Ординатура / Офтальмология / Английские материалы / Ocular Pathology_6th edition_Yanoff, Sassani_2009

A B

Fig. 15.16 Preproliferative retinopathy. Fundus (A) and fluorescein (B) appearance. Note numerous areas of nonperfusion. C, Trypsin digest of neural retina shows mainly nonviable capillaries. Some capillaries on left demonstrate endothelial cell proliferation and increased basement membrane deposition, representing intraretinal microvascular angiopathy. (A and B, Courtesy of Dr. GE Lang.)

C

vitreous body or, rarely, into the subneural retinal space.

F.Larger hemorrhages (i.e., globular and confluent) may herald the onset of the proliferative (malignant) phase

of the disease.

VI. Preproliferative retinopathy (Fig. 15.16; see also 15.12) consists of:

A.Increased neural retinal hemorrhages

B.Cotton-wool spots

C.Venous dilatation

D.Venous beading

E.Intraretinal microangiopathy

VII. PDR (“malignant” stage; Figs 15.17 to 15.20)

A.Classically, PDR has been characterized as a vascular response to a hypoxic neural retinal environment. Recently, numerous factors have been cited as contributing to its pathobiology.

1.Some of these factors include hyperglycemia, retinal arteriolar and capillary closure; hemodynamic alterations in retrobulbar circulation and microcirculation; retinal capillary basement membrane alterations; immunogenic mechanisms related to insulin; pregnancy; absence of female hormones; altered plasma proteins that cause platelet and red cell aggregation; increased blood viscosity; altered ability of the blood to transport oxygen; virus induction of DM; and abnormal metabolic pathways in the retinal capillaries.

Development of anemia in a diabetic patient may cause background retinopathy to progress rapidly to PDR.

a.An adequate number of functioning photoreceptors appears to be required for the development of proliferative retinopathy because neonatal mice with hereditary retinal degeneration fail to develop reactive retinal neovascularization in a model of oxygen-induced proliferative retinopathy.

2.Table 15.3 (p. 617) lists some of the myriad vitreous and serum factors that are altered in PDR. They may be produced, in part, by retinal cellular elements, and in turn, probably help modify the behavior of these cellular retinal constituents.

3.Among the mediators acting during the development of PDR, vascular endothelial growth factor

(VEGF) plays a key role.

VEGF is strongly expressed in the endothelial cells of the new blood vessels in fibrovascular membranes removed at vitrectomy for PDR. Conversely, pigment epitheliumderived factor (PEDF), which inhibits angiogenesis, is only weakly expressed in such membranes. VEGF levels are increased in the aqueous humor of diabetic patients, but PEDF levels are decreased in such individuals, particularly those with PDR. Moreover, lowered PEDF levels in aqueous

humor of diabetic patients strongly predicts those who will have progressive retinopathy. In a similar manner, levels of VEGF and endostatin, which is an inhibitor of angiogenesis, in aqueous humor and vitreous vary appropriately to reflect the severity of DR.

a.The VEGF family of growth factors utilizes several receptors that are selectively expressed in homeostasis and in disease. VEGF receptors (VEGFR)-2, -3, and -A may be particularly important in the development and progression of DR. Other contributing factors may be changes in the ratio of VEGF isoforms, and its interactions with various cellular regulators and factors.

b.Although the relationship between VEGF and

PDR is well established, VEGF levels may also

be elevated in other retinal disorders such as retinal detachment and proliferative vitreoretinopathy in nondiabetic patients.

4.Other factors that may contribute to the development of PDR that have been proposed, but still are speculative, include aldose reductase inhibition, nonenzymatic glycation (glycosylation) of proteins,

dysproteinemia, basic or acidic fibroblastic growth factors, and the adhesion receptor integrin αvβ3. Erythropoietin levels are significantly elevated in the vitreous of patients with PDR. Multiple other stimulatory and inhibitory relationships with VEGF seem to be elucidated on an almost daily basis.

5.It is important that the constituents of PDR membranes be compared to those resulting from other forms of intraocular proliferation in order to determine the characteristics of PDR. For example, pro-

E

teolytic activation appears to be involved in extracellular matrix production in PDR and in nondiabetic membranes.

a.Neovascular membranes in retinopathy of prematurity are associated with the glucose transporter GLUT1, which is lacking in proliferative retinopathy.

6.Decreased serum insulin and high glucose levels have been postulated to contribute to decreased fibroblast growth factor-2 production in the RPE and increased glial cell activation in the diabetic retina.

7.PEDF may help protect against pericyte apoptosis. It is suppressed by angiotensin II, which may contribute to exacerbation of DR in hypertensive patients. Conversely, blockade of the renin–angio- tensin system can confer retinal protection in experimental models of DR.

8.Elevated expression of matrix metalloproteinases in the diabetic retina may contribute to increased vascular permeability by a mechanism involving proteolytic degradation of the tight junction protein occludin and subsequent disruption of the tight junction complex.

a). Pregnant women are at particular risk for the development and progression of DR.

11.The new retinal vessels (neovascularization) in

PDR tend to arise from retinal venules, usually at the edge of an area of capillary nonperfusion. Rarely, they may arise from retinal arterioles.

12.The new retinal vessels contain both endothelial cells and pericytes.

a.Neovascular membranes that lie flat on the internal surface of the neural retina are called epiretinal neovascular membranes.

b.Elevated neovascular membranes are called preretinal neovascular membranes.

B.The neovascularization, which is initially intraretinal, usually breaks through the internal limiting membrane, and lies between it and the vitreous. Endothelial cellassociated proteinases can locally disrupt basement membrane (internal limiting membrane) and facilitate angiogenesis.

Vitreous shrinkage (i.e., detachment) may tear the new vessels, leading to a hemorrhage. If a subvitreal hemorrhage results (the common type of diabetic “vitreous” hemorrhage between the posterior surface of the vitreous body and the internal limiting membrane of the neural retina), it clears rapidly in weeks to a few months. If a hemorrhage extending into the formed vitreous (vitreous framework) results, it may take from many months to years to clear. In such patients, vitrectomy may be indicated.

C.Pure neovascularization is eventually accompanied by a

fibrous and glial (Müller cells and fibrous astrocytes) component; it is then called retinitis proliferans.

1.The membranes are composed of blood vessels,

fibrous and glial matrix tissue, fibroblasts, glial cells, scattered B and T lymphocytes, and monocytes, along with immunoglobulin, complement deposits, and class II major histocompatibility complex antigens.

2.Shrinkage of the fibroglial component often leads to a neural retinal detachment, which is usually nonrhegmatogenous (i.e., without a neural retinal tear or hole).

3.Ultimately, the whole process of PDR tends to “burn out” and become quiescent.

D.Fewer than 40% of patients who have PDR, even if they are not blind, survive 10 years; fewer than 25% of diabetic blind patients survive 10 years.

E.Cataract surgery and progression of DR (see earlier in this chapter under section Lens)

VIII. Proposed international clinical DR (diabetic retinopathy) and DME (diabetic macular edema) severity scales*

A.DR severity scale

1.No apparent retinopathy (no abnormalities)

2.Mild nonproliferative DR (microaneurysms only)

*Modified from Wilkinson CP, Ferris FL, Klein RE et al.: Proposed inter-

national clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 110:1677, 2003.

3.Moderate nonproliferative DR (more than just microaneurysms but less than severe nonproliferative DR)

4.Severe nonproliferative DR (any of the following:

greater than 20 intraretinal hemorrhages in each of four quadrants; definite venous beading in 2+ quad-

rants; prominent intraretinal microvascular abnormalities in 1+ quadrants)

5.PDR (neovascularization or vitreous/preretinal hemorrhage, or both)

B. DME severity scale

1.DME apparently absent

2.DME apparently present

a.Mild DME (some retinal thickening or hard exudates in posterior pole but distant from center of macula)

b.Moderate DME (retinal thickening or hard exudates approaching center of macula but not involving center)

c.Severe DME (retinal thickening or hard exudates involving center of macula)

VITREOUS

I.Vitreous detachment (Fig. 15.21; see also Figs 12.8 and 12.9)

A.Vitreous detachment (“contracture”) is more common in diabetic patients than in nondiabetic subjects and seems to occur at an earlier age.

B.The proliferating fibroglial vascular tissue from the optic nerve head or neural retina usually grows between the vitreous and the neural retina (i.e., along the inner surface of the internal limiting membrane of the neural retina), along the external surface of a detached vitreous, or into Cloquet’s canal.The proliferating tissue does not grow directly into a formed vitreous. A preoptic disc canal-like structure, probably Cloquet’s canal and the area of Martegiani, is associated with PDR.

In eyes with diffuse DME associated with vitreomacular traction and a thickened premacular cortical vitreous, ultrastructural examination demonstrates native vitreous collagen with single

cells interspersed within the collagenous layer or a cellular monolayer. Eyes with tangential vitreomacular traction exhibit multilayered membranes on a layer of native vitreous collagen. The predominant cell types are fibroblasts and fibrous astrocytes, with some myofibroblasts and macrophages. Thus, the vitreomacular interface is characterized by a layer of native vitreous collagen and a varying cellular component in eyes with diffuse DME.

II.Hemorrhage into vitreous compartment (Fig. 15.22; see

Fig. 15.21)

A.A hemorrhage into the subvitreal space is more common than into the vitreous body.

Vitreous hemorrhage does not seem to be related to activity. In fact, approximately 60% of vitreous hemorrhages follow sleep or resting. This fact may be related to an increased neural retinal blood flow that normally occurs in the dark (at night).

B.Organization of the hemorrhage with fibroglial overgrowth may occur, usually along the external surface of the detached vitreous.

III.Asteroid hyalosis—some studies show a correlation between asteroid hyalosis and diabetes; others do not. If

diabetes is correlated with asteroid hyalosis, it is probably a very weak correlation (see pp. 486–487 in Chapter 12).

OPTIC NERVE

I.Neovascularization (see Fig. 15.17)—the optic disc is a site of predilection for neovascularization, which often grows into Cloquet’s canal.

II.Ischemic (nonarteritic) optic neuropathy

A.Retrobulbar neuritis, papillitis, optic disc edema, and optic atrophy, all occurring infrequently, may be ischemic manifestations of diabetic microangiopathy in the optic nerve head when collateral circulation is inadequate.

B.Transient bilateral optic disc edema and minimal impairment of function (diabetic papillopathy) may develop in patients with juvenile-onset diabetes.

1.DR may be quite mild in those patients.

2.The condition usually resolves without treatment.

3.It should not be confused with neovascularization of the disc or central nervous system-induced papilledema.

4.It may also be found in older type II diabetics. DR and macular edema may be associated with it.

Diabetic papillopathy may rarely be associated with a rapidly progressive optic disc neovascularization. Transient optic disc edema secondary to vitreous traction in a quiescent eye with PDR may mimic diabetic papillopathy. The development of bilateral nonarteritic anterior ischemic optic neuropathy from diabetic papillopathy has been reported.

III.Central retinal vein occlusion (see pp. 406 and 407 in Chapter 11)

IV. Based on animal studies, diabetes is a risk factor for glaucomatous optic neuropathy. Diabetes is also among the risk factors for optic disc hemorrhages in glaucoma. Nerve fiber layer is decreased, particularly in the superior segment of the retina, in diabetic patients even before the development of clinical retinopathy. Nerve fiber layer thickness further decreases with the development of DR and with impairment of metabolic regulation. This finding may impact the evaluation of nerve fiber layer in glaucomatous diabetic patients.

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