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Core Messages

Branch retinal vein occlusion (BRVO) is a common retinal vascular disease and has public health significance

It is important to distinguish the two different types of BRVO, major and macular BRVO, since their prognosis and management are different

Optical coherence tomography (OCT) has become an indispensable tool for the evaluation of macular edema associated with BRVO, particularly for follow-up examinations, but fluorescein angiography (FLA) is still the gold standard at initial presentation in order to exclude macular ischemia

While modern diagnostic techniques have greatly facilitated the establishment of the exact extent of a BRVO, only limited information is available regarding its pathophysiology, optimal therapy, the timing of therapy and secondary prevention

The clinical course following BRVO is variable with the potential for minimal to severe permanent anatomical and functional damage Timely intervention can substantially reduce the incidence and severity of related complications and visual loss. A careful follow-up is recommended

While scatter laser coagulation (LC) was shown to be very effective in causing regression of neovascularization, grid LC was less effective in reversing vision loss due to macular edema Patients with reduced baseline visual acuity (VA) or nonperfused macular edema have a poor visual outcome

Pilot studies using isovolemic hemodilution, laser-shunting, thrombolytic agents, as well as surgical maneuvers such as arteriovenous sheathotomy and cannulation with tissue-type plasminogen activator administration suggest improvement over the natural history, but

the evidence of currently available data is limited

In recent years, pharmatherapeutic approaches with intravitreal injection of steroids or anti-vascular endothelial growth factor (VEGF) compounds appear promising. However, the beneficial effects on VA and macular thickness often regress as the compound is absorbed from the vitreous over several weeks to months and reinjections are necessary. Any successful therapy for BRVO would have to demonstrate proven benefit for a much longer period

nal diseases to be referred to a Retinal Center [68, 183]. Retinal vein occlusion including both central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) represents the largest group of vascular retinal affections after arteriosclerotic hypertensive changes and diabetic retinopathy [49, 77]. Retinal venous occlusive disease can involve the

21 III central trunk or branches of the venous circulation. BRVO is three times more common than CRVO [51, 183]. Population-based epidemiological studies found an overall prevalence of BRVO of between 0.6 % [136] and 1.6 % [42, 175] increasing with age [51]. Some studies reported that patients with BRVO are older than patients with CRVO at the primary onset of the disease [92, 108] while others found no significant difference [7, 8, 198]. Based on United

a

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States (US) census figures for 2000, as many as 95,000 persons per year develop BRVO in the US alone [242]. Thus, BRVO is an ocular condition that has public health significance. Recognition of retinal vein occlusions is of particular importance because their complications are a cause of significant visual morbidity. BRVO is unilateral in 90 % of patients and occurs most commonly in the 7th decade [51, 81, 122, 151], but it is not unknown in younger patients [1, 108]. At first onset of the disease 54 % of patients with BRVO are 65 years or older, 41 % are between 45 and 64 years old and 5 % are younger than 45 years [1, 108]. In 44 – 60 % of the patients with BRVO, the superotemporal vein is affected and most of the remainder (22 – 43 %) occur in the inferotemporal quadrant [27, 98, 136, 151]. Occlusions in the nasal quadrants are rarely seen, but their incidence may be higher than is documented, because they are often unsymptomatic and therefore not detected. It is interesting to note that in comparisons of visual acuity (VA) between patients without BRVO and those with, only patients with BRVO affecting the superior temporal quadrant compared have a poorer VA [136].

BRVO typically occurs at an arteriovenous (AV) crossing site or at the edge of the optic disk as a hemicentral retinal vein occlusion (HCRVO). The observation that BRVO occurs at AV intersections was made over 100 years ago by Leber [153]. HCRVO pathologically is a variant of CRVO [250], which affects half of the retina due to an anatomical variation and is addressed in Chapter 24.2. BRVO can be subdivided with respect to the extent and location of

c

the occluded area. Major BRVOs involve one of the major branch retinal veins usually near the optic disk affecting a quarter or more of the retina (Fig. 21.3.1a–c), and macular BRVOs involve one of the macular venules and a segment of the macular retina only (Fig. 21.3.2a–c) [107, 108, 109]. Clinical features, prognosis and management of the two types are different [108, 109]. Analogous to the classification of CRVO, ischemic and nonischemic types of BRVO can be differentiated.

Whereas retinal vein occlusions in general occur more frequently in males than in females, major BRVO is seen more often in females than males. Interestingly, BRVO affects the right eye more frequently than the left eye [108]. The proportion of patients who developed the same type of vein occlu-

a

b

sion in the same eye is 2.5 % within 4 years. The risk of being affected by a BRVO in the fellow eye within the following 3.3 years is 4.0 % for macular BRVO and 6.6 % within the following 4 years for major BRVO respectively [108].

The risk of recurrence of the same branch in the same eye is very low [108] and even the risk of anoth-

er major branch occlusion in the same eye is less than III 21 1 % after several years.

21.3.2 Anatomy and Histopathology

Essentials

BRVO typically occurs at arteriovenous crossing sites

Arterial overcrossings are at a higher risk of BRVO

The adjacent artery is usually narrowed and sclerotic, the obstructed branch vein dilated At the crossing sites the outermost compo-

nent of the vessel walls – the adventitia – fuse

The common wall may be extremely thin

Lymphocytes infiltrate the thrombus and vessel walls

The vein recanalizes, but with persisting retinal damage around it

The crossing of retinal vessels such that the artery lies over the vein was considered the normal anatomical configuration (Fig. 21.3.3). In 1936, however,

c

21 III

Fig. 21.3.3. Schematic drawing of an arteriovenous intersection with hypertensive changes. In the majority of patients an arterial overcrossing is present at the site of occlusion and patients have a positive history of systemic hypertension

Fig. 21.3.5. Schematic drawing of an arteriovenous overcrossing. The ophthalmoscopic appearance of compression may be caused by anatomic variations where the retinal vein actually dips deep into the retina

Fig. 21.3.4. Light microscopy of an arteriovenous crossing showing a common wall (from Seitz 1964) [214] predisposing the vein to degenerative changes in the arterial wall

Jensen [128] and Sallmann [207] observed that also venous overcrossings occur at 30 % of all AV intersections in normal eyes. Later, the presence of both types of crossings was demonstrated histologically by Seitz [214]. These findings were confirmed clinically by Weinberg et al, who found in a large series of patients arterial overcrossings in 77.7 % of eyes and venous overcrossings in 22.3 % [249]. Furthermore, a significantly higher proportion of artery over vein crossings occurred in second-order veins than in first-order veins [146, 226]. But at the site of a BRVO an arterial overcrossing was present in 97.6 % of eyes and a venous overcrossing only in 2.4 %. Reports of a BRVO at an intersection at which the vein crosses

over the artery are rare [47, 66, 128]. Thus, arterial overcrossings are at higher risk of BRVO than venous overcrossings [74, 80, 127, 248, 261]. Weinberg et al. further detected that the risk of BRVO in an eye is proportional to the number of arterial overcrossings in the eye [249] and they found that this type of overcrossing is most common in the temporal superior quadrant.

Histologic studies have demonstrated that as the branch retinal artery and vein converge on each other, the outermost components of their walls, the adventitia, fuse (Fig. 21.3.4). Histologically, the clinical impression of venous compression could not be proven [127, 214]. The vein deviates around the artery, dipping deep into the retina in arterial overcrossings (Fig. 21.3.5). Seitz attributed this prominent clinical appearance of crossing phenomena to the deeper position of the vein, rather than to true compression of the vessel. Seitz stated that the ophthalmoscopic appearance of compression is caused by thickening of the adventitial sheath and surrounding glial proliferation, both of which are less transparent tissues [214]. It has been shown that fusion of the vessel walls can continue until artery and veins share a common medium as they cross [139, 140, 219]. Recently, a histopathological examination of one patient with BRVO showed that the common wall measured 4 μm at the occlusion site [72].

Nonischemic and ischemic types of BRVO show similar histopathologic changes. They only differ in their extent of retinal destruction. The ischemic type represents a hemorrhagic infarct of the retina with an extracellular edema in the nerve fiber and ganglion cell layer. This causes dilation and congestion of vein and rhexis hemorrhages [138] from capillaries mainly in the nerve fiber layer (scattered superficial),

but also in deeper layers (spherical). In both types of BRVO, retinal hemorrhages and ischemic necrotic areas reabsorb after months, resulting often in a glial scar. During recirculation the affected capillaries reopen, and with the dilation AV anastomoses develop bridging the destructed area. In later stages irreversible fibrotic alterations of the vascular structure occur [50, 196, 197].

21.3.3 Pathogenesis

Essentials

The cause of BRVO is likely to be a multifactorial process including mechanical obstruction by degenerative changes in the arterioles, abnormal blood constituents and impedance of blood flow causing increased blood viscosity

Endothelial damage

Retinal veins are significantly influenced by the pathology of neighboring retinal arteries due to a common wall at the crossing site

BRVO may lead to partial occlusion of the lumen, but only rarely to complete obstruction

Inflammatory component in thrombus and vessel wall

Hypoxia stimulates increase of vascular endothelial growth factor

Vitreous attachment at the macula or at arteriovenous crossings may play an important pathogenetic role

Despite the great significance of BRVO in causing severe and sometimes permanent visual loss, its pathogenesis is not yet fully understood and has been the subject of some controversy.

Several authors have discussed the theory of mechanical obstruction [226, 248, 261] and others have suggested that BRVO is a result of arterial insufficiency [189, 197]. The pathological process at the site of the occlusion consists of degenerative changes in the vessel walls, abnormal blood constituents, and blood flow (stasis). These three classical components, known as Virchow’s triad, that play a role in thrombogenesis are interrelated. The components of changes in the vessel wall and blood flow have been investigated in humans and animals [84, 138, 196, 197]. The fact that BRVOs are typically located at arterial overcrossings suggests a hemodynamic difference between arterial and venous overcrossings. Frangieh et al. found fresh or recanalized venous thrombi in histological sections of nine eyes with

BRVO at an AV crossing site where both vessels share a common adventitial sheath [80]. They concluded that a thrombus of the branch vein was probably the primary event and the other vascular changes occurred secondarily. The deviation of the retinal vein at crossing sites (Fig. 21.3.5) may lead to consecutive hemodynamic turbulence and thus predispose

to thrombus formation at crossing sites, disputing III 21 the theory of mechanical compression by the artery.

A difference in the distension of the vein lying beneath the artery within the retina as opposed to between the internal limiting membrane and the artery may explain the disparity of risk between arterial and venous overcrossings [248, 249]. Experimental studies have demonstrated that most of the manifestations of BRVO in humans, including nonperfusion and secondary changes in the retinal arteries, can be reproduced by experimental occlusion of the retinal vein in animals [100, 101, 114, 115, 137, 138, 201].

Although a much debated point, a complete thrombotic occlusion of the vein is generally thought not to occur. There is always evidence of some venous flow as shown by fluorescein angiography [218]. A consideration of the rheological events at the time of occlusion may add further insight into the pathophysiology of the condition. Over the last few years especially hypercoagulability has attracted particular increasing interest. It is a well documented and accepted pathological finding that the primary event of retinal vein occlusion includes endothelial cell proliferation in the vein wall associated either with degeneration of the endothelium and secondary thrombus formation or with severe phlebosclerosis [100, 101]. The exact mechanism underlying this primary event is not clear, but clinical studies indicate that it is multifactorial [59, 61, 62]. Apart from hemodynamic factors, triggering of local or systemic cardiovascular risk factors such as hypertension and hyperlipidemia have to be considered (see 3.7). The theory of arterial occlusion producing the clinical features of BRVO has been discounted [218] but arterial disease is generally agreed to play a significant role in the aetiology. Population based studies have found strong associations between BRVO and hypertension, focal arteriolar narrowing and arteriovenous nicking [136, 257]. This findings are consistent with clinical experience [74, 226, 248]. Moreover, the arterial stiffness is increased in patients with BRVO [177]. Localized arteriosclerotic processes may contribute to stasis and occlusion in adjacent retinal veins, and may explain some of the association between retinal vein occlusion and the risk factors classically associated with arterial or arteriolar disease. In BRVO impedance of blood flow is virtually