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AGE-RELATED MACULAR DEGENERATION: Clinical and Fluorescein Angiographic Features
CHANDRAN ABRAHAM
Consultant Ophthalmologist, Apollo Cliniq (Unit of Apollo Hospitals), Chennai.
Symptoms of age-related macular degeneration may sometimes be absent, or noticed accidentally when a patient closes one eye. The symptoms include metamorphopsia, scotoma, micropsia, or defective vision. Fundus examination reveals a wide spectrum of findings, ranging from soft drusen to a cicatrized scar at the macula, and includes confluent drusen, retinal pigment epithelial (RPE) atrophy and hypertrophy, geographic atrophy, RPE detachment, and choroidal neovascularisation. There may be associated exudation, RPE tears, or choroidal haemorrhage. The condition is usually bilateral, with asymmetrical involvement. Fluorescein angiography helps to detect and classify choroidal neovasularisation, the component most often targeted in treatment. It also clarifies the nature of some of the associated changes. As treatment can minimise visual loss in a small, but well defined group of patients, and as most others need careful follow-up, further investigations, or counseling, it is important that the clinical and fluorescein angiographic features of this condition are fully appreciated.
INTRODUCTION
Age-related macular degeneration (ARMD) is a well recognised clinical entity, characterised by specific changes at the macula in patients who are 50 or more years of age. Though definitions and grading of ARMD vary among investigators of different epidemiological or clinical studies,[1-8] its clinical manifestations are well established, and agreed upon, though not completely understood.[9-12] Each of the fundus findings has been correlated with the findings on fluorescein angiography, optical coherence tomography, and histopathology. Some of the advanced changes or complications have been correlated with ultrasonography. These macular affections are compounded by ageing dioptric changes in the lens, and the decline in cerebral activities involved in perception.[13] As visual loss can be minimised in a small but definite group of patients by existing treatment procedures, and as new investigations and treatments are being explored, an understanding of the clinical manifestations of ARMD forms the basis of patient management. As with any clinical examination, a thorough history outlining the patient’s visual disability, his accustomed activity, current need, apprehension, and expectation must precede the examination, for consideration at its conclusion. Though fluorescein angiography has taught us a great deal about the nature of the fundus changes, it is not indicated in every case. It is most useful to determine the presence of a choroidal neovascular membrane, its characteristics, and its location in relation to the fovea. The angiogram must be of readable quality with adequate frames depicting the early, mid, and late phases of the dye transit. They must always be interpreted in the context of the fundus findings that should be available either in the form of a labeled sketch or as a readable photograph.
Symptoms
The specific symptoms of ARMD include metamorphopsia, micropsia, scotoma, monocular diplopia, blurred or defective vision. There could be difficulty in reading despite good distant vision. Some patients feel the need for more illumination to accomplish their accustomed tasks. The symptoms are sometimes noticed when one eye had to be shut for some reason. In others, the condition could be asymptomatic and detected during a routine examination. While some narrate the onset and progress of their symptoms with precision, others could be vague. The symptoms often correlate with the location and severity of the clinical findings, but the impact it has on different individuals varies considerably.
Visual Function
Beginning with the observation in 1864 that visual acuity declines with age, investigators until the late 1960’s had noted that ageing also resulted in decreased visual resolution, decreased visual reaction time, and increased threshold of dark adaptation.[13] Several sophisticated tests can today, measure visual function in patients with ARMD, and the degree to which visual dysfunction can be documented generally increases with the sensitivity of the test employed. Snellen visual acuity may be range from 6/6 to 3/60 depending on the location and severity of the lesions in relation to the fovea. Snellen acuity also correlates with the visual disability experienced by the patient.[14] However, small scotomas may prevent patients from seeing the first single-letter line on Snellen, but permit them to see a couple of letters below. The Bailey-Lovie or Early Treatment Diabetic Retinopathy Study charts overcome this problem and allow a more accurate estimate of visual acuity. Permanent blindness almost never occurs with this condition, and patients retain peripheral vision that keeps them mobile at least in a familiar environment. The extent of metamorphopsia, micropsia or scotoma if any, can be recorded on an Amsler’s chart unless the patient’s near vision in poor. Patients with early manifestations of the condition may show delayed dark adaptation,[15-17] prolonged macular recovery time[18,19] decreased contrast sensitivity,[20] decreased central field sensitivity,[15,18,21] impaired colour vision,[15,16] and impaired stereopsis.
FUNDUS AND FLUORESCEIN ANGIOGRAPHIC FEATURES
ARMD is characterised by a wide spectrum of fundus findings. The lesions that characterise the condition are soft drusen, confluent drusen, retinal pigment epithelial (RPE) atrophy and hypertrophy, geographic atrophy (GA), RPE detachment, choroidal neovascularisation, and end-stage scarring by atrophy, pigmentation or fibrosis. These are often associated with subretinal exudation of fluid or protein, RPE tears, or haemorrhage in the choroid, sub- RPE space, subretinal space, retina, or vitreous. One or more of these findings may predominate within the same eye, depending on the stage to which the condition has evolved. The fellow eye could be normal, or show involvement that may be symmetrical or asymmetrical. Almost all these changes can be recognised by direct ophthalmoscopy, indirect ophthalmoscopy, slit lamp biomicroscopy using contact or non-contact lenses, or by scanning laser ophthalmoscopy. Fluorescein angiography helps in detecting choroidal neovascularisation, the vital lesion currently targeted by treatment, and may be simultaneously combined with indocyanine green angiography. The fundus and fluorescein findings can be documented by analogue or digital photography.
While drusen were recognised and described nearly a century and a half ago,[22] soft drusen are now regarded as the hallmark of ARMD. Soft drusen are larger than 62 µm, yellowish-gray in colour, have irregular borders, and are located deep to the retina, beneath the RPE at varying distances from the fovea. They vary in number and in size, and may be discrete or confluent (Fig. 1). Soft drusen may disappear over time, increase in number, get larger, or coalesce. They may be featureless on a fluorescein angiogram, or show auto-fluorescence, early hyperfluorescence and delayed staining, but no leakage. Soft drusen must be distinguished from hard drusen and basal laminar drusen, which are smaller, and can occur at a younger age. Hard drusen are seen as window defects on fluorescein angiography, and laminar drusen are more extensive than seen ophthalmoscopically. Soft drusen invariably leave behind areas of RPE atrophy as they regress (Fig. 2). Areas of RPE atrophy appear hypopigmented on the fundus, and are typically less than 175 mm in size, diffuse, and often interspersed with areas of RPE hypertrophy that appear hyperpigmented. On fluorescein angiography, areas of RPE atrophy are seen as window defects, and areas of hypertrophy block underlying fluorescence. The atrophic lesions may gradually enlarge over the years, and are referred to as areas of geographic atrophy (GA) when they are 175 µm or larger. The pigmented lesions however, may fade but remain just at the border of the atrophic areas, giving the impression that the atrophic process enlarges towards areas of pigmentation. GA patches could continue to enlarge over several years, reaching a size of several disc diameters (Fig. 3). Large choroidal vessels may be occasionally seen within them. These patches may show early hypofluorescence on the fluorescein angiogram because of the associated choriocapillary atrophy, appear as window defects, or exhibit delayed staining that is actually an enhanced view of the normal scleral staining through an atrophic RPE and choroid. A characteristic and redeeming feature of GA is that it spares the fovea for a considerably long period, preserving useful, though somewhat disabling visual function. The presence of one or more of these changes constitutes what may be termed dry or atrophic ARMD, with drusen and RPE changes representing the early stage, and GA the late stage. The onset of dry ARMD is insidious, the progress slow, and the visual impact minimal. The annual risk for progression from early to late ARMD is low,[23,24] showing a moderate increase in eyes with pigment clumps and confluent drusen,[25] and a higher increase in those with bilateral affection.[23] Focal hyperpigmentation, drusen larger than 63 µm, five or more drusen, proximity of lesions to the fovea, and hypertension have been identified as risk factors for progression from early to late ARMD.[26] While slow progression allows ample time for institution of any therapeutic measures that may become available, it also calls for caution in the design, and analyses of results in therapeutic clinical trials.
Apart from regressing and leaving behind areas of RPE atrophy and GA, soft drusen may also enlarge and coalesce, resulting in a retinal pigment epithelial detachment (PED) that can be recognised clinically when it reaches a critical size (Fig. 4). This development is classified as wet or exudative ARMD, and is representative of the late stage of the condition. PEDs appear as blister-like elevations beneath the retina and may be associated with an overlying serous retinal detachment. Small PEDs appear orange-yellow, contain clear fluid, and have well-defined borders. They fluoresce early on the angiogram, become increasingly hyperfluorescent during the dye transit, and show pooling of the dye in the delayed phase without any dye leakage. They may remain unaltered, enlarge, or flatten spontaneously to leave behind an atrophic RPE that may represent GA. PEDs in ARMD (Figs. 5 and 6) are generally larger, with turbid fluid, irregular surfaces, ill defined or notched borders, might harbour a choroidal neovascular membrane that may not be apparent. They fill slowly and irregularly on the fluorescein angiogram with some delayed leakage and are referred to as fibrovascular PEDs.[27] Retinal pigment epithelial tears could occur along the borders of such large PEDs, resulting in a choroidal haemorrhage or sudden reduction in vision if the tear goes through the fovea. If observed soon after its occurrence, the torn edge may be found curled towards the attached part of the PED, allowing the choroid to be easily visualised.[28,29] The curled edge may or may not contain a choroidal neovascular membrane and the gap is quickly covered by reparative processes. When blood rather than fluid underlies the PEDs they are referred to as haemorrhagic (Fig. 7). They appear dark red in colour, and on fluorescein angiography block underlying choroidal fluorescence. Though varied but distinct fluorescein angiographic characteristics of PEDs have been recognised, simultaneous indocyanine green angiography would be necessary to rule out choroidal neovascularisation, or identify idiopathic polypoidal choroidal vasculopathy. The choroidal neovascular membrane (CNM) is perhaps the most vital component of ARMD today, because its development signals a serious threat to central vision, and because it constitutes the lesion that is specifically targeted by current treatment approaches. CNMs appear as a dirty white or dirty yellow membrane deep to the retina, with an adjacent streak of blood, pigment, or lipid, and are usually associated with an overlying serous detachment of the retina (Fig. 8). They tend to enlarge rapidly, most often towards the fovea. Fluorescein angiography demonstrates characteristic early hyperfluorescence in the choroidal or early arteriovenous phase that starts in the peripheral border of the membrane, with increasing hyperfluorescence that extends towards the centre, and delayed dye leakage. Such classical membranes are termed extrafoveal when their foveal border lies 200 to 2500 µm from the centre of the fovea, juxtafoveal when 1 to 199 mm from the centre of the fovea, and subfoveal when directly under the centre of the fovea.[30] Visual acuity depends not only on the location of these membranes, but also on the relationship of associated lesions such as serous retinal detachment or blood to the fovea. In general, extra and juxtafoveal membranes may cause only slight visual impairment, whereas subfoveal membranes are as sociated with more severe impairment. Choroidal neovascular membranes are not always so clearly demarcated, and may masquerade under the RPE as seen earlier. The presence of blood, pigment, or lipid should lead to a search for its presence. Ill-defined hyperfluorescence from a slow ooze of fluorescein appearing in the delayed phases of the angiogram without an identifiable source in the earlier phases is suggestive of a CNM that is probably occult. Many untreated eyes with exudative ARMD will develop a disciform stage where varying degrees of blood, exudates, and an overlying secondary sensory retinal detachment involve a substantial portion of the macula (Fig. 9). The blood may be located in the choroid, sub RPE space, subretinal space, retina, or vitreous. It may vary in size, shape, and colour depending on its location and duration. A large dark mound of altered choroidal haemorrhage may mimic a malignant melanoma of the choroid, but the presence of other ARMD features in the same or fellow eye should help in clarifying the diagnosis. Ultrasonography will readily make the distinction in doubtful situations. The exudates may be retinal or subretinal, minimal or extensive, and the fluid beneath the sensory detachment is usually turbid. Residual drusen, areas of RPE atrophy and hypertrophy, and residual PEDs may still be distinguishable in some areas. Though RPE tears could occur, they can seldom be identified. The disciform lesion then goes on to end-stage scarring. Almost all the findings described above gradually disappear, to be replaced by fibrous tissue, pigment, or atrophy in varying measures (Fig. 10) Distant and near visual acuity is considerably reduced, with significant central scotoma, but leaves the patient with peripheral vision that permits mobility in a familiar environment, often enabling him to attend to his basic daily needs.R EFERENCES
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