Ординатура / Офтальмология / Учебные материалы / Retinal Vascular Disease Joussen Springer

Nonischemic BRVO types may convert into ischemic types

The impact of macular ischemia on VA and prognosis is discussed inconsistently

Natural resolution of hemorrhages occurs over a period of between 9 and 12 months

21 III Fifty to 60 % of untreated patients have a final VA of 20/40 or better

Patients with VA of 20/60 or less have a small chance of spontaneous visual improvement

The presence of collateral vessels does not correlate necessarily with better visual prognosis

Little natural history data is available about the early and the late course of BRVO Regular funduscopic checks should be performed in patients especially with the ischemic type of BRVO since neovascularization and vitreous hemorrhage may also develop years after the occlusion

The prognosis of this disease is highly unpredictable because nonischemic types may convert into ischemic types within the first several weeks [108]. In each case in the initial stages, the only channel for the venous blood to exit the eye is blocked to a varying degree. Relatively little information is available on the natural history of BRVO; most of what exists is derived from clinical trials, including the Branch Retinal Vein Occlusion Study (BVOS). The natural history of BRVO depends on the size and location of the affected area and on whether there is associated CME, macular nonperfusion, retinal neovascularization and vitreous hemorrhage [46, 77, 98, 174]. Natural resolution of hemorrhages occurs between 9 and 12 months. The prognosis for visual acuity is often so variable that one can provide a patient only with a rough estimate of future outcome. Overall, the visual prognosis is good, with 50 – 60 % of untreated patients having a final VA of 20/40 or better. About 20 – 25 % of patients are left with 20/200 or worse, and the remainder have VA from 20/50 to 20/100. A final VA of only being able to see hand motions or worse occurs rarely [27, 29, 98, 174, 235]. The Collaborative Branch Vein Occlusion Study Group (BVOS) studied the VA prognosis for 35 untreated patients with macular edema after BRVO and loss of VA to 20/ 40 or worse. The study reported that only 37 % of eyes showed a spontaneous resolution of the macular edema and visual improvement. After 3 years a visual acuity of less than 20/40 was found in two-thirds of untreated eyes [235], which progressed to chronic cystoid macular edema. Gutman and Zegarra report-

ed a final visual acuity of 10/40 or less in 16 of 40 patients after 2 years [98]. Orth and Patz found that 53 % of patients with BRVO achieved a final VA of 20/40 or better and 25 % of the patients achieved 20/50 to 20/100 [183]. Eyes with smaller BRVO of shorter duration with less macular edema have better visual outcomes than eyes with large areas of venous obstruction, longer duration of disease, and persistent macular edema [46, 174]. As evidence for this, a study of small macular BRVO of less than 2 weeks duration demonstrated a significant spontaneous improvement in visual acuity after 3 months [187]. Typically, patients with VA of 20/60 or less have a small chance of spontaneous visual improvement. The development of collaterals across the horizontal raphe seems to help compensate for the venous occlusion in eyes without reperfusion of the retinal vein and contributes to spontaneous visual recovery [41], but the presence of collateral vessels does not correlate necessarily with better visual prognosis [236]. The collateral drainage capacity away from the affected area to areas with intact venous drainage also has a significant effect on the morphological outcome of the BRVO [41]. Collateral vessels develop usually within the first months of the occlusion and are not present at the first visit. But often by this time the potential for full visual recovery has been lost due to irreversible changes in the macular region. There is little natural history data available about the early course of BRVO. It cannot be obtained from the BVOS [235] because no patient was entered until 3 months after the occlusion due to the clinical impression that spontaneous improvement often occurred during that period. There is also inadequate long-term natural history information available. In the BVOS at 3 years there were only 35 untreated eyes with a BRVO of 3 – 18 months duration prior to study entry. It is unfortunately difficult to extract meaningful natural history information from such small numbers with such a variable duration of BRVO.

As in other retinal vascular disorders, exact mechanisms for the production of macular edema caused by BRVO, and for its spontaneous resolution, are poorly understood. The degree of initial macular edema was shown to be correlated with a poor final visual acuity and with persistent macular edema. Previous studies on BRVO have examined the correlation between a broken foveal capillary ring and visual prognosis [46, 77, 219]. However, the impact of macular ischemia on VA and prognosis is discussed inconsistently. In eyes with perfused macular edema, Finkelstein found a poorer prognosis [77], whereas Shilling and Jones [219] as well as Clemett [46] found a better prognosis. A retrospective small study of 23 eyes with nonperfused macular edema suggests that

90 % improve without treatment [77]. This difference was attributed to the separate mechanisms causing nonperfused and perfused edema. Initial features of the occlusion may also help to predict final prognosis. Reduced baseline VA, older age and the extent of initial retinal ischemia were correlated strongly to poor visual outcome and to the development of retinal ischemia [92].

In order to be able to judge the effectiveness of various treatment strategies, it is not only necessary to understand the mechanism through which they attain their success but it is also essential to know the natural history of the disease. Future studies analyzing the early natural course and the long-term history of the different types of BRVO are therefore imperative.

21.3.7Associated Systemic Disorders and Risk Factors

Numerous reports about associated local, systemic and hematologic disorders have been published over the years, but only few studies are performed prospectively and differentiate between the types of vein occlusions. The studies are often contradictory, differing markedly in case selection criteria, demographics or study design. It is beyond the scope of this chapter to discuss the whole literature concerning this issue. In the following chapter possible underlying or causative diseases are summarized, but it has to be kept in mind that the presence of a particular associated systemic disease does not necessarily imply a cause-and-effect relationship [107].

21.3.7.1 Systemic Risk Factors

Essentials

Sixty-five to 75 % of patients with BRVO have systemic hypertension, which is the main risk factor

Further major risk factors include diabetes mellitus type 2, obesity and hyperlipidemia

Systemic diseases with an increased risk of BRVO include hyperviscosity syndromes such as elevated erythrocyte aggregation rate, malignancy, myeloproliferative disorders and pregnancy

Treatment of the underlying medical conditions is able to reduce the rate of BRVO recurrence

As it stands, the generally accepted systemic risk factors in retinal vein occlusion are arterial hypertension and diabetes, conditions that appear more

closely correlated with arteriosclerosis and arterial thrombosis that may precipitate acute myocardial infarction and stroke, rather than being related to venous occlusion. In the case of a BRVO the close anatomical localization of arterial and venous branches have to be taken into account. Hence, the pathology of retinal veins may theoretically be sig-

nificantly influenced, if not dominated, by the III 21 pathology of neighboring retinal arteries. Arterio-

sclerotic changes in the retinal arteries are more likely to cause BRVO than CRVO because the vessels in the optic nerve lie side by side and do not cross. Patients with BRVO are known to have another prevalence of systemic risk factors than those with CRVO or HCRVO [107], but the risk factor profile is similar [223]. The prevalence rate of arterial hypertension, peripheral vascular disease, venous disease, peptic ulcers and other gastrointestinal diseases, an increased body mass index and the number of smokers is significantly higher than in patients with CRVO [7, 8, 107]. The Eye Disease Case-Control Study Group and other similar studies have identified risk factors such as aging, diabetes, hypertension, cardiovascular risk profile, and glaucoma [236]. In the majority of reports only the association with systemic arterial hypertension and retinal vascular manifestations of hypertension have been documented [6, 7, 27, 98, 107, 236]. Sixty-five to 75 % of patients with BRVO have systemic hypertension [236]. Also patients receiving antihypertensive medication have to be considered as risk patients.

Hayreh et al. showed that the prevalence of arterial hypertension in patients with major BRVO (65.7 %) was significantly higher than in a gen- der-matched and age-matched control population (29.9 %). They found the same relationships in young men with macular BRVO. Patients with both types of BRVO had a higher prevalence of cerebrovascular and chronic obstructive pulmonary disease, peptic ulcers, diabetes and thyroid disorders [107]. Earlier case control studies identified hypertension, diabetes mellitus type 2, obesity and hyperlipidemia as major risk factors of BRVO [6, 63, 129, 198]. No significantly greater incidence of estrogen use or use of birth control pills in patients with BRVO compared with their control group was found [58, 129, 236]. In a recent large population based study by Wong et al., different types of retinal vein occlusion were associated with carotid artery disease, hypertension, and other cardiovascular risk factors [257]. In addition, they found an association with body mass index, current cigarette smoking and increased plasma fibrinogen levels.

Further underlying systemic diseases with an increased risk of thrombosis include hyperviscosity syndromes [200], such as elevated erythrocyte

aggregation rate, malignancy, myeloproliferative disorders, pregnancy and less common conditions such as polycythemia, paraproteinemia, Beh¸cet’s disease and paroxysmal hemoglobinuria [95]. Treatment of the underlying medical conditions can reduce the severity of some of its complications [204]. It was further shown that treatment of system-

21 III ic risk factors is able to reduce the rate of recurrence from approximately 10 % to 1 % [62, 64].

This underlines the importance of searching for and identifying possible systemic risk factors. A profound meta-analysis by Janssen et al., however, concluded that in investigating a new patient with retinal vein occlusion, at first, one should test for the most common systemic risk factors such as hypertension, lipid abnormalities and diabetes mellitus only [126]. An extensive and expensive workup for thrombophilic disease at the initial presentation is unwarranted in the vast majority of patients.

21.3.7.2 Local Risk Factors

Essentials

BRVO patients show a higher incidence of hyperopia and a shorter axial length

The association between BRVO and glaucoma is uncertain

Glaucoma patients seem to acquire BRVO at a younger age than nonglaucomatous patients

Testing for patients with open-angle glaucoma should be part of the evaluation of patients with BRVO

Local risk factors include ocular findings and diseases associated with the occurrence of BRVO. A higher incidence of hyperopia and a shorter axial length has been found in patients with BRVO [7, 230]. The most important local risk factor, however, is chronic open angle glaucoma, although the explanation for the association with retinal vein occlusion has yet to be elucidated. The association between CRVO and chronic open angle glaucoma has been recognized for many years with a prevalence between 10 % and 40 %, but the association between BRVO and glaucoma is uncertain [22, 92, 45, 109, 111, 112, 223, 243] and appears to be less frequent with a prevalence between 6.6 % and 15 %. A lack of correlation between BRVO and open angle glaucoma or ocular hypertension compared to that in the general population was reported by Johnston et al. [129, 163]. However, another study found similar frequency rates of BRVO and CRVO in a glaucoma population [51]. Although the exact intraocular pressure at the

time of a retinal vein occlusion is not known, several authors suggest that the pressure may be raised and that the venous occlusive episode itself, subsequently, has a lowering effect on the pressure [81, 106]. It has been found that retinal vascular events tend to occur early in the course of the associated glaucoma [19, 22] and glaucoma patients seem to acquire BRVO at a younger age than nonglaucomatous patients [51]. However, the prevalence of associated medical conditions in patients with retinal vein occlusion either with or without glaucoma or ocular hypertension are markedly similar [48], implying that associated medical conditions may be of greater significance. Both conditions – glaucoma and BRVO

– may not be related etiologically but rather are both manifestations of some underlying vascular abnormality [188], and there is evidence available suggesting that testing for patients with open-angle glaucoma should be part of the evaluation of patients with BRVO [223].

Whether modern antiglaucomatous drugs affecting the regulation of retinal blood flow have a positive influence following BRVO is unclear and deserves further investigation.

21.3.7.3 Hematologic Risk Factors

Essentials

RVO has been reported to be associated with the antiphospholipid antibody syndrome, abnormalities in the physiological anticoagulant system such as protein C and protein S, factor XII deficiency, antithrombin III deficiency and defects in fibrinolytic mechanisms

Elevated blood viscosity, variously combined with increased hematocrit, fibrinogen, lipoprotein(a), 1-globulin or 2-globu- lin levels, may be implicated in BRVO

Patients with elevated total homocysteine are three times more likely to have BRVO

APC resistance as a cause of BRVO is described mainly in younger patients

Therapeutic strategies should only be drawn up together with a hematologist

To date, there is not enough data to recommend a standard anticoagulant therapy in patients with BRVO and an underlying genetic thrombophilic abnormality

Coagulation disorders which can lead to the formation of thrombi elsewhere in the body may also contribute to the formation of thrombi in the retinal vasculature [244]. Thrombophilic disorders are charac-

terized by a systemic dysfunction of the hemostatic pathway. However, in keeping with Virchow’s triad, the phenotype must arise from local changes in blood flow, disruption of the vascular wall, or vascular-bed- restricted alterations in the balance of anticoagulant and procoagulant factors. Meanwhile many congenital, and acquired, blood protein defects are known to account for hypercoagulability and thrombosis. Among the biochemical and hemostatic disturbances that have been associated with BRVO are antiphospholipid antibody (APA) syndrome [1, 2, 10, 23, 24, 25, 33, 195, 221, 224, 238, 244, 254], abnormalities in the physiological anticoagulant system and elevated hemostatic factors such as fibrinogen and lipoprotein Lp(a) [13, 160, 162, 234]. The coagulation sequence is held in check and inhibited by specific physiological anticoagulants including antithrombin III, protein C, and protein S. Deficiencies of these natural anticoagulants are associated with recurrent systemic thromboembolic events and have also been associated with the development of a BRVO [1, 23, 24, 27, 34, 43, 44, 88, 123, 178, 183, 189, 202, 221, 222, 237, 250]. These disorders as well as factor V Leiden [44, 53, 94, 247], activated protein C (APC) resistance [96, 143, 152, 194, 209, 256] and factor XII deficiency [1, 56, 88, 144] are addressed in Chapter 21.1 in detail. The role and impact of elevated plasma total homocysteine levels [30, 31, 42, 253] and low serum folate levels [31] in retinal vascular occlusive diseases are also thoroughly discussed in Chapter 21.1.

Further rheological abnormalities include thrombophilia [120], abnormal in vivo platelet function [60], hyperviscosity [1, 36, 90, 170, 193, 200, 239] and increased inflammatory activity [61]. A raised erythrocyte sedimentation rate is an important marker of raised plasma viscosity which may also influence blood viscosity and has been described in patients with BRVO by several investigators [36, 67, 90, 190, 200, 239].

Lowe et al. reported an increased blood viscosity in patients with capillary nonperfusion or neovascularization in the chronic phase of the disease and believed that an increased viscosity may play a role in the production of ischemia [161]. Peduzzi et al. confirmed this theory and found a significantly decreased erythrocyte deformability in patients with capillary nonperfusion and retinal vein occlusion [190]. Wiek et al., however, showed that the hematological profile of patients with BRVO is not different from control subjects matched for age, gender and risk factors. They found that the determination of plasma viscosity, red cell aggregation, red cell filterability, and hematocrit could not assist in the differentiation between ischemic versus nonischemic vein occlusion [255].

The association between hematologic risk factors and BRVO is discussed inconsistently. To date, there

21.3.8.1Improvement of Hemodynamic Properties and Secondary Prevention

Essentials

No beneficial effect of anticoagulation therapy could be proven, neither for prevention nor for the therapy of BRVO

Pentoxifyllin reduces blood viscosity by lowering the fibrinogen level and increases erythrocyte and leukocyte deformability, but no studies analyzing its effect on the outcome in BRVO patients exist

For isovolemic hemodilution and troxerutin a treatment benefit was shown in prospective randomized trials, but these therapies are controversial and have not gained general acceptance

Systemic thrombolysis with low dose intravenous recombinant tissue plasminogen activator (rt-PA) is a treatment option; however, the risk of life threatening hemorrhages has to be considered

The question of whether a therapeutic measure to alter the blood constituents could modify and moderate the morbidity of BRVO is very difficult to assess.

No beneficial effect of anticoagulation therapy with heparin or coumarin derivates could be proven, neither for prevention nor for the therapy of BRVO

21 III [57]. A review of the benefit of antithrombotic agents concluded that hemorrhagic complications seemed to outweigh the possible benefits [120]. Since systemic complications and progression of retinal hemorrhages have been described, the risks of secondary prevention seem inadequate [120, 250]. The only exception is the category of severe coagulation disorders (see Sect. 21.3.7.3), which might justify a prophylactic treatment.

Acetylsalicylic acid is often prescribed even after venous occlusions. No beneficial effect has been proven so far and also with this treatment is implicated the risk of new retinal hemorrhages [120] (Fig. 21.3.18). Pentoxifyllin reduces blood viscosity by lowering the fibrinogen level and increases erythrocyte and leukocyte deformability, but no studies analyzing its effect on the outcome in BRVO patients exist. Hemodilution decreases the hematocrit levels and should lower whole blood viscosity and improve retinal microcirculation. It leads to a decrease of AV passage time in the affected branch and to a significant reduction of erythrocyte aggregation [199]. Conclusions drawn from published hemodilution treatment studies [89, 103, 199], some being quite optimistic but of limited size, must include a great deal of caution. For isovolemic hemodilution [103] and troxerutin [89], a treatment benefit was shown in prospective randomized trials. Hansen et al. reported a visual acuity of 0.4 (20/50) or more in 85 % of the hemodiluted patients in contrast to 33 % of the nonhemodiluted patients after 1 year, and most improvements occurred in patients with ischemic

BRVO [103]. Due to the small number of patients included in these studies these therapies are controversial and have not gained general acceptance. Shalid et al. concluded in a recent review that isovolemic hemodilution is of limited benefit and should be avoided in patients with concurrent cardiovascular, renal or pulmonary morbidity [217].

The lesson learned from antithrombotic treatment in general is that there is not much chance of achieving reperfusion if antithrombotic measures are introduced weeks after precipitation of venous thrombosis.

21.3.8.2 Reduction of Macular Edema

21.3.8.2.1 Macular Grid Laser Coagulation

Essentials

Macular grid laser coagulation (LC) is an effective treatment for persistent, perfused macular edema associated with BRVO

In cases of persistent (> 3 months) decreased vision of 20/40 or less and macular edema without capillary nonperfusion (FLA necessary!), macular grid LC in the affected area is recommended

When foveal ischemia is present, no grid LC should be performed

It is necessary to wait for sufficient clearing of retinal hemorrhages before LC is performed

A pretreatment with intravitreal steroids may be helpful in very edematous retina

In cases of persisting macular edema, grid LC can be repeated after 3 months and visual improvement can be achieved despite multiple treatments

For macular BRVO no benefit of grid LC versus the natural course could be proven

21.3.8.2.2Macular Grid Laser Photocoagulation in BRVO – Technique

Fig. 21.3.18. Anticoagulation therapy may increase the risk of fresh and dense hemorrhages in the area of BRVO

Essentials

Argon green laser should be used using a contact area centralis lens (e.g., Goldmann) with 100 – 200 μm spot size, 100 – 200 mW power and 0.1 – 0.2 s duration in topical anesthesia

Medium white laser spots should be spaced approximately one burn width apart to the area of leakage no closer than 500 μm to the fovea (see Fig. 21.3.20)

The power should be increased in 50 mW increments from the initial setting until the desired intensity is achieved

Two to three rows with 100 μm spots should be applied along the edge of the foveal avascular zone (FAZ) followed by 200 μm spots to the major vascular arcades

In very edematous retina, it is advisable to increase pulse duration rather than power Excessive eye movements may require retrobulbar anesthesia in rare cases

Patients should be seen at 3 month intervals after grid LC and at 6 – 12 months once the macular edema is resolved

21.3.8.2.3 Corticosteroids

Essentials

Increased levels of vascular endothelial growth factor (VEGF) and IL-6 were found in vitreous samples of patients with BRVO indicating an inflammatory component in BRVO

Steroids may be useful in stabilizing the blood-retinal barrier, decreasing vascular permeability, and perivascular and intraluminal inflammation

High dose oral steroid therapy was found to improve vision only over the short term, and was associated with the systemic side effects of steroids

Intravitreal triamcinolone acetate (IVTA) can reduce macular edema and improve VA in patients with BRVO

The therapeutic effect of IVTA in BRVO is transient and once the steroids start to wear off, the macular edema recurs

IVTA is significantly more effective in reducing macular edema and improving VA than repeated retrobulbar injections

21.3 Branch Retinal Vein Occlusion 487

Preliminary results in small case series are promising, but as with IVTA, the effect is transient and appears to be of shorter duration

Essentials

The separation of the retinal artery from the underlying vein is called arteriovenous adventitial sheathotomy (AAS) and addresses a theoretical pathogenic mechanism of BRVO

AAS can lead to restoration of the blood flow in the occluded vein immediately after decompression

Eyes without rest perfusion did not benefit from AAS

In a considerable number of patients surgical separation of the vessels cannot be achieved

Potential complications of the procedure include laceration of vein or artery with consecutive hemorrhage or arcuate scotoma due to incision of the nerve fiber layer

Interestingly, also incomplete dissection of the vein may result in improved vision suggesting that freeing the vessels from their retinal bed or vitrectomy alone might be effective

The role of AAS has not yet been clarified

Removal of the posterior hyaloid alone and/ or additional removal of the internal limiting membrane may contribute to resolution of the macular edema and visual improvement

Recently successful cannulations of branch retinal arterioles and branch retinal venules were described and may offer new future treatment options

21.3.8.2.4 Antiangiogenic Therapy

Essentials

Increased VEGF levels were measured in patients with vein occlusion, and correlated with the extent of macular edema Anti-VEGF drugs could specifically reduce the permeability of retinal capillaries or might downregulate VEGF, but do not eliminate the cause of the disease

21.3.8.2.6Macular Grid-Laser Photocoagulation

Macular grid LC is an effective treatment for persisting, perfused macular edema associated with BRVO [9] and is still the gold standard (Fig. 21.3.19a–c). In the BVOS the mean vision in laser treated eyes improved from 20/40 to 20/50, compared with 20/70 in untreated eyes. The treatment effect was negligible when the initial vision was in the poorer range of 20/ 100 to 20/200. Other studies provide contrasting results.

c

Fig. 21.3.19. Major BRVO affecting the superotemporal vein of the right eye. a Before treatment and b after scatter laser treatment (arrow) showing partial regression of hemorrhages but an increase in macular edema (asterisk). c Following macular grid LC complete resolution of macular edema can be seen

Fig. 21.3.20. Schematic drawing of the grid LC pattern in persisting macular edema associated with BRVO. The laser treatment covers the area of capillary leakage and spares the foveal avascular zone

In cases of persisting visual decrease to 20/40 or less and macular edema without capillary nonperfusion, the BRVO Study group recommended macular grid LC in the affected area [235] (Fig. 21.3.20). When macular nonperfusion is the cause of visual loss, no grid LC should be performed [235].

Argon green laser is probably the wavelength of choice in the routine macular grid LC treatment using 100 μm spot size, 100 – 200 mW power and 0.1 – 0.2 s duration depending on the patient’s com-

pliance. Argon blue-green can also be used, but the blue wavelength is absorbed by the macular xanthophyll. The spots should be spaced approximately one burn width apart and directed at the area of capillary leakage identified by FLA, sparing the foveal avascular zone and not extending peripheral to the major vascular arcade. It is important to spare areas of collateral vessels during LC as well as areas with retinal hemorrhages which absorb the applied laser energy and lead to nerve fiber layer damage. Therefore, it is

necessary to wait for sufficient clearing of retinal hemorrhages before LC is performed. It has to be considered that an increase of the central scotoma was found in 50 % of patients after laser treatment [15].

In the BRVO Study, the effect of timing of the laser treatment was not examined. Since spontaneous remissions are commonly observed and no studies exist which have proven a less therapeutic effect of delayed therapy, early treatment does not seem justified. Most authors recommended waiting at least 2 – 3 months before considering grid LC. In cases of persisting macular edema, grid LC can be repeated after 3 months and visual improvement can be achieved despite multiple treatments [69]. The BVOS

21.3 Branch Retinal Vein Occlusion 489

recommendations, however, refer only to the occlusion of a major branch. No benefit of grid laser treatment versus the natural course could be proven [123, 187] in the subgroup of macular BRVO, but its therapeutic principle is also working (Figs. 21.3.21, 21.3.22). Recently, it was found that the presence of

III 21

d

Fig. 21.3.22. b FLA shows focal laser burns (arrow) and c a reduction in edema (arrow). d Complete resolution of foveal cysts (arrow) can be seen with OCT (scan, see a)

21.3.8.2.7Laser-Induced Chorioretinal Venous Anastomosis

Using an animal model of BRVO, MacAllister et al. successfully explored the possibility of creating an iatrogenic permanent anastomosis between the retinal and choroidal venous circulation [169] allowing for reperfusion of the affected retina. Collateral vessel formation in the early stages of the disease between a high pressure circulation, as in the circulation of an obstructed retinal vein, and a low pressure circulation, such as the choroidal venous system [26], could prevent closed loop circulation and its ischemic consequences.

Several lasers and settings were proposed to create a chorioretinal venous anastomosis as a therapeutic modality in CRVO and BRVO [70], directing the laser spot on the edge of or directly on top of a retinal vein adjacent to the occlusion site in order to achieve perforation of the retinal vein and rupture the underlying Bruch’s membrane. When successfully treated, promising visual results could be achieved [70]. However, due to severe complications such as choroidal neovascular membrane formation, preretinal fibrosis, traction retinal detachment, and vitreous hemorrhage [16], this treatment has not gained general acceptance.

21.3.8.2.8 Corticosteroids

Although steroids have antiangiogenic, antifibrotic, and antipermeability properties, the principal effects of steroids are stabilization of the blood-retinal barrier, resorption of exudation, and downregulation of inflammatory stimuli [79]. Since they have been shown to reduce macular edema also in a wide variety of other conditions, their effect may be nonspecific. Whereas it is clear that there is a breakdown in the blood-retinal barrier in BRVO, studies have shown that there may also be an inflammatory component that would respond to steroids [133]. Increased levels of VEGF and interleukin (IL)-6 were found in vitreous samples of patients with BRVO [180]. It is known that inflammatory cell infiltrates are present in the area of the thrombotic occlusion including lymphocytic infiltration within the thrombus. Therefore steroids may have a therapeutic effect not only on macular edema, but also on the thrombus. Thus steroids may be useful in BRVO stabilizing the blood-retinal barrier, decreasing vascular permeability, and perivascular and intraluminal inflammation.

Systemic Corticosteroids

High dose oral steroid therapy was found to cause transient reduction in macular edema and improve vision over the short term, but these effects proved not to be long lasting and were associated with the potential adverse effects linked with systemic administration of steroids [216]. Assuming a vasculitic component, younger patients, especially, were treated with systemic corticosteroids. Currently, no controlled trials exist.

Intravitreal Corticosteroids

The intravitreal administration of steroids provides for a more concentrated dose of steroid delivery to the eye, together with the advantages of a potentially longer duration of action through its associated vehicle, and limitation of systemic effects. Intravitreal injection of triamcinolone acetate (IVTA), a long acting corticosteroid, was first described by the group of Machemer [110] and has been used in the treatment of macular edema of different origin [167]. Although the mode of action by which triamcinolone induces resolution of macular edema remains poorly understood, in vitro studies and clinical observations indicate that triamcinolone has the capacity to reduce the permeability of the outer blood-retinal barrier [191].

Due to the anti-edematous and anti-angiogenic effects shown in experimental investigations and

clinical studies, IVTA has also been used in pilot studies on BRVO [35, 39, 52, 130, 131, 132, 185, 186, 260]. Case series have demonstrated that IVTA can reduce macular edema and improve VA in patients with BRVO (Fig. 21.3.23) [52, 130, 132, 134, 185, 186, 206]. In a recent randomized clinical trial IVTA was more effective than macular grid LC in patients with CME

due to retinal vein occlusion or diabetic macular ede- III 21 ma [11]. It is still controversial as to whether a combi-

nation of both is beneficial or not [11, 208]. The best point in time for grid LC is probably when the central macular thickness is maximally reduced between 6 and 12 weeks after IVTA [11, 113]. Jonas et al. reported that IVTA can significantly increase VA in nonischemic BRVO while no significant effect was found in the ischemic type [130, 131]. Jonas et al. used higher dosages of 20 – 25 mg triamcinolone, whereas in the majority of clinical studies between 4 and 8 mg