10.3 Hemicentral Retinal Vein Occlusion

Fig. 10.5 A 66-year-old woman with hypertension and a smoking habit suddenly lost vision in the right eye. A CRVO was found that reduced visual acuity to counting fingers. She was periodically observed without recovery of vision or development of neovascularization for 3 years. She then returned with further loss of vision to light perception and was found to have a dense vitreous hemorrhage. Ultrasonography showed no retinal detachment. The ultrasound image shows a hyperreflective detached posterior hyaloid face (the green arrows) with finely grained echoes in the liquid vitreous posterior to the detached hyaloid (the yellow oval). After a period of 1 year of observation with no clearing, she had a vitrectomy, but vision did not improve due to severe retinal ischemia

for and find the responsible retinal neovascularization subsequently (Fig. 10.5). For example, in the SCORE CRVO study, the 36-month incidences of PSNV and VH were 3.6% and 7.6%, respectively.5

10.3Hemicentral Retinal Vein Occlusion

Posterior segment neovascularization is more common in ischemic HCRVO than ASNV, unlike CRVO (Fig. 10.6). However, patients with HCRVO develop PSNV at a lower rate than patients with BRVO and at a rate more comparable to that after CRVO.26 Over a mean follow-up of 21 months, 11% (12 of 106 eyes) with HCRVO developed NVD and 9% (10 of 106) developed NVE.25 In another series, NVE developed in 24% and NVD in 17% of cases.10 Therefore, the consensus is that NVE and NVD after HCRVO occur with similar frequency. Although most eyes that develop NVD and NVE after HCRVO do so

Fig. 10.6 Fundus images of a 64-year-old man with hypertension and diabetes who developed a superior hemicentral retinal vein occlusion with subsequent neovascularization of the disc. (a) Color fundus photograph of the left eye at the baseline visit. Intraretinal hemorrhages are present in the superior half of the fundus. (b) Frame from the arteriovenous phase of the fluorescein angiogram taken at the baseline visit showing good capillary perfusion (the yellow oval). (c) Color fundus photo-

graph 4 years later. A tuft of neovascularization is present on the optic disc (the black arrow). (d) Frame from the arteriovenous phase fluorescein angiogram taken 4 years after the baseline visit demonstrating conversion to an ischemic hemicentral retinal vein occlusion. The area encircled in the yellow oval has no capillary perfusion and a new intraretinal shunt vessel (the turquoise arrow) traverses the ischemic zone. The tuft of new vessels on the optic disc leaks fluorescein

within 12 months, some PSNV occurs as late as 54 months after diagnosis, implying the need for long-term monitoring of such patients.25

10.4Treatment of Posterior Segment Neovascularization in Retinal Vein Occlusion

The treatment for all forms of PSNV is scatter laser photocoagulation to the ischemic zones.26 Treatment is generally not applied prophylactically for ischemia alone, but only if PSNV develops. Intravitreal injection of anti-VEGF drugs is also efficacious in all forms of posterior segment neovascularization, but has the disadvantage of requiring repetitive treatments. More detail is available in Chap. 13.

•PSNV does not occur after macular BRVO.

•An attached posterior vitreous is a risk factor for PSNV after BRVO.

•Approximately three-quarters of eyes with PSNV after BRVO will develop vitreous hemorrhage if left untreated.

•In a clinic setting, approximately one-fifth of eyes develop PSNV after CRVO.

•After ischemic CRVO, NVD is more common than NVE.

•A necessary condition for PSNV after CRVO is an attached posterior vitreous.

•NVD and NVE occur with similar frequency after HCRVO – approximately 15% of cases.

•Treatment of PSNV involves laser panretinal photocoagulation, which is not applied prophylactically for ischemia, but rather after neovascularization develops.

10.5 Summary of Key Points

•PSNV occurs after ischemic, but not nonischemic, RVO.

•In a clinic setting, approximately one-quarter of BRVOs develop PSNV.

•In BRVO, NVE is more common than NVD.

References

1. Avunduk AM, Cetinkaya K, Kapicioglu Z, Kaya C. The effect of posterior vitreous detachment on the prognosis of branch retinal vein occlusion. Acta Ophthalmol Scan. 1997;75:441–2.

2.Blankenship GW, Okun E. Retinal tributary vein occlusion: history and management by photocoagulation. Arch Ophthalmol. 1973;89(5):363–8.

3. Branch Vein Occlusion Study Group. Argon laser scatter photocoagulation for prevention of neovascularization

and vitreous hemorrhage in branch vein occlusion. Arch Ophthalmol. 1986;104:34–41.

4. Chan CC, Little HL. Infrequency of retinal neovascularization following central retinal vein occlusion. Ophthalmology. 1979;86:256–63.

5.Chan CK, Ip MS, VanVeldhuisen PC, Score study group, et al. Score study report #11: incidents of neovascular events in eyes with retinal vein occlusion. Ophthalmology. 2011;118:1364–72.

6.Elman MJ. Thrombolytic therapy for central retinal vein occlusion: results of a pilot study. Trans Am Ophthalmol Soc. 1996;94:471–504.

7.Evans K, Wishart PK, McGalliard JN. Neovascular complications after central retinal vein occlusion. Eye. 1993;7:520–4.

8. Gutman FA, Zegarra H. The natural course of temporal retinal vein occlusion. Trans Am Ophthalmol Soc. 1974;78:178–92.

9.Hayreh SS, Rojas P, Podhajsky P, Montague P, Woolson RF. Ocular neovascularization with retinal vascular occlu- sion-III; incidence of ocular neovascularization with retinal vein occlusion. Ophthalmology. 1983;90:488–506.

10.Hayreh SS. Retinal vein occlusion. Indian J Ophthalmol. 1994;42:109–32.

11.Hikichi T, Konno S, Trempe CL. Role of the vitreous in central retinal vein occlusion. Retina. 1995;15:29–33.

12.Kado M, Trempe CL. Role of the vitreous in branch retinal vein occlusion. Am J Ophthalmol. 1988;105:20–4.

13.Klein R, Klein BEK, Moss SE, Meuer SM. The epidemiology of retinal vein occlusion: the beaver Dam Eye Study. Trans Am Ophthalmol Soc. 2000;98:133–43.

14. Klein R, Moss SE, Meuer SM, Klein BEK. The 15-year cumulative incidence of retinal vein occlusion. Arch Ophthalmol. 2008;126:513–8.

15.Laatikainen L, Kohner EM. Fluorescein angiography and its prognostic significance in central retinal vein occlusion. Br J Ophthalmol. 1976;60:411–8.

16.Laatikainen L, Kohner EM, Khoury D, Blach RK. Panretinal photocoagulation in central retinal vein occlusion: a randomized controlled clinical study. Br J Ophthalmol. 1977;61:741–53.

17.Lee YJ, Kim JH, Ko MK. Neovascularization in branch retinal vein occlusion combined with arterial insufficiency. Korean J Ophthalmol. 2005;19:34–9.

18.Magargal LE, Brown GC, Augsburger JJ, Parrish RK. Neovascular glaucoma following central retinal vein obstruction. Ophthalmology. 1981;88:1095–101.

19.Magargal LE, Donoso LA, Sanborn GE. Retinal ischemia and risk of neovascularization following central retinal vein obstruction. Ophthalmology. 1982;89: 1241–5.

20. Margolis R, Singh RP, Kaiser PK. Branch retinal vein occlusion: clinical findings, natural history, and management. Compr Ophthalmol Update. 2006;7: 265–76.

21.Michels RG, Gass JDM. The natural course of retinal branch vein obstruction. Trans Am Acad Ophthalmol Otolaryngol. 1974;78:166–77.

22. Mitchell P, Smith W, Chang A. Prevalence and associations of retinal vein occlusion in Australia: the Blue Mountains Eye Study. Arch Ophthalmol. 1996;114:1243–7.

23.Murdoch IE, Rosen PH, Shilling JS. Neovascular response in ischaemic central retinal vein occlusion after panretinal photocoagulation. Br J Ophthalmol. 1991;75:459–61.

24.Quinlan P, Elman MJ, Bhatt AK, Mardesich P, Enger C. The natural course of central retinal vein occlusion. Am J Ophthalmol. 1990;110:118–23.

25.Sanborn GE, Magargal LE. Characteristics of the hemispheric retinal vein occlusion. Ophthalmology. 1984;91:1616–26.

26.Shilling JS, Kohner EM. New vessel formation in retinal branch vein occlusion. Br J Ophthalmol.

1976;60:810–5.

27. Tanaka M, Ninomiya H, Kobayashi Y, Qiu H. Studies on vitrectomy cases associated with complicated branch retinal vein occlusion. Jpn J Ophthalmol. 2001; 45:397–402.

28.Tolentino MJ, Miller JW, Gragoudas ES, Chatzistefanou K, Ferrara N, Adamis AP. Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch Ophthalmol. 1996;114: 964–70.

29. Zegarra H, Gutman FA, Conforto J. The natural course of central retinal vein occlusion. Am J Ophthalmol. 1979;86:1931–9.

Anterior segment neovascularization, like posterior segment neovascularization, is a consequence of retinal ischemia mediated by increased intraocular levels of vascular endothelial growth factor (VEGF). It differs in that it generally requires higher levels of VEGF to induce anterior segment neovascularization than to induce posterior segment neovascularization. Because levels of VEGF correlate with area of retinal ischemia, it is rare for anterior segment neovascularization (ASNV) to arise after branch retinal vein occlusion (BRVO). It can be seen occasionally after hemispheric BRVO, but is never seen after macular BRVO. Therefore, this chapter mostly concerns central retinal vein occlusion (CRVO). Abbreviations commonly used in discussing ASNV are listed in Table 11.1. Each abbreviation will be spelled out at its first occurrence.

11.1The Pathoanatomy and Pathophysiology of Iris and Angle Neovascularization

The normal iris and angle structures are shown in Fig. 11.1. The iris has zones denoted as the pupillary margin, the collarette, the ciliary zone, and the iris root. The iris vascular endothelium is nonfenestrated with tight junctions which comprise part of the blood-aqueous barrier. Fluorescein does not typically leak across the endothelium of

Table 11.1 Abbreviations used in anterior segment neovascularization in retinal vein occlusion

iris vessels, but often does in the elderly, in pseudoexfoliation, and in inflamed eyes.49,50

The innermost angle structure is the trabecular meshwork, which bridges between the peripheral cornea (Schwalbe’s line) and the scleral spur. Aqueous percolates through the meshwork as it leaves the avnterior chamber and then reaches Schlemm’s canal, a circumferential channel that rests against the sclera. Aqueous leaves this canal through collector channels that carry it back into the bloodstream via aqueous veins, with a smaller amount leaving by a transconjunctival route. Aqueous also leaves the eye by a non-trabecular

Fig. 11.1 Anatomy of the iris and anterior chamber angle showing the vascular supply and the structures through which aqueous humor passes (the thick black arrows) in

its route through the eye (Reproduced with permission from Browning10)

outflow pathway, primarily through the iris and the portion of the ciliary body that faces the anterior chamber.

Neovascularization occurring anterior to the retina in RVO arises secondary to retinal ischemia. Retinal ischemia induces production of VEGF in the retina, which diffuses into the vitreous gel and ultimately into the aqueous humor (see Chap. 2). Other growth factors may also be involved. Bathing the anterior and posterior surfaces of the iris and the anterior chamber angle, VEGF induces neovascularization in all these tissues with secondary scarring, synechiae formation, hemorrhage, obstruction of aqueous outflow, elevated intraocular pressure, and eventually, ciliary body detachment and hypotony with phthisis bulbi. Antibodies to VEGF can block this cascade of events (see Chap. 13).1,5,15

The most important factor determining whether ASNV develops in association with RVO is the concentration of VEGF in the aqueous humor.75 Vitreous levels of VEGF are significantly correlated with the severity of ischemia, and VEGF diffuses from the posterior chamber to the anterior chamber.2,3,21,48,73 VEGF in amounts comparable to those measured in human eyes with ASNV is sufficient to produce ASNV in a simian model.74 ASNV requires the continued presence of VEGF to persist.74 Thus, VEGF is both necessary and sufficient to produce ASNV.1 Other cytokines, such as basic fibroblast growth factor, may play a subsidiary role.64 The clinical correlate of elevated VEGF is area of capillary nonperfusion. Eyes with increasing ischemia have an increased risk of

ASNV.39,41,50

A primate model of NVI after multiple BRVO has provided insight into the pathologic stages in

NVI. Early on, iris vessels dilate and intense uptake of tritiated thymidine is observed in vascular endothelial cells. Following this, NVI, peripheral anterior synechiae, ectropion uvea, and elevated intraocular pressure develop. Lastly, a neovascular membrane covers the iris with anterior migration of iris stromal cells.52 Neovascularization of the iris is associated with a myofibroblastic membrane on the iris surface that effaces iris surface crypts and contraction furrows and produces the tractional forces leading to ectropion uvea and angle synechia.22 The new vessels lie beneath this myofibroblastic membrane (Figs. 11.2 and 11.3).35 Although the new vessels predominantly grow on the anterior iris surface, cases have been reported in which they grow on the posterior surface and on

the surface of the ciliary body.4,61 They also can grow over the pupil and adhere to the lens (seclusio pupillae).22 Untreated cases of NVI often progress to hyphema.22

The pathophysiology of ASNV in turn leads to an explanation of how treatment has beneficial effects. The photoreceptor-retinal pigment epithelial complex consumes two-thirds of the oxygen used by the retina. Laser photocoagulation selectively destroys the retinal pigment epithelium and photoreceptor layers, thus decreasing oxygen consumption of the outer retina and allowing more choroidal oxygen to diffuse to the remaining, viable inner retina.80 This downregulates the production of VEGF and leads to regression of ASNV.2