ACTA OPHTHALMOLOGICA VOL. 55 1977

XXlll MEETING OF NORDIC OPHTHALMOLOGISTS

Copenhagen, Denmark 2 5 2 8 May 1977

Department of O~htha lmology (Head . Henrik Forsius), University of Oulu, Oulu, Finland,

Samfundet Folkhulsan, Population Genetic Institute, (Head: Johan Fellman), Kauniainen, Finland

and T h e Johns Hopkins University, Applied Physics Laboratory, Laurel, Maryland, U S A

FLUORESCEIN AND INDOCYANINE GREEN FLUORESCENCE ANGIOGRAPHY IN STUDY

OF AFFECTED MALES AND IN FEMALE CARRIERS WITH CHOROIDERMIA

A Preliminary Report

BY

HENRIK FORSIUS, LEA HYVKRINEN, HElKKl NlEMlNEN and

ROBERT FLOWER

26 males and 13 female carriers of different ages with choroideremia of varying severity were investigated using sodium fluorescein (FAG) and/or indocyanine green (ICG) fluorescence angiography. Females with minor changes present in pigment epithelium may stay un- changed throughout life or gradually develop into a more advanced stage resembling the fundus picture of severely affected males. In moderately affected females there is a patchy degeneration of pigment epithelium in the macula. Peripapillary degeneration is seen also in indo- cyanine green fluorescence angiograms. In males, atrophic areas and the remaining choriocapillaris are clearly demonstrated in FAG and less well visible in ICG angiograms. ICG angio- grams show chorcidal vessels more clearly in cases where the pigment epithelium and the choriocapillaris are still present. In advanced cases in males and females, the choroidal blood circulation is slow.

Key words: choroideremia - blood circulation in eye ground - sodium fluorescein fluorescence angiography - indocyanine green fluorescence angiography - X-chromosomal disease.

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Henrik Forsius, Lea Hyvurinen, Heikki Nieminen and Robert Flower

Choroideremia, first described in 1872 by Mauthner, is a bilateral, hereditary, progressive degeneration of the choroid and retina characterized by night blindness and visual field constriction in affected males. In 1942 Goedbloed & Waardenburg in independent studies stated that choroideremia is carried as an intermediate sex-linked (X-chromosomal) trate. The normal carrier state is characterized by the combination of pigment clumping and depigmentation in the outer retinal layers, especially in the midperiphery.

No histological studies in carriers have been made, but ophthalmoscopically the changes in the slightly affected females are restricted to the pigment epi- thelial layer of the retina. Most authors held the fundus picture to be stationary during the carriers’ life (McCulloch & McCulloch 1948), but propression has been observed (Kurstjens 1965). Usually the females have no subjective visual symptoms even in old age, however, some females have been described with an almost homozygotic state in their eyegrounds; the opposite is also possible Kurstjens (1965) did not found any changes a t all in the fundi of one genetically confirmed conductor.

Few reports on pathological investigations have been made, and all were on totally blind, old males (Griitzner & Vogel 1973; Rafuse & McCulloch 1968). The conjunctival and ciliary vessels were normal as were the retinal vessels, but in those few choroidal vessels which remained, thickened and hyalinized vessel walls were seen. The Bruch’s membrane, the pigment epithelium and the outer retinal layers were totally destroyed. The cause for the disease is not known. The appearance in the carriers and in young males suggests a primary defect in the retinal pigment layer, but a primary defect in the choriocapillaris has also been discussed.

The fundus picture of an affected male varies with age. The earliest changes may be present a t birth; they have been observed a t the age of I* /2 years (Kurstjens 1965). These earlier changes were defective pigmentation in the pigment epithelium and pathologically visible choroidal vessels throughout the fundus. Atropic changes in the choroid develop during the first decades and result in difficulties with night vision and defects of visual fields. Later, atrophic areas enlarge, and a t the age of 40 to 50 years, only a small central island of functioning retina is left. Defective night vision usually is symptomatic at the age of 5-10 years, but some affected males first observe their difficulties in dark adaptation a t about 20 years of age. I n three boys aged 7 , 9 and 11 years, respectively, normal adaptation curves were found in the investigation of Kurstjens (1965) all 25 other patients had abnormal night vision curves.

Fluorescein angiography (FAG) shows narrow retinal vessels and intense fluorescence in areas where choriocapillaris is visible but no fluorescence where choroidal vessels are absent (Krill et al. 1968; Takki 1974). In addition angio-

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Fluorescence Angiografihy in Choroideremia

Slight changes

graphy during the late stages demonstrates a slowing of the choroidal and retinal circulations (Gass 1970).

This paper is a preliminary report of a follow-up study of patients with choroideremia. The purpose of the investigation is to document changes in both affected males and in female carriers during several years in hope to find some clues to the pathogenesis of this disease.

Severe disturbancies

Material and Methods

In northern Finland several families with choroideremia have been found. The families live f a r away from each other, and no genealogical connection between them has been proved in spite of the fact that the sparse population found in this area (660 000) suggests that the same defect gene is responsible for all those diseased. Our largest pedigree consists of 36 affected men and 69 female carriers. In a n earlier study (Forsius & Eriksson 1976) part of this largest pedigree was showed, and the connection of choroideremia with probably autoscmal dominant uveal coloboma with low penetrance was discussed.

A t the end of year 1976, 26 males and 13 females of different ages with choroideremia of varying severity were investigated a t the Department of Ophthalmology, University of Oulu. A clinical examination, visual fields, dark adaptation, fluorescein angiography and/or indocyanine green fluorescence angiography was performed (Table I).

Table I . Sodium fluorescein fluorescence angiography (FAG) and indocyanine green fluorescence

angiography (ICG). Distribution of the material.

I I

2 1 2 - 1 - 1 - FAG only 1 2 3

ICG only - - - - - -

FAGi-ICG 10 13 23 1 1 4 2 1 9 1

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C

E

D

F

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Fluorescence A n g i o g r a p h y in Choroideremia

Fluorescein angiography was performed using a standard Zeiss fundus camera modified for fluorescein angiography (Hyvarinen et al. 1969) and for indo- cyanine green fluorescence angicgraphy (Flower 8i Hochheimer 1976). Angio- grams were made at 0.8 second intervals. In indccyanine green (ICG) fluo- rescence angicgraphy, the excitation filter transmits energy from about 7500 to 8000 A, and the barrier filter transmits above 8000 A with peak transmission a t 8350 A corresponding to peak fluorescence of ICG in blood. In the lightly pigmented north European eyes, the infrared light passes easily through the retinal pigment epithelium, and since the indocyanine green dye does not difuse through the vessel walls as does sodium fluorescein, blood circulation through choroidal vessels, except choriocapillaris, can be visualized.

Results Female carriers

The degree of involvement in different female carriers varies greatly. Altogether five different stages of choroidal changes can be defined.

In cases belonging to the first category (stage I) no changes or changes only in the pigment layer of the midperipheral fundus are seen. Those with minor changes present in the pigment epithelium may stay unchanged throuh- out life or gradually develop into a mcre advanced stage; these patients have no subjective symptoms. The dispersion of granules in the pigment layer is best seen in fluorescein angiograms.

~ ~ ~~~~~~~

Fig. I A-F. Fig. 1 A. Fluorescein angiography (FAG) in a 12 year old boy (H S.). Retinal circulation is ncrmal, filling of choriocapillaris below the macula, above the macula and slightly lateral to fovea is defective. The pigment distribution in the pigment layer is granular.

Fig. I B. In corresponding indocyanine green angiography (ICG) angiograms the cho- roidal vessels are clearly demonstrated and the lumen is widely open. Smaller vessel branches are not seen well.

Fig. I C . 25 year old affected male (M. 0.) with pronounced choroidal degeneration Dark pigmentaticn in fovea region.

Fig. 1 D. Temporally to the macula choroidal vessels contain fluorescein in the vessel wall in late venous phase.

Fig. 1 E . 62 year old affected male (V. I.) with only a small residual island of func- tioning retina in the macula.

Fig. I F . Some choroidal vessels (arrows) are visible on a longer pathway in ICG angiogram compared to that in fluorescein angiogram.

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A

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Henrik Forsius, Lea Hyuurinen, Heikki Nieminen and Robert Flower

D

E

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Fluorescence Angiografhy in Choroideremia

In moderately affected females (stage 11) there is patchy degeneration of pigment epithelium and underlying choroid in the macula surrounding the disc.

In stage 111 the peripapillary changes are more marked. Small white dots resembling hyaloid bodies are found in the midperiphery in outer layers of retina. The peripapillary changes are visible also in ICG angiograms.

In stage IV (Fig. 4 D) the pigment layer in the macular area is greatly destroyed and the irregular peripapillary zone of degeneration is broad. There are numercus white dots scattered throughout in retina in addition to earlier mentioned pigment granules in the fundus. In the aged carriers there is severe choroideasclercsis in the peripapillary area and also elsewhere in the fundus. After 60 years of age, or even in some younger female carriers, choroidal changes develop which are quite comparable to those in affected young maies.

In stage V there is marked atrophy of choroid, slight difficulties in night vision and moderate decrease in visual acuity (Fig. 4 E, F). In one case large areas of retina and choroid were missing so that the fundus resembled that of a middle aged man with choroideremia combined with large visual field defects (Fig. 4 F).

In our series there were several old women in the two groups with advanced changes (IV-V) suggesting a progression of the disease in a carrier.

In affected males changes develop in very early years. In one 4-year-old boy only mottling in the pigment layer was seen, but in another 5-year-old boy typical atrophic changes of choroid connected with defects in the visual fields had already occurred: peripapillary atrophy, large areas of peripheral atrophy and uneven distribution of pigment in the central island of functioning

Fig. 2 A-E. Fig. 2 A. 22 year old carrier (I. V.) shows in fluorescein angiogram marked choroidal atrophy (stage 111) around the disc and disturbances in the pigment epithelium, also in the foveal area.

Fig. 2 B . In ICG angiogram the peripapillary choroidal atrophy around the disc is marked and large choroidal vessels are visible also in areas of the functioning chorio- capillaris (venous phase).

Fig. 2 C . 63 year old female carrier (E.V.) with marked atrophy (stage V) of chorio- capillaris both around the disc and in the macula. Note the uneven vessel wall in choroidal vessels (arrow) and the normal structure of retinal vessels.

Fig. 2 D. Only narrow bands of normal retina and choriocapillaris are visible around the disc, changes in this area closely resemble those seen in young affected males.

Fig. 2 E. In ICG angiogram of the same eye as in Fig. 2 C, D the choroidal arteries are clearly visible (5 seconds after first appearance of dye in choroid).

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Fluorescence A n g i o g r a p h y in Choroideremia

retina were seen. Investigation with Goldmann-Weekers adaptometer showed only photopic vision. Difficulties in night vision in our patients were present before the age of 20 years, and changes in dark adaptation could regularly be demonstrated with adaptometer before subjective symptoms appeared. The atrophic areas and the remaining choriocapillaris are clearly demonstrated in fluorescein angiograms and less well visible in ICG angiograms (Fig. 1 A, C).

In severely affected males the choroidal vessel walls seem to be damaged in such a way that they absorbe dye. This patchy staining of the vessel wall, especially in choroidal veins, is visible both in ICG angiograms (Fig. 3 D) and in fluorescein angiograms (Figs. 1 D, 3 F).

In cases where the pigment layer and the choriocapillaris are still present, ICG angicgrams show choroidal vessels more clearly than fluorescein angio- grams (Figs. 1 B, 2 B). In the most advanced cases only a few choroidal vessels are seen in ICG angiograms, and these cases are better studied in fluorescein angiograms.

In female carriers, except those most advanced, and in young bays, the filling of retinal and choroidal arteries starts almost simultaneously. The difference compaired with normal individuals is very slight. Normally the dye is visible

Fig. 3 A - F . Fig. 3 A. 44 year old female carrier (K. K.) with far advanced choroidal changes (stage V), same fundus as in picture (Fig. 4F). ICG angiogram at the moment the dye appears in two choroidal vessels and one retinal artery, the dye is already seen through the sclera. The remnants of choroidal pigmentation are visible as shadows against the light background.

Fig. 3 B. Very poor filling of choroidal vessels and almost no filling of choriocapillaris. Note the attenuated retinal vessels. During last few years the patient has had difficulties in night vision and her dark adaptation curve is two log units above normal. Normal visual acuity but advanced visual field changes.

Fig. 3 C . 36 year old affected male (H. V.). Fluorescein angiogram shows changes in peripheral choroidal anteries (early phase).

Fig. 3 D. He has normal configuration of the choroidal veins at the venous ampulla but some of the veins retain some ICG in their vessel wall (arrow). There is no choriocapillaris present in this area.

Fig. 3 E. 46 year old affected male (P. L.) demonstrates clearly the delayed fiiling of choroid which starts first in early venous phase of retinal circulation. Note the cilio- retinal artery at the temporal edge of the disc, filling at this time.

Fig. 3 F. Some choroidal veins retain fluorescein in their wall in late angiogram (arrow). There is only a small central island of functioning retina.

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Henrik Forsius, Lea Hyvarinen, Heikki Nieminen and Robert Flower

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F

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Fluorescence A n g i o g r a p h y in Choro ideremia

in the choroidal vessels slightly before it appears in the central retinal artery. In the most advanced female carriers and in all moderately or severely affected males, the filling of retinal vessels starts before choroidal vessels, and there is a definite delay in filling of choroidal arteries. This difference in filling is well demonstrated in a 46 year old affected male who has a cilioretinal artery which fills first in the early retinal venous phase (Fig. 3 E).

Discussion

At this stage of the study, examination of female carriers has shown that fundus changes vary greatly in their severity from one carrier to another, and the changes are possibly progressive as there are so many old female carriers in stages IV and V. There apparently are some young carriers with no fundus changes, however. The morphology of the fundus changes seems to be almost identical with changes seen in affected males. However, the symptoms in carriers rarely develop to the level of severity found in affected males.

In affected males the disease progresses so early that if the early stages of the disease in them is to be studied, the affected boys should be studied during their first years of life. The findings in young boys resemble those in middle-aged carrier females. The follow-up of the changes in carrier females may give us some clues about what occurs in the affected males during their first years of life.

Fig . 4A-F. Fig. 4 A . 12 year old boy (H. S.) with choroideremia. Peripapillary pigment and vessel free area. Pigment epithelium is dark in fovea. Same eye as in Fig. 1 A, B.

Fig. 4 B. 2.5 year old male (R. V.) with choroideremia. Pigment epithelium is destroyed and choroidal sclerosis seen in many areas.

Fig . 4 C. 62 year old affected male (V. I.) with choroideremia. Only a small residual island of functioning retina in the macula. Same eye as in Fig. 1 E, F.

Fig. 4 D. 17 year old female carrier (L H.) of choroideremia. Typical clumping of pigment in pigment epithelium. In addition some small hyaloid bodies in outer retinal retinal layers. Peripapillary degeneration visible.

Fig. 4 E . 62 year old female carrier (E. V.) of choroideremia. Destruction of pigment epithelium and choroidal atrophy. Same eye as in Fig. 2 C, D, E.

Fig. 4 F . 44 year old female carrier (K. K.) of choroideremia with advanced retinal and choroidal changes. Same eye as in Fig. 3 A, B.

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Henrik Forsius, Lea Hyvarinen, Heikki Nieminen and Robert Flower

Acknowledgment

The study has been supported from the Sigrid Jusklius Foundation, Helsinki, Finland.

References

Flower R. W. & Hochheimer B. F. (1976) Indocyanine green dye fluorescence and in- frared absorption choroidal angiography performed simultaneously with fluorescein angiography. T h e Johns Hopkins Medical Journal 138, 33-42.

Forsius H. & Eriksson A. W. (1976) Choroideremia. Proc. Vth Congress of European Society of Ophthalmology, Hamburg, 5-9 April.

Gass J. D. M. (1970) Stereoscopic atlas of macular diseases, pp. 110-112. Mosby, St. Louis.

Griitzner P. & Vogel M. H. (1973) Klinischer Verlauf und histologischer Befund bei progressiver tapeto-chorioidealer Degeneration (Chorioideremie). Klin. Mbl. Augen- heilk. 162, 206-217.

Hyvarinen L., Maumenee A. E., George T. & Weinstein G. W. (1969) Fluorescein angiography of the choriocapillaris. Amer . J . Ophthal. 67, 653-666.

Krill A. E., Newel1 Fr. W. & Chishti M. I. (1968) Fluorescein studies in diseases affecting the retinal pigment epithelium. Amer . J . Ophthal. 66, 470-484.

Kurstjens J. H. (1965) Choroideremia and gyrate atrophy of the choroid and retina. Docum. ophthal. 19, 1.

McCulloch C. & McCulloch R. J. P. (1948) A hereditary and clinical study of cho- roideremia. Trans. amer. Acad. Ophthal. Otolaryng. 52, 160-190.

Rafuse E. V. & McCulloch C. (1968) Choroideremia. A pathological report. Canad. J . Ophthal. 3, 347-352.

Takki K. (1974) Differential diagnosis between the primary total choroidal vascular atrophies. Brit. J . Ophthal. 58, 24-35.

Author’s address: Henrik Forsius, Department of Ophthalmology, University of Oulu, Kajaanintie 50, SF-90220 Oulu 22, Finland.

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