Documenta Ophthalmologica 40, 2: 383-389, 1976. RETINAL VASCULAR OBSTRUCTION W. A. MANSCHOT
(Rotterdam) In this paper, the approach to the understanding of retinal vascular disease as was adopted by Wise, Dollery & Henkind in their book on retinal circulation is used. This approach is based on the experience that retinal vascular disease has its chief impact on either the arterial side of the retinal circulation - as in arteriosclerosis and hypertension - or on the capillaries and veins - as in venous obstruction and diabetes. The deep capillary bed receives almost all its blood from the superficial capillary bed between the arteries and the veins and has little or no direct connection with precapillary arterioles. Therefore, the deep capillary bed is associated only with capillary and venous dysfunction. On the contrary, the superficial capillary bed - through its direct association with the arterioles - is more associated with arterial dysfunction. Signs of involvement of the superficial capillary bed, caused by arterial dysfunction, are: superficial oedema, macular figure, superficial haemorrhages, cotton-wool patches and neovacularization. Signs of involvement of the deep capillary bed, caused by capillary and venous dysfunction, are: deep oedema, microcystic macular oedema, deep haemorrhages, fatty exudates, microaneurysms and neovascularization. Much overlapping occurs but, nevertheless, grouping retinal vascular diseases and symptoms in this way is helpful in understanding their pathology. A macular star figure is usually left behind when superficial retinal oedema recedes from the macular area. Since Henle's layer - although lying superficially in the macular region - is a continuation of the outer plexiform layer, macular star figures are also common after deep retinal oedema. Large superficial haemorrhages are clinically often appreciated as preretinal haemorrhages, but, for the most part, they lie just under the internal limiting membrane. Cotton-wool patches are no 'small retinal infarcts' as is often stated ; this would imply a necrotic lesion resulting from total arterial obstruction. The underlying cause in every case is stagnant hypoxia or anoxia from focal circulatory failure which can be arterial, capillary or venous in origin. The
Ophthalmic Pathology Laboratory, Erasmus University, Rotterdam.
383
hypoxia causes endothelial damage and excessive permeability of the capillary walls. Microscopically, there is little tissue necrosis. Cotton-wool spots are composed of a zone of retinal oedema in which there is a cluster of socalled cytoid bodies which consist of the swollen end of fragmented exones. Neuro-pathologists would label them terminal swellings of Cajal. Deep retinal oedema from the deep capillary bed thickens the retina at the macula and sometimes throughout the posterior pole. Deep retinal oedema forms pockets in the outer plexiform layer but may extend into the nuclear layers. They arise from the deep capillary bed. Almost all peripheral haemorrhages are of this type. Exudates are common in diseases attacking capillaries and veins and are not seen in arterial obstructions. They lie in the deep retina in the outer plexiform layer. For a long time it has been accepted that they consist of fats liberated from dead retinal cells and of lipophages. More recently, it has been postulated that the fatty material might have seeped through defective capillary or venous walls, or that it represents a by-product of the altered metabolism of subnormally oxigeneted but still viable retinal ceils. Both hypotheses might be true. Microneurysms are not specific for diabetes and have been reported after venous obstruction and in many other diseases such as dysproteinaemias, Coats' and Leber's diseases, retinoblastoma and chronic glaucoma. After central retinal vein obstruction, their wall is not thickened as is often found in diabetes. The etiology of neovascularization is still hypothetical. It is generally accepted that hypoxic retinal cells elaborate a vasoproliferative factor. So far, this actual factor has not yet been isolated. New vessels predominantly arise from capillaries and veins, although with fluorescein angiography some early proliferating vessels fill during the arterial phase. Light microscopy shows no difference in the structure of normal retinal capillaries and newly-formed vessels, but they differ physiologically in the profuse leakage of fluorescein from even the smallest neovascular formations. In eyes with retinal vascular obstruction, neovascular growth on the anterior surface of the iris in the chamber angle is frequently associated with retinal neovascularization. Their simultaneous occurrence suggests a common aetiologic factor, viz. retinal hypoxia, by which the vasoproliferative factor is produced which diffuses into the anterior chamber. Branch retinal artery obstructions are mostly due to embolism and almost all occur at bifurcations. Severe branch arteriosclerosis does not cause retinal infarction until more than two-thirds of the lumen is occluded. The vast majority of retinal emboli are transient and do not cause an infarction. In severe arteriosclerosis, branch artery obstruction is not limited to bi-
384
furcations and may occur at any site on the arterial tree. The embarrassed area shows a faint haze due to superficial oedema. Minor superficial haemorrhages are indicative of existing hypertension. Collateral vessels may form after branch artery occlusion, but they are small and can only be seen by fluorescein angiography. Most central retinal artery obstructions occur in patients with hypertension and arteriosclerosis. Once the central artery has become occluded, the retina becomes oedematous, white and opaque. Arterioles are narrowed, the veins darken; sludglng appears first in veins and afterward in arteries. Preservation of some central retinal function after C.R.A. occlusion indicates the presence of a cilioretinal artery. No less than 25 per cent of humans possess a cilioretinal artery. So-called clinical improvement within One or two weeks following C.R.A. occlusion only means that the patient has learned to use a small viable retinal area adjacent to the disc, supplied by a cilioretinal artery. After total arterial obstruction, ischaemic infarction occurs. Gliosis replaces the inner retinal layers. The outer retinal layers are undamaged. The retinal opacity clears within several weeks; the arteries may remain irregularly narrowed and show fine white striping. The disc may be clearly outlined and pale; sometimes gllosis produces a dirty grey disc color. The site of obstruction of the C.R.A. is usually at the lamina cribrosa, but it may also be located more centrally. The obstruction can be due to either emboll, atheroma or other vascular pathology (Fig. 1). A remarkable histopathologlcal finding in two cases of central retinal artery obstruction was a rather thick prepapillary and peripapillary neovascular layer. We have seen such a prepapillary neovascular membrane in cases of glaucoma after C.R.A. occlusion only, and never in glaucoma after C.R.V. obstruction. In one of these two eyes, the inferior temporal branch artery was also severely sclerotic. Preretinal rete neovascularization was present in the region supplied by this artery (Fig. 2) and a remarkable flower-like type of neovascularization had occured at the margin of the disc (Fig. 3). A delicate fibrovascular membrane had developed in the chamber angle, covering the entire trabecula. The origin of the newly-formed vessels in the chamber angle from the root of the iris was clearly visible. Elsewhere in the angle, the delicate membrane had developed into a vascular layer which had caused a peripheral anterior synechia. Glaucoma following C.R.A. occlusion has been a well-established clinicopathologic entity since a study by Perraut & Zimmerman in 1959. In early stages, these authors found a delicate fibrovascular membrane along the
385
Fig. 1. Central retinal artery obstruction - prepapillary and peripapillary neovascular layer covering the cupped disc. Lab. no.: 0.686 ;van Gieson-elastin, x 60. Neg. EUR-P.A.: 8049.
Fig. 2. Central retinal artery obstruction - preretinal rete neovasculafization in region supplied by severely sclerotic branch artery. Lab. no.: 0 . 6 7 6 ; P A S , x 150. Neg. EUR-P.A.: 8048.
Fig. 3. Central retinal artery obstruction - flower-like intravitreal neovascularization from disc margin. Lab. no.: 0.676;van Gieson-elastin, x 16. Neg. EUR-P.A.: 80047. inner surface of the trabecula which obstructed the outflow. In all their cases, glaucoma had developed between five and nine weeks after the artery occlusion. This interval is significantly shorter than that after C.R.V. occlusion, for which the term 'one hundred day glaucoma' is often used. Such cases of glaucoma after C.R.A. obstruction, in which no retinal haemorrhages occur, form a strong argument for abandoning the name 'haemorrhagic' glaucoma following retinal vascular occlusion and for adopting the term 'neovascular' glaucoma.
387
Branch retinal vein obstruction shows the same retinal phenomena as central retinal vein obstruction except that in branch vein obstruction only part of the retina is involved. Collateral vessels are mostly found in two places: (1) about the point of blockage connecting the peripheral obstructed segment with the central patent segment or (2) at either side of the macula connecting the superior and inferior temporal veins if either of the latter is obstructed. After ~some time, the obstructed vein wall develops a halo sheathing, a hazy white discoloration over the venous blood column and denser white stripes to either side of it. This sheathing is due to an increase in collagen in the venous wall; the lumen remains fully patent. Microaneurysms invariably form in the drainage area of the obstructed vein 3 months or more after branch venous obstruction. Fatty exudates may appear after 2 months following the obstructive episode. Branch vein obstructions occur mostly secondary to arteriosclerosis and always at arteriovenous crossings. At these sites the normal common arteriovenous wall is thinner than the free arterial wall and consists of the arterial media covered on both sides by endothelium. Thickening of the arteriolar wall by fibrosis and hyalinization gradually narrows the venous lumen. The clinical picture of acute branch vein obstruction may be preceded by Bonnet's prethrombosis signs viz. dilation, darkening and tortuosity of the vein distal from the crossing, small superficial haemorrhages, a white halo about the vein and a pale transudate in the area. Most branch vein obstructions occur in the temporal branches, because there are more crossings at this side. Central retinal vein obstruction mostly involves the entire retina. In acute apoplectiform cases, massive retinal haemorrhages are not confined to the deep retinal layers but extend to the retinal surface. In central retinal vein obstruction collaterals develop only at the disc. The presence of such collaterals is definite proof of prior central retinal vein obstruction. The argument whether retinal vein obstruction is due to true thrombosis as was defended by Coats - or by intimal proliferation - as was defended by Verhoeff - has not yet been decided. Most probably, either view can be correct in certain cases. Primary thrombosis as the basic mechanism for C.R.V. obstruction is thought to be rare; a terminal thrombotic episode following pathologic alterations of the venous wall seems likely in many cases. A case of central retinal vein obstruction following phlebitis in a girl aged 17 was presented. In this case, the venous obstruction had been due to a thrombotic process following inflammatory alterations of the venous wall. The -
388
wall of the central retinal artery was not remarkable. Four other cases also showed the clinical picture of acute central retinal vein obstruction followed by neovascular glaucoma, while no histopathologic changes in the arterial wall could be found (Fig. 4). These findings do not substantiate the conclusion by Hayreh that haemorrhagic retinopathy in occlusive vascular disorders can be due only to a combined central venous and arterial obstruction. According to Hayreh, central venous obstruction alone causes no retinal damage. In central retinal vein obstruction, thrombosis as well as intimal proliferation can be the primary lesion.
Fig. 4. Central retinal vein obstruction - fibrotic thrombus; adjacent arterial wall and lumen are unremarkable. Lab. no.: 0.831 ;van Gieson-elastin, x 185. Neg. EUR-P.A.: 8053.
389
(Rotterdam) In this paper, the approach to the understanding of retinal vascular disease as was adopted by Wise, Dollery & Henkind in their book on retinal circulation is used. This approach is based on the experience that retinal vascular disease has its chief impact on either the arterial side of the retinal circulation - as in arteriosclerosis and hypertension - or on the capillaries and veins - as in venous obstruction and diabetes. The deep capillary bed receives almost all its blood from the superficial capillary bed between the arteries and the veins and has little or no direct connection with precapillary arterioles. Therefore, the deep capillary bed is associated only with capillary and venous dysfunction. On the contrary, the superficial capillary bed - through its direct association with the arterioles - is more associated with arterial dysfunction. Signs of involvement of the superficial capillary bed, caused by arterial dysfunction, are: superficial oedema, macular figure, superficial haemorrhages, cotton-wool patches and neovacularization. Signs of involvement of the deep capillary bed, caused by capillary and venous dysfunction, are: deep oedema, microcystic macular oedema, deep haemorrhages, fatty exudates, microaneurysms and neovascularization. Much overlapping occurs but, nevertheless, grouping retinal vascular diseases and symptoms in this way is helpful in understanding their pathology. A macular star figure is usually left behind when superficial retinal oedema recedes from the macular area. Since Henle's layer - although lying superficially in the macular region - is a continuation of the outer plexiform layer, macular star figures are also common after deep retinal oedema. Large superficial haemorrhages are clinically often appreciated as preretinal haemorrhages, but, for the most part, they lie just under the internal limiting membrane. Cotton-wool patches are no 'small retinal infarcts' as is often stated ; this would imply a necrotic lesion resulting from total arterial obstruction. The underlying cause in every case is stagnant hypoxia or anoxia from focal circulatory failure which can be arterial, capillary or venous in origin. The
Ophthalmic Pathology Laboratory, Erasmus University, Rotterdam.
383
hypoxia causes endothelial damage and excessive permeability of the capillary walls. Microscopically, there is little tissue necrosis. Cotton-wool spots are composed of a zone of retinal oedema in which there is a cluster of socalled cytoid bodies which consist of the swollen end of fragmented exones. Neuro-pathologists would label them terminal swellings of Cajal. Deep retinal oedema from the deep capillary bed thickens the retina at the macula and sometimes throughout the posterior pole. Deep retinal oedema forms pockets in the outer plexiform layer but may extend into the nuclear layers. They arise from the deep capillary bed. Almost all peripheral haemorrhages are of this type. Exudates are common in diseases attacking capillaries and veins and are not seen in arterial obstructions. They lie in the deep retina in the outer plexiform layer. For a long time it has been accepted that they consist of fats liberated from dead retinal cells and of lipophages. More recently, it has been postulated that the fatty material might have seeped through defective capillary or venous walls, or that it represents a by-product of the altered metabolism of subnormally oxigeneted but still viable retinal ceils. Both hypotheses might be true. Microneurysms are not specific for diabetes and have been reported after venous obstruction and in many other diseases such as dysproteinaemias, Coats' and Leber's diseases, retinoblastoma and chronic glaucoma. After central retinal vein obstruction, their wall is not thickened as is often found in diabetes. The etiology of neovascularization is still hypothetical. It is generally accepted that hypoxic retinal cells elaborate a vasoproliferative factor. So far, this actual factor has not yet been isolated. New vessels predominantly arise from capillaries and veins, although with fluorescein angiography some early proliferating vessels fill during the arterial phase. Light microscopy shows no difference in the structure of normal retinal capillaries and newly-formed vessels, but they differ physiologically in the profuse leakage of fluorescein from even the smallest neovascular formations. In eyes with retinal vascular obstruction, neovascular growth on the anterior surface of the iris in the chamber angle is frequently associated with retinal neovascularization. Their simultaneous occurrence suggests a common aetiologic factor, viz. retinal hypoxia, by which the vasoproliferative factor is produced which diffuses into the anterior chamber. Branch retinal artery obstructions are mostly due to embolism and almost all occur at bifurcations. Severe branch arteriosclerosis does not cause retinal infarction until more than two-thirds of the lumen is occluded. The vast majority of retinal emboli are transient and do not cause an infarction. In severe arteriosclerosis, branch artery obstruction is not limited to bi-
384
furcations and may occur at any site on the arterial tree. The embarrassed area shows a faint haze due to superficial oedema. Minor superficial haemorrhages are indicative of existing hypertension. Collateral vessels may form after branch artery occlusion, but they are small and can only be seen by fluorescein angiography. Most central retinal artery obstructions occur in patients with hypertension and arteriosclerosis. Once the central artery has become occluded, the retina becomes oedematous, white and opaque. Arterioles are narrowed, the veins darken; sludglng appears first in veins and afterward in arteries. Preservation of some central retinal function after C.R.A. occlusion indicates the presence of a cilioretinal artery. No less than 25 per cent of humans possess a cilioretinal artery. So-called clinical improvement within One or two weeks following C.R.A. occlusion only means that the patient has learned to use a small viable retinal area adjacent to the disc, supplied by a cilioretinal artery. After total arterial obstruction, ischaemic infarction occurs. Gliosis replaces the inner retinal layers. The outer retinal layers are undamaged. The retinal opacity clears within several weeks; the arteries may remain irregularly narrowed and show fine white striping. The disc may be clearly outlined and pale; sometimes gllosis produces a dirty grey disc color. The site of obstruction of the C.R.A. is usually at the lamina cribrosa, but it may also be located more centrally. The obstruction can be due to either emboll, atheroma or other vascular pathology (Fig. 1). A remarkable histopathologlcal finding in two cases of central retinal artery obstruction was a rather thick prepapillary and peripapillary neovascular layer. We have seen such a prepapillary neovascular membrane in cases of glaucoma after C.R.A. occlusion only, and never in glaucoma after C.R.V. obstruction. In one of these two eyes, the inferior temporal branch artery was also severely sclerotic. Preretinal rete neovascularization was present in the region supplied by this artery (Fig. 2) and a remarkable flower-like type of neovascularization had occured at the margin of the disc (Fig. 3). A delicate fibrovascular membrane had developed in the chamber angle, covering the entire trabecula. The origin of the newly-formed vessels in the chamber angle from the root of the iris was clearly visible. Elsewhere in the angle, the delicate membrane had developed into a vascular layer which had caused a peripheral anterior synechia. Glaucoma following C.R.A. occlusion has been a well-established clinicopathologic entity since a study by Perraut & Zimmerman in 1959. In early stages, these authors found a delicate fibrovascular membrane along the
385
Fig. 1. Central retinal artery obstruction - prepapillary and peripapillary neovascular layer covering the cupped disc. Lab. no.: 0.686 ;van Gieson-elastin, x 60. Neg. EUR-P.A.: 8049.
Fig. 2. Central retinal artery obstruction - preretinal rete neovasculafization in region supplied by severely sclerotic branch artery. Lab. no.: 0 . 6 7 6 ; P A S , x 150. Neg. EUR-P.A.: 8048.
Fig. 3. Central retinal artery obstruction - flower-like intravitreal neovascularization from disc margin. Lab. no.: 0.676;van Gieson-elastin, x 16. Neg. EUR-P.A.: 80047. inner surface of the trabecula which obstructed the outflow. In all their cases, glaucoma had developed between five and nine weeks after the artery occlusion. This interval is significantly shorter than that after C.R.V. occlusion, for which the term 'one hundred day glaucoma' is often used. Such cases of glaucoma after C.R.A. obstruction, in which no retinal haemorrhages occur, form a strong argument for abandoning the name 'haemorrhagic' glaucoma following retinal vascular occlusion and for adopting the term 'neovascular' glaucoma.
387
Branch retinal vein obstruction shows the same retinal phenomena as central retinal vein obstruction except that in branch vein obstruction only part of the retina is involved. Collateral vessels are mostly found in two places: (1) about the point of blockage connecting the peripheral obstructed segment with the central patent segment or (2) at either side of the macula connecting the superior and inferior temporal veins if either of the latter is obstructed. After ~some time, the obstructed vein wall develops a halo sheathing, a hazy white discoloration over the venous blood column and denser white stripes to either side of it. This sheathing is due to an increase in collagen in the venous wall; the lumen remains fully patent. Microaneurysms invariably form in the drainage area of the obstructed vein 3 months or more after branch venous obstruction. Fatty exudates may appear after 2 months following the obstructive episode. Branch vein obstructions occur mostly secondary to arteriosclerosis and always at arteriovenous crossings. At these sites the normal common arteriovenous wall is thinner than the free arterial wall and consists of the arterial media covered on both sides by endothelium. Thickening of the arteriolar wall by fibrosis and hyalinization gradually narrows the venous lumen. The clinical picture of acute branch vein obstruction may be preceded by Bonnet's prethrombosis signs viz. dilation, darkening and tortuosity of the vein distal from the crossing, small superficial haemorrhages, a white halo about the vein and a pale transudate in the area. Most branch vein obstructions occur in the temporal branches, because there are more crossings at this side. Central retinal vein obstruction mostly involves the entire retina. In acute apoplectiform cases, massive retinal haemorrhages are not confined to the deep retinal layers but extend to the retinal surface. In central retinal vein obstruction collaterals develop only at the disc. The presence of such collaterals is definite proof of prior central retinal vein obstruction. The argument whether retinal vein obstruction is due to true thrombosis as was defended by Coats - or by intimal proliferation - as was defended by Verhoeff - has not yet been decided. Most probably, either view can be correct in certain cases. Primary thrombosis as the basic mechanism for C.R.V. obstruction is thought to be rare; a terminal thrombotic episode following pathologic alterations of the venous wall seems likely in many cases. A case of central retinal vein obstruction following phlebitis in a girl aged 17 was presented. In this case, the venous obstruction had been due to a thrombotic process following inflammatory alterations of the venous wall. The -
388
wall of the central retinal artery was not remarkable. Four other cases also showed the clinical picture of acute central retinal vein obstruction followed by neovascular glaucoma, while no histopathologic changes in the arterial wall could be found (Fig. 4). These findings do not substantiate the conclusion by Hayreh that haemorrhagic retinopathy in occlusive vascular disorders can be due only to a combined central venous and arterial obstruction. According to Hayreh, central venous obstruction alone causes no retinal damage. In central retinal vein obstruction, thrombosis as well as intimal proliferation can be the primary lesion.
Fig. 4. Central retinal vein obstruction - fibrotic thrombus; adjacent arterial wall and lumen are unremarkable. Lab. no.: 0.831 ;van Gieson-elastin, x 185. Neg. EUR-P.A.: 8053.
389
