Central Areolar Choroidal Dystrophy

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Disease Entity

Central Areolar Choroidal Dystrophy is recognized by the International Classification of Diseases (ICD) nomenclature, with the following code:

ICD-10: H31.2

(synonyms: Areolar atrophy of the macula; Choroidal areolar choroidal sclerosis; Choroidal macular dystrophy; Choroidal angio-sclerosis) [IMAGE]

Disease

Central Areolar Choroidal Dystrophy (CACD) is a rare inherited retinal disorder (mostly in an autosomal-dominant trait) that primarily affects the centre of the macula and is characterized by a well-circumscribed round or oval area of atrophy of retinal pigment epithelium (RPE) and choriocapillaris in end-stage disease. It leads to progressive decrease/absence of macular photoreceptors, ultimately resulting in a severe decline in central visual acuity and visual disability. It usually presents between the ages of 30-60 and may be classified in four clinical stages (see Diagnosis section).[1][2][3][4]

CACD was initially described and named Central Senile Areolar Choroidal Atrophy based on the ophthalmoscopic appearance (Nettleship, 1884). Decades later, Sorsby (1939) renamed the condition to Choroidal Angio-Sclerosis and revealed the hereditary nature of the disease. Later studies described the histological appearance of Central Areolar Choroidal Dystrophy without features of sclerosis (Ferry, 1972). [5][6]

Epidemiology

The estimated prevalence of CACD is 1-9 per 100 000 individuals (from orphanet.org). There is no predilection for gender.[1][7]

Genetics

CACD is a genetically heterogeneous disorder, but in the majority of cases it is inherited in an autosomal-dominant pattern. Autosomal-recessive inheritance, as well as some sporadic cases, have been reported.[1]

Autosomal dominant CACD is most commonly caused by mutations in the peripherin/RDS (peripherin-2 or PRPH2) gene, with complete or almost complete penetrance. Five different mutations in the PRPH2 gene have been identified in autosomal dominant (AD) CACD: p.Arg142Trp, p.Arg172Trp, p.Arg172Gln, p.Arg195Leu, and p.Leu307fsX83. [1][8][9][10][11][12][13]

The main CACD subtypes have been described as CACD1 and CACD2, which involve variations in several causative genes:

  • CACD1 (#215500 OMIM, AD transmission) is caused by heterozygous mutation in the GUCY2D gene on chromosome 17p13.[14][15]
  • CACD2 (#613105 OMIM, AD transmission) is caused by is caused by heterozygous mutation in the PRPH2 gene on chromosome 6p21.
  • CACD3 subtype (%613144 OMIM), also transmitted in an AD pattern, has been described in a large consanguineous Tunisian family, whose individuals demonstrated similar clinical features to CACD, as well as some cases with overlying drusen. The responsible gene(s) have not yet been mapped [16].


Additionally, some studies have reported that CACD macular dystrophy may be associated with dominant drusen in individuals carrying the Arg142Trp mutation in the peripherin/RDS gene.[7] Since they are allelic disorders of the peripherin/RDS gene, it was suggested that drusen and CACD are variable expressions of the same disease.

Mutations in the peripherin/RDS gene have also been linked with retinitis pigmentosa, progressive macular degeneration, cone-rod dystrophy, and pattern dystrophy.[6][12]

Pathophysiology and histology

Histopathologic studies made in the past showed a consistent absence of photoreceptors, RPE cells, and choriocapillaris in the affected macular area of atrophy, and these findings were in line with the clinical features of CACD. The rest of the retina and choroid is normal outside of the atrophic zone.[3][4] However these studies were carried out on non-genotyped CACD patients.

Further analysis and clinical observations showed that this disease appears to be a primary dystrophy of the RPE, with secondary involvement of the choriocapillaris. More recent reports have suggested that the abnormal peripherin/RDS protein structure results in a dysmorphic cone (and possibly rod) outer-segment structure, which impedes photoreceptor function and consequently interactions between photoreceptor outer-segments and the RPE. These alterations would increase the levels of toxic byproducts and lipofuscin, with subsequent lesion and death of photoreceptors and RPE cells. Eventually, when atrophy of the RPE and choriocapillaris occurs, the typical “punched out” CACD lesion arises.[1][17]

Diagnosis

The clinical diagnosis of CACD is based on clinical findings, ophthalmological examination, fluorescein angiography, autofluorescence, optical coherence tomography and electroretinography. It may be confirmed molecularly by the detection of pathogenic variants of the causative genes.[1][2][5][8]

The hallmark feature of the disorder is a well-defined and bilaterally symmetric central region of atrophy involving both the RPE and choriocapillaris.

Symptoms

The main initial symptom of CACD is decreased central visual acuity, which generally deteriorates in the 4-5th decade of life. However, the mean age at onset of visual loss as well as the degree of photoreceptor dysfunction on full-field ERG is influenced by the peripherin/RDS mutation.[1] The onset of visual symptoms in CACD caused by the mutations p.Arg172Trp or p.Arg195Leu is usually before the age of 40, in contrast with the p.Arg142Trp-related CACD in which these symptoms usually only become evident in the middle of the 5th decade. It also shows variable expressivity amongst family members[18].

Other less common visual disturbances include central scotoma (corresponding to the area of RPE atrophy), micropsia, metamorphopsia, colour vision abnormalities (protandeutan moderate defect) and nyctalopia[1].

Exam Findings

Fundus examination early in the course of the disease reveals a non-specific granular mottling of the RPE in the fovea, which may be hard to notice/diagnose when the patient is young and/or asymptomatic. A sharply demarcated area of RPE atrophy with gradually develop, along with underlying loss of choriocapillaris which progressively leaves intermediate and large choroidal vessels visible. As the disease progresses, the macular area of atrophy slowly expands in a centrifugal manner and may become irregular in shape, but almost never involve the peripapillary region or expand beyond the vascular arcades. The optic disc, retinal vessels, and RPE outside the macular area are usually normal in appearance. [19][20][21]

The macular lesions seen in some cases of CACD (mostly in end-stage disease) may resemble a “bull’s eye” pattern, which obligates differential diagnosis with other causes of bull’s eye maculopathy.[1][6]

Four clinical stages of the disease have been described based only on ophthalmoscopy, that may be documented with colour fundus photography:[1][2]

  • Stage I: subtle focal parafoveal pigmentary RPE changes.
  • Stage II: oval-to-round, mildly atrophic hypopigmented area of 1.5 to several disc diameters.
  • Stage III: one or more patches of well-demarcated RPE and choriocapillaris atrophy outside the fovea.
  • Stage IV: the chorioretinal atrophic area affects the fovea, with profound decrease in vision acuity.


Patients with CACD usually do not feature flecks or drusen, but in some cases this condition is associated with drusen-like deposits[1][6][7], making the differential diagnosis with other retinal diseases more difficult.

Systemic findings: to date, there are no reports of associated systemic disease or features.

Laboratory Tests

Gene analysis is helpful for diagnosis confirmation and identifcation of the pathogenic allelic variant. In CACD, gene sequencing of PRPH2 and GUCY2D genes may allow identification of pathogenic variants, which confirms the clinical diagnosis and is an indication for family studies. The absence of variations in the investigated genomic regions does not exclude the diagnosis and may be due to sequence variations in gene regions not investigated by the test or variations in other genes not investigated by the test.[22]

Fluorescein Angiography

Early in the course of CACD, Fluorescein Angiography (FA) revels discrete abnormalities such as parafoveal hyperfluorescent changes due to increased transmission of the normal underlying choriocapillaris through RPE atrophy, which is called window effect. In later stages (III and IV), FA outlines the remaining choroidal vessels (intermediate and large) in the chorioretinal atrophy area. The margins of the lesion show hyperfluorescence in later phases of FA because of leakage from choriocapillaris at the edges.

FA is a sensitive imaging exam for CACD diagnosis, mainly in its earlier stages, where it may identify minor areas of RPE atrophy that may not be readily seen on ophthalmoscopy or fundus autofluorescence.[1][2][19] Furthermore, as FA demonstrates varying degrees of choriocapillaris loss within RPE area, it correlates well with the degree of visual function loss.[21]

Fundus Autofluorescence

Fundus Autofluorescence (FAF) is used to detect RPE atrophy and lipofuscin increase, which appear as dark macular regions and as bright macular spots respectively. In early stages of CACD, FAF shows a speckled fundus autofluorescence pattern that is sharply demarcated from the surrounding retina, regularly oval shaped and confined to the parafoveal area. As diseases progresses, the total area of FAF abnormalities, as well as the area of absent FAF (corresponding to RPE atrophy) gradually increase, becoming more evident in stages III and IV.[1][6][8][23]

FAF has been shown to be a useful tool for the follow-up of CACD patients. Subclinical lesions may be identified, and enlargement of the abnormalities and progression of chorioretinal atrophy can be closely monitored. Within 11 months of follow-up, Boon et al noted that substantial changes within the same CACD stage were observed on FAF imaging.[1]

Optical Coherence Tomography

Optical Coherence Tomography (OCT) is becoming an important tool in the investigation, diagnosis and differential diagnosis of CACD, specially with Age-Related Macular Degeneration.[8]

OCT findings in the initial stages I and II include focal areas of photoreceptors and RPE abnormalities, accumulation of hyperreflective material under the fovea (clumps of photoreceptor outer segments), disruption of the interface of inner and outer segments and loss of the external limiting membrane. In later stages, OCT reveals the absence of the junction of the inner and outer segments and atrophy of all outer retinal layers. Moreover, sharp disruptions of the RPE and rosette-like structures (outer retinal tubulations) may be seen adjacent to areas of atrophy, mostly in stage IV.[8][21]

Electroretinography

Electroretinography (ERG) may also be a valuable tool in the diagnostic chain of CACD. Bilaterally abnormal pattern visual evoked potentials and pattern ERGs were one of the first reported electrophysiologic findings in CACD patients and were shown to be sensitive electrophysiologic tests of macular dysfunction before symptom onset.[24][25]

Later on, multifocal ERG recordings (which show topographic information on retinal function) show significant macular dysfunction that extends beyond the atrophic areas seen clinically[26][27] .

The full-field ERG is usually normal but may show generalized cone or cone-rod dysfunction in more advanced cases CACD.[1][25]

Moreover, the degree of photoreceptor dysfunction on full-field ERG is strongly influenced by the type of peripherin/RDS mutation. The CACD phenotype associated with the p.Arg142Trp mutation seems to be confined to the macula both ophthalmoscopically and electrophysiologically, and even in patients with advanced (stage IV) disease caused by this mutation, the photopic and scotopic full-field ERG generally remain normal. The mutations p.Arg172Trp and p.Arg195Leu mutation were associated with a more widespread cone or cone–rod dystrophy.[1][13]

The electro-oculogram is normal or slightly subnormal in later stages. [1][2][18]

Visual Field Testing

Early in the course, visual fields are normal, but with disease progression a relative and eventually absolute paracentral scotoma may be demonstrated, corresponding to the area of advanced atrophy. The peripheral visual field is usually normal.[21][24][27]

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.[8][23]

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), the absence of drusen on clinic observation 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. [8][23]

  • 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.[20][21]

Management and prognosis

Therapeutic options for CACD are currently limited. However, ophthalmologists should include CACD in the differential diagnosis in young patients with vision loss and absence of flecks and/or drusen. Early in the disease, visual acuity is excellent, but may progressively decline to 20/400 as chorioretinal atrophy advances.

Knowing the expected progression of the disease, patients should undergo early intervention in vision rehabilitation services to learn how to use low vision devices. The children and family of patients should be aware of the hereditary nature of the disease and given the opportunity to undergo genetic testing.

The development of gene therapy appears to be the most promising approach in the future.[6][8][22]

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