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Graefe’s Arch Clin Exp Ophthalmol (2000) 238:158–162 © Springer-Verlag 2000 Received: 28 April 1999 Revised version received: 9 August 1999 Accepted: 6 September 1999 Abstract Purpose: To report the indocyanine green angiographic find- ings in patients with a fundus dystro- phy characterized by subretinal de- posits, macular atrophic or neovascu- lar degeneration and peripheral cho- rioretinal atrophy which is most likely Sorsby’s fundus dystrophy. Methods: A series of 11 clinically affected patients and 4 asymptomatic carriers, belonging to one autosomal dominant pedigree were examined with stereoscopic funduscopy, fluo- rescein and indocyanine green angiography. Results: Subretinal deposits were found in 20 eyes of 10 patients. These deposits stained slightly on indocyanine green angio- graphy, causing a reticular pattern. Two eyes had a disciform lesion and 3 geographic atrophy in the macula. A peripheral disciform lesion was found in 1 eye. Indocyanine green an- giography identified peripapillary choroidal neovascularization in 2 eyes. Peripheral chorioretinal atrophy was found in 8 eyes of 4 patients, associ- ated with peripheral plaques that could only be identified by indocya- nine green angiography in 6 eyes of 3 patients. Conclusion: Indocya- nine green angiography in Sorsby’s fundus dystrophy may indicate the presence of homogeneously staining, well-demarcated peripheral areas of hyperfluorescence associated with chorioretinal atrophy. These plaques correspond in our opinion to choroi- dal neovascularization which is other- wise unsuspected. CLINICAL INVESTIGATION Bart A. Lafaut Eric De Backer Takeya Kohno Jean-Jacques De Laey Françoise M. Meire Indocyanine green angiography in Sorsby’s fundus dystrophy Introduction In 1949, Sorsby et al. described five families with a dominantly inherited dystrophy that was characterized by choroidal neovascularization, subretinal hemorrhages and disciform degeneration with onset usually in the fifth decade [14]. Progressive central and peripheral cho- rioretinal atrophy occurred later in life [14]. At least three of the original families reported by Sorsby et al. showed evidence of drusen-like deposits [6]. One of his families, the Kempster pedigree, had a deposit of yellow subretinal material throughout the fundus which tended to become less apparent with age [6]. We studied the indocyanine green angiographic charac- teristics of persons with a fundus dystrophy which is most likely Sorsby’s fundus dystrophy. Several patients suffered from visual loss due to exudative and/or atrophic maculo- pathy. Linkage analysis with 22q12.1-q13.2 was signifi- cantly positive (J.J.M. Assink et al., submitted) and sup- ported the diagnosis because Weber and associates linked Sorsby’s fundus dystrophy with markers on 22q13 [16]. Indocyanine green angiography is an adjunct exami- nation method in the study of choroidal vascular diseas- es. It allows better definition of occult choroidal neovas- cularization in age-related macular degeneration. We ap- plied this technique to find out whether choroidal lesions could be identified in Sorsby’s fundus dystrophy and compared indocyanine green angiography with fundus- copy and fluorescein angiography. Methods Fifteen persons, 11 clinically affected and 4 carriers, belonging to a Flemish pedigree with an autosomal dominant fundus dystrophy were B.A. Lafaut ( ) · E. De Backer · T. Kohno J.-J. De Laey · F.M. Meire Department of Ophthalmology, University Hospital Gent, De Pintelaan 185, B-9000 Gent, Belgium

Indocyanine green angiography in Sorsby’s fundus dystrophy

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Page 1: Indocyanine green angiography in Sorsby’s fundus dystrophy

Graefe’s Arch Clin Exp Ophthalmol (2000)238:158–162 © Springer-Verlag 2000

Received: 28 April 1999Revised version received: 9 August 1999Accepted: 6 September 1999

Abstract ● Purpose: To report theindocyanine green angiographic find-ings in patients with a fundus dystro-phy characterized by subretinal de-posits, macular atrophic or neovascu-lar degeneration and peripheral cho-rioretinal atrophy which is most likelySorsby’s fundus dystrophy.● Methods: A series of 11 clinicallyaffected patients and 4 asymptomaticcarriers, belonging to one autosomaldominant pedigree were examinedwith stereoscopic funduscopy, fluo-rescein and indocyanine green angiography. ● Results: Subretinaldeposits were found in 20 eyes of 10 patients. These deposits stainedslightly on indocyanine green angio-graphy, causing a reticular pattern.Two eyes had a disciform lesion and

3 geographic atrophy in the macula.A peripheral disciform lesion wasfound in 1 eye. Indocyanine green an-giography identified peripapillarychoroidal neovascularization in 2 eyes.Peripheral chorioretinal atrophy wasfound in 8 eyes of 4 patients, associ-ated with peripheral plaques thatcould only be identified by indocya-nine green angiography in 6 eyes of 3 patients.● Conclusion: Indocya-nine green angiography in Sorsby’sfundus dystrophy may indicate thepresence of homogeneously staining,well-demarcated peripheral areas ofhyperfluorescence associated withchorioretinal atrophy. These plaquescorrespond in our opinion to choroi-dal neovascularization which is other-wise unsuspected.

C L I N I C A L I N V E S T I G AT I O N

Bart A. LafautEric De BackerTakeya KohnoJean-Jacques De LaeyFrançoise M. Meire

Indocyanine green angiography in Sorsby’s fundus dystrophy

Introduction

In 1949, Sorsby et al. described five families with adominantly inherited dystrophy that was characterizedby choroidal neovascularization, subretinal hemorrhagesand disciform degeneration with onset usually in thefifth decade [14]. Progressive central and peripheral cho-rioretinal atrophy occurred later in life [14]. At leastthree of the original families reported by Sorsby et al.showed evidence of drusen-like deposits [6]. One of hisfamilies, the Kempster pedigree, had a deposit of yellowsubretinal material throughout the fundus which tendedto become less apparent with age [6].

We studied the indocyanine green angiographic charac-teristics of persons with a fundus dystrophy which is mostlikely Sorsby’s fundus dystrophy. Several patients sufferedfrom visual loss due to exudative and/or atrophic maculo-

pathy. Linkage analysis with 22q12.1-q13.2 was signifi-cantly positive (J.J.M. Assink et al., submitted) and sup-ported the diagnosis because Weber and associates linkedSorsby’s fundus dystrophy with markers on 22q13 [16].

Indocyanine green angiography is an adjunct exami-nation method in the study of choroidal vascular diseas-es. It allows better definition of occult choroidal neovas-cularization in age-related macular degeneration. We ap-plied this technique to find out whether choroidal lesionscould be identified in Sorsby’s fundus dystrophy andcompared indocyanine green angiography with fundus-copy and fluorescein angiography.

Methods

Fifteen persons, 11 clinically affected and 4 carriers, belonging to aFlemish pedigree with an autosomal dominant fundus dystrophy were

B.A. Lafaut (✉) · E. De Backer · T. KohnoJ.-J. De Laey · F.M. MeireDepartment of Ophthalmology, University Hospital Gent, De Pintelaan 185, B-9000 Gent, Belgium

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investigated. Since a significant linkage with the locus of Sorsby’sfundus dystrophy was demonstrated in the clinically affected olderfamily members, the diagnosis of Sorsby’s fundus dystrophy wasconfirmed in the pedigree (J.J.M.Assink et al., submitted). In a secondstep, the carriers amongst the younger family members, identified bygenetic means, were invited for ophthalmologic investigation.

Fundus photography, fluorescein and indocyanine green angi-ography were performed in addition to a standard clinical ophthal-mologic examination. Indocyanine green angiograms were ob-tained with the Topcon Imagenet system after intravenous in-jection of 50 mg indocyanine green dye. The arterial filling wasconsidered as the arterial phase of the indocyanine green angio-gram, the venous phase corresponded with positively staining cho-roidal veins (early venous phase 30 s to 5 min, mid-venous phase8–15 min, late venous phase 15–25 min) and the late phase cor-responded to negatively staining choroidal veins with onset about30 min after intravenous injection.

Informed consent was obtained from all subjects.

Results

No fundus abnormalitieswere seen on stereoscopic fun-duscopy and fluorescein angiography in four asymptom-atic carriers, aged 29–40 years. Indocyanine green angi-ography did not reveal any peculiarity either.

Subretinal depositswere found in seven patients(cases 1–7, Fig. 1) with normal visual acuity aged 48–59years. The appearance of the fundi was symmetric inthese patients. Six patients had rather pisciform flecksalong the temporal vascular arcade and in the midperiph-ery as well as nasally to the disc. In two of these pa-tients, small midperipheral patches of chorioretinal atro-phy were not associated with such deposition. Four pa-tients presented yellow, round drusen-like deposits at thelevel of the macular retinal pigment epithelium. Retinalpigment epithelial window defects as seen on fluoresceinangiography corresponded with the deposits, while onindocyanine green angiography a reticular pattern withstaining of the deposits was found along the arcades andnasally to the disc.

Atrophy and neovascularization:Macular geographicatrophy and nummular patches of chorioretinal atrophyunder the arcades and nasally to the disc extending intothe midperiphery were seen in both eyes of a 60-year-oldfemale patient whose visual acuity was 0.1 in the righteye and 0.2 in the left (case 8, III9 , Fig. 2). A delicateline of pigmentary hyperplasia bordered a fibrotic peri-papillary choroidal neovascular membrane in the righteye. The fluorescein angiography indicated extensivemacular atrophic changes as well as scattered midperiph-eral window defects. Indocyanine green angiography re-vealed a large peripapillary plaque in the right eye and asmall peripapillary plaque in the left. Additionally sever-al midperipheral plaques, otherwise unsuspected, werefound adjacent to chorioretinal atrophy. The area of mac-ular atrophy was hypofluorescent in the venous phase ofthe indocyanine green angiogram, but the hypofluores-cence became less marked in the late phase.

Fine scattered and a few larger deposits were observedin the right macula of another 60-year-old female patient(case 9, III7 ; visual acuity: 1.0 in the right eye and 0.01 inthe left). Areas of chorioretinal atrophy and a disciformscar were found in the periphery of the right eye (Fig. 3).An extensive macular disciform lesion with subretinalhemorrhage as well as peripheral atrophic changes werefound in the left eye. Indocyanine green angiography re-vealed vascular structures within the disciform lesionsand indicated the presence of peripheral plaques in botheyes not observed by fluorescein angiography.

A 60-year-old male patient (case 10, III15; visual acu-ity: light perception in the right eye and 0.5 in the left)had a macular disciform lesion in the right eye and geo-

Fig. 1A–C Left eye, case 3, III10. A Red-free photograph of a pa-tient with normal visual acuity, showing pisciform deposits alongthe temporal vascular arcade, in the midperiphery and nasally tothe disk, as well as a few macular deposits. B Late-phase fluores-cein angiogram shows retinal pigmentary changes at the level ofthese deposits. C Late-phase indocyanine green angiogram revealsa reticular pattern

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Fig. 4A,B Left eye, case 10, III15. A Early venous-phase in-docyanine green angiogram. B Late-phase angiogram. Severalmidperipheral plaques are seen in the late phase (arrow), some ofthem are surrounded by atrophic areas (asterisk)

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graphic atrophy of the left macula. Almost confluentnummular atrophy was seen in the midperiphery of botheyes with atypical pigmentary clumping. Indocyaninegreen angiography showed several plaques in the midpe-riphery surrounding atrophic zones (Fig. 4). The area ofmacular atrophy was hypofluorescent in the venousphase but became isofluorescent in the late phase whilethe midperipheral chorioretinal atrophy remained hypo-fluorescent throughout the different phases of the angio-gram.

Fig. 2A–H Right eye, case 8, III9 . A,B At presentation; C–H11/2 years later. A Late-phase fluorescein angiogram of the tempo-ral periphery shows peripheral retinal pigmentary changes andchorioretinal atrophy. B Venous-phase fluorescein angiogram ofposterior pole indicates macular chorioretinal atrophy and retinalpigmentary changes. C Late-phase fluorescein angiogram of thetemporal periphery, progression of peripheral atrophy and appear-ance of midperipheral atrophic patches is seen. D Late-phase fluo-rescein angiogram of the posterior pole: striking progression ofchorioretinal atrophy is observed, as well as a fine peripapillarypigmented line (arrow) bordering the plaque observed on indocya-nine angiography. E Venous-phase indocyanine green angiogramof the posterior pole: several defects in the choriocapillaris filling(arrow) are readily recognized and a peripapillary hyperfluores-cent lesion is suspected. F Late-phase indocyanine green angio-gram of the posterior pole: the hypofluorescence seen in the ve-nous phase is hardly recognized and a peripapillary plaque is iden-tified. G,H Late-phase indocyanine green angiogram of the su-perotemporal and inferotemporal periphery, respectively: severalplaques, some isolated and others confluent, are visualized sur-rounding relatively hypofluorescent areas

Fig. 3A–D Right eye, case 9, III7 . A Red-free photography of aperipheral hemorrhagic disciform lesion. B Corresponding ve-nous-phase fluorescein angiogram. C Venous-phase indocyaninegreen angiogram shows a vascular net. D Late-phase indocyaninegreen angiogram indicates staining of the lesion

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Extensive peripheral chorioretinal atrophy was foundin both eyes of an 80-year-old male patient (case 11,II13), but both maculae appeared relatively preserved.The visual acuity was 0.4 in the right eye and 0.01 in theleft (amblyopia). Fluorescein angiography revealed an ir-regular mottling of the macular retinal pigment epitheli-um in both eyes and no abnormalities were detected byindocyanine green angiography. Peripheral atrophy cor-responded with hypofluorescence on indocyanine greenangiography. Peripheral plaques were not seen.

Discussion

The clinical appearance of this autosomal dominant fun-dus dystrophy with subretinal deposits, macular degener-ation and midperipheral chorioretinal atrophy suggestsSorsby’s fundus dystrophy. The subretinal deposits ap-pear in the fifth decade, characteristically under the ar-cades, and are a striking feature of our pedigree. Somedeposits resemble hard drusen, other are reminiscent offlavimaculate flecks. In the sixth decade, atrophic and/ordisciform macular changes cause loss of central vision,while peripheral vision is lost in the following decadesdue to extensive midperipheral chorioretinal atrophywith pigmentary clumping.

Sorsby’s fundus dystrophy shows some phenotypicvariation in the families initially described by Sorsby [2,5, 9, 13, 14]. The interfamilial variations are in fact oftenintrafamilial as three of the four autosomal dominantpedigrees described by Sorsby and others descend from asingle ancestor with Ser181Cys mutation [4]. The mac-ulopathy, which is usually neovascular and associatedwith a rapid decline of the visual acuity, develops at ap-proximately 40 years of age in Sorsby’s fundus dystro-phy and is followed by peripheral chorioretinal atrophyin later decades. Neovascular or atrophic maculopathywas observed somewhat later in our family, namely atthe end of the sixth decade, simultaneously with the ap-pearance of peripheral atrophy.

Weber and colleagues linked Sorsby’s fundus dystro-phy with markers on 22q13 [16]. Apte and colleaguesisolated a tissue inhibitor of metalloproteinases-3(TIMP-3) and localized it to 22q12.1-q13.2 [1]. Severalmutations, confined to exon 5 of the TIMP-3 gene, wereidentified in Sorsby’s fundus dystrophy [4, 16]. Linkageanalysis in our family was significantly positive with thelocation of the TIMP-3 gene, but known mutations in thepatients belonging to our pedigree could not be identi-fied (J.J.M. Assink et al., submitted).

The indocyanine green angiographic characteristics ofone patient with Sorsby’s fundus dystrophy have recent-ly been reported by Lim et al. [12]; our findings extendthe knowledge in that we report the angiographic charac-teristics in different stages of the disease and confirm thefindings of this previous case report.

The subretinal deposits under the temporal vasculararcade correspond with window defects on fluoresceinangiography and a reticular pattern on indocyanine greenangiography. The macular deposits are not visualized onindocyanine green angiography. The deposits becomefunduscopically invisible when atrophy develops.

Midperipheral atrophy appears as sharply delineatednummular patches under the arcades, outside the arcadesand nasal to the disc. In older patients more confluentatrophic patches are seen. Indocyanine green angiographyindicates loss of the choriocapillaris in these areas as hy-pofluorescence is seen in the venous and late phase. Themacular atrophy has somewhat different indocyaninegreen angiographic characteristics in three eyes. It can beseen as a slightly hypofluorescent area in the early andmid-venous phase. The hypofluorescence becomes lessapparent or even disappears in the late phase, in contrastwith the late sharply demarcated hypofluorescence ob-served on indocyanine green angiography in age-relatedmacular degeneration with geographic atrophy in the pos-terior pole. The adjacent tissue (retinal pigment epitheli-um, Bruch’s membrane, choriocapillaris and even chor-oid), also being diseased, may not be able to build up nor-mal late-phase fluorescence. On the other hand, the de-gree of atrophy available may cause the contrast to beless obvious in the late phase. The latter hypothesis seemsless likely to us since the atrophy was rather pronounced.

Disciform lesions were found centrally in two eyesand peripherally in one eye. These lesions were readilyidentified by either funduscopy, fluorescein or indocya-nine green angiography. They appeared earlier during theindocyanine green angiography with demonstration of avascular network. Late diffusion caused a poor definitionof their contours in the late phase.

The striking indocyanine angiographic feature in ourfamily is the indication of peripheral plaques that are invis-ible by funduscopy or fluorescein angiography. Theseplaques are often continuous with atrophic areas. They be-come visible in the venous phase (after 5–10 min). A vas-cular network is not observed in the early- or venous-phaseindocyanine green angiogram of these lesions. The periph-eral plaques are homogeneous and well delineated in thelate phase of the angiogram. These characteristics differen-tiate them from the disciform lesions that had already beenvisualized by funduscopy and fluorescein angiography.

Only limited information about indocyanine green an-giography in fundus dystrophies is available. Peripheralplaques are unusual in association with age-related mac-ular degeneration, but such lesions have been found inassociation with angioid streaks [11] and idiopathic pol-ypoidal choroidal vasculopathy [17]. Angioid streaks,which correspond to fibrovascular tissue in Bruch’smembrane [7], may be confluent on indocyanine greenangiography with ameboid plaques, not only in the peri-papillary area but also in the midperiphery. The peripher-al plaques described in idiopathic polypoidal choroidal

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vasculopathy are associated with a cluster of dilated ves-sels that are visible at least in the early and venous phaseof the angiogram. Such vessels have not been observedin this series.

Kuntz and coworkers [10] reported on an autosomaldominant pedigree with late-onset retinal degenerationthat shared clinical and pathologic characteristics withSorsby’s fundus dystrophy as well as with the patientspresented in this report. The first ophthalmoscopic signis clusters of yellow-white punctate lesions. The diseaseprogresses with appearance of midperipheral scotomasand severe loss of central vision. They observed a con-fluent layer of periodic acid–Schiff-positive material be-tween the basement membrane of the retinal pigmentepithelium and the inner collagenous layer of Bruch’smembrane in a donor eye. Capon et al. reported a similarintra-Bruch’s membrane deposition in a descendant froman autosomal dominant pedigree initially reported by Sorsby [2]. The characteristic accumulation found in

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age-related macular degeneration appears similar but liesbetween the retinal pigment epithelium and its basalmembrane and is less amorphous [3, 8]. Kuntz et al. [10]reported extensive chorioretinal atrophic changes, in-cluding marked loss of retinal pigment epithelium, pho-toreceptor cells and choriocapillaris as well as prominentsubretinal pigment epithelium choroidal neovasculariza-tion in degenerated retinal areas, including the formationof a macular disciform lesion. These pathologic findingscorrespond with the clinical observations in our cases.We believe that the plaques revealed by indocyaninegreen angiography indicate such subretinal pigment epi-thelial neovascularization.

In conclusion, indocyanine green angiography in-dicates peripheral plaques, probably representing choroi-dal neovascularization and otherwise unsuspected, in Sorsby’s fundus dystrophy.AcknowledgementsThis study was supported by a grant fromLes Amis des Aveugles, Ghlin.