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

Figure 2: Traction retinal detachment from proliferative diabetic retinopathy - pathologic changes. Predominant abnormalities include anteroposterior vitreous traction caused by funnel-shaped configuration of posterior vitreous surface (A) and transverse traction from thickened posterior vitreous surface bridging over macular area (B). Hemorrhage is present in the vitreous gel (C) associated with fibrovascular proliferation from the optic nerve (D) and ring-like configuration of fibrovascular proliferation along temporal vascular arcades (E). Vitreoretinal traction has caused retinal detachment (F). (Art from Jaypee-Highlights Medical Publishers).

Retinal tears occurring under these circumstances are often difficult to detect, as they are frequently obscured by retinal or vitreous hemorrhages and at the edge of fibrovitreous membranes. Subretinal fluid and an area of mobile retina, together with signs of released vitreous traction may give clues to the presence of retinal tears.

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Rapid Neovascular Growth

There are two important stimuli of retinal neovascularization. When retinal ischemia is significantenoughtoresultinextensiveareasof capillary non-perfusion, an angiogenic stimuli is postulated to be present to stimulate the proliferation of retinal new vessels. These new vessels typically occur at the area of the retina bordering the area of capillary non perfusion. There is also a second stimulus for neovascularization, namely a mechanical stimulus represented by a partial posterior vitreous separation. The separated posterior hyaloid surface provides a scaffold for new vessels to proliferate. A partial posterior vitreous separation promotes rapid neovascular growth.

I have followed a group of diabetic patients and correlated the course of their retinopathies with the status of the vitreous body on initial examination. In those eyes which had no posterior vitreous separation or had a complete posterior vitreous separation on initial examination, 95% of the eyes had stable retinopathy over an average course of 5 or more years. But in eyes which showed a partial posterior vitreous separation, 55% of the eyes had a progressive retinopathy while 38% of eyes had stable retinopathy. The difference is statistically significant.

There are other clinical observations to support the hypothesis that partial posterior vitreous separation is a powerful stimulus to rapid neovascular proliferation. New vessels are generally not detected on areas of retina

from which the vitreous has separated. Also, in eyes with proliferative diabetic retinopathy, if no posterior vitreous separation is evident, the new vessels generally progress very slowly. And in eyes in which posterior vitreous separation is complete, neovascularization tend to be quite stable and progress very little if at all. Furthermore, in eyes with early new vessels, when a complete posterior vitreous separation later takes place, new vessels can be observed to regress. Another observation includes the regression of neovascularization after vitrectomy when the posterior hyaloid membrane is excised and this regression may occur even without intraoperative or postoperative laser treatment. These are all clinical observations to support the thesis that partial posterior vitreous separation is a powerful stimulus for rapid new vessel growth.

Implications of a Partial Posterior Vitreous Separation

Based on the above clinical observations, it seems that laser treatment for diabetic retinopathy is most effective if undertaken before partial posterior vitreous separation has begun. Complete posterior vitreous separation seems to offer good prognosis in proliferative diabetic retinopathy even if new vessels are present. In eyes with proliferation changes, a partial posterior vitreous separation indicates a poor prognosis and warrants prompt and aggressive treatment. Finally, in eyes with no retinopathy or non-proliferative retinopathy, the presence of a complete posterior vitreous separation seems to protect the eyes from new vessels proliferation and progressive changes of the retinopathy. The status of

the vitreous is a good clinical parameter to follow diabetic patients with no retinopathy or early retinopathy.

A Three-Dimensional Concept

There appears to be two processes racing against time in a diabetic eye. On a twodimensional surface, there is an angiopathy represented by neovascularization, which occurrence is dependent upon the duration and severity of the metabolic derangement. On another level, and on a three-dimensional consideration,thereisavitreopathyrepresented by vitreous shrinkage and posterior vitreous separation, which occur as an aging process and accelerated by diabetic changes.

Therefore, in early onset diabetes, chronic and extensive angiopathy stimulates new vessel growth before the vitreous is totally detached. Partial posterior vitreous separation results and proliferative changes and their inherent complications of vitreous hemorrhage, tractional and rhegmatogenous retinal detachment and accelerated new vessel growth frequently follow.

In late onset diabetes, posterior vitreous separation occurs before angiopathy has been significant enough to stimulate new vessel growth. Thus, non-proliferative diabetic changes generally result.

In conclusion, diabetic proliferative changes result from a race in the course of time between diabetic angiopathy and diabetic vitreopathy (posterior vitreous separation).

Diabetic Vitreoretinopathy

It is thus proposed that whereas “diabetic retinopathy” is a two-dimensional term describing the changes, mostly angiopathy, on the retinal surface, “diabetic vitreoretinopathy” or “DVR” is a three dimensional term more accurately depicting the three-dimensional dynamics between the retinal surface and the vitreous body. Therefore, proliferative diabetic retinopathy (PDR) should become proliferative diabetic vitreo retinopathy (PDVR), and non-proliferative diabetic retinopathy (NPDR) shouldbecomenon-proliferativediabeticvitreo retinopathy (NPDVR). At least, these terms prompt us to think of the vitreous and examine the vitreous in diabetic eyes.

Vitreous Involvement in

Diabetic Retinopathy

The vitreous has three strong attachment areas with the retina. The strongest attachment straddles the most anterior area of the retina (ora serrata) where a 4-mm circular band forms the vitreous base. Traction at the vitreous base usually is transmitted to the adjacent peripheral retina. The next strong attachment of the vitreous is at the circular zone around the optic nerve head. This zone becomes progressively weakened with increasing age, and it becomes easily separated with posterior vitreous detachment.

Bleeding from neovascular and fragile vessels in proliferative diabetic retinopathy, proliferative sickle cell retinopathy, ischemic

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retinopathy secondary to retinal vein occlusion, and retinopathy of prematurity are among the most common pathological causes of vitreous hemorrhage.

The most common pathogenesis of bleeding in this group of disorders is believed to be retinal ischemia causing the release of angiogenic vasoactive factors, most notably vascular endothelial growth factor (VEGF), basic fibroblast growth factors (bFGF), and insulin-like growth factor (IGF). The second most frequent pathological mechanism for vitreous hemorrhage is tearing of the retinal vessels caused by either a break in the retina or detachment of the posterior vitreous, while the cortical vitreous is adherent to the retinal vessels. In addition, patients with sickle cell retinopathy may show a salmon-patch hemorrhage caused by blowout in the vessel wall following abrupt occlusion in the arterioles by aggregated sickled red blood cells. Other less common pathological mechanisms of vitreous hemorrhage include subretinal bleeding with secondary extension into the vitreous cavity.

Neovascularization is observed at the borders of perfused and non-perfused retina and most commonly occur along the vascular arcades and at the optic nerve head. New vessels break through and grow along the surface of the retina and into the scaffold of the posterior hyaloid face. By themselves, these vessels rarely cause visual compromise. However, they are fragile and highly permeable. These delicate vessels are disrupted easily by vitreous traction, which leads to hemorrhage into the vitreous cavity or the preretinal space.

Much confusion exists in the literature because central and branch retinal vein occlusions (BRVO) often are clumped and studied together. The natural history and complication rate for each entity is quite different. The treatments and their results vary from one condition to the other. Hemiretinal vein occlusions (HRVO) are probably variants of central retinal vein occlusions and, as such, will not be included in this discussion.1 This chapter deals exclusively with BRVO.

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 0.6% in patients older than 43 years.3 The 15 year cumulative incidence of BRVO was 1.8% in the Beaver Dam Eye Study.4 A cross sectional study from 6 communities across the US

reported that the prevalence of BRVO was 0.9%. Furthermore this same study showed that the prevalence of BRVO was similar across different ethnic and racial groups.5 In a population-based study from Australia, the Blue Mountains Eye Study, the prevalence of BRVO in the population older than 48 years was 1.1%.6 The Singapore Malay Eye Study reported a 0.6% prevalence of BRVO in the Malay population of 40-80 years old living in Singapore.7 The Beijing Eye Study reported that the prevalence of BRVO in a Chinese population of people ≥ 40 years of age was 1.3%.8 No racial or gender predilection for the disease is apparent. The patients who are affected are usually in their fifth or sixth decade of life.3-7 The Eye Disease Case Control Study identified systemic hypertension as an important risk factor for BRVO. Unlike central retinal vein occlusion, diabetes mellitus and open angle glaucoma were not found to be risk factors for BRVO.9

Classification

Depending on the anatomic site of the arteriovenous crossing, BRVO may be classified into major BRVO and macular BRVO.10 Some authors also include HRVO as a variant of BRVO.10,11 However, Hayreh and Hayreh1 have shown that a HRVO arises from an occlusion of one of the trunks in an eye with a dual trunk central retinal vein. Thus a HRVO should be considered as part of the spectrum of a central retinal vein occlusion rather than a BRVO.

Etiology

Anatomic, hypertensive, atherosclerotic, inflammatory,orthrombophilicconditionsmay lead to retinal endothelial vascular damage withsubsequentintravascularthrombusformation. Inflammatory conditions that have been associated with a BRVO include sarcoidosis,12 Lyme disease13 and serpiginous choroiditis.14 Thrombophilic conditions such as protein S deficiency,15 protein C deficiency,16 resistance to activated protein C (factor V Leiden),15 antithrombin III deficiency,15 antiphospholipid antibody syndrome,17 lupus erythematosus17 and gammopathies have also been associated with BRVO.

However, the major risk factor in the development of a BRVO appears to be anatomic. Eyes with arteriovenous crossings appear to be at risk of developing BRVO.18-23 In these eyes, the thick walled artery is anterior to the thin wall vein in most cases. In the presence of systemic vascular disease the risk of oc-

clusion may be accentuated when arteriolar sclerosis results in an increased rigidity of the crossing artery which causes compression of the underlying vein. Compression of the vein diminishes the lumen by as much as a third of its baseline diameter. Turbulent flow results which in turn damages the vascular endothelium creating a local environment favorable to intravascular thrombus formation. Once the venous flow is compromised or interrupted, retinal ischemia ensues downstream from the site of occlusion. Retinal ischemia is one of the most important up-regulators of vascular endothelial growth factor (VEGF) production.24 Several animal models of BRVO have shown that occlusion of a branch retinal vein leads to VEGF upregulation.25,26 VEGF has been shown to be a key mediator in the pathogenesis of macular edema and intraocular neovascularization.27 Increased aqueous VEGF levels have been reported in human eyes with BRVO.28 Furthermore the levels of VEGF correlate with the degree of macular edema and retinal ischemia.29 Therefore, VEGF appears to be a promising therapeutic target in the treatment of BRVO.

Clinical Findings

The diagnosis of a BRVO is usually straightforward. Leber first described the condition ophthalmoscopically in 1877.2 Most occlusions occur in the superotemporal quadrant since most arteriovenous crossings occur in this location. During the acute phase, intraretinal hemorrhages (usually flame shaped), retinal edema, and cotton-wool spots are seen in the distribution of a retinal vessel. Serous detachment of the macula may also be seen.30

Figure 1: Branch Retinal Vein Occlusion. (A) Shows a fundus view of a branch retinal vein occulsion which produces hemorrhages (H) within the nerve fiber layer of the retina and cotton wool spots (C). (B) Shows a magnified cross section of retina (R) and choroid (D). Note the hemorrhages (H) and cotton wool spots (C) located within the nerve fiber layer (N). One can also see the retinal vein (V). (Art from Jaypee-Highlights Medical Publishers).

The horizontal raphe is respected. During the chronic stage, hemorrhages may be absent. Macular edema may be the only sign present. Telangiectatic vessels that extend across the horizontal raphe usually can be demonstrated angiographically. The upstream side of the occlusion may become fibrotic. In certain eyes with large areas of non-perfusion, retinal neovascularization may be seen. Vitreous hemorrhagewithtractionalretinaldetachments may ensue. Further traction may create retinal breaks,creatingcombinedrhegmatogenousand

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tractional retinal detachments. Neovascular glaucoma and neovascularization at the disc are rare events with BRVO (Figure 1).

Work-Up

The Branch Vein Occlusion Study (BVOS) has recommended against extensive testing in patients with a typical BRVO.31 In atypical cases, i.e., young patients, bilateral cases, or patients with a personal or family history for thromboembolism, certain laboratory studies maybeofuse.Prothrombin time(PT),activated partial thromboplastin time (aPTT), protein C, protein S, factor V Leyden, antithrombin III, homocysteine levels, folate levels, antinuclear antibody (ANA), lupus anticoagulant, anticardiolipin, serum protein electrophoresis (SPEP) and fasting lipid levels (triglycerides included) should be ordered in these circumstances.

Angiographic Findings

(Fluorescein and ICG)

Inthehealthyfundus,arteriovenouscrossing sites are not associated with venous compression, but in the presence of arteriosclerotic or hypertensive arteriolar changes, increased compression of the vein causes a visible narrowing at the crossing site, sometimes with marked upstream dilation of the vein. Early stages of BRVO with partial venous occlusion often show this phenomenon very clearly.

In the acute stage of a partial or complete venous occlusion the fluorescein angiography shows venous engorgement upstream of the crossing, resulting in ischemia, hemorrhage

and cotton-wool spot formation. If fluorescein angiography is performed when the intraretinal hemorrhages are still present, a hypofluorescent area corresponding to the blood will block both the retinal and choroidal circulations during the early phases. In the late phases, some leakage which results from the endothelial cell damage and the increased intracapillary pressure may be seen extending beyond the hemorrhages. No other details will be seen. Therefore our recommendation is to wait until the hemorrhages have cleared before performing a fluorescein angiogram. Typical angiographic findings following clearing of the intraretinal hemorrhages include a prolonged retinal circulation time, perivenous staining in the obstructed area, evidence of capillary leakage, macular leakage consistent with cystoid macular edema, areas of capillary non-perfusion and in certain cases retinal neovascularization. With time collateral vessel remodeling and maturation may occur. These collaterals usually support enough flow to maintain some retinal function. They are best seen angiographically around the foveal avascular zone and over the temporal watershed zone. The collaterals bypass the occlusion by draining the venous blood into adjacent venous drainage areas and gradually distend, generally resulting in reduced leakage. It typically takes 6 to 24 months for the collaterals to mature and stabilize. Reduction of leakage and edema often results in an improvement in visual acuity, provided that no irreversible foveal damage has occurred.

The BVOS recommends that a fluorescein angiogram should be obtained as soon as the hemorrhages have cleared if vision is still depressed, usually 3 months after the event.31 The purpose is to determine the cause of visual loss (i.e., macular edema or macular ischemia) (Figures 2 and 3). If the visual loss is secondary to macular edema, laser photocoagulation in a grid pattern may be of benefit.31 Conversely, if macular ischemia is responsible for the loss of vision, laser photocoagulation should not be offered to the patient.32

Over the past decade there has been a renewed interest in indocyanine green (ICG) angiography. Due to its fluorescence in the infrared, ICG penetrates blood much better than fluorescein. Even though ICG may be performed in the acute phase while the intraretinal hemorrhages are still present;33 no one has been able to show that the information gathered from an ICG is useful in the management of a BRVO. Fluorescein angiography remains the gold standard in the management of BRVO.

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.34 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.35,36 Nevertheless, it should be emphasized that there is only a modest correlation 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.37

Treatment

The 3 most common causes of visual loss following a BRVO are macular edema, macular non-perfusion and vitreous hemorrhage secondary to intraocular neovascularization.2 Of these, macular edema is the most common. The BVOS has shown that macular grid laser photocoagulationiseffectiveinthetreatmentof macular edema.31 If the fluorescein angiogram reveals macular non-perfusion, laser is not warranted and observation is recommended. Finkelstein reported that eyes with macular edema secondary to non-perfusion had a good visual prognosis. The median visual acuity in his series was 20/30.32 In eyes with retinal neovascularization, the BVOS has also shown that scatter photocoagulation is the treatment of choice. In eyes with other complications such as vitreous hemorrhage, tractional and rhegmatogenousretinaldetachment,vitrectomy techniques should be employed.38-41

Macular Grid Laser

Photocoagulation

The current recommendation is to wait 3 months to allow for spontaneous improvement in vision and clearance of the intraretinal hemorrhages. If no improvement is seen and the hemorrhages have mostly cleared from the macular area, a fluorescein angiogram is obtained. If the fluorescein angiogram shows leakage in the macular area responsible for the decrease in vision, a macular grid laser is recommended. The laser parameters for macular grid photocoagulation used in the BVOS included a duration of 0.1 second, a spot size of 100 μm and a sufficient power to cause a medium white retinal burn. The burns were placed one spot size apart from each other in a grid fashion over the area of leakage identified in the fluorescein angiogram. The laser spots came to the edge of the capillary free zone and extended to the major arcades but not beyond them.31 After 3 years of follow-up care, 63% of laser treated eyes improved 2 or more lines of vision compared to 36% of control eyes.31 In laser treated eyes, the average improvement of visual acuity was only 1.3 lines from baseline, 40% of eyes ended up with a visual acuity ≤ 20/40 and 12% remained with a visual acuity ≤ 20/200.31 Given the modest benefits of macular photocoagulation in eyes with macular edema, new modalities have been explored in the hopes of improving these results.