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

Fig. 1.18. Left 3rd order superior branch vein occlusion. Areas of inner retinal ischemia (Is) are bordered by dilated, incompetent, capillaries

Sudden increases in venous intraluminal pressure during central/branch vein occlusion/venular obstruction cause an acute rise in venous pressure and induce dilatation, flow stasis and transudation of fluid/blood into the perivascular retina (Fig. 1.16). In such disorders, blood is shunted into the non-obstructed circulation (central vein–ciliary circulation) via competent capillary/venular collaterals which border the regions of the occluded circulation (Fig. 1.17a–c). Venous macroaneurysms may develop and varying degrees of capillary collapse persist according to the

order of vein occlusion, residual perfusion pressure (arterial sufficiency) and efficiency of formed collaterals (Fig. 1.18). Upon achieving a steady state, retinal veins become sclerosed to varying degrees (refer to Fig. 1.16), reflecting persistent stresses. Retinal arterial macroaneurysms may reflect longstanding arteriolar stress in patients with hypertension (Fig. 1.19).

A reduction in intraocular pressure may cause macular edema with cystoid degenerative changes and secondary atrophic alterations at the outer retina. Similarly, a reduction in retinal perfusion pressure, often linked to carotid/ophthalmic artery insufficiency, can have similar retinal manifestations and

10

1 I

zation (Fig. 1.23a). When the angiogenic stimulus is sufficiently strong pre-retinal new vessels can arise from unaffected, normal venules (Fig. 1.23b). Systemic changes in blood rheology such as alterations in plasma viscosity, an enhanced pro-coagulative state or physical changes in shape, rigidity and oxygen carrying capacity of red cells can greatly alter laminar flow, increase shear forces within the retinal circulation and cause vascular endothelial damage and microvascular occlusion, e.g., sickle cell disease.

The unique branching pattern of the retinal circulation is engineered to maintain smooth laminar flow of a very dynamic circulation in relatively small vessels. Alterations in branching angles following vascular obstruction and formation of collaterals can induce eddying and turbulence of flow and compromise the vascular endothelium. Key pathological changes to the intraretinal microvasculature following blood flow changes include vascular dilatation, tortuosity, shunt formation and varying degrees of closure of capillary bed. Lack of capillary perfusion or impaired oxygen carrying capacity has a profound influence on the inner retina similar to that outlined above.

1.2.2 Oxygen Saturation Changes

The retina can readily adapt to physiological variations in oxygen saturation or other blood gases to maintain adequate oxygenation of the neuropile. This efficient autoregulation of retinal blood flow

maintains retinal homeostasis over a considerable range of blood oxygen levels and evidence suggests that this is normally altered diurnally in response to oxygen usage by the retinal photoreceptors; not only in the intraretinal microvasculature, but also in the choroidal circulation [26]. Reduced oxygen saturation rapidly affects the metabolically demanding retinal neuropile, which can release metabolites such as adenosine and lactate, and this triggers local vasodilatation and increased blood flow as a direct consequence of vasogenic agents (e.g., NO). This is counterbalanced by integrated release of vasoconstrictors (e.g., endothelin-1).

When levels of oxygenation reach extreme levels this can have a profound influence on the retina and its microcirculation. Sustained hyperoxia has an exaggerated effect on immature retinal vessels with vascular closure and death of growth factor sensitive retinal vascular cells (covered elsewhere). By the same token, hypoxia due to circulatory failure/ obstruction/stasis results in persistent vasodilation, vascular tortuosity and microvascular incompetence due to adverse hemodynamic events and hypoxia induced release of growth factors (e.g., VEGF) (Fig. 1.24a, b). Chronic hypoxia induces vascular endothelial cell proliferation to revascularize metabolically deprived retina and a perturbation of this response causes pre-retinal neovascularization with aphysiological, incompetent, fragile and unsupported vessels ramifying in the pre-retinal and vitreous spaces.

1.2.3 Occlusion – Ischemia

Collapse of the downstream circulation in occlusive disorders is characterized by dilated capillaries, venovenous shunts, microaneurysms, adventitial sclerosis and areas of capillary closure where the intraluminal pressure falls below the critical closing pressure of the affected vessel. In the case of central/ branch retinal artery occlusion, involutionary sclerosis of the compromised artery is common. Whatever the cause of the occlusion and the nature of the vessel, this hypoxic insult has a profound influence on the wellbeing of the affected retinal neuropile (apoptosis, necrosis, glial scar). If severe or uncompensated, these disorders can lead to focal retina ischemia (microinfarct, cotton-wool spot and disordered axoplasmic transport; Fig. 1.25) and significant damage to the neuropile in the form of macular edema, cystoid degeneration, focal atrophy of macular photoreceptors, glial cell abnormalities and pathophysiological changes in the retinal pigment epithelium (RPE). The disordered metabolism of the hypoxic retina, particularly the accumulation of growth factors (e.g., VEGF), has a profound effect on the residual vasculature, e.g., retinal arterioles traversing ischemic retina dilate, stain with dye on angiography and show varying degrees of incompetence (Fig. 1.26). Pre-retinal neovascularization reflects a “wounding” response to non-perfusion and the persistence of viable but metabolically disadvantaged retinal cells. Where there is acute infarction followed

R

O

Fig. 1.25. Left inferotemporal artery occlusion producing retinal edema within the ischemic retina. Demarcation lines denote orthograde (O) and retrograde (R) obstruction of axoplasmic flow

recovery of sufficient circulation to service the residual atrophic gliotic retina (central retinal/branch artery occlusion) retinal neovascularization is not a feature.

13

I 1

Fig. 1.26. Angiogram proliferative/ischemic diabetic retinopathy. Arterioles traversing areas of ischemic retina dilate, show. endothelial staining with dye and incompetence (arrows). On entering perfused retina, arterioles show more normal features

Fig. 1.27. Right superotemporal branch vein occlusion. A collection of new, competent, intraretinal vessels invade non-per- fused retina in linear fashion. The growing front leaks dye (arrow), possibly as the vessels gain the pre-retinal space

14 I Pathogenesis of Retinal Vascular Disease

1 I

S

Fig. 1.29. Advanced age-related macular degeneration with disciform scar (S). Large macular venules (arrows) penetrate the scar to communicate with the choroidal circulation

When a critical threshold of hypoxia (plus associated metabolites and growth factors) is reached, intraretinal new vessels, usually from the vicinity of vein or major venules, breach the internal limiting membrane and proliferate unimpeded by the physical constraints of the densely cellular inner retina, at the vitreoretinal interface (Fig. 1.23b). The form and orientation of these new vessels is determined by concentration gradients of growth factors, e.g., VEGF, TGF, and availability of angiogenic stem cells. At sites of abundant scar tissue, e.g., disciform degeneration of the macula (age-related macular degeneration), the retinal circulation may establish connections (anastomoses) with the choroidal circulation (Fig. 1.29).

1.2.5 Metabolic Stresses

The retinal microvasculature can be influenced by a range of systemic disorders such galactosemia, Fabry’s disease, hyperlipidemia and homocystinuria. Many of these are associated with venous stasis and a variety of occlusive events. Perhaps the most common and well-studied systemic disorder that has a profound influence on the retinal vessel condition is diabetes. Type 1 and Type 2 diabetes is characterized by failure to regulate blood glucose, but these patients also experience hypertension and dyslipidemia that is linked to their disease. Together these metabolic insults result in considerable histopathological alterations to the retina and its microvasculature.

Diabetic retinopathy is often regarded as a quintessential disease of the intraretinal vasculature, but it should be appreciated that there is also a subtle concurrent neuropathy associated with this disorder. Neural defects, which may be linked to oxygenation and vascular function, include early alterations in the electroretinograph (ERG) [37], decreased color and contrast sensitivity, neuronal/glial abnormalities and eventual depletion of ganglion cells [12]. Microscopical choroidal vascular changes may also occur; however, it remains uncertain whether these influence vision.

Retinal vascular dysfunction commences soon after the onset of diabetes and is characterized by impaired autoregulation in the microvasculature which may be an important factor in the initiation and progression of the vascular lesions in diabetic retinopathy [1, 17]. Most clinical hemodynamic studies in diabetes conclude that increased blood flow and impaired autoregulation are features of diabetic retinopathy [30]. Although autoregulatory mechanisms are blunted in these vessels during diabetic retinopathy, they do still show a significant regulatory response to oxygen [14]. Hemodynamic abnormalities associated with diabetes are almost certainly accentuated by the increases in the retinal capillary and venular pressures and diameters that are observed in diabetic patients [30] and which possibly represent a direct consequence of arteriolar dysfunction.

The lesions that are manifest in the retinal vasculature in postmortem specimens from diabetic patients and in appropriate long-term diabetic animal models include retinal capillary BM thickening, which is thought to be a direct consequence of increased synthesis of BM components (e.g., collagen IV, fibronectin and laminin) and/or reduced degradation by catabolic enzymes [18, 28, 32, 34] (Fig. 1.30a, b). It remains uncertain if BM thickening is of primary or secondary importance in the development of diabetic retinopathy but it has been speculated that such matrix modifications may contribute to impaired endothelial–pericyte communication, defects in capillary autoregulation or inappropriate cell interaction with constituent BM proteins [4, 24, 35]. Pericyte loss is a hallmark of diabetic retinopathy and is manifest in trypsin digest preparations by the appearance of pericyte ghosts (Fig. 1.31a, b). Also in the retinal capillary unit, the demise of the endothelial cells follows soon after pericyte loss with formation of acellular capillaries (Fig. 1.31c) and this is more evident in the vessels adjacent to the arterial side of the circulation, often in close association with microaneurysms (Fig. 1.32).

Death of vascular smooth muscle cells (VSMC) also occurs in diabetic retinal arteries and arterioles

Fig. 1.31. a Trypsin digest of 4-year diabetic dog showing a pericyte ghost stained red by the PAS technique (large arrow). A viable pericyte staining strongly with hematoxylin is also apparent on the capillary wall (small arrow). b Electron micrograph of a 4-year-old diabetic dog shows a pericyte ghost (PG) represented as a pocket of vesicular debris within the basement membrane. Endothelial cell (E) remains viable. L lumen. c Electron micrograph of an acellular capillary from a Type 2 diabetic patient. No viable vascular cells are present within the thick, laminated basement membrane (BM) tube. L lumen

[11, 38] (Fig. 1.33a, b) and is observed in trypsin digests by the appearance of cell “ghosts.” In electron microscopic sections, VSMC ghosts appear as pockets of vesicular debris, encapsulated within the arteriolar basement membrane (Fig. 1.33b). Loss of VSMC in the pre-capillary arteriole has important

implications for autoregulation of the downstream c capillary bed with major impact on endothelial cell permeability and survival.

PG

E

BM

L

1 I

PA

Fig. 1.32. Trypsin digest specimen from elderly Type 2 diabetic patient shows massive loss of smooth muscle from a pre-capil- lary arteriole (PA), numerous microaneurysms and acellular vessels in the capillary bed immediately downstream of this vessel (arrows)

The microaneurysm is a hallmark of retinal microvascular disease in diabetic patients. Using the ophthalmoscope, microaneurysms may appear as dark red or white spots (occluded) in the fundus while fluorescein angiography typically outlines perfused microaneurysms as discrete hyperfluorescent spots. Clinicopathological studies of diabetic retinopathy in which exact correlations were made between fluorescein angiograms and trypsin digest preparations have confirmed that regions of capillary acellularity corresponded to non-perfused microvasculature angiographically [5, 16, 19] often downstream from areas where microaneurysms were abundant (Fig. 1.31). One of the earliest abnormalities that predisposes to formation of microaneurysms during diabetic retinopathy is the loss of pericytes [33, 40, 41], and it is likely that localized increases in hydrostatic pressure could account for capillary wall stretching at weak points and subsequent microaneurysm formation [33]. Uncontrolled hydrostatic pressure in capillary

V

V

P

Fig. 1.34. Trypsin digest preparation from Type 2 diabetic showing vascular remodeling with formation of IRMA (arrows) between pre-capillary arterioles (P) and adjacent postcapillary venules (V) that bridge regions of confluent capillary loss in the periarterial zone

beds could result from, or at least be greatly exacerbated by, selective loss of smooth muscle cells in the arteries and pre-capillary arterioles. The effects of intraluminal pressure in microaneurysm formation are further underlined by the presence of similar lesions in other, non-diabetic, conditions such as hypertension [39] where high capillary pressure results from failure of autoregulation, obstruction of venous return or development of high-flow shunts.

Increasing closure of capillaries may be linked with cotton-wool spots in the neural retina and also the occurrence of so-called intraretinal microvascular abnormalities (IRMA). These striking lesions are represented in trypsin digests by wide caliber multicellular channels within the capillary bed [5, 16]. IRMA contain large numbers of endothelial-like cells and occur in association with acellular capillaries close to the arterial side of the circulation (Fig. 1.34). They could reflect increasing retinal ischemia and an attempt to revascularize hypoxic neuropile, possibly to form shunt-like channels.

A

BM

SMG

E

L

17

I 1

M

Fig. 1.37. Fibroglial scar right inferotemporal macula. Disorganization macular circulation, microaneurysms, distorted vessels (arrows). M macula

1.2.7 Drug Toxicity

Systemic delivery of therapeutic agents can often influence the retinal blood vessels. For example, oua-

bain can produce severe and extensive atrophy of the outer retina and, as in radiation retinopathy, this may induce movement of retinal capillaries into the subretinal space. Another example is quinine or chloroquine, traditionally used for protection against malaria. If used in high doses for prolonged periods, these drugs lead to subtle closure of the capillary beds in the retina, secondary to atrophy of the neural retina and the retinal pigment epithelium.

1.2.8 Inflammation

The retinal microvasculature is central to retinal inflammatory processes by transporting inflammatory cells to sites of disease and removing unwanted products of inflammation and cell breakdown from the extravascular space by anionic pump mechanisms. There can be leakage by the retinal vessels which is often observable on fluorescein angiography but without overt retinal thickening. Subclinical inflammatory processes such as postcataract maculopathy (Fig. 1.42) and early diabetic retinopathy may result in intraretinal fluid accumulation and retinal thickening.