Ординатура / Офтальмология / Английские материалы / Diabetes and Ocular Disease Past, Present, and Future Therapies 2nd edition_Scott, Flynn, Smiddy_2009
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34 Diabetes and Ocular Disease
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Figure 3.6. (A) Cotton wool spots are present throughout the fundus (arrows). (B) Microinfarction of the nerve fiber layer is present with swelling, thickening, and cytoid body formation (asterisk).
be reversed by a return to normoglycemia [81]. In the hyperglycemic state, retinal blood flow is increased and oxygen autoregulation decreases. Increasing impairment of autoregulation correlates with increasing severity of diabetic retinopathy [82,83], which may explain venous dilation. Venous loops almost always form adjacent to large areas of capillary nonperfusion and may form secondary to focal vitreous contraction [84]. Venous beading describes focal dilation of the venous retinal vessel, is a sign of severe NPDR, and may occur in the setting of capillary closure and IRMAs.
Proliferative Diabetic Retinopathy. PDR occurs superimposed on nonproliferative retinal changes and is defined clinically as the presence of vitreous or preretinal hemorrhage, neovascularization of the disc (NVD) and/or neovascularization elsewhere (NVE). As defined by the diabetic retinopathy study (DRS) and ETDRS, NVD is new vessel or fibrous proliferation on or within one disc area of the optic nerve head (Fig. 3.7). NVE is defined as new vessel growth on the retina in locations greater than one disc area from the optic nerve head [31] (Fig. 3.8).
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Figure 3.7. (A) Rubeosis iridis: slit lamp photograph discloses proliferation of blood vessels on the surface of the retina (asterisk) and ectropion uveae (arrow). (B) Proliferation of blood vessels on the surface of the iris (black arrows), with adherence between the peripheral iris and cornea (angle closure, asterisk), contraction of the neovascular tissue with resultant rotation of the iris pigment epithelium anteriorly (ectropion uveae, white arrow). (C) High power of the neovascular proliferation on the surface of the iris (arrows).
Proliferative retinopathy may occur in up to 50% of patients with type 1 diabetes [85] and 10% of patients with type 2 diabetes [86] who have had the disease for at least 15 years. The new vessels are seen most frequently in the posterior fundus, within 45 degrees of the optic disc [87,88], grow into the vitreous cavity perpendicular to the retina and have been shown to arise from the superficial veins and venules in the retinal vasculature [89]. The new vessels may grow in a carriage wheel configuration with new vessels forming a network and radiating peripherally to an encircling vessel. New vessels may also grow in irregular networks or grow across the retina for several disc diameters without forming networks. The rate of growth of these new vessels is variable with some patches of vessels showing no change over many months while the growth of other vessels may occur over a period of weeks. New vessels follow a pattern of proliferation and partial to complete regression [87,90]. Vessel regression in a carriage pattern of vessels begins with a decrease in the caliber and number of blood vessels in the center of the network, which is followed by replacement with fibrous tissue. The vessels in the periphery of the network tend to narrow while at the same time may increase in
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Figure 3.8. (A) Neovascularization of the disc: Proliferation of new blood vessels on the surface of the optic nerve (arrow). (B) Proliferation of immature blood vessels (between arrows) arising from the surface of the optic nerve head (asterisk).
length. New vessels may emanate from regressing vessels and vessel growth may be at different stages in different areas of the eye. Vessel sheathing may occur, which represents thickening of the vessel wall [91].
The risk of developing PDR is greatest in patients with severe NPDR. The features of severe NPDR may not be present when preretinal neovascularization is recognized because of the transient nature of the retinal lesions. Cotton-wool spots may disappear in 6 to 12 months and after extensive capillary closure, blot hemorrhages, and IRMAs may disappear. This clinical picture is called a featureless retina.
The cause for the vascular proliferation in diabetic retinopathy appears to be ischemia of the inner retinal layers secondary to closure of segments of the retinal capillary system [62,92–95] with subsequent production of vessel stimulating growth factors by the ischemic retina [93,95–97]. One vessel stimulating growth factor currently being studied is VEGF. VEGF is a group of proteins that initiates
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angiogenesis and increases permeability at blood–tissue barriers. VEGF is produced by the retina, choroid, and retinal pigment epithelium [98] and levels of VEGF are greatly increased in the aqueous and vitreous fluid of persons with diabetic retinopathy [99].
Vessel proliferation into the vitreous cavity first occurs with proliferating endothelium in the absence of accompanying intramural pericytes. Fibrosis, composed of fibrocytes and glial cells [100,101] later forms around the newly formed vessels. The new blood vessels have a propensity to rupture and cause vitreous hemorrhage, because of their delicate structure [102,103], lack of surrounding support [102] and traction placed on these vessels by surrounding fibrous tissue [90]. If the hemorrhage occurs in the subhyaloid space (between the vitreous and the retina) it may assume a boat shape with a rounded bottom and horizontal fluid level. Hemorrhage into the vitreous may remain localized or diffuse throughout the vitreous cavity. Scarring with shrinkage of the surrounding fibrotic tissue may occur and place traction on the vitreous and retina. This traction may cause a partial posterior vitreous detachment, which normally begins near the posterior pole in the region of the superotemporal vessels, temporal to the macula, and above and below the optic disc [87]. In addition, traction may lead to cystic degeneration of the retina and retinoschisis. Contraction of the fibrovascular tissue may also cause distortion of the macula, displacement of the macula, or macular holes by putting tangential traction on the retina and pulling it toward the area of fibrosis. A retinal detachment can result if the vitreous traction occurs in the area of new vessel formation and the retina is pulled with the new vessels and fibrotic material in a direction perpendicular to, and away from, the retinal pigment epithelium [50]. If contraction does not occur, new vessels can grow and regress without causing any visual disturbances to the patient [91]. With complete vitreous detachment from all areas of the retina, PDR may enter the burned-out, or involutional stage, which is characterized by vascular attenuation, optic nerve pallor, pigmentary dispersion, and replacement of neovascularization by avascular glial cells [104].
Other Diabetic Ocular Changes. The crystalline lens of diabetics may undergo cataractous changes. It has been demonstrated that there is an accumulation of sorbitol in diabetic lenses and may lead to an osmotic swelling of the lens and subsequent cataract formation [105]. In addition, sorbitol accumulation may damage the lens epithelium. Transient myopia in diabetics during periods of hyperglycemia is thought to be secondary to the osmotic swelling of the lens [106].
Corneal sensitivity and corneal epithelium adherence may be reduced in the setting of diabetes mellitus. Recurrent corneal erosions often develop in persons with diabetes. This may be due to a reduced adhesion of the epithelium to the basement membrane [107] secondary to decreased penetration of anchoring fibrils from the corneal epithelial basement membrane into the corneal stroma [108–110].
Involvement of the choriocapillaris may occur in diabetes. Basement membrane material of the choroidal vessels may thicken and may obliterate the lumen of vessels in the choriocapillaris [111]. The basement membrane of the pigmented ciliary epithelium may also become diffusely thickened [112] (Fig. 3.9).
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Figure 3.9. (A) Neovascularization elsewhere (NVE): Proliferation of blood vessels on the surface of the retina (arrow). (B) Proliferation of blood vessels through the internal limiting membrane (asterisks) onto the surface of the retina (arrows).
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Neovascularization may occur along the anterior border of the iris in diabetics and is referred to as rubeosis iridis (Fig. 3.10A). The new vessel growth is thought to be initiated by vascular growth factors from the ischemic retina and these new vessels may arise from anywhere along the anterior iris border. Iris neovascularization is associated with significant retinal ischemia [113]. Neovascularization that involves the anterior chamber angle may cause a secondary open-angle glaucoma when the neovascular tissue blocks the outflow of aqueous through the trabecular meshwork and may progress to a closed-angle glaucoma caused by the formation of peripheral anterior synechiae. In addition, the neovascular tissue may cause the pupillary border of the iris to turn anteriorly and develop an ectropion uveae configuration (Fig. 3.10B and C). This is due to shrinkage of the neovascular membrane with traction placed on the iris pigment epithelium and subsequent pulling of the epithelium around the pupillary border [114]. Lacy
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Figure 3.10. (A) Panretinal photocoagulation scars: gray white spots secondary to argon laser photocoagulation (arrow). (B) Intact outer retina (arrows) adjacent to an area of laser photocoagulation demonstrating loss of the inner choroid, retinal pigment epithelium, and scarring and gliosis of the outer neural retina (asterisk).
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vacuolization, which is glycogen-containing vacuoles within the iris pigment epithelium, may occur in diabetic eyes. It is highly characteristic of diabetes mellitus although it may be seen in glycogen storage diseases [115–117]. If the vacuoles are manipulated during anterior chamber surgery, iris pigment epithelium may be released into the posterior chamber (so-called Schwarz-wasser or black water), and may be seen as pigment flowing through the pupil into the anterior chamber.
Macroglial and neuronal cells are also altered in diabetic retinopathy. Macroglial cells include astrocytes and Muller cells. These cells are responsible for integrating neuronal and vascular activity of the retina. Glial fibrillary acidic protein (GFAP) production is decreased in the astrocytes [118,119] and increased in the Muller cells [120] of patients with diabetes mellitus. These changes indicate that the macroglial cells, responsible for maintaining the blood-retinal barriers, have disrupted activity in diabetes. Neuronal cells, which include photoreceptors, bipolar, amacrine, and ganglion cells, are directly affected in diabetes. Retinal ganglion cells and inner nuclear layer cells degenerate by apoptosis early in the course of diabetes mellitus [121]. Color vision and contrast sensitivity are reduced in diabetics [122] and there is a reduction in the oscillatory potential of the electroretinogram (ERG) [123] sometimes before the onset of visible microvascular lesions [124].
TREATMENT
Treatment for macular edema and PDR includes the use of laser photocoagulation. The laser light is absorbed by the retinal pigment epithelium leading to coagulation of the retinal pigment epithelium, choriocapillaris, and outer segments of the photoreceptors (Fig. 3.11). The amount of coagulation is dependent on the amount of laser energy delivered. Endothelial cells in the retinal vessels have been shown to absorb the laser, which causes proliferation of these cells [125,126]. A
Figure 3.11. Basement membrane thickening of the pigmented ciliary epithelium (arrows).
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chorioretinal scar develops, depending on the amount of laser delivered, and the scar is typically composed of retinal pigment epithelium hyperplasia and gliosis. Theories that explain the efficacy of photocoagulation for macular edema include: endothelial proliferation and occlusion of leaking microaneurysms, increased oxygen perfusion from the vitreous through the thinned retina in areas of lasering, with constriction of previously dilated blood vessels and reduction in hydrostatic pressure [127]. Theories that explain the efficacy of photocoagulation for PDR include decreased oxygen demand of the retina by destruction of the retinal pigment epithelium and outer segments of photoreceptors in areas of ischemic retina, destruction of VEGF-producing areas of the ischemic retina and retinal pigment epithelium [128], and production of angiogenesis inhibitors by cells in the chorioretinal scar [129].
CONCLUSION
In conclusion, the histopathologic changes in diabetic retinopathy are the result of retinal microvascular dysfunction in the setting of systemic hyperglycemia. Histological findings that occur before the disease is apparent clinically include pericyte dropout and thickening of the vascular basement membrane. The earliest clinical finding is microaneurysm formation, which is a preproliferative change. Other preproliferative changes include macular edema, cotton-wool spots (soft exudates), hard exudates, intraretinal hemorrhages, IRMAs, and venous caliber abnormalities (venous beading and dilation). Proliferative changes occur superimposed on the preproliferative changes and include vascular and fibrous tissue proliferation in the preretinal space, onto the vitreous framework and into the vitreous cavity. Numerous pathways and mechanisms have been proposed to explain the pathologic changes seen in diabetes mellitus. It is likely that the morphologic changes are the result of an interaction of numerous pathways leading to altered gene expression and protein function in the setting of systemic hyperglycemia. Understanding the pathophysiologic mechanisms of diabetic retinopathy allows the clinician to better identify and treat the vision-threatening changes encountered in patients. The information also provides researchers with potential new targets for therapy as attempts are made to decrease the morbidity from this sightthreatening disease.
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