Early drusen formation in the normal and aging eye and their relation to age related maculopathy: a clinicopathological study.

AIM: To describe the early formation of drusen and their relation to normal aging changes at the macula and to the development of age related maculopathy (ARM). METHOD: Histopathological features of 353 eyes without histological evidence of ARM are described and correlated with the clinical appearance. In addition, 45 of these eyes were examined by transmission electron microscopy. RESULTS: Drusen were detected histopathologically in 177 (50%) eyes but were seen clinically in only 34% of these. Drusen were mainly small hard drusen with an occasional soft distinct drusen: no soft indistinct drusen were seen. Only those drusen deposits larger than 25-30 microns in diameter were detectable clinically. Preclinical drusen in eyes with only an occasional drusen were seen on electron microscopy as entrapment sites of coated membrane bound bodies which formed adjacent to the inner collagenous zone of Bruch's membrane. In contrast, preclinical drusen deposits in eyes with many drusen were seen as accumulations of amorphous material which appeared hyalinised by light microscopy. A distinct feature were rows of dense hyalinised microdrusen (1-2 microns in diameter), over which larger globular hyalinised drusen formed. CONCLUSION: Histological and ultrastructural examination can recognise and distinguish the earliest drusen formed as a result of normal aging from those associated with ARM. In eyes without diffuse deposits, histologically all drusen were of the hard hyalinised variety or their derivatives; no soft drusen composed of membranous debris were found. These findings support and explain those of other authors who do not consider the presence of a few small hard drusen to be a risk factor for the development of ARM.

Treatment of choroidal neovascularisation in age-related macular degeneration with interferon alfa-2a and alfa-2b.

Forty eight eyes of 42 patients with choroidal neovascular membranes and age-related macular degeneration who received three different dose regimens of systemic interferon alfa-2 were studied retrospectively. The response to treatment of 41 eyes of the 37 patients who received at least 4 weeks' treatment was analysed with respect to the change in size of the choroidal neovascular membrane and the visual acuity compared with pretreatment levels. The size of the membrane at the end of the course of treatment had decreased in seven (17%) eyes overall, not changed in 16 (39%), and increased in 18 (44%). At the end of treatment, the visual acuity had improved in seven (17%) eyes, not changed in 27 (66%), and deteriorated in seven (17%). With an average follow up of 10 months after treatment, the visual acuity had deteriorated compared with the pretreatment value in 21 out of 41 (51%) eyes. Vision improved in some fellow eyes with disciform scars. Side effects were common and often severe. The data suggest that one of the major effects of interferon alfa may be to decrease vascular permeability. While further research may identify a place for interferon alfa in the treatment of choroidal neovascularisation, we were unable to demonstrate that the treatment regimens of systemic interferon alfa we used caused a dramatic benefit to patients with exudative age-related macular degeneration.

Adult vitelliform macular degeneration: a clinical spectrum.

Adult vitelliform macular degeneration (adult Best's disease) has a spectrum of clinical appearances which may include focal macular pigment clumps as well as the more typical small, yellow lesions. We surveyed 81 patients with this diagnosis retrospectively. Ages ranged from 36 to 87 years, with an average age of 67 years. Males and females were almost equally represented. Median visual acuity at presentation was 6/12 for eyes with yellow lesions, and 6/9 for eyes with pigment clumps. Of 17 cases followed for an average of 3.6 years, there was a decrease in visual acuity of two lines or more in five cases. A significant proportion of patients also had other manifestations of age-related macular degeneration. Adult vitelliform macular degeneration probably falls within the spectrum of age-related macular degeneration.

Macrophages related to Bruch's membrane in age-related macular degeneration.

This report describes focal thinning of Bruch's membrane in age-related macular degeneration and suggests a role for macrophages in this process. Electron microscopy was performed on four eyes ranging from normal ageing to age-related macular degeneration with early subretinal neovascularisation. As degeneration progressed multiple segments of thinning of Bruch's membrane were observed and macrophages appeared to engulf fragments of the outer collagenous zone. An associated finding at this stage was the shedding of membranous debris by the retinal pigment epithelium and its deposition within Bruch's membrane. This debris forms the basis of soft drusen but in the presence of this material thinning of Bruch's membrane was also observed beneath hard drusen. It is suggested that the widespread accumulation of phospholipid-containing membranes together with the focal concentration of lipid in hard drusen attract macrophages.

Evolution of geographic atrophy of the retinal pigment epithelium.

The aim of this study was to trace the evolution of geographic atrophy (GA) by clinical documentation and by clinico-morphological correlation in representative eyes. Geographic atrophy commonly commenced within a parafoveal band of incipient atrophy of varying width, characterised by semisolid drusen and a microreticular pigment pattern. Progression of atrophy mostly skirted fixation and visual acuity was a poor guide to the functional impact, an estimate of the percentage of fovea involved proving a more useful clinical parameter. The rate of progression slowed once GA had involved all the retina affected by incipient atrophy and the risk of choroidal neovascularization appeared to decline. An earlier histological classification of the evolution of GA is revised according to the ultrastructural findings. Membranous debris was not previously recognised and its contribution to the findings in incipient atrophy and to dot-like drusen is described.

Evolution of soft drusen in age-related macular degeneration.

The pathways by which soft drusen are formed are illustrated by representative clinical and clinicopathological cases. One type is derived from small hard drusen which first tend to aggregate into clusters and then fuse, forming larger deposits termed hard clusters. Breakdown of the hard drusen results in varying degrees of softening and confluence. These soft clusters may appear in middle age and, like the preceding hard drusen, remain a focal pathology. Soft clusters commonly lead to the atrophic form of age-related macular degeneration. Another type of soft drusen is formed from membranous debris as part of a diffuse disturbance of the retinal pigment epithelium. These membranous soft drusen first appear in the seventh decade and are commonly associated with choroidal neovascularisation.

Morphology of early choroidal neovascularisation in age-related macular degeneration: correlation with activity.

The purpose of this study was to describe the morphology of early choroidal neovascularisation (CNV) and compare the findings in two patients, in the first of whom the vessels appeared inactive and in the second progressive. Changes common to both included a diffuse deposition of membrane coils external to the basement membrane (BsM) of the retinal pigment epithelium (RPE), and macrophages and foreign body giant cells beneath thinned segments of Bruch's membrane (BrM). In the first patient small activated vessels surrounded by enlarged pericytes were found in the choroid beneath these areas and pursued a convoluted course, bulging into or through BrM, but without spreading in the sub-RPE space. This choroidal phase of CNV may be common and unrecognised. In the second patient there was spread of CNV in the sub-RPE space with extravasation of red cells and fibrin. The tips leaking fibrin were covered by a thick BsM-like material and naked endothelial cells were not seen. Pericytes were absent here but were observed at the non-leaking edge. The difference in activity of CNV in the two patients appeared to correlate with the quantity of membranous debris present.

Reticular pseudodrusen. A risk factor in age-related maculopathy.

BACKGROUND: Reticular pseudodrusen refer to a yellow interlacing network 125 microns to 250 microns wide appearing first in the superior outer macula and then extending circumferentially and beyond. Unlike true drusen, they do not fluoresce on fluorescein or indocyanine green angiography, and are best seen in red-free light or with the He-Ne laser of the scanning laser ophthalmoscope. METHODS: One hundred patients have been seen in our retinal practice with this clinical feature in the past 3 years. RESULTS: All had some manifestation of age-related maculopathy (ARM), and 66% had or subsequently developed subretinal new vessels in one or both eyes. The appearance is attributed to changes in the choroid. CONCLUSIONS: Reticular pseudodrusen are an easily recognizable clinical sign, and may be an important risk factor for choroidal neovascularization in ARM.

Adult vitelliform macular degeneration: a clinicopathological study.

AIMS/BACKGROUND: The yellow lesions of adult vitelliform macular degeneration (AVMD) slowly fade, progressing to hyperpigmentation or atrophy. This study aims to provide further observations on the location and nature of the vitelliform material. METHODS: This report describes the clinicopathological correlation of four eyes with AVMD. A retrospective histopathological study of a further 526 aged eyes previously graded for the stage of age-related macular degeneration (AMD) found another 10 eyes with similar pathology. RESULTS: The predominant finding was a collection of extracellular material beneath the sensory retina at the fovea. This material was derived internally from photoreceptor outer segments and externally from the retinal pigment epithelium (RPE), the latter first undergoing hypertrophy and then disruption and attenuation. Fallout of foveal cones occurred over these lesions and the inner retina was thinned, which may explain macular hole formation in this condition. All affected eyes showed histopathological evidence of AMD. CONCLUSIONS: This study confirms that the vitelliform lesions of AVMD lie beneath the sensory retina. In contrast to previous reports, however, it is proposed that the lesions comprise mainly extracellular material consisting of photoreceptor debris, possibly the result of faulty phagocytosis by the RPE, mixed with pigment liberated as the RPE undergoes disruption. The vitelliform lesions therefore are a marker for the area of maximal RPE disturbance.

Prophylactic perifoveal laser treatment of soft drusen.

PURPOSE: To assess the efficacy and safety of perifoveal laser to cause drusen to resorb, and establish a treatment protocol. METHODS: Treatment technique was determined by the outcome in one patient with 15-year follow-up. In an uncontrolled series a perifoveal ring of gentle laser was applied to 30 eyes of 28 patients, 18 with bilateral drusen and 10 with exudative disease in the fellow eye. Comparison was made between treated and untreated eyes in 14 patients with bilateral drusen. Mean follow-up was 16.8 months (range, three to 42 months). RESULTS: Soft drusen resorbed in all treated eyes in the vicinity of laser and within the fovea. Large soft confluent drusen (> 500 microns) responded most rapidly. Visual acuity improved one or more lines in 12 (40%) treated eyes, was unchanged in 16 (53%) and deteriorated in two (7%). In 14 patients with bilateral drusen in whom only one eye was treated, VA remained unchanged in 10 eyes and improved in four treated eyes while none of the untreated eyes improved (P = 0.03, chi 2) and decreased in four eyes. Atrophic expansion of laser burns was minimal. CNV developed in two of 30 eyes (7%). CONCLUSION: Perifoveal laser treatment appears to expedite the regression of soft drusen within the fovea. The risks of complications may be reduced by treating eyes early, before pigment changes develop and by applying a minimum number of burns at a distance greater than 750 microns from the foveal centre. Treatment should currently be administered only in the context of a prospective clinical trial, which is required to assess whether this treatment results in lowered risk of visual loss from CNV or geographic atrophy.