Fluorescein Angiography of the Hereditary Chorioretinal Dystrophies*
KENNETH G. NOBLE
Table Of Contents
GENERALIZED CHORIORETINAL DYSTROPHIES|
RETINAL VASCULAR DYSTROPHIES
The hereditary chorioretinal dystrophies for the most part affect visual processing at various loci. As such., they are best studied by diagnostic modalities that evaluate visual function, such as the electroretinogram, electro-oculogram, visual-evoked potential, dark adaptation, and visual fields. Fluorescein angiography highlights abnormalities in the vascular system and within the pigmented layers, and even in its relatively limited role, it has been helpful in diagnostic evaluation and pathogenesis.
|GENERALIZED CHORIORETINAL DYSTROPHIES|
RETINITIS PIGMENTOSA (RP)
In retinitis pigmentosa (RP), the pigment abnormalities of atrophy, migration, and clumping are made apparent by transmitted hyperfluorescence and blocked hypofluorescence (Fig. 1A). Patients who have very minimal pigmentary alterations (pauci pigmentary RP) or no pigment abnormalities (RP sine pigmento) may show the abnormalities on fluorescien angiography (FA). It is uncommon to see choriocapillaris atrophy except in the late stages. This finding corresponds to the histopathology, which shows that the earliest abnormalities are in the photoreceptors and that the choroid is normal.1
Dye leakage in RP may occur from the retinal vessels or at the level of the retinal pigment epithelium (Fig. 1B).2–4 The leakage may be seen in the macula and posterior pole, along the vascular arcades in the distribution of the radial peripapillary capillaries, and in the periphery (where an exudative vasculopathy resembling Coats' disease is suggested).
Of more clinical importance is the role of FA in the diagnosis and treatment of cystoid macular edema (CME) (Fig. 1C and D). Stereoscopic FA indicates that the leakage, which may be diffuse or have the typical petaloid stellate appearance of CME, can come from the perifoveal retinal capillaries, from the choroid through the RPE, or from a combination of both sources.4 With the recent suggestion that CME in RP may be successfully treated with acetazolamide,5, 6 FA is thus important to document the diagnosis of CME, establish the origin(s) of leakage, and follow patients during and after therapy.
The carrier female with XLR RP, who has the golden tapetal sheen reflex, has normal FA findings. This suggests that the abnormal reflex is not due an abnormal pigment layer or deposition7 (Fig. 2A and B).
CONGENITAL STATIONARY NIGHT BLINDNESS
FA is normal in congenital stationary night blindness (CSNB) with a normal fundus. However, in the two types of CSNB with an abnormal fundus (Oguchi's disease, fundus albipunctatus) FA does provide some interesting information.
In Oguchi's disease the hallmark fundus finding is a yellow metallic sheen (Fig. 2C). A similar sheen has been seen in progressive cone dystrophies and juvenile macular degeneration.7 In all these diseases the abnormal reflex does not affect the normal transmission of fluorescein dye (Fig. 2D). The normal FA suggests that, like findings in the carrier female in XLR RP, the abnormal retinal reflex in this disease is unrelated to pigment concentration or distribution.
Fundus albipunctatus typically shows multiple, small white dots, which are deep in the retina, regular, and monotonous in their similar size, shape, and color and which involve the entire posterior pole into the equator while sparing the macula (Fig. 3A). These multiple dots are not apparent on FA. There may be a mottling of the background choroidal fluorescence and small areas of irregular transmission hyperfluorescence (especially surrounding the macula), but neither of these findings corresponds to the observed white dots8,9 (Fig. 3B).
Fluorescein angiography highlights observable fundus findings. In patients with a golden reflex the FA is normal (Fig. 2E, F) or shows a mild transmission hyperfluorescence.7
The choroidal dystrophies may be generalized (choroideremia, gyrate atrophy, generalized choroidal dystrophy) or localized to the posterior pole (central areolar choroidal dystrophy, peripapillary or pericentral choroidal dystrophy, Bietti's crystalline retinopathy). The hallmark finding in all these disorders is an atrophy of the choriocapillaris early in the course of the disease. Subtle loss of the choriocapillaris is documented and confirmed by FA in which there is persistent visualization of the mid-sized choroidal vessels.10 In this regard, FA helps to differentiate disorders that affect the choroid early in the course of the disease from disorders that initially affect the retinal pigment epithelium (RPE). It is also an excellent way to determine if there is progression in the course of the disease.
In the early stages of choroideremia, before choroidal atrophy is funduscopically obvious and when the picture resembles RP, FA indicates diffuse choroidal atrophy throughout the entire retina. Only the macular area remains preserved (Fig. 4A and B).
The typical carrier female, with focal or diffuse pigment mottling, does not show choroidal atrophy. However, a few carrier females have a more severe form with focal areas of choroidal atrophy. The presence of these areas, and possible progression, can be documented by FA (Fig. 4C and D). These carriers exhibit a mosaicism, which is explained by the Lyon hypothesis of random X-chromosome inactivation.
Unlike choroideremia, gyrate atrophy funduscopically has well-demarcated scalloped areas of choroidal atrophy. A hyperpigmented border separates the normal and abnormal tissue. These lesions begin as isolated areas in the midperiphery, which then merge to form a garland wreath, with progression peripherally and centrally, sparing only the macula.
FA demonstrates the sharp demarcation between normal and abnormal tissue, the former showing normal background fluorescence, the latter atrophy of the choriocapillaris (Fig. 5). Thus, the normal choriocapillaris background fluorescence in the early stages of gyrate atrophy is in contradistinction to the diffuse choriocapillaris atrophy in the early stages of choroideremia.
Generalized Choroidal Dystrophy
Generalized choroidal dystrophy is usually noted in middle-aged mildly symptomatic individuals who show a predominantly peripapillary or pericentral distribution of choroidal atrophy. Gradually, over the years these areas enlarge to eventually involve the entire retina. These changes are vividly seen on FA (Fig. 6).
Central Areolar Choroidal Dystrophy
Although central areolar choroidal dystrophy (CACD) and peripapillary (pericentral) choroidal dystrophy are not generalized, but rather localized disorders, they are discussed here as part of the choroidal dystrophies because the angiographic findings are similar.
In CACD the bilateral macular lesions are solitary, circumscribed, and circular or ovoid in shape. They are unassociated with other findings such as drusen or flecks. FA will confirm the well-circumscribed area of choriocapillaris atrophy and further document that there are no associated findings that would lead to secondary choroidal atrophy in disorders such as age-related macular degeneration, Stargardt's fundus flavimaculatus, or dominant drusen of Bruch's membrane11 (Fig. 7 A and B).
Peripapillary (Pericentral) Choroidal Dystrophy
Peripapillary choroidal atrophy radiates from the optic nerve along the temporal vascular arcades. The macula is affected later in the course, and this is usually responsible for the onset of visual symptoms. FA shows the choroidal atrophy and the early macular changes (Fig. 7C and D).
Crystalline Retinopathy (of Bietti)
Crystalline retinopathy (of Bietti) is usually localized to the posterior pole but can be progressive. Glistening yellow crystals appear scattered throughout the retina (Fig. 7E). The angiogram has a typical and unique appearance. In the area of the crystals there is a transmitted hyperfluorescence; adjacent to these areas, where there are no crystals, choriocapillaris atrophy is evident (Fig. 7F). Progression of the disease is documented by FA,12 which shows enlarging areas of choriocapillaris atrophy.
|The vitreotapetoretinal dystrophies are a heterogeneous group of diseases
that share the association of vitreous abnormalities with a tapetoretinal
dystrophy. The initial triad of diseases included under this heading
were juvenile retinoschisis, Goldmann-Favre disease, and
Wagner's dystrophy. Additional disorders that qualify for inclusion
include Stickler's syndrome (hereditary progressive arthro-ophthalmopathy), snowflake degeneration, and autosomal dominant
When the macula has typical superficial linear plications radiating from the fovea seen with schisis (e.g., juvenile retinoschisis, Goldmann-Favre disease), FA is normal (Fig. 8A and B). This indicates that the pathology is in the inner retina (probably Henle's fiber layer, considering the spokewheel pattern). However, when the schisis flattens, it is not uncommon to see a transmitted hyperfluorescence suggesting a secondary atrophy to the RPE (Fig. 8C and D).
The periphery may show schisis or vascular sheathing. Histopathology of the peripheral schisis in juvenile retinoschisis documents a splitting of the nerve fiber layer.13 FA shows retinal vascular abnormalities, including capillary nonperfusion, focal and diffuse vascular leakage, and intraretinal neovascularization, in many of these disorders.14 These may or may not be associated with schisis.
As with generalized tapetoretinal dystrophy (RP), FA clearly delineates retinal vascular decompensation in some of these patients. What remains to be answered is whether this is part of the basic disease process or a secondary reaction to it.
|RETINAL VASCULAR DYSTROPHIES|
|There are a few uncommon hereditary dystrophies in which the retinal vascular
system seems to be the primary abnormality. In these cases FA is
helpful, and sometimes essential, in making the diagnosis and determining
The most common disorder in this group is familial exudative vitreoretinopathy (FEVR), which clinically resembles retinopathy of prematurity, although it is dominantly inherited and unassociated with prematurity or perinatal supplemental oxygen therapy. The mildest changes, documented by FA, are similar to those of the retinopathy of prematurity, namely peripheral retinal capillary nonperfusion and arteriovenous anastomoses. In family members at risk who have a normal-appearing periphery, FA will reveal abnormalities in affected family members and is therefore a sensitive indicator of disease.15
Perifoveal retinal capillary obliteration16 (which may occur throughout the retina and involve the brain)17 requires FA to define this unusual inherited disorder. Inherited retinal venous beading, reported in two dominant pedigrees,18,19 has focal areas of retinal capillary nonperfusion in the posterior pole associated with retinal capillary leakage and intraretinal neovascularization.
STARGARDT'S DISEASE (FUNDUS FLAVIMACULATUS)
In Stargardt's disease, thes most common hereditary macular dystrophy, FA has a variety of functions. In the mildest fundus presentation, with visual symptoms and visual function out of proportion to the observed maculopathy, FA can confirm or even make the diagnosis and can avoid a mistaken diagnosis of malingering, hysteria, or central nervous system disease (Fig. 9A and B). When a maculopathy is present without surrounding parafoval flecks, FA may show patchy areas of transmission hyperfluorescence in the posterior pole, indicating a more diffuse involvement (Fig. 9C and D).
In a large majority of patients (86% in one study),20 there is an absence or decrease in the background choroidal fluorescence (which is referred to as the “silent” or “dark” choroid) (see Fig. 9B). This warrants special attention because it occurs so frequently, is rarely found in other retinal disorders,21 and may be related to histopathology that shows an increase in lipofuscin in the RPE.22
BEST'S VITELLIFORM MACULAR DYSTROPHY
The intact solid yellow egg yolk lesion in Best's vitelliform macular dystrophy (BVMD) typically shows hypofluorescence on FA due to blockage of the underlying choroidal fluorescence with the overlying retinal vasculature visible (Fig. 10A and, B). This finding places the lesion in front of the choroid, possibly within the RPE, but probably not within the neurosensory retina. There is no histopathology of the intact lesion to confirm this.
Histopathology in later stages of BVMD has shown an increase in lipofuscin in the RPE throughout the retina.23 If lipofuscin were within the intact egg-yolk lesion, this would block fluorescence. However, it is surprising that the “silent,” “dark” choroid seen in another disease with diffuse RPE lipofuscin accumulation (Stargardt's disease) does not occur in BVMD.
There are several acquired macular degenerations of different etiologies that have a macular lesion similar to the vitelliform stage of BVMD. FA may be helpful in identifying these cases of pseudovitelliform degeneration by showing leakage from the retinal capillaries or through the RPE and late staining of the lesions (Fig. 10C–E). However, the electro-oculogram remains the most discriminating test because it is always abnormal in BVMD and usually normal in pseudovitelliform macular degeneration.
PIGMENT PATTERN DYSTROPHIES
The fundus abnormalities in pigment pattern dystrophies may be subtle, especially when the pigmentary changes are orange and yellow in color. However, FA is most dramatic in highlighting these abnormalities. Thus, FA will confirm, and in some circumstances provide, the diagnosis (Fig. 11A–E). Although there is no histopathologic confirmation, the fundus and angiogram suggest that an abnormal deposition of lipofuscin in the RPE is responsible for the clinical picture.
DOMINANT DRUSEN OF BRUCH'S MEMBRANE
There is no clear agreement as to what constitutes dominantly inherited drusen and what constitutes age-related degenerative drusen. There is a distinct group of younger individuals with bilateral, symmetric, uniformly small, round, discrete, yellow and white drusen. Histopathology demonstrates a nodular thickening of the RPE basement membrane, and these drusen have therefore been referred to as basal laminar, or cuticular, drusen.24
FA shows a characteristic pinpoint area of transmission hyperfluorescence corresponding to the drusen and reveals many more than are appreciated clinically (Fig. 12). Secondary changes such as pigment atrophy and dispersion, exudative and nonexudative detachments, and occasionally a neovascular membrane, will be revealed by FA (Fig. 12E).
HEREDITARY HEMORRHAGIC MACULAR DYSTROPHY (PSEUDOINFLAMMATORY MACULAR DYSTROPHY OF SORSBY)
FA plays an important role in the understanding of this rare disorder. In the earliest manifestations of the disease, FA shows a single, isolated choroidal neovascular membrane unassociated with other causes of a membrane, such as drusen or angioid streaks (Fig. 13).25 Presumably this membrane is the cause of the subsequent hemorrhagic maculopathy with secondary disciform scarring, occurring initially in the macula but often extending throughout the retina.
Abnormal choroidal perfusion, manifested on FA as a delay in choriocapillaris filling, has been seen in the restudy of some of Sorsby's initial pedigrees.26 This unusual pattern has been related to the histopathologic finding of a “confluent, lipid-containing, amorphous deposit found between the basement membrane of the RPE and the inner collagenous layer of Bruch's membrane.”27
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|* Supported in part by a grant from the Retinitis Pigmentosa Foundation, the Research to Prevent Blindness and The Kirby Eye Institute.|