Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Retinal Disease_Wright, Spiegel, Thompson_2006
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FIGURE 4-19. Large drusen in the left eye of a 60-year-old patient with 20/40 vision. Most of the retinal pigment epithelial abnormality is confined to an area two by three disc diameters in size. At the periphery of this zone, the drusen are rather small; near the center, they coalesce into larger accumulations that may be more appropriately termed retinal pigment epithelial detachments.
FIGURE 4-20. Cuticular drusen in the right eye of a 42-year-old patient with 20/15 vision. Note the uniformly sized yellow deposits at the level of the retinal pigment epithelium, believed to be nodular thickenings of Bruch’s membrane. With time, more typical drusen can become admixed with these cuticular drusen, as is beginning to occur centrally in this patient. In some cases, a vitelliform pigment epithelial detachment can occur. (From Ref. 26, with permission.)
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FIGURE 4-21. Cuticular drusen in a midvenous-phase fluorescein angiogram of the patient in Figure 4-20. The drusen hyperfluoresce early and stain in later frames of the study (not shown). The lesions are often more dramatically seen on the angiogram than by ophthalmoscopy.
individuals and are most easily recognized as a myriad of equalsized hyperfluorescent dots in the early phase of a fluorescein angiogram (Fig. 4-21). With increasing age, typical drusen are often admixed with the cuticular ones, and in late stages even a vitelliform RPE detachment can occur.26
The natural history of drusen is variable. Some patients experience a progressive loss of central vision while others have essentially normal vision for many years. The most common presenting symptom is decreased central visual acuity or a recent onset of metamorphopsia. In the latter case, a choroidal neovascular membrane is often found. There are no known systemic manifestations of macular drusen. The most important laboratory test is a fluorescein angiogram for the detection of choroidal neovascularization. As are the other disorders discussed in this chapter, typical drusen are characterized histopathologically by abnormalities of Bruch’s membrane and an accumulation of organelles and macromolecules within and beneath the RPE.19,48,56,73 This appearance could be the result of a defect in metabolism of the RPE or macular retina, but the autosomal dominant nature of the condition would be more compatible with a structural abnormality in Bruch’s membrane.
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Basal laminar drusen are even more likely to result from a structural abnormality in Bruch’s membrane.
The drusen seen in Malattia Levetinese and Doyne honeycomb retinal dystrophy are autosomal dominant and occur in children as well as adults. Mutations in the EFEMP1 gene on chromosome 2 are the cause.69 Another form of autosomal dominant drusen has been reported that may present as early as 3 years of age with fine drusen, most conspicuous in the macula, with or without atrophic maculopathy. This form has been mapped to chromosome 6q14.68 It is of interest that Alport’s syndrome, which is associated with fine drusen-like deposits at the level of the RPE, has been shown to be caused by a defect in type IV collagen.4
The treatment of drusen consists of identifying choroidal neovascular membranes as early as possible and treating them with laser photocoagulation. Many of these patients also benefit from referral to low-vision specialists as the disease progressively affects their central visual acuity.
NORTH CAROLINA MACULAR
DYSTROPHY
North Carolina macular dystrophy was initially described by Lefler et al. in 1971.39 It was further described by Frank and coworkers in 1974,25 who termed the disease dominant progressive foveal dystrophy. This condition has recently been shown to be the same as central areolar pigment epitheliopathy.61 In fact, the individual illustrated in this chapter (Fig. 4-22) was initially reported as part of a series of central areolar pigment epitheliopathy,32 but was later found to be related to the original large North Carolina dystrophy family.61
The most common presenting symptom in North Carolina macular dystrophy is decreased central vision. The onset of disease is very early in life, and the macular lesion probably stabilizes in most patients by 10 years of age. Visual acuity can range from 20/20 to 20/200. Small63 reexamined 22 individuals originally reported by Frank and coworkers and found that only 1 patient showed evidence of progression of the disease during the two decades that separated the two reports.
The ocular manifestations of the more severe grades of North Carolina dystrophy are clear cut. The center of the lesion appears to be a staphyloma with little if any choroidal or retinal
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FIGURE 4-22. North Carolina macular dystrophy, showing the right eye of an 11-year-old patient with 20/200 vision. Photographs of this patient at age 9 have been previously published.61 The lesion and the visual acuity has been stationary since early childhood. Typical features of the disease are the staphylomatous-appearing crater surrounded by a gliotic rim. The base has a shiny appearance similar to that seen in some patients with Stargardt’s disease.
pigment epithelial tissue remaining at the base. There is a hypertrophic rim of tissue surrounding the lesion (see Fig. 4-22). Typical-appearing drusen may be observed in the periphery. There are no known systemic manifestations of the disease.
The disease is inherited in an autosomal dominant fashion. The gene that causes the disease was mapped to the long arm of chromosome 6 in 1992 by Small, and the locus has since been further refined. There is no evidence for genetic heterogeneity in this disease.64 Electroretinography and electro-oculography are normal in North Carolina macular dystrophy. Despite the hypertrophic “disciform” appearance of the edge of these lesions, no active choroidal neovascular membrane has been demonstrated in these patients.62 Thus, fluorescein angiography is probably not warranted in these patients unless other conditions are being considered.
The pathophysiology of the disease is unknown, but its very early onset, dominant inheritance, and slow progression suggest a structural abnormality at the level of the basement membrane of the RPE.
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There is no treatment for North Carolina macular dystrophy. Fortunately, the disease is stable in most patients.
SORSBY’S FUNDUS DYSTROPHY
In 1949, Sorsby et al. reported an extensive study of four large English families affected with an autosomal dominant maculopathy.66 Although some features of these families are common to dominant drusen and the pattern dystrophies, there are sufficient differences to warrant recognition as a specific entity.
The central feature of Sorsby’s fundus dystrophy is the development of bilateral subfoveal choroidal neovascular membranes at about the age of 40 years. The macular lesions evolve into a picture of geographic atrophy with pronounced black pigmentation occurring in clumps around the central atrophic zone. Continued peripheral migration of the atrophy results in atrophic areas extending well beyond the temporal arcades with the loss of even ambulatory vision in many patients (Fig. 4-23).
The original families reported by Sorsby and coworkers were later reexamined and reported.9,34,53 These papers reported an additional early feature of the disease, the appearance of numerous fine drusen or a confluent plaque of yellow material beneath the RPE of the posterior pole. A fluorescein angiographic abnormality was also identified that suggested a decreased perfusion of the choriocapillaris. An additional report described the histopathological features of the disease.10 A confluent, lipidcontaining deposit was seen between the basement membrane of the retinal pigment epithelium and the inner collagenous layers of Bruch’s membrane. This deposit differed from that of age-related macular degeneration in that the abnormalities were almost totally limited to the vitreal side of the elastic lamina of Bruch’s membrane.
In summary, the term Sorsby’s dystrophy should be reserved for an autosomal dominant condition in which central choroidal neovascular membranes occur in the relative absence of typical drusen. It is distinguished from the pattern dystrophies by its relatively poor visual prognosis. That is, many of Sorsby’s patients had vision of 20/200 or worse before reaching their sixth decade whereas most patients with pattern dystrophy maintain visual acuities of 20/50 or better in this age range. Moreover, choroidal neovascular membranes occur in only about 5% of patients with the pattern dystrophies. Most families with
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FIGURE 4-23. Sorsby’s macular dystrophy, showing the right eye of a 69- year-old man with 20/2000 vision. His 95-year-old mother is similarly affected. Characteristic features include a large area of RPE atrophy extending beyond the temporal arcades. Clumps of hyperpigmentation are admixed with subretinal fibrosis. It is not uncommon for these patients to lose even ambulatory vision by the sixth decade.
Sorsby’s fundus dystrophy have been found to harbor mutations in the TIMP3 gene.75
There is no curative medical treatment for Sorsby’s fundus dystrophy, nor are there any data in the literature regarding the effectiveness of laser treatment for the choroidal neovascular membranes. However, the progressive centrifugal RPE atrophy that occurs even in the absence of overt neovascularization suggests that laser treatment would not be beneficial. There is some evidence that vitamin A supplementation may be beneficial in this disorder.36
FENESTRATED SHEEN MACULAR DYSTROPHY
Fenestrated sheen macular dystrophy is an extremely rare autosomal dominant macular dystrophy. Only four families have been described in the literature.13,49,59,65 The disease is characterized by sharply demarcated small red lesions that are located in the outer retina (Fig. 4-24). No thickening or thinning of the
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FIGURE 4-24. Fenestrated sheen macular dystrophy, showing the left eye of a 7-year-old patient originally reported by Sneed and Seiving.65 The reddish discolorations have no associated elevation. With time, the redness fades and is replaced by a more atrophic RPE change. (Courtesy of Sneed and coworkers, used with permission.)
retina is associated with the lesions, only the abnormal color. The red lesions are most noticeable in the first decade of life. In older patients, the red lesions fade and a retinal pigment epithelial mottling appears in its place.
Most affected patients are asymptomatic and come to attention when the retinal lesions are noticed during routine ophthalmoscopy. Sneed and Sieving65 reported significantly diminished photopic and scotopic ERGs in affected patients. There are no known systemic manifestations of this disease, and the visual prognosis is excellent.
CRYSTALLINE RETINAL DYSTROPHIES
In 1937, Bietti described patients with a disorder of the retinal pigment epithelium and choroid characterized by scattered yellow-white crystals in the posterior pole.8 These patients also had superficial crystals in the cornea near the limbus. The disorder began in the third decade of life. The presence of crystalline retinal dystrophy in siblings suggested the possibility
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of autosomal recessive inheritance. More recently, histopathological examination of two such cases revealed crystals resembling cholesterol inclusions in the fibroblasts of the cornea and conjunctiva, as well as in circulating lymphocytes.80 Abnormalities of fatty acid metabolism and absence of fatty acid binding by two cytosolic proteins have been noted. Patients have progressive night blindness and visual field loss. Autosomal recessive Bietti crystalline dystrophy has been linked to chromosome 4q35.37
In 1990, Richards and coworkers55 reported an autosomal dominant family in which nine individuals were affected with a crystalline dystrophy indistinguishable from that described by Bietti (Fig. 4-25). The proband of that family had a subnormal ERG and pericentral scotomas with visual field testing. The proband also had crystal formation in the lysosomes of circulating lymphocytes.
The differential diagnosis of crystalline retinopathy includes oxalosis, exposure to methoxyflurane, cystinosis, and exposure to certain other drugs including tamoxifen, canthaxanthine, and talc. The crystalline retinopathy and keratopathy of cystinosis begin in childhood.
FIGURE 4-25. Crystalline macular dystrophy, showing the right eye of a 54-year-old patient originally reported by Richards et al.55 Deposition of crystalline material is seen within the retina and associated areas of atrophy of the retinal pigment epithelium. (Courtesy of Richards and coworkers, used with permission.)
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Acknowledgments. The text and figures in this chapter were derived largely from those prepared by Edwin M. Stone, MD, PhD, in the previous edition of this textbook. Dr. Drack is supported in part by the Georgia Lions Children’s Eyecare Center and Research to Prevent Blindness.
References
1.Aaberg TM. Stargardt’s disease and fundus flavimaculatus: evaluation of morphologic progression and intrafamilial co-existence. Trans Am Ophthalmol Soc 1986;84:453–487.
2.Allikmets R, Singh N, Sun H, et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 1997;15(3):236–246.
3.Arden GB, Barrada A, Kelsey JH. New clinical test of retinal function based upon the standing potential of the eye. Br J Ophthalmol 1962;46:449–467.
4.Barker DF, Hostikka SL, Zhou J, et al. Identification of mutations in the COL4A5 collagen gene in Alport Syndrome. Science 1990;248: 1224–1227.
5.Bastiaensen LAK, Hoefnagels KLJ. Patterned anomalies of the retinal pigment epithelium: dystrophy or syndrome? Doc Ophthalmol 1983; 55:17–29.
6.Benedikt O, Werner W. Retikulare pigmentdystophie der Netzhaut. Klin Monatsbl Augenheilkd 1971;159:794–798.
7.Best F. Uber eine hereditare maculaaffektion: Bietrage zur vererbungslehre. Z Augenheilkd 1905;13:199–212.
8.Bietti GB. Ueber familiares Vorkommen von retinitis punctata albescense (verbunden mit’dystrophia marginalis cristallinea cornea’): Glitzern des Glaskorpers und anderen degenerativen Augenveranderungen. Klin Monatsbl Augenheilkd 1937;99:737– 756.
9.Capon MRC, Polkinghorne PJ, Fitzke FW, Bird AC. Sorsby’s pseudoinflammatory macula dystrophy—Sorsby’s fundus dystrophies. Eye 1988;2:114–122.
10.Capon MRC, Marshall J, Krafft JI, Alexander RA, Hiscott PS, Bird AC. Sorsby’s fundus dystrophy: a light and electron microscopic study. Ophthalmology 1989;96:1769–1777.
11.Chopdar A. Reticular dystrophy of retina. Br J Ophthalmol 1976;60: 342–344.
12.Cibis GW, Morey M, Harris DJ. Dominantly inherited macular dystrophy with flecks (Stargardt). Arch Ophthalmol 1980;98:1785–1789.
13.Daily MJ, Mets MB. Fenestrated sheen macular dystrophy. Arch Ophthalmol 1984;102:855–856.
14.de Jong PTVM, Delleman JW. Pigment epithelial pattern dystrophy; four different manifestations in a family. Arch Ophthalmol 1982; 100:1416–1421.
CHAPTER 4: HERITABLE DISORDERS OF RPE, BRUCH’S MEMBRANE |
131 |
15.Deutman AF, Rumke AML. Reticular dystrophy of the retinal pigment epithelium. Arch Ophthalmol 1969;82:4–9.
16.Deutman AF, van Blommestein JDA, Henkes HE, Waardenburg PJ, Solleveld van Driest E. Butterfly-shaped pigment dystrophy of the fovea. Arch Ophthalmol 1970;83:558.
17.Deutman AF. Benign concentric annular macular dystrophy. Am J Ophthalmol 1974;78:384–396.
18.Donoso LA, Frost AT, Stone EM, et al. Autosomal dominant Stargardt-like macular dystrophy: founder effect and reassessment of genetic heterogeneity. Arch Ophthalmol 2001;119(4):564–570.
19.Feeney-Burns L, Ellersieck MR. Age-related changes in the ultrastructure of Bruch’s membrane. Am J Ophthalmol 1985;100:686–697.
20.Ferrell RE, Mintz-Hittner H, Antoszyk JH. Linkage of atypical vitelliform macular dystrophy (VMD-1) to the soluble glutamate pyruvate transaminase (GPT1) locus. Am J Hum Genet 1983;35:78– 84.
21.Fish G, Grey R, Sehmi KS, Bird AC. The dark choroid in posterior retinal dystrophies. Br J Ophthalmol 1981;65:359–363.
22.Fishman GA, Farber M, Patel DS, Derlacki DJ. Visual acuity loss in patients with Stargardt’s macular dystrophy. Ophthalmology 1987;94:809–813.
23.Forgacs PJ, Bozin I. Manifestation familiale de pigmentations groupees de la region maculaire. Ophthalmologica 1966;152:364– 368.
24.Frangieh GT, Green WR, Fine SL. A histopathologic study of Best’s macular dystrophy. Arch Ophthalmol 1982;100:1115–1121.
25.Frank HR, Landers MB, Williams RJ, Sidbury JB. A new dominant progressive foveal dystrophy. Am J Ophthalmol 1974;78:903–916.
26.Gass JDM, Jallow S, Davis B. Adult vitelliform macular detachment occurring in patients with basal laminar drusen. Am J Ophthalmol 1985;99:445–459.
27.Gass JDM. A clinicopathologic study of a peculiar foveomacular dystrophy. Trans Am Ophthalmol Soc 1974;72:138–156.
28.Gass JDM. Stereoscopic atlas of macular diseases. St. Louis: Mosby, 1987:60–91.
29.Gass JDM. Stereoscopic atlas of macular diseases. St. Louis: Mosby, 1987:92–97.
30.Giuffre G, Lodato G. Vitelliform dystrophy and pattern dystrophy of the retinal pigment epithelium: concomitant presence in a family. Br J Ophthalmol 1986;70:526–532.
31.Gutman I, Walsh JB, Henkind P. Vitelliform macular dystrophy and butterfly-shaped epithelial dystrophy: a continuum? Br J Ophthalmol 1982;66:170–173.
32.Hermsen VM, Judisch GF. Central areolar pigment epithelial dystrophy. Ophthalmologica 1984;189:69–72.
33.Hittner HM, Ferrell RE, Borda RP, Justice J. Atypical vitelliform macular dystrophy in a five-generation family. Br J Ophthalmol 1984; 68:199–207.