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Senile Macular Degeneration
SENILE MACULAR
DEGENERATION
C L I N I C O P A T H O L O G I C CORRELATIONS OF A C A S E I N T H E PREDISCIFORM ROBERT N .
FRANK,
M.D.,
W.
AND IRVIN P .
RICHARD GREEN,
POLLACK,
STAGE
M.D.,
M.D.
Baltimore, Maryland Since the first reports in the 19th and early 20th centuries 1 " 4 there have been many descriptions, both clinical and histopathologic, of the changes which occur in the pre disciform stages of senile macular degenera tion. More recently, additional clinical infor mation has been gained about macular diseases with the high magnification and stereoscopic viewing afforded by the slit lamp and fundus lens, and by fluorescein angiography. 5 - 1 1 Despite the considerable volume of published clinical information, we are aware of no well-documented clinicopathologic cor relation of the predisciform lesions of senile macular degeneration. T h e present report describes one such patient who was studied by slit lamp and contact lens examination, fundus photography, and fluorescein angiography of the involved maculas. Following death, serial sections through both maculas were used to reconstruct a large portion of the fundi to scale. W e were thus able to make correlations between the clinical a p pearance of the eyes and the histopathology.
ish bodies resembling confluent drusen. Photographs of the maculas were obtained on March 21, 1969 (Figs. 1 and 2). A fluorescein angiogram of the right disk and macula was obtained the same day, and selected frames are shown in Figures 3-5. The fluorescein appearance was felt to be compatible with multiple drusen; serous detachments of the pigment epithelium were considered but thought to be less likely. No treatment was recommended. In February, 1971, the clinical appearance of the mac ulas was unchanged, as documented by photographs, but visual acuity had deteriorated to RE : 20/70 and L E : 20/50. Examination with the slit lamp and fundus contact lens revealed no evidence of serous detachment of the retinal pigment epithelium or of the sensory epithelium. Fluorescein angiography was not repeated. Again, no treatment was advised. The patient died at the Johns Hopkins Hospital on May 15, 1971, with regional enteritis complicated by acute, renal failure and Pseudomonas sepsis. The eyes were removed at autopsy and fixed in forma lin. Gross examination was normal. METHODS
Segments of each globe, about 8 m m thick, were cut through the central area to include the macula and optic nerve. T h e segments were dehydrated, embedded in paraffin, and
C A S E REPORT
A 66-year-old white man was first examined at the Wilmer Institute on March 16, 1969, complain ing of decreased visual acuity in both eyes. A previ ous examination in 1961 revealed 20/20 vision in each eye. Bright yellow bodies resembling drusen were observed in each macula. In 1966, vision was RE : 20/20 and LE : 20/30 and the fundus appear ance was unchanged. On initial examination at Wil mer, corrected vision was found to be RE : 20/40 + 2 and LE: 20/30 + 1. Ophthalmoscopically, the macula of each eye showed areas of apparent depigmentation beneath the retina with irregular, yellowFrom the Eye Pathology Laboratory, The Wil mer Ophthalmological Institute, The Johns Hop kins University School of Medicine and Hospital, Baltimore, Maryland. Reprint requests to W. Richard Green, M.D., Eye Pathology Laboratory, Wilmer Institute, Johns Hopkins Hospital, Baltimore, Maryland.
Fig. 1 (Frank, Green, and Pollack). Clinical pho tograph of the right macula on March 21, 1969, taken 26 months before death. 587
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step-sectioned to the parafoveal area. Serial sections, 8 μ thick, were then taken through the parafoveal and foveal areas. Alternate sections were stained either with hematoxylin-eosin or with periodic acid-Schiff ( P A S ) . The intervening, unstained sections were reserved, and some of these were later stained with the Verhoeff-van Gieson stain for elastic tissue, the colloidal iron stain for acid mucopolysaccharides either with or without hyaluronidase, or the Masson trichrome stain. Stained sections were exam ined under a microscope equipped with an ocular micrometer, and important features from each section were then transcribed to scale on sheets of graph paper. A recon Fig. 2 (Frank, Green, and Pollack). Clinical pho tograph of the left macula on March 21, 1969. Pho struction of that portion of each retina con tographs taken two years later, in February, 1971, taining the optic nerve and macula, and ex showed no change. tending from temporal ora serrata to nasal ra serrata, could thus be made (Fig. 6 ) . Beluse the temporal-to-nasal extent of the ret-
Fig. 3 (Frank, Green, and Pollack). Right mac ula. Fluorescein angiogram taken March 21, 1969. Arteriovenous phase, 23 seconds after injection. Comparison with the fundus photograph (Fig. 1) shows that some of the yellowish lesions (seen as pale, mottled areas in the photograph) are hyperfluorescent, while others blockfluorescenceand ap pear dark. They were interpreted clinically as con fluent drusen, since pigment epithelial detachments would stain more evenly withfluorescein,and would have sharper borders.
Fig. 4 (Frank, Green, and Pollack). Right mac ula. Fluorescein angiogram of March 21, 1969. Late phase, 12 minutes and 20 seconds after injection. Some of the lesions are seen to retain the fluorescent dye after it has been almost entirely washed out of the retinal and choroidal vessels.
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rescein photographs. It is unlikely therefore that the "drusen" seen clinically are in fact multiple pigment epithelial detachments. Histologie examination of serial sections through each macula demonstrates only min imal changes in the pigment epithelium in the macular regions. In some areas there is RESULTS loss or displacement of pigment epithelial Comparison of the clinical photographs cell nuclei (Fig. 7), with minimal evidence and fluorescein angiograms (Figs. 1-5) with of loss of pigment and flattening of the cells the drawings reconstructed from histologie themselves. There is no vacuolization of the sections (Fig. 6) reveals at once a striking cells suggesting lipid deposition—one possi discrepancy : No lesions are seen microscopi ble explanation of the clinical appearance12 cally that correspond to the "confluent dru —nor is there evidence of hypertrophy or sen" which appear clinically; while on the hyperplasia of the pigment epithelial cells. other hand, clinical examination revealed no Flattening and dropout of the pigment epi evidence of serous detachments of either the thelial cells and thickening of Bruch's mem retinal pigment epithelium or of the neuro- brane is consistently seen only in the region sensory epithelium. These latter abnormali immediately adjacent to the optic nervehead ties, moreover, do not appear in the recon (Figs. 6 and 8 ) , a histopathologic appear structed drawings in a position correspond ance that is known to correlate clinically ing to their location in the clinical and fluo- with hyperfluorescence of the peripapillary choriocapillaris (Fig. 5). on fluorescein angiography." True drusen are seen histologically only in the retinal peripheries (Figs. 6 and 9 ) . Most of these are no more than 3050 μ in diameter. They are exaggerated in size in the drawings (Fig. 6) in order to make them visible at this scale. Although serous detachments of the pig ment epithelium and neurosensory epithe lium of the retina were not seen clinically in our patient, they were prominent in histo logie sections of his eyes (Figs. 6, 7, 10, and 11). The serous fluid in both types of de tachment was PAS-positive. Unlike the ma terial in drusen, however,13 it did not stain for acid mucopolysaccharides with colloidal iron. In many sections, the fluid beneath the pigment epithelium could clearly be seen to lie between the intact basement membrane of the pigment epithelial cells and that of the choriocapillaris (Fig. 7)—i.e., it was located Fig. 5 (Frank, Green, and Pollack). Fluorescein within the substance of Bruch's membrane. angiogram of March 21, 1969. Left disk two min At no place was there evidence of a physical utes after injection. Fluorescence of the peripapil- break in Bruch's membrane or the layer of lary choriocapillaris is seen through the thinned, atrophie pigment epithelium. The histologie appear pigment epithelial cells, and in only one re ance of this lesion is seen in Figure 8. gion of the left fundus (Figs. 6 and 11) did
ina (about 4 cm) was so much greater than the superior-to-inferior width of the section (about 2 mm), the scale of the drawings is expanded in the vertical direction so that all of the structures shown are elongated along the vertical axis.
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Fig. 6 (Frank, Green, and Pollack). Scale drawings of portions of both fundi reconstructed from serial sections viewed under the microscope. Compare the macular regions with photographs and fluorescein angiograms of Figures 1-5. Fig. 7 (Frank, Green, and Pol lack). Portion of a section in the macular region of the left eye showing distal retina, pigment epi thelium, Bruch's membrane, and choriocapillaris. There is some flattening of the pigment epithelial cells and loss of pigment granules. Nuclei are not lined up evenly, and some are absent. This is the most severe abnormality seen in pigment epithelial cells in the macu lar regions of either eye. Beneath the pigment epithelium there is a collection of serous fluid detach ing the pigment epithelial cells from the underlying choriocapil laris. Note that the fluid lies be tween the clearly visible basement membrane of the pigment epithe lium (open arrows) and that of the choriocapillaris (solid arrows) (PAS, X350).
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Fig. 8 (Frank, Green, and Pol lack). Portion of a section from the left eye showing pigment epi thelium and Bruch's membrane at the temporal margin of the optic disk. Note marked atrophy of pig ment epithelial cells and diffuse thickening of Bruch's membrane. This is the histopathologic equiva lent of the lesion seen on fluorescein angiography in Figure 5 (PAS, X350).
Fig. 9 (Frank, Green, and Pol lack). A drusen (arrow) lying on Bruch's membrane in the nasal periphery of the right eye (PAS, X350).
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Fig. 10 (Frank, Green, and Pol lack). A large serous detachment of the neurosensory epithelium in the macular region of the right eye (PAS, X145).
a detachment of the pigment epithelium lie in contiguity with a serous detachment of the neurosensory retina. The choriocapillaris and deeper layers of choroidal blood vessels were remarkably nor mal in appearance throughout both eyes; thickening of the intercapillary pillars, which is said to occur frequently in senile macular degeneration,9·11 was not seen commonly in these sections. Unfortunately, we can say little about the pathologic changes in the outer retinal layers
Fig. 11 (Frank, Green, and Pol lack). Portion of a section show ing macular region of the left eye with a large serous detachment of the neurosensory retina with a smaller serous detachment of the pigment epithelium immediately be neath. This is located at the in ferior margin of the fovea, as shown in the drawing of the left eye in Figure 6. The apparent thickening of the pigment epithe lium at the left margin of the serous pigment epithelial detach ment is an artefact resulting from tangential sectioning of the pig ment epithelial layer (PAS, X145).
due to postmortem autolysis which destroyed most of the photoreceptor outer segments, and to folds in the retina which distorted the cellular architecture and which also appear to represent a postmortem artefact which ren dered retinal structures difficult to recognize in many regions of the macula. COMMENT
The most significant finding in this case report is that those lesions in the macula which are seen frequently in the predisci-
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form stage of senile macular degeneration, and which are sometimes considered to rep resent drusen,9"12'14 in our patient are not drusen at all. Despite the clinical appearance of the fundi in this case, true drusen were seen histopathologically only in the retinal peripheries, and were much smaller than the lesions observed with the ophthalmoscope during life. Although the patient died three months after his last ophthalmoscopic exam ination, it is unlikely that these lesions disap peared in that interval, since ophthalmo scopic examinations and fundus photographs documented that the appearance of his macu las had been unchanged over at least the pre vious two years. On the other hand, careful examination of the patient's fundi with a slit lamp and contact lens four months before death failed to reveal detachments of the pig ment epithelium or of the neurosensory ret ina, yet these were demonstrated in histo logie sections. We suggest that these serous detachments may represent agonal changes related to the patient's prolonged terminal illness and not to his ophthalmic disease. Similar changes have been observed in eyes obtained at autopsy from individuals dying from a variety of diseases, but without a his tory of ophthalmic difficulties.8 In a recent publication, Wise, Dollery, and Henkind 12 have also suggested that these le sions in the predisciform stage of senile macular degeneration are not drusen. Their conclusion was based on a series of over 70 cases examined histopathologically by Wangvivat and Wise. 15 Unfortunately, there were no clinicopathologic correlations of in dividual cases. Although it is clear that these macular le sions in senile macular degeneration are not drusen, we cannot say from our material just what they do represent. One possibility is suggested by the work of Klien,18 who noted, in microscopic sections from a case of senile macular degeneration, regions in which the retinal photoreceptor outer segments had disappeared, and the empty spaces were par tially filled with hyperplastic pigment epithe-
593
lium. We have not observed such lesions in our case, although this negative finding might partially be explained by the marked autolytic changes present in the outer retinal layers. On the other hand, it is difficult to reconcile such lesions as Klien described with the fluorescein angiographie appearance (Figs. 3 and 4 ) . Another and perhaps more likely explana tion is that these lesions represent lipid depo sition either in the pigment epithelium or in the outer retinal layers.12 Lipid is not seen in our histologie preparations because they had been fixed in formalin, dehydrated in alco hol, and embedded in paraffin. On the other hand, we did not see intracellular vacuoles or extracellular spaces in our microscopic sec tions that could have represented previous sites of lipid deposition. The question can only be resolved by careful study of addi tional cases, with material obtained soon af ter death and studied by frozen-section tech nique and lipid stains. SUMMARY
A 66-year-old man had lesions in the mac ulas of both eyes which were considered, on the basis of ophthalmoscopic examination and fluorescein angiography, to represent multiple, confluent drusen. The fundus ap pearance did not change over two years, al though visual acuity decreased by three to four lines. Following death, segments of each globe containing the maculas and optic nerves were serially sectioned and these por tions of the fundi were reconstructed to scale, using graph paper and a microscope equipped with an ocular micrometer. No drusen were found in either macula, and changes in the pigment epithelium and choriocapillaris were minimal. Large serous de tachments of the neurosensory and pigment epithelium were present in each eye but did not correspond in location to the lesions ob served during life; nor were such detach ments seen during life when the fundus was examined with the slit lamp and contact lens. These detachments may represent an agonal
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change. We conclude that the drusen-like le sions often seen clinically in the predisciform stage of senile macular degeneration are not always true drusen, although their precise nature was not evident from our study. Reconstruction of the fundus to scale from serial microscopic sections is a useful way to correlate clinically observed abnor malities with lesions seen histopathologically. ACKNOWLEDGMENTS
The patient discussed in this report was referred by Frank Constantine, M.D., and he was seen in consultation with Arnall Patz, M.D. REFERENCES
1. Nagel, A. : Hochgradige Amblyopie, bedingt durch glashäutige Wucherungen und krystallinische Kalkablagerungen an der Innenfläche der Ader haut. Klin. Mbl. Augenheilk. 13: 338, 1875. 2. Haab, O. : Erkrankungen der Makula lutea. Cbl. Augenheilk. 9:384, 1885. 3. Harms, C. : Anatomisches über die senile Makulaaffektion. Klin. Mbl. Augenheilk. 42:448, 1904. 4. Behr, C. : Die Anatomie der "senilen Makula" (der senilen Form der makularen Heredodegeneration). Klin. Mbl. Augenheilk. 67:551, 1921. 5. Norton, E. W. D., Gass, J. D. M., Smith, J. L., Curtin, V. T., David, N. J., and Justice, J., Jr.: Fluorescein in the study of macular disease. Tr.
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Am. Acad. Ophth. Otolaryng. 69:631, 1965. 6. Maumenee, A. E. : Macular diseases : Pathogenesis. Tr. Am. Acad. Ophth. Otolaryng. 69:691, 1965. 7. Kimura, S. J. : Slit lamp examination of the macula. Tr. Am. Acad. Ophth. Otolaryng. 69:643, 1965. 8. Maumenee, A. E. : Further advances in the study of the macula. Arch. Ophth. 78:151, 1967. 9. Gass, J. D. M. : Pathogenesis of disciform de tachment of the neuroepithelium. III. Senile disciform macular degeneration. Am. J. Ophth. 63:617, 1967. 10. : Pathogenesis of disciform detachment of the neuroepithelium. IV. Fluorescein angiographie study of senile disciform macular degeneration. Am. J. Ophthal. 63:645, 1967. 11. ■ -: Stereoscopic Atlas of Macular Dis eases. A Funduscopic and Angiographie Presenta tion. St. Louis, C. V. Mosby, 1970. 12. Wise, G. N., Dollery, C. T., and Henkind, P. : The Retinal Circulation. New York, Harper and Row, 1971, p. 478. 13. Farkas, T. G., Sylvester, V., Archer, D., and Altona, M. : The histochemistry of drusen. Am. J. Ophth. 71:1206, 1971. 14. Bedell, A. J. : The macula in the elderly. Am. J. Ophth. 33 :1681, 1950. 15. Wangvivat, Y., and Wise, G. N. : Unpub lished study. 16. Klien, B. A. : The heredodegeneration of the macula lutea. Diagnostic and differential diagnostic considerations and a histopathologic report. Am. J. Ophth. 33:375, 1950.
DEGENERATION
C L I N I C O P A T H O L O G I C CORRELATIONS OF A C A S E I N T H E PREDISCIFORM ROBERT N .
FRANK,
M.D.,
W.
AND IRVIN P .
RICHARD GREEN,
POLLACK,
STAGE
M.D.,
M.D.
Baltimore, Maryland Since the first reports in the 19th and early 20th centuries 1 " 4 there have been many descriptions, both clinical and histopathologic, of the changes which occur in the pre disciform stages of senile macular degenera tion. More recently, additional clinical infor mation has been gained about macular diseases with the high magnification and stereoscopic viewing afforded by the slit lamp and fundus lens, and by fluorescein angiography. 5 - 1 1 Despite the considerable volume of published clinical information, we are aware of no well-documented clinicopathologic cor relation of the predisciform lesions of senile macular degeneration. T h e present report describes one such patient who was studied by slit lamp and contact lens examination, fundus photography, and fluorescein angiography of the involved maculas. Following death, serial sections through both maculas were used to reconstruct a large portion of the fundi to scale. W e were thus able to make correlations between the clinical a p pearance of the eyes and the histopathology.
ish bodies resembling confluent drusen. Photographs of the maculas were obtained on March 21, 1969 (Figs. 1 and 2). A fluorescein angiogram of the right disk and macula was obtained the same day, and selected frames are shown in Figures 3-5. The fluorescein appearance was felt to be compatible with multiple drusen; serous detachments of the pigment epithelium were considered but thought to be less likely. No treatment was recommended. In February, 1971, the clinical appearance of the mac ulas was unchanged, as documented by photographs, but visual acuity had deteriorated to RE : 20/70 and L E : 20/50. Examination with the slit lamp and fundus contact lens revealed no evidence of serous detachment of the retinal pigment epithelium or of the sensory epithelium. Fluorescein angiography was not repeated. Again, no treatment was advised. The patient died at the Johns Hopkins Hospital on May 15, 1971, with regional enteritis complicated by acute, renal failure and Pseudomonas sepsis. The eyes were removed at autopsy and fixed in forma lin. Gross examination was normal. METHODS
Segments of each globe, about 8 m m thick, were cut through the central area to include the macula and optic nerve. T h e segments were dehydrated, embedded in paraffin, and
C A S E REPORT
A 66-year-old white man was first examined at the Wilmer Institute on March 16, 1969, complain ing of decreased visual acuity in both eyes. A previ ous examination in 1961 revealed 20/20 vision in each eye. Bright yellow bodies resembling drusen were observed in each macula. In 1966, vision was RE : 20/20 and LE : 20/30 and the fundus appear ance was unchanged. On initial examination at Wil mer, corrected vision was found to be RE : 20/40 + 2 and LE: 20/30 + 1. Ophthalmoscopically, the macula of each eye showed areas of apparent depigmentation beneath the retina with irregular, yellowFrom the Eye Pathology Laboratory, The Wil mer Ophthalmological Institute, The Johns Hop kins University School of Medicine and Hospital, Baltimore, Maryland. Reprint requests to W. Richard Green, M.D., Eye Pathology Laboratory, Wilmer Institute, Johns Hopkins Hospital, Baltimore, Maryland.
Fig. 1 (Frank, Green, and Pollack). Clinical pho tograph of the right macula on March 21, 1969, taken 26 months before death. 587
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step-sectioned to the parafoveal area. Serial sections, 8 μ thick, were then taken through the parafoveal and foveal areas. Alternate sections were stained either with hematoxylin-eosin or with periodic acid-Schiff ( P A S ) . The intervening, unstained sections were reserved, and some of these were later stained with the Verhoeff-van Gieson stain for elastic tissue, the colloidal iron stain for acid mucopolysaccharides either with or without hyaluronidase, or the Masson trichrome stain. Stained sections were exam ined under a microscope equipped with an ocular micrometer, and important features from each section were then transcribed to scale on sheets of graph paper. A recon Fig. 2 (Frank, Green, and Pollack). Clinical pho tograph of the left macula on March 21, 1969. Pho struction of that portion of each retina con tographs taken two years later, in February, 1971, taining the optic nerve and macula, and ex showed no change. tending from temporal ora serrata to nasal ra serrata, could thus be made (Fig. 6 ) . Beluse the temporal-to-nasal extent of the ret-
Fig. 3 (Frank, Green, and Pollack). Right mac ula. Fluorescein angiogram taken March 21, 1969. Arteriovenous phase, 23 seconds after injection. Comparison with the fundus photograph (Fig. 1) shows that some of the yellowish lesions (seen as pale, mottled areas in the photograph) are hyperfluorescent, while others blockfluorescenceand ap pear dark. They were interpreted clinically as con fluent drusen, since pigment epithelial detachments would stain more evenly withfluorescein,and would have sharper borders.
Fig. 4 (Frank, Green, and Pollack). Right mac ula. Fluorescein angiogram of March 21, 1969. Late phase, 12 minutes and 20 seconds after injection. Some of the lesions are seen to retain the fluorescent dye after it has been almost entirely washed out of the retinal and choroidal vessels.
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rescein photographs. It is unlikely therefore that the "drusen" seen clinically are in fact multiple pigment epithelial detachments. Histologie examination of serial sections through each macula demonstrates only min imal changes in the pigment epithelium in the macular regions. In some areas there is RESULTS loss or displacement of pigment epithelial Comparison of the clinical photographs cell nuclei (Fig. 7), with minimal evidence and fluorescein angiograms (Figs. 1-5) with of loss of pigment and flattening of the cells the drawings reconstructed from histologie themselves. There is no vacuolization of the sections (Fig. 6) reveals at once a striking cells suggesting lipid deposition—one possi discrepancy : No lesions are seen microscopi ble explanation of the clinical appearance12 cally that correspond to the "confluent dru —nor is there evidence of hypertrophy or sen" which appear clinically; while on the hyperplasia of the pigment epithelial cells. other hand, clinical examination revealed no Flattening and dropout of the pigment epi evidence of serous detachments of either the thelial cells and thickening of Bruch's mem retinal pigment epithelium or of the neuro- brane is consistently seen only in the region sensory epithelium. These latter abnormali immediately adjacent to the optic nervehead ties, moreover, do not appear in the recon (Figs. 6 and 8 ) , a histopathologic appear structed drawings in a position correspond ance that is known to correlate clinically ing to their location in the clinical and fluo- with hyperfluorescence of the peripapillary choriocapillaris (Fig. 5). on fluorescein angiography." True drusen are seen histologically only in the retinal peripheries (Figs. 6 and 9 ) . Most of these are no more than 3050 μ in diameter. They are exaggerated in size in the drawings (Fig. 6) in order to make them visible at this scale. Although serous detachments of the pig ment epithelium and neurosensory epithe lium of the retina were not seen clinically in our patient, they were prominent in histo logie sections of his eyes (Figs. 6, 7, 10, and 11). The serous fluid in both types of de tachment was PAS-positive. Unlike the ma terial in drusen, however,13 it did not stain for acid mucopolysaccharides with colloidal iron. In many sections, the fluid beneath the pigment epithelium could clearly be seen to lie between the intact basement membrane of the pigment epithelial cells and that of the choriocapillaris (Fig. 7)—i.e., it was located Fig. 5 (Frank, Green, and Pollack). Fluorescein within the substance of Bruch's membrane. angiogram of March 21, 1969. Left disk two min At no place was there evidence of a physical utes after injection. Fluorescence of the peripapil- break in Bruch's membrane or the layer of lary choriocapillaris is seen through the thinned, atrophie pigment epithelium. The histologie appear pigment epithelial cells, and in only one re ance of this lesion is seen in Figure 8. gion of the left fundus (Figs. 6 and 11) did
ina (about 4 cm) was so much greater than the superior-to-inferior width of the section (about 2 mm), the scale of the drawings is expanded in the vertical direction so that all of the structures shown are elongated along the vertical axis.
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Fig. 6 (Frank, Green, and Pollack). Scale drawings of portions of both fundi reconstructed from serial sections viewed under the microscope. Compare the macular regions with photographs and fluorescein angiograms of Figures 1-5. Fig. 7 (Frank, Green, and Pol lack). Portion of a section in the macular region of the left eye showing distal retina, pigment epi thelium, Bruch's membrane, and choriocapillaris. There is some flattening of the pigment epithelial cells and loss of pigment granules. Nuclei are not lined up evenly, and some are absent. This is the most severe abnormality seen in pigment epithelial cells in the macu lar regions of either eye. Beneath the pigment epithelium there is a collection of serous fluid detach ing the pigment epithelial cells from the underlying choriocapil laris. Note that the fluid lies be tween the clearly visible basement membrane of the pigment epithe lium (open arrows) and that of the choriocapillaris (solid arrows) (PAS, X350).
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Fig. 8 (Frank, Green, and Pol lack). Portion of a section from the left eye showing pigment epi thelium and Bruch's membrane at the temporal margin of the optic disk. Note marked atrophy of pig ment epithelial cells and diffuse thickening of Bruch's membrane. This is the histopathologic equiva lent of the lesion seen on fluorescein angiography in Figure 5 (PAS, X350).
Fig. 9 (Frank, Green, and Pol lack). A drusen (arrow) lying on Bruch's membrane in the nasal periphery of the right eye (PAS, X350).
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Fig. 10 (Frank, Green, and Pol lack). A large serous detachment of the neurosensory epithelium in the macular region of the right eye (PAS, X145).
a detachment of the pigment epithelium lie in contiguity with a serous detachment of the neurosensory retina. The choriocapillaris and deeper layers of choroidal blood vessels were remarkably nor mal in appearance throughout both eyes; thickening of the intercapillary pillars, which is said to occur frequently in senile macular degeneration,9·11 was not seen commonly in these sections. Unfortunately, we can say little about the pathologic changes in the outer retinal layers
Fig. 11 (Frank, Green, and Pol lack). Portion of a section show ing macular region of the left eye with a large serous detachment of the neurosensory retina with a smaller serous detachment of the pigment epithelium immediately be neath. This is located at the in ferior margin of the fovea, as shown in the drawing of the left eye in Figure 6. The apparent thickening of the pigment epithe lium at the left margin of the serous pigment epithelial detach ment is an artefact resulting from tangential sectioning of the pig ment epithelial layer (PAS, X145).
due to postmortem autolysis which destroyed most of the photoreceptor outer segments, and to folds in the retina which distorted the cellular architecture and which also appear to represent a postmortem artefact which ren dered retinal structures difficult to recognize in many regions of the macula. COMMENT
The most significant finding in this case report is that those lesions in the macula which are seen frequently in the predisci-
VOL. 75, NO. 4
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form stage of senile macular degeneration, and which are sometimes considered to rep resent drusen,9"12'14 in our patient are not drusen at all. Despite the clinical appearance of the fundi in this case, true drusen were seen histopathologically only in the retinal peripheries, and were much smaller than the lesions observed with the ophthalmoscope during life. Although the patient died three months after his last ophthalmoscopic exam ination, it is unlikely that these lesions disap peared in that interval, since ophthalmo scopic examinations and fundus photographs documented that the appearance of his macu las had been unchanged over at least the pre vious two years. On the other hand, careful examination of the patient's fundi with a slit lamp and contact lens four months before death failed to reveal detachments of the pig ment epithelium or of the neurosensory ret ina, yet these were demonstrated in histo logie sections. We suggest that these serous detachments may represent agonal changes related to the patient's prolonged terminal illness and not to his ophthalmic disease. Similar changes have been observed in eyes obtained at autopsy from individuals dying from a variety of diseases, but without a his tory of ophthalmic difficulties.8 In a recent publication, Wise, Dollery, and Henkind 12 have also suggested that these le sions in the predisciform stage of senile macular degeneration are not drusen. Their conclusion was based on a series of over 70 cases examined histopathologically by Wangvivat and Wise. 15 Unfortunately, there were no clinicopathologic correlations of in dividual cases. Although it is clear that these macular le sions in senile macular degeneration are not drusen, we cannot say from our material just what they do represent. One possibility is suggested by the work of Klien,18 who noted, in microscopic sections from a case of senile macular degeneration, regions in which the retinal photoreceptor outer segments had disappeared, and the empty spaces were par tially filled with hyperplastic pigment epithe-
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lium. We have not observed such lesions in our case, although this negative finding might partially be explained by the marked autolytic changes present in the outer retinal layers. On the other hand, it is difficult to reconcile such lesions as Klien described with the fluorescein angiographie appearance (Figs. 3 and 4 ) . Another and perhaps more likely explana tion is that these lesions represent lipid depo sition either in the pigment epithelium or in the outer retinal layers.12 Lipid is not seen in our histologie preparations because they had been fixed in formalin, dehydrated in alco hol, and embedded in paraffin. On the other hand, we did not see intracellular vacuoles or extracellular spaces in our microscopic sec tions that could have represented previous sites of lipid deposition. The question can only be resolved by careful study of addi tional cases, with material obtained soon af ter death and studied by frozen-section tech nique and lipid stains. SUMMARY
A 66-year-old man had lesions in the mac ulas of both eyes which were considered, on the basis of ophthalmoscopic examination and fluorescein angiography, to represent multiple, confluent drusen. The fundus ap pearance did not change over two years, al though visual acuity decreased by three to four lines. Following death, segments of each globe containing the maculas and optic nerves were serially sectioned and these por tions of the fundi were reconstructed to scale, using graph paper and a microscope equipped with an ocular micrometer. No drusen were found in either macula, and changes in the pigment epithelium and choriocapillaris were minimal. Large serous de tachments of the neurosensory and pigment epithelium were present in each eye but did not correspond in location to the lesions ob served during life; nor were such detach ments seen during life when the fundus was examined with the slit lamp and contact lens. These detachments may represent an agonal
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change. We conclude that the drusen-like le sions often seen clinically in the predisciform stage of senile macular degeneration are not always true drusen, although their precise nature was not evident from our study. Reconstruction of the fundus to scale from serial microscopic sections is a useful way to correlate clinically observed abnor malities with lesions seen histopathologically. ACKNOWLEDGMENTS
The patient discussed in this report was referred by Frank Constantine, M.D., and he was seen in consultation with Arnall Patz, M.D. REFERENCES
1. Nagel, A. : Hochgradige Amblyopie, bedingt durch glashäutige Wucherungen und krystallinische Kalkablagerungen an der Innenfläche der Ader haut. Klin. Mbl. Augenheilk. 13: 338, 1875. 2. Haab, O. : Erkrankungen der Makula lutea. Cbl. Augenheilk. 9:384, 1885. 3. Harms, C. : Anatomisches über die senile Makulaaffektion. Klin. Mbl. Augenheilk. 42:448, 1904. 4. Behr, C. : Die Anatomie der "senilen Makula" (der senilen Form der makularen Heredodegeneration). Klin. Mbl. Augenheilk. 67:551, 1921. 5. Norton, E. W. D., Gass, J. D. M., Smith, J. L., Curtin, V. T., David, N. J., and Justice, J., Jr.: Fluorescein in the study of macular disease. Tr.
APRIL, 1973
Am. Acad. Ophth. Otolaryng. 69:631, 1965. 6. Maumenee, A. E. : Macular diseases : Pathogenesis. Tr. Am. Acad. Ophth. Otolaryng. 69:691, 1965. 7. Kimura, S. J. : Slit lamp examination of the macula. Tr. Am. Acad. Ophth. Otolaryng. 69:643, 1965. 8. Maumenee, A. E. : Further advances in the study of the macula. Arch. Ophth. 78:151, 1967. 9. Gass, J. D. M. : Pathogenesis of disciform de tachment of the neuroepithelium. III. Senile disciform macular degeneration. Am. J. Ophth. 63:617, 1967. 10. : Pathogenesis of disciform detachment of the neuroepithelium. IV. Fluorescein angiographie study of senile disciform macular degeneration. Am. J. Ophthal. 63:645, 1967. 11. ■ -: Stereoscopic Atlas of Macular Dis eases. A Funduscopic and Angiographie Presenta tion. St. Louis, C. V. Mosby, 1970. 12. Wise, G. N., Dollery, C. T., and Henkind, P. : The Retinal Circulation. New York, Harper and Row, 1971, p. 478. 13. Farkas, T. G., Sylvester, V., Archer, D., and Altona, M. : The histochemistry of drusen. Am. J. Ophth. 71:1206, 1971. 14. Bedell, A. J. : The macula in the elderly. Am. J. Ophth. 33 :1681, 1950. 15. Wangvivat, Y., and Wise, G. N. : Unpub lished study. 16. Klien, B. A. : The heredodegeneration of the macula lutea. Diagnostic and differential diagnostic considerations and a histopathologic report. Am. J. Ophth. 33:375, 1950.