DRUSEN AND THEIR RELATIONSHIP TO SENILE MACULAR DEGENERATION

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1 Council Lecture DRUSEN AND THEIR RELATIONSHIP TO SENILE MACULAR DEGENERATION Shirley H. Sarks, F.R.A.C.O., F.R.C.S., M.D. (N.S.W.) Summary This study is based on the clinico-pathological examination of 572 eyes As senile macular degeneration developed drusen appeared to alter in consistency and become more fluid This resulted in a spectrum of clinical appearances classified as hard, semisolid, soft or serous, and regressing Histologically the hyaline contents of the drusen changed to a pale-staining amorphous material which electron microscopy showed to consist of vesicles This membranous debris first appeared beneath the pigment epithelium /n normal aged eyes but its later accumulation led to a widespread shallow separation of the basement membrane The softening of drusen was most evident in group /V in which subretinal neovascularization was first detected At this stage the retinal pigment epithelium also showed its greatest proliferative activity and the formation of abnormal basement membrane material It is a great honour to give the Council Lecture for 1979 and I would like to take this opportunity of acknowledging the support received from the College over the years to continue this study of senile macular degeneration. A common and often conspicuous feature of this disease is the presence of drusen of Bruch's membrane, formerly called colloid bodies in the English literature. Drusen may be present for many years without affecting vision but they are also known to predispose to the development of subretinal neovascularization and geographic atrophy of the retinal pigment epithelium.' The aim of this study was to investigate the relationship between drusen and senile macular degeneration, with particular reference to these two complications. Clinico-pathological examination has now been performed on 512 eyes from 300 patients whose ages at death ranged from 43 to 97. Previous reports have described the selection of material such that eyes with unrelated diseases affecting the macula were excluded, as well as detailing the clinical and histological methods used.' The same classification was again employed, the eyes being divided into 6 groups according to the histological appearance of a basal laminar deposit at the base of the retinal pigment epithelium. In this classification the first two groups represented normal ageing, groups I11 and IV the progressive development of senile macular degeneration and groups V and VI the end-results of geographic atrophy and disciform degeneration. In 30 patients one &ye was examined by light microscopy and the fellow eye by electron microscopy. Dnisen versus basal luminar deposit Drusen are localised deposits lying beneath the basement membrane of the retinal pigment Presented at the 11th Annual Scientific Congress of the Royal Australian College of Ophthalmologists. October 9th Sydney. Reprinr Reqrrests: Dr S. H. Sarks, 14 Norton Street, Leichhardt N.S.W DRUSEN AND THEIR RELATIONSHIP TO SENILE MACULAR DEGENERATION 117

2 Fixitre I : Section through macular area of eye from group IV. showing degeneration of pigment epithelium and patchy loss of choriocapillaris. Thick basal laminar de osit is raised over small hyalinised druse at left (arrowhead) angseparated from Bruch's membrane at right where two layers can be recognised in the deposit, the inner heing hyalinised and raised into drusenoid excrescences (arrow) while the outer retains the more characteristic pale-staining. finely striated appearance. Picru-Mallory stain. X 500. F ~ 2: Another ~ ~ eye, from~ group ~ 1v. ~~~~l laminar materia] (short arrows) surrounds clusters of membranous structllres and extends upwards between degenerating retinal pigment cells. It consists of light and dark clumps of amorphous. finely filamentous or banded material. Vesicles are accumulating between Bruch's membrane and the basement membrane (long arrow). X 3,500. Figiw 3: Different histological appearances of drusen. Top right: Hyalinised druse. Globular sha e causes abrupt elevation of pigment epithelium. Small clumps of hasement membrane material occur over tfe surface. Clinically thkse drusen are the small hard variety which produce punctate window defects on fluorescein angiopraphy. Top left: Pale-staining, amorphous or very finely granular type of drusen which clinically are usually lar Jer and have softer margins. Because they behave like serous detachments of the retinal pigment epithelium k e y are referred to as soft or serous drusen. Lower: Serogranular druse. This type contains a variable amount of hyalinised material broken up into globules of varying size, while their clinical apperance is semisolid. Margins may be sharp or soft but most appear to retain dye. Pi&-Mallory stain. Top: X 3w. Lower: X 150

3 epithelium (Figure, 3). The basal laminar deposit, on the other hand, lies between the basement membrane and the plasma infoldings of the cells and consists of abnormal basement membrane material. There has been some confusion between these subpigment epithelial deposits, to both of which the descriptive term aolloid has been applied. The long stretches of this material commonly found on Bruch s membrane in the periphery and the mounds lying over the termination of the membrane adjacent to the disc are both composed of basement membrane material, although typical drusen can also occur in these situations. A thick layer of basement membrane material may also occur in the macular region, a finding which characterises eyes in group IV. When the pigment epithelium is particularly degenerate the deposit may form a hyalinised and PAS-positive layer with drusenoid excrescences on its internal surface, although the outer aspect retains the pale-staining, finely striated appearance found in less degenerate eyes (Figure I). Hyalinization of the basal laminar deposit and a tendency for it to separate from Bruch s membrane were particularly evident in those eyes harbouring subretinal neovascular membranes. The same stratification of the basal laminar deposit can be recognised on electron microscopy (Figure 2). light and dark clumps of finely filamentous or amorphous material lying internal to banded basement membrane. Degeneration of the retinal pigment epithelium in these eyes was associated with the formation of membranous structures and with the accumulation of vesicles beneath the basement membrane. These vesicles, however, were first noted in eyes belonging to group I1 and at that stage were therefore regarded as a normal ageing change. There is still no general agreement on how drusen are formed. Thus Yanoff and Fine3 believe that most drusen are abnormal basement membrane products, the remainder representing exudative material from the choriocapillaris. That drusen may be derived from the bloodstream is suggested by their distribution in relation to the underlying choriocapillaris4 and from the resemblance between some drusen and serous detachments of the retinal pigment epithelium, the DRUSEN AND THEIR RELATIONSHIP TO SENILE MACULAR DEGENERATION significance of which was first recognised by Gass. Most observers, however, believe that drusen result from abnormal secretory activity by the pigment epithelium. Farkas, Sylvester and Archer suggested that lysosomal breakdown initiated a pathological autolysis of the pigment epithelium and that this resulted in drusen formation. Hogan demonstrated substances passing through the cytoplasm of the cells towards Bruch s membrane and proposed that the accumulation of undigested material within the cells was followed by its transfer to Bruch s membrane, drusen representing localised deposits of this excretory material. Types of drtrsen At the present time there is no satisfactory classification which takes into account the different clinical and histological features of drusen. The principal physical property which distinguishes one type of drusen from another appears to be a difference in their consistency. The more fluid the drusen the greater the tendency to spread and become confluent, the more rapid will be their progression and regression, and the greater the permeability to fluorescein. On this basis four broad groups can be recognised, the corresponding histology being illustrated in figure 3: (a) Hard drusen are mostly pin-point in size and act as window defects on fluorescein angiography, demonstrating early hyperfluorescence and late fading. Small hard drusen have a hyaline structure and stain like hyalinised Bruch s membrane, being PAS-positive and staining deeply with Picro- Mallory stain. (b) Soft or serous drusen have soft edges and readily become confluent. They are often widespread but remain faint except in the foveal region where they can enlarge to a considerable size, characteristically acquiring a cruciate pigment figure over the surface and closely resembling serous detachments of the retinal pigment epithelium. Fluorescein enters these drusen early in the angiogram and there is late staining. Histologically serous drusen are pale-staining and appear amorphous or very finely granular. (c) Between these two extremes are a range of semisolid drusen. Most are round or oval in shape with a tendency to occur in clusters which may be 1 I9

4 Figitre 4: Early hyaline drusen. The smaller would not be detected clinically. Note deeply stained material on the outer surface of Bruch s membrane beneath even the smallest drusen. Picro-Mallory stain. X 500. f t, y t t w 5: Fundus of 73-year-old man. vision 6/6 part. Arrow points to just discernible-cluster o f small. hard drusen. Patient suffered from mild hypertension. copper-wiring evident in retinal arterioles. AUSTRAI.IAN J O U R N A L O F 0I HTHAI.MOI.OGY

5 paramacular. Some, appear waxy and occasionally become confluent, others retain sharp margins which may be surrounded by a reddish halo. However, some penetration by fluorescein is evidenced by late staining in the angiogram. These drusen consist of hyalinised globules lying in the amorphous substance and their structure is described as serogranular. Another variety with indistinct outlines is referred to as smudgy. These are commonly associhted with the small hard variety from which they appear to be derived. In general, the greater the proportion of pale-staining amorphous material within the druse the more likely it is to lose its globular shape and to spread along Bruch s membrane. (d) Regressing drusen. As the overlying retinal pigment epithelium degenerates the contents of the drusen become inspissated and they appear whiter and denser. Shrinking causes the margins to become irregular and calcification is common. Incidence of drusen The incidence of drusen could not be assessed in eyes in which the macula was affected by geographic atrophy of the pigment epithelium or disciform degeneration (groups V and VI), nor in the eyes submitted to electron microscopy. In the remainder (427 eyes) the percentage of eyes containing 10 or more, macular drusen, based on both clinical and histological examination, rose from 8q1 of eyes in group I to 27F in group IV. In the eyes with more advanced macular degeneration there was also a greater proportion of serous and serogranular drusen. In groups I and I1 these types were found in only 21% of the eyes containing drusen, whereas in group IV they were noted in 65% of affected eyes and were often the predominant types. Hvaline driisen Hyaline drusen initially form shallow or hemispherical elevations on Bruch s membrane, becoming globular as they enlarge. The smallest drusen which did not exceed half the height of the retinal pigment cells and did not distort the inner surface of this layer had not been detected by ophthalmoscopy (Figure 4). This would account for the greater number revealed by fluorescein angiography. Once the pigment epithelium becomes elevated and stretched. small hyaline drusen are seen as hard yellowish dots (Figures 5 and 6). The ultrastructure of these drusen consists of a mass of finely granular or amorphous material containing a variable number of pale and bristle-coated vesicles, tu be-like structures and occasionally abnormal collagen as described by Hogan (Figure 7). Another finding. noted in relation to even the smallest drusen, was a deeply staining and electron dense material on the outer surface of Bruch s membrane beneath the drusen (Figures 4 and 7). 40 : of the eyes in groups I and I1 were found to have a small number of hyaline drusen in the macular region and most of these were only detected on histological examination, numbering less than 3 per section. A few small hyaline drusen at the macula were therefore regarded as a normal ageing change. The incidence of hypertension in patients with a few small hyaline drusen was more than double that in patients without drusen. Soft or seroirs drirsen The earliest histological appearance of serous drusen was a shallow and sometimes widespread separation of the pigment epithelium from Bruch s membrane (Figure 8). Unlike post-mortem separation this space contained vesicles, apparently an exaggeration of the accumulation first detected in the region of the basement membrane in eyes belonging to group 11. Confluence of these drusen results in the fundus appearance of a pale yellow reticular pattern which may spread thoughout the central area. Those located at the macula become more prominent, appearing initially as shallow fuzzy deposits of various shapes (Figure 10). In the foveal region they may enlarge and co I I esce. closely resembling serous detachments of the retinal pigment epithelium. Histologically these drusen consist predominantly of pale-staining. amorphous material as shown in figure 3, while electron microscopy shows that they contain membranous debris, mostly as vesicles of different sizes (Figure I I). Degeneration of the retinal pigment epithelium was also more advanced over DRUSEN AND THEIR RELATIONSHIP TO SENILE MACULAK IIEGENLKA I ION 121

6 FiKwe 6: Small hyaline drusen in sections through the macula (top) and paramacular area (lower) of the eye shown in figure 5. demonstratinf the sjze of drusen apparent clinically. Note also subintimal hya inintion in a choroidal artery. Picro-Mallory stain. Top: X 75. Lower: X 300. F i p r e 7: Electron micrograph of the right eye of a 68-year-old man whose fundi had shown small drusen similar to those in figure 5. Vision had been 6/6 in both eyes. The left eye. examined by light microscopy, contained small hyaline drusen with deeply staining material beneath, similar to appearance shown in figure 4.The druse contains coiled fibres, vesicles and a finely granular material. Note the electron dense material on the outer surface of Bruch's membrane beneath the druse. The small black dots are a staining artefact. X 8, AUSTRALIAN JOURNAI. O F OPHTHALMOLO<iY

7 f i g m 8: One micron section of an eye from an 81-year-old patient, showing widespread shallow separation of basement membrane of the pigment e ithelium from Bruch s membrane. The contents of this space are shown in fi m e 9. Small hyaline drusen are afw present. Stain: methylene blue - basic fuchsin. Top: X 500. Lower: X 1,006. Figifre 9: Electron micrograph from area close to section shown in figure 8. Short arrow points to patch of banded basement membrane material, long arrow oints to actual basement membrane of retinal igment epitheeum. S ace between basement membrane and grpch s membrane is!ned with membranous debris consisting of vesicles of various sizes. X 3,800. Figure 10: Right fundus of 79-year-old man, showing faint serous drusen at macula (arrow). Prominent druse below arrow was not sectioned, two other spots are light reflexes. Vision was 6/9. DRUSEN A N D THEIR RELATIONSHIP TO SENILE MACULAR DEGENERATION 123

8 Figirve 12: Left fundus of 74-year-old man. During 5 year period of observation r t i e n t developed faint smudgy drusen on a background o f t e small hard variety. A faint pigmentary disturbance developed before he died 18 months after this photograph was taken. but vision remained 619. Figure I / : Section through one of the serous drusen shown in figure 10. Some of the contents have been lost during preparation but the predominant constituent is an accumulation of membranous debris. Note hasal laminar deposit over surface of druse. X F@rre 13: Section throu h the mucular area of the eye shown in figure 12. The druse at right, magnified below, appears to have been a?&line druse which has undergone serous transformation. A cap of hyaline material remains but the remainder of the druse has been converted to a pale-staining, amorphous material. Note the broad base. extending in this case in one direction to form a tail, which would account for the softer clinical margins of these smudgy drusen. Picro-Mallory stain. Top: X 75. Lower: X 500.

9 these drusen, with the formation of a thick basal laminar deposit. Conversion of hard h-valine drusen into soft serous drusen Clinical observations suggest that some hyaline drusen enlarge slightly and lose their sharp margins, developing a smudgy appearance (Figure 12). This generally occurs when a fine pigmentary disturbance is also becoming evident in the fundus. Histological examination of these drusen demonstrated a change in the staining characteristics from the hyaline to the pale-staining, amorphous or serous variety. This serous transformation generally commenced at the base of the drusen and extended upwards in an irregular fashion until only a cap of hyalinised material remained. At the same time the drusen appeared to undergo a change in consistency, losing the typical globular shape and developing a broad base which was sometimes prolonged more in one direction to form a tail. Figures 13 and 14 illustrate these histological findings which explain the enlargement, confluence and softening of hyaline drusen. These changes coincide with a progressive pigmentary disturbance such as characterises eyes in groups I11 and IV. When the transformation of the drusen was complete the overlying pigment epithelium demonstrated its maximal proliferative activity with migration of cells into the retina and the formation of a thick basal laminar deposit (Figure 15). Conversion of hyaline drusen into serogranular drusen Serogranular drusen probably represent hyaline drusen which have been partially converted into the soft serous type, the remaining hyaline material being broken up into fragments. The individual particles, which may be angular in shape but are usually round, are either surrounded by a pale-staining halo or have lost their deep staining altogether. (Figure 15.) Some of these round membranous structures have been identified as lysosomes by Farkas et al6 Serogranular drusen appear to have a consistency intermediate between that of the hard hyaline drusen and the soft serous type. Those which retain a greater proportion of hyaline Jmaterial present clinically as semisolid but discrete drusen while others which are softer tend to become confluent (Figure 16). The ultrastructure of these drusen also shows considerable variation in the size, shape and density of the constituents, while the well-developed basal laminar deposit confirms the abnormal activity of the retinal pigment epithelium occurring at this stage of macular degeneration (Figure 17). In general, however, the pigment epithelium showed less proliferative activity over the serogranular drusen than over the serous type, although the same widespread shallow separation of the basement membrane from Bruch s membrane was also present around the serogranular drusen. This space was packed with vesicles which also comprised one of the constituents of the serogranular drusen. These vesicles could be traced passing through Bruch s membrane except where the inner surface of the membrane was raised up as small dense elevations referred to as microdrusen (Figure 18). Complications of drusen Throughout their development and subsequent regression, the changes in drusen relate to the state of the retinal pigment epithelium. Thus hard hyaline drusen may remain unaltered for long periods but are converted or incorporated into serous or serogranular drusen when the pigment epithelium reaches a certain stage of degeneration, confirmed by the excessive formation of basement membrane material over these drusen. As the abnormal proliferative activity of the pigment epithelium declines again, drusen are invaded by macrophages and their contents replaced by fibrous tissue or they become calcified. Figures 19 and 20 represent the left eye of the same patient whose right eye was illustrated in figure 16. As the retinal pigmentary disturbance progressed the large confluent druse was noted to become whiter and inspissated, regressing as a small area of geographic atrophy developed. Histological examination showed that most of the drusen in the background had a serogranular structure, but that where the pigment epithelium had largely disappeared the drusen were becoming calcified or undergoing replacement by metaplastic fibrous DRUSEN AND THEIR RELATIONSHIP TO SENILE MACULAR DEGENERATION 125

10 14: Macular drusen from another eye in which the fundus had also shown a combination of hard and smudgy drusen, very similar to the appearance illustrated in figure 12. The hyaline drusen at top are undergoing serous transformation which is complete in druse below. The resulting change in shape and confluence of the hyaline drusen is clearly demonstrated. Picro-Mallory stain. Top: X 300. Lower: X 500. Figure IS: Section through macula of an eye in which a coarse pigmentary disturbance had been observed in association with drusen. Many small hyaline drusen were present, showing all stages of conversion to serous and serogranular drusen. Top: Proliferation of retinal pigment cells into the retina can be seen over a serous druse (arrowheads). Arrow at right oints to serogranular druse. Lower: bigher magnification of serogranular druse. Hyaline contents have been broken down to large angular clumps or smaller globules. These hyaline fra ments are surrounded by pale haloes, possibly membranes. Picro-Mallory stain. Top: X 75. Lower: X 5d.

11 Figure 16: Semisolid drusen becoming confluent in right eye of patient who died aged 75, 3 years after this photograph was taken. A faint pigmentary disturbance was evident before death but vision remained unchanged at 6/18. F;pre /7: Serogranular druse from eye illustrated in figure 16. DIIISK lies beneath basement membrane of retinal pigment epithelium (short arrow), basal laminar deposit is above basement membrane. Contents of druse comprise cellular and membranous debris, including membrane-bound clumps of amorphous or finely granular material (long arrow). Compare rlobular. and angular outlines of these clumps to histological iicture in figure 15. X Figirre 18: Another serogranular druse from the eye shown in figure 16. In addition to membranous debris the contents include small vesicles which also extended beneath the adjacent pigment epithelium. The inner surface of Bruch s membrane presents a scalloped appearance due to electron dense elevations which histologically are referred to as microdrusen. Note that the vesicles are passing throu h Bruch s membrane between the microdrusen (arrow). X IZj00. DRUSEN AKI) THEIR RELA.IWNSHIP -ro SENILE MA<UI.AR DEG~NERATION 127

12 i Figwe 19: Left fundus of patient whose right eye appears in Figure 20: Same eye shown in figure 19, h figure 16. showing the same background of serous drusen. The graphed 3 years later when vision had faion large. confluent druse at the fovea became whiter and the edges 6/60. The large central druse has faded, leal irregular as it regressed while the overlying pigment epithelium a depigmented area (arrow). degenerated. Photograph was taken 5 years before death, when vision was 619. Figure 21: Sections through macular area of eye shown in figures 19 and 20. Top: microdrusen and small serogranular drusen. Lower: regressing druse. partly replaced by avascular fibrous tissue. Note hyalinised basal laminar deposit and virtual absence of retinal pigment epithelium over surface. Picro-Mallory stain. X AUSTRALIAN JOURNAL O F OPHTHALMOLOGY

13 Figure 22: Serogranular drusen from another eye with geographic atrophy and calcifying drusen. The round purple bodies in the drusen at top stain positively with special calcium stains. These drusen lay just outside the area of geographic atrophy but the retinal pigment epithelium over the drusen is also beginning to disappear. Note the remains of the original hyaline drusen in the lower section. Picro-Mallory stain. Top: X 150. Lower: X 500. Figure 23: Further section from the same eye, illustrating the complication of neovascularization associated with drusen. A sheet of fibrovascuiar tissue lies on Bruch s membrane at left, merging into a serogranular druse at right. Picro-Mallory stain. X 150.

14 tissue (Figure 21). The microdrusen noted in the other eye were widespread. The two eyes of this patient showed the spectrum of formation and regression of serogranular drusen in the central area where there were parallel changes in the retinal pigment epithelium. As the pigment epithelium degenerates, granular drusen also develop particles which stain for calcium (Figure 22). The pigment epithelium over calcified drusen ultimately disappears, producing small areas of geographic atrophy which gradually expand and coalesce. Narrowing and obliteration of the choriocapillaris occurs in a like distribution and follows the loss of pigment epithelium.8 Geographic atrophy of the retinal pigment epithelium and secondary choroidal atrophy is therefore one end result of eyes with macular drusen. Driisen trnd sirbretinal neovuscirlurizution Small hyaline drusen are rarely complicated by a disciform response. On the other hand, new vessels are found in eyes in which softening and confluence of drusen has taken place (Figure 23). Gregor, Bird and Chisholm' identified the patients at greatest risk of developing a disciform lesion in the second eye were those with large confluent drusen in which there is progressive leak of fluorescein. Thus it is the serous drusen which are commonly associated with new vessels and it is noteworthy that both clinical and histological observations suggest that shallow serous drusen may be very widespread. This separation of tissue planes may set the stage for subretinal neovascularization but serous drusen also indicate the stage of maximal proliferative activity of the pigment epithelium and the attendant formation of thick basement membrane, the stage when the formation of a vasoformative factor may be at its maximum. The risk of neovascularization gradully declines as drusen regress and calcify, becoming non-existent wherever the pigment epithelium disappears. A ckno wdedgeni& ts I am indebted to Professor A. W. J. Lykke and Dr M. R. Dickson for the provision of facilities in the Biomedical Electron Microscope Unit, University of New South.Wales. I especially wish to acknowledge the assistance of Miss D. van Driel, B. Sc., Research Assistant, for the preparation of the electron micrographs and for her valuable advice. Thanks are also due to Mr H. Bachelor and Mr M. Killingsworth for their technical assistance. This work was supported in part by the Unit of Clinical Investigation, Lidcombe Hospital, and Grants from the National Health and Medical Research Council, O.P.S.M. Research and Charitable Foundation Ltd, Lions Save Sight Foundation and the Ophthalmic Research Institute of Australia. References I. Gass. J. D. M.: Druxn and discifonn rnacular detachment and degeneration. Arch. Ophthal Sarks, S. H.: Ageing and degeneration in the macular region: a clinico-patholqical study. Brit. J. Ophthal I. 3. Yanotf. M. and Fine. B. S.: Oculx Pathology. A Text and Atlas, p 638. New York: Harper & Row, Oosterhuis. J. A,: The architecture of the choroidal vascular system in clinical ophthalniologv. XXIII Concilium Ophthalmologicum, Kyoto, p Excerpta Medica: Amsterdam-Oxford Gass. J. D. M.: Pathogenesis of disciforrn detachment of the neuroepithelium. Parts I-VI. Amer. J. Ophthal , 63, I. 6. Fnrkas. T. G., Sylvester. V. and Archer. D.: The ultrastructure of dhsen. Amer. J. Ophthal., Hogan. M. J.: Role of the retinal pigment epithelium in macular disease. Trans Amer. Acad. Ophthal. Otolaryng Sarks, S. H.: Changes in the region of the choriocapillaris in ageing and dyneration. XXIII Concilium Ophthalmologicum, Kyoto p Gregor. Z.. Bird, A. C. and Chisholm. 1. H.: Senile disciform macular degeneration in the second eye. Brit. J. Ophthal , AUSTRALIAN JOURNAL OF OPHTHALMOLOGY