Fina C. Barouch,
George K. Asdourian,
John I. Loewenstein
Sickling hemoglobinopathies are caused by the presence of one or a combination of abnormal hemoglobins in red blood cells. Normal hemoglobin, which is referred to as hemoglobin A (HbA), is composed of two ?-peptide and two ?-peptide chains.[1] A mutation can lead to a single amino acid substitution in the sixth position of the ?-chain (valine for glutamic acid), producing hemoglobin S (HbS), whereas a different substitution at the same position (lysine for glutamic acid) will produce hemoglobin C (HbC). The various hemoglobins can occur in combinations resulting in hemoglobins such as hemoglobin AS (sickle-cell trait), hemoglobin SS (sickle-cell disease or anemia), hemoglobin SC (sickle-cell hemoglobin C disease), and others. A mutation can also induce failure or inadequate production of one of the two peptide chains (? or ?) (?- and ?-thalassemia), which in combination with sickle hemoglobin, leads to sickle-cell thalassemia (S-thal) disease. Sickle cell is the most common hemoglobinopathy affecting humans, with ~8% of African-Americans having the gene for HbS. Other less common genotypes of sickle-cell disease have also been described.
Normal red blood cells are round or oval, flexible, and can squeeze through capillaries. Under conditions of hypoxia and other metabolic conditions (pH, temperature), the red blood cells containing HbS become rigid and adopt an elongated sickle-shaped configuration.[1] This occurs because of the formation of intracellular aggregates of long polymers in a crystalline gel. With recurring sickling, the membranes of the red blood cells become damaged and can no longer assume a normal configuration on reoxygenation and become irreversibly sickled. As the sickle cells increase in number in the circulation, they increase the viscosity of the blood and lead to sluggish blood flow, erythrocytic aggregation, increased adhesion to the vascular endothelium, and eventual vasoocclusion of the vessel. In the fundus, the peripheral retina and the macula are the areas most susceptible for vascular occlusions. The vascular occlusions usually occur in the arterioles, especially in patients with a large number of irreversibly sickled cells, since these rigid red blood cells cannot enter the capillaries. Using fluorescein angiography, prolonged transition times of blood have been well documented in the peripheral retina of sickle-cell patients.[2,3]
The systemic and ocular manifestations of the different hemoglobinopathies do not go hand in hand. Although patients with hemoglobin SS disease manifest the worst systemic symptoms, patients with hemoglobin SC and hemoglobin S-thal hemoglobinopathies exhibit the most severe ocular complications. The reason for this discrepancy is poorly understood.
The sickling process can produce vasoocclusion and secondary tissue changes in all the vascular structures of the eye, including the conjunctiva (conjunctival sickling sign),[4-6] the iris (iris atrophy and neovascularization),[7,8] the choroid (occlusion of the posterior ciliary vessels),[9-12] the optic disk,[13] and the retina. The constellation of retinal abnormalities observed in these patients constitutes the retinopathy of sickle cell.[4,14-24]
The posterior segment abnormalities can be divided into the following categories:
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Optic disk changes |
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Posterior retinal and macular vascular occlusions |
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Chronic macular changes |
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Choroidal vascular occlusions |
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Nonproliferative retinal changes |
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Proliferative retinal changes |
OPTIC DISK CHANGES
Similar to vascular occlusions elsewhere, the small vessels on the surface of the optic disk can exhibit intravascular occlusions (disk sign of sickling).[13] These occlusions are seen ophthalmoscopically as dark red intravascular spots (Fig. 172.1) and probably represent plugs of deoxygenated erythrocytes occurring in the small surface vessels of the disk. Fluorescein angiography (Fig. 172.2) shows linear or Y-shaped segments of hypofluorescence corresponding to these red spots but does not reveal any substantial impairment of blood flow in these vessels.
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FIGURE 172.1 The disk sign of sickling. Blocked small vessels are seen as dark spots or lines. |
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FIGURE 172.2 Fluorescein angiography of the optic disk shows several plugged vessels (arrows). |
These occlusions are transient and do not produce clinically detectable visual impairment. Although disk changes have been found in patients with hemoglobin SS, hemoglobin SC, and hemoglobin S-thal diseases, they are most common in patients with hemoglobin SS disease (29%).[13]
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Optic disk neovascularization is uncommon in patients with sickle-cell retinopathy but has been documented in patients with SC disease, hemoglobin SS, and hemoglobin SA.[25,26] Scatter peripheral retinal photocoagulation has been found to be effective in stimulating regression of disk neovascularization.[25]
POSTERIOR RETINAL AND MACULAR VASCULAR OCCLUSIONS
Acute major retinal vascular occlusions - central and branch retinal artery occlusions and peripapillary and macular arte riolar occlusions - although infrequent, have been reported (Fig. 172.3).[27-36] These occlusions occur more commonly in patients with hemoglobin SS disease, although their occurrence in various other sickling genotypes has been reported. The occlusions can occur in one eye or simultaneously in both eyes and result in complete loss of vision or debilitating central and paracentral scotoma. Arterial occlusions in sickle-cell patients have also been reported as a complication of retrobulbar anesthesia,[29,37] after ocular compression during photocoagulation,[38] during airplane travel,[18] after trauma,[39] and with extreme dehydration.[11]
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FIGURE 172.3 (a) Several cotton wool spots in a patient with sickle-cell disease. (b) Macular infarction in a patient with sickle-cell thalassemia. |
Retinal venous occlusions - central and branch retinal vein occlusions - are very uncommon in patients with sickle-cell disease and one should suspect other underlying causes for their occurrence in these patients.
CHRONIC MACULAR CHANGES (SICKLING MACULOPATHY)
Apart from the acute vascular occlusions of the macular region, chronic vascular changes of the posterior pole have been reported in patients with hemoglobin SS, hemoglobin SC, hemoglobin S-thal, and hemoglobin AS diseases. They occur in ~30% of patients with sickle-cell disease.[19-21,40-43] These occlusions are insidious, progressive, and clinically difficult to detect. They consist of alterations in the normal architecture of the fie vasculature of the macula, perimacular region, and region of the horizontal raphe lying temporal to the macula. They may be transient with a continuous remodeling of the macular vasculature. Careful direct ophthalmoscopy, contact lens examination, and fluorescein angiography are necessary to detect these abnormalities. Microaneurysms, dark and enlarged segments of terminal arterioles representing occluded precapillary arterioles, hairpin-shaped vascular loops, an abnormal foveal avascular zone (FAZ) with adjacent areas of capillary nonperfusion (pathologic avascular zones (PAZs)), and areas of retinal depression (Figs 172.4 and 172.5) may be seen.[44] Sanders and co-workers found the mean largest diameter of the FAZ in patients with hemoglobin SC and hemoglobin SS disease to be 1.0 mm compared with 0.61 mm in normal subjects.[40] However, there was no significant difference in the FAZ diameters within the sickle-cell group in regard to the degree of retinopathy, type of sickle-cell disease, or the visual acuity. The areas of retinal depression are best seen by direct ophthalmoscopy and are thought to be the result of atrophy of the inner retina (secondary to capillary closures) (Fig. 172.6). These depressed areas produce a concavity that appears as a dark retinal area with a bright central reflex.
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FIGURE 172.4 The left macula of a patient with sickle-cell hemoglobin C (SC) disease with an enlarged FAZ. |
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FIGURE 172.5 (a) Fluorescein angiography of the macular area shows an occluded vessel. (b) Fluorescein angiography shows a PAZ, as well as microaneurysmal formation of the perifoveal capillaries. (c) Fluorescein angiography shows an enlarged FAZ. (d) Fluorescein angiography of the macular area shows an enlarged FAZ, microaneurysmal formation, and hairpin loops. (a-c) |
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FIGURE 172.6 Color photograph of the right macula shows the retinal depression sign. |
Even when the innermost arcades of the FAZ are occluded, patients are usually asymptomatic and the visual acuity, color vision, and central visual fields may be normal. However, with more sophisticated clinical tests and static perimetry, absolute and relative scotomas can be detected that correspond to these areas of vascular abnormalities. Furthermore, these macular vascular changes may be the cause of unexplained visual loss or amblyopia in young patients with sickle-cell disease.
CHOROIDAL VASCULAR OCCLUSIONS
Choroidal vascular occlusions are reported to occur in patients with sickle hemoglobinopathies, but their occurrence is rare and clinically difficult to document. Condon and colleagues described three patients with unusual chorioretinal degeneration and suggested that this may be the sequelae of posterior ciliary artery occlusions.[12] Dizon and associates reported on the clinical findings of a patient with hemoglobin SS disease that suggested a posterior ciliary artery occlusion.[9] They also reported the histopathology of three eyes in patients with hemoglobin SS and hemoglobin SC disease that may have sustained small posterior ciliary artery occlusions. Clinically, acute posterior ciliary vessel occlusions appear as white, circumscribed triangular patches at the level of the retinal pigment epithelium (RPE). Eventually, these areas heal with a mottled appearance of the RPE. Acute choroidal infarctions have been well documented after feeder vessel laser photocoagulation of peripheral retinal neovascularization.[45]
Peripheral spontaneous chorioretinal neovascularization has also been reported. Liang and Jampol reported a patient with hemoglobin SS anemia who developed peripheral chorioretinal neovascularization in the center of a black sunburst that was thought to be the result of massive mid-peripheral retinal hemorrhage.[46] Choroidal neovascularization has also been implicated in the formation of angioid streaks and black sunbursts,[10] although the evidence to support the relationship is not very strong.
NONPROLIFERATIVE RETINAL CHANGES
Changes in the retina referred to as nonproliferative or background sickle retinopathy include venous tortuosity; salmon-patch hemorrhage, schisis cavity, and iridescent spots; the black sunburst; and other nonproliferative sickle changes.
VENOUS TORTUOSITY
Although venous tortuosity (Fig. 172.7) was one of the first ophthalmoscopic signs of sickling to be described, it is neither pathognomonic nor of any diagnostic value, since it occurs in a great number of other ocular diseases. It has been reported in up to 47% of patients with hemoglobin SS disease and 32% of patients with hemoglobin SC disease.[18] The tortuosity may be due to arteriovenous shunting that occurs in the retinal periphery of these patients.
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FIGURE 172.7 The left fundus of patient with sickle-cell (SS) disease shows vascular tortuosity. |
SALMON-PATCH HEMORRHAGE, SCHISIS CAVITY, AND IRIDESCENT SPOTS
Salmon-patch hemorrhages are preretinal or superficial intraretinal hemorrhages that occur mainly in the mid-peripheral retina, adjacent to a retinal arteriole.[47] Because of their peripheral location, they do not produce any visual symptoms. These hemorrhages are thought to occur after sudden arteriolar occlusions, with subsequent 'blowout' of the vessel wall, presumably from ischemic necrosis.[29] These hemorrhages are round or oval and are initially bright red (Fig. 172.8). Over several days, however, they acquire an orange-red coloration and have been referred to as salmon patches or salmon hemorrhages (Fig. 172.9). Histologic studies have shown these hemorrhages to be limited by the internal limiting membrane, although some may dissect internally into the vitreous cavity or into the retina and the subretinal space (Fig. 172.10).[48] With the resorption of the hemorrhages, the retina may resume a normal appearance at the site of the hemorrhage, may be marked by a subtle retinal dimple (usually highlighted by the light reflection from the internal limiting membrane), or more frequently, may show a schisis cavity with multiple glistening yellow spots (Fig. 172.11). The schisis cavity represents the space created by the resorption of the intraretinal portion of the hemorrhage, whereas the glistening refractive bodies in the schisis cavity, referred to as iridescent spots, represent macrophages that are filled with iron and blood breakdown products (Fig. 172.12).
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FIGURE 172.8 Acute preretinal hemorrhage. The hemorrhage is bright red. Anterior to the hemorrhage, a black sunburst lesion is seen. |
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FIGURE 172.9 Same lesion as in FIGURE 172.8, 4 weeks later. The hemorrhage is pink (salmon patch) with a surrounding schisis cavity. |
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FIGURE 172.10 Histopathologic appearance of an acute superficial retinal hemorrhage (salmon patch). |
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FIGURE 172.11 Same lesion as in FIGURE 172.8, 6 weeks later. A schisis cavity is seen with multiple iridescent spots. |
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FIGURE 172.12 Histopathologic appearance of a schisis cavity containing proteinaceous material and hemosiderin-laden macrophages (clinical iridescent spots). |
THE BLACK SUNBURST
Round or ovoid black chorioretinal scars, ranging in size from 0.5 to 2 disk diameters and characteristically located in the equatorial fundus, are called black sunbursts (Fig. 172.13).[2,18,21,49] They usually have stellate or spiculate borders caused by perivascular accumulation of pigment. They are sometimes associated with iridescent spots. Because of their peripheral location, these lesions do not produce any visual symptoms.
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FIGURE 172.13 The black sunburst sign. |
On fluorescein angiography, these lesions are hypo- and hyperfluorescent, denoting changes in the RPE (Fig. 172.14). Histologically, these scars represent focal areas of RPE hypertrophy, hyperplasia, and migration (Fig. 172.15).[48] Occasionally, there is a distinct perivascular localization of the pigment in the sensory retina.
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FIGURE 172.14 Fluorescein angiogram of a black sunburst shows areas of focal hyperfluorescence and hypofluorescence. |
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FIGURE 172.15 Histopathologic appearance of a black sunburst shows marked proliferation of the RPE. |
OTHER NONPROLIFERATIVE SICKLE CHANGES
Mottled geographic flat, dark brown areas have been reported in the posterior pole and the fundus periphery (Fig. 172.16).[21,50] These lesions are not associated with any hemorrhagic changes or vascular occlusions, are transient, and disappear over a period of time. Angioid streaks have also been reported to occur in 22% of adult patients with hemoglobin SS disease and less frequently in patients with hemoglobin SC disease.[51-53] Their presence is age dependent, occurring in less than 2% of hemoglobin SS patients less than 40 years of age.[22] They are rarely associated with loss of central vision secondary to choroidal neovascularization. Epiretinal membranes[54] and macular holes[55] have also been reported.
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FIGURE 172.16 Fundus photograph shows a mottled brown area. |
PROLIFERATIVE RETINAL CHANGES
Proliferative sickle retinopathy (PSR) is the most severe ocular complication of sickle-cell disease, since it can lead to severe visual disability secondary to vitreous hemorrhage or retinal detachment. Although neovascularization of the disk and the temporal macula have been reported,[26,56] PSR is overwhelmingly a peripheral retinal disease. PSR occurs more frequently in the temporal retina and tends to be more rapidly progressive in children and adolescents than adults. It is more prevalent in patients with hemoglobin SC and hemoglobin S-thal disease than in those with hemoglobin SS disease. In a study of selected patients from Jamaica, the incidence of PSR was reported to be 2.6% in SS patients,[21] 14% in S-?-thal patients,[19] and 32.8% in SC patients.[20] The development of PSR is also age dependent, with the highest risk period of 20-34 years in SC disease and 40-50 years in SS disease.[22] PSR has also been reported in patients with other hemoglobinopathies such as hemoglobin AS[24] and AC.[23]
The development of PSR follows a relatively orderly sequential course. On the basis of longitudinal clinical studies and with serial fluorescein angiographies, the development of PSR has been classified by Goldberg[14] into five stages (Fig. 172.17):
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Peripheral arteriolar occlusions |
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Peripheral arteriolar-venular anastomoses |
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Neovascular proliferation |
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Vitreous hemorrhage |
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Retinal detachment |
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FIGURE 172.17 Classification of PSR. |
STAGE I: PERIPHERAL ARTERIOLAR OCCLUSIONS
Stage I is the earliest abnormality that can be visualized in the fundus periphery and can be seen even in children with no other evidence of PSR. These occlusions are arteriolar rather than venular and result in the failure of the dependent capillary bed to fill with resultant anteriorly located avascular zones. The occluded arterioles can be seen as dark red lines but eventually turn into white 'silver-wire' vessels (Fig. 172.18). Fluorescein angiography clearly delineates the occluded vessels and the surrounding avascular and abnormal capillary bed (Fig. 172.19).
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FIGURE 172.18 Stage I PSR. Peripheral arteriolar occlusions are seen as 'silver-wire' vessels. |
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FIGURE 172.19 Stage I PSR. Fluorescein angiography shows the occluded peripheral vessels with the adjacent avascular retina. |
STAGE II: PERIPHERAL ARTERIOLAR-VENULAR ANASTOMOSES
With the arteriolar occlusions, a vascular remodeling process ensues, with some vessels remaining occluded and others demonstrating partial or complete reopening. As the blood is diverted from the occluded arterioles to the nearest venules, arteriolar-venular anastomoses develop. Anterior to these arteriolar-venular changes, the retina remains devoid of any perfusion. On fluorescein angiography, there is no evidence of any leakage of dye from these anastomoses, since they do not represent true neovascularization (Fig. 172.20).
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FIGURE 172.20 Stage II PSR. Fluorescein angiography shows the arteriolar-venular anastomoses with the adjacent avascular retina. |
STAGE III: NEOVASCULAR PROLIFERATION
At the interface of vascular and avascular retina, new blood vessels arise from the arteriolar-venular anastomoses and grow peripherally into the preequatorial ischemic retina. The growth of these new blood vessels is thought to be in response to growth factors such as vascular endothelial growth factor and basic fibroblast growth factor.[57,58] These neovascular fronds initially are small, lie flat on the surface of the retina, may be mistaken for microaneurysms or telangiectasia, and are difficult to detect ophthalmoscopically (Fig. 172.21). With time, these neovascular tufts grow, acquire a characteristic fan-shaped appearance resembling the marine invertebrate Gorgonia flabellum, and are known as sea fan neovascularization (Fig. 172.22).[18]
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FIGURE 172.21 Early retinal neovascularization, which may be mistaken for microaneurysms or telangiectasia. |
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FIGURE 172.22 (a) Fluorescein angiography of characteristic sea fan neovascularization. (b) The sea fan neovascularization shows evidence of leakage of dye. Inferior to the neovascularization, the arteriolar-venular anastomosis is seen with early neovascularization. |
Small sea fans usually have a single feeding arteriole and a draining venule. As they grow in size and number they acquire additional feeding and draining vessels and may show progressive circumferential growth leading to neovascularization of the entire retinal periphery. Fluorescein angiography shows leakage of dye from these tufts (Fig. 172.23).
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FIGURE 172.23 (a) Sea fan neovascularization with a single feeder vessel and two draining venules. (b) Sea fan neovascularization with multiple feeder arterioles and draining venules. |
With time, these neovascular tufts may become fibrotic and can be pulled into the vitreous cavity, appearing as elevated neovascular tissue.
STAGE IV: VITREOUS HEMORRHAGE
Peripheral neovascular tufts can bleed spontaneously or secondary to a variety of conditions such as trauma. Spontaneous bleeding occurs secondary to contraction of the vitreous adjacent to the neovascular tufts or due to traction of vitreous bands and membranes resulting from previous vitreous hemorrhages. With PSR, the risk factors for vitreous bleeding are hemoglobin SC disease, more than 60° of perfused sea fans, and the presence of old blood in the vitreous.[59]
STAGE V: RETINAL DETACHMENT
Vitreous traction and fibrous membranes can also produce traction on the sea fan and adjacent retina, resulting in traction retinal detachment or traction retinoschisis.[60] Localized traction detachments may remain stationary or may progress posteriorly. Full-thickness retinal breaks can occur due to traction and lead to total rhegmatogenous retinal detachment. Exudative retinal detachments are rare and may resolve after photocoagulation of the neovascularization.[61]
PSR may progress rapidly in some patients, however in a majority of patients PSR appears to progress slowly and severe visual dysfunction is relatively uncommon. This may be due to the tendency of the neovascular tufts to involute or undergo autoinfarction[62] (reported to occur in 20-60% of eyes with PSR) (Fig. 172.24). Involution may occur because of strangulation of the neovascular tufts by fibroglial tissue, whereas autoinfarction is thought to be secondary to a spontaneous occlusion of the arteriolar feeding vessel.
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FIGURE 172.24 (a and b) Autoinfarcted sea fan neovascularization. (c) A perfused, leaking sea fan neovascularization. (d) Same area several days later shows lack of perfusion. |
Because PSR is progressive and is the major cause of visual morbidity in these patients (12% of eyes showing evidence of visual disability), especially in young persons, obliteration of the neovascular tissue should be accomplished before a major vitreous hemorrhage has occurred.[63]
TREATMENT OF PSR
The aim of therapy is to eradicate new vessels, thus eliminating the complications of vitreous hemorrhage and retinal detachment.[64] The mainstay of treatment is argon laser photocoagulation[64-68] although cryotherapy may be useful when vitreous hemorrhage prevents visualization of the retina. Fluorescein angiography may be useful to localize areas of peripheral leakage prior to treatment.
The neovascular tufts can be directly treated with photocoagulation if the neovascularization is flat on the retina. Another technique favored in the past that has been shown to reduce vitreous hemorrhage and visual loss is feeder vessel treatment, whereby the feeder arterioles and subsequently the draining venules of the neovascularization are directly photocoagulated until the blood flow is obliterated (Fig. 172.25).[65] Feeder vessel treatment is now rarely performed due to complications such as choroidal hemorrhages, choroidal ischemia, and choroidal neovascularization that are associated with the intense burns needed to obliterate the vessels (Fig. 172.26).[45,69,70]
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FIGURE 172.25 Feeder vessel photocoagulation. Both feeder arterioles and draining venules have been photocoagulated. The neovascular tuft is not treated. |
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FIGURE 172.26 (a) Feeder vessel photocoagulation. A localized hemorrhage is noted adjacent to the sea fan neovascularization. (b) Anteriorly located triangular gray areas represent areas of choroidal ischemia. (c) Heavy treatment has resulted in breaks in Bruch's membrane (dark areas in the center of photocoagulation spots). (d) Same patient as in (c). Choroidal neovascularization has occurred at the site of the break in Bruch's membrane. (e-h) Same patient as in (c). Rapid-sequence fluorescein angiography shows choroidal neovascularization occurring after heavy photocoagulation, which resulted in breaks in Bruch's membrane. Center arrows show filling of main choroidal vascular trunk before retinal arterial filling (open arrows). Lower arrows show another but smaller neovascular tuft. |
Most physicians currently favor scatter photocoagulation applied in either a localized area[68] - confied to the area anterior to perfused neovascular fronds (Fig. 172.27) - or in a 360° peripheral circumferential manner (Fig. 172.28).[66,67,71] Both of these techniques show evidence of neovascularization regression with minimal complications.
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FIGURE 172.27 (a) Fluorescein angiogram demonstrates a leaking sea fan neovascularization. (b) Complete regression of the lesion occurred after scatter photocoagulation. |
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FIGURE 172.28 Fundus drawing illustrates the technique of peripheral circumferential retinal scatter photocoagulation. |
Patients with nonclearing vitreous hemorrhages, tractional or rhegmatogenous retinal detachments, or epiretinal membranes can be treated with vitrectomy or scleral buckling.[72,73] However, these surgical procedures can be associated with both ocular and systemic complications. Ocular complications include, anterior segment ischemia (particularly from encircling scleral buckles)[74] and intraoperative hemorrhages with secondary glaucoma. These complications have stimulated the preoperative use of prophylactic exchange transfusions or erythrophoresis.[75] How ever, the risks involved with these transfusion procedures - acquired infections (human immunodeficiency virus, non-A, non-B hepatitis) - have stimulated a reevaluation of this routine. At present, improved vitreoretinal techniques and the use of pre- and postoperative oxygen and intraoperative measures (avoiding excessive manipulation of extraocular muscles, avoiding encircling scleral buckles, limiting the use of intraocular gases) to reduce complications have almost eliminated the need for preoperative exchange transfusions. Systemic complications include thromboembolic complications such as pulmonary or cerebral embolism or thrombosis. Patients who need vitreoretinal surgery should be evaluated by experienced medical personnel to decrease the systemic complications of surgery.
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