infiltration of Exudates in Central Retinal Vein Occlusion with VEGF Trap-Eye (GALILEO) studies received 6-monthly injections of either VEGF Trap-Eye at a dose of 2 mg or sham injections. Patients in both trials were randomized in a 3:2 ratio, with 114 patients randomized to receive VEGF Trap-Eye and 73 ran¬domized to the control arm in COPERNICUS, and 104 patients randomized to receive VEGF Trap-Eye and 68 randomized to the control arm in GALILEO. At the end of the initial 6 months, all patients randomized to VEGF Trap-Eye are dosed on a pro re nata (as needed) basis for another 6 months. In the COPERNICUS trial, patients randomized to sham injections in the first 6 months were eligible to cross over to VEGF Trap-Eye pro re nata dosing in the second 6 months. During the second 6 months of the studies, all patients were eligible for rescue laser treatment. In the COPERNICUS trial, 56.1% of patients receiving VEGF Trap-Eye 2 mg monthly gained at least 15 letters of vision from baseline, compared with 12.3% of patients receiving sham injections. In the GALILEO study, 60.2% of patients receiving VEGF Trap- Eye 2 mg monthly gained at least 15 letters of vision from baseline, compared with 22.1% of patients receiving sham injections, the pri¬mary end point of the study. Patients receiving VEGF Trap-Eye 2 mg monthly gained, on average, 18 letters of vision, compared with a mean gain of 3.3 letters with sham injections, a secondary end point. VEGF Trap-Eye was generally well tolerated, and the most common adverse events were those typically associated with intra¬vitreal injections; serious ocular adverse events in the VEGF Trap- Eye group were uncommon (3.5%) and were more frequent in the control group (13.5%). The incidence of nonocular adverse events was generally well-balanced between the treatment arms. Stewart and Rosenfeld compared the intravitreal binding activ¬ity of VEGF Trap and intravitreal ranibizumab against VEGF using a time-dependent and dose-dependent mathematical model. The conclusion is that at 10 weeks after an injection, the intraocu¬lar biological activity of VEGF Trap is theoretically compared with the activity of ranibizumab at 30 days. This prolonged biological activity can be explained by the higher VEGF-binding affinity of VEGF Trap and its presumed longer intravitreal half-life when compared with ranibizumab. If the reported theoretical model is correct, then the advantages of VEGF Trap will include less fre¬quent drug administration, less cumulative risk from intravitreal injections and an improved patient compliance.
It has been fully established in the CVOS Study that there is no apparent benefit in performing PRP before development of iris and angle neovascularization, provided frequent follow-up examinations can be performed, since prophylactic treatment does not totally prevent iris and angle neovascularization. Furthermore, regression of iris and angle neovascularization in response to PRP is more likely to occur in eyes that have not been treated previously. Prompt laser PRP (1500–3000 burns, 0.5–0.1 second, spaced one burn width apart) should be performed in eyes in which iris and angle neovascularization develops. Some cases require further treatment if rubeosis fails to regress or continues to progress. Intravitreal anti-VEGF injections may be used adjunctivally in selected cases. It is important to screen patients monthly for the development of iris or angle neovascularization as discussed in the CVOS.
Prompt PRP is needed if neovascularization develops in order to prevent further damage from neovascular glaucoma. The relatively high risk (around 30%) of this has led to the term 90-day glaucoma in eyes with CRVO.
Vitreous hemorrhage can lead to sudden vision deterioration and can hinder PRP. There has not been a standard tratment until recently for CRVO with vitreous hemorrhage: currently, for unresolved vitreous hemorrhage, pars plana vitrectomy performed concurrently with intraoperative PRP is the management strategy. The benefits of vitrectomy for vitreous hemorrhage secondary to CRVO are obvious. Firts, it removes the opaque hemorrhage and clear the visual axis, which can improve vision. Second, PRP can be performed completely during surgery. Furthermore, studies have indicated that vitrectomy elevate oxygen tension for many months, relatively decreasing the ischemic situation after CRVO and preventing neovascular glaucoma. There is very little information about the anti-VEGF treatment of vitreous hemorrhage secondary to CRVO. Theoretically, anti-VEGF could play a potential role in the treatment of CRVO with vitreous hemorrhage because it shares a similar pathogenesis to diseases such as vitreous hemorrhage secondary to proliferative diabetic retinopathy.
In cases that do not subsequently become ischaemic, the prognosis is reasonably good with return of vision to normal or near normal in about 50%. The main cause for poor vision is chronic macular oedema, which may lead to secondary RPE changes. To a certain extent the prognosis is related to initial visual acuity as follows:
- 20/60 or better, it is likely to remain so
- 20/80-20/200, the clinical course is variable, and vision may subsequently improve, remain the same, or worsen
- Worse than 20/200, improvement is unlikely
The prognosis of ischemic CRVO is extremely poor due to macular ischaemia. Rubeosis iridis develops in about 50% of eyes, usually between 2 and 4 months (100-day glaucoma), and there is a high risk of neovascular glaucoma. The development of opticociliary shunts may protect the eye from anterior segment neovascularization and probably indicates a dramatic reduction in risk. Retinal neovascularization occurs in about 5% of eyes.
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- AP Ciardella, M Morara, F Pichi, M Alkabes, S Romano, P Nucci. Management of macular edema secondary to retinal vein occlusions. Expert Review of Ophthalmology 6 (5), 557-564
- Gewaily D, Greenberg PB. Intravitreal steroids versus observation for macular edema secondary to central retinal vein occlusion. Cochrane Database Syst. Rev. 1, CD007324.
- The SCORE study research group. 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. Ophthalmol. 127, 1101–1114.
- The SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to branch retinal vein occlusion. The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study Report 6. Arch. Ophthalmol. 127, 1115–1128.
- Ip MS, Oden NL, Scott IU et al. SCORE Study Investigator Group. SCORE Study report 3: study design and baseline characteristics. Ophthalmology 116, 1770–1777.
- Campochiaro PA, Hafiz G, Shah SM et al Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator. Mol. Ther. 16, 791–799.
- 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. Ophthalmology 117, 1124–1233.
- Brown DM, Campochiaro PA, Singh RP et al.; CRUISE Investigators. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology 117(6), 1124–1133.e1.
- Haller JA, Bandello F, Belfort R et al. Randomized, sham controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 117, 1134–1146.
- Haller JA, Bandello F, Belfort R Jr et al.; Ozurdex GENEVA Study Group. Dexamethasone Intravitreal Implant in Patients with Macular Edema Related to Branch or Central Retinal Vein Occlusion Twelve-Month Study Results. Ophthalmology DOI: 10.1016/j ophtha.2011.05.014.