6.3 Ocular Associations

Ocular conditions that might be associated with RVO include glaucoma, elevated IOP, focal arteriolar narrowing and arteriovenous nicking, short axial length, hyperopia, optic disc drusen, and prepapillary vascular loops.32,181,190 A reproducible observation has been that primary open-angle glaucoma (POAG) is the strongest ocular association with all forms of RVO, and that it is more strongly associated with CRVO and HCRVO than with BRVO.68,181 In theory, POAG can produce changes in the lamina cribrosa that may restrict retinal venous outßow and predispose to formation of a thrombus at the lamina cribrosa (CRVO) or at an arteriovenous crossing further upstream of the lamina cribrosa (BRVO).85

Because of the association of POAG and RVO, patients with RVO should be checked for unsuspected POAG. It is not uncommon for RVO to be the sentinel event for the diagnosis of POAG.67

6.3.1 Pooled Retinal Vein Occlusion

In the BMES, there was no association of refractive error with the 10-year incidence of RVO.32 In the Ocular Hypertension Treatment Study (OHTS), the mean spherical equivalent of subjects who developed pooled RVOs was +0.3 D compared with −0.6 D for those subjects not developing RVOs (P = 0.067).12

In a case-control study of pooled RVO, POAG increased the risk 2.89 times (95% CI 1.38Ð6.05) compared to the control group.151 In the OHTS, in which 1,636 patients with ocular hypertension were randomized to ocular hypotensive drug therapy or observation, the 10-year cumulative incidence of pooled RVO was 2.1% in the observation group and 1.4% in the medication group (P =0.14).

In a prospective observational study of 450 cases of pooled RVO, the mean cup-to-disc ratio (CDR) was signiÞcantly higher in the RVOs sited at the optic cup (0.65) compared with non-optic cup-sited RVOs (0.45Ð0.48). The proportion of cases with CDR of 0.7 or more was signiÞcantly higher in the RVOs sited at the optic cup (39.1%) compared with the rest of the non-optic cup-sited

RVOs (0Ð6.3%).15 In the OHTS, subjects who went on to develop pooled RVOs had a baseline mean horizontal CDR of 0.46 ± SD0.19 compared with 0.36 ± SD21 for those who did not develop RVOs (P = 0.016).12

In the BMES, POAG, but not ocular hypertension, was associated with the prevalence of pooled RVO (OR 7.2, 95% CI 3.6Ð14.8).131 The association was so strong that all other associations were adjusted for this factor.133 The prevalences of POAG among subjects with and without pooled RVO were 19.0% and 2.6%, respectively (P =0.0001).31 Baseline IOP was not a risk factor for the 10-year incidence of pooled RVO.32 In the BDES, the prevalence of POAG was higher among subjects with than those without pooled RVO (11.8% and 4.1%, respectively, P =0.02).31 In the BDES, subjects with higher cup-to-disc ratios were more likely to develop pooled RVO (mostly BRVO) over 10 years of follow-up with a 40% increase in incidence per 0.1 increase in baseline C/D ratio.94 Excluding patients with glaucoma did not change the result.94

In the BMES, focal arteriolar narrowing, arteriovenous nicking, and arteriolar wall opaciÞcation were all signiÞcant risk factors for 10-year incidence of pooled RVO. The order of strength of association was as follows: severe arteriovenous nicking (age-adjusted OR 5.70 [95% CI 1.90Ð 17.18])>arteriolar wall opaciÞcation (age-adjusted OR 4.89 [95% CI 2.00Ð12.07])>mild arteriovenous nicking (age-adjusted OR 3.78 [95% CI 1.60Ð9.00])>focal arteriovenous narrowing (age adjusted OR 3.37 [95% CI 1.40Ð8.13]).32

Ocular perfusion pressure is a neither a pure systemic nor pure ocular variable as its deÞnition involves SBP, DBP, and IOP. In the BMES, increasing ocular perfusion pressure was a signiÞcant factor for incident pooled RVO with an age-adjusted OR of 1.71 per 10 mmHg increase in ocular perfusion pressure.

6.3.2 Branch Retinal Vein Occlusion

In case-control studies, short axial length has been associated with BRVO (see Chap. 1).10,176 Hyperopia has been associated inconsistently

with BRVO.6,58,84,93,139 Part of the explanation for the inconsistency may be that some studies fail to isolate short axial length, which on balance seems to be associated with BRVO, from hyperopia due to other causes, which seems on balance not to be associated. In the BDES, neither myopia nor hyperopia was associated with prevalent BRVO or with 5-year incident BRVO.95

The pathophysiologic linkage of POAG to BRVO is not as plausible as that of POAG to CRVO, nevertheless epidemiologic information suggests that there is an association, if not as strong as that between POAG and CRVO. Prevalences of POAG in case series of BRVOs have ranged from 14% to 25%, which is higher than expected for age-matched controls.6,17,58,84,168 In a case series, the prevalence of POAG was higher in patients with BRVO that were sited at the optic cup (prevalence = 39.1%), but not in patients with BRVO occurring at an arteriovenous crossing remote from the optic cup (prevalence = 4.1%).15 The distribution of IOP and CDRs among subgroups of patients with BRVO classiÞed by presence of optic nerve head swelling also supported this Þnding.15 In one study, the IOP of patients with BRVO was signiÞcantly higher than a randomly chosen eye from control patients.52 Unlike the situation with CRVO, the IOP of the fellow eyes of patients with BRVO was not signiÞcantly different than the IOP of fellow eyes of control patients.52 A series of four cases of normal-tension glaucoma with BRVO in one eye and a contralateral neural rim hemorrhage in the fellow eye raised the hypothesis that neural rim hemorrhages in glaucoma may have a pathogenetic mechanism common to BRVO.91 Various case-control studies have been inconsistent in Þnding an association between BRVO and POAG.84,114 In a case-control study of BRVO, the horizontal and vertical CDRs did not differ between cases and controls.180 Small sample sizes of most case-control studies limits their statistical power to detect differences. In the BDES after adjusting for age, CDR was not associated with 15-year incidence of BRVO.96

In a population-based study from China, BRVO was signiÞcantly associated with glaucomatous disc damage (P = 0.019, 95% CI 1.32Ð24.4).115

In the BDES, glaucoma, ocular hypertension, and elevated IOP were not associated with the prevalence or 5-year incidence of BRVO. On the other hand, a multivariate analysis of BDES showed that glaucoma was associated independently with 15-year incidence of BRVO with OR 2.61 (95% CI 1.12Ð6.08, P = 0.03).96 Although there is consensus that an association of POAG and BRVO is not as strong as the association between POAG and CRVO, some authorities go further. Hayreh stated, Òglaucoma and raised IOP play no role in the pathogenesis of BRVO.Ó77

In the BDES, arteriolar narrowing and arteriovenous nicking were strongly associated with the prevalence of BRVO with ORs of 16.75 (95% CI 7.33, 38.24) and 22.86 (95% CI 8.43, 62.03), respectively.95 Focal arteriolar narrowing was also strongly associated with 5- and 15-year incidence of BRVO.95,96 After adjusting for age, arteriovenous nicking, smaller retinal arterial diameter, and larger retinal venular diameter were not associated with 15-year incidence of BRVO.96

Perfusion pressure is a variable that is derived from a systemic and ocular variables, thus it is a hybrid variable related to glaucoma risk. In the BDES, perfusion pressure was associated with prevalence of BRVO with an OR of 2.09 (95% CI 1.45, 3.02), but was not associated with 5-year or 15-year incidence of BRVO.95,96

A history of a previous RVO in the same or fellow eye is a risk factor for an incidence of BRVO (Fig. 6.1). In a case-control study of 225 patients with BRVO, 11% had bilateral BRVOs and 6% had more than one BRVO per eye.84

Case reports in which ophthalmic diseases have been associated with BRVO are common. Many of these associations may be chance occurrences. In other cases, a plausible rationale for association exists, but demonstration of association is not proven. Many of these conditions involve local inßammation in the retina. An example is the reported association of BRVO and serpiginous choroiditis.51

The single protective ocular factor is the anatomic situation in which a retinal vein lies anterior to the artery.27

Fig. 6.1 Example of a patient with two branch retinal vein occlusions in the same eye. A 68-year-old female with diabetes and hypertension was examined with a complaint of blurred vision of the right eye for 2 months. The visual acuity was 20/60 right, 20/20 left. (a) The right eye had superior hemispheric retinal hemorrhages and macular edema. In addition, there was hemorrhage inferonasally in the distribution of the right inferonasal branch vein (yellow arrow). (b) There was evidence of an older inferonasal BRVO with large caliber collateral vessel connecting the inferonasal drainage to the inferotemporal branch retinal vein (green arrow). (c) A frame from the early phase ßuorescein angiogram of the right eye shows good retinal perfusion. (d) A magniÞed view of the optic

disc from panel (c) shows the collateral vessel connecting to the inferotemporal branch retinal vein (the orange arrow). (e) A frame from the late-phase ßuorescein angiogram demonstrated late cystoid hyperßuorescence. The purple arrow denotes the collateral vessel connecting the inferonasal venous drainage to the inferotemporal branch retinal vein. (f) OCT shows macular cysts involving the nerve Þber layer, inner nuclear layer, and outer nuclear layer, as well as inspissated subfoveal exudate (turquoise arrow). This case illustrates the occurrence of two RVOs in the same eye at different times. The inferonasal BRVO was asymptomatic and detected only when a symptomatic superior HCRVO brought the patient to medical attention

6.3.3Central Retinal Vein Occlusion and Hemicentral Retinal Vein Occlusion

In several case-control studies, hyperopia has been associated inconsistently with CRVO or HCRVO.6,58,68,93 The mean axial length of eyes with CRVO has been found to be signiÞcantly shorter than that of fellow eyes and of eyes from

age-matched controls (see Chap. 1).10 There was no difference in the prevalence of hyperopia (31%) or in the mean axial length (23.3 ± 0.8 mm) between involved eyes and fellow eyes or between involved eyes and eyes of a normal control group of 45 subjects (hyperopia prevalence 33%, mean axial length 23.1 ± 0.6 mm) in a prospective study of 13 consecutive patients with unilateral HCRVO.93 Such a small sample size implies a low power to detect differences.

Fig. 6.2 Example of central retinal vein occlusion developing in the context of POAG. An 82-year-old man treated for POAG noted loss of vision in his left eye 2 weeks before presenting for examination. His best corrected visual acuity was 20/40 in the left eye. (a) A pattern of intraretinal hemorrhages throughout the posterior pole is shown without venous dilation. The image suggests a central retinal vein occlusion that is much older than the 2 weeks of noted symptoms inasmuch as there is little venous distention and relatively few hemorrhages. The yellow arrows indicated intraretinal hemorrhages and the green arrow a spared central macular zone. These should be compared to the OCT image in (e). (b) MagniÞed optic disc photograph showing advanced glaucomatous optic atrophy with neural rim thinning inferiorly (the yellow arrow). (c) Frame from the mid-phase ßuorescein angio-

gram showing good perfusion of the retinal capillaries. This is a nonischemic CRVO. (d) Frame from the latephase ßuorescein angiogram showing leakage of ßuorescein dye from the paramacular capillaries. (e) Horizontal OCT line scan shows marked macular thickening. The locations above the yellow arrows correspond to areas of intraretinal hemorrhage. These hemorrhages block imaging of the inner segment/outer segment (IS/ OS) junction and the retinal pigment epithelium (the yellow arrows). The clear central macular zone (compare to a) is occupied by a large cyst (the green arrow). The retinal pigment epithelium is well imaged, but the IS/OS junction is not seen. (f) Contemporaneous visual Þeld of the left eye shows advanced Þeld loss with split Þxation superiorly corresponding to the advanced optic disc neural rim atrophy inferiorly

It has been hypothesized that a small scleral outlet or decreased CDR might be important in contributing to turbulent blood ßow in the central retinal vein, possibly predisposing a patient to CRVO.120,175 In case-control studies, there were no differences between horizontal optic disc diameter and CDR in eyes with CRVO and fellow eyes or control eyes.120,175

The association of POAG and CRVO has long been noted (Fig. 6.2).12 The prevalence of POAG has been reported to range from 23% to 42% in case series of CRVO, which is elevated compared to age-matched controls.6,58-60,76,117,168,185,186 Casecontrol studies have found that persons with a history of POAG have a 4.4Ð5.3 times higher risk of developing CRVO than persons without a

history of glaucoma.99,181 In one study, IOPs of fellow eyes at baseline were grouped into three levels. Those with fellow eye baseline IOPs in the highest level had a 4.5 times higher risk of developing CRVO than patients with fellow eye IOPs in the lowest level.183 Patients with CRVO and POAG are, on average, older than patients with CRVO without POAG, and the proportion that are ischemic is higher than in patients without POAG.185

The IOP of patients with CRVO is signiÞcantly higher than a randomly chosen eye from control patients.52 Moreover, the IOP of the fellow eyes of patients with CRVO is signiÞcantly higher than the IOP of fellow eyes of control patients.52 The IOP of the affected eye of patients with CRVO is not signiÞcantly different than the fellow eyes of affected patients.52 An acute CRVO leads to a transient drop in IOP afterward.78

The prevalence of POAG was higher in patients with CRVO not associated with optic nerve head swelling (18.1%) in one study.15 When CRVO was associated with optic nerve head swelling, there was no association with POAG, IOP, or glaucomatous disc cupping.15 The prevalence of POAG in the latter group was 9.8%.15 The distribution of IOP and CDRs among subgroups of patients with CRVO classiÞed by presence of optic nerve head swelling also supports this Þnding.15 Previous studies did not identify such associations, a result that has been attributed to failure to divide cases according to the site of occlusion and presence

of disc swelling. Pseudoexfoliation material is more common in the anterior segment structures of eyes enucleated for neovascular glaucoma following CRVO than in control enucleated eyes, but the material is not found in the CRV or CRA. The association of the anterior segment material is considered due to the known relationship of pseudoexfoliation material and POAG, which in turn has an association with CRVO.33 In the BDES, a multivariate analysis showed that glaucoma was associated independently with 15-year incidence of CRVO with OR 10.71 (95% CI 3.74Ð 30.67, P < 0.001).96

In a case series of 28 patients with HCRVO, the prevalence of elevated IOP was 28.6%.6 There is a higher prevalence of POAG in patients with HCRVO than in the general population.76 In the EDCCS, a history of glaucoma, an increased IOP in the fellow eye, and an increased CDR in the fellow eye were all associated with an increased prevalence of HCRVO.174

A history of a previous RVO in the same or fellow eye is a risk factor for an incident CRVO. The prevalence of a previous CRVO in an eye that has an acute new CRVO is 5Ð10%.150,179 The prevalence of any retinal vascular occlusion (CRVO, BRVO, BRAO) is 9Ð16%.150,179 The prevalence of any type of retinal vein occlusion in the fellow eye has varied from 8% to 15%.150,163,178 In the CVOS, 6% of fellow eyes had previous CRVOs and 2% had previous BRVOs.178