Ординатура / Офтальмология / Английские материалы / Retinal Vascular Disease_Joussen, Gardner, Kirchhof_2007

702 III Pathology, Clinical Course and Treatment of Retinal Vascular Diseases

27 III

Fig. 27.1.2. b At higher magnification, a short hairpin loop (straight arrow) is apparent in one of the AV anastomoses. c A section through the white area in a and b indicated with a curved arrow shows collagenous tubes that represent the feeder vessels of an autoinfarcted sea fan. d When the area shown in b is viewed with bright field illumination, a black sunburst lesion is apparent just peripheral to the border of perfused and nonperfused retina (open arrow in a, b). e A section through the black sunburst lesion in d shows that hypertrophic RPE cells have formed acinar-like formations in this area of atrophic retina

Connections form between occluded arterioles and adjacent terminal venules by way of preexisting capillaries, resulting in arteriovenous anastomoses at the border separating the vascularized and the ischemic peripheral retina (Fig. 27.1.2). The anastomoses do not show leakage on fluorescein angiography, confirming that they indeed represent enlargement of preexisting vessels with intact blood-retinal barrier properties, rather than true neovascularization [13, 31, 32].

Occlusion within a portion of a vein may exert substantial backpressure within the proximal vessel and result in focal vascular extrusion [29] (Fig. 27.1.5). This extruded vessel or loop may further enlarge as the elevated intraluminal pressure persists. Stretching of the vascular structures may lead to endothelial cell proliferation [7] and neovascularization [38].

27.1.2.2 Causes of Vaso-occlusions

Density separation of sickle erythrocytes demonstrates that there is a heterogeneous population of erythrocytes ranging from dense irreversibly sickled cells to lightest density, younger reticulocytes [19]. Although dense cells have been traditionally implicated in vaso-occlusive events in the sickle hemoglobinopathies, there is emerging evidence that the pathophysiology of vaso-occlusion involves more than simple mechanical obstruction by rigid, dense, irreversibly sickled erythrocytes. At sites of occlusion like the arteriovenous crossing in Fig. 27.1.3, packed sickle RBCs often precede platelet fibrin thrombi and leukocytes. Leukocytes [23] and lowdensity circulating reticulocytes [18, 20, 28, 34] both express adhesion molecules that promote abnormal adherence to the vascular endothelium. Some young reticulocytes express integrin 41 (VLA-4), enabling the cells to bind to vascular cell adhesion molecule-1 (VCAM-1) found on the surface of activated endothelial cells. Sickle reticulocytes also express the non-integrin glycoprotein IV (CD 36), which may mediate binding to vascular endothelial cells [18]. Red cell–endothelial adhesion is further promoted by the direct activation of endothelial cells, leading to the expression of adhesion molecules such as ICAM-1 (intracellular adhesion molecule- 1),VCAM-1, E-selectin, and P-selectin [35]. We have observed a significant increase in polymorphonuclear leukocytes (PMNs) in sickle cell retina compared to control subjects and in the same sickle cell subjects a significant increase in ICAM-1 and P-selec- tion, adhesion molecules responsible for PMN rolling and firm adherence respectively [23]. Sickle reticulocyte and leukocyte adherence to the vascular endothelium creates microvascular stasis, which in turn leads to increased red cell transit time, further polymerization of hemoglobin S, and complete vessel occlusion. Dense, irreversibly sickled cells do not adhere well to the vascular endothelium because they lack the adhesion molecules present on lowdensity reticulocytes and because their rigidity prohibits large areas of surface contact with endothelial cells; however, they can obstruct blood vessels in which reticulocytes and leukocytes are adherent.

Other research has examined the role of inflammatory cytokines, such as tumor necrosis factoralpha (TNF-) and interleukin-1-beta (IL1-), which may contribute to vaso-occlusion by accelerating the production of adhesion molecules on the vascular endothelium and by activating polymorphonuclear leukocytes [10]. These cytokines may be released under conditions of stress, such as systemic infection or tissue hypoxia. Other investigators have theorized that some form of imbalance in the fibrinolytic sys-

tem may also contribute to microvascular occlusions through enhanced deposition of fibrin and increased thrombin activity [9, 25]. Perhaps cytokine activation of the vascular endothelium is the critical event in leukocyte and reticulocyte adherence and in the initiation of the clotting cascade. Hematocrit also plays a role in vaso-occlusion by affecting the blood

viscosity [15]. III 27 This may provide a partial explanation for the dis-

crepancy in the severity of ocular and systemic manifestations in the various sickling hemoglobinopathies. HbSC and HbSThal subjects tend to have substantially higher hematocrits than HbSS subjects, contributing to higher viscosity with potentially more pronounced vaso-occlusion in the retinal microvasculature during any given sickling event. Even though HbSS patients have a larger number of circulating sickled red cells, their overall lower hematocrit may provide relative protection from vaso-occlusion in the small-caliber vessels of the retina [14]. An alternative theory proposes that the retinal vascular occlusions in HbSS disease may actually be so complete that total infarction and retinal necrosis occur, with no viable tissue remaining that is capable of initiating an angiogenic response. In contrast, the occlusions in HbSC disease may be less severe, resulting in chronic ischemia, but less complete infarction, and therefore with continuous secretion of angiogenic substances by the damaged tissues [12].

We propose a third theory. Using a rat model, we demonstrated that high-density HbSS erythrocytes (dehydrated dense discocytes and irreversibly sickled cells) are easily trapped in retinal capillaries and precapillary arterioles under hypoxic conditions, whereas HbSC cells (normaland high-density cells) show very little retention in the retinal microvasculature, regardless of oxygen concentration [26]. Retention of HbSC cells does occur, however, after stimulation of the vascular endothelium with the cytokine TNF- (unpublished data). We demonstrated further that TNF- exposure causes SC and SS reticulocytes to adhere in retina and this is associated with VLA-4 on erythrocytes and fibronectin on retinal endothelial cells [27]. Perhaps vaso-occlusion in HbSC disease actually depends more on extra-eryth- rocytic factors, such as abnormalities in the fibrinolytic system, leukocyte interactions, activation of vascular endothelium, and the induction of adhesion molecule expression, than on the mechanical trapping of dense, rigid, sickled cells. This subtle difference in pathophysiology may very well provide an explanation for the discrepancy in the severity of systemic and ocular findings seen in subjects with HbSC and HbSS disease.

27.1.2.3Hemorrhage, Schisis Cavities, Iridescent Spots, and Black Sunbursts

The occlusive processes are also associated with intraretinal hemorrhages. Salmon patch hemorrhages as they are called are round to oval areas of hemorrhage located within the superficial retina.

27 III The lesion may be up to 2 mm in diameter, with welldefined boundaries and either a flattened or a domeshaped configuration. Such hemorrhages, which usually occur in the midperipheral retina adjacent to an intermediate arteriole, are thought to result from a blowout of vascular walls weakened by prior episodes of occlusion and ischemia. Although the hemorrhage is initially red, it may turn salmon-col- ored over time because of progressive hemolysis [11, 33].

After resorption of the salmon patch hemorrhage, the retina may appear entirely normal, without any evidence of residual blood. In the location of the hemorrhage, however, there may also be a faint indentation or depression representing thinning of the inner retina. This appears on ophthalmoscopy as a dimple, which may contain multiple glistening, refractile, yellowish granules, which are hemosider- in-laden macrophages. Histopathologic examination demonstrated that the granules and macrophages may be enclosed in retinoschisis cavities and both intracellular and extracellular iron may be present in the area [33].

The black sunburst lesion has also been associated with intraretinal hemorrhages [40]. These lesions

appear as a flat, round to oval black patch, about 0.5 – 2 mm in size (Fig. 27.1.2D). Glistening, refractile granules, similar to those observed in iridescent spots, may be present. Histopathologic study discloses focal hypertrophy of the retinal pigment epithelium (RPE) along with areas of RPE hyperplasia and migration (Fig. 27.1.2E). Also present are diffuse iron deposits, hemosiderin-laden macrophages, and pigment deposition. Romayanada et al. hypothesized that the black sunburst represents intraretinal migration of hyperplastic RPE in response to blood that had dissected between the RPE and neurosensory retina [33] but the etiology of the black sunburst may be multifactorial. The black sunburst may evolve directly from a salmon patch hemorrhage depending on the plane of dissection of the resulting hemorrhage [1] as has been clearly demonstrated in a 17-year-old man with SC disease during a 6-year follow-up period [39]. However, it is interesting that hemorrhages occur often in diabetic retinopathy; yet no black sunburst-like lesion occurs in diabetic subjects. Others have observed choroidal neovascularization (CNV) within the black sunburst lesion [24, 25] and may develop following a localized choroidal occlusion [3, 41]. This suggests that RPE migration into retina may be associated with choroidal dysfunction in some cases. We have found that most black sunburst lesions are in atrophic, nonperfused regions of retina and associated with high levels of transforming growth factor beta (TGF-), which is associated with fibrosis [25].

27.1.3 Proliferative Retinopathy

Peripheral retinal vascular occlusion is the initiating event in the pathogenesis of proliferative sickle retinopathy. Clinically, arteriolar closure appears to preferentially occur at or near Y-shaped bifurcations [37]. Occlusions also often occur at arteriovenous crossings [30] (Fig. 27.1.6). The occlusive process presumably produces local ischemia, which stimulates the production of vascular growth factors.

Peripheral retinal neovascularization (Fig. 27.1.7) often assumes a frond-like configuration, resembling the marine invertebrate Gorgonia flabellum (sea fan), but intraretinal neovascularization (IRMA) can also be found at sites of active angiogenesis (Fig. 27.1.8). The majority of the neovascular sea fan formations are found at the interface between

the superotemporal quadrant, followed, in order, by the inferotemporal, superonasal, and inferonasal quadrants (Fig. 27.1.6) [14]. They usually are limited to the equatorial retina, rarely extending to the posterior pole. Sea fans represent true neovascular tissue and thus show profuse leakage of intravascular fluorescein dye and human serum albumen by immunohistochemistry, indicating loss of the bloodretinal barrier. The clinician can take advantage of this property by using intravenous fluorescein angiography or angioscopy to detect subtle patches of neovascularization not evident during standard ophthalmoscopy [14].

Both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) are associated with sea fans [2]. In a recent study, we ironically observed extremely high levels of the antiangiogenic factor pigment epithelial growth factor (PEDF) and VEGF associated with sea fans (Fig. 27.1.9) [22]. Using densitometric analysis of the reaction products, we found that the ratio of VEGF to PEDF was

reduced and shifted in the sea fans to 1:1, suggesting that the increase in VEGF alone shifted the balance toward angiogenesis [22].

As sea fans grow into the vitreous cavity, traction on their delicate vascular channels results in bleeding at irregular intervals for years. Traction-induced hemorrhage may occur in the setting of minor ocular trauma, normal vitreous movement, or contraction of vitreous bands induced by previous hemorrhage. Vitreous hemorrhage may be asymptomatic, if it remains localized to the region adjacent to the sea fan. The end result is the emergence of sea fanshaped neovascular fronds that are predisposed to vitreous hemorrhage, subsequent tractional vitreous membrane formation, and ultimately retinal detachment [14, 17].

Vitreous bands and condensed contractile membranes are common sequelae of chronic vitreous hemorrhage and plasma transudation from incompetent neovascular tissue. They serve as key mechanical players in the progression to tractional and/or

Fig. 27.1.9. PEDF and VEGF immunolocalization in retina and feeder vessel (A–C) and sea fan neovascular structure (D–F) in a 58-year-old SC disease subject. A, B Heparan sulfate proteoglycan perlecan immunolocalization demonstrates only viable retinal blood vessels and a feeder vessel (double arrow) that supplies the sea fans’ viable vascular channels (arrow in A, D). PEDF immunoreactivity is present in the retinal vessels, feeder vessel, and sea fan but also is prominent in the matrix components of the sea fan (asterisk) (B, E). VEGF immunoreactivity is present predominantly in viable retinal blood vessels and the feeder vessel in C and viable vessels in the sea fan (F). (Red AEC immunoreaction reaction product and hematoxylin counterstain) (Fig. 3 from [22])

27.1 Histopathology of Sickle Cell Retinopathy 709

III 27

rhegmatogenous retinal detachment. As one would expect, retinal detachment is found most frequently in SC subjects [40], since these are the patients most plagued by proliferative disease. Retinal detachment is rarely present in HbAS [16] or HbSS [4, 21] subjects.

Sea fan fronds may regress over time with an eventual rate as high as 60 % because of the process of autoinfarction [5, 11]. Although not completely understood, the pathophysiology of autoinfarction is probably multifactorial. In a milieu of chronic hypoxia and ischemia, multiple recurrent episodes of thromboses and sickling within sea fans may eventually lead to permanent infarction of the lesion. Kunz Matthews et al. found greatly elevated numbers of PMNs in sea fans, which was associated with elevated P-selectin, VCAM-1 and ICAM-1 [23]. Undoubtedly, PMNs contribute to autoinfarction of sea fans. We also observed high levels of PEDF in autoinfarcted sea fans while VEGF levels were very low, which could predispose the neovascular formation to regress [22]. The atrophic sea fans may slough off into vitreous leaving a stalk containing the major feeding and draining blood vessels (Fig. 27.1.2).

Major nutrient vessels may also become kinked or even avulsed by vitreous traction (Fig. 27.1.5), resulting in complete interruption of feeder vessel flow [29].

Although sea fans may autoinfarct in one region of the eye, they may continue to flourish in other regions of the same eye (Fig. 27.1.6). For this reason, most neovascular lesions are considered potentially dangerous and ordinarily should be treated and obliterated.

27.1.4 Choroidopathy

Described numerous times in patients with sickling hemoglobinopathies [6, 8, 29, 36], choroidal nonperfusion is thought to result from occlusive events in the posterior ciliary arterial circulation. As in retina, adhesion of reticulocytes with VLA-4 to endothelium may play a role [28]. Some investigators have suggested that vaso-occlusive events in the choroidal vasculature may be involved in the formation of the black sunburst lesion [3, 41]. Histopathologic features associated with choroidal vaso-occlusion include impacted erythrocytes, increased fibrin, and platelet-fibrin thrombi [25, 29].

Occlusions of the choroidal vasculature may also contribute to the orange-red or brown streaks that emanate radially in the fundus from the optic nerve called angioid streaks. These appear as crack lines in choroid and are thought to be due to calcification and brittleness of Bruch’s membrane, the limiting membrane between retina and choroid.

27.1.5 Conclusions

Sickle cell vaso-occlusions are at the origin of most pathological changes in sickle cell retina and choroid. Sickle erythrocytes are certainly the major cell type involved in the occlusive process, but leukocytes and the fibrinolytic system may contribute to

27 III the process as well. Occlusions are common at arteriovenous crossings, as they are in branch vein occlusion, and they cause salmon hemorrhage and associated iridescent spots and retinoschisis cavities as well as contributing to the formation of black sunburst lesions. Vasoproliferation occurs in this ischemic retinopathy in the formation of hairpin loops, IRMA, and sea fan formations.

Acknowledgements. The author acknowledges his collaborators D. Scott McLeod, Carol Merges, MES, Michaela Kunz-Matt- hews, and Jingtai Cao, who contributed substantially to the studies discussed in this manuscript. D. Scott McLeod is responsible for creating all of the figures shown and performed all of the ADPase analysis of the sickle cell retinas. This work was supported by NIH grants EY 01765 (Wilmer Institute) and HL45922 (GL), the Reginald F. Lewis Foundation (GL), and Research to Prevent Blindness (Wilmer). Gerard A. Lutty is an American Heart Association Established Investigator and the recipient of a Research to Prevent Blindness Lew Wasserman Merit Award.

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