Jonathan Gunther,
Ingrid U. Scott,
Michael Ip
INTRODUCTION
Retinal vein occlusion (RVO) is the second most common retinal vascular disease following diabetic retinopathy.[1] There are three distinct types of RVO: branch retinal vein occlusion (BRVO), central retinal vein occlusion (CRVO), and an anatomical variant of CRVO, namely, hemiretinal vein occlusion (HRVO) (Table 132.1). Retinal venous occlusive disease typically occurs at an arteriovenous crossing in BRVO or at the lamina cribrosa in CRVO and HRVO. Retinal vein occlusions have a characteristic, although somewhat variable, appearance with intraretinal hemorrhage, cotton-wool spots, tortuous and dilated retinal veins, retinal edema and, occasionally, optic disk swelling. These fidings are present segmentally in BRVO, in either the superior or inferior two quadrants in HRVO, and in all quadrants of the fundus in CRVO. Vision loss can vary from minimal or no vision loss to complete blindness. Causes of vision loss associated with RVO include macular edema, macular nonperfusion, epiretinal membrane, dense intraretinal hemorrhages, vitreous hemorrhage, neovascular glaucoma, or tractional retinal detachment (TRD).[2-6] Timely intervention can reduce the incidence and severity of these complications. Many systemic diseases are risk factors for RVO development. Recognition and treatment of an underlying systemic disease can benefit the patient visually and improve overall health.
TABLE 132.1 -- Key Characteristics of Vein Occlusions
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RVO type |
Occlusion location |
Area involved |
Neovascular location |
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BRVO |
Retinal A-V crossing |
Segmental |
Posterior pole |
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CRVO |
Lamina cribrosa |
4-Quadrant |
Anterior segment |
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HRVO |
Lamina cribrosa |
2-Quadrant (vertical) |
Post. Pole>ant. segment |
The overall incidence of RVO in population-based studies varies depending on age and the study. In a large population-based study in Israel, the 4 year incidence of retinal vein occlusion was 2.14/1000 among persons aged 40 years and older, and 5.36/1000 among individuals older than 64 years.[7] In the Blue Mountains Eye Study[8] (BMES) in Australia, the prevalence of retinal vein occlusion was 0.7% among persons aged 49-60 years, 1.2% for persons aged 60-69 years, 2.1% for those 70-79 years, and 4.6% for persons 80 years and older. The mean age of onset of vein occlusion was 63 years. Hayreh[9] reported that after any RVO in one eye, the incidence of developing a second vein occlusion in the next 4 years was 2.5% in the same eye and 11.9% in the fellow eye. Of all the RVO in the BMES, 69.5% were BRVO, 25% CRVO, 5.1% HRVO, and 5.1% were bilateral.
BRANCH RETINAL VEIN OCCLUSION
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INTRODUCTION
The fundoscopic fidings of BRVO are similar to those of CRVO; however, the extent of retinal involvement is typically much less. The involved vein takes on a dilated and tortuous appearance, deep and superficial retinal hemorrhages form, cotton-wool spots can be observed, and retinal edema may develop. A BRVO typically occurs at the crossing of a retinal artery and vein. The involved area is usually wedge-shaped with the apex near the site of the occlusion, extending outward to the periphery (Fig. 132.1). The area drained by the involved vein defies the extent of retinal involvement. The greater the area of retinal involvement, the greater the impact it is likely to have on vision. The location of the occlusion is an important factor in the visual prognosis. In general, the closer the occlusion occurs to the optic nerve, the more extensive the retinal damage and visual impact.[10-12] The clinical course and visual outcome of BRVO is highly variable.
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FIGURE 132.1 Large superotemporal branch retinal vein occlusion (BRVO) occurring at an arteriovenous intersection near the superior margin of the disc. |
EPIDEMIOLOGY
BRVO is more than twice as common as CRVO and more than 10 times as common as HRVO.[7,8,13,14] Numerous studies have assessed the incidence of venous occlusive diseases over the years. The Beaver Dam Eye Study[13] was a population-based study of 4926 residents of Beaver Dam, WI aged 43-84 years. Initial RVO evaluation was performed between 1988 and 1990 with follow-up examinations 5 years later (1993-1995). Diag nosis of RVO was made by grading 30° stereo fundus photographs. The prevalence and 5 year incidence of BRVO were each 0.6%. Prevalence increased with age and there was no gender predilection.
The Blue Mountain Eye Study[8] in Australia was a prospective study including 3654 participants aged 49 years or older. Follow-up consisted of detailed eye examinations including stereoscopic fundus photography. Diagnosis of RVO was based on clinical fidings and fundus photographic grading. The overall incidence of BRVO was 1.1% with a strong age-related predilection and no gender predilection.
PATHOPHYSIOLOGY
BRVO is defied as a focal occlusion of a retinal vein.[15-17] With rare exceptions, such as in association with sarcoidosis and other ocular inflammatory disorders, BRVO develops at arteriovenous crossing sites where the artery passes anteriorly (superficially) to the vein.[16-19] In normal eyes, retinal arteries cross over retinal veins in 70-75% of the intersections.[15,17] The most common location of a BRVO is the superotemporal quadrant of the retina. This may be due to a higher risk of occlusion in this area, or may be due to increased diagnosis due to increased symptoms of a temporal versus a nasal occlusion. Most BRVOs involve the area inside the temporal vascular arcades (macular BRVO), whereas peripheral BRVOs are observed less commonly, likely because they tend to be less symptomatic. Of temporal BRVOs, ?62% occur in the superotemporal quadrant and 38% in the inferotemporal quadrant.[10,11,15,17,20-23]
The precise mechanism causing the venous occlusion is poorly understood. Multiple theories, often contradictory, exist. Histological examination has shown that BRVO is associated with arteriosclerotic changes in the retinal arterioles.[17] The resultant thickening of the artery could cause compression of the adjacent vein, a process that may be aggravated because, at arteriovenous crossing sites, the two vessels are confied within a common adventitial sheath.[24] With increased compression, venous blood flow velocity at the crossing site may gradually increase until local shear stress causes endothelial cell loss, thrombus formation, and vein occlusion.[24-26] Theoretically, shear stress is maximal when the velocity is high enough to induce transition to a turbulent flow pattern.[27]
Another theory is that venous compression is not the cause of BRVO. Seitz demonstrated histologically that the retinal vein is not compressed by the artery at intersections at which nicking is observed.[28]Jefferies found that the vein took a much more pronounced deviation around an artery when the artery overlies the vein, compared to when the vein overlies the artery. He also found focal stratification of the venous endothelial basement membrane opposite the point of contact with the artery. Localized venous luminal narrowing was not typical. Jefferies proposed that hemodynamic variations due to venous contouring are responsible for the much higher risk in artery over vein intersections.[29]
It has been suggested that BRVO is the result of arterial insufficiency.[24,25] However, in a histopathologic study of nine cases of BRVO, Franghieh demonstrated that all cases had fresh or recanalized venous thrombus at the site of occlusion. He concluded that branch vein thrombosis was likely the primary event and that the other vascular fidings occurred secondarily.[30] Other studies have demonstrated that the manifestations of arterial insufficiency can be reproduced in animals by experimental occlusion of the retinal veins.[31-36]
The average age of patients with BRVO is between 60 and 70 years.[7,8,13,14] The incidence increases with age.[8] Certain systemic diseases have also been shown to be risk factors for BRVO. The Eye Disease Case-Control Study Group reported 'cardiovascular risk profile' as a risk factor for BRVO.[37,38] A significantly increased risk was found for systemic hypertension, history of cardiovascular disease, smoking, increased body mass index and higher serum levels of alpha2-globulin. One-half to two-thirds of patients in large series of BRVO have been reported to have systemic hypertension.[10-12,20,39,40] A decreased risk of BRVO was associated with alcohol consumption and higher levels of high density lipoprotein (HDL) cholesterol. Diabetes mellitus and open angle glaucoma occurred more frequently among BRVO patients than among controls, but the differences were not statistically significant.[41]
CLINICAL FEATURES
Patients with BRVO may complain of painless, decreased vision, complete loss of vision, or a blind spot in their visual field. Others may be asymptomatic. Vision loss in BRVO may be due to macular edema, macular nonperfusion, dense intraretinal hemorrhages, vitreous hemorrhage, neovascular glaucoma, epiretinal membrane, or tractional retinal detachment.[2,42]
A complete ocular examination should be performed, including evaluation for iris or angle neovascularization and a dilated fundus examination to evaluate for macular edema, neovascularization of disk and/or retina, presence of intraretinal hemorrhages, cotton wool spots, vitreous hemorrhage, narrowing and sheathing of the adjacent artery. Close attention should be paid to the distribution of the involved area of the fundus.
Visual acuity is generally less affected in BRVO when compared to CRVO. However, there can be great variation in visual outcome ranging from no visual impairment to severe vision loss. Typically, patients presenting with visual complaints have associated retinal hemorrhage, edema, and/or nonperfusion. Symptoms may worsen or improve with time. At later stages, visual complications may include macular edema, vitreous hemorrhage from neovascularization, epiretinal membrane, or retinal detachment. Generally, the visual prognosis of BRVO is quite good. Approximately 50-60% of untreated patients will have a fial visual acuity of 20/40 or better. However, severe vision loss is not uncommon, with 20-25% of patients having a visual acuity of 20/200 or worse. A fial visual acuity of hand motion or worse is uncommon.[2,10,11,20,42]
The classic fundus fidings of BRVO are similar to CRVO, although the area of distribution is distinct. BRVO fundus fidings may include optic disk swelling, retinal swelling, including the macula, markedly dilated and tortuous retinal veins, superficial and deep retinal hemorrhages radiating outward from the optic disk, and cotton-wool spots (Fig. 132.2). However, a small or peripheral BRVO may produce fidings that are much more subtle and difficult to detect on examination. With time, the fundus fidings may become less distinct and appear similar to what one would expect to see in diabetic retinopathy, hypertensive retinopathy, or other systemic diseases causing retinal microaneurysms and hemorrhages. Clues suggestive of an old BRVO include segmental microvascular abnormalities and intraretinal collateral vessels draining across the median raphe. In nonperfused cases, sclerosis and sheathing of the retinal veins and arteries in the distribution of the occlusion may be observed.[43,44]
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FIGURE 132.2 BRVO with hemorrhage, cotton-wool spots, and fibrous sheathing of the retinal veins. |
Intravenous FA can assist in evaluating BRVO. Angiographic fidings reflect changes in vessel permeability, caliber, and patency and assist in identifying areas of macular edema, neovascularization, and nonperfusion. Vitreous or retinal hemorrhage may impair the utility of FA. Venous filling delay is often noted in the area drained by the occluded vein. The venous tributaries often appear narrowed. Occasionally, early hyperfluorescence just proximal to the site of occlusion is observed.[10,45] Retinal edema often appears as diffuse hyperfluorescence on angiography. The edema is commonly found within the area of distribution of the occluded vein. Macular edema often takes on a petalloid pattern typical of cystoid macular edema. When evaluating for macular edema, it is important to note whether capillary perfusion is present. Retinal nonperfusion appears on fluorescein angiography (FA), as areas of capillary hypofluorescence. Neovascularization of the retina or disk appear as early hyperfluorescent, thin, tortuous vessels that leak in the later stages of testing.
COMPLICATIONS
Microvascular changes result in numerous fidings. Leaking vessels lead to retinal edema and deposition of hard exudates. Retinal edema becomes much more visually significant when it involves the fovea (Fig. 132.3). Macular edema is the most common complication, and leading cause of vision loss, associated with BRVO.[10,46] In patients with perfused macular edema, approximately one-third will regain some vision spontaneously. However, this becomes less likely the longer the edema persists. Spontaneous visual improvement is less common in nonperfused macular edema. Interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) have been implicated in the development of macular edema following nonperfused BRVO.[47]
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FIGURE 132.3 A small inferotemporal BRVO. Although the area of affected retina is small, the hemorrhage and edema extend into the fovea and are associated with reduced vision. |
Other microvascular changes result in dilated capillaries, causing formation of microaneurysms and dot-blot hemorrhages.[48,49] Retinal vessels may become fibrosed leading to sheathing. Collateral vessels may develop between an area of nonperfused and an area of perfused retina. Collateral vessels appear as small, tortuous venous channels that cross the horizontal raphe and drain into an uninvolved venous circulation (Fig. 132.4). Collateral vessels are distinct from neovascular vessels in that collaterals are flat while neovascular vessels are elevated; the former do not leak on FA while the latter leak.
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FIGURE 132.4 Appearance of venous collaterals after a BRVO. The channels cross the median raphe temporal to the fovea and drain from the affected to the nonaffected quadrant. |
Retinal hemorrhage is one of the most striking features of BRVO. Intraretinal hemorrhages located within the macula can cause severe vision loss. Vision often will improve as the hemorrhage resolves. Retinal hemorrhages typically resolve over weeks to months, but can persist for years. Hemorrhage blocks fluorescence on angiography and can impair the usefulness of such evaluation. Vitreous hemorrhage, if it occurs, is typically observed later in the course of BRVO. Vitreous hemorrhage may develop after rupture of thin, friable neovascular vessels that grow in response to retinal nonperfusion. The majority of eyes with retinal or disk neovascularization will develop vitreous hemorrhage if left untreated.[10,11,39,42]
Nonperfusion can lead to both early and late complications of BRVO. Early in the course of BRVO, nonperfusion can result in permanent vision loss. The closer the nonperfusion is to the macula, the more significant the visual loss will be. Large areas of persistent retinal nonperfusion can lead to neovascularization of the retina or disk (Fig. 132.5). It is important to recognize that perfused BRVO may progress to the nonperfused type during the ensuing weeks, months and even years after the initial insult.[39,42,44,50]
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FIGURE 132.5 Fluorescein angiogram of a nonperfused BRVO demonstrates widespread capillary nonperfusion and staining of the retinal veins. The two areas of intense hyperfluorescence (arrows) are due to retinal neovascularization. |
The most common site of neovascularization following BRVO is the retina (Fig. 132.6). Optic disk neovascularization is much less common and iris neovascularization is rare in BRVO. When disk neovascularization does occur, retinal neovascularization typically is present as well.[39] Numerous studies have reported a 20-30% incidence of retinal neovascularization following BRVO.[10,20,42,51] The Branch Vein Occlusion Study (BVOS)[42] was a multicentric, randomized, controlled clinical trial designed to answer questions regarding the management of complications of branch vein occlusion. These questions included: 'Can peripheral scatter argon laser photocoagulation prevent the development of neovascularization?', and 'Can peripheral scatter argon laser photocoagulation prevent vitreous hemorrhage?' In the BVOS, retinal neovascularization developed in 22% of all eyes with BRVO. The incidence of retinal neovascularization increased to 36% in eyes with five disk-diameters or more of retinal nonperfusion. Shilling and Kohner reported a 62% incidence of neovascularization among eyes with greater than four disk-diameters of nonperfusion and 0% among eyes with less nonperfusion.[39]Retinal neovascularization typically develops at the border between perfused and nonperfused retina; it rarely develops outside the area of nonperfusion. Neovascular vessels are believed to form in response to the release of angiogenic factors (such as VEGF and IL-6) from nonperfused retina. Retinal neovascularization typically forms in the first 6-12 months following a BRVO; however, it may develop years later also.[51]
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FIGURE 132.6 A tuft of retinal neovascularization (arrow) along the vascular arcade in an eye with long-standing inferotemporal BRVO. |
Tractional retinal detachment (TRD) can form following BRVO if fibrovascular proliferation develops. Rhegmatogenous retinal detachments are a rare complication of BRVO. They typically form following posterior retinal breaks caused by fibrovascular proliferation and traction.[52-55] Nonperfused retina can lead to degeneration and retinal hole formation following BRVO.[55-58] Exudative retinal detachments can occur in the area of occlusion and are usually associated with nonperfusion.[54,59,60]
Other visually significant complications of BRVO include epiretinal membrane formation, retinal pigment epithelial irregularity, and subretinal scarring.[54,59,60]
DIFFERENTIAL DIAGNOSIS
Diabetic retinopathy can present with fidings similar to BRVO with dot-blot hemorrhages, microaneurysms, and neovascularization. In diabetic retinopathy, the retinal fidings are generally bilateral and involve all four quadrants. In BRVO, the retinal hemorrhages are almost always unilateral, except in the infrequent case of a bilateral BRVO. Also, the retinal hemorrhages involve only the sector of retina that is drained by the occluded vein.
Hypertensive retinopathy is another disease that must be considered in the differential diagnosis of BRVO. Distinguishing characteristics of hypertensive retinopathy include bilateral narrowed retinal arterioles and hemorrhages that involve the entire fundus.
Radiation retinopathy may be unilateral or bilateral. A history of irradiation is essential for the diagnosis. Similar to BRVO, disk swelling, disk hemorrhages, retinal neovascularization, and cotton-wool spots may be present.
TREATMENT
The treatment of BRVO is continually evolving. Available data concerning many of the reported treatment modalities are based on case series without controls or randomization. As our understanding of the disease improves, the standard of care is likely to continue to evolve.
Medical Treatment
Evaluation should include a thorough medical history, including past ocular history, review of current medications, and a thorough review of systems. The most common reported risk factors associated with BRVO are systemic hypertension, diabetes, hyperlipidemia, glaucoma, smoking, and age-related atherosclerosis.[10-12,20,39-41] Identifying and treating individual risk factors are important in the early treatment and prevention of future RVO. Systemic evaluation of commonly associated risk factors is an important part of the examination process. Extensive work-up following BRVO is typically not necessary in older individuals as the common risk factors are often elicited on basic screening. However, in patients under age 50 years or with bilateral vein occlusions, a more thorough work-up may be warranted. The primary care physician should be notified when a patient is diagnosed with a BRVO. Initial evaluation may include testing for hypertension, diabetes, and a hypercoagulable state. Initial testing may include a fasting blood glucose level, complete blood count with differential and platelets, coagulation studies, and erythrocyte sedimentation rate. Systemic anticoagulation has not been shown to be of ocular benefit in patients with BRVO and may potentially worsen concurrent or future intraretinal hemorrhage.[61] Further cardiovascular disease evaluation may be needed; however, the primary care physician often is helpful in coordinating this. Follow-up generally consists of ophthalmologic evaluation every 1-3 months for the first year, followed by every 3-12 months thereafter.
Grid Pattern Laser Photocoagulation
In 1984, the BVOS[2] reported the results of a randomized trial of no treatment versus grid laser photocoagulation for treatment of macular edema associated with BRVO in patients with a visual acuity of 20/40 to 20/200. Patients with distinct areas of macular capillary nonperfusion were excluded. At 3 years, 65% of treated eyes gained two or more lines of visual acuity compared to 37% of untreated eyes. The mean visual acuity improvement was 1.3 ETDRS lines in the treated group versus 0.2 lines in the untreated group. Overall, mean visual acuity in the treatment group was 20/40 to 20/50, compared to 20/70 in the untreated group.
Although it is not understood how laser treatment to the retinal pigment epithelium reduces retinal edema, experimental studies in the normal primate have shown a decrease in capillary diameter when this form of therapy is administered.[62] Grid treatment may produce retinal thinning that permits the choroidal vasculature to provide oxygen to the inner retina; this may lead to autoregulatory constriction of the retinal vasculature, which may result in decreased macular edema.
Grid pattern photocoagulation is typically delayed for at least 3 months after the development of a BRVO to allow for spontaneous resolution of edema and intraretinal blood. Treatment may be considered in patients with a visual acuity of 20/40 or worse in the absence of capillary nonperfusion. Grid laser is applied to the area of macular edema. Suggested treatment parameters include argon green laser with a spot size of 50-100 ?m, 0.1 second duration and a power setting sufficient to produce a light to medium white burn. The laser should be focused on the edematous retina within the arcades and the areas of perifoveal capillary leakage as identified by FA. Laser photocoagulation should not be placed over substantial intraretinal hemorrhage, as the nerve fiber layer may be damaged, producing preretinal fibrosis. The fovea should be avoided in the treatment process. When significant intraretinal edema is present, higher laser powers may be necessary for adequate uptake.
Typical follow-up is approximately 8-12 weeks after treatment. If macular edema persists and the acuity and other clinical fidings have not improved, repeat FA is suggested. If residual fluorescein leakage is observed, another session of grid laser photocoagulation may be indicated.[63]
Scatter Laser Photocoagulation
Retinal and disk neovascularization can lead to visually compromising vitreous hemorrhage. The BVOS showed that scatter sectoral laser photocoagulation reduces the risk of developing retinal neovascularization from 22% to 12%. However, the study concluded that treatment should be reserved until after the development of retinal neovascularization. In eyes with retinal neovascularization, subsequent laser photocoagulation reduces the risk of vitreous hemorrhage from 60% to 30%.[2] If vitreous hemorrhage is already present, staged sessions of scatter laser photocoagulation may be necessary, or peripheral cryoablation may be performed. Scatter photocoagulation is not without its own set of complications. Most notably, some patients report peripheral scotoma following scatter photocoagulation,[64] and this has been confirmed with visual field testing showing peripheral visual field loss.[65]
Commonly, scatter laser photocoagulation is applied with the argon green laser to achieve 'medium' white burns (200-500 ?m in diameter) spaced one burn width apart and covering the entire area of capillary nonperfusion, as defied by fluorescein angiogram. Treatment should extend no closer than two disk-diameters from the center of the fovea.
Conventional Pars Plana Vitrectomy for Complications of BRVO
Various studies have shown favorable surgical result in subjects who undergo vitrectomy for complications of BRVO.[57,59,60,66-70] Surgical indications include vitreous hemorrhage, TRD involving the macula, epiretinal membrane, removal of loculated preretinal subhyaloid hemorrhage, removal of subfoveal laser-induced choroidal neovascularization, and complications of ghost cell glaucoma.
Several preoperative clinical features are associated with better postoperative visual acuity outcome, including better preoperative visual acuity, absence of an afferent pupillary defect, and absence of macular edema. The presence of disk neovascularization, retinal tear, or retinal detachment are associated with a less favorable outcome.[67]
Pars Plana Vitrectomy Alone for Macular Edema
Pars plana vitrectomy (PPV) with the creation of a posterior vitreous detachment (PVD) has been reported to be effective in reducing macular edema and improving visual acuity, although the mechanisms that contribute to this have not been elucidated.[71,72] It may not be intuitive that vitrectomy with posterior hyaloid removal alone would improve macular edema, because macular traction is uncommon in eyes with BRVO.[73] However, it has been suggested that removal of the posterior hyaloid by vitrectomy may improve oxygenation of the retina resulting in vasoconstriction and thus decreased vascular leakage and macular edema.[74] Another theory postulates that vitrectomy may facilitate diffusion of harmful cytokines that promote increased vascular permeability, such as VEGF, away from the retina.
Arteriovenous Adventitial Sheathotomy
Most BRVOs are believed to occur at an arteriovenous crossing site, where the arteriole and venule share a common adventitial sheath. Arteriovenous adventitial sheathotomy (AAS) is an attempt to decompress the involved venule by separating the overlying retinal artery from the underlying branch vein by sectioning the shared adventitial sheath. Patients who have macular edema recalcitrant to grid laser photocoagulation may be candidates for AAS.[75]
Numerous nonrandomized studies have demonstrated improved visual acuity, reduction in intraretinal hemorrhage, return of retinal perfusion and reduction of macular edema after AAS surgery.[76-96] In one such series, Mason et al[79] reported a prospective, nonrandomized interventional trial of 40 eyes with decreased visual acuity secondary to BRVO. Twenty of the eyes underwent vitrectomy and surgical decompression by means of arteriovenous sheathotomy with a microvitreoretinal blade and were compared with 20 control eyes (10 observation and 10 grid laser photocoagulation at a mean of 9 months after diagnosis). The mean preoperative visual acuity was 20/250 in the surgical group and 20/180 in the control group (statistically similar in the observation group and laser-treated group). The mean 14 month visual acuity was 20/63 in the surgical group and 20/125 in the control group (P = 0.02). Seventy-five percent of the surgical group halved their visual angle compared with 40% of the control group (40% observation versus. 40% laser; P = 0.025). Average lines of visual acuity gained were 4.55 in the surgical group and 1.55 in the control group (P = 0.0226; 1.1 lines in observation group and laser-treated group). Reported complications include retinal gliosis at the incision site, nerve fiber layer defects, vitreous hemorrhage, retinal tears, retinal detachment and acceleration of nuclear sclerosis.[95] It is important to recognize that AAS has not been investigated in a large-scale, prospective, randomized controlled clinical trial.
Intraocular Corticosteroids
Corticosteroids have been proposed for the management of macular edema due to various retinal vascular disorders. Intravitreal triamcinolone acetonide has been investigated for persistent macular edema in RVO, diabetic retinopathy, chronic uveitis, proliferative vitreoretinopathy, and postsurgical cystoid macular edema.[97-100] The mechanism of action of corticosteroids in the treatment of macular edema in RVO is not entirely clear. Experimental studies have shown that functional and structural changes occur in the retinal capillaries induced by the hypoxic environment after venous occlusion, leading to increased capillary permeability and accompanying retinal edema possibly mediated in part by VEGF, a 45kDa glycoprotein.[35] Triamcinolone has been shown experimentally to reduce the breakdown of the blood-retinal barrier by inhibiting such factors as prostaglandins, interleukins, VEGF and protein kinase C.[101,102]
Small case studies have suggested that there may be a benefit from intravitreal injection of steroids for macular edema and vision loss associated with BRVO.[103-109] Some patients with BRVO may have a favorable anatomical response to this treatment, as demonstrated by optical coherence tomographic (OCT) images, measurements demonstrating reduction in macular thickness, and resolution of the large cystic spaces in the outer plexiform layer within several weeks of injection. However, a favorable visual acuity response may be more likely in patients with perfused rather than nonperfused macular edema. Re-treatment may also be performed in some patients due to recurrent macular edema. A human pharmacokinetics study of nonvitrectomized eyes, found a single 4 mg intravitreal injection of triamcinolone to have a mean half-life of 18.6 days with measurable concentrations expected to last approximately 3 months.[110] Reported side effects include cataract, increased intraocular pressure and injection-related complications including noninfectious and infectious endophthalmitis, retinal detachment, vitreous hemorrhage, and lens injury.
The Standard Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) study is a multicenter, randomized, phase III National Eye Institute-sponsored study that is investigating the efficacy and safety of standard care versus intravitreal injection(s) of triamcinolone for macular edema secondary to BRVO and CRVO.[111] Individuals with BRVO or CRVO with associated macular edema of up to 24 months duration and best-corrected visual acuity between 19 and 73 ETDRS letters (corresponding to approximately 20/40 to 20/400 Snellen visual acuity) are eligible for participation in the SCORE study.
Another prospective randomized study (Posurdex Trial) is underway to evaluate treatment with extended delivery of a bioerodable dexamethasone PLGA (polylactic acid polyglycolic acid) copolymer complex in patients with RVO.
Isovolemic Hemodilution
BRVO has been reported to be associated with hyperviscosity, due to higher hematocrit and plasma viscosity.[112] Higher blood viscosity is less important when blood flow is rapid but in conditions of low flow, as is likely in a vein predisposed to occlusion, the effect of viscosity becomes increasingly significant as a result of increased red cell aggregation. Viscosity is dependent primarily upon the hematocrit (the greater the number of red cells, the larger the aggregates) and plasma fibrinogen (required for aggregation to occur). Studies have demonstrated that hypervolemic[113] or isovolemic hemodilution,[114]commenced within 3 months of the onset of symptoms of a BRVO, accelerates the rate of visual recovery and also has a positive effect on the fial visual acuity at 1 year. However, reported complications of hemodilution include deep-vein thrombosis and hypotension.[115]
Antivascular Endothelial Growth Factor (Anti-VEGF)
Experimental studies have shown that functional and structural changes occur in the retinal capillaries induced by the hypoxic environment after RVO. This can lead to increased capillary permeability and accompanying retinal edema. This appears to be mediated, at least in part, by VEGF, a 45 kDa glycoprotein.[35] Intravitreal VEGF levels have shown to be increased in patients with macular edema with BRVO and are correlated significantly with the area of nonperfusion and the severity of macular edema.[116] The role of anti-VEGF agents in the treatment in BRVO has yet to be determined.
CENTRAL RETINAL VEIN OCCLUSION
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INTRODUCTION
CRVO typically presents in a fairly acute and dramatic fashion, often permitting early diagnosis. Classically, a CRVO presents with marked dilation and tortuosity of the retinal veins, extensive retinal edema, pronounced superficial and deep retinal hemorrhages radiating outward from the optic disk in all quadrants, cotton-wool spots, and optic disk swelling (Fig. 132.7). In its acute phase, the diagnosis is often made with little doubt. In less severe instances or late in the course of the disease, the diagnosis may be less obvious. With time, the dramatic retinal fidings may resolve and the diagnosis may become more difficult.
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FIGURE 132.7 Typical appearance of a fresh central retinal vein occlusion (CRVO), with disk edema, venous dilatation and tortuosity, cotton-wool spots, and retinal hemorrhages in all quadrants. |
In its mildest form, CRVO may consist of only vascular dilatation and tortuosity, disk hyperemia, and a few retinal hemorrhages (Fig. 132.8). In this form, the condition is likely to resolve without sequelae. At the other extreme, there may be nearly confluent retinal hemorrhages, cotton-wool spots, massive retinal and macular edema, and extensive capillary nonperfusion. In the latter cases, one expects to observe severe visual impairment and a tendency for the development of macular edema and anterior segment neovascularization, including neovascular glaucoma.
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FIGURE 132.8 CRVO demonstrates disk hyperemia and venous dilatation and tortuosity, with mild retinal hemorrhages. |
While early diagnosis of a dramatic presentation of a CRVO may not require much effort on the part of the clinician, predicting the clinical course and choosing treatment options can be much more difficult and challenging. The pathogenesis and treatment of CRVO continues to be highly debated. Research continues to direct the understanding and treatment options of the disease.
EPIDEMIOLOGY
CRVO is a relatively common cause of severe vision loss. The majority of patients who develop CRVO are over the age of 50 years and 50-70% have associated hypertension, cardiovascular disease, or diabetes mellitus.[117] Numerous studies have assessed the incidence of CRVO with varying results. In the Beaver Dam Eye Study,[13] the incidence of CRVO was 0.2% during the 5-year follow-up study of 4926 residents of Beaver Dam, WI aged 43-84 years. There was no gender predilection. In the BMES[8] the overall incidence of CRVO was 0.4% with an increasing incidence with age. The BMES also showed no gender predilection.
PATHOGENESIS
The pathogenesis of CRVO is not completely understood, despite being first described by Leibreich in 1855.[118] Numerous theories have been presented over the years, without consensus on the pathogenesis of the disease. Hayreh has suggested that perfused CRVO occurs after occlusion of retinal venous flow, while nonperfused CRVO develops after occlusion of venous and arterial flow. His studies were based on animal models with occlusion of the retinal vessels at their entry into the optic nerve.[83-85] However, Fujino's pathologic studies found that occlusion of the retinal vein alone could produce clinical fidings similar to nonperfused CRVO.[86]
Green et al reported a histopathologic study which supports the theory of thrombus formation as the inciting event causing CRVO.[87] In this study, a fresh or a re-canalized thrombus was observed in 29 eyes from 29 patients with CRVO. The study considered the temporal aspects (6h to 10 years from onset) of the cases, and noted the different morphologic features of the occlusion. These observations explain most of the variability of the changes observed in previous reports and are likely to be associated with the evolution of the thrombus. Endothelial cell proliferation was a conspicuous feature in 14 (48.3%) of the eyes, chronic inflammation in the area of the thrombus and/or vein wall or perivenular area was observed in 14 (48.3%), arterial occlusive disease in seven (24.6%), and cystoid macular edema in 26 (89.7%) of the eyes. Most of the eyes included in the study had chronic, nonperfused CRVO and had been enucleated for neovascular glaucoma. The few recent-onset occlusions occurred in patients in the terminal stages of severe systemic disease. Eyes with recent-onset and perfused CRVOs were underrepresented in this series.
The reason that thrombus formation tends to occur in the region of the lamina cribrosa is unknown. The close anatomic association of the central retinal artery and the central retinal vein in this region, as well as the narrowing of the central retinal vessels as they pass through the lamina cribrosa, may contribute to turbulent flow and thrombus formation.[119]
Numerous risk factors for CRVO have been identified, including systemic, ocular, and localized abnormalities. A concurrent systemic disease is present in at least half of the patients. The Eye Disease Case-Control Study found an increased risk of either type of CRVO in persons with systemic hypertension and diabetes mellitus.[120] Other studies have shown that approximately 60% of patients diagnosed with CRVO have a history of hypertension. Vasculitis associated with diseases such as sarcoid, syphilis, systemic lupus erythematosus is also a risk factor. Retrobulbar external compression from thyroid disease or orbital tumor also increases the risk of CRVO.[25,121-126]
Systemic disease appears to play a significant role in CRVO development. Atherosclerosis has been reported to be a major risk factor for CRVO development. One theory is that atherosclerosis of the adjacent central retinal artery compresses the central retinal vein in the region of the lamina cribrosa, secondarily inducing thrombosis in the lumen of the vein. Younger patients with CRVO have been reported to have an increased risk of cardiovascular death and collagen vascular disease.[121,127,128] However, much of these data have come from case series without control groups. Elman compared the prevalence of hypertension, diabetes, cardiovascular and cerebrovascular disease, and mortality among CRVO patients and a control group from the Wilmer Ophthalmological Institute and another control group from a national survey.[129] He found a higher prevalence of hypertension in the CRVO patients when compared to both control groups, but diabetes was more prevalent only when compared with the national survey control group. Rates of cardiovascular disease, cerebrovascular disease, and mortality did not differ significantly among the groups. When comparing with a general ophthalmology patient population, Rath found a higher association of CRVO with male gender, systemic hypertension, and open-angle glaucoma.[126] Elevated serum lipid levels have also been reported to be associated with increased risk.[125,130] The Eye Disease Case-Control Study Group compared patients with CRVO to age-matched controls. There was a higher cardiovasacular risk profile, which included hypertension or diabetes, less physical activity, and decreased alcohol consumption, among patients with CRVO. The association was more significant in patients with nonperfused rather than perfused CRVO. In women, the risk increased with higher erythrocyte sedimentation rates and decreased with use of postmenopausal estrogen.[120]
Certain hematologic abnormalities are risk factors for CRVO, especially in young adults. Thrombophilic factors have been shown to be associated with an increased risk of RVO. Hyperhomocysteinemia appears to be one of the most common and significant thrombophilic risk factors for development of CRVO. Less evidence exists for Factor V Leiden mutation, protein C and S deficiency, antithrombin deficiency, antiphospholipid antibodies, activated protein C resistance, prothrombin gene mutation, anticardiolipin antibodies, abnormal fibrinogen levels, and lupus anticoagulant.[120,131-148]
Homocysteine is a naturally occurring molecule in the body and is required in several reactions that occur within the cells. If the pathways to either cysteine or methionine are blocked, then homocysteine levels may rise. A patient who is heterozygous for this mutation has no evidence of hyperhomocysteinemia or increased risk of thrombotic disorders. Patients who are homozygous for the defect can develop hyperhomocysteinemia. Additionally, deficiencies in vitamin B6 and folate can lead to increased levels of homocysteine. Other causes include certain medications and kidney disease. The prevalence of hyperhomocysteinemia in the general population is not known. Hyperhomocysteinemia can be treated with vitamin supplementation; folate and vitamin B12 have shown to decrease serum homocysteine levels. However, there is no convincing data that decreasing homocysteine levels with vitamin supplementation will reduce the risk of CRVO.[143,144,148]
Protein C is a naturally occurring anticoagulant. Protein C deficiency is a rare cause of RVO; however, activated protein C resistance is the most common identifiable cause of systemic venous thrombosis.[149,150] The inheritable condition is transferred in an autosomal dominant pattern. While systemic levels of protein C are normal, the usual anticoagulation response is abnormal leading to increased thrombosis. One study of 31 patients younger than 50 years with a CRVO found that 26% of the subjects had activated protein C resistance, compared with 2-7% in the general population.[151] Some studies have suggested that factor V Leiden is a risk factor for the development of CRVO in patients younger than 60 years of age,[152,146] however, other studies have not supported this notion.[140,145]
Lupus anticoagulant factor is a circulating immunoglobulin that may cause mild prolongation of coagulation studies, especially partial thromboplastin time, but paradoxically is associated with thrombosis. This factor can be seen in some patients with systemic lupus, but can be present in the absence of lupus. Patients with this factor frequently test positive for antiphospholipid antibodies, including anticardiolipin, and may test falsely positive on Venereal Disease Research Laboratory (VDRL) testing. Systemic manifestations of the disease include retinal vein, retinal artery, and choroidal occlusions as well as spontaneous abortions and systemic occlusions.[149,153-158]
Hyperviscous states such as elevated hematocrit, increased erythrocyte aggregation, decreased erythrocyte deformability, elevated fibrinogen, dehydration, polycythemia, lymphoma, leukemia, sickle cell disease, multiple myeloma, cryoglobulinemia, and Waldenstrom macroglobulinemia have been associated with CRVO.[159-161] Common medications that can contribute to hematologic abnormalities that may increase the risk of CRVO include diuretics and oral contraceptives. Abnormal platelet function can also contribute to CRVO formation. Some have speculated that increased blood viscosity may increase the risk of nonperfused CRVO.[112,125,132,162-164]
Certain ocular fidings have been shown to be risk factors for CRVO; however, the mechanism affecting the risk of CRVO is poorly understood. An increased risk has been noted in eyes with open-angle glaucoma. In uncontrolled studies, 40% of patients with CRVO had preexisting open-angle glaucoma, or developed glaucoma during follow-up.[165,166] The Eye Disease Case-Control Study found that patients with a CRVO were five times more likely than age-matched controls to have either glaucoma or an intraocular pressure greater than 20 mmHg.[120]
Other ocular fidings associated with increased risk of CRVO include increased cup-to-disk ratio (independent of glaucoma and increased introcular pressure),[167] ischemic optic neuropathy, tilted optic nerve head, optic nerve head drusen, optic disk traction syndrome, pseudotumor cerebri, external compression of the optic nerve and globe from thyroid-related ophthalmopathy, and mass lesions or head trauma with orbital fracture.[117]
Systemic workup is a vital part of the examination process if no identifiable risk factor is known. Many of the risk factors for CRVO are treatable systemic diseases that, if left untreated, can result in high morbidity and mortality. Common diseases associated with CRVO include hypertension, diabetes mellitus, and atherosclerosis.[25,120-126,129] However, other diseases should be considered, especially in persons younger than 56 years of age and in those with bilateral CRVO. In general, further work-up is not indicated in persons older than 55 years of age with known systemic vascular risk factors for CRVO.[168,169]
CLINICAL FEATURES
Historically, confusion has existed regarding the classification of CRVO subtypes. In 1904, Coats was the first to describe two types of CRVO. He recognized that one group of patients often had marked vision loss and a poor prognosis, while another group had much less visual disturbance and had a better prognosis.[170] With the advent of FA, these two types of CRVO were then classified based on retinal capillary perfusion characteristics. Multiple terms have been used in an attempt to differentiate the two clinical pictures. Terms used to refer to the more severe type include 'hemorrhagic retinopathy', 'complete', 'nonperfused', or 'ischemic CRVO'. Conversely, the more benign type has been referred to as 'venous stasis retinopathy', 'partial', 'perfused', or 'nonischemic'.[8] Our discussion will use the terms perfused and nonperfused. It is important to understand the distinguishing features of the two groups in order to guide patient counseling, understand prognosis, and guide treatment (Table 132.2).
TABLE 132.2 -- Common Clinical Findings in CRVO
|
Test |
Perfused |
Nonperfused |
|
Fluorescein angiogram |
Uniform capillary fluorescence |
Patchy capillary hypoflouresence |
|
Afferent papillary defect |
Minimal/absent |
Present |
|
Visual acuity |
>20/400 |
<20/400 |
|
Electroretinogram |
Normal/supernormal |
Delayed |
|
Risk of neovascularization |
Low risk |
High risk |
A common presenting symptom in CRVO is abrupt decrease in vision. However, some patients will describe transient vision loss lasting a few seconds to minutes over the preceding days to weeks. Some patients will report symptoms of photophobia and red eye; however, these symptoms, if present, typically last for a few days to weeks only. Rarely, presenting symptoms include pain, blurry vision from corneal haze, and increased intraocular pressure. These patients may have a subacute or chronic CRVO that has not been detected and has resulted in the more severe complication of neovascular glaucoma.
Initial evaluation should include distinguishing between perfused and nonperfused CRVO. Typically, two-thirds of all CRVOs are perfused, while the remaining one-third are nonperfused.[51,121,171] Clinical examination combined with FA are most commonly used to differentiate between the two broad categories. Electrophysiologic testing and visual field testing may also be helpful in the evaluation process when FA cannot demonstrate the extent of nonperfusion (e.g., in cases with extensive intraretinal hemorrhage). Serial monitoring of the CRVO subtype is important during follow-up examinations, as up to one-third of perfused CRVOs progress to nonperfused over the course of the disease.[4,51,121,123,172] The Central Vein Occlusion Study (CVOS)[4-6] was a multicentric, international clinical trial sponsored by the National Eye Institute evaluating 725 patients and 728 eyes with CRVO followed at least 3 years. Eyes were entered into four predefied study groups: perfused, nonperfused, indeterminate, and macular edema. The CVOS reported that in the first 4 months of follow-up, 81 (15%) of the 547 eyes with perfusion converted to nonperfusion. During the next 32 months of follow-up, an additional 19% of eyes were found to have converted to nonperfusion for a total 34% after 3 years. Risk factors for progression include worse presenting visual acuity, severe macular edema, and progressive intraretinal hemorrhage.[172]
Nonperfused CRVO is often more dramatic in its presentation and is associated with a worse visual outcome than perfused CRVO.[119] The nonperfused type typically presents with multiple cotton-wool spots, extensive retinal hemorrhage, a relative afferent pupillary defect, visual acuity worse than 20/400, widespread capillary nonperfusion on FA, and abnormal electroretinography (ERG) testing. One of the great difficulties in evaluating CRVO is understanding the risks associated with varying degrees of retinal nonperfusion. Retinal nonperfusion rarely occurs throughout the entire fundus. Often, only certain areas appear nonperfused on evaluation. Retinal hemorrhage may prevent correct quantification of retinal nonperfusion due to blockage of fluorescence in the area of hemorrhages. Although no standard criteria have been established, the CVOS defied 'ischemia' (synonymous with nonperfusion in our discussion) as 10 or more disk areas of nonperfusion on FA.
Perfused CRVO typically has mild fundus changes, no afferent pupillary defect, visual acuity better than 20/400, less extensive capillary nonperfusion on FA, and nearly normal ERG testing. Ocular neovascularization rarely develops in perfused CRVO eyes and visual prognosis is generally more favorable.
A complete ocular examination, including intraocular pressure measurement, slit-lamp biomicroscopy, gonioscopy to rule out neovascularization of the iris or angle, and a dilated fundus examination is recommended at the initial presenta-tion and at monthly follow-up examinations during the first 9 months. Neovascularization of the iris or angle is an ominous sign of potential development of neovascular glaucoma.
Visual Acuity
There is wide variability in visual acuity following a CRVO; however, the presenting visual acuity is highly predictive of fial visual outcome. Visual acuity can range from 20/20 to hand motion, or even no light perception in those with end stage neovascular glaucoma. The CVOS[4-6] reported that in 65% of patients with presenting visual acuity better than 20/40, the vision remained stable. Patients with poor visual acuity at presentation (<20/200) had an 80% chance of having a visual acuity worse than 20/200 at the fial visit.
Visual acuity can be helpful in distinguishing perfused versus nonperfused CRVO. Patients with perfused CRVO tend to have better visual acuity; however, vision may still be quite poor due to macular edema or other complications.[51,121,122] While poor visual acuity can be seen in either perfused or nonperfused CRVO, relatively good initial visual acuity is suggestive of perfused CRVO. Hayreh reported a visual acuity better than 20/200 (6/60) in 58% of the eyes with perfused CRVO, as compared to only 1.7% of eyes with nonperfused CRVO. A visual acuity better than 20/400 (6/120) was measured in 81% of eyes with perfused CRVO, compared to about 7% of the eyes with nonperfused CRVO. A visual acuity of 20/400 or worse was measured in only 19% of the eyes with perfused CRVO, compared to 93% of the eyes with nonperfused CRVO.[119]
Afferent Pupillary Defect
Evaluation for a relative afferent pupillary defect can be helpful in distinguishing perfused and nonperfused CRVO. Eyes with nonperfused CRVO are much more likely to have a relative afferent pupillary defect. Ninety percent of eyes with perfused CRVO were found to have a relative afferent pupillary defect of 0.3 log units or less. However, 91% of eyes with nonperfused CRVO had a relative afferent pupillary defect of 1.2 log units or more.[173]
Intraocular Pressure
Relative intraocular pressure difference is less helpful in the evaluation process. However, immediately after CRVO, the intraocular pressure is typically slightly lower in the affected eye as compared to the fellow eye. This relative difference in intraocular pressure diminishes with time, and symmetry returns over the ensuing weeks to months.[174]
Visual Field Testing
Visual field testing is widely variable in CRVO, but may be beneficial for better understanding the patient's visual perception. Abnormalities are more common and more severe in eyes with nonperfused rather than perfused CRVO.[175]
Fluorescein Angiography (FA)
FA can be very helpful in evaluating the extent and mechanism of retinal dysfunction based on perfusion characteristics. The characteristic fidings in CRVO are due to changes in vascular caliber, vascular permeability, and capillary nonperfusion. Wide-angle FA using a 60° fundus camera is helpful in evaluating peripheral retinal perfusion. The overall arterial perfusion time after injection is normal to slightly delayed in CRVO; however, the delay in arteriovenous transit time is typically significantly delayed (Fig. 132.9).[43] A delay beyond 20 seconds is associated with a greater risk of iris neovascularization.[123]Nonperfused areas may be visualized as patchy areas of hypofluorescence with a ground-glass appearance (Fig. 132.10). Staining of the walls of the retinal veins has been demonstrated to be an indicator of nonperfusion. Retinal capillary nonperfusion is an important feature in identifying those eyes at greatest risk of developing neovascularization.[171,176,177] There are no defiite guidelines for assessing the risk of neovascularization; however, the CVOS used 10 disk diameters of nonperfusion as its cut-off for predicting risk.[4] The location of the nonperfusion is also important in terms of predicting long-term visual potential. Nonperfusion near the fovea is associated with worse visual prognosis. Overlying retinal hemorrhage may impede the ability to evaluate the underlying capillary perfusion status.
|
|
|
|
FIGURE 132.9 Delayed filling of the retinal venous system in a CRVO. This frame, taken 14 s after the appearance of fluorescein in the retinal arteries, shows minimal filling of the retinal venous system. |
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|
|
|
FIGURE 132.10 Fluorescein angiogram of a profoundly nonperfused CRVO. Note the nearly complete absence of retinal capillaries. |
FA is also helpful in evaluating causes of central vision loss. Central vision loss is common following CRVO and can be the result of macular edema, parafoveal capillary nonperfusion, intraretinal hemorrhage, or retinal pigment epithelial damage due to deep retinal or subretinal hemorrhage. In macular edema, FA shows parafoveal and paramacular capillary leakage that appears as hyperfluorescence that increases in size and intensity with time, often in a petalloid type pattern. The hyperfluorescence persists longer than that of normal retinal tissue. Hemorrhage causes persistent blocking of the fluorescence throughout the angiographic evaluation.
Electrophysiologic Testing
Electrophysiologic testing with electroretinogram (ERG) may be helpful in distinguishing between perfused and nonperfused CRVO.[178] Matsui et al reported that the ERG b/a-wave amplitude ratios, photopic and scotopic b-wave amplitudes, and flicker amplitudes were significantly smaller in eyes with extensive capillary nonperfusion, than in eyes without. When the photopic or scotopic b-wave amplitudes were normal or supernormal, extensive capillary nonperfusion on FA was absent in all eyes. When the b/a-wave ratios were greater than or equal 1.0, or when the b-wave amplitudes with white flash or flicker amplitudes were normal or supernormal, extensive capillary nonperfusion was present in less than 32% of eyes. When the b/a ratio was less than one, there was a higher probability of retinal nonperfusion and a higher risk of developing iris neovascularization.[179]
Optical Coherence Tomography (OCT)
OCT is a helpful tool in evaluating the macula following CRVO. The OCT can aid the clinician in evaluating macular edema, epiretinal membrane formation, and subretinal fluid accumulation following CRVO.[180,181]
COMPLICATIONS
The clinical course after a CRVO is highly variable. The retinal hemorrhages and microaneurysms may resolve over weeks or may persist for years. The Blue Mountains Eye Study reported a 10% incidence of residual retinopathy lesions (microaneurysms, hemorrhages, hard or soft exudates) at the 5 year follow-up in nondiabetic patients.[182] Macular edema may resolve quickly, persist chronically, vary intermittently, or develop late in the course of the disease. Neovascularization typically occurs on the iris in CRVO; however, neovascularization may develop on the disk and, or retina. Fundus neovascularization very rarely develops in eyes with perfused CRVO.[8,121,123,176,183,184] If neovascularization develops, it usually is present within the first 7 months of the CRVO. The venous dilatation and tortuosity typically resolve with time, and marked fibrous sheathing of the retinal veins and arteries may develop. The disk swelling slowly resolves and may develop disk pallor in nonperfused cases. Collateral vessels at the optic disk may develop.
Macular dysfunction is common following CRVO. The visual disturbances may be transient or chronic. A common cause of macular dysfunction is retinal edema. Retinal edema may develop from abnormal vascular permeability following CRVO in any part of the retina. It often presents as a petalloid pattern of cystoid macular edema.[180] Severe macular edema is a risk factor for progression of perfused CRVO to nonperfused.[172] The exact mechanism causing the leakage is unknown, but may be due to vascular congestion, capillary damage, or localized inflammatory reactions.
Serous retinal detachment has also been described following CRVO. With the advent of better cross-sectional retinal imaging using OCT, serous retinal detachments are reported to occur more frequently than recognized previously.[181]
Microaneurysms are a common fiding following CRVO (Fig. 132.11). Less commonly, macroaneurysms may develop.[48] Hard exudates are a less common fiding following CRVO. Large amounts of hard exudates are associated with nonperfusion, poor visual acuity, and elevated serum triglyceride levels.[185,186] The hard exudates typically resolve with time. Retinal hemorrhage can vary in its presentation; however, at least mild retinal hemorrhage is virtually always present following CRVO. The location of the hemorrhage is typically intraretinal and superficial. Occasionally, vitreous hemorrhage may develop following an acute CRVO; vitreous hemorrhage is usually a result of neovascularization of the retina or disk at a later stage of the disease.
|
|
|
|
FIGURE 132.11 Large capillary aneurysms that occurred after a CRVO. Peripheral to the aneurysms is a large area of nonperfusion. |
Iris and angle neovascularization are dreaded complications of CRVO because of the risk of developing neovascular glaucoma. Neovascular glaucoma often leads to intractable elevated intraocular pressure, blindness, and extreme eye pain. Evisceration or enucleation, is all too often the fial treatment option once neovascular glaucoma becomes medically uncontrollable. Of those that develop neovascular glaucoma, 66-71% do so within the first 6 months of CRVO development. The incidence of rubeosis among all CRVOs is approximately 20%. Among non-perfused eyes, the incidence is 45-80%. In perfused eyes, the rate of iris neovascularization is one to ten percent. Of eyes that develop iris neovascularization, approximately two-thirds will develop neovascular glaucoma without treatment.[51,121,123,176,183] Early treatment of neovascularization of the iris with PRP results in resolution of the iris neovascularization in approximately two-thirds of the cases.[187] VEGF appears to play an important role in the development of neovascularization and macular edema. Hypoxia-induced upregulation of VEGF may be an important factor in retinal ischemia with iris and retinal neovascularization in CRVO. Upregulation of VEGF production appears to occur most consistently in the inner nuclear layer in hypoxic retina.[188-190]
The clinician must take care not to confuse disk neovascularization with optociliary shunt vessels of the disc. Optociliary shunt vessels develop commonly following CRVO (Fig. 132.12). The vessels form as collateral channels between the retinal and ciliary circulations. The shunt vessels are typically larger in caliber and do not leak on FA as compared to typical disk neovascularization. Opinions differ as to whether optociliary vessel formation is associated with an improved visual prognosis;[121,127,191,192] there may be a decreased risk of developing anterior segment neovascularization in eyes with retinochoroidal collateral vein formation.[167]
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|
|
|
FIGURE 132.12 Typical, tortuous appearance of disk collaterals after a CRVO. |
DIFFERENTIAL DIAGNOSIS
Diabetic retinopathy can present with fidings similar to CRVO with dot-blot hemorrhages and microaneurysms. However, in diabetic retinopathy, the retinal fidings are generally bilateral, compared with CRVO, in which the insult is typically unilateral. Bilateral CRVO is an uncommon presentation.
Ocular ischemic syndrome due to carotid occlusive disease must also be distinguished from CRVO. In the ocular ischemic syndrome the veins are similarly dilated and irregular, but are not as tortuous as those seen in CRVO. Neovascularization of the disk may be present in either disease without disk swelling or hemorrhages. Retinal hemorrhages are typically seen in the mid-periphery in ocular ischemic syndrome. Patients with ocular ischemic syndrome may have a history of amaurosis fugax, transient ischemic attacks, or orbital pain. Intraocular pressure may be low.
Papilledema may present similarly to CRVO. Disk swelling is generally bilateral due to increased intracranial pressure. Similar disk hemorrhages may be observed; however, the hemorrhages are generally localized to the optic disk with papilledema and typically do not involve the peripheral retina.
Radiation retinopathy may be unilateral or bilateral. A history of irradiation is essential for the diagnosis. Similar to CRVO, disk swelling, disk hemorrhages, retinal neovascularization, and cotton-wool spots may be present.
Hypertensive retinopathy also may be considered in the differential diagnosis of CRVO. Distinguishing characteristics of hypertensive retinopathy include narrowed retinal arterioles and bilateral involvement of the retinal hemorrhages.
TREATMENT
Medical Treatment
Identification and treatment of systemic vascular risk factors in conjunction with the internist is important in individuals with CRVO. In general, a systemic workup is not indicated in persons older than 55 years of age with known systemic vascular risk factors for CRVO.[168,169] If no known systemic vascular risk factor is present, initial investigation may include checking blood pressure, intraocular pressure, complete blood count, glucose levels, and a lipid panel on all patients with CRVO. More extensive evaluation may be considered if the initial screen does not reveal the presence of a systemic risk factor. The role of systemic anticoagulation in CRVO is unclear, as there is no evidence that agents such as aspirin, heparin or warfarin prevent or alter the natural history of CRVO. Patients taking warfarin have been reported to develop CRVO despite maintaining therapeutic levels of anticoagulation.[193] Limited data suggests that systemic hemodilution and/or pentoxifylline (lowers blood viscosity) may be beneficial in improving visual acuity and macular edema, and reducing the risk of progression to ischemic CRVO.[194,195]
Laser Photocoagulation
One of the most feared complications of CRVO is neovascular glaucoma. Early signs of developing neovascular glaucoma include neovascularization of the iris and angle. The CVOS[4-6] found that the most important predictive factor of iris neovascularization in CRVO is poor visual acuity. Other risk factors identified included increasing amounts of retinal capillary nonperfusion and intraretinal blood. The study found that, prophylactic PRP decreased the risk of iris neovascularization compared to untreated eyes, but the difference was not statistically significant. Laser treatment after the development of iris or angle neovascularization was followed by prompt regression (within 1 month) in 18 (56%) of 32 previously untreated eyes and in four (22%) of 18 eyes that had undergone prophylactic PRP. The authors recommended PRP be delivered promptly after the development of iris or angle neovascularization in eyes with nonperfused CRVO. Hayreh et al conducted a prospective, study of argon laser PRP in nonperfused CRVO over a 10 year period in 123 eyes. On comparing the laser-treated eyes versus the eyes not treated by laser, there was no statistically significant difference between the two groups in the incidence of development of angle neovascularization (NV), neovascular glaucoma (NVG), retinal and/or optic disk NV, or vitreous hemorrhage, or in visual acuity. The study, however, did show a statistically significant (P = 0.04) difference in the incidence of iris NV between the two groups, with iris NV less prevalent in the laser group than in the nonlaser group, but only when the PRP was performed within 90 days after the onset of CRVO.[196] The delivery of PRP before the development anterior segment neovascularization may be considered in eyes with nonperfused CRVO when monthly ophthalmologic examination is not possible. However, 20% of these patients will develop iris-neovascularization despite laser photocoagulation treatment. It should be kept in mind that some patients who undergo PRP will have permanent peripheral visual field defects following treatment.[196]
Patients with CRVO who present with neovascular glaucoma should undergo PRP, or, if the media is hazy, cryoablation. Topical intraocular pressure lowering drugs should be given and a surgical glaucoma procedure may be indicated.
The CVOS also studied the effectiveness of grid pattern argon laser photocoagulation in improving visual acuity in eyes with perfused macular edema and 20/50 acuity or worse. Laser treatment involved a grid pattern in the area of leaking capillaries within two disk diameters of the foveal center but not within the foveal avascular zone. There was no significant difference in mean visual acuity between treated (20/200) and untreated (20/160) eyes at 36 months. There was angiographic resolution of the macular edema by 1 year in 31% of treated eyes (compared with 0% of untreated eyes), but there was a lack of visual recovery likely secondary to widespread damage to the perifoveal capillary network. Therefore, the CVOS did not recommend grid laser photocoagulation for CRVO-associated macular edema. However, in the younger patients there was a trend toward improved visual acuity in the treatment group. This possibly was not statistically significant given the small sample size.
Chorioretinal Venous Anastomosis
Laser-induced chorioretinal venous anastomosis was initially described by McAllister and Constable.[197] The goal is to bypass the occluded vein in perfused CRVO. Overall, the treatment consists of producing an intense focal laser burn directed at or near a tributary vein in an attempt to disrupt the wall of the vein and rupture underlying Bruch's membrane.[198,199] Various laser wavelengths have been employed, including argon green, argon blue-green, dye yellow, and Nd-YAG. Successful anastomosis formation is achieved in 33-100% of cases with variable visual function recovery.[197,198,200-202]However, the treatment is associated with complications in up to 67% of cases; these complications include posterior vitreous detachment, choroidal or vitreous hemorrhages, preretinal fibrosis, choroidal neovascularization, segmental retinal ischemia, choriovitreal neovascularization, and retinal detachment.[197,198,200-206]
Some surgeons have attempted to create a successful chorioretinal venous anastomosis by means of surgery, especially in nonperfused CRVO.[207,208] This technique may offer improved visual status in eyes with perfused CRVO and BRVO, but the precise treatment variables and method to reliably create an anastomosis while minimizing complications have yet to be determined.
Conventional Pars Plana Vitrectomy for Complications of CRVO
Pars plana vitrectomy techniques are often employed to address complications of CRVO, especially nonclearing vitreous hemorrhage.[209] At the time of vitrectomy, evacuation of the hemorrhage can be combined with removal of epiretinal membranes and endolaser photocoagulation if warranted.
Pars Plana Vitrectomy for Macular Edema
Some authors believe that the absence of posterior vitreous detachment can contribute to the occurrence or the persistence of macular edema in CRVO and that relieving the vitreous traction over the macula by means of vitrectomy-induced posterior vitreous detachment may assist in improving the macular edema.[71,209,210] Sekiryu et al[211] reported on five patients with macular edema caused by CRVO that were examined using OCT. The retinal thickness through fixation was reduced in all five eyes. Preoperatively, the retina thickness at the foveola was more than 500 ?m in three eyes and more than 1000 ?m in two eyes. The retina thickness was reduced to 311+/- 80 ?m within 2 weeks on average. Visual acuity was improved by two or more lines in three of five eyes.
Radial Optic Neurotomy
Opremcak et al[212] hypothesized that the pathogenesis of CRVO may be similar to 'compartment syndromes' elsewhere in the body, where pressure within a confied space results in tissue ischemia. According to this hypothesis, an anatomic 'bottleneck' exists at the lamina cribrosa where the central retinal artery, central retinal vein and optic nerve lie within a 1.5 mm-diameter area with dense connective tissue encircling these structures, restricting the central retinal vein luminal diameter.[213] Optic nerve sheath decompression was initially attempted using an external approach by Vasco-Posada[214] and Arcienigas.[215] More recently, Opremcak proposed radial optic neurotomy to achieve the decompression of the scleral outlet via an internal, vitreoretinal approach.[212] Such a surgical approach was performed in 11 cases, achieving visual acuity improvement in eight cases (73%). Seven of the 11 eyes (64%) achieved a fial visual acuity of 20/200 or better, and five (45%) achieved a fial acuity of 20/70 or better. No significant complications were observed postoperatively. Other authors have noted varying degrees of clinical improvement following surgical radial optic neurotomy including a decline in macular edema and decreased or resolved intraretinal hemorrhages.[216-220] However, others have reported no statistically significant improvement of vision following the procedure.[221,222] Reported complications associated with this procedure include optic nerve damage, vitreous hemorrhage, subretinal hemorrhage, peripapillary retinal detachment, choroidal neovascularization, and temporal visual field defect.[223-230]
Tissue Plasminogen Activator
Thrombolytic agents have been proposed as a treatment directed against a suspected thrombus in the central retinal vein. Recombinant tissue plasminogen activator (r-tPA) is a synthetic fibrinolytic agent that converts plasminogen to plasmin and destabilizes intravascular thrombi. Reduction in clot size may facilitate dislodging of the entire thrombus or re-canalization of the occluded retinal vein. As therapy for CRVO, r-tPA has been administered by several routes: systemic, intravitreal, subretinal and via endovascular cannulation of retinal vessels.
Systemic administration of low-dose (50 mg) front-loaded r-tPA has been attempted in two pilot studies with visual acuity improvement in 30-73% of patients.[229,231] However, this treatment has been associated with serious complications, including patient mortality, which have curbed the use of systemic administration of r-tPA for CRVO.
Intravitreal delivery of r-tPA has potential advantages including directed delivery to the retinal vessels as well as decreased risk of ocular and systemic complications. Of 47 persons in three studies of intravitreal r-tPA for both ischemic and nonischemic CRVO of less than 21 days duration, 28-44% experienced three lines of visual acuity improvement with 6 months follow-up.[232-234] However, the significance of the visual outcome is severely limited, as none of the studies included a control group. Administration of r-tPA did not significantly alter fial perfusion status. Ghazi et al reported intravitreal r-tPA in 12 eyes with acute nonperfused CRVO of less than 3 days duration.[235] In all eyes, perfusion status remained unchanged at last follow-up. Nine patients (75%) had best-corrected visual acuity of 20/200 or worse at presentation compared with four patients (33%) at the last follow-up after treatment. Five (55%) of these nine patients had fial visual acuity that improved to 20/50 or better. The remaining four patients did not have improvement or their vision continued to worsen. Overall, eight (67%) of 12 patients had a fial visual acuity of 20/50 or better. No side effects related to tPA injection were observed. This report suggests that prompt use of intravitreal r-tPA, especially in perfused CRVO, may provide significant visual improvement, although study limitations, such as the lack of a control group, preclude defiitive conclusions to be drawn.
Lam et al[236] reported subretinal peripapillary tPA injection with vitreopapillary and epipapillary membrane dissection and peripheral photocoagulation in a patient with unresolved CRVO at 4 months with a modest improvement of visual acuity from figer counting to 20/400. Endovascular delivery of r-tPA involves cannulation of retinal vessels, either through a neuroradiologic[237] or a vitreoretinal approach[238-240]and allows for delivery of minute quantities of r-tPA directly to the occluded vessels. Retinal endovascular surgery (REVS) involves vitrectomy followed by insertion of a microcannula into branches of the retinal vasculature with injection of pharmacologic agents such as tPA. Weiss and Bynoe have reported their technique of pars plana vitrectomy followed by cannulation of a branch retinal vein with injection r-tPA toward the optic nerve head.[239] Of 28 eyes with CRVO of greater than 1 month duration and worse than 20/400 preoperative acuity, 50% recovered more than three lines of acuity with a mean follow-up of 12 months. There was a trend toward increased perfusion on FA attributed in part to the resolution of intraretinal hemorrhages after the procedure. Complications included vitreous hemorrhage in seven eyes and retinal detachment in one eye.
Intraocular Corticosteroids
High-dose oral corticosteroids have been reported to be associated with a transient reduction in macular edema with improved vision over the short term in a small number of patients with CRVO, but were associated with systemic side effects and recurrence of macular edema.[242] Small case studies have suggested that there may be a transient benefit from intravitreal injection of steroids for macular edema and vision loss associated with CRVO.[243-251] The outcome appears to be dependent on whether the CRVO is perfused or nonperfused. One such study by Ip et al[248] reviewed the medical records of 13 consecutive patients (13 eyes) with macular edema associated with CRVO who were treated with an injection of intravitreal triamcinolone acetonide (4 mg) at the University of Wisconsin and the Bascom Palmer Eye Institute. Each intravitreal injection was delivered through the pars plana using a 27- or 30-gauge needle. The median age of the 13 patients was 67 years (interquartile range, 57-77 years), and the median duration of symptoms before injection was 8 months (interquartile range, 4-9 months). Mean baseline visual acuity was 20/500 in the affected eye. Mean visual acuity at the 6 month follow-up examination was 20/180 in the affected eye. All 13 patients completed the 6 month examination. Eyes with perfused CRVO (n = 5) demonstrated a significant improvement in visual acuity, whereas eyes with nonperfused CRVO (n = 8) demonstrated a nonsignificant visual acuity improvement. No patient had a decrease in visual acuity. Mean baseline foveal thickness as measured by OCT was 590 ?m (retinal thickening = 416 ?m). Mean foveal thickness as measured by OCT at the 1 month follow-up examination in 12 patients was 212 ?m (retinal thickening = 38 ?m). Between the 3- and 6-month follow-up examinations, four patients developed a recurrence of macular edema. Three of the four patients were retreated with a second injection of triamcinolone. Two of these three patients experienced an improvement in visual acuity following retreatment. At the 6 month follow-up examination, mean foveal thickness as measured by OCT for 13 patients was 281 ?m (retinal thickening = 107 ?m).
The mechanism of action of corticosteroids for macular edema in CRVO is not clear and has been discussed above with BRVO. Most patients with CRVO, both nonperfused and perfused, may have a favorable anatomical response to this treatment as demonstrated by OCT images and measurements demonstrating reduction in macular thickness and resolution of the large cystic spaces in the outer plexiform layer within several weeks of injection. However, a favorable visual acuity response appears more likely in patients with perfused CRVO. Re-treatment may also be necessary in some patients due to the recurrence of macular edema. There may be intravitreal steroid-related adverse events (including cataract and increased intraocular pressure) and injection-related adverse events (including noninfectious and infectious endophthalmitis, retinal detachment, vitreous hemorrhage, and lens injury) that could negate the benefit of reduction in macular edema. The SCORE study and the Posurdex trial will further clarify the role of corticosteroids in CRVO.
Anti-VEGF Agents
Experimental studies have shown that functional and structural changes occur in the retinal capillaries induced by the hypoxic environment after venous occlusion. This leads to increased capillary permeability and accompanying retinal edema. VEGF, a 45kDa glycoprotein redundant,[35] appears to play a role in this process. Numerous anti-VEGF agents are available. Pegaptanib (Macugen) and ranibizumab (Lucentis) have been approved by the Food and Drug Administration (FDA) for the treatment of neovascular age-related macular degeneration. The use of pegaptanib in a small, randomized series of patients with CRVO is currently in progress. Another anti-VEGF medication is bevacizumab (Avastin), which is approved by the FDA for the treatment of metastatic colon cancer, but has been used in off-label settings for the treatment of numerous ocular conditions. A single case report of intravitreal injection of bevacizumab in CRVO reported resolution of macular edema and improvement in visual acuity from 20/200 to 20/50 maintained at 4 weeks.[252] A retrospective study of 16 eyes in 15 patients with macular edema secondary to CRVO supported the previous case report. The series included nine patients who had received previous intravitreal triamcinolone injections but had either not improved or developed intraocular pressure (IOP) elevation. The patients received a mean of 2.8 injections of 1.25 mg in 0.05 mL of bevacizumab per eye. The mean baseline acuity was 20/600 that improved to a mean of 20/200 at 1 month, and 20/138 at 3 months. Halving of the visual angle was observed in 14 of the 16 eyes.[253] There is a published report of intravitreal bevacizumab injection for treatment of neovascular glaucoma after failed intraocular pressure control with transscleral cyclophotocoagulation and PRP; the intraocular pressure improved within 2 days and the patient experienced marked improvement in comfort.[254] The long term risks and effects of intravitreal anti-VEGF therapy remain unclear.
Until the results of long-term, randomized studies are available, the optimal management of CRVO will remain unclear.
HEMIRETINAL VEIN OCCLUSION
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INTRODUCTION
Epidemiology
HRVO is the least common type of venous occlusive disease. As discussed previously, HRVO makes up only a fraction of the incidence of vein occlusions. In the BMES, the overall incidence of RVO was 1.6% and only 5.1% of those were HRVO.[8]
Pathogenesis
In approximately 20.3% of humans, a two-trunked central retinal vein persists proximal to the lamina cribosa.[255] One of the two trunks may become occluded near the lamina cribrosa, as in CRVO, to produce a HRVO.[256,257] The trunks typically drain the superior and inferior halves of the retina, respectively. The risk factors of HRVO appear to be similar to those for CRVO.[258]
Clinical Features
HRVO presents clinically with involvement of either the superior or inferior retinal hemisphere, (Fig. 132.13) although it may involve one-third to two-thirds of the retina.
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FIGURE 132.13 Typical appearance of an inferior hemicentral retinal vein occlusion. Findings are similar to those of CRVO but affect only half of the retina. |
Visual prognosis appears to be better in HRVO than in CRVO. Macular edema is common. Prognosis appears to correlate with the extent of retinal perfusion. The extent of nonperfusion has been reported to correlate positively with a worse prognosis.[259] In one study including 97 eyes, 32% of HRVO were nonperfused, while 68% were perfused. Like CRVO, neovascularization is uncommon in perfused HRVO. The distribution of neovascularization is distinct from CRVO. The study showed that 13% of nonperfused HRVO developed iris neovascularization, 29% developed disk neovascularization, and 42% developed retinal neovascularization.[51] Collateral vessels may form at the disk as in CRVO as well as across the median raphe, as in BRVO.[257]
Differential Diagnosis
The differential diagnosis of HRVO is similar to that of CRVO and BRVO, including diabetes mellitus, hypertensive retinopathy, ocular ischemic syndrome, and radiation retinopathy.
Treatment
Although the utility of photocoagulation for prevention and treatment of complications in HRVO has not been established, prophylactic application of scatter photocoagulation in the affected retinal hemisphere has been suggested in view of the relatively higher rate of neovascular complications after nonperfused HRVO. Many of the treatment modalities for BRVO and CRVO may be beneficial in HRVO; however, formal studies have not been performed due to the low incidence of HRVO. Treatment decisions for HRVO will continue to be based on the discretion of the clinician until more study results become available.
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