PATHOGENESIS OF AMD

AMD appears to result from defects in the RPE cell–Bruch’s membrane–choriocapillaris complex and is thought to be a collection of heterogeneous disorders associated with multiple genetic and environmental factors. Much current research centres on defects in the RPE cell and Bruch’s membrane (see Ch. 13). In normal ageing progressive thickening of Bruch’s membrane occurs with accumulation of lipids, noncollagenous proteins and other extracellular material such as advanced glycation endproducts, collagen and elastin changes and increased calcification. By the fourth decade all eyes show accumulation of membranous debris within both collagenous layers. With time, a second series of changes is seen with deposition of diffuse material both between the RPE and its basement membrane (basal linear deposit) and between the basement membrane and the inner collagenous layer (basal laminar deposit). The latter can become extensive with a complex morphology and may be confused with diffuse or soft drusen, drusen being focal accumulations between the RPE basement membrane and the inner collagenous layer of Bruch’s membrane. Lipofuscin accumulates with age in the RPE cell from metabolism of photoreceptor outer segments from oxidative damage or RPE overloading by failed photoreceptors. The specific mechanisms underlying these changes are not fully understood, but it is thought that the resultant increase in thickness and reduction in molecular transport through Bruch’s membrane and the RPE cell may contribute to photoreceptor cell death and AMD. In addition, anatomical changes and delayed filling on fluorescein angiography are seen in the choroidal circulation.

AMD can be dominantly inherited and many classical features of AMD (drusen, pigment epithelial detachment (PED), CNV, atrophy) are also seen in inherited disorders such as Sorsby’s fundus dystrophy, North Carolina macular dystrophy, and Doyne’s dominant drusen, suggesting common underlying cellular mechanisms between these dystrophies and AMD.

These are important for the potential clue that they give to the underlying cellular process involved. In Stargardt’s macular dystrophy, mutation of the ABCA4 gene causes lipofuscin to accumulate in RPE; a similar process might occur in AMD leading to RPE dysfunction and eventual death. In Sorsby’s fundus dystrophy, mutation of the TIMP3 gene (tissue inhibitor of metalloproteinase 3 inhibits matrix degradation) is associated with thickening of Bruch’s membrane. In AMD, TIMP3 concentration is also increased and associated with thickening of Bruch’s membrane. Increased lipid deposition is also found in Bruch’s membrane and epidemiological risk factors for cardiac disease (although not serum cholesterol) are also associated with AMD.

Fig. 16.1 Histological examination shows the pathological appearances of hard (top) and soft (middle) drusen. Preparations stained to demonstrate TIMP3. The red stain demonstrates its presence in the drusen and along Bruch’s membrane (bottom). Note the patchy loss of the RPE over the drusen.

Fig. 16.2 Scanning electron micrograph of a 45-year-old eye shows RPE cells distended with lipofuscin granules (middle). The RPE is stretched over a large drusen (top), which can be seen to contain lipofuscin granules (bottom).

DRUSEN AND ATROPHIC MACULAR CHANGES

Drusen lie in Bruch’s membrane and stain progressively during fluorescein angiography. They are assessed more easily by fluorescein angiography than by fundoscopy as angiography shows RPE atrophy more clearly. Different drusen staining patterns emerge during angiography. Conventionally, drusen that stain readily are taken to be ‘hydrophilic’, whereas those that do not are ‘hydrophobic’. Hydrophilic drusen are more proteinaceous and are associated with an increased risk of choroidal neovascularization; hydrophobic drusen have increased lipid and are more associated with PED. Other factors, such as drusen size and extracellular matrix characteristics probably influence staining too. However, it is the extent of RPE atrophy seen as window defects (see Ch. 13) on angiography or as blackness on autofluorescence imaging—rather than drusen—that better reflects visual loss.

Fig. 16.3 Drusen come in various patterns, shapes and sizes with variable amounts of RPE change. Some patients develop widespread drusen throughout the posterior pole.

Fig. 16.4 The drusen in this patient’s macular area are relatively hydrophobic, failing to stain as angiography progresses.

Fig. 16.5 This patient has more hydrophilic drusen. Note the submacular hyperfluorescence, which probably denotes early occult choroidal neovascularization.

Fig. 16.6 Calcific drusen have a flat, glistening, white and refractile appearance (left). These eyes tend to lose vision from RPE atrophy rather than neovascularization, as seen in the more gross example (right).

Fig. 16.7 This patient has a large area of confluent drusen under the macula. Such patients have a considerable risk of developing choroidal neovascular lesions.

Fig. 16.8 The degree of RPE atrophy varies considerably. This patient has small, sparse drusen, subretinal pigmentation from RPE hyperplasia and a central–paracentral RPE defect, accounting for an acuity of 20/100 and a paracentral scotoma.

Fig. 16.9 Central areolar choroidal atrophy can be dominantly inherited but it is also a phenotypic variant of AMD in which there is a sharp circumscribed demarcation line between normal and abnormal retina with central atrophy of the choriocapillaris, RPE and photoreceptors revealing large choroidal vessels in the base (left). These lesions start in the macular area and gradually increase in extent over time with severe loss of visual acuity. Drusen are not normally seen. (right) Angiogram of the same patient shows the large window defect due to loss of the RPE and choriocapillaris. Large choroidal vessels are seen in the base and fill normally. Note the relative hyperfluorescence of the rim of the lesion from scleral staining (see Ch. 13).

RETINAL PIGMENT EPITHELIAL DETACHMENT

As part of the degenerative process, fluid may collect between the RPE and Bruch’s membrane to induce a PED in the posterior pole. This is seen clinically as a well demarcated, localized elevation in the macular area that can be distinguished from central serous retinopathy by its rather more solid and better defined appearance. PEDs vary from 0.5 to 2 or 3 disc diameters in size. Fluorescein angiography confirms the diagnosis by showing a steadily increasing diffuse and even pattern of leakage. Marked, well defined pooling is seen in the later stages. Uneven intensity or focal hyperfluorescence indicates associated subretinal neovascularization. PEDs are thought to be caused by hydrophobic drusen material being deposited in Bruch’s membrane. This restricts fluid outflow into choroid by RPE cell ‘pumping’, so that fluid accumulates and cleaves the RPE off Bruch’s membrane.

In younger patients, the visual prognosis is relatively good and no treatment is indicated; the detachment may persist for many years without vision being affected significantly. In elderly patients controlled trials have not shown any benefit from argon laser photocoagulation and the effect of in photodynamic therapy has not yet been studied. The condition is thus best left untreated in all patients. Visual acuity may suddenly be lost if the detached RPE tears, resulting in the pathological event known as a pigment epithelial tear or ‘rip-off’ syndrome. Tears may flap back under themselves and sometimes cause simultaneous haemorrhage. In some patients, especially those of Oriental or African Caribbean descent, the differential diagnosis of idiopathic polypoidal choriovasculopathy (IPCV) should also be considered.

Fig. 16.10 Colour photograph showing the well circumscribed elevation of the macula, which has a more prominent and thicker appearance than that seen with central serous retinopathy (see Fig. 16.38). In elderly patients other signs of macular degeneration such as drusen, pigmentation and atrophy are frequently seen. Any surrounding lipid exudate or haemorrhage strongly suggests choroidal neovascularization within the lesion.

Fig. 16.11 The fluorescein angiogram shows early diffuse leakage which increases in intensity as the run progresses but remains localized to the area of the lesion. Other degenerative changes in the RPE are often seen.

Fig. 16.12 Elderly patients may have an underlying neovascular membrane, which is indicated by any unevenness of staining or hyperfluorescence within the lesion.

Fig. 16.13 Excessive tension within the PED causes it to rip and fold back on itself. This is often associated with haemorrhage into the lesion and acute loss of acuity in the eye. Characteristically RPE rips show a dark area where the RPE has folded back on itself separated by a straight line from the area of denuded RPE.

By courtesy of Ms H Jackson.

CHOROIDAL NEOVASCULAR MEMBRANES

Disciform degeneration of the macula is an old name derived from the elevated mass of fibrosis and exudate that is seen replacing the macula in the terminal stages of the disease. The earliest pathological changes are rupture of Bruch’s membrane with penetration of a neovascular membrane derived from the choriocapillaris. This invades drusen material and the subretinal pigment epithelial and subretinal spaces. The process occurs in the posterior pole of the eye, either under the macula, in the paramacular area, or occasionally adjacent to the optic disc. Similar lesions in the equatorial or peripheral retina can occasionally occur in diseases such as pars planitis or retinitis pigmentosa. In common with neovascular tissue elsewhere, these vessels bleed and leak, producing subretinal exudate and fibrosis with consequent disruption of the macular anatomy and destruction of central vision.

While CNV is usually associated with AMD it is also the end-result of a group of diverse conditions that appear to have in common the ability to affect the posterior pole and damage Bruch’s membrane. The stimulus for the neovascular process is thought to be the release of neovascular factors such as vascular endothelial growth factor (VEGF) from the RPE, induced by metabolic changes and hypoxia from thickening of Bruch’s membrane with age. This is modulated by a complex interaction of other stimulatory factors and inhibitory factors such as pigment epithelium-derived factor (PEDF) in a way analogous to that seen with retinal neovascularization.

Fig. 16.14 CNV can grow between Bruch’s membrane and the RPE (type 1) or in the subretinal space between the RPE and photoreceptors (type 2); combinations of these occur as well. The appearance of CNV on angiography depends on the amount of haemorrhage, pigment hyperplasia and RPE atrophy. Based on FFA findings, choroidal neovascular membranes (CNV) are divided into classical and occult forms. Classical CNV is defined as well demarcated areas of hyperfluorescence that can be seen in the early phase of fluorescein angiography with progressive leakage of dye obscuring the boundaries of the CNV as angiography progresses; these may correspond to type 2 membranes. Occult CNV is either a fibrovascular PED with areas of irregular elevation of RPE producing an area of stippled hyperfluorescence as the angiogram progresses or late leakage from an undetermined source; these may correspond to type 1 membranes. An alternative explanation of the different angiographic appearances is that a classical CNV represents a type 1 membrane with overlying RPE atrophy. Further clinical pathological studies are needed.

Fig. 16.15 Serial sections of eyes with drusen have shown that neovascularization of drusen in the posterior pole is not uncommon and that only a minority of these lesions progress to a clinically apparent CNV. Pathology of end-stage disciform macular degeneration shows a layer of vascularized fibrous tissue replacing the photoreceptors (left). In a gross example (right) the retina is completely destroyed by an elevated mass of vascularized fibroglial tissue.

Fig. 16.16 The typical classical CNV lesion, no matter what the aetiology, consists of subretinal elevation either beneath or adjacent to the fovea. Recent lesions often have a pale, raised appearance with variable amounts of lipid or haemorrhage. A subretinal haemorrhage in the macular area should always raise the suspicion of a neovascular cause. Presenting symptoms are either metamorphopsia or blurring of vision, depending on the size and site of the lesion. Early-phase fluorescein angiography of the same lesion shows the classical appearance of a neovascular complex lying beneath the retina which, because it is derived from the choroid, fills early in angiography. Individual vessels in the neovascular membrane may be identified in the earliest stages as a net-like membrane. In common with other neovascular tissue, the capillaries in the neovascular membrane have loose endothelial cell junctions and in late stages the membrane shows intense leakage into the adjacent retina, blurring the membrane. These lesions are amenable to photodynamic treatment.

Fig. 16.17 Occult CNV membranes are more common than classical lesions. This patient presented with distortion and blurring of vision to 20/80. Angiography shows an irregular leakage in the lesion, staining intensively in the later phases. These lesions do not benefit as much from photodynamic treatment.

Fig. 16.18 CNV is often associated with subretinal haemorrhage which may produce a sudden drop in visual acuity causing the patient to present. In this situation haemorrhage may mask the true extent of the membrane and fluorescein angiography should be postponed until sufficient haemorrhage has been absorbed for visualization. ICG angiography may help in these circumstances as it reveals the extent of the membrane despite the overlying haemorrhage.

Fig. 16.19 An exudative reaction may occur around a disciform lesion producing a circinate subretinal exudate with central subretinal neovascularization. In some patients exudates are the major feature of the fundus appearance.

Fig. 16.20 CNV may resolve leaving subretinal fibrosis with some improvement in vision (left) or progress to leave massive disciform subretinal fibrosis (middle) or RPE scarring (right).

ANGIOID STREAKS

Fig. 16.21 Angioid streaks are splits in Bruch’s membrane. They appear as linear fractures extending from the optic disc and ramifying towards the periphery mimicking retinal blood vessels. They are usually reddish brown but may show degenerative pigmentary changes. Their appearance on angiography depends on the degree of associated pigmentary disturbance and RPE loss. The majority of streaks are hyperfluorescent, although early in the run they may mask background choroidal fluorescence. Subretinal neovascularization in the papillomacular region or alongside the optic disc is a frequent complication. Angioid streaks occur as an isolated ocular finding or with systemic associations which include elastic tissue disorders such as pseudoxanthoma elasticum and Ehlers–Danlos syndrome.

Fig. 16.22 Pseudoxanthoma elasticum is a recessively inherited disorder affecting connective tissue elastic fibres. Patients have cutaneous, ocular and vascular manifestations and suffer premature hypertension, atheroma, cardiac valve disorders and gastrointestinal haemorrhage. This patient has the characteristic ‘chicken skin’ changes on her neck, which she disguises by wearing a polo-neck shirt.

Fig. 16.23 Remarkably conspicuous angioid streaks radiate from the patient’s optic disc which also has the well recognized association of pronounced optic disc drusen. Juxtapapillary and subretinal fibrosis from neovascularization can be seen underlying the macula. This patient has widespread RPE changes within and adjacent to areas of subretinal neovascularization; visual prognosis is poor.

By courtesy Mr R K Blach.

Fig. 16.24 In patients with pseudoxanthoma elasticum, Bruch’s membrane and the RPE may also be altered, giving the fundus a slightly mottled, yellowish and refractile appearance known as ‘peau d’orange’. This is most noticeable in the posterior pole and contrasts with the normal appearing periphery.

CHOROIDAL RUPTURE

‘Choroidal rupture’ is caused by severe blunt injury to the eye but the appearance is in fact due to rupture of Bruch’s membrane (see Ch. 14). CNV can develop some time later in lesions extending into the macular area.

Fig. 16.25 In this patient, rupture is seen as a typical chorioretinal scar lying concentric to the optic disc with fresh, pale, submacular fluid that has caused recent onset of blurring and distorted vision. Fluorescein angiography demonstrates the extent of the RPE and choriocapillaris disruption with a subfoveal CNV. Photodynamic therapy has a potential role in the managment of these patients.

OCULAR HISTOPLASMOSIS AND PUNCTATE INNER CHOROIDOPATHY

The ocular histoplasmosis syndrome describes a pattern of fundus abnormalities related to endemic Histoplasma capsulatum infection in the North American Midwest. Similar fundal appearances are seen in European patients in the absence of histoplasmosis infection and are known as punctate inner choroidopathy (PIC).

Fig. 16.26 The typical appearance of the fundus comprises the triad of atrophic changes around the optic disc, localized punched-out areas of pigment epithelial atrophy in the posterior pole and atrophic, usually linear, RPE lesions in the equatorial retina (bottom left). Atrophic changes in the macular region carry a substantial risk of developing CNV, typically in early middle age.

PERIPAPILLARY CNV

Choroidal neovascularization may develop adjacent to the optic disc, either spontaneously or in association with disc abnormalities such as tilting or chronic pathological disc swelling or drusen of the disc (see Ch. 17).

Fig. 16.27 Lesions extending into the papillomacular region cause a profound loss of central vision but more eccentric membranes do not necessarily affect vision. This patient has chronic papilloedema with an adjacent CNV and subretinal fluid.

RUBELLA

Fig. 16.28 Congenital rubella can produce large patches of RPE change. If these affect the macula there is a high risk of CNV in middle age.

MYOPIC MACULAR DEGENERATION

Fig. 16.29 High myopes have an increased risk of developing atrophic macular degeneration—seen as chorioretinal thinning or atrophy, posterior staphylomata and splits in Bruch’s membrane termed ‘lacquer’ cracks—and also peripheral lattice degeneration. This patient shows a large myopic crescent on the temporal side of the optic disc. Retinal vessels are pulled straight as they enter the enlarged posterior pole. In the macula there is patchy pigmentary disturbance and fine cracks in Bruch’s membrane.

Fig. 16.30 This patient shows marked myopic chorioretinal atrophy in both eyes with exposed sclera at each posterior pole.

Acuity was reduced to HM in the right eye and CF in the left. There is gross chorioretinal atrophy of the macula in the right eye with exposed bare sclera.

Fig. 16.31 Magnetic resonance imaging demonstrates a large posterior pole staphyloma extending posteriorly to the optic disc in the right eye.

Fig. 16.32 High myopes have an increased risk of developing CNV in early adulthood, usually presenting with a fairly small localized haemorrhage (Foster–Fuchs’ spot). Extensive exudate or serous detachment does not occur and the condition resolves to leave a small pigmented scar. Visual recovery is much better than with other types of CNV lesion. Photodynamic therapy may improve the prognosis.

CLASSIFICATION OF INHERITED RETINAL DISEASE

Clinically inherited retinal dystrophies are classified by natural history (stationary or progressive), mode of inheritance (autosomal dominant, autosomal recessive, X-linked recessive, mitochondrial or, less commonly, multiallelic inheritance) and putative site of dysfunction within the retina. The latter may be inferred from the results of psychophysical and electrophysiological testing (see Ch. 1) and the various methods of fundus imaging such as fluorescein angiography, autofluorescence imaging and optical coherence tomography. This approach has limitations and a more robust classification which more accurately reflects disease pathogenesis awaits the identification of the many genetic mutations associated with retinal disease. More than 90 genes and 140 loci associated with inherited retinal degeneration have now been identified with many more yet to be discovered. At present, routine molecular diagnostic testing is available for only a few disorders but the numbers will increase as advances are made in the technology of molecular genetic analysis.

MANAGEMENT OF RETINAL DYSTROPHIES

Inherited retinal disorders are not amenable to any form of treatment, except in a few rare disorders (e.g. abetalipoproteinaemia, Refsum disease, and gyrate atrophy) where a metabolic defect is known. However, all patients and their families benefit from genetic counselling, educational and occupational advice and supportive measures such as visual rehabilitation and the treatment of concurrent ocular problems (e.g. myopia and cataracts). Advances in molecular biology have led to the identification of many of the causative genetic mutations and it is likely that over the next few years the underlying molecular pathology of most disorders will be known which should offer new therapeutic prospects. Treatment strategies aimed at prolonging photoreceptor survival with exogenous growth factors, stem cells, gene therapy and RPE or photoreceptor transplantation are currently being investigated in animal models and some will be the subject of therapeutic trials in the near future. Another approach is the development of an artificial retina that would utilize residual ganglion cell function in patients with complete loss of photoreceptor function.

AUTOSOMAL RECESSIVE INHERITANCE

Stargardt disease and fundus flavimaculatus (FFM)

Autosomal recessive Stargardt macular dystrophy (STGD) is the most common inherited macular dystrophy with a prevalence of 1 in 10000. Most patients present with central visual loss in their early teens but STGD may also present in adult life when the visual loss is usually milder. The electrophysiological abnormalities detected are variable. An abnormal electro-oculogram (EOG), suggestive of RPE dysfunction is a common finding. The pattern electroretinogram (PERG) and focal ERG are usually abolished or markedly reduced indicating macular dysfunction. The full-field ERG may be normal at diagnosis or over time may show changes consistent with widespread retinal dysfunction. Patients who show an abnormal full-field ERG at diagnosis have a poorer long-term visual prognosis.

The locus for STGD–FFM has been mapped to chromosome 1 p and the causative gene, ABCA4, characterized. Mutations in ABCA4 have also been implicated in other disorders, including retinitis pigmentosa (RP) and cone–rod dystrophy (CORD). It is currently believed that homozygous null mutations cause the most severe phenotype of autosomal recessive RP; combinations of a null mutation with a moderate missense mutation result in autosomal recessive CORD; and combinations of null/mild missense or two moderate missense mutations cause STGD–FFM. ABCA4 encodes a transmembrane rim protein located in the discs of rod and foveal cone outer segments that is involved in ATP-dependent transport of retinoids (intermediates in the vitamin A recycling pathway) from photoreceptor to RPE. Failure of this transport results in deposition of a major lipofuscin fluorophore, A2E (N-retinylidene-N-retinyl-ethanolamine), in the RPE. It is thought that this accumulation may be deleterious to the RPE with consequent secondary photoreceptor degeneration. Growing evidence from in vitro studies and mouse models suggests that the deleterious effects of A2E can be alleviated by a variety of interventions that either antagonize the toxic effects of A2E or inhibit its biosynthesis.

Fig. 16.42 The term fundus flavimaculatus (FFM) is often used to describe a phenotype in which there are multiple white flecks without significant macular atrophy. It appears that STGD and FFM are caused by mutations in the same gene and both patterns may be seen within the same family.

Fig. 16.43 Typically there is macular atrophy with white flecks at the level of the RPE at the posterior pole. The flecks may be fish tail-shaped (pisciform), round, oval or semilunar. The area of macular atrophy may in the early stages have a ‘beaten bronze’ appearance.

Fig. 16.44 Fluorescein angiography classically reveals a dark or masked choroid. The reduced visualization of the choroidal circulation in the early phase of fundus fluorescein angiography (FFA) is believed to be secondary to excess lipofuscin accumulation in the RPE obscuring the fluorescence emanating from choroidal capillaries. The retinal flecks appear hypofluorescent on FFA early in their evolution but at a later stage they appear hyperfluorescent as a result of RPE atrophy.

Fig. 16.45 Progressive macular atrophy can be seen in this patient. The photographs were taken 6 years apart.

AUTOSOMAL DOMINANT INHERITANCE

Best disease (vitelliform macular dystrophy)

Best disease is dominantly inherited and characterized clinically by the classical feature of a round or oval yellow subretinal macular deposit. Full-field ERG is normal but the EOG shows a very reduced or absent light rise indicating that there is widespread dysfunction of the RPE. The visual prognosis in Best disease is surprisingly good with most patients retaining reading vision into the fifth decade of life or beyond. The disease shows very variable expressivity although the majority of individuals who carry mutations in the VMD2 gene have an abnormal EOG; this is extremely useful in assigning disease status when counselling in Best disease. Family members who carry a mutation in the VMD2 gene and who have minimal macular abnormality or a normal fundus appearance (but abnormal EOG) in early adult life usually retain near-normal long-term visual acuity. The protein product of VMD2, bestrophin, has been localized to the basolateral plasma membrane of the RPE, where it forms a component of a chloride channel. It has been suggested that impaired fluid transport in the RPE secondary to abnormal chloride conductance may lead to accumulation of fluid and/or debris between the RPE and photoreceptors and between the RPE and Bruch’s membrane, leading to detachment and secondary photoreceptor degeneration.

Fig. 16.46 The phenotype has been classified into five stages. Stage 0 (previtelliform) is characterized by a normal fundus appearance in an asymptomatic gene carrier with an abnormal EOG. In stage I, minor RPE changes are seen. The classical vitelliform lesion (stage II) is characterized by the ‘egg yolk’ macular lesion that masks the underlying choroidal fluorescence. This appearance is usually seen during the first or second decades, often associated with normal, or slightly reduced, visual acuity.

Fig. 16.47 The ‘egg yolk’ begins to break up secondary to resorption of the yellow material lying between the RPE and sensory retina (stage IIa) with visual impairment usually being noticeable at this stage.

Fig. 16.48 Stage III (pseudohypoyon) is seen when part of the lesion is resorbed, leaving the appearance of a ‘fluid level’ at the macula. The yellow material is completely resorbed over time, leaving an area of RPE atrophy (stage IVa) and often subretinal fibrosis (IVb). Choroidal neovascularization is an established complication leading to severe visual loss (IVc).

Adult vitelliform macular dystrophy

Adult vitelliform macular dystrophy (AVMD) is often confused with Best disease although, as the name suggests, it has a later onset, lacks the typical course through different stages of macular disease seen in classical Best disease and often has a normal EOG. Mutations in the peripherin/RDS gene on chromosome 6 p have been identified in approximately 20 per cent of patients with AVMD.

Fig. 16.49 The typical clinical appearance is of bilateral, round or oval, yellow, symmetrical, subretinal lesions, typically one-third to one-half optic disc diameter in size. The autofluorescence image shows increased autofluorescence corresponding to the macular lesion suggesting that this is due to accumulated lipofuchsin.

By courtesy of Mr Andrew Webster.

Pattern dystrophy

The pattern dystrophies are a group of inherited disorders of the RPE characterized by bilateral symmetrical yellow-orange deposits at the macula in various distributions, including butterfly or reticular-like patterns, most likely representing lipofuscin accumulation. They are often associated with a relatively good visual prognosis although in some cases a slowly progressive loss of central vision occurs secondary to atrophic macula changes. The age at presentation is variable and is usually between the second and fifth decades of life. Electrophysiological findings usually reveal abnormal EOG and pattern ERG with normal full-field ERG. Mutations in the peripherin/RDS gene have been identified in some patients but other genes remain to be identified. The peripherin/RDS protein is a membrane-associated glycoprotein restricted to photoreceptor outer segment discs in a complex with ROM1. It may function as an adhesion molecule involved in the stabilization and maintenance of the compact arrangement of outer segment discs.

Fig. 16.50 This patient has bilateral orange-yellow deposits at the macula in a reticular-like distribution associated with some RPE atrophy in the left eye. Autofluoresence imaging suggests that the deposits contain lipofuscin.

By courtesy of Mr Andrew Webster.

Doyne honeycomb retinal dystrophy (malattia leventinese; autosomal dominant drusen)

In this disorder small round yellow-white deposits under the RPE begin to appear in early adult life characteristically distributed at the macula and around the optic disc. Visual acuity is maintained through the fifth decade but patients often become legally blind by the seventh decade. Visual loss is usually due to macular atrophy and less commonly from subretinal neovascularization. A single mutation (arginine-345-to-tryptophan) in the gene EFEMP1 on chromosome 2 p has been identified in the majority of patients. This is a widely expressed gene predicted to encode an extracellular matrix glycoprotein. It has been proposed that misfolding and aberrant accumulation of this protein within RPE cells and between the RPE and Bruch’s membrane may be the underlying defect.

Fig. 16.51 The yellow-white drusen-like deposits classically appear to radiate like the spokes of a wheel from the macula and characteristically surround the optic disc.

North Carolina macular dystrophy

North Carolina macular dystrophy (NCDR1) is an autosomal dominant disorder that is characterized by a variable macular phenotype and a nonprogressive natural history. EOG and ERG are normal indicating that there is no generalized retinal dysfunction. It has been described in various countries including Europe and all cases have mapped to a locus on chromosome 6q16. The identification of the gene responsible is keenly awaited as this will help to improve our understanding of the pathogenesis of drusen and subretinal neovascular membrane (SRNVM).

Fig. 16.52 Bilaterally symmetrical fundus appearances in MCDR1 range from a few small (less than 50μm) yellow drusen-like lesions in the central macula (grade 1) to larger confluent lesions (grade 2) and macular colobomatous lesions (grade 3). Occasionally MCDR1 is complicated by SRNVM at the macula.

Sorsby fundus dystrophy

Sorsby fundus dystrophy (SFD) is a rare, autosomal dominant macular dystrophy with onset of night-blindness in the third decade and loss of central vision from macular atrophy or SRNVM by the fifth decade. A tritan colour defect has been suggested as an early sign. The tissue inhibitor of metalloproteinase 3 (TIMP3 gene on chromosome 22q) is implicated. An abnormal tertiary protein structure is thought to alter TIMP3-mediated extracellular matrix turnover leading to the thickening of Bruch’s membrane and the widespread accumulation of abnormal material beneath the RPE seen histologically. High doses of oral vitamin A reverse the night-blindness and suggest that retinal dysfunction may be due to a reduction in the permeability of Bruch’s membrane resulting in defective vitamin A transport from the choriocapillaris to the photoreceptors by accumulated extracellular debris beneath the RPE. TIMP3 has also been shown to be a potent inhibitor of angiogenesis which may account for the recognized complication of choroidal neovascularization seen in SFD.

Fig. 16.53 This patient has widespread RPE atrophy and drusen with an island of RPE preserved centrally. The patient had acuities of 20/100 and 20/40 with a paracentral ring scotoma in each eye.

X-LINKED INHERITANCE

X-linked juvenile retinoschisis (XLRS)

XLRS is a vitreoretinal degeneration that presents either in a male infant with nystagmus or, more commonly, in childhood with mild loss of central vision. Full-field ERG typically reveals a negative waveform with the a-wave larger in amplitude than the b-wave indicating inner retinal dysfunction. Prognosis is good in most affected males as long as retinal detachment or vitreous haemorrhage does not occur. XLRS has been linked to Xp22.2 and mutations in the gene XLRS1 (also referred to as RS1), which is expressed in photoreceptors and bipolar cells have been identified. XLRS shows both intrafamilial and interfamilial variability in the phenotype. XLRS1 encodes the protein retinoschisin (RS1), which contains a highly conserved discoidin domain implicated in cell–cell adhesion and cell–matrix interactions, functions that correlate well with the observed splitting of the retina in XLRS. Female carriers have a normal fundus appearance and normal EOG and ERG.

Fig. 16.54 The characteristic fundus abnormality is a cystic spoke wheel-like maculopathy (foveal schisis) in virtually all affected males.

Fig. 16.55 Peripheral retinal abnormalities including bilateral cavities, vascular closure, inner retinal sheen and pigmentary retinopathy are seen in approximately 50 per cent of cases.

MITOCHONDRIAL INHERITANCE

Maternally inherited diabetes and deafness (MIDD)

MIDD is a subtype of diabetes mellitus that co-segregates with an adenine-to-guanine transition at position 3243 of mitochondrial DNA (A3243G) in a transfer RNA leucine-encoding region. Mitochondrial inheritance is matrilineal because sperm do not contribute mitochondria to the zygote. Both sexes can therefore be affected by MIDD but the disorder is passed on only by affected mothers. Prognosis is generally good with the majority of patients retaining very good central vision. As the prevalence of macular dystrophy in MIDD is high, the association of a macular dystrophy with diabetes should always raise the possibility of screening for a mitochondrial DNA mutation.

Fig. 16.56 A bilateral macular dystrophy is present in the majority of patients with MIDD characterized by RPE atrophy that can surround the macula or be more extensive and encompass the optic disc. In advanced cases areas RPE atrophy encircling the macula may coalesce and involve the fovea at a late stage.

STATIONARY RETINAL DYSTROPHIES

Most dystrophies are progressive but others, notably stationary night-blindness and some cone dysfunction syndromes, are stationary. Three forms of stationary night-blindness are recognized: congenital stationary night-blindness (CSNB), fundus albipunctatus and Oguchi disease.

Fundus albipunctatus

Patients with this autosomal recessive form of stationary night-blindness usually have normal visual acuity; the condition is nonprogressive in the majority of affected individuals. The rod-specific ERG is undetectable under standard conditions but becomes normal following prolonged dark adaptation, in contrast to Oguchi disease. Mutations in RDH5 the gene encoding 11-cis-retinol dehydrogenase, a component of the visual cycle, have been identified in fundus albipunctatus. The function of the protein product of RDH5 is consistent with the delay in the regeneration of photopigments characteristic of the disorder.

Fig. 16.57 There is a characteristic fundus appearance with multiple white dots scattered throughout the retina at the level of the RPE. The dots are most numerous in the mid-periphery and are usually absent at the macula. Patients present either with night-blindness or because the abnormal retinal appearance is noted on routine fundoscopy.

STATIONARY CONE DISORDERS (CONE DYSFUNCTION SYNDROMES)

ROD–CONE DYSTROPHIES

The rod–cone dystrophies—often referred to as retinitis pigmentosa (RP)— are a clinically and genetically heterogeneous group of disorders in which there is progressive loss of rod and later of cone photoreceptor function leading to severe visual impairment. They may be inherited as an AD, AR or XL trait.

Leber congenital amaurosis

Leber congenital amaurosis (LCA) is a rod–cone dystrophy that presents at birth or the first few months of life with poor vision and nystagmus; the full-field ERG is absent or substantially abnormal. Inheritance is autosomal recessive. Affected infants have roving eye movements or nystagmus, and poor pupillary responses to light. Eye-poking, the ‘oculodigital’ sign, is common. Fundus examination is usually normal but disc pallor, vessel attenuation and peripheral pigmentary retinopathy may occasionally be seen. Affected infants often have high hyperopia.

Molecular genetic testing may be helpful in making a more specific diagnosis. To date six genes have been identified and account for approximately half of all patients with LCA. These genes are expressed preferentially in the retina or the RPE and their putative functions are diverse, including retinal photoreceptor development (CRX), photoreceptor cell structure (CRB1), phototransduction (GUCY2D), protein trafficking (AIPL1, RPGRIP1) and vitamin A metabolism (RPE65). Establishing a molecular diagnosis of LCA may facilitate advice about prognosis and allows improved genetic counselling, the potential for prenatal diagnosis and, in the future, the selection of patients for gene-specific therapies. This is of special interest as gene replacement therapy with subretinal injection of recombinant adeno-associated virus encoding an RPE65 transgene has been assessed in a dog model with promising results. Marked improvements in visual behaviour and ERGs occurred as early as 4 weeks after surgery in affected animals with a gradual progressive improvement in ERG responses over time. Trials of gene therapy in patients with LCA due to mutations in RPE65 are likely in the near future.

Fig. 16.58 Although the majority of patients have normal fundi in infancy most develop signs of a pigmentary retinopathy in later childhood with optic disc pallor and retinal arteriolar narrowing.

Retinitis pigmentosa

Retinitis pigmentosa (RP) is a term used for a genetically diverse group of disorders characterized by night-blindness and visual field loss. ERGs are either undetectable or show the rod system to be more severely affected than the cones with dysfunction at the level of the photoreceptor. The age of onset is very variable. Inheritance can be AR, AD or XL. XL and AR RP tend to have an earlier onset and to be more severe than AD disease. The disease may be confined to the eye or the retinal dystrophy may be part of a systemic disorder. In most cases visual acuity is normal at presentation, although central visual loss may occur later as a result of posterior subcapsular cataract, macular oedema or macular involvement. Early visual field changes are seen as small scotomata in the mid-peripheral retina and are more common in the upper visual field. These field defects gradually coalesce to give the classical peripheral ring scotoma and visual field constriction in advanced disease.

Genetics of RP

RP may be inherited as an AD, AR or XL recessive disorder, but approximately 50 per cent of patients have no family history of RP or evidence of parental consanguinity. It is unlikely that all such patients have AR disease. Some males may have XL disease transmitted via asymptomatic female carriers; other cases may represent new AD mutations or AD disease in a family with reduced penetrance. A significant number of patients with sporadic RP have mild disease, and a proportion of these probably have new AD mutations. It is also important to remember that RP-like changes can be mimicked by posterior segment inflammatory disease, trauma, infection and drugs. Such patients with acquired disease may have uniocular signs and frequently have better visual function and retinal electrophysiology than is found with inherited disease.

Prior to counselling it is important to examine other family members, especially the mothers of severely affected males who may show fundus or electrophysiological abnormalities suggestive of an XL heterozygote. To date, 39 loci have been implicated in nonsyndromic RP for which 30 genes are known. These encode a wide range of proteins including components of the phototransduction cascade, proteins involved in vitamin A metabolism and cell–cell interaction, photoreceptor structural proteins and transcription factors, intracellular transport proteins and splicing factors.

Mutations in 14 genes have now been identified for AD RP with mutations in the rhodopsin gene being the commonest. Clinically rhodopsin gene mutations account for about 25 per cent of patients with AD RP and more than 60 different mutations have been identified; there is considerable variation in the ocular phenotype seen with the different mutations. Mutations in 14 genes have been identified to date in AR RP encoding many components of the rod phototransduction cascade including rhodopsin, subunits of rod cGMP-phosphodiesterase, subunits of rod cGMP-gated cation channels and arrestin. In addition, mutations in four genes coding for components of the visual cycle involved in recycling vitamin A have been identified in AR RP. Mutations in two genes have been identified in XL RP, RPGR and RP2. Most families with XL RP have mutations in RPGR. It has been suggested that the protein RPGR may act as a regulator of a specific type of membrane transport or trafficking that is particularly active in the retina or RPE.

Fig. 16.59 The appearance of the fundus in the early stages of RP is variable but may include mild pigment epithelial atrophy in the mid-periphery often with small white dots at the level of the RPE. Later typical bone spicule pigment deposition is seen in the equatorial retina with arteriolar narrowing and optic disc pallor.

Fig. 16.60 Retinitis punctata albescens, a variant of RP. Fundus photograph showing multiple white deposits scattered throughout the retina with macular atrophy.

Fig. 16.61 The classical fundus appearance of optic disc pallor, retinal arteriolar attenuation and peripheral retinal pigment epithelial atrophy with ‘bone corpuscle’ pigmentation is seen in advanced disease. The typical intraretinal bone corpuscular pigmentation is produced by RPE migration into the inner retina following photoreceptor loss. Other changes include vitreous cells, posterior subcapsular cataract, optic disc drusen and macular oedema. Occasionally, retinovascular changes similar to those in Coats’ disease are seen. In sector RP, the disease may remain confined to the lower retina and this is reflected in upper field loss. This form of the disease is usually inherited as an AD trait and has an excellent long-term visual prognosis.

X-linked RP

XL RP is a severe form of RP with early onset of night-blindness and progression to legal blindness by the third to fourth decade. Most affected males show symptomatic night-blindness before the age of 10 years, are often myopic, and show fundus abnormalities and ERG changes in early childhood. Female carriers of XL RP can be identified with certainty if they have affected sons or fathers and are therefore obligate gene carriers or may be shown by molecular genetic testing to carry the causative mutation. In other female family members carrier detection depends upon recognition of the abnormal fundus appearance seen in the heterozygote or on the results of electrophysiological testing. The retinal dysfunction in some XL carriers appears to be progressive with symptoms of night-blindness, detectable field loss and more extensive retinal pigmentation.

Fig. 16.62 Fundus abnormalities are common in XL heterozygotes. A prominent tapetal reflex may be seen at the posterior pole or mild pigment epithelial thinning and pigmentation may be present in the equatorial retina. The ERG is usually abnormal in heterozygotes with delay in the 30-Hz flicker response probably being the most frequently found abnormality, although reduced rod amplitude may also occur.

Syndromic RP

RP is associated with systemic disease in a group of rare syndromes in which renal, neurological or hearing problems are often other features. Some of these, such as Refsum disease (comprising RP, peripheral neuropathy, deafness, cardiomyopathy and ichthyosis from deposition of phytanic acid) and abetalipoproteinaemia (RP, acanthocytosis of red blood cells, fat malabsorption, spinocerebellar ataxia and an absence of β (low density) lipoproteins in plasma) are important as the biochemical defect is known and treatment can modify the natural history. Another well known disorder is Usher syndrome (RP and congenital sensorineural deafness). In type 1 Usher syndrome there is profound deafness with no intelligible speech, absent or very abnormal vestibular responses to rotation and calorics with variable ataxia. The ERG is usually absent at the time of diagnosis. In type 2 Usher syndrome the hearing loss is more variable and may be quite mild in some patients. The hearing loss is most apparent at high frequencies; patients develop speech and vestibular responses are normal. The retinal dystrophy is of later onset and is less severe and a small ERG can usually be recorded. A third form of Usher syndrome (type 3) has been described that is similar to type 2 but characterized by progressive sensorineural hearing loss. To date, 12 loci and four genes have been identified in Usher syndrome with more remaining to be discovered.

The mitochondrial cytopathies are an uncommon group of multisystem disorders in which there is biochemical, histopathological or genetic evidence of mitochondrial dysfunction. Clinical abnormalities often begin in childhood and may include lactic acidosis, anaemia, myopathy, neurological abnormalities, endocrine disturbance, renal disease, neurosensory hearing loss and an RP-like dystrophy. A number of syndromes have been recognized including Kearns–Sayre syndrome or chronic progressive external ophthalmoplegia (see Ch. 2).

Fig. 16.63 The Bardet–Biedl syndrome (BBS) is an autosomal recessive disorder characterized by obesity, intellectual impairment, polydactyly, hypogonadism and a progressive RP-like dystrophy. Renal failure, due to ureteric reflux, and hypertension are common and are the main causes of death. Early macular involvement is common; a ‘bull’s eye’ maculopathy may be seen. To date, seven loci and five genes have been identified. The Laurence–Moon syndrome is a closely related rare autosomal recessive disorder in which there is no obesity or polydactyly but affected patients have a short stature, hypogonadism, intellectual impairment, ataxia, spinal paraparesis and RP-like dystrophy.

CONE AND CONE–ROD DYSTROPHIES

The inherited cone and cone–rod dystrophies are a heterogeneous group of disorders characterized by variable photophobia, reduced central vision, abnormal colour vision and abnormal cone ERGs. AR, AD and XL recessive inheritance have all been reported. When an inheritance pattern can be established reliably, it is most commonly AD. The functional deficit is confined to the photopic system in some forms of cone dystrophy but in the majority there is later evidence of rod dysfunction (cone–rod dystrophy; ‘CORD’). The age of onset of visual loss and the rate of progression show wide variability in different families but visual acuity usually deteriorates over time to 20/200 or counting fingers. In pure cone dystrophies or in the early stages of CORD, ERG shows abnormal cone responses with normal rod responses. With later disease generalized abnormalities of rod and cone responses are seen with the cone ERG being more abnormal than the rod ERG. Obligate carriers of XL cone dystrophy may show evidence of cone dysfunction on electrophysiological testing.

Several loci and causative genes have been identified in the progressive cone and cone–rod dystrophies. Currently six genes encoding various proteins, including a transcription factor, phototransduction proteins and a synaptic protein, have been associated with AD disease (CRX, GUCY2D, GUCA1A, RIM1, peripherin/RDS and AIPL1) with more yet to be discovered. Currently, mutations in ABCA4 have been shown to be the commonest cause of AR CORD and mutations in RPGR have been associated with XL CORD.

Fig. 16.64 In cone dystrophies fundus examination may show a typical ‘bull’s eye’ maculopathy with annular RPE atrophy and central sparing.

Fig. 16.65 In some cases there may only be minor macular RPE atrophy. The optic discs show a variable degree of temporal pallor and these patients can be misdiagnosed as having optic nerve disease. In this patient autofluorescence imaging shows RPE changes more clearly. The retinal periphery is usually normal in pure cone dystrophies although rarely white flecks similar to those seen in fundus flavimaculatus may be seen.

Fig. 16.66 In patients with CORD fundus examination shows macular atrophy or a bull’s eye maculopathy in the early stages (left, middle). Peripheral RPE atrophy, retinal pigmentation, arteriolar attenuation and optic disc pallor are often seen in the late stages of the disease process and can resemble advanced RP (right).

CHOROIDERAEMIA

Choroideraemia is an XL recessive disorder characterized by progressive atrophy of the RPE and choriocapillaris with subsequent loss of the overlying photoreceptors. Affected males usually present in early childhood with night-blindness and progressive field loss, but central vision is usually preserved until late in the disease. In affected males the earliest fundus signs are fine pigment epithelial atrophy and pigmentation in the equatorial retina; at this stage the clinical appearance may be confused with RP. Later there is marked atrophy of the RPE and choriocapillaris. The choroideraemia gene (CHM) has been mapped to Xq21 with many different mutations in CHM having been identified. The product of this gene, Rab escort protein (REP-1), is involved in the posttranslational lipid modification and subsequent membrane targeting of Rab proteins, small GTPases that play a key role in intracellular trafficking.

Fig. 16.67 Focal areas of atrophy of the RPE and choriocapillaris develop as the disease progresses. These areas coalesce to a widespread atrophic appearance throughout the equatorial retina. This later spreads to involve the peripheral and more posterior retina; the macula is spared until late in the disease. The ERG is markedly abnormal at an early stage and is usually undetectable in adult life.

Fig. 16.68 Female carriers, although usually asymptomatic, show atypical fundus appearances with widespread patchy RPE atrophy and granular pigment deposition in the mid-peripheral retina.

GYRATE ATROPHY

Gyrate atrophy of the choroid and retina is a rare autosomal recessive disorder characterized by progressive chorioretinal atrophy, hyperornithinaemia and a deficiency of the pyridoxal phosphate-dependent mitochondrial enzyme ornithine aminotransferase (OAT). The level of OAT activity in obligate carriers of the gene has been shown to be about 50 per cent of normal. Children may present with night-blindness, progressive myopia or field loss, although the diagnosis of gyrate atrophy may be made in early infancy when a raised level of plasma ornithine is found in a child with a family history. Most patients maintain a reasonable level of visual acuity until their forties or fifties, although with a constricted field that corresponds to the degree of choroidal and RPE atrophy. There are small mid-peripheral scotomata in the early stages; progression of disease leads to marked peripheral constriction. The EOG is abnormal in most patients and ERG changes reflect the severity of disease; early in the disease both rod and cone amplitudes are reduced, but later the ERG is usually undetectable. Nonocular features reported include structural abnormalities of the hair, EEG abnormalities and mild intellectual impairment, peripheral neuropathy and mitochondrial abnormalities in a variety of tissues.

The human ornithine-Δ-aminotransferase gene has been cloned. A large number of different mutations of the OAT gene have been identified in patients with gyrate atrophy including some in which the OAT is responsive to pyridoxine. Three different approaches to treatment have been used. A minority of patients are responsive to pyridoxine (B₆) supplements. In nonresponders, plasma ornithine levels may be reduced by adhering to an arginine-restricted diet and proline supplementation has been reported to slow the progress of retinal degeneration in some patients.

Fig. 16.69 The earliest fundus changes are seen as small discrete areas of choroidal and RPE atrophy in the mid and far peripheral fundus. The atrophic areas subsequently coalesce and enlarge towards the posterior pole, with a characteristic scalloped appearance at the leading edge.

By courtesy of Professor Alan Bird.

BATTEN DISEASE

Batten disease (neuronal ceroid lipofuscinosis) is an autosomal recessive disorder that occurs in infantile, late infantile and juvenile forms. In the infantile and late infantile forms, neurological deterioration and seizures precede the visual deterioration, which is due to a progressive retinal dystrophy. The ERG is extinguished at an early stage and there is marked optic atrophy, arteriolar attenuation and a mild pigmentary retinopathy. Juvenile Batten disease may present first to the ophthalmologist as the visual deterioration may precede the neurological signs. Visual loss usually starts between 5 and 8 years of age and is later followed by intellectual regression, seizures and neurological deterioration. Death usually occurs by the late teens. The causative gene (CLN3) has been identified. Most affected individuals are homozygous for a 1.02-kilobase deletion in CLN3 with the remainder having a combination of the deletion and a second mutation. Molecular genetic diagnosis is routinely available.

Fig. 16.70 Fundoscopy usually initially shows macular atrophy with later arteriolar attenuation and peripheral retinal atrophy and pigmentation. The ERG is substantially abnormal at an early stage. This diagnosis should be excluded in children aged between 5 and 8 years who present with visual loss and show evidence of macular atrophy and an abnormal full-field ERG by looking for the presence of vacuolated lymphocytes in the peripheral blood. The diagnosis can be confirmed by molecular genetic testing.

TAY–SACHS DISEASE

This is a neuronal storage disorder. It is a rare, recessively inherited, neurolipidosis usually seen in Jewish infants in the first few months of life. Patients present with progressive neurological deterioration and die in the first 2–3 years of life. Tay–Sachs disease is caused by mutations in the gene HEXA which is located on chromosome 15 and codes for the α-subunit of the enzyme β-hexosaminidase A; deficiency of this enzyme leads to excessive accumulation of ganglioside GM₂ in neurones.

Fig. 16.71 The abnormal material is deposited in the retinal neurones and is seen as a whitish ring around the macula where the retinal ganglion cells are thickest, contrasting to the redness of the relatively neurone-free macula.

By courtesy of Mr M D Sanders.

ANTIMALARIALS

Chloroquine and hydroxychloroquine are used in malarial prophylaxis and treatment and as disease-modifying drugs in connective tissue disorders such as systemic lupus erythematosus (SLE). Retinal toxicity can occur with both drugs but hydroxychloroquine is much less toxic and for this reason has now replaced chloroquine in rheumatic therapy. Although the drugs bind to melanin, their action appears to be related to their effect on protein synthesis. Toxicity is related to daily dosage in milligrams per kilogram and to duration of treatment. Patients can take chloroquine for many years for malaria prophylaxis without retinal toxicity provided the dosage regimen is not exceeded. Patients with SLE can take hydroxychlorqine in dosages of 6.5–7 mg/day (200–400 mg/day) for up to 10 years without problem provided they have normal renal and liver function. The first signs of toxicity are perifoveal granularity at the level of the RPE and loss of the foveal reflex; continued use may lead to a bull’s eye maculopathy and eventually to a retinitis pigmentosa-like appearance. Initial symptoms include decreased visual acuity and paracentral scotomata. Once toxicity is established, progressive retinal damage may continue despite ceasing therapy. Corneal epithelial whorls are seen with chloroquine but are of no visual significance (see Ch. 6).

Fig. 16.72 This girl was treated for several years with chloroquine for rheumatoid arthritis without adequate supervision. Examination shows bilateral ‘bull’s eye’ maculopathy. Visual acuities were reduced to CF in both eyes.

THIORIDAZINE (MELLERIL)

Fig. 16.73 Phenothiazines bind to melanin and concentrate in the pigment of the uveal tract and RPE. Thioridazine (Melleril) is used as a psychotrophic drug in schizophrenia. It will produce a pigmentary retinopathy in dosages in excess of 600 mg/day for over 8 weeks’ duration. Early toxicity is associated with fine granular RPE changes that become more pronounced with progression. Later, hyperpigmentary changes resembling a salt-and-pepper retinopathy may develop as may chorioretinal atrophy. Some recovery follows drug withdrawal although in some cases retinal changes will progress.

TAMOXIFEN

Fig. 16.74 Tamoxifen is an oestrogen receptor antagonist widely used in the treatment of breast carcinoma. Retinopathy is very rare at normal dosages but deposition of a metabolite in the inner retina is occasionally seen in patients who have taken high dosages. Cystoid macular oedema is the main cause of visual loss.

QUININE

Fig. 16.75 Quinine is toxic to the neuroretina. With acute poisoning it produces a similar retinal appearance to central retina artery occlusion, with cloudy intracellular oedema of the neuronal layer and a cherry-red spot. This is due to neuronal toxicity and swelling rather than vascular infarction. Acute poisoning can be treated by extracorporal haemoperfusion to remove the drug from the blood. The changes resolve over some weeks, leaving a pale disc and marked arterial attenuation. This patient took quinine as an attempted suicide. He had a final acuity of 20/20 with grossly constricted visual fields and night-blindness.