Retinal Degenerations: Retinal Dystrophies

Published on 08/03/2015 by admin

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16 Retinal Degenerations

Retinal Dystrophies

Normal vision depends on the proper functioning of the macula which, when disturbed by disease, affects central vision and often causes the patient to present for the first time. Central distortion of vision (metamorphopsia) or minification of the image are pathognomonic for macular disease. Other symptoms apart from loss of acuity include photophobia, glare and dazzle (which can be severe), poor colour perception, night-blindness and a central or paracentral scotoma. Macular disease in infants frequently presents as congenital nystagmus.

Classifying macular disease by the anatomical layer that is primarily affected—choriocapillaris, Bruch’s membrane, retinal pigment epithelium (RPE), photoreceptors or neuroretina—is a commonly used and helpful way to conceptualize and diagnose retinal problems. Stereoscopic examination of the fundus with an indirect biomicroscopy lens through a dilated pupil is essential to assess the location of a lesion within the retina and its relationship to the superficial retinal vessels. However, although examination can infer the initial site of the lesion in many retinal diseases the primary defect cannot be precisely localized to a single cell layer as defects in one retinal layer produce changes in adjacent structures. For example, retinitis pigmentosa is associated with photoreceptor degeneration and also RPE and choriocapillaris atrophy with later neuroretinal degeneration and vascular attenuation. Our understanding of the pathogenesis of various retinal diseases has improved in recent years with advances in molecular genetics and cell biology and some diseases that were thought to affect, for example, primarily the photoreceptors have now been shown to have their defect in the RPE. Fundus photography, fundus fluorescein angiography (FFA), indocyanine green (ICG) angiography, optical coherence tomography (OCT) and autofluorescence (AF) imaging are valuable investigations for diagnosis and documentation. Many macular lesions are small and produce scotomas that are difficult to demonstrate; an Amsler grid can help in these cases. Electrodiagnostic tests and psychophysical testing are time consuming but very useful for diagnosing, documenting and assessing the prognosis of inherited retinal disease (see Ch. 1).

Occasionally deciding whether visual loss is caused by macular or optic nerve disease can be difficult as both reduce acuity and colour vision and can cause central scotomas. Retinal lesions tend to produce a ‘positive’ scotoma in which patients are aware of dark obscuration or something in front of their vision in contrast to the ‘negative’ scotoma of neurological disease (for example, patients do not notice a hemianopic field defect as ‘dark’). An afferent pupillary defect indicates optic nerve disease unless the macular lesion is extensive. Another useful and easily performed test is the photostress test in which recovery of visual acuity following dazzle with a bright light is delayed with macular lesions whereas vision recovers normally with optic nerve disease. Retinal lesions produce a blue-yellow pattern of colour deficit in contrast to the red-green pattern of optic nerve disease (see Ch. 19). These clinical tests are subjective, however, and less reliable than pattern electroretinography (PERG) which in most cases can distinguish macular from optic nerve disease (see Ch. 1).

Most retinal dystrophies and degenerations are untreatable and any treatment measures are largely supportive in the form of low visual aids. Perhaps the most important aspect of management is to establish a correct diagnosis as this aids prognosis; genetic and occupational counselling are very important. It is unusual for macular diseases to progress to total blindness and patients are often reassured to know this; most will have a central scotoma with good peripheral vision and are able to lead independent lives.


This is the commonest cause of legal blindness in the developed world. It predominantly affects the elderly Caucasian population and is much less common in other races. The hallmarks of age-related macular degeneration are drusen, RPE atrophy and choroidal neovascularization.

Major studies have devised various systems for describing the fundus changes. Age-related maculopathy (ARM) and age-related macular degeneration (AMD) distinguish early disease from end-stage disease. ARM describes drusen and/or RPE abnormalities. AMD is subdivided into dry (geographical RPE atrophy without neovascularization) or neovascular (RPE detachment, haemorrhages and/or scarring due to choroidal neovascularization (CNV) forms. The Age Related Eye Disease Study (AREDS) subdivides ARM into four categories and allows rapid classification. Drusen type is divided into small (<63 mm), intermediate (63 to 124 mm) and large (greater than 124 mm). Atrophy of the RPE is either centred or noncentered (not involving the fovea).

CNV occurs as ‘classical’ or ‘occult’ forms. In classical CNV, fluorescein angiography shows a well demarcated neovascular membrane with hyperfluorescence that progressively leaks dye from early on to obscure the lesion’s boundaries over time. Occult CNV is associated with late leakage from an undetermined source at the level of the RPE. It can also appear as a fibrovascular pigment epithelial detachment which is seen on fluorescein angiography as early (less than 2 minutes) stippled hyperfluorescence representing irregular RPE elevation. The Treatment of Age Related Macular Degeneration with Photodynamic Laser Study (TAP) subdivided CNV into predominantly classical (more than 50 per cent of CNV lesions with a classical component), minimally classical (less than 50 per cent classical) and purely occult (no classical CNV).


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.


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.


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.


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.


Neovascularization through Bruch’s membrane occurs in a wide range of fundus disorders that have in common the ability to disrupt or damage the RPE or Bruch’s membrane in the macular area.