A C T A O P H T H A L M O L O G I C A V O L . 5 7 1 9 7 9

The Department of Ophthalinology (Head: Jan Y t t eborg ) , Ullevdl sykehus, Oslo

FUNDUS FLUORESCEIN ANGIOGRAPHY IN FUNDUS FLAVIMACULATUS AND STARGARDTS DISEASE

BY

NILS ANMARKRUD

Three siblings who had fundus flavimaculatus and two patients who had Stargardts disease were studied by means of fundus fluorescein angio- graphy. The angiograms revealed in all cases an abolished visibility of the chorioidal circulation. New flecks a re usually non-fluorescent. Later on, hyperfluorescent areas a re seen at identical places both in the pre- retinal and retinal phases, strongly indicating a window effect of the re- tinal layer. The missing chorioidal flush is probably due to a blocking effect of the emitting and exciting light. Some of the retinal flecks may fade away, leaving corresponding areas of hyperfluorescence that usually persist. In some cases, however, a previous fluorescent area may become non-fluorcscent. The similar angiographic picture may indicate that fun- dus flavimaculatus and Stargardts disease are different expressions of the same disease.

K e y words: fundus flavimaculatus - Stargardts disease - fundus fluor- escein angiography - chorioidal circulation.

Stargardt described in 1909 a bilateral, hereditary macular degeneration oc- curring in young people. In addition to an atrophic-macular lesion, perimacu- lar yellow-white flecks were also noticed.

Franceschetti (1963) introduced the term fundus flavimaculatus to separate a special form of tapetoretinal degeneration. In these cases, the fundi were characterized by yellow-white or yellow flecks a t the level of the retinal pig- ment epithelium in the posterior pole. In 500/0 of the patients, Franceschetti noticed an atrophic-appearing niacular degeneration. Others have found ma-

Received October 16. 1978.

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Fundus Flavimiciila~ii.s mid Slurgurdls Discasc

cular degeneration in 67 Oio (Klien 8i Krill 1967). In these cases, the distinction between fundus flavimaculatus and Stargardts disease is difficult, if a t all possible. In the last years, the view has been put forward that these two reti- nal degenerations are in fact different manifestations of the same disease. This is now commonly accepted (Deutman 1971; Irvine & Wergeland 1972; Fran- Gois et al. 1975; Hadden 5; Gass 1976).

Fluorescein angiographic studies in fundus flavimaculatus were first men- tioned by Ernest 8i Krill (1966). They concluded that the flecks and drusen were similar in location, involving the retinal pigment epithelium.

We have examined a family in which some of the members had reduced vision due to fundus flavimaculatus. In addition, we have examined two pa- tients with Stargardts disease. The purpose of this study is to describe the angiographic pattern seen in these two diseases. If Stargardts disease and fundus flavimaculatus are different expressions of the same disease, it would be of interest to study whether there exists a similarity in the angiographic picture.

Material and Methods

The clinical material consists of 7 siblings (Fig. I ) , fair-haired norwegian people. Their parents were healthy with no eye symptoms and no consanguinity. Three of the siblings suffered from reduced vision due to fundus flavimacu- latus. In addition, we have examined two patients with Stargardts disease.

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0 f e m a l e Fig. 1.

Pedigree of family with fundus flavimaculatus. Black symbols indicate affected members.

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Nils Anmorkrud

A complete ophthalmological examination was performed in every patient, including fundus examination by miomicroscopy, Goldman perimetry, ERG during scotopic conditions, dark adaptation, Ishihara colour screening and fluorescein fundus angiography. The angiograms were performed with a Zeiss fundus camera. The film used was Kodak Plus-X pan. After injection of 5 ml sodium fluescein solution (100 mg/ml) into an antecubital vein, the angio- grams were taken automatically every second during the transit of dye and then 2, 5 and 10 min after injection. W e used Zeiss interference filter KP 500 as excitation filter and Kodak Wratten No. 15 as barrier filter.

Case Reports

Case I (11-3). A 29-year-old man developed bilateral decreased central vision a t the age of 22 years. In 1973, visual acuity was 6/20 in right eye, 6/12 in the left eye. ERG and darkadaptation were normal. H e identified only the first of the Ishihara plates and a central scotoma was present in each eye. Ophthalmoscopy revealed a normal optic disc and normal retinal vessels. The macula in each eye showed a peri- foveal atrophic lesion. In the posterior pole, many retinal yellow-white flecks of various shapes and sizes were seen (Fig. 2 A). Angiograms showed numerous hyper- fluorescent areas, both in preretinal and arteriovenous phases with abolished visibility of the chorioidal circulation between these areas (Fig. 2 B and Fig. 2 C).

In 1976, the visual acuity had deteriorated to c. f. 5 m right eye, c. f . 2 m left eye. Thc atrophic macular lesions had increased in size, but the yellow-white flecks were of about the same number. Some of the flecks had faded away, while new ones had been added (Fig. 3 A). The angiogram showed increased number of hyperfluorescent areas. Some of the earlier yellow-white flecks with no hyperfluorescence had faded away, and, corresponding to these flecks, the angiogram now revealed hyperfluores- cence (Fig. 3 B).

Case 2 (11-3). A 23-year-old woman, sister of case 1, developed decreased central vision in both eyes a t the age of 14 years. Visual acuity was c. f. 5 m in each eye. ERG and dark adaptation were normal. She identified only the first of the Ishihara plates. A central scotoma was found in each eye. Ophthalmoscopy revealed a normal optic disc and normal retinal vessels. The macula in each eye showed an atrophic pigmentary lesion with irregular margins. Surrounding the macula were many yellow- white flecks (Fig. 4 A). Angiograms showed numerous hyperfluorescent areas with abolished visibility of the chorioidal circulation (Fig. 4 B and Fig. 4 C).

Case .3 (114). A 20-year-old man, the youngest brother of case 1, noticed reduced central vision in both eyes at the age of 18 years. Visual acuity was 6/12 in the right eye, 6/20 in the left eye. ERG and dark adaptation were normal. He identified only the first of the Ishihara plates and a centrnl scotoma was present in each eye. In each macula, most pronounced in the left one, were some deepseated yellow-white flecks.

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Fig. 2 A . Case 1, 1973. Right eye. A. An atrophic perifoveal lesion surrounded by numerous flecks. B. Angiogram (preretinal phase) showing numerous hyperfluorescent areas. C. Angiogram (arteriovenous phase) showing areas of hyperfluorescence of greater intensity than in B, hut the shape, size and location are identical. (Vertical arrows points to identical hyperfluorescent areas. The long horizontal arrow demonstrates a retinal fleck showing fluorescence. The short horizontal arrow demonstrates non- fluorescent flecks). Note the abolished chorioidal circulation between the hyper-

fluorescent areas.

Fig. 2 B. Fig. 2 C.

Ni l s Anmarkrid

Fig. 3 A. Fig. 3 B. Case 1, 1976. Right eye. A. A marked atrophic lesion and numerous fleck are seen. B. Angiogram (arterio-venous phase) showing more fluorescent areas than flecks. Since 1973 a fleck has become non-fluorescent (long horizontal arrow) and a previous

non-fluorescent flecks now shows fluorescence (short horizontal arrow).

Most of them were round, others with a more linear shape (Fig. 5 A ) . The angiogram (Fig. 5 B) showed no hyperfluorescent areas and no visibility of the chorioidal cir- culation.

In these three cases, a diagnosis of fundus flavimaculatus was made. The other siblings were also examined. All had normal retinal findings and normal fundus angiography (Fig. 6).

Case 4. A 24-year-old woman, in good health with no eye disorders in her family, noticed reduced central vision in both eyes a t the age of 15 years. Visual acuity was 6/40 in each eye. ERG and dark adaptation were normal. She identified only the first of the Ishihara plates. The macula in each eye showed an atrophic pigmentary lesion with beaten margins. No flecks were seen (Fig. 7 A). The angiogram showed almost no chorioidal flush and a hyperfluorescent macular area (Fig. 7 B).

Case 5 . A 46-year-old man, in good health with no eye disorders in his family, no- ticed central vision of the age of 29 years. Visual acuity was 4/40 in each eye. A central scotoma was found in each eye. In each macula an atrophic lesion with beaten margins was seen surrounded by some yellow-white flecks. Some of them were round, others were linear or pisiform with indistinct margins and a tendency towards con- fluence. No flecks were seen outside the main vessels truncks (Fig. 8 A). The angio- gram showed abolished visibility of the chorioidal circulation, hyperfluorescent foveal area and hyperfluorescent areas in the macula (Fig. 8 B).

I n the last two cases a diagnosis of Stargardts disease was made.

Fundus Flavimaculatus and Sturgardts Disease

Fig. 4 A . Case 2. Right eye. A. A n atrophic macular lesion surrounded by numerous flecks. R. Angiogram (preretinal phase) showing numerous hyperfluorescent areas. C. Angio- gram arterio-venous phase) showing areas of hyperfluorescence of greater intensity than in B, but the shape, size and location a re identical. (Vertical arrows points to identical hyperfluorescent areas). Note the abolished chorioidal circulation between

the flecks.

Fig. 4 B .

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Fig. 4 C.

Acta ophthal. 57, 2 12

N i l s Anrnarkrud

Fig . 5 A . Fig . 5 R. Case 3. Left eye. A. In macula some deeply seated retinal flecks are present. B. Angio- gram (arteriovenous phase) showing complete abolished visibility of the chorioidal

circulation, but normal filling of the retinal vessels.

Fig. 6 . A healthy brother (11-4) in the family with fundus flavimaculatus. Left eye. Angio-

gram (early arteriovenous phase) showing normal angiographic pattern.

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Fundus Flavimaculatus and Stargardts Disease

Fig. 7 A . Fig. 7 B. Case 4. Right eye. A. An atrophic macular lesion with between margins, no flecks. B. Angiogram (arteriovenous phase) showing hyperfluorescence of the macular lesion and normal filling of the retinal vessels. There is complete abolished visibility of

the chorioidal circulation.

Fig. 8 A. Fig. 8 B. Case 5. Right eye. A . A macular atrophic lesion with beaten margins surrounded by some flecks. B. Angiogram (arteriovenous phase) showing fluorescence of the atrophic lesion and and some of the flecks. There is normal filling of the retinal vessels,

but complete abolished visibility of the chorioidal circulation.

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N i l s Anninrkriid

Results

Changes in the chorioidal circulation

The three members of the family with fundus flavimaculatus demonstrate a peculiar abnormal angiographic pattern: abolished visibility of the chorioidal circulation. This is most pronounced in case 3 (Fig. 5 B), which is a very early stage of the disease. W e also observed the same change in the chorioidal cir- culation in case 1 (Fig. 2 C) and case 2 (Fig. 4 B) although the marked hyper- fluorescence tends to mask it. But between the hyperfluorescent areas, there is no visibility of the chorioidal circulation. Case 4 and case 5, which fulfil the criteria of Stargardts disease, also show the same invisibility of the chorioidal circulation (Fig. 7 B and Fig 8 B). The siblings not affected by fundus flavi- maculatus had a completely normal chorioidal pattern, although all were fair- haired with the same degree of retinal pigmentation (Fig. 6).

Hypo-hyperfluorescence of the retinal flecks

In the very early stage of fundus flavimaculatus, only some minor yellow- white flecks are seen in the macular area (Fig. 5 A). The angiograms demon- strate very few changes except the missing chorioidal flush (Fig. 5 B). As the disease progresses, more flecks are seen, and the angiograms now reveal nu- merous hyperfluorescent areas. The flecks are usually found to be non-fluor- escent and the fluorescent areas in the angiograms are either seen between the flecks or adjacent to the retinal flecks.

The retinal flecks are often found to fade away (Fig. 2 A and Fig. 3 A). Corresponding to the previous fleck a hyperfluorescent area is now formed. Since the retinal flecks may fade away and the hyperfluorescent areas usually persists, a disproportion is made between the number of retinal flecks and hyperfluorescent areas. In some few cases we have seen a hyperfluorescent area to disappear, but this is unusual (Fig. 2 C and Fig. 3 B).

The areas of hyperfluorescence are seen before filling of the retinal arteries, both in fundus flavimaculatus and Stargardts disease. They have identical shape, size and location to those seen in the arterial and arteriovenous phases of the angiograms although the intensity increases (Fig. 2 B and Fig. 2 C, Fig. 4 B and Fig. 4 C). In no cases was late staining seen.

Discussion

The abolished visibility of the chorioidal circulation is a peculiar in our pa- tients with fundus flavimaculatus and Stargardts disease. The siblings not affected by fundus flavimaculatus all had a normal angiographic pattern. In

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Fzindus Flavimaculatzis and Stargardts Disease

fundus flavimaculatus and in Stargardts disease some alteration must exist with regard to the chorioidal circulation. The angiographic pattern could either be due to occlusion of the chorioidal circulation or something in front of the choriocapillaris that could obstruct the view of an otherwise normal chorioidal circulation.

In the preretinal phases of the angiograms, numerous hyperfluorescent areas were seen. The location, size and configuration were identical to those seen in the retinal phases of the angiograms. The fluorescent areas increased in intensity during the arterial and arteriovenous phases and faded away simul- taneously to normal chorioidal fluorescence. Between the hyperfluorescent areas, no sign of chorioidal fluorescence was seen. The angiographic pattern of the hyperfluorescent areas in the preretinal and retinal phases are highly suggestive of normal chorioidal circulation which is seen through “window- defects” in the retinal layers. The invisibility of the chorioidal circulation is probably due to a masking effect between chorioidea and the retinal vessels. The chorioidal circulation is obviously present, but is only partly seen through the “window-defects”.

As far as I know, only Bonnin et al. (1976) have stressed similar alterations in certain posterior retinal degenerations and have called it “le signe du silence chorioidien”.

Klien & Krill (1976) made the only histopathologic examination of an eye with fundus flavimaculatus. They found distinctive changes in the pigment epithelium, while neuroepithelium, Rruchs membrane and chorioid were nor- mal. The lesion appeared to be produced by an acid mucopolysaccharide lo- cated inside the pigment epithelium. The morphologic changes with displace- ment of the nucleus toward the center of the cell, and the peculiar line of con- densation of pigment granules near the inner surface of the cell can possibly explain increased absorption of the emitting and exciting light. A diffuse de- posit of acid mucopolysaccharide will further increase absorption of the light.

The abolished visibility of the chorioidal circulation may thus be due to physical problems concerning the filtering of the emitting and exciting light. It is highly suggestive that a diffuse deposit at the level of pigment epithe- lium, Bruchs membrane or the outer segment of the retina blocks the trans- mission of light.

The missing chorioidal flush is not a constant sign in these two retinal diseases (Bonnin et al. 1976). The reason for this is uncertain, but the sign may be related to various amount of diffuse deposits in the retina.

New flecks are usually non-fluorescent. As the disease progresses, they be- come fluorescent. The location, size and shape of the hyperfluorescent areas strongly suggest a pigment epithelial window-defect.

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Some of the flecks has been shown to fade away. W e have also found that earlier hyperfluorescent areas can be non-fluorescent, although most of them persist. The reason for this is uncertain.

The similar angiographic picture with abolished visibility of the chorioidal circulation and time-related angiographic changes of the retinal flecks may be a further evidence that fundus flavimaculatus and Stargardts disease is the same disease with a different expression.

References

Bonnin P., Passot M. & Triolaire-Cotton M. (1976) Le signe du silence choroidien dans les degenerscences tapcto-retiniennes posterieures. In: Le Laey J. J., Ed. Internatio- nal Symposizim on Fluorrscein Angiograplzy. pp. 461-463. Dr. J. Wunk by Pub- lishers, The Hague.

Deutman A. F. (1971) The hcreditnry dystrophies of the posterior pole of tlrc eye. Charles C . Thomas, Springfield, Illinois.

Ernest J. T. & Krill A. E. (1966) Fluorescein studies in fundus flavimaculatus and drused. Amrr. J. Ophthal. 62, 1-6.

Franceschetti A. (1963) Ueher tapeto-retinale Degeneration im Kindesalter (kongeni- tale Form (Leber), amaurotische Idiotie, rezessive-geschlechtsgebundene tapeto- retinale Degenerationen, Fundus albipunctatus cum hemeralopia, Fundus flavima- culatus. In: Enke F., Ed. Entwicklung i i n d Fortschritt i n der Atigenlzeilkunde, pp. 107-120. Enke Verlag, Stuttgart.

FranGois P., Turut P., Puech B. & Ilache J. C.: (1975) Maladie de Stargardt et fundus flavimaculatus. Arch. Oplithal. (Paris) 3 . 5 , 81 7-846.

Hadden 0. B. & Gass J. D. M. (1976) Fundus flavimaculatus and Stargardts disease. Amer. J. Ophthal. 82, 527-539.

Irvine A. R. & Wergeland F. L. Jr. (1972) Stargardts hereditary progressive macular degeneration. Brit. J. Ophthal. 56, 81 7-826

Klien B. A. & Krill A. E. (1967) Fundus flavimaculatus. Clinical functional and histopathologic observations. Anwr. 1. Ophthal. 64, 3-23.

Stargardt K. (1909) Ueher familiare, progressive Degeneration in der Makula gegend des Auges. AlbrecAt v. Graefes .Arch. Ophthal. 7 1 , 534-550.

Author’s addrrss: Nils Anmarkrud, M. D., Eye Department, Ullevll sykehus, Oslo 1 , Norway.

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