Chapter 6
Systemic and Ocular Associations
of Retinal Vein Occlusions
6.1 Introduction
Epidemiologic studies show that certain systemic and ocular factors are associated with the prevalence and incidence of retinal vein occlusions (RVO). These associations have provided clues for understanding the pathogenesis and have provided a rationale for treating the manifestations of RVO.203 An ophthalmologist naturally considers using laser treatment, intravitreal injections, or surgery in patients with RVO. However, optimizing the systemic and ocular factors that inßuence RVO is prudent, may reduce the risk of subsequent RVO in the same or the fellow eye, and may reduce the severity of subsequent problems in the affected eye.203
Studies of association are problematical. Some are case series with possibilities of referral bias. Also, in the absence of a control group, valid comparative statements regarding suspected associations cannot be made.6 Attempts to overcome this ßaw by comparing proportions of patients with associated diseases to proportions from an age-matched national sample or from historical controls are invalid.
Internal controls speciÞc to the study are essential, as populations differ geographically and over time.175
Even in better-designed studies, there may be differences in associations between ethnic groups, as well as varying times over which population characteristics may change. For example, association of RVO and stroke appears to vary between Caucasians and Chinese.
Case-control studies have suggested that hyperlipidemia is less signiÞcant as a risk factor for RVO in Hispanic as compared to non-Hispanic populations.7 Diabetic control appears to have improved over US populations between the 1980s and 2000s, making associations of diabetes and RVO from one era suspect when generalized to the other.
Comparing different studies that examine the same factors can be compromised by differences in deÞnitions. For example, in some studies, hyperlipidemia is deÞned as a fasting serum cholesterol greater than 250 mg/dl or fasting serum triglyceride level greater than 177 mg/dl, whereas in others, it is deÞned as fasting total cholesterol level greater than 200 mg/dl or currently being treated with a lipid-lowering medication.142
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6 Systemic and Ocular Associations of Retinal Vein Occlusions |
Problems with the Case-Control Study Design When Investigating Systemic Associations of Retinal Vein Occlusions
Although the case-control study is the most common type of systemic and ocular association study, its design has several ßaws. One is that the control group can inßuence the interpretation.151,200 For example, one study compared two choices of a control group, one from the photographic Þles of the department and another from the attendees of a general ophthalmology clinic. The relationship of diabetes and race to CRVO changed simply by choice of the control group. The control group chosen from photography Þles biased prevalence toward presence of diabetes.151 In another example, the authors chose a control group composed of 33 patients with treated hypertension and seven hospital staff members.39 No difference was found in the proportion of patients with CRVO having hypertension compared to the control group, but had the control group been chosen differently, for example, 40 age-matched hospital staff, the result may have been different. A control group rich in subjects with hypertension could bias the outcome away from detecting a difference. Finally, in a study on proportions of patients with RVO having antiphospholipid antibodies (APLAs), the control group was chosen from among patients with trauma, a group signiÞcantly younger than those of the cases (mean ages 52 and 29 for the cases and controls, respectively).13 The choice of younger controls could bias toward a lower prevalence of APLAs. At best, case-control studies usually match based on age and gender but do not match for other relevant factors such as body mass index, renal function, smoking, and intraocular pressure. Mismatches on factors that may be related to pathogenesis could bias the results.142
Case-control studies also suffer from omission bias. If a condition was not considered at the time of the patient encounter, it will have no chance of being discovered as an association.151 Prospective studies prespecify the associations to be tested and obtain the relevant data in a standardized way. Prospective, population-based studies are thus more reliable for determining systemic associations.
In association studies, it is important to adjust for possible confounding factors. In a retrospective study using a national insurance database, the 5-year risk of stroke among patients with RVO was signiÞcantly higher than in controls in several age strata before, but not after, adjusting for hypertension and hyperlipidemia.81 There is evidence that the presence of glaucoma and the increasing risk of RVO with age are such strong associations that all other factors must be assessed after adjusting for them, but this adjustment is not commonly made.132 For statistical reasons, studies with smaller numbers of cases will have more difÞculty detecting associations. Because studies report fewer cases of HCRVOs than CRVOs or BRVOs, it is more difÞcult to Þnd factors associated with HCRVO.174
Association studies can suggest, but cannot prove, causality because the associations may represent a situation in which the systemic factor and the RVO are both related to a third factor. For example, increased blood viscosity, hematocrit, Þbrinogen, factor VIII, increased beta-thrombo-
globulin, and decreased platelet count have been associated with RVO but are also associated with atherosclerosis. The association of these factors with RVO may be coincidental to the fact that both the factors and RVO are associated with atherosclerosis.184
Many more associations are present with univariate testing than with multivariate testing, suggesting that the information carried by these associations may be redundant. Therefore, predictive variables found on multivariate testing are more reliable than those found by univariate testing. In addition, the important predictive factors are not always the same for different endpoints. For example, in the Beaver Dam Eye Study (BDES), baseline ocular perfusion pressure was associated with prevalence, but not 5-year incidence, of RVO.95 Likewise, a history of hypertension was associated with prevalence, but not 5-year incidence, of BRVO.95 In studies testing associations with many variables, care must be taken to statisti-