Fig. 13.1 An axial section of the eye of a 20-mm fetus (6 weeks’ gestation) shows the inner and outer layers of the optic cup; these will form the neurosensory retina and RPE respectively. The primary vitreous and hyaloid vascular system are visible, and the inner retina already shows signs of dividing into the inner and outer neuroblastic layers.

Fig. 13.2 An axial section of a 35-mm foetus (9–10 weeks gestation) shows that the eye is much larger and better developed. The inner and outer neuroblastic layers are well formed.

Fig. 13.3 The retinal cell layers are listed on the left and the apparent layers that these cells give rise to are shown on the right.

Fig. 13.19 This photograph of normal rat retina (left), together with a freeze-dried preparation taken after the injection of fluorescein (right), demonstrates that dye is kept intravascularly by the inner blood retinal barrier of the retinal circulation. Dye leaks from the choriocapillaris into the choroidal extravascular space and spreads posteriorly to stain the sclera but is prevented from entering the retina by the outer blood–retinal barrier of the RPE.

Fig. 13.23 ICG using SLO imaging of a normal eye. In the early phase (left) there is filling of the retinal and choroidal circulations with better definition of choroidal vessels compared to FFA. In the late phase (right), the empty retinal circulation is seen against the uniform background of choroidal fluorescence from extravasated dye from the choriocapillaris.

By courtesy of Mr Ethan Priel.

Fig. 13.24 OCT image of the normal macular region; (right) shows vitreoretinal traction to an early macular hole.

By courtesy of Mr P Stanga.

Fig. 13.25 The image of a normal eye (left) shows a darker area in the macular region due to the presence of macular pigment. In Best’s disease (right), increased increased hyperfluoresence is seen in the macular lesion.

Fig. 13.26 (Left) These fresh, fluffy cotton-wool spots are seen around the optic disc in a patient with recent-onset radiation retinopathy. Their localization to the superficial retina can be seen by the way they overlay the retinal vessels. At this acute stage the nerve fibre layer appears intact. Nerve fibre loss produces grooves in the nerve fibre layer; these take about 6 weeks to appear ophthalmoscopically. (Right) The fluorescein angiogram shows that the cotton-wool spots correspond exactly to small areas of hypofluorescence in the retinal capillary network. These persist throughout the angiogram and are not associated with extravascular leakage confirming their aetiology as microvascular infarcts.

Fig. 13.27 Photographs from a patient with an inflammatory arteritis show a fluffy cotton-wool spot with some haemorrhage in the acute stage (left). Note also the arteritic changes of focal sheathing in the superior temporal artery. Six weeks’ later (right), the cotton-wool spot is absorbing and remains only as small, well circumscribed spots. The arteritic changes are less prominent and a nerve fibre defect has appeared.

Fig. 13.28 The distinction between retinal infarction and axonal infarction is shown by this patient with a recent lower temporal branch artery occlusion. The retina supplied by the obstructed artery appears pale due to cloudy intracellular oedema of the infarcted neuroretinal layers (which are supplied by the retinal circulation to the depth of the outer plexiform layer). A patch of viable retina remains in this territory, however, supplied by a cilioretinal artery. These retinal ganglion cells are still able to generate orthograde axoplasmic flow which passes along the axon until it reaches the area of ischaemia where it becomes held up as a thin, whiter frill of axoplasm corresponding to a cotton-wool spot.

Fig. 13.29 (Top) Light microscopy of a cotton-wool spot shows the distended and disrupted axons in the nerve fibre layer. Eosinophilic inclusions are seen in the axons and resemble a cell nucleus, giving rise to the term ‘cytoid body’. The true nature of cytoid bodies as swollen axonal stumps is clearly demonstrated in silver preparations. In this case (bottom right), the axons have been damaged as they pass over an area of photocoagulated retina, and the axonal stumps swollen with axoplasm can be clearly seen. Electron microscopy (bottom left) demonstrates that these are crammed with mitochondria and degenerating membranes.

Fig. 13.30 In this patient circinate exudates are seen surrounding the macula. They have a circumscribed yellowish appearance deep to the retinal vessels. In the macular area they adopt a more linear pattern from deposition within Henlè’s layer. Fluorescein angiography demonstrates that the leakage originates from a previous macular branch vein occlusion.

Fig. 13.31 (Left) A photograph taken 2 weeks after argon laser treatment to the leaking area of retina shows that the exudates are beginning to break up and absorb, especially inferiorly where the photocoagulation is heaviest. Occasionally following photocoagulation the amount of hard exudate may transiently increase before starting to absorb. (Middle) The angiogram demonstrates scarring of the RPE from the laser and less pronounced vascular leakage. (Right) Several months later the hard exudation has completely absorbed leaving RPE scars in the affected areas.

Fig. 13.32 A partial macular star and circumpapillary subretinal hard exudate is seen in a patient with a pale, swollen and infarcted optic disc. Note the linear radial deposition in the fibre layer of Henle on the nasal side of the macula indicating the optic disc to be the site of leakage.

Fig. 13.33 Histological appearance of hard exudates showing amorphous deposition of eosinophilic protein and lipid in the outer plexiform layer. Müller cells probably limit the lateral spread of exudate.

Fig. 13.34 Preretinal haemorrhages result from bleeding into the subhyaloid space between the internal limiting membrane of the retina and the posterior vitreous face. Sometimes a haemorrhage causes a localized detachment of the internal limiting membrane and then settles with gravity forming a horizontal fluid level. The preretinal location is demonstrated by masking of the retinal blood vessels. Preretinal haemorrhage is caused by bleeding from retinal tears, superficial retinal neovascularization or bleeding within the retina rupturing the internal limiting membrane. With any persistent haemorrhage the haemoglobin can absorb from the erythrocytes to leave white erythroclasts.

Fig. 13.35 Microscopy shows haemorrhage stripping the internal limiting membrane of the retina.

Fig. 13.36 Nerve fibre layer haemorrhages tend to be seen in the posterior pole where the nerve fibre layer is at its thickest. They have a linear, flame-shaped appearance caused by tracking along the retinal axons and usually absorb with relatively little damage. This patient also has areas of white retinal infarction from multiple emboli.

Fig. 13.37 Blotchy haemorrhages lie deeper in the retina in the plexiform or inner nuclear layers or are seen in the peripheral retina where the nerve fibres are thin. In these regions the vertical arrangement of the Müller fibres and neurones limit lateral spread.

Fig. 13.38 Full-thickness retinal haemorrhage has a dark brownish, patchy appearance. This is usually a feature of venous occlusions or diabetic retinopathy and is a sign of severe retinal ischaemia with retinal capillary closure indicating a high risk of subsequent retinal neovascularization if this is extensive.

Fig. 13.39 Dark brownish patchy haemorrhages are seen with full-thickness retinal haemorrhage. This is usually a feature of venous occlusions or diabetic retinopathy and is a sign of severe retinal ischaemia with retinal capillary closure, indicating a high risk of subsequent retinal neovascularization.

Fig. 13.40 Subretinal haemorrhage appears as a blotchy red area (left) underlying the retinal blood vessels with the retina usually elevated by the blood. In the macula these haemorrhages are frequently associated with choroidal subretinal neovascularization but, in the absence of this, can also occur with trauma or excessive Valsalva manoeuvres. The density and extent of the haemorrhage can mask an underlying neovascular membrane and, if treatment is to be considered, the patient must be observed until the haemorrhage clears sufficiently to allow visualization of angiographic subretinal fluorescence which might take 2–3 weeks or longer. (Right) A subretinal haemorrhage associated with a traumatic choroidal rupture. As the haemorrhage absorbs over a period of weeks, it can become depigmented with a whitish-yellow appearance as a result of the absorption of haemoglobin from the red blood cells leaving white erythroclasts.

Fig. 13.41 The RPE masks the redness of subpigment epithelial haemorrhages which consequently appear dark greenish brown, as in this patient with a bleed from a macroaneurysm. The haemorrhage has burst through the RPE and retina to produce a rim of subretinal haemorrhage and some preretinal haemorrhage. Large subpigment epithelial haemorrhages can even be mistaken for a malignant melanoma.

Fig. 13.42 Roth’s spots are haemorrhages with a white centre that correspond to a cotton wool spot or a collection of polymorphs. Often thought of as a manifestation of subacute bacterial endocarditis, they are a nonspecific sign tending to be seen more frequently in patients with blood dyscrasias, anaemia or metastatic endophthalmitis.

Fig. 13.43 Macular oedema is difficult to diagnose by direct ophthalmoscopy (left) and can be satisfactorily studied only with biomicroscopy and a fundus lens (see Ch. 1). It occurs either as a diffuse thickening of the retina with a dull light reflex or, in more severe cases, as cystoid oedema where cystic accumulations of fluid surround the macula in a petaloid appearance, as in this patient with posterior uveitis. Early (middle) and late (right) phases of the fluorescein angiogram demonstrate dilatation and leakage from the veins and capillaries of the retina and optic disc showing pooling of fluorescein in the extravascular tissue spaces corresponding to the cystic areas. Macular oedema is usually, but by no means always, associated with reduced visual acuity. It may persist for prolonged periods of time and with resolution can leave a relatively normal macular appearance; alternatively coalescence of the cystic spaces can form a partial thickness hole or leave central RPE atrophy.

Fig. 13.44 As the neural retina has limited intercellular space, fluid can accumulate only by physical movement of cells or their components. In the outer retina oedema occurs predominantly in the nerve fibre layer of Henle but may extend between the outer limiting membrane and the outer plexiform layer. The large spaces opened up in the retina show compression of retinal elements against the fibre cores of the Müller cells; although the spaces appear to be individual cysts on angiography or histological examination they are, in fact, interconnected as a single fluid-filled space.

Fig. 13.45 Benign pigment epithelial hypertrophy is a common finding in Caucasian fundi and is a good example of a lesion that masks choroidal fluorescence. The flat, jet black lesion is avascular and well circumscribed. It results from hypertrophy of RPE cells which contain more and large melanosomes and is totally benign and easily distinguished from a choroidal naevus or melanoma by its flat well-circumscribed appearance. With time, the central pigmentation may atrophy leaving a depigmented centre with surrounding pigmentation.

Fig. 13.46 RPE hypertrophy can take a variety of patterns collectively known as ‘grouped pigmentation’ or, more colloquially, as ‘bear tracks’ from their morphological appearance. Such patients may have Gardner’s syndrome (dominantly inherited intestinal polyposis and bony osteomas with a very high risk of adenocarcinoma of the colon).

Fig. 13.47 RPE hypertrophy must be distinguished from intraretinal pigmentation, which is always pathological and is usually seen in various patterns as a sign of retinal dystrophy, degeneration or inflammation. In the late stages of retinitis pigmentosa, areas of black spidery ‘bone corpuscular’ pigmentation are characteristically seen in the retina, frequently adjacent to blood vessels. RPE cells migrate into the neural retina and colonize outside of the basement membrane of retinal capillaries. Concomitant atrophy of the RPE is always present (see Ch. 16).

Fig. 13.48 This eye has a macular scar, probably from toxoplasmosis, with areas of retinal pigment atrophy and hyperplasia. In addition, there is white subretinal fibrosis, probably from previous subretinal neovascularization. Angiography shows the masking effect of the pigmentation and associated window defects in the atrophic area. In addition the surrounding RPE has been damaged much more widely than is apparent on ophthalmoloscopy.

Fig. 13.49 RPE atrophy is almost invariably accompanied by loss of the choriocapillaris; extensive loss exposes the large choroidal vessels.

Fig. 13.50 Mechanical breakdown of the outer blood retinal barrier of the RPE is illustrated in this patient with central serous retinopathy. A blister of subretinal fluid has accumulated between the RPE and outer segments of the photoreceptors thus elevating the macula. Angiography demonstrates a focal leak in the RPE through which this fluid has been derived. Although this stains with increasing intensity as more fluorescein leaks out during angiography, it lacks the early and sharply increasing intensity of neovascular leakage.

Fig. 13.51 RPE detachments are not uncommon being seen either as isolated lesions (usually in young people), as part of the spectrum of age-related macular disease (see Ch. 16) or in some types of inflammatory disease such as the Vogt–Koyanagi–Harada syndrome (see Ch. 10). They are due to the RPE separating from Bruch’s membrane. Their distinguishing angiographic feature is uniform hyperfluorescence that accumulates during dye transit to delineate the area of RPE detachment. Bright hyperfluorescence or uneveness of fluorescence suggests underlying choroidal neovascularization, which is an important diagnostic feature for prognosis and management.

Fig. 13.52 Scleral staining is seen in the late phases of angiography around areas devoid of RPE and choriocapillaris, such as a myopic crescent, of which this patient is an example. The choriocapillaris in the healthy retina leaks fluorescein into the sclera; this slowly spreads laterally to show as a hyperfluorescent ring adjacent to the healthy retina.

Fig. 13.53 Although iris neovascularization can occasionally occur with ocular tumours or posterior uveitis in the absence of capillary closure, retinal capillary closure is almost always seen as a precursor of retinal neovascularization no matter what the primary cause may be. In this patient with an inferior hemisphere vein occlusion, capillary closure can be inferred from the dark blotchy full-thickness retinal haemorrhages. Fluorescein angiography shows massive capillary closure in the affected area.

Fig. 13.54 This patient had an antiphospholipid antibody syndrome. He presented with rubeotic glaucoma in the right eye and sudden visual loss in the left. Colour photography shows arterial and venous thrombosis with retinal infarction. Angiography shows that in the left eye only a small area of peripapillary retina remains perfused. Such an eye has a grave risk of developing rapid iris as well as retinal and optic disc neovascularization.

Fig. 13.55 The optic disc is particularly prone to developing neovascularization, possibly because it is itself an interface between the retinal and choroidal circulations. Neovascularization is seen as fine thready vessels that start to leak fluorescein early during angiography and stain and leak intensively as the angiogram progresses. This diabetic patient shows minute changes on the disc, recognizable only on angiography.

Fig. 13.56 Neovascularization on the optic disc or retina induces partial vitreous detachment. New vessels are pulled forwards and are more vulnerable to minor trauma and haemorrhaging when the gel moves and causes traction.

Fig. 13.57 The end-result of untreated optic disc neovascularization is visual loss from tractional retinal detachment and vitreous haemorrhage.

Fig. 13.58 In the retina, neovascularization is usually seen at the boundary between perfused and nonperfused retina and is well illustrated in this patient with sickle cell retinopathy. Note the vascular shunt.

Fig. 13.59 Neovascularization can occur intraretinally, particularly in the area of venous occlusion or in areas of diabetic vascular closure. This angiographic sequence shows the development of fine, stunted, intraretinal new vessels and vascular remodelling over a period of several months following a branch retinal vein occlusion. These intraretinal new vessels, known as intraretinal microvascular anomalies (IRMAs), are a common phenomenon adjacent to areas of retinal ischaemia but they remain stunted and do not grow progressively. They do not cause any ocular morbidity or have the blinding sequelae of superficial neovascularization and can be thought of as an abortive attempt at revascularizing the ischaemic retina.

Fig. 13.60 Choroidal neovascularization is most commonly seen as part of the spectrum of age-related macular disease in which it tends to underlie the macula and destroys vision by causing haemorrhage, lipid exudation and subretinal fibrosis (see Ch. 16). Choroidal new vessels fill with the choroid during early angiography and leak over time. This leakage is much more intense and brighter than that seen, for example, with central serous retinopathy (see Fig. 13.47) or RPE detachment (see Fig. 13.48).

Fig. 13.61 Subretinal fibrosis is seen as white tissue. It frequently ocurs as the end-result of choroidal neovascularization.

Fig. 13.62 Sub-RPE deposits. (Top left) Hard drusen lying between basement membrane of the RPE and the inner collagenous layer of Bruch’s membrane. (Top right) Soft drusen lying in a similar position; they are less homogenous and less sharply defined. (Bottom left) Calcified drusen beneath a detached retina (Bottom right) Basement membrane deposit lying between RPE cell and its basement membrane.

Fig. 13.63 Drusen are commonly found in the macular area, but may be found anywhere in the posterior pole. The distribution in both eyes is usually symmetrical. They are yellowish circumscribed areas of differing sizes, varying in appearance from fine granular deposits to large, juicy confluent areas or hard, glistening calcific lesions (see Ch. 16). Drusen are distinguished from hard exudates by their deeper, less defined appearance, their topographical location and bilaterality, and the absence of a concomitant retinal vascular focus of leakage. During fluorescein angiography, drusen usually take up dye, which fades towards the later phases of the angiogram. If more intense leakage occurs within a drusen, this may be a sign of early microscopic choroidal neovascularization (see Ch. 16).

Fig. 13.64 Associated atrophy and hypertrophy of the RPE is common with more pronounced disease.

Fig. 13.65 Histological examination shows wrinkling of the retinal surface by an epiretinal membrane.

Fig. 13.66 Cellophane maculopathy is the mildest form of epiretinal membrane formation and usually presents with slight blurring of acuity and metamorphopsia. Some epiretinal membranes will simulate macular oedema or a macular hole. In this patient, a preretinal membrane lying inferior to the macula, which is clearly seen on red-free photography, mimics a pseudomacular hole. It is not unusual to find that traction and distortion of retinal vessels in the affected area cause vascular leakage and macular oedema. OCT can be very useful in distinguishing the underlying pathology.

Fig. 13.67 This patient has a more marked membrane, reducing visual acuity to 20/60. Angiography shows distortion of the normal vascular pattern.

Fig. 13.68 This patient shows a more severe membrane with an epicentre on the superior temporal vessels. There are prominent retinal folds, with traction and distortion of the macula producing metamorphopsia. Such membranes are amenable to removal by vitrectomy.

Fig. 13.69 Retinal folds are seen as fine striations of the retinal surface. They do not alter the fluorescein angiographic appearance.

Fig. 13.70 In contrast, choroidal folds cause hypofluorescence and hyperfluorescent troughs on the angiogram as a result of folding of the RPE.