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

Scatter Photocoagulation

Neovascularization usually occurs at the border between ischemic and non-ischemic retina. Eyes with neovascularization of the disc (NVD) are believed to have more extensive ischemia than those without NVD. According to the BVOS, approximately 40% of eyes with large areas of ischemia (>5 disc areas of non-perfusion) are at risk of developing neovascularization.42 Of the eyes that do develop neovascularization, 60% will have vitreous hemorrhage. The BVOS demonstrated that scatter photocoagulation reduces the prevalence of neovascularization by one half (from 40% to 20%). However, if one were to treat all eyes with non-perfusion, a large percentage of patients (60%) who would never develop neovascularization would be treated with scatter photocoagulation. If one were to treat only the eyes that develop neovascularization, the events of vitreous hemorrhage also would drop by one half (from 60% to 30%). Therefore, the recommendation is to wait until neovascularization actually develops before considering scatter photocoagulation.

Alternative Treatments for Macular Edema

Anti-VEGF

Several anti-VEGF agents are currently available in clinical practice. Both pegaptanib sodium (Macugen®, Eyetech, NY,

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NY USA),43-45 an aptamer against VEGF165, and ranibizumab (Lucentis®, Genentech, San Francisco, CA, USA),46-51 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.52,53 Of these anti-VEGF agents, bevacizumab has been the most widely used in the treatment of BRVO.

Several retrospective and prospective case series have demonstrated that intravitreal bevacizumab at doses of 1mg up to 2.5 mg of intravitreal bevacizumab causes an improvement in visual acuity concomitant with a reduction in CMT in the short term.54-60 In a small open labeled prospective trial of short duration, Campochiaro et al 48 randomized 20 eyes with macular edema secondary to BRVO to 3 consecutive intravitreal injections of 0.3 mg or 0.5 mg of ranibizumab. At the primary endpoint of 3 months, the visual acuity improved 10 and 18 letters. By 1 week, over 80% of the excess foveal thickness was eliminated in both dose groups. In most cases multiple injections are required to maintain the benefits of therapy. The optimum dose and dosing sequence for intravitreal bevacizumab is still undetermined. It is unclear if a higher dose can provide better outcomes and/or a longer disease

free interval and reduce the burden of more frequent injections. When Rosenfeld and

eyes with BRVO. Holecamp et al 62 reported the vitreous levels of VEGF in 9 eyes with exudative ARMD to be 39.3 pg/mL which is much lower than the values obtained in eyes with BRVO. The Pan American Collaborative Retina Study (PACORES) Group compared the visual acuity, central macular thickness (CMT) and number of injections of 1.25 mg and 2.5 mg of intravitreal bevacizumab in eyes with macular edema secondary to BRVO with 6 months of follow-up. They found that there were no differences in any of these parameters between both doses at 6 months of follow-up.54 One of the main weaknesses of most studies reporting on intravitreal bevacizumab for macular edema secondary to BRVO is the lack of a laser control group.54-60 This precludes a direct comparison of intravitreal bevacizumab with thegoldstandardofmacularphotocoagulation. A recent prospective comparative study of 30 eyes with 12 months duration has shown that 1.25 mg of intravitreal bevacizumab was more effective in restoring visual acuity and central macular thickness than macular photocoagulation.63 All of these results suggest that in BRVO, VEGF does indeed play a major role in the pathogenesis of macular edema since blocking VEGF results in substantial improvement in macular edema.

Corticosteroids

Due to its potent anti-permeability and anti-inflammatory properties corticosteroids have been used to treat macular edema from different etiologies.64 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.65-68 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.69 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. 67, 70 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. A handful of cases of macular edema secondary to BRVO treated with an intravitreal triamcinolone injection have been reported.70,71 The Standard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE) Study randomized 403 eyes with BRVO 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.11,37 In the hopes of reducing the possible complications from an intravitreal injection of triamcinolone, some authors have reported the use of periocular triamcinolone.72,73 Hayashi and colleagues compared repeated retrobulbar injections of 40 mg of triamcinolone to one intravitreal injection of 4 mg of triamcinolone and found that intravitreal triamcinolone was more effective than the retrobulbar injections at the 3 month follow-up.

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 BRVO. The short term results appear quite promising.74

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.75,76 An increase in intraocular pressure and cataractogenesis are known side effects of steroids in general.77,78 Further study is warranted to define what role if any, intravitreal corticosteroids will have in the management of macular edema secondary to BRVO.

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Laser-Induced Chorioretinal

Anastomosis

Bypass of the normal retinal venous drainage channels is attempted by creating a communication between the obstructed vessel and the choroid by literally blasting a hole through the RPE and choriocapillaris with a high energy Argon or YAG laser.79 Problems with this technique are the lack of reliability in creating an anastomosis (most series report a 30-50% success rate) and its complications.80 Complications from the procedure include tractional retinal detachment and vitreous hemorrhage.

Vitrectomy

Vitrectomy has been shown to increase the oxygenation in the vitreous cavity.81-83 In a cat model of BRVO, the pre-retinal oxygen tension was significantly decreased in nonvitrectomized eyes as compared to vitrectomized eyes.84 Several series have documented the benefits of vitrectomy for eyes with macular edema secondary to BRVO.85, 86 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.

Since virtually all BRVO’s occur at arteriovenous crossings and arterial compression is thought to be the major cause of this condition, Osterloh and Charles87 recommended

lifting the artery from the underlying vein to relieve the compression. In this technique a regular 3 port pars plana vitrectomy is performed. The intraocular pressure is raised to prevent bleeding. The site of the obstruction is identified with the help of a pre-operative fluorescein angiogram. Then with a bent MVR blade or a special knife, the sheath is opened and the artery lifted from the vein. Several uncontrolled small series have reported good results with regards to improving macular edema and macular perfusion.87-89 On the other hand, others have reported a lack of efficacy of this procedure. In fact the benefits ascribed to sheathotomy may be explained by the vitrectomy itself.90-92 Some surgeons have also recommended peeling of the internal limiting membrane.93,94 However, Arai et al95 in a comparative trial found no additional benefit from peeling the internal limiting membrane in eyes with macular edema secondary to BRVO.

Final Remarks

BRVO is a common retinal vascular condition. Perfused macular edema is responsible for most cases of visual dysfunction following a BRVO. Despite all the promising results from experimental therapies such as vitrectomy, anti-VEGF agents and corticosteroids; macular photocoagulation remains the treatment of choice. Before any of these alternative treatments can be adopted as the standard of care, they must be proven to be more efficacious than macular photocoagulation.

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58.Gunduz K, Bakri SJ. Intravitreal bevacizumab for macular edema secondary to branch retinal vein occlusion. Eye 2008;22(9):1168-71.

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The exact pathogenesis of the thrombotic occlusion of the central retinal vein is not known. Various local and systemic factors play a role in the pathological closure of the central retinal vein.1

The central retinal artery and vein share a common adventitial sheath as they exit the optic nerve head and pass through a narrow opening in the lamina cribrosa. Because of this narrow entry in the lamina cribrosa, the vessels are in a tight compartment with limited space for displacement. This anatomical position predisposes to thrombus formation in the central retinal vein by various factors, including slowing of the blood stream, changes in the vessel wall, and changes in the blood. Up until the third month of intrauterine life, the fetal central retinal vein consists of a dual trunk that surrounds the central retinal artery. Right before birth, one of the trunks disappears. However in up to 20% of eyes, the dual trunk persists. If one of the trunks becomes occluded a hemi retinal vein occlusion will result.1 This chapter deals exclusively with CRVO.

Epidemiology

Retinal vein occlusions (branch and central) are the second most common retinal vascular diseases after diabetic retinopathy.2 The Beaver Dam Study reported a prevalence of 0.1% in patients older than 43 years.3 The 15 year cumulative incidence of CRVO was 0.5% in the Beaver Dam Eye Study.4 A cross sectional study from 6 communities across the US reported that the prevalence of CRVO was 0.2%. Furthermore this same study showed that the prevalence of CRVO was similar across different ethnic and racial groups.5 In a population-based study from Australia, the Blue Mountains Eye Study, the 10 year cumulative incidence of CRVO in the population older than 48 years was 0.4%.6 The Singapore Malay Eye Study reported a 0.2% prevalence of CRVO in the Malay population of 40-80 years old living in Singapore.7 The Beijing Eye Study reported that the prevalence of CRVO in a Chinese population of people ≥ 40 years of age was 0.1%.8 No racial or gender predilection for the disease is apparent.

Epidemiologic studies have identified cardiovascular disease, diabetes mellitus, age over 55 years, hypertension and glaucoma as important associations with CRVO.9 Despite these associations, most authorities believe that medical treatment of the associated systemic conditions bear little influence in the outcome of the ocular complications.

Pathogenesis

TheexactpathogenesisofaCRVOiscurrently unknown. Akey component in the pathogenesis of a CRVO is narrowing of the central retinal vein. The central retinal artery and vein share a common adventitial sheath at the level of the lamina cribrosa.10,11 Here the vessel walls touch one another. Long standing systemic hypertension and arteriosclerosis cause enlargement and hardening of the central retinal artery which compresses the adjacent central retinal vein narrowing its lumen. Other conditions such as papilledema, optic disc drusen and inflammation may also cause narrowing of the central retinal vein. When the lumen of the central retinal vein becomes narrow enough, turbulent flow ensues creating the proper conditions for thrombus formation.12 Histopathologic studies have shown that CRVO occurs secondary to thrombus formation at the level of the lamina cribrosa or posterior to it.12,13 Once a thrombus forms, blood becomes stagnant causing the capillary and venous pressure to rise. At the same time the retina becomes hypoxic from the stagnant blood leading to damage of the capillary endothelial cells and extravasation of blood and its constituents into the extracellular space. There is increasing evidence that VEGF

plays a key role in the pathogenesis of macular edema and intraocular neovascularization secondary to CRVO. Experimental models have shown that hypoxia triggers VEGF up-regula- tion.14-16 In enucleated human eyes with CRVO and neovascular glaucoma, in situ hybridization techniques localized the VEGF producing retinal cells to the ischemic regions of the retina.17 In eyes with ischemic CRVO, there was correlation between increasing VEGF aqueous levels, retinal neovascularization and vascular permeability.18 Intravitreal injections of VEGF into a non-human primate eye produces a retinopathy that mimics the clinical picture of a CRVO.19 VEGF inhibition in non-human primate eyes reverses iris neovascularization in a CRVO model.20 Increased aqueous VEGF levels have been reported in human eyes with CRVO.21 Furthermore the levels of VEGF correlate with the degree of macular edema and retinal ischemia.22 Therefore, VEGF appears to be a promising therapeutic target in the treatment of CRVO.

Classification

Over the years it has been recognized that CRVO encompasses a wide spectrum of disease. Thus many terms such as impending, incipient, partial, incomplete, venous stasis retinopathy, hemorrhagic, perfused, non-perfused, indeterminate, ischemic and non-ischemic have appeared in the literature.23-26 In essence there is a recognition that some CRVO are mild and have a relatively good prognosis whereas other CRVO are severe and have catastrophic visual consequences. Currently the most accepted terms are non-ischemic or non-perfused vs ischemic or perfused.26