patient to the patientÕs internist or family practitioner to determine if arterial hypertension is truly present, as determined by multiple blood pressure recordings under less stressful conditions, than to make a potentially spurious diagnosis of arterial hypertension based on a single reading in the ophthalmologistÕs ofÞce on the day of diagnosis of an RVO.

13.3Mechanism of Action of Specific Ophthalmic Treatments

13.3.1Treatments for Macular Edema

Treatments for ME associated with RVO include intravitreal injections and implants of corticosteroids, intravitreal injections of anti-VEGF drugs, hyperbaric oxygenation, pars plana vitrectomy, arteriovenous sheathotomy, chorioretinal anastomosis, thrombolysis, intravitreal injections of plasmin, and grid laser photocoagulation (Fig. 13.1). Treatments for ME from RVO can potentially work by multiple mechanisms, although the proportion of beneÞt from each mechanism may differ across treatments. Apart from their beneÞcial effects in reducing ME, in some cases these treatments improve oxygenation of the retina and reduce the commonly associated serous detachment of the macula, both of which may also beneÞcially affect VA.260 These ancillary beneÞts may explain some of the differences in VATR across treatments.

Grid laser for macular edema would be expected to improve inner retinal oxygenation and the balance of VEGF and pigment epithelial derived growth factor (PEDF) (Fig. 13.2).172,201,265 Increased retinal oxygenation would be predicted to have a vasoconstrictive effect, which should beneÞcially affect ME.266 The effect of GL to constrict macular arterioles and veins has been found in two studies, but not in another.7,169,172 In an experimental model using cynomolgus monkeys, GL reduced retinal capillary area in the

region treated.299 The photoreceptors and retinal pigment epithelial cells between burns were not altered beyond a few days.299 Although laser photocoagulation transiently increases the expression of VEGF and intercellular adhesion mole- cule-1 (ICAM-1) in animal models, the persistent effect of increased oxygenation of the retina predominates in the long term and reduces vascular permeability.199

Vitrectomy for ME associated with RVO may work by:

¥Removing vitreomacular traction

¥Removing the scaffold for growth of new vessels

¥Removing cytokines that increase retinal vascular permeability

¥Improving retinal oxygenation via convection currents of aqueous bringing posteriorly more oxygenated ßuid from the ciliary body or in the case of BRVO from other regions of the retina not drained by occluded veins

¥Facilitating egress of blood and extracellular ßuid out of the retina (possibly ampliÞed by ILMP)

¥Improving perifoveal capillary blood ßow

(Fig. 13.3)60,171,176,177,200,205,253,265,269,282,287,288,310,312

In particular, vitrectomy may reduce the intravitreal concentration of VEGF. A greater effect of this intervention has been seen in eyes with higher preoperative concentrations of VEGF.312 Peeling of the internal limiting membrane may amplify its effects (Fig. 13.4).176 It has been suggested that vitrectomy accelerates the maturation of collateral vessels after BRVO, but no evidence exists one way or the other.311

Arteriovenous sheathotomy (AVS) for BRVO is usually accompanied by vitrectomy, which itself reduces ME.310 The sheathotomy may also work by improving perfusion to the retina drained by the occluded vein, reducing intravascular venous pressure, and therefore decreasing the driving force for ME.265 In most eyes with RVO examined by timed ßuorescein angiography after AVS, the circulation time to the involved retina decreases. However, it is unknown whether this represents an improvement over the natural history, since controls have not been studied.309

Systemic, periocular, and intravitreal corticosteroids work in treating macular edema associated with RVO presumably by downregulating the expression of cytokines and chemokines including VEGF, tumor necrosis factor-a

(TNF-a), ICAM-1, macrophage inhibitory pro- tein-1b, and interleukin-1b (IL-1b).183,193,198,222 In a pig model of BRVO, IVTI downregulated VEGF and prevented a decrease in occludin.183 These effects lead to reestablishment of the

Fig. 13.2 Effect of laser photocoagulation on retinal oxygenation. After laser photocoagulation, choroidal oxygen passes more readily through the photocoagulation scars to the inner retina, thus raising tissue oxygen concentration (Redrawn from Stefansson et al.269)

O2

Occluded blood vessels

Vitreous

Retina

PE

O2

Choroid

Fig. 13.3 Effect of vitrectomy on retinal oxygenation. After vitrectomy, oxygen from the ciliary body and from nonischemic zones of the retina circulates in the ßuid of the vitrectomized eye and carries oxygen to the ischemic zone of retina (shaded region on the right side), thereby raising the oxygen tension of the tissue (Redrawn from Stefansson et al.269)

bloodÐretina barrier and less expression of inßammatory markers and secondary leukostasis. Corticosteroids may also have a neuroprotective effect. After intravitreal injection of corticosteroids, a fraction of eyes develop elevated intraocular pressure, which by itself tends to reduce macular edema through the action of StarlingÕs law (see Chap. 2).124 The intraocular pressure-raising side effect of steroids seems to derive from alterations in the extracellular matrix of the trabecular meshwork with decreased intertrabecular spaces.152

Intravitreal anti-VEGF drugs block the angiogenic and vasopermeability effects of VEGF.265 VEGF stimulates endothelial production of nitric oxide, a vasodilator. Anti-VEGF drugs, thus, theoretically reduce nitric oxide leading to vasoconstriction, a common effect observed in the fundus after intravitreal injection of these drugs. Vasoconstriction reduces macular edema independent of the effect on vascular permeability.

Fig. 13.4 Hypothesized mechanism of action of internal limiting membrane peeling to reduce macular edema associated with CRVO. (a) In the normal retinal capillary, there is no excess leakage of the plasmatic component of the blood from the vascular space into the interstitium. (b) In CRVO, the vessel is hyperpermeable from the effects of cytokines such as VEGF. (c) A thickened and contracted internal limiting membrane exerts traction and increases vessel permeability more (Redrawn from Kuhn et al.153)

a

Internal limiting membrane

Capillary

b Internal limiting membrane

Capillary

c

Internal limiting membrane

Capillary