procedures [38, 39]. Second, compromised retinal and optic nerve microvasculature introduces a risk of macular and/or optic nerve infarction as the eye is pressurized intraoperatively [40]. During surgery, inadvertent retinal breaks occur with relative ease because of the presence of thin, ischemic peripheral retina, ischemic retina, as is vitreous hemorrhage from traction on sea-fan neovascularization. Vitreoretinal surgery is also complicated in sickle cell patients because of an increased risk of postoperative glaucoma caused by sickled RBCs clogging the trabecular meshwork. Acetozolamide is contraindicated intraor postoperatively because it lowers serum pH and contributes to increased sickling [41]. Routine exchange transfusion is advocated by some to decrease the risk of sickling perioperatively, though other authors believe this is probably unnecessary [42–44].

Several systemic treatments are used to address the complications of SCD. Hydroxyurea is a commonly used agent in the management of SCD and has been shown to decrease hospitalization rates and prolong survival. Transfusions are used to lower the percentage of sickle hemoglobin in the circulation and may help prevent pain crises and stroke. Deferoxamine, an iron chelator used to prevent iron overload, is associated with a toxic retinopathy. There are no effective available treatments for non-proliferative complications of sickle cell retinopathy, although

insights into the pathogenesis of sickle cell vasculopathy may promote new treatments that can prevent sickling and end-organ ischemia. Sildenafil, which increases intracellular cyclic guanosine monophosphate; bosentan, an endothelin receptor blocker already in use for treatment of pulmonary hypertension; and other treatments that are aimed at raising nitric oxide levels are being evaluated in clinical trials [45]. Allogeneic hematopoietic stem cell transplantation appears to be a dramatic but promising method that can reverse the sickle phenotype in severely affected patients [46]. Case reports have reported improvement in ischemic maculopathy with transfusion exchange [47, 48].

Thalassemia

The thalassemias are a group of diseases characterized by decreased production of alpha or beta chains that comprise normal adult hemoglobin, resulting in an imbalance in the alpha to beta chain ratio and decreased hemoglobin production. The minor thalassemias are characterized by decreased production of one alpha or beta chain and are largely asymptomatic. Patients with intermediate thalassemia syndromes are frequently asymptomatic until adolescence and have a decreased production of one of the alpha and beta chains in addition to an abnormal hemoglobin (e.g., sickle cell thalassemia, HbE/

beta-thalassemia). Patients with beta-thalassemia major lack both beta chains and are dependent on regular blood transfusions for survival.

Ocular findings include venous tortuosity, degenerative RPE changes, and angioid streaks. RPE degeneration is more common in patients with thalassemia major than thalassemia intermediate and is likely related to deferoxamine rather than anemia [49].

Deferoxamine Toxicity

Deferoxamine is used as treatment of iron overload in transfusion-dependent patients with thalassemia. Deferoxamine-associated pigmentary retinopathy and optic neuropathy may be reversible upon discontinuation [50–52]. Routine screening for retinopathy in patients on chronic treatment with deferoxamine is recommended [53]. In patients on continuous intravenous infusion for severe iron overload, retinopathy may reach advanced stages over as little as 3 weeks [54].

Glucose-6-Phosphate

Dehydrogenase Deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common enzyme deficiency that leads to acute intravascular hemolysis upon exposure to certain foods, drugs, and infections that overload the G6PD pathway, which is essential to maintain reduced glutathione necessary to protect RBCs against oxidative damage. G6PD deficiency appears to be associated with a lower risk of retinal venous occlusion than in patients with normal levels. The mechanism behind this protective effect is unclear, though alteration in intracellular cholesterol metabolism has been proposed [55].

Paroxysmal Nocturnal

Hemoglobinuria

The molecular pathophysiology in paroxysmal nocturnal hemoglobinura (PNH) points to a defect in the glycosylphosphatidylinositol (GPI)

anchor, leading to an absence of GPI-anchored membrane proteins, resulting in increased complement activation. Hemolysis, thrombophilia, and bone marrow failure are the main clinical features. Retinal venous and arterial occlusive diseases have been described [56]. Serous retinal detachment has also been reported [57]. Venous sinus thrombosis can occur secondary to the general hypercoagulable state with resultant fundus findings [58]. Eculizumab, a humanized monoclonal antibody that targets C5 and prevents assembly of the membrane attack complex, has recently been shown to be effective in reducing hemolysis and thrombosis [59].

Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA) is characterized by antibodies against RBC components resulting in splenic sequestration and extravascular destruction. Retinal hemorrhage and serous macular detachments have been described in case reports [60, 61]. Phlebitis has been reported, although this may have been due to coexisting autoimmune conditions—which are common in patients with AIHA [62].

Thrombotic Thrombocytopenic

Purpura

Microangiopathic hemolytic anemia and thrombocytopenia, in association with renal or neurologic dysfunction, are the defining features of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). TTP and HUS, the former characterized by neurologic dysfunction, the latter by renal failure, are now thought to be related clinical syndromes of the same underlying pathology. Demonstrating schistocytosis (mechanically fractured RBCs) on a peripheral blood smear is essential to the diagnosis. ADAMTS13 deficiency, a von Willebrand factor (vWF) protease, has been implicated in cases of TTP. Deficiency of ADAMTS13 leads to a rise in vWF multimers with resultant platelet aggregation and formation of platelet thrombi in the

microvasculature—a hallmark histologic feature of TTP [63]. HUS, a common cause of renal failure in children, is primarily caused by Shiga-like toxin associated with foodborne infection with

Escherichia coli E157:H7 [64].

Other disorders, such as disseminated intravascular coagulation, connective tissue disease such as lupus or scleroderma, antiphospholipid antibody syndrome, or malignant hypertension, may mimic HUS/TTP and should be considered in the differential diagnosis. Kidney biopsy is sometimes necessary to establish the diagnosis. Timely diagnosis is essential as plasma exchange therapy is usually curative.

Fundus findings in patients with TTP/HUS include serous macular detachment, retinal hemorrhages, cotton-wool spots, a Purtscher-like retinopathy, and retinal artery and vein occlusions [65–68]. Ocular findings often resolve after plasma exchange therapy [69]. Panretinal photocoagulation and anti-VEGF agents have been successfully used in treating associated neovascularization [70].

Antiphospholipid Antibody Syndrome

Antiphospholipid antibodies (APL) are associated with a vaso-occlusive vasculopathy. Common features are cotton-wool spots, arteriolar nonperfusion, neovascularization, and vitreous hemorrhage [71]. Retinal vein and artery occlusions have also been reported [72]. However, antiphospholipid antibodies are frequently a nonspecific finding. They may be found in asymptomatic patients or can be seen in association with other systemic autoimmune disorders such as systemic lupus erythematosus. The incidence of ocular pathology in patients with antiphospholipid antibodies is not clear. However, there does appear to be an increased risk for the presence of antiphospholipid antibodies in patients with retinal vein or artery occlusions, particularly in the absence of other risk factors for vascular occlusions [73, 74].

A portion of patients with detectable APL will have the antiphospholipid antibody syndrome (APLS). APLS is defined as vascular (arterial or venous) thrombosis or pregnancy loss

in the presence of two positive laboratory tests performed at least 6 weeks apart [75]. Castanon et al. studied 17 patients with APLS, and fundus abnormalities were present in 15 of them. Choroidal ischemia was detected in 2/17 patients, and areas of retinal nonperfusion were seen in 5/17 patients [76]. Other findings included venous tortuosity, optic nerve swelling, cottonwool spots, vitreous hemorrhage, and serous macular detachment. APLS has also been reported to mimic serpiginous chorioretinitis with an occlusive vasculitis [77].

Patients with APLS should be maintained on antiplatelet and anticoagulant therapy with aspirin and Coumadin, with a target international normalized ratio (INR) between 2.0 and 3.0 [78]. Patients with severe acute vision loss due to vaso-occlusive retinopathy may respond to acute treatment with cytotoxics and/or plasmapheresis [79].

Hemophilia and Platelet Disorders

Platelet disorders result in spontaneous intraretinal hemorrhages, similar to the way platelet disorders characteristically produce skin petechiae. Hemophilia and other clotting factor disorders may cause spontaneous hemorrhage if the factor deficiency is severe; however, in most cases, hemorrhage occurs following trauma or surgery [80]. Vitreous, retinal, and choroidal hemorrhage have all been reported [81–83].

Surgery can be performed safely in patients with inherited deficiencies if accompanied with administration of ddAVP (desmopressin acetate tablets) and infusions of clotting factor concentrate [84, 85]. Acquired factor deficiency, or resistance to circulating factor sometimes caused by autoantibodies, can be treated with clotting factor infusion and systemic immunosuppression [86].

Myelodysplastic Disorders

It is the development of dysplasia, or “bad formation,” along with ineffective hematopoiesis that characterizes this group. The hematologic findings manifest as a cytopenia in one or more