Ординатура / Офтальмология / Английские материалы / Retinal and Vitreoretinal Diseases and Surgery_Boyd, Cortez, Sabates_2010

It must be emphasized that the differentiation between an ischemic vs non-ischemic CRVO can’t be made with just a biomicroscopic examination of the fundus.27 Of all the funduscopic features of a CRVO, the degree of intraretinal hemorrhages is the only finding with a small correlation with ischemia. Other features such as optic nerve edema, cotton wool spots, venous dilation and macular edema have no correlation whatsoever. The presence of an afferent pupillary defect, a visual acuity of ≤ 20/200, reduced b-wave and decreased b/a amplitude in the electroretinogram, peripheral constriction on perimetry and capillary occlusion > 10 disc diametersonfluoresceinangiographyallcorrelate with ischemic CRVO. Thus to accurately classify an eye with CRVO as ischemic or nonischemic all the above information is necessary.27,28

Clinical Findings

Most patients complain of a sudden loss of vision. Some patients may complain of transient obscurations of vision that last from a few seconds to minutes followed by complete recovery to normal. Patients with neovascular glaucoma complain of ocular pain and redness.

Acutely, CRVOs are characterized by some degree of dilation and tortuosity of the retinal veins. Intraretinal hemorrhages are seen in all four quadrants (Figure 1). The severity of these hemorrhagesvaryfromafewscatteredsuperficial hemorrhages to extensive full retinal thickness hemorrhages with break through into the vitreous cavity. Patches of cotton wool spots may be seen. The optic nerve is usually swollen. In the chronic stages, the hemorrhages may have disappeared. Optic nerve head collaterals and macular edema may be the only residual

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Figure 1: Central Retinal Vein Occlusion. (A) The fundus view shows the main features of central retinal vein occlusion. They include: optic disc swelling (N), dilation of the retinal veins (V), retinal hemorrhages (H), macular edema (M), and cotton wool spots (C). (B) Shows the ophthalmoscopic view through the pupil and its corresponding cross section. (Art from JaypeeHighlights Medical Publishers).

ophthalmoscopic evidence that a prior CRVO had occurred. The major complications resulting from CRVO are macular edema resulting from diffuse capillary leakage and neovascular glaucoma as a result of the secretion of angiogenic factors such as vascular endothelial growth factor (VEGF) from areas of non-perfused retina. The development of neovascular glaucoma usually occurs within the first 3 months following development of a CRVO (90 day glaucoma).

The angiographic findings depend on great part on the ophthalmoscopic findings at the time of the fluorescein angiogram. In all eyes there is a delay in the filling of the retinal circulation. Blockage of the underlying retinal circulation and choroidal circulation may occur if extensive intraretinal hemorrhages are present. Invariably there is some degree of capillary non-perfusion. This may range from minimal to extensive and serves as the basis of the classification of CRVO into perfused or non-perfused types. There is also some leakage from the optic nerve head secondary to disc edema. The walls of the retinal vessels are damaged from the disease process and become stained with fluorescein in the late stages.

Optical Coherence

Tomography

Traditionally, biomicroscopic examination of the macula in combination with fluorescein angiography has been used to diagnose and manage macular edema. However, it has been shown that visual function correlates better with macular thickness as compared to fluorescein leakage.29 In addition, angiographic leakage is a qualitative test whereas retinal thickness, as measured by instruments such as the OCT, is a quantitative test. OCT has proven its value in the management and follow-up of patients with macular edema.30,31 Nevertheless, it should be emphasizedthatthereisonlyamodestcorrelation between OCT measured center point thickness and visual acuity. Thus OCT is a very useful tool for the diagnosis and measurement of the response to treatment but it can’t be used as a surrogate for visual acuity measurements.32

The Central Vein Occlusion Study (CVOS)

The CVOS was a multicenter, randomized controlled clinical trial that studied the visual outcomes following grid laser photocoagulation in eyes with macular edema, following panretinal photocoagulation in eyes with nonperfused CRVO, and the natural history of eyes with perfused CRVO.26,33-35 In the CVOS, eyes were arbitrarily classified as non-perfused if the fluorescein angiogram revealed more than 10 disc areas of capillary non-perfusion. This differentiation is important because up to one third of non-perfused eyes in the CVOS developed anterior segment neovascularization. In some eyes, fluorescein angiography was unable to determine perfusion status because the hemorrhages blocked the underlying capillaries. Once the hemorrhages cleared allowing a good quality fluorescein angiogram to be performed, it became apparent that these eyes behaved like non-perfused eyes. It is noteworthy that 15% of eyes initially classified as perfused became non-perfused after 4 months of follow-up. An additional 19% progressed to non-perfusion after 3 years of follow-up. Risk factors for disease progression included a baseline visual acuity of 20/200 or worse, recent onset and extensive intraretinalhemorrhages.Presentingvisualacuity is an important prognostic factor. Two thirds of eyes with an initial visual acuity of 20/40 or better retained that level of vision whereas 74% of eyes with an initial visual acuity of 20/250 or worse maintained that degree of visual loss (Figures 2 and 3).

The CVOS demonstrated that grid laser treatment of macular edema was of no visual benefit despite the elimination of the macular edema in those eyes that were treated. It also showed that the best strategy in non-perfused eyes was to delay panretinal photocoagulation until 2 clock hours of iris neovascularization or any angle neovascularization was observed. In order to achieve this, the CVOS has recommended a monthly visit for the first 8 months where undilated slit lamp examination of the pupillary border and gonioscopy are performed to detect early neovascularization. Panretinal photocoagulation is effective in controlling anterior segment neovascularization. About 8.5% of eyes that developed anterior segment neovascularization progressed to neovascular glaucoma that was refractory to medical treatment despite panretinal photocoagulation. None of these eyes required enucleation.

Alternative Treatments

Anti-VEGF

Several anti-VEGF agents are currently available in clinical practice. Both pegaptanib sodium (Macugen®, Eyetech, New York, NY USA),36-38 an aptamer against VEGF165, and ranibizumab (Lucentis®, Genentech, San Francisco, CA, USA),39-44 a fragment of a humanized monoclonal antibody against all VEGF isoforms, have been shown to be beneficial in the treatment of CNV secondary to age-related macular degeneration (ARMD), diabetic macular edema and central retinal vein occlusion. Bevacizumab (Avastin®, Genentech, San Francisco, CA, USA)

is a humanized, recombinant monoclonal IgG antibody that binds and inhibits all VEGF isoforms. Rosenfeld et al introduced intravitreal injection of bevacizumab into clinical practice.45,46 Of these anti-VEGF agents, bevacizumab has been the most widely used in the treatment of CRVO.

Several uncontrolled retrospective and prospective case series have demonstrated that intravitreal bevacizumab at doses of 1mg up to 2.5 mg causes an improvement in visual acuity concomitant with a reduction in CMT in the short term.47-57 However in other studies, the visual acuity did not improve despite the improvement in CMT.58-61 Similar results have been obtained in 3 small uncontrolled prospective case series studying ranibizumab for CRVO.40,41,44 A multicenter, randomized, double masked Phase 2 trial showed that pegaptanib sodium was also beneficial in the short term.38 Experience has shown that multiple injections are required in these eyes. All of these results suggest that in CRVO, VEGF does indeed play a major role in the pathogenesis of macular edema since blocking VEGF results in substantial improvement in macular edema.

Isovolemic Hemodilution

Some patients with CRVO exhibit abnormal red cell deformability, increased plasma viscosity, increased hematocrit and an increased fibrinogen level. By reducing hematocrit levels, plasma viscosity is lowered which may lead to improved retinal microcirculation and perfusion. Several randomized clinical trials have documented an improvement in visual acuity, arteriovenous

passage time and clinical appearance.62-64 The procedure appears to be well tolerated. Despite the improvements in visual acuity these studies suffer from several limitations. The numbers were usually small and multiple interventions such as xenon photocoagulation, pentoxyfilline, prednisolone that were not controlled for were used.62-64

Corticosteroids

Due to its potent anti-permeability and antiinflammatory properties corticosteroids have been used to treat macular edema from different etiologies.65 The problem lies in delivering therapeutic concentrations of the medication to the posterior segment of the eye. High doses of systemic corticosteroids are needed to achieve these therapeutic concentrations but at the cost of significant systemic side effects. Intravitreal delivery of corticosteroids avoids the systemic side effects from systemic therapy and at the same time permits high drug concentrations at the target tissue. Of the different corticosteroids available, intravitreal triamcinolone has been the most commonly used because of its long half life.66-69 Even though the current commercial preparation of triamcinolone has not been specifically formulated for intraocular use, animal studies have shown a lack of toxicity in the usual doses used.70 The optimal dose has not been determined. Most retinal specialists use a dose of 4 mg in 0.1 cc however doses up to 25 mg of triamcinolone have been injected. 68,71 It is not clear when to inject, when to reinject or whether to use the triamcinolone as an adjunct to laser treatment or as a primary treatment. Several studies have reported improved visual outcomes and a reduction in central macular thickness following intravitreal triamcino-

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lone.72-74 The StandardCareversusCorticosteroid for Retinal Vein Occlusion (SCORE) Study randomized 262 eyes with CRVO to macular photocoagulation vs 4 mg of intravitreal triamcinolone vs 1 mg of intravitreal triamcinolone. The study is fully enrolled but the results have not been published yet.32,75

Dexamethasone is a more potent corticosteroid than triamcinolone. Furthermore, intravitreal injections of dexamethasone achieves high intravitreal drug levels without any toxic effects. The main drawback of dexamethasone is its short intraocular half life of 3 hours. A biodegradable intravitreal dexamethasone implant has been designed and tested in patients with macular edema secondary to CRVO. The short term results appear quite promising.76 A long acting intravitreal fluocinolone acetonide sustained drug delivery implant has recently been approved by the FDA for the use in macular edema secondary to chronic uveitis.77 Fourteen eyes with macular edema secondary to CRVO were implanted with the fluocinolone implant and followed for 1 year.78 There was an improvement in visual acuity and central macular thickness but at a relatively high price. Cataract developed in all the 5 phakic eyes and 13 out of 14 eyes required a medical or surgical intervention to decrease intraocular pressure.78

Several complications arising from an intravitreal triamcinolone injection have been reported. Among them the most serious is endophthalmitis. Sterile technique is essential to avoid this uncommon but dreaded complication. A sterile endophthalmitis, presumably secondary to the preservatives, has also been reported.79,80 An increase in intraocular pressure and cataractogenesis are known side effects of steroids in general.81,82

A recent review concluded that there was inadequate evidence for the use of intravitreal steroids for macular edema secondary to CRVO due to a lack of randomized clinical trials and well designed observational studies.83 Further study is warranted to define what role if any, intravitreal corticosteroids will have in the management of macular edema secondary to CRVO.

ized study compared 6 laser treated eyes with 5 control eyes. All laser treated eyes had a patent chorioretinal anastomosis documented on fluorescein angiography. Although there was no statistically significant change in vision in the laser treated eyes, a trend towards better vision and decreased central macular thickness were observed in the laser treated eyes.89

In an attempt to restore venous outflow, McAllister and Constable84, 85 have pioneered the creation of a chorioretinal anastomosis in order to bypass the occlusion in eyes with perfused CRVO. To successfully create a chorioretinal anastomosis, Bruch’s membrane and the retinal vein must be ruptured with the laser. They recommend rupturing Bruch’s membrane first with a 50 μm spot size, 0.1 sec duration and argon power levels of 2.5 to 3 W. Once Bruch’s is ruptured, a second spot is placed at the edge of the retinal vein. Successful rupture of the vein is seen in about a third of cases treated with the argon laser. In those cases where the vein hasn’t ruptured, 3.5 to 5 mJ of YAG laser power is used to rupture the vein. Using the above technique, a chorioretinal anastomosis can be created in 67% of cases. Complications arising from this treatment include distal vein closure, fibrovascular proliferation and vitreous hemorrhage.84,85 They caution against using this technique in non-perfused eyes. Rapid fibrovascular proliferation that requires immediate panretinal photocoagulation may be seen in those eyes. Others have attempted to create a chorioretinalanastomosesviaasurgicalapproach using a variety of different surgical techniques with varying results.86-88 A small random-

Forty patients diagnosed with a CRVO of less than a week duration were randomized to an intravenous streptokinase infusion of 100 000 units/hr in 100 mL of saline for 72 hours vs observation.After a year of follow-up, there were only 5 eyes that were treated with streptokinase that suffered a decrease in vision as compared to 12 eyes in the control group. However, 3 eyes in the streptokinase group developed a massive vitreous hemorrhage and remained blind. It must be beared in mind though, that this study was reported in 1974 when vitrectomy techniques were just being developed.90 Systemic thrombolytic therapy with tissue plasminogen activator (t-PA) was found to be effective in a pilot study. However, the complications from such treatment included a fatal stroke and 3 patients developed severe intraocular bleeding.91 In view of these complications, local intravitreal t-PA delivery has been tested in a few uncontrolled case series.92-94 Cannulation of the retinal venous system with injection of t-PA following a standard vitrectomy has been successfully accomplished.95,96 Nevertheless the significance of the results remains unclear since the procedures have not been compared to controls or even standard vitrectomy.

Vitrectomy

Vitrectomy has been shown to increase the oxygenation in the vitreous cavity.97-99 In a cat model of BRVO, the pre-retinal oxygen tension was significantly decreased in non-vitrectomized eyes as compared to vitrectomized eyes.100 Several series have documented the benefits of vitrectomy for eyes with macular edema secondary to BRVO.101,102 Several theories exist as to how a vitrectomy improves macular edema. These include an increased oxygenation of the vitreous cavity, removal of cytokines such as VEGF from the vitreous cavity and the release of vitreomacular traction.

The posterior hyaloid may exert tangential traction that contributes to the pathogenesis of macular edema in CRVO.103-105 In eyes with non-ischemic CRVO with macular edema, the prevalence of macular edema was reduced from 76% in eyes with the posterior hyaloid attached to 25% in eyes with a posterior vitreous detachment.103 A number of retrospective case series have reported improved visual acuity and a reduction in central macular thickness following vitrectomy.105-107

Opremcak108 postulated that a CRVO is the result of a compartment syndrome where the scleral outlet forms the bottleneck. He proposed that relieving pressure on the occluded vein via a radial optic neurotomy would improve venous outflow. In this technique, following a standard vitrectomy a single radial incision is made into the scleral ring and adjacent sclera on the nasal part of the optic disc. Radial optic neurotomy remains controversial and several case series have reported numerous complications.109

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In summary several different surgical techniques based on vitrectomy including radial optic neurotomy, internal limiting membrane peeling and posterior hyaloid peeling have been advocated for the treatment of CRVO.101,108,110 Unfortunately, most of these studies are uncontrolled, have small numbers and the use of multiple interventions does not allow for direct comparisons between studies.

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