Central Areolar Choroidal Dystrophy

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Article initiated by:

Margarida L Baptista, Priya Rasipuram Chandrasekaran FRCS (Glasgow)

All contributors:

Maria Picoto Passarinho, MD, Koushik Tripathy, MD (AIIMS), Margarida L Baptista, Priya Rasipuram Chandrasekaran FRCS (Glasgow), Neelakshi Bhagat, MD, FACS

Assigned editor:

Neelakshi Bhagat, MD, FACS

Review:

Assigned status Up to Date

 by Neelakshi Bhagat, MD, FACS on December 16, 2024.

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Introduction

Central Areolar Choroidal Dystrophy (CACD) is a rare hereditary dystrophy of the macular area, with fewer than 50,000 persons living with this disorder. It is a well circumscribed, bilateral and symmetrical lesion with loss of retinal and choroidal tissue in the macular area. The retinal pigment epithelium (RPE), choriocapillaris and neurosensory retina are absent in the area of dystrophy exposing the atrophic choroid with large choroidal vessels coursing over the bare sclera. Macular changes usually begin between 20 and 40 years of age and progress gradually leading to severe vision loss between the fourth and seventh decade. The optic nerve, retinal vessels and peripheral retina are unaffected.

CACD was called by various names in the past as central senile areolar choroidal dystrophy, choroidal angio-sclerosis, central areolar choroidal sclerosis, familial central areolar choroidal atrophy and central areolar choroidal atrophy. The term CACD was coined by Dr. Carr and then used by Ferry and Noble.

Genetic association

Central areolar choroidal dystrophy is an inherited monogenetic disorder characterized by progressive choriocapillaris atrophy and retinal degeneration that usually presents in the 3rd decade. It is a rare disease with an incidence of 1/100,000 and is associated with mutations in the PRPH2 gene. It is inherited in an autosomal dominant pattern. Autosomal recessive and sporadic patterns have also been described. Autosomal dominant CACD is genetically heterogenous with mutations in the Peripherin/RDS gene (PRPH2 or peripherin-2) is the most common one.

Mutations of PRPH2 in autosomal dominant CACD include – p.Arg142Trp, p.Arg172Trp, p.Arg172Gln, p.Arg195Leu and p.Leu307fsX83. Disease caused by p.Arg142Trp occurred in the middle of the fifth decade while that caused by p.Arg172Trp presented before 40 years of age. P.Arg142Trp caused disease which was confined to macula while that caused by p.ARG172Trp caused pan retinal cone or cone-rod dystrophy. Mutations in p.Arg142Trp has been shown to be associated with inherited drusen in certain families. Hughes et al and others have localized the gene causing CACD on chromosome 17p13 in specific group of patients.

Stages of CACD

Stage 1 – Minimal focal parafoveal pigmentary RPE changes which are observed ophthalmoscopically.

Stage 2 – Round to oval area of atrophic hypopigmented area which is poorly demarcated.

Stage 3 – One or more patches of well demarcated area of RPE atrophy which are present outside the central fovea and within the area of mild hypopigmentation.

Stage 4 – Atrophic area which is well-defined and involves the fovea. This causes profound loss of vision.

Histopathological features

Histopathological features of the macular area show a discrete and well demarcated lesion of about two to four disc diameters in area. Retinal pigment epithelium, choriocapillaris and photoreceptors are absent in the area of dystrophy with greater reduction in the number of photoreceptor nuclei in the outer nuclear layer. The external limiting membrane is in direct apposition with the Bruch’s membrane. The choroid in the macular area is thin with obliteration of choriocapillaris. Choriocapillaris nasal and temporal to the area of lesion can be well preserved. There is no fibrosis or sclerosis of the large choroidal vessels traversing the area of involvement. Posterior ciliary artery supplying the involved area of choroid is normal.

Clinical diagnosis

Patients can present with bilateral central scotoma or bilateral loss of vision. If patients do not complain of vision loss, then macular lesion may just be observed on a routine fundus examination. The macular lesion can vary from an area of hypopigmentation to complete atrophy exposing the underlying large choroidal vessels and sclera. Color vision may be decreased. It is a bilateral lesion and findings are present in both eyes symmetrically in the macular area. Drusen may be present.

Investigations

Visual fields 

Reveals, with disease progression, a central scotoma corresponding to the atrophic area. The peripheral visual field is usually normal.

Fundus autofluorescence

Stage 1 – Increased fundus autofluorescence corresponding to the area of hypopigmentation.

Stage 2 – Speckled areas of increased and decreased autofluorescence corresponding to the lesion. Increased autofluorescence predominates initially but with time and as RPE atrophy progresses decreased autofluorescence becomes more prominent.

Stage 3 – Decreased to absent fundus autofluorescence in the areas of chorio-retinal atrophy.

Stage 4 – Absent fundus autofluorescence corresponding to the area of chorio-retinal atrophy involving the fovea bordered by a small residual band of increased autofluorescence.

Fundus fluorescein angiography 

Stage 1 - Fluorescein angiography shows hyperfluorescence in the parafoveal area.

Stage 2 - Fluorescein angiography shows speckled hyperfluorescence corresponding to partial RPE atrophy.

Stage 3 - Fluorescein angiography clearly outlines the remaining choroidal vessels in the area of chorio-retinal atrophy. At the later phase, discrete leakage of the dye is seen at the edge of the lesion corresponding to the area of incomplete atrophy of choriocapillaris.

Stage 4 – Fluorescein angiography shows a well-defined area of chorio-retinal atrophy with enhanced visibility of the underlying residual choroidal vessels.

Indocyanine angiography

Two distinct phenotypes were observed.

Type 1 – Hyperfluorescent or normofluorescent in the early phase and normofluorescent in the late phase.

Type 2 – Hypofluorescent in the early phase and late phase showing normofluorescence with pinpoint hyperfluorescence corresponding to the incomplete closure of choriocapillaris.

Optical coherence tomography

Stage 1 – Subtle changes with focal thickening and irregular reflectivity of photoreceptor outer segments and RPE (POS - RPE). Changes are predominantly in fundus autofluorescence in this stage.

Stage 2 – Increase in distance between inner photoreceptor segments and POS-RPE band along with thickening of RPE- Bruch’s membrane.

Stage 3 and stage 4 – Loss of outer retina upto the external limiting membrane and thinning of RPE-Bruch’s membrane complex in the atrophic area. The atrophic area was bordered by disrupted and swollen outer retina with loss of reflectivity and retinal elevation. There were rosettes and plaque-like structures beneath the retinal elevation but no drusen-like deposits in the sub pigment epithelial space as would be seen in geographic atrophy.

Multifocal electroretinogram

Though reduction of both scotopic and photopic responses have been reported in the literature, majority of the patients showed reduction in photopic response with full field electroretinogram. The highlighting feature was the reduction in cone b-wave amplitude and prolonged b-wave implicit time with full field ERG. Pathology has been shown to extend beyond the central atrophic area as in central serous retinopathy. Full field ERG gives a summated response of the entire retina and hence can give normal results in cases with CACD wherein only a small central area of the retina is involved.

Multifocal electroretinogram (MERG) has been promising in detecting small areas of retinal (macular) dysfunction through simultaneous recording of multiple separate electroretinograms covering a small but specific area. K1 in MERG showed significant reduction in amplitude from the central and paracentral area. The peak time was also found to be delayed. K1 was decreased outside the atrophic area where no abnormality was detected by fundus examination, and this might indicate the progression of the disease in the future. The amplitude of K2 was depressed along with delay in the peak time both in the central and paracentral areas and outside the atrophic area.

The problem of fixation can be monitored by a camera or a refractor for monitoring fixation. The stray light causing reflection from the atrophic area has also shown to influence the response with MERG.

Differential Diagnosis

• Age-related macular degeneration (AMD) with geographic atrophy:

CACD may be confused with atrophic AMD mainly due to the overlap in age of onset (in cases of late-onset CACD), the variable expression of the diseases and similar morphologic characteristics (hyperpigmentation, abnormal FAF and atrophy of the outer retinal layers in OCT in advanced stages), and the possible association with drusen-like lesions, chorioretinal atrophy and/or RPE changes.

Features which may help to distinguish CACD from AMD include an earlier onset in the majority of cases, a positive family history (with autosomal-dominant inheritance pattern), usually the absence of drusen on clinical examination and OCT, and the genetic analysis results (detection of mutation in PRPH2 gene). Moreover, the alterations in AMD are usually less regularly shaped, less well demarcated, and often extends beyond the macular area, in contrast with CACD. The rosette-like structures observed in CACD, mainly located at the border of the atrophic area, are not usually observed in AMD, and appear to be a morphologic feature of CACD.

• Central areolar dystrophy of RPE;
• Myopic degeneration;
• Stargardt disease;
• Cone dystrophy;
• North Carolina macular dystrophy;
• Best’s disease;
• Pattern dystrophy.

Some cases of CACD may reveal a bull’s eye appearance of pigment epithelial atrophy, which is also an important feature for the differential diagnosis with other causes of bull’s eye maculopathy. These include chloroquine and hydroxychloroquine retinopathy, Benign concentric annular macular dystrophy and advanced Stargardt disease.

Treatment

There is no treatment due to the hereditary nature of the disease. Low vision rehabilitation will however be useful in affected individuals. The disease affects only the central vision sparing the peripheral vision in these patients. Gene therapy appears to be promising.

Genetic Counselling

As CACD is genetically transmitted, predominantly as autosomal dominant pattern of inheritance, proper genetic and vocational counselling should be given to the affected individuals and their family. Initial stages of the disease can mimick any of the heredo-macular degenerations or dystrophy making the diagnosis challenging, however, a proper history and examination of the other family members will confirm the diagnosis.