(55%) as in patients with unilateral CRVO

(21.6%) in whom there was already an increased prevalence compared to a control group (P = 0.003).188 This study has been criticized for failing to match cases and controls.19 The study by Martin showing an association has been criticized because cases were older than controls, and homocysteine concentration is age-depen- dent.19,125 In a meta-analysis of eight case-control studies through 2003, six supported an association of hyperhomocysteinemia and CRVO.22 Since that meta-analysis, three of eight additional case-control studies have found a positive association of hyperhomocysteinemia and CRVO (Table 6.4).

An interaction of hyperhomocysteinemia with perfusion status in CRVO has been sought and sometimes found. Lattanzio and colleagues found no dependence on perfusion status of the association of hyperhomocysteinemia and CRVO in 56 patients with CRVO less than 56 years old.111 Others have found an association of prevalence of ischemic CRVO with hyperhomocysteinemia, but no association for nonischemic CRVO.54,188,189 Bilateral CRVO has been associated with hyperhomocysteinemia in 55% of patients.188 Taking

the evidence in total, the association of homocysteine and CRVO is weak if present.

Some studies looking at the association of plasma homocysteine and HCRVO have pooled these cases with cases of CRVO.23 The results for HCRVO have not been analyzed separately.23

6.2.8 Serum Folate

Serum folate may have a direct and indirect association with RVO. Increasing serum folate causes a decrease in plasma homocysteine.22 The evidence supporting a role for serum folate in RVO is inconsistent. In a case-control study of 20 cases of pooled RVOs and 20 controls, there was no difference between the mean serum folate level of cases and controls.20 In a case-control study of 84 patients with BRVO and 84 genderand age-matched controls, mean serum folate was signiÞcantly lower in the BRVO group (4.5 ± 2.1 ng/ml vs. 5.6 ± 2.1 ng/ml, P = 0.007).194 In a conditional logistic regression model including several signiÞcant risk factors including plasma homocysteine, an increase of serum

folate of 1 ng/ml was associated with an OR of 0.83 (95% CI 0.72Ð0.98, P = 0.03), suggesting that serum folate has a protective effect independent of its effect on plasma homocysteine.194 The same researchers also reported signiÞcantly lower serum folate levels in 78 cases of CRVO compared to 78 controls in a study from Austria.193 However, in a case-control study of 29 South Asian Indian patients with CRVO between ages 20 and 40 and 57 ageand gendermatched controls, there was no signiÞcant difference in mean levels of serum folate.137 On balance, insufÞcient information has been published to establish an association of low serum folate and RVO.

6.2.9 Serum B12

A low serum B12 level can cause plasma homocysteine concentration to secondarily increase. Four case-control studies of RVO have failed to Þnd a difference in serum vitamin B12 levels between cases and controls. One studied pooled RVOs, one BRVO, and two CRVO.20,137,193,194 Although only 211 patients with RVO have been studied in these four reports, there is little to suggest that vitamin B12 is an important risk factor for RVO.

6.2.10 Smoking

The literature on smoking and its relationships to pooled RVO, BRVO, and CRVO is inconsistent. In both the BDES and the BMES, there was no association between a history of smoking and the prevalence of pooled RVO.31 When adjusted for glaucoma and age, however, a smoking history was a protective factor against prevalent RVO with an OR of 0.5 (95% CI 0.3Ð0.9).131 There was no association between smoking and the 10-year incidence of pooled RVO in the BMES.32 In a population-based study from Japan, there was no

association between a history of smoking and prevalence of BRVO.206

In the EDCCS, presence of smoking was a risk factor for BRVO.180 Another study conÞrmed the association, but two case-control studies found no association.39,193,195 In the BDES, past or present smoking history was not associated with prevalent BRVO. In addition, past smoking was not a risk factor for 5-year incident BRVO. However, current smoking was a risk factor for 5-year incident BRVO with an OR of 4.43 (95% CI 1.53, 12.84).95 In the BDES, after adjusting for age, smoking was not associated with 15-year incidence of BRVO.96

Smoking was not associated with CRVO in the EDCC, but was associated with CRVO in another case-control study. Smoking was a suggestive factor in predicting progression from nonischemic to ischemic CRVO in one study.178

6.2.11 Alcohol Consumption

The literature on alcohol consumption and risk of pooled RVO, BRVO, and CRVO is inconsistent. A population-based study from Japan found no association between alcohol intake and prevalence of pooled RVO.206 In the BMES, there was no association with alcohol consumption and 10-year incidence of pooled RVO (age-adjusted OR 5.70 [95% CI1.90Ð17.18]).32

In the EDCCS, presence of light-to-moderate alcohol consumption was a protective factor against BRVO.180 In the BDES, neither alcohol consumption nor a heavy drinking history was associated with prevalent or 5-year incident BRVO.99 In the BDES after adjusting for age, alcohol consumption was not associated with 15-year incidence of BRVO.96

A case-control study found that a person who consumes alcohol had half the risk of developing CRVO compared to a person who had never consumed alcohol.181 Increasing alcohol consumption using a three-step scale was associated with protection against HCRVO.174

Retrobulbar optic nerve meningiomas, increased orbital pressure in thyroid orbitopathy, orbital hematomas from trauma and orbital fracture, and increased cerebrospinal ßuid pressure can increase the venous pressure behind the globe. This in turn may reduce the pressure differential for retinal blood ßow through the eye and predispose to thrombus formation in the central or a branch retinal vein.85

Case reports in which systemic diseases are associated with BRVO are common. Many such associations may be chance occurrences. A partial list of case report associations includes use of anabolic steroids and diuretics by bodybuilders, human immunodeÞciency virus infection, lipemia retinalis, ChurgÐStrauss syndrome, giant cell arteritis, BehcetÕs disease, congenital arteriovenous communication of the retina, sarcoidosis, dehydration associated with fasting, acute intermittent porphyria, pANCA vasculitis, neuroÞbromatosis, breath

miscellaneous laboratory abnormalities have been reported in association with BRVO. In the BDES, a multivariate analysis showed that serum creatinine 1.4 mg/dl or more, increased serum phosphorus level, and increased serum ionized calcium level were each independently associated with a 15-year incidence of BRVO. In a case series that compared prevalences of systemic associations to gender-, race-, and age-matched national cohort, chronic obstructive pulmonary disease, peptic ulcer, and thyroid disease were more prevalent in BRVO than in the comparison group.75 In the BDES, multivariate analysis showed that a history of migraine was independently associated with 15-year incidence of BRVO. The OR was1.99 (95% CI 1.08Ð3.67, P =0.03).96 In the BDES, cancer was not associated with prevalent, 5-year incident BRVO, or 15-year incident BRVO.95,96 Although these reports might suggest consideration of these conditions in a patient with BRVO and no vascular risk factors, their number, variety, and remote relevance makes the recommendation pointless.28

Similarly, case reports in which systemic and ocular diseases are associated with CRVO and HCRVO are common. Again, many such

associations may be chance occurrences. A partial list of associations from case reports includes HIV infection, syphilis, herpes zoster ophthalmicus, preeclampsia, sarcoidosis, primary pulmonary hypertension, optic neuritis, arteriovenous communications of the retina, papilledema, dehydration associated with long-distance running or fasting, BehcetÕs disease, cavernous sinus thrombosis, acute posterior multifocal placoid pigment epitheliopathy, mitral valve prolapse, retinal periphlebitis, pANCA vasculitis, acute idiopathic frosted branch angiitis, meningeal carcinomatosis in which tumor cell inÞltration between the optic nerve and its sheath was suspected of compressing the central retinal artery and vein, peptic ulcer disease, other unspeciÞed gastrointestinal diseases, and the Valsalva maneuver associated with playing wind

instruments.2,4,5,43,44,47,53,64,68,75,80,83,86,101,126,165,167,177,202

Many hematological conditions have been associated with CRVsswO including polycythemia vera, lymphoma, leukemia, sickle hemoglobinopathies, multiple myeloma, cryoglobulinemia, and WaldenstromÕs macroglobulinemia.68,128,182 When simultaneous bilateral CRVO is discovered, it may be worthwhile to investigate for an underlying hematologic disorder such as WaldenstromÕs macroglobulinemia. An effective test for exploring this diagnosis is a serum protein electrophoresis.3 In a case series that compared prevalences of systemic associations to those of a gender-, race-, and age-matched national database, peptic ulcer and thyroid disease were more prevalent in pooled CRVO and HCRVO than in the comparison group.75

6.2.14No Underlying Vascular Risk Factor

It is difÞcult to compare the prevalence of absence of a vascular risk factor across studies because different groups investigate the issue with varying levels of diligence. A higher prevalence may represent a more superÞcial investigation rather than a true lower prevalence of vascular risk factors. In one case series, 20% of patients with RVO had no vascular risk factor.60