Ординатура / Офтальмология / Учебные материалы / Ophthalmic Pathology An illustrated guide for clinicians K.W. Sehu and W. R. Weng 2005

An idiopathic condition with the key feature being abnormal retinal telangiectatic vessels with intraand subretinal leakage of lipoproteinaceous fluid.

Clinical presentation

In a child aged 3–5 years, the classic presentation is that of a leucocoria with reduced vision and strabismus.

Most cases are unilateral (80%).

Depending on the extent of vascular abnormality and, hence, leakage of lipoprotein, the fundus appearance varies from localised yellow subretinal exudates to total exudative retinal detachment. Telangiectatic vessels and microaneurysms may be apparent in the periphery.

Further investigations with ultrasound, fluorescein angiogram, and CT may be necessary to differentiate this condition from other causes of leucocoria (see Chapter 11).

Pathogenesis

The presence of abnormal endothelium in sectors of the retinal vasculature leads to a breakdown of the blood– retinal barrier with resultant exudation.

In an enucleated globe, Coats’ disease should be suspected if the gelatinous subretinal exudate contains numerous cholesterol crystals and yellow clusters of cells. It may be possible to demonstrate a thickened area of retina which would represent the sector of telangiectasia (Figure 10.24). There may be evidence of extensive laser treatment.

Microscopic

Serial sections are required to identify areas of abnormal vasculature. These are recognised by spaces around the endothelium of the affected vessels. Endothelial dysfunction permits the leakage of red cells and plasma into the vessel wall and the adjacent retina. Inflammatory cell infiltration (macrophages and lymphocytes) is a secondary phenomenon (Figures 10.25–10.27).

Figure 10.21

Figure 10.21 At a much later stage, the exudate is removed and clusters of foamy macrophages are present in the outer plexiform layer. Resolution is slow due to the inability of macrophages to migrate out of the retina. In this autopsy specimen, the photoreceptors are autolysed and the retinal pigment epithelium (RPE) is detached by artefact. ONL outer nuclear layer.

Figure 10.22

Figure 10.22 A 7 year old boy known to be suffering from von Hippel’s disease developed a cataract. Surgery was complicated by corneal wound dehiscence, iris prolapse, retinal detachment, and hypotonia. In this specimen, the angioma can be seen as an orange mass in the stalk of the detached and congested retina.

Acquired

theory, free radicals of oxygen stimulate mesenchymal spindle cells and may be a source of angiogenic growth factors.

A vascular proliferative retinopathy of premature, low birth weight infants exposed to high and fluctuating levels of oxygen partial pressures. It is important to appreciate that in the developing premature infant, migration of the retinal vessels is incomplete, leaving an avascular zone in the periphery. The basis of this condition is an abnormal proliferation of the developing retinal blood vessels at the junction of vascularised and avascular retina.

Clinical presentation

The clinical ROP classification is summarised in Table 10.2.

Risk factors

1Low birth weight (LBW) <1000 g.

2Short gestational age <29 weeks.

3Multiple births.

4Race (there is a twofold increase in progression to severe disease in whites compared with blacks). Gender is not associated with progression.

Pathogenesis

Common theory (fluctuating oxygen)

1Exposure to high O2 partial pressures: suppresses stimuli for vessels to penetrate the avascular retina; vasoobliteration of existing vessels.

2Return to normal O2 partial pressures: results in relative retinal hypoxia; upregulation of vascular endothelial growth factor (VEGF) production initiates vasoproliferation.

Alternate theory The common theory does not explain ROP in LBW infants who did not receive oxygen. In the alternate

Depending on the severity of disease:

1Observation.

2Laser photocoagulation of peripheral non-vascularised retina.

3Vitrectomy and retinal detachment surgery in selected cases.

Clinicopathological correlation

In the most severe form, blindness is the result. It is rare for the pathologist to receive specimens in the early stages of the disease. Most enucleations for ROP would follow failed treatment for the complications of longstanding detachment (Figures 10.28, 10.29). Compared with Coats’ disease, in ROP the integrity of the endothelium in the vasculature is preserved so that exudation is absent.

Three main criteria determine the severity of ROP and the possible need for intervention (as recommended by the Committee for the Classification of Retinopathy of Prematurity and its Management, 1984 and 1988):

1Stage: Table 10.2 shows the clinicopathological correlation of the five stages of ROP.

2Plus disease: vascular shunting of blood causes posterior venous engorgement and arterial tortuosity involving one or more quadrants. This is seen clinically as:

•dilatation and tortuosity of peripheral retinal vessels

•iris vascular engorgement

•pupillary rigidity

•vitreous haze.

Plus disease is the hallmark of rapidly progressive disease.

Proliferation of immature endothelial cells occurs at the periphery of the avascular zone

Further hyperplasia of spindle cells, with proliferation of endothelial cells of the rearguard mesenchymal tissue (Figure 10.30)

Extraretinal neovascular proliferation. Proliferation of endothelial cells occurs along small, thin-walled vessels

Fibrovascular bands and tractional detachment

of the retina. Condensation of vitreous into sheets and strands orientated anteriorly toward the lens equator.

Hence, tractional retinal detachment occurs with the peripheral retina drawn centrally and anteriorly The subretinal space contains serous exudate

3Location:

•zone 1: optic disc to radius twice the distance from the disc to the fovea

•zone 2: radius of zone 1 to temporal equator

•zone 3: temporal crescent of retina, not encompassed by the other zones.

NB: If nasal retina is vascularised fully, it is labelled zone 3 by convention.

Hypertension

Ocular disease from uncontrolled systemic hypertension is now rarely encountered as this condition is diagnosed early and treated effectively.

may be complicated by thrombotic occlusion of the central retinal vein (CRVO) or a branch retinal vein (BRVO).

Aetiology/pathogenesis

Most cases of hypertension are of the essential variety and of unknown aetiology. Acute hypertension is rare but preclampsia/eclampsia would be the commonest association. Other causes include phaeochromocytoma, chronic renal failure, and renal artery stenosis.

It is speculated that the high pressure in the retinal arterioles leads to spasm and endothelial damage in the acute disease. In the chronic disease, the vessels become hyalinised and less prone to spasm.

Possible modes of treatment

Clinical presentation

Although there is bilateral involvement, there may be asymmetry in progression. The patient is usually asymptomatic although decreased vision may be experienced.

The appearances of the fundus will depend on whether the onset is acute or chronic:

1 Acute (malignant): hard exudates/macular star, retinal oedema, cotton wool spots, flame haemorrhages, focal chorioretinal infarcts (Elschnig’s spots), and disc oedema. In extreme cases, there may be retinal detachment and vitreous haemorrhage.

2Chronic: arteriovenous (AV) nipping with retinal arteriolar sclerosis (“copper” or “silver” wiring), retinal oedema and cotton wool spots, disc oedema, flame haemorrhages, and arterial macroaneurysms. Hypertension

Any underlying cause should be determined and treated with antihypertensive drug therapy.

Macroscopic

Acute malignant hypertension has been encountered in autopsy cases by pathologists (Figure 10.16). The appearances mirror those outlined in the clinical description.

Microscopic

Fibrinoid necrosis as seen in the renal arterioles is not a feature of retinal arteriolar disease, although the choroidal vessels undergo fibrinoid necrosis. The secondary effects of retinal arteriolar spasm (haemorrhage and microinfarction) have already been described (see Table 10.1).

Figure 10.28 Stage V pathology in retinopathy of prematurity (ROP) is based on proliferation of fibrovascular tissue on the inner surface of the retina (see

Figure 10.29). Macroscopic examination (left) reveals a retinal stalk beneath a thickened band of white tissue extending from ora to ora. Often, in longstanding retinal detachments, large cysts (macrocysts) form within the retina. In a section from the same globe (right), the detached retina is thrown into folds beneath an epiretinal fibrovascular membrane. Calcification in the lens is common in ocular disorders in childhood and results in artefactual tissue disruption when the sections are prepared.

Figure 10.29 Contraction of the epiretinal fibrovascular tissue seen in Figure 10.28 causes marked distortion of the retina which is thrown into folds seen as circular and linear bands of the outer nuclear layer (left). At a higher power (right), small vessels extend from the inner retina into the fibrovascular

mass. It is likely that these vessels are fragile and bleed, and this explains the breakdown products of blood (in the form of iron deposits) in the membrane. ILM = inner limiting membrane.

avascular zone

Figure 10.30

absent GCL atrophic INL vacuolated OPL

normal PR layer

normal PR layer

Retina - Vascular disease

Central retinal artery occlusion

Figure 10.32

bifurcated central retinal vein

to eye

central

retinal artery

overlying Fibrin stain (red) fibrin

thrombus

atheromatous plaque

Retina - Vascular disease

Central retinal artery occlusion

Figure 10.34

Central retinal artery occlusion (CRAO)/branch retinal artery occlusion (BRAO)

This is a rare condition where there is interruption in the blood supply to the retina by a thrombus or an embolus. In the case of CRAO, the artery is obstructed behind the lamina cribrosa. Obstruction of a branch arteriole can occur anywhere along the vascular bed.

Clinical presentation

A CRAO presents with unilateral sudden painless loss of vision and is more common in males.

Depending on the extent of vascular occlusion, there may be a relative afferent pupillary defect.

The retina is initially normal in appearance but gradually opacifies after several hours. The underlying choroidal vasculature beneath the macula may be visible (“cherry red spot”). The arterioles are attenuated. The opacified retina progressively resolves over 4–6 weeks and optic disc pallor ensues (in the case of CRAO).

Secondary neovascularisation (intraretinal or rubeosis iridis) may occur but is rare.

Further investigations with fundus fluorescein angiography and electrophysiology (ERG) may be necessary in atypical cases.

It is essential to investigate for primary causes of embolism and to include laboratory tests for giant cell arteritis and systemic vascular disease.

The sector of infarcted retina to occlusion of a branch retinal artery is initially opaque but later becomes atrophic.

Pathogenesis

Atheromatous or thrombotic emboli are the commonest causes of occlusion.

Possible modes of treatment

1Acute: controversial but involves decompression of globe, anticoagulation, steroid therapy, and locoregional fibrinolysis.

2Chronic: treatment of secondary retinal neovascularisation and neovascular glaucoma.

Macroscopic

Enucleation specimens, autopsy, or surgery for neovascular glaucoma in CRAO/BRAO are rare. In autopsy material, the appearances are never as striking as those seen in vivo. A BRAO in a well demarcated area of infarction that can be distinguished from the non-ischaemic tissue is shown in Figure 10.31.

Microscopic

Retina Initially, the inner layers of the retina are oedematous and this is followed by a total atrophy of the inner retinal layers as far as the inner nuclear layer (Figure 10.32).

Central retinal vessels Occasionally, it is possible to identify an atheromatous embolus in the central retinal artery (Figure 10.33) or an organising thrombus (Figure 10.34).

Central retinal vein occlusion (CRVO)/branch retinal vein occlusion (BRVO)

Retinal venous occlusive disease is relatively common, with incidence rising with age. CRVOs are subdivided into ischaemic and non-ischaemic groups; the latter patients have a better visual prognosis. BRVOs usually originate at the sites of arteriovenous crossings. Ischaemic central retinal venous disease is more commonly encountered by the pathologist and will form the main basis of the following description.

Clinical presentation

Painless loss of vision in the acute event – this is almost always unilateral. A relative afferent pupillary defect may be present. Late presentations may be in the form of neovascular glaucoma.

Fundus examination reveals dilated tortuous veins, intraretinal haemorrhages, macular and retinal oedema, microinfarcts (cotton wool spots), and optic disc swelling. Neovascularisation within and on the surface of the retina can lead to tractional retinal detachment.

Regular follow-up, including gonioscopy of the angle for neovascularisation in ischaemic cases of CRVO, is essential.

Further investigations with a fluorescein angiogram (to determine the extent of ischaemia) and electrophysiology may be necessary.

It is important to consider the following associated disorders:

1Ocular associations: open angle glaucoma.

2Systemic associations: diabetes, hypertension, serum hyperlipidaemia, and hyperviscosity syndromes.

Pathogenesis

The precise nature is unknown as investigation of CRV pathology is limited to end-stage disease. At this stage, evidence of CRA and arteriolar occlusive degenerative disease is present so that underperfusion and venous stasis could initiate thrombus formation in the vein within or behind the lamina cribrosa. The normal vein narrows within the lamina cribrosa and two of the criteria for thrombus formation are fulfilled – stasis and turbulence. The thrombosed vein is recanalised later and collaterals within the optic nerve head open so that some blood flow is re-established. The haemorrhages are eventually cleared from the retina by macrophages.

In the case of BRVO, disease of the adjacent arterial wall may be responsible for compression of the venous wall at the AV crossing.

Possible modes of treatment

Treatment of glaucoma and any underlying medical disorders are essential.

Panretinal photocoagulation (PRP) for neovascularisation has markedly reduced the incidence of enucleation. Macular oedema generally does not respond well to grid laser therapy.

Macroscopic

The pathological appearances of the retina and vitreous following CRVO vary quite markedly depending on the extent of haemorrhage and the interval between the acute event and enucleation. Haemorrhage within the retina can vary from the small dot blot varieties (Figures 10.35, 10.36) to massive involvement (Figure 10.37), often with evidence of longstanding glaucoma.

Retinal neovascularisation often follows an ischaemic vein occlusion. Preretinal neovascular fronds arise in the walls of hyalinised blood vessels and spread across the posterior hyaloid face to form sheets or nodules (Figure 10.38). Bleeding from these vessels into the vitreous produces complicated fibrovascular proliferations depending on the state of organisation of the blood (Figures 10.39, 10.40).

Microscopic – retina

Acute stage Haemorrhage follows the patterns described previously (Figure 10.13, 10.41), but is mainly restricted to the inner retinal layers. Resolution of a massive retinal haemorrhage leads to deposition of haemosiderin within a gliotic retina (Figure 10.42).

Late stage Ischaemia of the inner retinal layers stimulates vasoproliferation with the release of VEGF and other

vasoformative factors. Endothelial cell proliferation can take the form of small capillary buds within and on the surface of the retina (Figure 10.43). Commonly, the endothelial cell proliferation arises in the walls of hyalinised blood vessels (Figures 10.44, 10.45). Progression of the ischaemia and endothelial cell damage result in the formation of lipoproteinaceous (hard) exudates and microcysts in the posterior retina. Ultimately, contraction of the fibrovascular membranes distorts the retina with progression to tractional retinal detachment (Figure 10.46).

Microscopic – central retinal vein within the optic nerve

The opportunity to study the central retinal vein in the initial occlusion has arisen only rarely in autopsy material. Thrombus formation occurs in the vein at the level of or behind the lamina cribrosa. The thrombosed vessel becomes recanalised and this is the usual appearance by the time a surgical enucleation becomes necessary (Figure 10.47).

Pathological evidence of treatment

There may be evidence of panretinal photocoagulation (Figure 10.48) and surgery to treat neovascular glaucoma.

Diabetes

Although diabetes is a metabolic disorder, involvement of the eye has the characteristics of a vascular disease. Previously, diabetic eye disease was one of the commoner conditions submitted to the pathologist. Effective screening, metabolic control, and prompt treatment with panretinal laser photocoagulation have reduced the incidence of enucleation. Nonetheless, the topic is dealt with in detail owing to the increasing prevalence of the disorder and the implications for clinical practice.

previous trabeculectomy with iris prolapse

scattered

dot-blot haemorrhages

Figure 10.35

Figure 10.35 Pathological experience in central retinal vein occlusion is most commonly obtained from globes which are enucleated for intractable neovascular glaucoma. In this case, an iris prolapse is an indication of failed glaucoma surgery. Many of the original retinal haemorrhages have resolved, with those remaining confined to dots and blots in the mid-periphery.

artefactual

iris pigment on lens surface

corneal ulcer with hypopyon

Retina - Vascular disease

Central retinal vein occlusion

Figure 10.36

Figure 10.36 Corneal decompensation with ulcerative keratitis is a common sequel to end-stage neovascular glaucoma in ischaemic central retinal vein occlusion. In this example, the disc is cupped and, as is often the case, the retinal vessels are hyalinised. Most of the haemorrhage has resolved leaving sparse dots and blots.

Retina - Vascular disease

Central retinal venous occlusion

cupped optic disc

preretinal haemorrhage

hard exudate

Figure 10.38

Retina - Vascular disease

Central retinal vein occlusion

Organised vitreous haemorrhage

partial traction detachment of retina

Figure 10.40

Figure 10.37 In this example of central retinal vein occlusion, the haemorrhage is so massive as to involve the entire retina. Again, the retinal vessels are sclerotic.

Figure 10.38 In the fundus at a later stage of ischaemic central retinal vein occlusion, intraretinal haemorrhage clears and neovascularisation dominates the picture. Further bleeding from preretinal neovascularisation is present. The retinal vessels are sclerosed to an advanced degree.

Figure 10.39 At a late stage in the pathology of untreated ischaemic central retinal vein occlusion, it is common to see massive bleeding into the vitreous from preretinal neovascularisation. In this specimen, there were two phases of haemorrhage – the first was into the vitreous, and at this stage there was early organisation which has led to vitreous detachment, and the second was a recent haemorrhage in the subhyaloid space

Figure 10.40 In the vitreous, blood eventually clears to leave behind lipid and cholesterol deposits. Pale white areas in the retina indicate photocoagulation, which was probably limited due to the late presentation of the patient with obscuration by the opaque vitreous. This eye was enucleated due to intractable pain from neovascular glaucoma.

Figure 10.41 In a recent retinal vein occlusion, the outer retina and choroid are preserved and haemorrhages are present in the nerve fibre layer, ganglion cell layer (GCL), inner nuclear layer (INL), and outer plexiform layer (OPL). RPE retinal pigment epithelium.

Retina - Vascular disease Central retinal vein occlusion Resolving haemorrhage

gliotic inner retina

Retina - Vascular disease Central retinal vein occlusion Early neovascularisation

Figure 10.43

Retina - Vascular disease Central retinal vein occlusion Late stage / Neovascularisation

vitreous strands

retinal cysts containing exudates in OPL layer

tree-like proliferation of fibrovascular tissue within the vitreous

hyalinised feeder vessel

Figure 10.44

Retina - Vascular disease

Central retinal vein occlusion

Neovascularisation of optic disc

blood vessels in organised vitreous

hyalinised blood vessels

cyst formation in outer retinal layer

subretinal exudate

reactionary proliferation of RPE

Figure 10.46

Figure 10.45

Figure 10.42 The red cells break down leaving haemosiderin, which stains positively for iron salts (Prussian blue stain). At this stage, there is atrophy and gliosis of the inner retina. The magnifications are identical in Figures 10.41 and 10.42 – compare the relative thickness of the inner retina in each.

Figure 10.43 Early neovascularisation within an ischaemic retina is manifest as buds of proliferating endothelial cells arising in the walls of blood vessels.

ILM inner limiting membrane.

Figure 10.44 In elderly patients following ischaemic central retinal vein occlusion, fibrovascular membranes arise from hyalinised feeder vessels (venules and arterioles). This fibrovascular membrane appears to extend into the subhyaloid space between the inner limiting membrane and the posterior vitreous face.

Figure 10.45 The detached vitreous can form a scaffold for the proliferating fibrovascular tissue so that a tree-like configuration is adopted. In this end-stage central retinal vein occlusion, there is extensive cyst formation in the outer plexiform layer (OPL). The inner retina is atrophic but in this and the above examples, the photoreceptor layer is preserved.

Figure 10.46 In many pathological specimens in central retinal vein occlusion, neovascularisation of the optic disc is a major feature. In this example there is tractional retinal detachment at the peripapillary retina accompanied by subretinal exudation. The disorganised cystic retina contains hyalinised blood vessels. Atrophy of the photoreceptors and proliferation of the retinal pigment epithelium (RPE) provides evidence of prolonged retinal detachment. The inset shows a low magnification of the optic nerve head and peripapillary retina.

Retina - Vascular disease

Central retinal vein occlusion

Recanalisation

Figure 10.47

Figure 10.47 Transverse sections behind the lamina cribrosa in a late stage central retinal vein occlusion reveal a recanalised central retinal vein. The original vein wall is highlighted by a stain for the internal elastic lamina (right). The central retinal artery is recognisable by the smooth muscle cells in the vessel wall. Because such patients are elderly, the artery often shows reduplication of the internal elastic lamina. The inset shows the relative dimensions of the normal central retinal vessels.

Retina - Vascular disease

Central retinal vein occlusion

Pan retinal photocoagulation

Figure 10.48

Figure 10.48 Evidence of photocoagulation is often obtained in cases of neovascularisation in central retinal vein occlusion (and diabetic retinopathy, see below). These appear as sectors of outer retinal destruction (upper) or total retinal destruction (lower) depending on the energy level and wavelength employed. Müller cells are thought to be the source of the glial cells in the scars: these cells have large irregular nuclei.

Clinical presentation

Diabetes may involve many ocular tissues and the cranial nerves:

1 Cornea: recurrent surface erosions secondary to decreased sensitivity and reduced epithelial adhesion to the underlying basement membrane.

2Glaucoma: increased incidence of primary open angle glaucoma and neovascular glaucoma.

3Lens: earlier onset of cataract (subcapsular). NB: An acute elevation in the blood glucose level may give rise to a temporary cataract.

4Optic neuropathy: acute disc oedema can occur in young diabetics. A subclinical optic neuropathy may be evident in visual-evoked potential studies.

5Cranial neuropathy: neuropathy involving cranial nerves (CN) III, IV, and VI may result in an extraocular muscle palsy. This condition is due to a localised infarction in the surrounding myelin sheath (mononeuritis multiplex). In cases involving CN III, there may be sparing of the pupillary reflex.

6Retinopathy: this is the most significant ocular pathology and is classified in four stages:

(a)Early non-proliferative diabetic retinopathy (NPDR): microaneurysms, dot blot haemorrhages, and hard exudates. Macular oedema may occur at any stage of retinopathy, and when hard exudates and cyst formation occur there is a sharp decrease in visual acuity.

(b)Moderate NPDR: as above plus cotton wool spots, venous beading, or loops.

(c)Severe NPDR: as above with four quadrants of intraretinal haemorrhages, two quadrants of venous beading, or one quadrant of intraretinal microvascular abnormalities (IRMA). The features of IRMA are

flat retinal neovascularisations with absence of leakage on fluorescein angiography.

(d)Proliferative diabetic retinopathy: as above with neovascularisation of the disc (NVD) or elsewhere (NVE). The preretinal fibrovascular tissue may result

in tractional retinal detachment or vitreal haemorrhage. Secondary glaucoma may occur with neovascularisation of the angle (NVA) or iris (NVI).

Further investigations will include fluorescein angiography to determine areas of capillary non-perfusion, neovascularisation and exudation.

In the differential diagnosis, CRVO (which may be secondary to diabetes), radiation retinopathy, and hypertension should be considered.

Pathogenesis

The incidence and severity of diabetic eye disease is dependent upon the following factors:

1Duration of condition post puberty.

2Degree of metabolic control – good control delays the onset and decreases the severity of the disease.

3Other exacerbating factors: pregnancy, hypertension, hyperlipidaemia, cigarette smoking, and renal disease.

Diabetes affects the retinal vasculature in several ways. The arterioles undergo degenerative changes with sclerosis (luminal narrowing and reduction in blood flow) and there is also arteriolar occlusion, both of which lead to patchy areas of non-perfusion. The precise mechanism of vascular occlusion is not understood.

Metabolic disturbances selectively affect the capillary pericytes (see below).

The most important results of the diabetic vasculopathy are exudation and neovascularisation. The latter leads to vitreous haemorrhage, vitreous traction, and retinal detachment.