Ординатура / Офтальмология / Английские материалы / Ophthalmic Pathology An Illustrated Guide for Clinicians_Sehu, Lee_2005

The abnormal metabolic pathways in the development of diabetic retinopathy are poorly understood, as exhibited by the various theories of pathogenesis:

1 Vasoproliferative factors: release of VEGF from the hypoxic retina has been theorised to be the stimulant for neovascularisation. This theory has formed the basis of panretinal photocoagulation which attempts to control the level of VEGF by the destruction of ischaemic cells. There is currently much interest in the development of agents that may suppress the effects of VEGF.

2Aldose reductase: an intracellular enzyme which converts sugars to alcohol and is found in high quantities in lens epithelium, pericytes, and Schwann cells. The increased glucose load in diabetes may damage pericytes, leading ultimately to cell death.

3Growth hormone: remission has been obtained in patients subjected to hypophysectomy, but this procedure has been abandoned due to a high mortality.

4Platelets and blood viscosity: altered platelet adhesion characteristics may cause focal capillary occlusion and retinal ischaemia.

5Apoptosis: large fluctuations in blood glucose levels cause pericyte death in vitro.

6Autoimmune disease: levels of circulating antibodies to pericytes are raised in patients with diabetes.

Possible modes of treatment

1Prophylaxis: careful metabolic control.

2Treatment: timely argon laser panretinal photocoagulation for proliferative disease. Clinically significant macular oedema is treated with focal/grid argon laser therapy. Vitreoretinal surgery is employed for persistent vitreous haemorrhage, removal of epiretinal membranes, and for tractional retinal detachment.

Cataract surgery is performed if required.

Macroscopic

Most of the specimens submitted to the pathologist are globes complicated by extensive treatment for neovascular glaucoma or tractional retinal detachment. In many specimens, the effects of diabetic retinopathy (Figure 10.49) resemble those illustrated in CRVO, and indeed CRVO may be an accompaniment. In diabetes, there is, however, a greater tendency to leakage of lipoproteinaceous exudate, which may be predominant (Figure 10.50). The macula is especially prone to oedema and exudation (Figure 10.51). Venous congestion with preretinal traction of dilated vessels into the vitreous (omega loops) is an uncommon pathological finding (Figure 10.52).

It is now more frequent to perform a vitrectomy or membrane peel procedure for sight-threatening cases of tractional retinal detachment or epiretinal membrane formation.

Microscopic

Non-specific features These are secondary to focal arteriolar ischaemia, for example microinfarction, haemorrhage (see above), and neovascularisation.

Microaneurysms Microaneurysms located in the posterior pole are characteristic of diabetes. These are easily identified clinically and by fluorescein angiography but only with difficulty in routine paraffin sections (Figure 10.53). Previously, retinal digest preparations were useful in demonstrating the distribution of microaneurysms and changes in the relative density of the endothelial cells and pericytes (Figure 10.54). There is a preferential loss of pericytes in diabetes, although some capillaries are totally acellular (Figures 10.55, 10.56).

Retina - Vascular disease

Diabetes / Advanced proliferative retinopathy

neovascularisation along posterior vitreous face

with haemorrhage

massive exudation

into retina

optic disc

intact retina

Figure 10.49

Figure 10.49 Neovascularisation arising from the optic disc and penetrating the vitreous with secondary haemorrhage is common to central retinal vein occlusion and diabetes. The presence of massive exudation into the peripapillary retina is suggestive of a diabetic aetiology.

Retina - Vascular disease

Diabetes / Severe nonproliferative retinopathy

extensive intraretinal exudation

glaucomatous

cupped disc

sclerotic vessels

Figure 10.50

Figure 10.50 In some cases of severe exudative diabetic retinopathy, extensive

areas of the retina contain yellow exudates.

Retina - Vascular disease

Diabetes / Maculopathy

optic disc

scattered blot haemorrhages

microaneurysms

endothelial cells

microaneurysm

acellular capillaries

sparse pericytes

Figure 10.55

hyalinised

vessel lipid in and around vessel wall

preretinal venous (omega) loop

atrophy of GCL and NFL

Retina - Vascular disease

Diabetes / Omega vessel loops

Figure 10.52

Retina - Vascular disease

Diabetes / Microaneurysm

Digest preparation

microaneurysms

capillary-free zone

arteriole

Figure 10.54

Figure 10.51 The macula is especially prone to the effects of exudation and oedema (it acts like a sponge) in diabetic retinopathy. In this autopsy specimen, some of the retinal opacification and thickening adjacent to the macula is due to autolysis and formalin fixation.

Figure 10.52 The macroscopic and microscopic appearances of one of the consequences of venous congestion in diabetic retinopathy. The enlarged vessels break through the inner limiting membrane and form loops into the vitreous (omega loops). The upper illustration also shows lipid around the wall of a sclerotic vessel (see Figure 10.57). GCL ganglion cell layer, NFL nerve fibre layer.

Figure 10.53 The retinal capillaries loop down into the inner nuclear layer (INL). In this diabetic retina, microaneurysms can be identified by their larger size in comparison with normal capillaries. The INL is disrupted, presumably due to leakage from the microaneurysms (autopsy material, PAS stain). PR photoreceptor.

Figure 10.54 This is a retinal digest at low power to show the arterioles (thinner) and venules (thicker) with the intervening capillary network in a diabetic retina (PAS stain). Arterioles are identified by the relative absence of adjacent capillaries. Microaneurysms are scattered throughout the capillary bed. Compare with Figure 10.9 but note that the control tissue is from the peripheral retina where the capillary bed is sparser.

Figure 10.55 At an early stage in diabetic retinopathy, small microaneurysms form (possibly as capillary loops) and pericyte numbers are reduced by comparison with the normal endothelial cell density. Some of the capillaries are acellular. Compare with Figure 10.10.

Precapillary arteriolar disease Although microaneurysms and pericyte loss are pathognomonic of diabetes, it is important to appreciate that degenerative disease (hyalinisation, thrombus formation, and embolisation) in the precapillary arterioles contributes significantly to retinal ischaemia (Figure 10.57). Not all arterioles are affected to the same degree, which accounts for the patchy distribution of ischaemic damage.

Neovascularisation The vitreous forms a scaffold for preretinal neovascularisation. Separation and movement of the vitreous lead to vascular disruption and haemorrhage, which stimulates further fibrovascular proliferation. Subsequent fibrosis and contraction result in distortion of the retinal surface (Figure 10.58) and tractional retinal detachment (Figures 10.49, 10.59, 10.60). Membranes removed surgically in diabetic vasoproliferative retinopathy consist of a fibrous mass containing numerous capillaries (Figure 10.60). The absence of an inner limiting membrane on the surface of the optic disc gives free access for blood vessels to grow into the vitreous. The consequent distortion is identical to that seen in CRVO (Figure 10.46).

Diabetic maculopathy This abnormality is attributed to the fact that the capillaries, derived from the surrounding arteriolar arcades do not extend to the macula (“capillary free zone”). Diabetic vasculopathy in surrounding vessels (see above) results in leakage into the macula, a site where fluid resorption is ineffective due to avascularity. Hard exudate formation (Figure 10.61) is especially significant at the macula where intraretinal oedema and cyst formation are additional complications (Figure 10.62).

Specific features For the pathologist, a histological diagnosis of diabetic eye disease can be made by examination of the iris pigment epithelium and the basement membrane of the ciliary body.

1Iris: the pigment epithelium is vacuolated and the cystic spaces contain PAS positive glycoprotein (Figures 10.63, 10.64).

2Ciliary body: the basement membrane thickening is best recognised with a PAS stain (Figure 10.65).

Pathological evidence of treatment – laser burn pathology

The appearances of the treated outer retina are identical to those seen in CRVO (Figure 10.48).

endothelial cells within microaneurysm

Figure 10.56

Retina - Vascular disease

Diabetes / Neovascularisation

fibrovascular membrane

distorted retinal surface

Figure 10.57

Figure 10.56 In the evolution of a microaneurysm, a sack-like “blowout” of the capillary is filled by endothelial cells. Later, the content is replaced by basement membrane material. In this advanced diabetic state, pericytes are not identified.

Figure 10.57 Two of the possible causes of retinal underperfusion are illustrated: (i) arteriolar walls become thickened (left) and there is potential damage to the lining endothelial cells which may predispose to thrombus formation; (ii) it is also possible that lipid emboli could occlude the vessel which later recanalises (right). The effect of ischaemia is seen at this stage as oedematous disruption of the inner nuclear layer (INL, left) and leakage of lipid into the surrounding retina (manifest as accumulation of foamy macrophages, right). The figure on the right was taken from an area of perivascular lipid exudation shown in Figure 10.52. IPL inner plexiform layer.

Figure 10.58 Despite an innocuous appearance, contraction of a fibrovascular membrane on the retinal surface can lead to significant tissue distortion. In this diabetic retina, exudation from the hyalinised vessels in the centre of the image has led to leakage with disruption of the inner nuclear layer (INL). The apparent retinal detachment is an artefact – fragments of photoreceptor tips are present in the inner surface of the retinal pigment epithelium.

intraretinal cyst

with schisis formation

Figure 10.59

Retina - Vascular disease

lipid laden macrophages

Diabetes / Hard exudates within lipoproteinaceous exudates thick ganglion cell layer

(macula)

Figure 10.63

VITREOUS

SIDE

Retina - Vascular disease

Diabetes / Neovascularisation

Membrane peel

Figure 10.60

subretinal exudate

subretinal exudate

Retina - Vascular disease

Diabetes / Maculopathy

Figure 10.62

Figure 10.59 Gross distortion of the retina and disc occurs when fibrovascular tissue extends across the retinal surface and into the posterior vitreous face. Contraction of the tissue has led to secondary cyst formation and splitting of the outer plexiform layer (retinoschisis).

Figure 10.60 Vitreoretinal surgery is often employed to remove the tractional fibrovascular bands which are submitted for pathological examination. These specimens are formed by fibrovascular tissue and the inner aspect is lined by a hypercellular layer formed by proliferating endothelial cells and capillaries.

Figure 10.61 At an early stage of diabetic maculopathy, the inner retinal layers are preserved and the outer plexiform layer is disrupted by leakage of lipoproteinaceous exudate with subretinal extension. The lipoprotein has attracted macrophages which are identified by their large size, small nuclei, and clear or foamy cytoplasms.

Figure 10.62 In advanced diabetic maculopathy, there is extensive cystic degeneration in the outer plexiform layer (OPL) and secondary degeneration of the photoreceptors over a subfoveal proteinaceous exudate. The concentration of lipoprotein varies within the cysts – condensation in some cysts forms darker red structures. The upper and lower figures are taken at different levels through the macula.

Figure 10.63 Vacuolation of the iris pigment epithelium (diabetic iridopathy) is a well recognised feature of diabetes but the aetiology is poorly understood. The material within the vacuoles stains positively with PAS (inset). More importantly, the presence of a vascular membrane on the iris surface with loss of crypts indicates neovascularisation and implies the presence of neovascular glaucoma.

Neovascularisation

fibrous loose stroma

dilator pupillae pigmented epithelium

Figure 10.64

Figure 10.64 Very few cases of diabetic iridopathy show vacuolation of the pigment epithelium. In pathological material, in almost every case there will be a well developed fibrovascular membrane on the anterior surface (upper). Compare this with the crypts and loose stroma of a normal iris (lower).

PAS stain

non-pigmented epithelium pigmented epithelium

PAS Stain

Retina - Vascular disease

Diabetes / Ciliary body changes

Figure 10.65

Figure 10.65 A thickened basement membrane beneath the epithelium of the ciliary processes is a pathognomonic feature of diabetes (PAS stain). The inset shows the membrane at a higher magnification.

Radiation

Radiation retinopathy is discussed in Chapter 9.

Sickle cell disease

Within the family of haemoglobinopathies, sickle cell disease is the most important in ophthalmology. This inherited condition results in the replacement of either one or both alleles of adult haemoglobin (Hb AA) by abnormal Hb S and/or C. Individuals of African origin are most commonly affected, and the resultant retinal pathology is a consequence of ischaemia. The pathogenesis is based on the decreased malleability of red cells under certain conditions (such as reduced oxygen tension) leading to microvascular occlusion. The patient is usually visually asymptomatic unless there is direct involvement of the macula or the visual axis.

Retinal pathology is most commonly seen clinically as macular ischaemia, peripheral vascular non-perfusion, and neovascularisation.

Severe complications are rare and an enucleation would be exceptional.

The five stages of proliferative sickle cell retinopathy are:

1 Peripheral arteriolar occlusions: characteristic retinal haemorrhages may be present:

•black sunbursts: subretinal haemorrhage with disruption of the RPE layer located in the equator

•salmon patches: intraretinal and preretinal haemorrhages with tracking along a retinal arteriole.

2Arteriolar–venular anastomoses.

3Neovascular proliferation (“sea fan appearance”).

4Vitreous haemorrhage.

5Retinal detachment.

Dystrophies

Retinitis pigmentosa

The term “retinitis pigmentosa” (RP) is a misnomer in that the disease is a retinal dystrophy without evidence of inflammation. RP represents a group of inherited retinal disorders involving progressive dysfunction and death of photoreceptors (rods more than cones).

Clinical presentation

Typical RP is bilateral with symmetrical loss of rod photoreceptors. The following symptoms are common:

1 Nyctalopia: poor night vision with prolonged dark adaptation.

2Loss of peripheral vision, which is explained by the fact that the density of rods is greater towards the periphery.

3Loss of central vision at the final stage. Classic fundus findings are:

1Bone spicules in the peripheral retina: there may be a preferential distribution to perivascular regions or to sectors of the retina; the degree of pigmentation varies among patients.

2Retinal arteriolar attenuation.

3Optic disc pallor.

4Atrophy of RPE and choriocapillaris.

5Vitreous cells in some cases.

Other associated ocular findings are:

1Maculopathy: cystoid macular oedema, epiretinal membrane formation, and/or macular atrophy.

2Subcapsular cataract.

Management would include a full clinical work-up to confirm the diagnosis and, to identify the subgroups known to exist (see below for genetics), a careful family history is required. Visual field and electrophysiological investigations are useful, for example to show markedly reduced responses in affected rod photoreceptors. The following conditions are examples of disorders, which have a similar fundus appearance to classic RP and should be considered in the differential diagnosis:

1Usher’s syndrome: autosomal recessive associated with deafness.

2Kearns–Sayre syndrome: a group of mitochondrial cytopathies associated with weakness of skeletal muscle.

3Refsum’s disease: skeletal abnormalities.

4Hereditary abetalipoproteinaemia: fat intolerance and malabsorption resulting in fat-soluble vitamin (A and E) deficiency and neurological impairment.

5Bardet–Biedl syndrome: polydactyly, obesity with short stature.

The reader should consult the clinical texts for a more

extensive list.

Pathogenesis

The exact mechanisms of photoreceptor degeneration are unknown but the final pathway involves apoptosis of the rod photoreceptors with cone degeneration at a later stage. The RPE responds to photoreceptor atrophy by proliferation into the retina. The pigmented cells accumulate around atrophic retinal blood vessels, which explains the classical “bone-spicule” fundus appearance.

Genetics

Variants of RP are mostly inherited, with all forms represented (AD, AR, and X-linked). Isolated cases are usually attributable to autosomal recessive inheritance. Intensive research has been undertaken to identify genetic abnormalities in the different subgroups. The most significant are shown in Table 10.3.

Table 10.3 The most significant subgroups in retinal pigment epithelium.

Female carriers of X-linked disease may have patchy involvement of the retina due to random inactivation of one of the X chromosomes (Lyon hypothesis) and resultant cluster expression of RP.

Possible modes of treatment

There are no definitive treatments for RP. Systemic acetazolamide is often successful in treating selected cases of cystoid macular oedema. Intraocular surgery may be used to treat cataract and in certain cases of epiretinal membrane formation.

Dietary supplementation with vitamins A, E and other lipids (for example docosahexaenoic acid) have been recommended, but opinions and study results are varied, as are the potential side effects.

Macroscopic

RP sufferers are often willing to allow pathological examination of their eyes post mortem. The retina shows the typical perivascular bone spicule patterns with a variable degree and distribution of pigment clumping (Figures 10.66, 10.67).

Microscopic

From animal models, it is assumed that photoreceptor atrophy is the initial event and the study of human material suggests that this is also the case (Figure 10.68). The atrophic outer retina becomes gliotic and the hyperpigmented RPE migrates into the retina (Figure 10.69). The macula is often better preserved in pathological specimens (Figure 10.70), although there is marked loss of nuclei in the outer nuclear layer.

Degenerations

Central

Age-related macular degeneration (ARMD)

ARMD is the commonest cause of visual impairment in individuals aged over 50 years in developed countries. There are two variants: atrophic (dry) and neovascular (wet/exudative), with the latter being less common and accountable for more severe visual loss. Involvement is usually bilateral although there may be asymmetry in progression.

Clinical presentation

In both dry and wet forms, the disease may be detected in the following circumstances:

•Incidental finding and asymptomatic.

•Decreased visual acuity. The onset is usually gradual, although sudden loss implies haemorrhage from neovascular ARMD.

•Metamorphopsia. Distortions in the visual image – this is more common in the wet form.

ora serrata

bone spicule pigmentation

pigment clumps

Retina - Dystrophy Retinitis pigmentosa

Figure 10.66

INL

OPL

surviving ONL

Figure 10.68

photoreceptor atrophy

Retina - Dystrophy

Retinitis pigmentosa / Maculopathy

Figure 10.70

macular oedema

atrophic optic disc

Retina - Dystrophy

Retinitis pigmentosa

Figure 10.67

Retina - Dystrophy

Retinitis pigmentosa

atrophic retina

perivascular migration of pigment epithelium

capillary

outer retinal gliosis (fused

with Bruch’s choroidal melanocytes membrane)

Figure 10.69

Figure 10.66 The atrophic retinal periphery in retinitis pigmentosa contains numerous retinal pigment epithelium clumps. The retinal vessels are surrounded by retinal pigment epithelial cells. The radiating appearance of the perivascular pigmented tissue resembles the osteocyte canaliculae in bone, hence the term “bone spicule”.

Figure 10.67 The pigmentary disturbance progresses from the periphery towards the flat white atrophic disc but the macula is spared. However, there is maculopathy in the form of oedema.

Figure 10.68 At the stage when the pathologist has the opportunity to study retinitis pigmentosa, atrophy of the outer nuclear layer (ONL) is advanced with a residue of inner segments beneath the outer limiting membrane (OLM) of the retina. Hyperpigmentation of the retinal pigment epithelium (RPE) is patchy. INL inner nuclear layer, OPL outer plexiform layer, PR photoreceptor.

Figure 10.69 Migration of hyperpigmented retinal pigment epithelial cells into the retina, particularly around blood vessels, is a characteristic feature of retinitis pigmentosa. In this example, gliosis has resulted in fusion between the retina and Bruch’s membrane. Inner retinal atrophy is advanced.

Figure 10.70 The photoreceptor layer is best preserved at the macula although the density of nuclei is reduced markedly. In this example the retinal pigment epithelium is heavily pigmented but there is no evidence of migration into the avascular macula. (Abbreviations as in Figure 10.68.)

Appearance of the macula

1Atrophic ARMD: geographic atrophy characterised by pale areas of patchy loss of the RPE. These areas may grow in size and coalesce.

2Exudative ARMD: characterised by the presence of a subretinal neovascular membrane. There may be associated subretinal exudation, haemorrhage, or a fibrovascular (disciform) scar. The haemorrhage may track through the retina into the vitreous. Pigmented epithelial detachment (PED) may develop in subretinal neovascularisation with serous exudate or haemorrhage.

Associated findings

1Drusen – subretinal pale areas are either small and discrete (hard) or are larger with indistinct edges (soft).

2Irregular pigment hyperpigmentation (clumping). Investigations may include the usage of fluorescein and

indocyanine green angiography to diagnose and ascertain the severity of subretinal neovascularisation.

Aetiology and pathogenesis

Multiple aetiologies have been implicated including choroidal arteriosclerosis, oxidative stress, diet, inflammation, and genetics for both dry and wet forms of ARMD. Much interest has also centred on changes in Bruch’s membrane (for example calcification and lipid accumulation) which could interfere with metabolism of the RPE cells.

The various pathological features of ARMD are introduced by means of diagrams (Figures 10.71–10.75).

Atrophic ARMD may involve choroidal sclerosis and obliteration of the choriocapillaris that could explain total photoreceptor atrophy (Figure 10.71).

Cigarette smoking and hypertension are risks factors for the development of neovascular ARMD.

The following deposits between Bruch’s membrane and the retinal pigment epithelium are commonly found in ARMD.

1 Hard drusen are easily identified clinically as tiny, discrete, non-pigmented elevations beneath the retina between the basement membrane and Bruch’s membrane, but are not considered to be precursors of neovascularisation (Figure 10.72).

2 Soft drusen possess indistinct borders and may be more easily identified with fluorescein angiography (Figure 10.73). These structures are located between the cell basement membrane and Bruch’s membrane and are implicated in the attraction of blood vessels beneath the RPE (choroidal/subretinal neovascularisation).

3A third deposit has been variously termed basal linear/basal laminar/basement membrane deposit (Figure 10.74). This material is located between the cell membrane and the basement membrane and is so thin that it can be difficult to identify clinically. This deposit is often found in relation to neovascular tissue proliferating beneath the macula.

Some authors use the term “basal linear deposit” as syn-

onymous with confluent soft drusen which adds to confusion in the literature. For the purposes of this text, the terms “soft drusen” and “basement membrane deposit” are preferred.

Soft drusen and the basement membrane deposit stimulate cellular infiltration between Bruch’s membrane and the RPE, and are therefore presumed to be the precursors of neovascular ARMD (Figure 10.75).

Neovascular ARMD (subretinal neovascular membrane – SRNVM) occurs after Bruch’s membrane is penetrated by capillaries beneath the RPE (type 1 SRNVM). Plasma leakage and bleeding lead to progression of the RPE detachment and to rupture of the monolayer. Bleeding and neovascularisation then occur in the subretinal space (type 2 SRNVM).

Genetics

Unclear, although ARMD appears to favour white races, and family clusters can exist.

Retina - Central degeneration

ARMD

Dry/Geographic atrophy

PR inner segments

PR outer segments

RPE

RPE basement membrane

Inner collagenous layer

Elastic layer

Outer collagenous layer

Choriocapillaris

Figure 10.71

Figure 10.71 Diagram based on ultrastructural features. In atrophic age-related macular degeneration (ARMD), for reasons unknown, the photoreceptor layer in the macula disappears, and is replaced by glial tissue. The edge of the area of atrophy is sharply demarcated. The choroidal vessels and the choriocapillaris are atrophic in some cases. (Abbreviations as in Figure 10.68.)

Retina - Central degeneration

ARMD

Deposits - Hard drusen

ONL

PR inner segments

PR outer segments

RPE

RPE cell cytoplasmic membrane

RPE basement membrane Inner collagenous layer Elastic layer Outer collagenous layer Choriocapillaris

Figure 10.72

Figure 10.72 Diagram based on ultrastructural features. Hard drusen project as round or ovoid masses into the retinal pigment epithelium which becomes atrophic. The overlying photoreceptor outer segments are reduced in height but the adjacent photoreceptors are unaffected. (Abbreviations as in Figure 10.68.)

Possible modes of treatment

Prophylaxis and definitive treatment are not available for atrophic ARMD.

The argon laser is the only clinically proven treatment used to photoablate well demarcated subretinal neovascularisation (the reader should consult clinical texts with reference to the findings of the Macular Photocoagulation Study).

Other treatments with limited success include photodynamic therapy (PDT) and macular surgery.

Recurrence of neovascularisation is a problem with all current therapy. Preventative measures using dietary supplements such as zinc and fat-soluble vitamins have been suggested but much controversy exists.

Macroscopic and microscopic

ARMD is a common finding in elderly eyes enucleated for other conditions. Appearances vary according to progression of the disease and depend on whether the disease takes the form of dry atrophic or wet exudative ARMD.

NB: In the microscopic examination of a globe, location of abnormalities within the macular region can be confirmed by a thickened ganglion cell layer and the presence of the inferior oblique muscle on the adjacent sclera.

1Atrophic ARMD: a well demarcated area of depigmentation is seen at the macula. The depigmented oval areas

Retina - Central degeneration

ARMD

Deposits - Soft drusen

ONL

PR inner segments

PR outer segments

RPE cell cytoplasmic RPE membrane

RPE basement membrane Inner collagenous layer

Elastic layer Outer collagenous layer Choriocapillaris

Figure 10.73

Retina - Central degeneration

ARMD - Wet/Neovascular

Sub-RPE (Type I)

RPE

RPE basement membrane

have a petaloid pattern and are surrounded by a rim of hyperpigmentation (Figure 10.76). At the histological level, there is total atrophy of the outer retina in the region of the fovea (Figure 10.77). Hard drusen (Figures 10.78, 10.79) are not a significant aetiological factor in dry ARMD and are commonly present throughout all ageing retinae.

2Exudative ARMD precursors:

(a)Soft drusen (Figure 10.80) can be recognised by irregular tapering edges and a fluffy eosinophilic content.

(b)Basement membrane deposits (other names: basal linear, basal laminar – see above for explanation) are different to soft drusen in their location, staining characteristics, and ultrastructural appearance. The deposits form broad strips beneath the RPE and have a striated pattern (Figures 10.81–10.83).

3Exudative ARMD: at the early stage, small capillaries are present between the RPE and Bruch’s membrane (Figure 10.84). This abnormality is referred to as a type 1 SRNVM and progression takes the form of an established fibrovascular membrane in which arterioles and venules can be identified. A vicious circle arises when the small capillaries leak or burst with further inflammation and fibrovascular repair. Subsequently, interference with photoreceptor metabolism is followed by atrophy and degeneration of the outer retina (Figure 10.85).

Retina - Central degeneration

ARMD

Deposits - Basement membrane deposit

PR inner segments

PR outer segments

RPE cell cytoplasmic RPE membrane

RPE basement membrane

Inner collagenous layer

Elastic layer

Outer collagenous layer

Choriocapillaris

Figure 10.74

Figure 10.73 Diagram based on ultrastructural features. The term soft drusen is used to describe the accumulation of what appears to be cell debris between the basement membrane of the retinal pigment epithelium and the inner collagenous layer. Compared with hard drusen, the area affected is wider and the photoreceptor outer segments are more severely affected. (Abbreviations as in Figure 10.68.)

Figure 10.74 Diagram based on ultrastructural features. Basement membrane deposit differs from soft drusen because the accumulating material is between the basal cytoplasmic membrane and the basement membrane of the retinal pigment epithelium (RPE) cells. One component takes the form of linear strands identical to the basement membrane, and the other component is cellular debris, presumably secreted by the RPE. PR photoreceptor.

Figure 10.75 Diagram based on ultrastructural features. The presence of cell debris (in the case of soft drusen and basement membrane deposits) beneath the retinal pigment epithelium (RPE) appears to act as a chemoattractant for macrophages which, in turn, stimulate fibrovascular ingrowth. This initiates a vicious circle of plasma leakage, haemorrhage, and further neovascularisation.

vitreous veils

atrophic macula

swollen disc

Retina - Degeneration

ARMD - Atrophic/Dry/Geographic

Figure 10.76

Retina - Central degeneration / ARMD

Deposits - Hard drusen

hard drusen

choroidal vessels

PAS stain

Figure 10.80

Figure 10.77

hyperpigmented RPE

hard drusen

Figure 10.79

Figure 10.76 A corneal donor eye by chance was found to have a typical petaloid area of atrophic age-related macular degeneration (ARMD). Coincidentally the disc was swollen (cause unknown) and the vitreous contained veils.

Figure 10.77 This is a chance finding of atrophic (dry/areolar) age-related macular degeneration (ARMD) in a surgical enucleation for glaucoma – note the inner retinal atrophy (upper). In atrophic ARMD, the central macular region becomes completely atrophic and gliotic, and this is sharply demarcated from the adjacent normal outer retina (lower). In the atrophic region, the gliotic retina fuses with Bruch’s membrane and residual retinal pigment epithelium cells are hyperplastic (lower). In this specimen, the choriocapillaris appears to be patent but the vessels are small – ischaemia is one of the proposed pathogenetic mechanisms. (Abbreviations as in Figure 10.68.)

Figure 10.78 In autopsy material it is possible to strip off the retina to expose the underlying hard drusen, which appear as small, discrete, pale areas (upper). A PAS stain demonstrates the glycoprotein within small hard drusen beneath the macula with relative sparing of the photoreceptor layer (lower). The apparent overlying retinal detachment is artefactual due to autolysis.

Figure 10.79 Hard drusen are also present in the peripheral retina. As they increase in size, there is more focal damage to the outer retina. Note the homogeneous pink appearance with sharp edges in comparison with soft drusen (see below). (Abbreviations as in Figure 10.68.)

Figure 10.80 Soft drusen appear as elevations of the retinal pigment epithelium (RPE) over dome-shaped spaces containing flocculent material (upper). The RPE may be hypoor hyperpigmented. The edges are indistinct in comparison to hard drusen. The Picro-Mallory V stain (lower) demonstrates a pink appearance within the soft drusen compared with the blue appearance of basement membrane deposit (see below). PR photoreceptor.