0 Aeolus Press Ophthalmic Paediatrics and Genetics 0167-6784/93/118$ 3.50 (Accepted 4 January 1994)

A variant of central areolar choroidal dystrophy

AMRESH CHOPDAR

Department of Ophthalmology, East Surrey Hospital, Three Arch Road, Redhill, Surrey, UK RHI SRH

ABSTRACT. This article describes the variable ophthalmoscopic features of a macular disorder in five generations of one family. This disease shares similarities with central areolar choroidal dystrophy and other progressive dominant macular dystrophies but demonstrates significant differences that required further consideration. The milder affected individuals had confluent hyperfluorescence around the macular area while the more severe lesions consisted of marked chorioretinal atrophy of the macula. The visual fields revealed a central scotoma. The disorder was transmitted as an autosomal dominant trait.

Key words: macular dystrophy; central areolar choroidal dystrophy; fluorescein angiography; autosomal dominant

INTRODUCTION

Central areolar choroidal dystrophy (CACD) is a hereditary disease affecting the fundus oculi with well-circumscribed chorioretinal atrophic lesions involving the macular region. Nettle- ship’ was the first to record the case of a 60-year- old woman. Later Thompson2 described similar lesions in a 78-year-old patient. S ~ r s b y ~ - ~ , in a report to The Royal Society of Medicine, first observed the familial occurrence of this dis- order. He reported the cases of two brothers suffering from this condition. He later pub- lished a paper entitled ‘Choroidal angiosclero- sis with special reference to its hereditary cha- racter’. He identified three clinical forms. He named one of them: Central Senile Choroidal Atrophy (CSCA) referring to the family stu- dy of the two brothers reported earlier. Since then many authors have also described various types of progressive dominant macular dystro-

phies6-lg, some of which shared similarities to the cases described in this paper. I describe a fa- mily with chorioretinal macular dystrophy in five generations. I observed significant differ- ences from previously described macular dys- trophies that merited further discussion. A thorough search of the literature failed to show any report of an identical disorder suggesting either a new condition or a variant of CACD.

PATIENTS AND METHODS

The author examined the members of a large fa- mily (ES12054109, Fig. 1) in order to detect af- fected individuals. The members from third generations onwards were available to attend the retina clinic for examination. A total of 21 in- dividuals were examined. They were questioned about their visual and medical status. All had a thorough medical examination by the resident of the retina unit. The author personally carried

Ophthalmic Paediatrics and Genetics - 1993, Vol. 14, No. 4, pp. 151-164 0 Aeolus Press Buren (The Netherlands) 1993

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I- T

11

- - = Consanguinity 0 = Normal

0 = Presumed t o be affected f = Proband

9 = AErected 8 = Asthma

= Examined

0 = Deceased 1

E = Epilepsy

Fig. 1. Drawing of the family tree showing the pattern of inheritance of the disease in five generations.

out biomicroscopy and indirect ophthalmosco- py with the +20 and +78 dioptrical lenses. Fun- dus photographs were taken in all cases except in the very young. Colour vision was tested on 1 1 family members. Visual field analysis was possi- ble only in five members due to marked visual loss in the majority of patients. Eight patients had fundus fluorescein angiography and only four were subjected to electrodiagnostic tests.

CASE REPORT

Case 1. GL (111-4) was a 49-year-old female re- gistered blind three years previously for gradual deterioration of vision since age 20 and referred by her general practitioner to the retina clinic for a second opinion and assessment for low visual aids. Her corrected visual acuity was finger counting at

18 inches in each eye. There was no gross abnor- mality of the anterior segment. The testing of visual fields and colour vision were not possible due to low visual acuity. The right fundus showed a large area of clearly defined chorioretinal atrophy in- volving the macula and posterior pole. The lesion extended up to one disc diameter beyond the nasal border of the optic disc margin medially and up to about three disc diameters laterally from its tem- poral border. The upper and lower borders extend- ed just beyond the temporal vessels’ arcade. The edges of the lesion showed some pigment accumu- lation. The very central part including the macular area seemed to produce some degree of posterior staphyloma resembling a macular coloboma. There were several areas of retinal pigment epithelial atrophic spots scattered outside the macula. The temporal periphery showed clumps of pigment deposited along retinal blood vessels. The left mac- ula also revealed a large area of chorioretinal

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Central areolar choroidal dystrophy

atrophy, but without ectatic changes. Retinal pig- ment epithelial changes elsewhere in the fundus were similar to those seen in the right eye. Fundus fluorescein angiography showed marked absence of the choriocapillaris (CC) and atrophy of the reti- nal pigment epithelium (RPE) in the posterior pole. The outline between affected and unaffected fun- dus was sharp and abrupt with almost normal CC and RPE in the unaffected areas. The retinal blood vessels travelled uninterrupted across the lesion. The late phase of fluorescein angiography showed no evidence of leakage (Fig. 2). The dark adapted eye electrooculogram (EOG) showed 103% light rise in the right and 124% in the left eye. This is se- verely subnormal as compared to the normal values in our laboratory. The pattern visual evoked re- sponse (VER) was abolished in the right eye. The left eye detected a delayed pattern VER (165 msec) and rose only to 1 pV. The flash electroretinogram (ERG)s and VERs were also extremely subnormal and there was a particularly poor response to flicker stimuli.

Case 2. DS (111-6). This 56-year-old-male first be- came aware of deterioration of vision when he was 25 years old. He became registered blind at the age of 34 years. The visual acuity was finger counting in each eye at 18 inches. The maculae in both fundi showed an oval circumscribed area of chorioretinal atrophy. Radially arranged larger choroidal vessels were observed through this de- fect. The choroid surrounding the optic disc was also atrophic. The fluorescein angiogram showed a well-defined boundary between the clinically af- fected and unaffected fundus. There was also con- siderable atrophy of both CC and RPE in the macular area and around the optic discs. There re- mained a narrow strip of RPE between the disc and macula (Fig. 3).

Case 3. AL (IV-10). This 27-year-old male had no visual symptoms. His visual acuities were 6/6 in the right eye and 6/12 in the left, improving to 616 by means of a small myopic correction. The colour vi- sion was normal. The Humphrey visual field analy- sis showed a relative central scotoma with reduced threshold. Ophthalmoscopy showed a darker cen- tral fovea surrounded by a ring of diffuse RPE changes. The fluorescein angiogram revealed a cen-

tral hypofluorescence surrounded by a wider area of punctate hyperfluorescence as seen in many forms of hereditary progressive macular dys- trophies. His EOG light rise was 213% in the right and 215% in the left eye. The pattern ERG and VER were minimally subnormal. Flash global ERGS and VERs were of borderline calibre, but those from macular stimulation with red flicker measured 30 Hz (Fig. 4).

Case 4. JH (IV-13). This 24-year-old male myope had noticed gradual deterioration of vision over two years in both eyes. His best-corrected visual acuity was 6/12 in the right and 6/18 in the left eye. He was colour blind and could not read any of the Ishihara plates except the control plate. The fundus appearance was similar to AL (case 3) (Fig. 5).

OBSERVATIONS

The author examined 21 members of the fami- ly in three generations and obtained history of two earlier generations, thus extending the study to five generations. Out of 21 cases exa- mined 15 (71.42%) were found to display the clinical evidence of the disease. Another seven possibly affected patients were identified from the previous two generations, bringing the total to 22 individuals out of 36 (61%) (Table 1). An interesting aspect of the disease is the extent and variation of chorioretinal atrophy of the macular area amongst affected individuals.

Consanguinity

A definite consanguinity was detected in the first generation, where the grandparents of the proband were first cousins. The grand- mother reputedly had very poor vision start- ing at the age of 30 years and was blind in her older years. All of their six children, including the proband’s mother, suffered from the same blindness. The same ocular disorder has con-

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Fig. 2. A. Black-and-white photograph of the right fundus showing a large area of chorioretinal atrophy involv- ing the entire posterior pole. Note the sharp outline a t the macular area with ectatic change resembling a macu- lar coloboma and pigmentation surrounding the atrophic lesion. B. Black-and-white photograph of the left fundus showing chorioretinal atrophy of the central area of the reti- na. Some of the changes extend beyond the posterior pole. The optic disc and the retinal blood vessels remain unaffected. C. Fluorescein angiogram of the right eye during the venous phase shows a few remaining choroidal vessels. The edge of the affected area, particularly the upper part, already shows some staining. The retinal blood vessels are within normal range. The choriocapillaris loss extends beyond the temporal vessels arcade and also covers part of the nasal retina. D. Fluorescein angiogram during the late venous phase of the left eye shows staining of the underlying tissues through the atrophic RPE. Only a few choroidal vessels remain. The extent of the lesion is similar to that of the right eye.

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Fig. 3 . A. Fundus photograph of the right eye showing typical round area of chorioretinal atrophy of the macu- lar area and the optic disc. Note the remains of larger sized choroidal vessels radiating in a fan-shaped manner. A small strip of normal looking retina remains between the disc and the macula. B. Black-and-white fundus photograph of the left fundus showing a typical round area of chorioretinal atrophy of the macular area identical to the right fundus. C. Late phase of the fundus fluorescein angiogram of the right eye showing marked loss of CC and RPE from the macular area. Some staining is seen at the edges of ‘the lesion and around the optic disc. A narrow strip of normal fluorescence separates the macular area from the margin of the optic disc. D. The late phase of the fluorescein angiogram of the left eye showing the sharp outline between the severely affected macular area. Further punctate hyperfluorescence is seen extending outwards. The edges of the most severely affected area show some staining around the macula and optic disc. The choroidal vessels are well ex- posed within the atrophic area.

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Fig. 4. A. Black-and-white photograph of the right fundus of a 27-year-old man showing dark-red reflex at the fovea, surrounded by mottled retinal pigment epithelial degeneration. B. Black-and-white photograph of the left fundus showing changes similar to those of the right eye. C. Early transit phase of the fluorescein angiogram of the right eye showing hypofluorescence at the centre of the fovea surrounded by confluent punctate hyperfluorescence. D. The late transit phase of the fluorescein angiogram of the left eye showing the changes limited to the macular area only.

tinued to beset the family ever since, affecting individuals in every generation. No case has yet been identified in the fifth generation.

Age of onset

The visual symptoms usually began in the third decade of life. The youngest age at which symp-

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Fig. 5 . A. Black-and-white photograph of the right eye of a 24-year-old man showing very early retinal pigment epithelial changes at the macula and a slightly red contrasting appearance of the fovea. B. The black-and-white photograph of the left eye shows similar changes as in the right eye. C . Fluorescein angiogram of the right eye during the late phase shows confluent hyperfluorescence of the macu- la due to retinal pigment epithelial degeneration. D. Fluorescein angiogram of the left eye during the late phase showing similar changes.

toms first appeared was 20 and the latest was 30 years. The youngest member examined in this series was 23 months and the oldest 69 years of age.

Sex

In five generations I have been able to trace 36 members with equal numbers in either sex. Out of 18 females 13 (72.22%) showed the evidence of the disease, while only nine out of 18 (50%) males suffered from the same illness.

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TABLE 1. The detailed examination findings of all cases examined ~

No. Name POT Sex Age OA RV LV CV Fields Fundus findings

1 MG 111-1 F 69 27 CF CF CB NT Chorioretinal atrophy of posterior pole includ- ing the disc and macula. There was total loss of CC and RPE in the affected area

2 DR 111-2 F 62 28 CF CF CB NT Mild degree of RPE changes in both maculae 3 MC 111-3 F 55 30 6/24 6/9 CD CS Mild degree of RPE changes in both

4 GL 111-4 F 49 30 CF CF NT NT Both fundi showed clearly defined chorioreti- Chorioretinal atrophy of posterior pole

nal atrophy of the posterior pole including the disc and macula with total loss of CC and RPE. Some pigment degeneration was also seen in the peripheral retina

chorioretinal atrophy

in the macular region

5 DS 111-6 M 56 30 CF CF NT CS Both maculae showed typical oval-shaped

6 ARH 111-7 F 53 29 HM HM NT NT A large circular area of chorioretinal atrophy

7 JM IV-3 F 41 NS 6/6 6/6 NAD NT NAD 8 NG IV-4 M 37 NS 6/6 6/6 CD NT RPE degeneration in both maculae. Some

hyperpigmentation of the fovea. Resembles a bull’s eye macula

9 SC IV-5 F 36 20 6/12 6/12 CD CS Mottled RPE at both maculae 10 GL IV-7 M 42 NS 6/6 6/6 NT NT Circular area of chorioretinal atrophy in the

11 CA IV-8 F 30 20 6/18 6/12 CB CS Bull’s eye macula 12 AL IV-10 M 27 NS 6/6 6/6 NAD CS Bull’s eye macula 13 SL IV-11 M 25 NS 6/6 6/6 NAD NT NAD 14 JS IV-12 F 24 21 6/12 6/12 CB NT Bothmaculae showedoval-shaped RPE

15 JH IV-13 M 24 20 6/12 6/12 CD NT Bothmaculae showed oval-shaped RPE

macular region

changes

changes

CB = Colour blind, CD = Colour defect, CF = Counting fingers, CS = Central scotoma, HM = Hand move- ment, LV = Left visual acuity, NA = Not available, NAD = No abnormality detected, NT = Not tested, POT = Position on family tree, RV = Right visual acuity.

Frequency of transmission Visual acuity

The frequency of transmission is almost 100% affecting the second and the third, but only 70% in the fourth generation. So far we have seen the disease appearing in every generation except the fifth. Thus there seems to be a dominant trans- mission over three generations.

Severely affected eyes always showed marked loss of vision. However, mild affection did not guarantee good vision. There was no predilec- tion towards any particular type of refractive error.

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TABLE 1. Continued

FFA findings Electrophysiology Comments

Sharp demarcation between the diseased and healthy retina. Loss of CC and RPE was con- firmed

NT

Punctate hyperfluorescence

Both eyes showed total loss of CC and RPE of the central fundus and minimal changes in the periphery. There was a sharp outline between the central and peripheral retina

Total loss of CC and RPE in the macular area

Marked loss of CC and RPE from the affected area

NT

Masking of fluorescence at the central fovea contrasted by punctate hyperfluorescence from the surrounding macula showed a typical bull’s eye pattern

Punctate hyperfluorescence of the macular area

NT

RPE changes extending up to the temporal vessels arcade above and below, and up to the temporal border of the optic disc, showing a typical bull’s eye macula

Central hypofluorescence and surrounding hyperfluorescence showed a typical bull’s eye macula

NT

Not tested None

NT

NT

N/A

Subnormal EOGs in both eyes. VERs were abolished in the right but delayed in the left eye

See case report 1 for more detail

NT

NT

NT

NT

NT

NT

Subnormal EOGs and full field ERGs. VEPs were slightly subnor- mal and delayed

Subnormal EOGs, pattern ERGs and VERs. Flash ERGs and VERs were borderline

Subnormal EOGs light rise. Pattern flash ERGs and VERs were bor- derline

NT

NT

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Colour vision

I have been unable to carry out sophisticated colour vision testing other than using Ishihara plates. Out of 11 members tested, three were normal, four showed mild protan deutan ano- malies, and four were unable to recognise any of the colour plates.

maculae. The chorioretinal scar was extensive and the right fundus showed a posterior staphy- loma that resembled a macular coloboma. Only one person (111-6) showed lesions typical of CACD. The other two showed a variable degree of advanced chorioretinal atrophy of the macu- lar area.

Optic disc Visual fields

Computerised field analysis was carried out in only five cases using the Humphrey automated field analyser. This showed a variable depth of central scotoma in all cases. The field analysis was the most sensitive test in detecting abnor- malities even in members with normal vision.

Fundus findings

A wide range of ophthalmoscopic changes was observed in various members of this family af- fecting the macular area.

Macula

The macular changes can be divided into three main categories: mild, moderate, and severe.

Mild (IV-3, 5 & 11). Only three members out of 15 showed very mild involvement. The ophthalmoscopic examination showed a slightly altered shimmering foveal reflex. There was no easily detectable gross RPE degeneration.

Moderate (111-2, 3, IV-4, 7, 8, 10, 12 & 13). Eight members showed a moderate degree of in- volvement of the macular area. The macula showed a definite oval area of punctate RPE change surrounding a darker-red looking fovea.

Severe (111-1, 4, 6 & 7). Only four members had the severe form of the disease. The proposi- ta showed the most severe involvement of her

The colour, size and blood vessels on the discs were within normal range. Even the most severe case did not show evidence of optic atrophy.

Blood vessels

There was no gross abnormality of retinal blood vessels in any of the patients examined irrespec- tive of the severity of the disease.

Retinal periphery

Only the proposita showed some RPE atrophy and pigment change in the peripheral retina. All the rest had no ophthalmoscopic abnormalities of the peripheral retina.

Fundus fluorescein angiography findings

Mild. In cases of milder involvement the macula showed only punctate hyperfluorescence with- out any evidence of leak. The rest of the retina appeared normal.

Moderate. In cases of moderate degeneration confluent punctuate hyperfluorescence sur- rounded the hypofluorescent fovea. This looked similar to other types of foveal dystrophies. There was no evidence of late leakage. The rest of the peripheral retina was normal (Figs. 4, 5).

Severe. In cases of severe degeneration, the transit showed a distinct demarcation between

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Central areolar choroidal dystrophy

the affected and unaffected areas. The affected area showed marked atrophy of RPE and loss of CC, exposing the underlying sclera. In some cases the degenerative lesion extended to include the peripapillary area and the nearby nasal reti- na. In some cases the central fundal area also showed RPE changes (Figs. 2, 3).

Electrophysiology

Unfortunately most of the electrophysiologic data are drawn from the report filed in the case notes. The electrophysiologic tests were carried out only in four cases: one with severe, two moderate and one mild. The severely affected in- dividual showed subnormal EOG light rise (light peak and dark trough). The pattern VERs were abolished in the most severely affected eye. However, the less severely affected eye showed a small rise of 1 pV followed by a markedly delayed response. The mildly affected eye from IV-10 showed a normal EOG. The flash ERGS and VERs were of borderline amplitudes.

DISCUSSION

Terminology. Several types of choroidal sclero- sis have been described since the 1880s. Sorsby (1935, 1953)3-5 classified choroidal sclerosis into three main types: central senile areolar chofoidal sclerosis (CSACS), massive peripapil- lary choroidal sclerosis, and generalised choroi- dal sclerosis.

Some of the cases described in this paper closely resemble patients with CSACS. This en- tity was first described by Nettleship’ in 1884 using the same name. Thompson2 in 1905 reported a similar case and called it central senile choroiditis. After an intensive study of the sub- ject Sorsby5 renamed the same condition as Central areolar choroidal sclerosis (CACS).

Later Sandvig13>14 described the same condition and changed the name to Central areolar choroi- dal atrophy, presumably due to the atrophic changes of the retina and choroid. Carr15 first linked together the hereditary and atrophic changes and coined the term Central areolar choroidal dystrophy (CACD).

The wide range of intrafamilial ophthalmo- scopic changes observed in this pedigree is in- teresting. DS (111-6) was the only member to show fundus appearance typical of CACD. The proband on the other hand showed the most ex- tensive degenerative changes affecting the macu- lae and posterior pole associated with the ectatic changes similar to those seen in the third stage of a newly dominant progressive foveal dystrophy described by Frank et al. l 2 in 1974, now popu- larly known as ‘North Carolina macular dystro- phy’. The other members with milder and mo- derate form showed widespread RPE changes as those seen in various types of dominant progres- sive macular dystrophy reported by several author^^-'^. In particular Hoyng et a1.I6 have reported the perifoveal hyperfluorescence seen in early cases of CACD. Central pigmentary sheen dystrophyI9 showing yellowish sheen of the macular area is associated with scattered yellowish dots and normal periphery and may be confused with the disease presented in this article. However, the significant difference was the absence of yellowish dots in the macular area in my cases. Deutman6 has also reported similar dominant macular dystrophies that he collec- tively calls ‘dominant progressive foveal dys- trophy’. The mild and moderately affected individuals from this series showed several fea- tures common to the progressive foveal dys- trophy.

The case described by Nettleship’ mentioned that the father of the patient was blind but no de- tail was available. Sorsby describing the same

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condition in two brothers’ first in 19353 and later in 19394 and 19535 with extensive family study over many generations has provided con- vincing arguments in favour of autosomal dominant inheritance. Sandvigl31l4, C a d 5 , Hoyng et a1.16, Noble18, Weber et all have confirmed the autosomal inheritance theory. This same pattern has been reflected in the present series. The disease appears to affect the central part of the retina predominantly.

The present study provides a profile for this disease. It affects more females than males. The disease progressed mainly in two different forms. In both instances the visual symptoms began during the third decade. In one group the vision deteriorated rapidly to registrable blind- ness within ten years. In the other group the wor- sening of vision was gradual and remained modest. The fundus fluorescein angiographic findings reflected the variation showing marked loss of CC and gross atrophy of RPE in the first group, and minimal changes in the second. Milder changes in the fundi were not a guarantee for good vision. The colour vision and the visual fields showed that the disease caused maximum damage to the macular area. The electrophysio- logical tests were normal in early stages. Whether these intrafamilial variations were due to difference in gene expressivity is unknown.

Histopathologic study

Ashton21 and Ferry and others22 provided histo- logic studies on eyes enucleated from patients with CACD. Ashton obtained the eyes from a female patient who was originally described by Sorsby and died of coronary thrombosis. He in- jected one eye with Neoprene and found com- plete absence of the choriocapillaris from the macular area. The other eye was subjected to routine histopathologic study. This second eye

showed a well demarcated zone of choroidal atrophy extending to the disc margin. Within this area the choriocapillaris was almost com- pletely absent except for a few remaining large parent vessels. There was loss of outer retinal layers including rods, cones, and outer molecu- lar layer. Ferry’s22 specimen was also from a fe- male patient whose eye had been enucleated for thrombotic glaucoma. He showed a discrete, sharply outlined zone of atrophy in the macular area. The outer layers of the retina were marked- ly atrophic. The photoreceptors and retinal pig- ment epithelium were completely absent in this region. There was no evidence of glial repair. The external limiting membrane was adherent to Bruch’s membrane. The choroid underlying the macular area was thinner than normal. In most affected areas the choriocapillaris could not be identified. The choriocapillaris was remarkably normal in the unaffected areas. The posterior ciliary arteries were of normal calibre and showed no sign of occlusion.

There are not many systemic diseases associat- ed with CACD. M a n ~ o u r ~ ~ was the first to report association of the disease with pseu- doachondroplastic spondyloepiphyseal dyspla- sia in a family he reported in 1987. In this present series I have discovered two members suffering from epilepsy and one from asthma, all in the fifth generation where the eye signs are yet to be observed. Weber et noted familial hyperlipidaemia associated with CACD and also found crystalline lipid deposits in the fundus of such patients. No such correlation was found in this present series.

CONCLUSION

The ophthalmoscopic observations of the cases presented in this series show marked intrafamili- a1 variation in the expressivity of the disease that

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may be due to a gene. The choriocapillaris and RPE show marked degeneration affecting the macular area. The disease tends to progress in two different forms: a rapid one leading to marked visual loss, and another to insidious and mild progression. In both types the visual sym- ptoms begin around age twenty. There are certain features similar to CACD and pseudo in- flammatory choroidal dystrophy. This disease should also be differentiated from a number of

other dominantly inherited progressive macular dystrophies such as ring maculopathy and butterfly macular dystrophy9. The extensive chorioretinal atrophies described here are not dissimilar to those seen in the advanced stage of North Carolina macular d y ~ t r o p h y ’ ~ > ~ ~ . The milder type of fundus changes may need to be excluded from fenestrated sheen macular dystrophyI7 and central pigmentary sheen dys- trophyl9.

REFERENCES

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