Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Retinal Disease_Wright, Spiegel, Thompson_2006

to the classical genetic marker GPT-1, which was localized to the long arm of chromosome 8.20 Their family had some clinical features that were not typical of classic Best’s disease. Specifically, some affected individuals had normal or nearnormal EOG ratios, and none of the patients had vitelliform lesions larger than one disk diameter in size.33 Bestrophin, the product of the VMD2 gene, localizes to the basolateral plasma membrane of the retinal pigment epithelium.43 The function remains unknown.

Without question, the best laboratory study to establish the presence of Best’s disease is the electro-oculogram (Fig. 4-12). This test is based on the measurement of an electrical potential that is generated at or near the interface between the retinal pigment epithelial cells and the photoreceptors. In a normal eye, this potential responds to changes in illumination in the following way. If an eye is light adapted, and the lights are subsequently turned off, the resting potential falls gradually to a “dark trough” 10 to 15 min later. When the light is switched on again, this potential rises over the next 10 to 12 minutes to a value that is roughly twice the magnitude of the dark trough. The EOG test result is usually expressed as the Arden ratio3 of the light peak to dark trough. This ratio is insensitive to variations in skin conductivity and other variables that do affect the magnitudes of the individual voltages. The exact magnitude of the Arden ratio is dependent on the size and intensity of the light stimulus but is fairly reproducible with a given instrument. In a patient with Best’s disease, there is little change in this resting voltage regardless of the light condition. Thus, when the lights are turned off the voltage falls very little and when the lights are turned on again the voltage rises little if at all. Thus, patients with Best’s disease have a light peak to dark trough ratio of less than 1.5. This electrical abnormality is probably present at birth and can precede the development of ophthalmoscopically visible lesions by several decades. Figure 4-12 shows the EOG patterns from two siblings from a family affected with Best’s disease. One can see that the affected brother has a diminished Arden ratio (1.2–1.3) whereas the unaffected brother has ratios greater than 2.0.

Our understanding of the pathophysiology of Best’s disease is limited. The few specimens that have been studied histopathologically have revealed lipofuscin accumulations within retinal pigment epithelial cells and in the sub-RPE space.24,50,77 Some material has also been described within the

retina itself. Unfortunately, no pathological specimen of an early vitelliform lesion has been studied. Thus, we do not have any direct knowledge of the exact configuration of the vitelliform lesion. It seems likely that the “egg yolk” lies beneath the retinal pigment epithelium because patients with such lesions can still have normal visual acuity. Thus, it is unlikely that this material is between the retinal pigment epithelial cells and the photoreceptors. Some authors believe that the material is confined to the retinal pigment epithelial cells themselves, but the pseudohypopyon appearance of some lesions (Fig. 4-13) argues for an extracellular location of this material. It is not known whether this material accumulates because of a defect in macular metabolism, or whether the lipofuscin is a normal metabolic by-product that simply has difficulty transiting Bruch’s membrane to reach the circulation of the choriocapillaris. The autosomal dominant nature of the disorder would be

FIGURE 4-13. Pseudohypopyon appearance of a vitelliform lesion in Best’s disease, showing the left eye of a 12-year-old patient who is the grandson of the patient shown in Figure 4-10. The visual acuity in this eye was 20/50 at the time of this photograph but improved to 20/20 before age 20. Note that the lipofuscin material has “layered out” with a thicker component below and a serous component above. This figure suggests that the vitelliform collection of lipofuscin is in the sub-RPE space. If it were confined to the retinal pigment epithelial cells, it would not be able to layer gravitationally. If it were present in the subretinal space, the visual acuity would not be 20/50.

more compatible with a structural abnormality than an enzymatic one.

There is no medical treatment for Best’s disease. As already mentioned briefly, choroidal neovascular membranes occur in a few percent of affected eyes and in some cases might be amenable to laser photocoagulation. Such treatment would be complicated by the fact that the membranes would most likely develop beneath the lipofuscin pigment, which would make visualization difficult. It is also important to recognize that these patients rarely have aggressive disciform processes evolving from such membranes. Thus, it is probably hazardous to extrapolate the laser treatment benefits obtained in agerelated macular degeneration to patients with Best’s disease.

THE PATTERN DYSTROPHIES

Between 1950 and 1977, at least eight different hereditary maculopathies were reported in the ophthalmic literature as new and distinct entities (Fig. 4-14). As a group, these disorders are characterized by relatively good vision in the first five decades of life, a striking pattern of yellow or black pigmentation at the level of the retinal pigment epithelium, and a relative absence of typical drusen. Most of the pattern dystrophies have normal or near-normal findings on psychophysical and electrophysiological tests. The notable exception is that affected individuals in some pedigrees have a moderately abnormal EOG.16

Sjogrens’s reticular dystrophy15,58 is an autosomal recessive disease characterized by a network of pigmented lines surrounding the macula that resembles a fishnet with knots at the intersections of the lines. Autosomal dominant pedigrees of reticular dystrophies have also been reported. The EOG is abnormal.38 Fundus pulverulentus60 is a presumably autosomal dominant condition with RPE mottling in the posterior pole and near periphery. Slezak and Hommer considered that this disorder was distinguishable from Sjogren’s dystrophy by the absence of reticular lines. Benedikt and Werner6 reported a family affected with an autosomal dominant condition that shared features of reticular dystrophy and fundus pulverulentus. One affected patient had the classic reticular lines, whereas others had granular pigmentation without definite lines. Mesker’s macroreticular dystrophy45 is characterized by a reticular pigmentation in which the mesh size of the “net” is approximately one disc diameter

FIGURE 4-14. Four different definitions of pattern dystrophy. The individual disorders that are commonly considered as one of the pattern dystrophies are listed at the left. Four of the many publications in the literature that discuss the concept of grouping these as a single clinical entity are indicated by lowercase letters across the top of the figure: a, Marmor and Byers 1977;42 b, Hseih, Fine, and Lyons 1977;35 c, Watzke, Folk, and Lang 1982;74 d, de Jong and Delleman 1982.14 Black dots indicate the component dystrophies that each group included in their definition of pattern dystrophy.

in size (at least twice as large as that in Sjogren’s cases). Butterfly dystrophy16 is an autosomal dominant disorder in which yellow deposits are seen in the macula at the level of the RPE, radiating from the fovea in a pattern reminiscent of a butterfly’s wings (Fig. 4-15). In 1974, Gass27 described a peculiar foveomacular dystrophy characterized by symmetrical, round or oval, yellow lesions in the fovea, approximately one-third disc diameter in size, with a central hyperpigmented spot (Fig. 4-16). Singerman et al.57 reported a large family with a similar condition that they termed dominant progressive macular dystrophy.

Benign concentric annular macular dystrophy17 is an extremely rare autosomal dominant disorder characterized by a fairly stationary bull’s-eye maculopathy that resembles chloroquine toxicity. Some affected patients have electroretinographic, color vision, and dark adaptation abnormalities and some

authors would classify this among the cone dystrophies. However, its good visual prognosis (20/25 at age 68 in one reported patient), coupled with the ophthalmoscopic and angiographic evidence of a macular RPE injury, makes it clinically similar to the other pattern dystrophies discussed here.

The ophthalmoscopic similarity of some of these entities, coupled with their similar clinical course, led several authors14,35,42,74 to propose grouping these entities under the term pattern dystrophy. Unfortunately, there have been nearly as many different groupings of the component entities as there are entities themselves (see Fig. 4-14). It is curious that none of the authors who proposed pattern dystrophy groupings included dominant Stargardt’s disease or the dominant slowly progressive macular dystrophy of Singerman et al.57 as the clinical and electrophysiological findings in the latter conditions overlap those of the entities they chose to include. The existence of these different classification schemes in the literature has rendered the term pattern dystrophy fairly nonspecific. Nonetheless, it is important to recognize that there are a number of heritable maculopathies that are distinct from familial drusen and from early-onset Stargardt’s disease and which in general, have a better prognosis than the latter two disorders.

The most common presenting symptom of one of the pattern dystrophies is a slightly diminished visual acuity or metamorphopsia in a patient in their twenties or thirties. Almost as often, the patients are asymptomatic and come to attention because of the discovery of unusual macular lesions during routine ophthalmoscopy. Individuals affected with one of these disorders will often have relatively young children, nieces, or nephews whom they will ask their ophthalmologist to examine for evidence of the disease. The latter situation is the usual way a pediatric ophthalmologist will encounter these conditions. Some of the pattern dystrophies can definitely be manifest in the first decade of life.11,15,54

The most important entity in the differential diagnosis of pattern dystrophy is early-onset Stargardt’s disease, which has a much poorer visual prognosis. The finding of a masked choroid on fluorescein angiography (see Fig. 4-3) can help establish the latter diagnosis but the absence of this sign does not rule it out. The presence of a dot or flecklike maculopathy with reduced vision in a patient less than 20 years of age should always be considered to be Stargardt’s disease (and a somewhat guarded visual prognosis should be given) unless a number of older

family members (a parent, a grandparent, aunts, or uncles) can be shown to have similar lesions with good vision. Another entity that can be distinguished fairly readily from the pattern dystrophies is Best’s disease. One can usually find classic vitelliform lesions in at least one family member with the latter disease and, although the EOG Arden ratio can be depressed in pattern dystrophy, it is rarely 1.1 or 1.2 whereas it is usually that low in Best’s. It has been my experience that the moderately depressed EOGs in pattern dystrophy occur in older patients with more advanced disease, whereas in Best’s disease the EOG ratio can be very low even in ophthalmoscopically normal affected patients in their first decade of life.

With the exception of Sjogren’s original family in which spherophakia, iris abnormalities, and deafness were associated with the reticular dystrophy, pattern dystrophies are rarely associated with systemic disorders. Anecdotal association with Crohn’s disease has been reported. One important association is with maternally inherited diabetes and deafness (MIDD), a mitochondrial disorder in which approximately 85% of adult patients have been reported to exhibit a linear pigmentary maculopathy. The maculopathy appears to be rare in childhood.44 The pathophysiology of these disorders is largely unknown. One interesting observation is that the distribution of the abnormal pigment in the pattern dystrophies seems to correspond in size and shape with the margins of the choriocapillaris lobules.42 Such a pattern is fairly nonspecific and can be seen in other retinal disorders,5 including Best’s disease (Fig. 4-17).

Many of the remarks made at the opening of this chapter concerning the genetic heterogeneity of the RPE dystrophies apply directly to the “pattern dystrophies”; that is, nearly every author who has studied one of these families has remarked that certain individuals in the family have ophthalmoscopic appearances compatible with one of the individual dystrophies while other family members appear to have another. Occasionally this occurs in two eyes of one patient.30,31 One interesting paper reports a 10-year follow-up of a single patient whose lesions evolved through a series of stages, each mimicking one of the individually described pattern dystrophies.52

We and others have identified mutations in the RDS/ peripherin gene in some patients with pattern dystrophies.46,47,79 However, linkage analysis has excluded the RDS/peripherin gene from involvement in the pattern dystrophy of other large families,76 indicating that at least two genes must exist that are

FIGURE 4-17. Reticular pigmentation in a patient with Best’s disease, shown in fluorescein angiogram from the right eye of a 49-year-old man who is the father of the patient shown in Figure 4-13. The orientation and periodicity of the hyperpigmentation are similar to that seen in the reticular dystrophies. This distribution has been previously noted to correspond to the interfaces between choriocapillaris lobules.

capable of causing this phenotype. There are reports of the same peripherin/RDS mutations causing clinical presentations appearing such as retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in different members of the same family78; this reinforces the concept that different genetic defects can produce identical clinical pictures while the same defect can produce different clinical appearances in different people and even in the same person over time.

The treatment of pattern dystrophy is similar to that of other conditions in this chapter. Choroidal neovascular membranes occur in a few percent of affected eyes and may be amenable to laser treatment. Patients should monitor their vision with an Amsler grid and report any sudden changes immediately. However, because the natural history of the disease is fairly benign, and the pattern lesions can stain with fluorescein even in the absence of neovascularization, laser treatment should probably be reserved for patients with discrete, well-visualized, juxtaor extrafoveal membranes. Indocyanine green videoangiography may be useful in some cases.41