macular degeneration syndromes for which there are characteristic clinical macular anatomic appearances. Stargardt macular dystrophy (STGD) [1–3], Best macular dystrophy (BMD) [2, 4, 5] and juvenile X-linked retinoschisis (JXRS) [2, 6–8], the so-called juvenile macular degenerations, were initially characterized by distinctive fundus findings [187]. The genetic basis of these conditions was recognized early on. They have been the focus of much interest lately, in part because they are among the most frequent causes of blindness in children, and in part because an understanding of the underlying mechanisms may be relevant for the much more common age-related forms of macular dystrophy. Other forms of juvenile hereditary retinal dystrophies, such as Leber’s congenital amaurosis, rod cone monochromacy, and blue cone monochromacy, in which a macular degeneration is not a pathognomonic clinical anatomic characteristic are reported elsewhere (e.g., 4). We do not include a focus on cone degenerations which are panretinal in nature and are treated elsewhere.

11.1.1  Stargardt Macular Dystrophy

STGD, first described in 1909 by Karl Stargardt [9] is by far the most common form of juvenile macular degeneration. STGD is characterized by discrete yellowish irregular deposits within the posterior pole (Fig. 11.1). One variant of STGD, fundus flavimaculatus (FF), describes patients with yellow–white pisciform flecks throughout the fundus, who typically retain good visual acuity until later in life [10]. STGD

and FF appear to represent a spectrum of disease presentation.

11.1.1.1  Clinical Features: STGD

STGD is a bilateral progressive macular degeneration that typically begins in the first or second decade of life. Presenting symptoms include blurred central vision or visual acuity that cannot be corrected to 20/20 when identified on routine examination. On initial presentation the visual acuity can range from 20/20 to 5/200. Patients with initially good central vision may have a change in its quality. Typically, there is a fairly rapid decline in acuity during the teenage years, with final acuity of 20/200– 20/400 by adulthood [11]. Patients usually prefer decreased light levels and frank photophobia is uncommon. Color perception is usually normal. Nyctalopia is also uncommon, except perhaps late in the disease. Although the prevalence of 1 in 10,000 is frequently cited, precise estimates are not available. The macula commonly has a beaten metal or bronze metal reflective appearance in association with the outer retinal yellow flecks that appear at the level of the retinal pigment epithelium (RPE). Initially, there may be only a broadening of the foveal light reflex or fine granularity to the RPE or pinpoint white dots. Initially discrete, the spatially irregular yellow lesions associate with the focal areas of RPE atrophy, which may appear gray in color by fundoscopy. The flecks vary in shape, size, and distribution. The number of fleck-like lesions increases over time, which can be documented by serial fundus photographs. Focal RPE atrophy occurs in immediate spatial association with the

Fig. 11.1  Fundus photos of three patients with STGD at different stages of the disease. (a) Yellow flecks are evident throughout the macula while visual acuity is 20/16. (b) Atrophic regions

appear within the macula and acuity is 20/60. (c) Extensive atrophy with areas of hypoand hyperpigmentation. Acuity is 20/250

yellow flecks of material. A macular bulls-eye appearance may emerge. Affected regions can expand and coalesce to form larger regions of chorioretinal atrophy. There may be temporal optic nerve head pallor in association with large areas of macular chorioretinal atrophy. The optic nerve head and vasculature do not have the waxy appearance and attenuation, respectively, which are commonly found in cone or cone–rod dystrophies. The impact on central visual acuity depends on the location and the extent of the lesions relative to the fovea and foveola. Initial loss of RPE cells promotes the loss of overlying photoreceptors that explains the loss of central visual sensitivity and scotomas that emerge.

At the tissue level, the yellow flecks are associated with RPE cells that are engorged with granules of fluorescent lipofuscin (LF)-like material that cause the cells to expand to many times their normal size [182]. Such islands of engorged RPE cells (flecks) commonly reside in a setting of surrounding RPE cells that have normal size, but these cells also contain accumulative LF-like material. Focal RPE cell loss occurs in association with the nonuniform distribution of populations of engorged cells. If the surrounding healthier RPE cells cannot expand their surface area to fill the void left by dying engorged RPE cells, then the local overlying photoreceptors supported by the patch of RPE cells will also be lost. Coalescing central microscotomas can emerge by this process leading to the central and paracentral scotomas that are commonly identified by visual field testing.

11.1.1.2  Diagnostic Features: STGD

The age of the patient and the clinical retinal anatomic appearance of macula or more widespread yellow flecks contribute strongly to the diagnosis. Visual acuity on presentation can be good to poor depending upon the foveal and foveolar involvement. Progressive loss of lines of visual acuity over time can occur depending upon the extent and localization of patches of RPE atrophy. Color vision is usually normal or with a mild red/ green deficiency axis. Paracentral scotomas are common, and ring scotomas are also possible in a bulls-eye fashion depending upon the location and the size of the patches of fleck-associated RPE and photoreceptor loss. Peripheral constriction of the visual field is uncommon (e.g., in FF). The Ganzfeld or full-field electro­ retinogram (ERG) generally shows cone photopic signal amplitudes at the lower limit of normal or mildly

attenuated, and normal scotopic signals. In older individuals where the macular disease is more progressed, the attenuation of both photopic and scotopic signals occurs in proportion to the spatial extent of macular involvement. While the full-field ERG is useful for ruling out more widespread forms of retinal degeneration [12], it is of little use for following patients since it tends to remain normal until late in the disease. The electrooculogram (EOG) has a light peak (LP) to dark trough (DT) ratio that is usually abnormal for the age in most cases, and this is consistent with the disease pathogenesis focused on the RPE cell layer. The final dark adapted threshold is usually normal for the age or slightly elevated and there may be slowing in the kinetics to final threshold, especially late in the disease [13].

The intravenous fluorescein angiogram (IVFA) is pathognomonic for the STGD/FF disease. Patients with STGD/FF have a characteristic dark or silent choroid in the early phases of the angiogram when initial choriocapillaris perfusion occurs. Normally, the lobular perfusion of the choriocapillaris vascular architecture can be visualized through the RPE with appropriate optical excitation of the fluorescein dye. In STGD/FF, the RPE cells (normal sized or engorged) contain abundant LF-like materials (e.g., bis-retinoids such as A2E and Retinal dimers) that have a strong absorption in the blue component of the spectrum and overlaps with the fluorescein excitation band generated in standard fundus camera systems used for IVFA. Because of these accumulated materials in the RPE, the excitation of fluorescein dye in the choriocapillaris by the blue flash is prevented or significantly attenuated, and no to minimal green–yellow emission from the dye can occur. The dark choroid sign extends throughout the entire retina in STGD and FF and is not just a macular feature. The image contrast resulting from the dark choroid sign can support the visualization of the extensive inner retinal capillary network in some patients. The dark choroid is an important sign in the differential diagnosis of STGD/ FF (see below). Yellow fleck lesions of STGD are either nonfluorescent or have an irregular hyperfluorescence on IVFA. This occurs in comparison to drusen which hyperfluoresce on the IVFA in correspondence to their true size. In the yellow fleck lesions as patches of engorged RPE cells die and the embodied LF-like materials are reabsorbed, tiny transmission window defects appear in the IVFA as long as the underlying choriocapillaris is intact. As the disease progresses, there may be a coalescence of such patches and frank chorioretinal

atrophy may occur leaving a macular window defect that shows no choriocapillaris flush, but only the perfused underlying trunk vessels of the choroid proper.

11.1.1.3  Differential Diagnosis: STGD

A variety of retinal diseases, both hereditary and not, may need to be differentiated from STGD/FF. Fundus albipunctatus is an autosomal recessive night blindness syndrome (one disease gene is RHD5) associated with discrete white dots at the RPE level throughout the retina, but not generally involving the macula, and not causing a pigmentary disturbance. Stationary nyctalopia is a common finding and there are no central visual field disturbances. Fundus albipunctatus is easy to differentiate from STGD/FF on the clinical anatomic appearance, the psychophysical findings, and the lack of a dark choroid on IVFA. Retinitis punctata albescens. Patients with this syndrome have symptoms and findings similar to retinitis pigmentosa (RP). They also have punctate yellow white lesions at the RPE level with a wide distribution that includes the macula. There is substantial pigmentary disturbance in association with the fleck-like lesions that creates window defects in IVFA and staining. The dark choroid sign of STGD/FF is not present. Dominant familial drusen is a disease with small, round, yellow often clustered lesions at the RPE level in the macular region. This can be differentiated from STGD/FF because the drusen fluoresce uniformly (STGD flecks are irregular in shape and nonuniform in fluorescence appearance), and dominant familial drusen does not cause a diffuse dark choroidal pattern on IVFA. Kandori flecked retina. This nonprogressive syndrome has irregular, dirty yellow flecks that spare the macular region and occur between the macula and the equator. Night blindness is a common differentiating symptom. Delayed dark adaptation occurs. The lesions cause pigmentary disturbances and are hyperfluorescent on IVFA. Cone dystrophies. Cone dystrophy is a progressive panretinal degeneration that causes a decrease in central vision, sometimes associated with acquired nystagmus, profound decrease in color vision, photophobia, and marked and progressive loss of photopic ERG signals. Central or ring scotomas are common in visual field testing. There is a waxy temporal pallor to the optic nerve head in association with vascular attenuation. There is generally a granular pigmentary pattern to the macula with loss or blunting of the foveal light

reflex, and rare peripheral pigmentary changes (where cone density is much lower). There are no fleck-like lesions. There may be a bulls-eye pattern of window defect on the IVFA but the dark choroid sign is not found. Cone–rod dystrophy (CRD) shares features with cone dystrophy except that there is both photophobia and nyctalopia, the photopic and scotopic ERG signals are affected, there is constriction of the visual field, and there are peripheral pigmentary changes consistent with the spatial distribution of rod photoreceptors in the retina. Again, there are no flecks and the dark choroid sign is absent. BMD. STGD/FF is differentiated from juvenile BMD on the basis of the dark choroid sign in STGD/FF and the marked EOG changes in BMD. Central areolar choroidal atrophy. This is a late onset disease pattern with an atrophic macula [189, 190]. There are no flecks and the dark choroid sign is absent. Dominant macular dystrophy. This familial syndrome affects only the posterior pole with a granular pigmentary atrophy without flecks. Again, there is no dark choroid sign on IVFA. Disseminated chorioretinopathy. There may be yellow and atrophic spots at the level of the RPE with pigment clumping on the margins (not found in STGD flecks). There is a general asymmetry between the eyes (STGD is generally symmetric), central vision is preserved unless the macula/ fovea are involved, there is no family history, and there is no dark choroid sign (except possibly in areas of active inflammation). Angioid streaks. In pseudoxanthoma elasticum, the p’eau d’orange appearance of the retina might be confused with the flecks of STGD/FF. There is a diffuse mottled appearance of the macula and extramacular regions. There is no dark choroid sign. Inverse RP. This may be a form of cone dystrophy, with waxy pallor of the optic nerve head, and vascular attenuation. There are no yellow flecks and the dark choroid sign is absent on IVFA. Kjellin syndrome. The rare Kjellin syndrome causes retinal lesions that resemble those in FF. As an apparently unique IVFA finding, the flecks in Kjellin syndrome block fluorescence centrally but transmit on the border. This is a true syndrome of retinopathy associated with dementia and spastic paraplegia. Chloroquine retinopathy. Chlo­ roquine can cause a bulls-eye maculopathy that simulates early STGD. However, there is a history of drug exposure and no family history. On IVFA, there is a mottled appearance to the entire RPE and the dark choroid sign is absent. Crystalline retinopathies. Bietti’s crystalline retinal dystrophy, primary hyperoxaluria, methoxyfluorane toxicity, and tamoxifen retinopathy create