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Occlusions of the retinal arterial and venous circulations are common causes of severe visual decline and can affect all age groups. Acute retinal arterial obstruction is often associated with critical cerebrovascular and cardiovascular disease that may require systemic treatment. Retinal venous obstruction may be the presentation of significant systemic hypertension, diabetes mellitus, and a greater risk for cardiovascular morbidity. Additional metabolic and hematologic abnormalities have been identified in patients with retinal occlusive disease. The authors review recent advances in the study of systemic conditions associated with retinal vascular occlusions and offer guidelines for appropriate medical evaluation of patients with retinal occlusive disease.