Previtelliform or Carrier Stage

Although vitelliform lesions have been observed as early as the first week of life, the fundi of most patients probably are normal during the first few months or years of life ( Figures 5.01 A and 5.02 A). Many carriers never manifest a change in the fundus.

Best’s disease.

A–C: Changes occurring over a 21-year period in this 27-year-old man with Best’s disease. His fundi were considered as normal at age 4 years (A). At age 7 years, he had developed a typical vitelliform lesion in both macular areas (B). Visual acuity was 20/30 and J-1 in both eyes. At age 27 his visual acuity was 20/30 right eye and 20/25 left eye (C).

D–F: The brother of the patient illustrated in A–C was 10 years old when his fundi showed partly scrambled vitelliform lesions (D). His visual acuity in the right eye was 20/15. At age 12 years, he returned complaining of blurred vision in his right eye. Note the submacular hemorrhage (E). Angiogram showed evidence of a choroidal neovascular membrane. At age 30 years his visual acuity was 20/50 right eye and 20/20 left eye. Note the white subretinal scar in F.

G and H: A 19-year-old boy with Best’s disease who complained of blurred vision in both eyes. His electro-oculographic findings were 1.00 in both eyes. Four months later the vitelliform lesions and surrounding retinal detachment (G) had disappeared (H). Visual acuity was 20/20.

I and J: This 13-year-old female had bilaterally symmetric vitelliform macular lesions and a visual acuity of 20/15. Angiograms showed minimal fluorescence of both eye lesions (probably pseudofluorescence corresponding to the vitelliform lesion) (J).

K and L: A vitelliform lesion was present in both eyes of this 9-year-old boy (K), and in the right eye (L) of his 73-year-old grandfather who had a scar in the left macula.

(G and H courtesy of Dr. Mark J. Daily; K and L courtesy of Dr. Michael W. Hines.)

Best’s Disease-correlation of clinical appearance to schematic diagram

A: Schematic diagram of probable histopathologic changes in Best’s disease. Previtelliform stage (see Fig. 5.01A). Sunny-side-up vitelliform stage (see Fig. 5.01G). RPE cells (arrows) are distended with yellow pigment. Vitelliruptive stage (see Figs. 5.01D and 5.03D). Disruption of RPE with yellow pigment beneath the retina and atrophy of the receptor elements. Serous detachment of the retina may occur over the vitelliform (see Figs. 5.01G and 5.04A and B), the atrophic or neovascular stage (see Fig. 5.03E). Atrophic stage. Choroidal neovascularization and cicatricial stage (see Fig. 5.03F).

B and C: This 36 year old male with 20/80 and 20/200 vision respectively had a pseudo hypopyon appearing vitelliform lesion on the right and an atrophic lesion on the left.

D to G: This young woman was noted to have bilateral maculopathy at age 7. Photographs done at age 10 shows multifocal vitelliform deposits in both macula (D and E). Eleven years later, at age 21, there was an increase in the yellow material with a partial scrambled egg appearance in both eyes (F and G). Her visual acuity at age 24 was best corrected to 20/40 right eye and 20/25 left eye. EOG revealed an Arden ratio of 1.26 on the right and 1.40 on the left.

Courtesy: B and C, Dr. Paul Sternberg, D -G, Dr. Edward Cherney.

Vitelliform Stage

In infancy or in early childhood patients may develop a sharply circumscribed subretinal lesion that has been likened to the yolk of a sunny-side-up fried egg ( Figures 5.01 B and I, 5.02 A, and 5.03 G). Visual acuity at this stage of the disease is usually normal. Biomicroscopy and stereophotography reveal a discrete lesion beneath the retina that is ½–2 disc diameters in size, yellowish, and usually round or oval. Early in the disease, little or no elevation of the retina occurs. Subsequently the lesion appears elevated as the yellow material increases in amount, and is found in the outer photoreceptor zone, subretinal space, and within the RPE layer. The color and pattern of the RPE surrounding the lesion are usually normal. Variations in size and stage of development of the lesion may be present in the eyes of the same patient ( Figure 5.03 A and B). The lesion initially may be evident only in one eye. In some patients the fellow eye may remain near normal with 20/20 acuity throughout life. The vitelliform lesion may occasionally disappear spontaneously ( Figure 5.01 G and H). The lesions may be eccentrically located and may be multiple ( Figure 5.04 ). In a few patients they may be unusually large and geographic in shape ( Figure 5.04 G–I). Some patients may show a finely mottled pattern of yellowish change in the RPE throughout the fundus ( Figure 5.03 F). Each of the affected family members illustrated in Figure 5.04 A–F had several small, focal, yellow lesions scattered in the fundus of each eye. These yellow punctate lesions may be the only manifestation of the disease in some family members.

Best’s disease.

A–C: This 13-year-old black girl, one of three siblings with Best’s disease, showed a partially scrambled vitelliform lesion in the right eye and a small disciform scar and serous macular detachment in the left eye (A and B). Visual acuity in the right eye was 20/20 and in the left eye was 20/40. Arteriovenous phase angiogram showed evidence of choroidal neovascular membrane (arrow, C).

D and E: This 14-year-old boy had the vitelliruptive stage of Best’s disease. Note loss of yellow material in the superior portion of the lesion and layering of this material inferiorly. Angiography (H) showed evidence of fluorescence superiorly but not inferiorly in the region of the yellowish material inferiorly. Later angiograms showed definite evidence of leakage of dye in the superior half of this lesion.

F: The 37-year-old mother of the patient illustrated in D had a visual acuity of 20/300. Note the elevated fibrous scar beneath the retina and atrophy of surrounding retinal pigment epithelium (RPE). There is a fine mottled pattern of yellow discoloration of the RPE throughout the posterior pole. Angiography revealed staining of the subretinal scar.

G–L: This 8-year-old girl was noted to have vitelliform lesions in both maculas at age 4. An “egg yolk”-like lesion in the right macula (G) is brilliantly autofluorescent (H) and fills the subretinal space without overlying inner retinal damage (I). The left eye has a scrambled-egg appearance (J) with a fibrotic scar that is irregularly hyperautofluorescent (K). The fibrous scar is associated with subretinal fluid, implying subretinal neovascularization (L).

(G–L courtesy of Dr. Franco Recchia.)

Multiple vitelliform lesions in Best’s disease.

A–E: This 25-year-old physician complained of mild visual blurring. Visual acuity in the right eye was 20/20 and in the left eye was 20/15. Note the multiple slightly elevated lesions scattered throughout the posterior pole of both eyes (A and B). Clinically, these lesions resemble somewhat a serous detachment of the retinal pigment epithelium (RPE). Note the ill-defined borders of the yellowish material in the large central lesions. Late angiogram (C) in the left eye revealed no evidence of staining of the large central lesion. The slight fluorescence of the paracentral lesions was probably caused by pseudofluorescence. The patient’s electro-oculographic findings were definitely abnormal (1.1 right eye and 1.3 left eye). Several months after these photographs, he became asymptomatic and remained so for approximately 1 year, when the symptoms returned for approximately 6 months. He again became relatively asymptomatic. Photograph of the left fundus taken 21 months after A and B shows that the central lesion has largely resolved (D). The other lesions appear smaller, more discrete, and yellow in appearance. Similar findings were present in the right eye. His visual acuity at this time was 20/30 in the right eye and 20/15 in the left eye. Angiography (E) showed evidence of some thinning of the RPE inferior to the foveal area. The paracentral lesions appeared nonfluorescent.

F: The left fundus of the 15-year-old sister of the patient illustrated in A–E. Note the multiple, small, discrete, yellowish lesions scattered in the posterior pole (arrows). Another brother and the father had similar punctate yellow spots in the fundi. All three had a markedly subnormal electro-oculogram. The fundi and electro-oculographic findings of another sibling and the mother were normal.

G–I: Large multifocal vitelliform lesions in a 46-year-old woman who gave a 2-year history of blurred vision. Her mother had failing vision in late adulthood, and a maternal cousin had macular degeneration. Note the partly disrupted lesion in the right macula (G) and the large nondisrupted lesions in the left macula (H). Twenty months later the central macular lesion had enlarged (I). Visual acuity was 3/200 in the right eye and 20/40+3 in the left eye. Her electrooculographic findings were definitely abnormal. Her electroretinographic findings were normal. Angiography revealed the intact vitelliform lesions to be nonfluorescent.

Pseudohypopyon Stage

Usually by the time the patient reaches puberty the yellowish lesion shows evidence of disruption ( Figures 5.01 D and 5.03 A and D). It appears that the yellow material is partly taken up by the RPE cells and the heavier material gravitates inferiorly in the subretinal space. Some shifting of this material may occur when the patient’s head is tilted for 60–90 minutes. There is thinning of the RPE and occasionally some clumping of pigment in the superior portion of these lesions.

Scrambled-Egg Stage

With further disruption of the vitelliform lesion, multiple irregular yellowish subretinal deposits produce a picture likened to a scrambled egg. Multifocal yellow deposits may occasionally be arranged in a more orderly ring distribution near the periphery of these lesions ( Figure 5.04 G). The visual acuity is often decreased to the level of 20/30 to 20/40 in the presence of extensive scrambling of the vitelliform lesion.

Atrophic Stage

Eventually all of the yellow pigment may disappear and leave an oval area of atrophic RPE ( Figure 5.03 F).

Cicatricial and Choroidal Neovascular Stage

Many patients develop evidence of one or more plaques of white subretinal fibrous tissue, and in some cases there is evidence of choroidal neovascularization and hemorrhagic detachment of the macula ( Figures 5.01 E and 5.03 B, C, and J). These latter patients eventually develop a white or partly pigmented disciform scar ( Figures 5.01 F and 5.03 F). The central vision is generally 20/100 or less at this stage of the disease. Serous detachment of the retina may occur at any stage of the development of vitelliform lesions ( Figures 5.01 G, 5.03 A, B, and D, and 5.04 A and B).

In the vitelliform stage the early phases of angiography demonstrate complete obstruction of the choroidal fluorescence by the lesion ( Figure 5.01 J). There is no generalized obscuration of the choroidal fluorescence such as occurs in Stargardt’s disease. During the later stages of angiography, the vitelliform lesion may appear nonfluorescent or may appear to fluoresce slightly. Possible explanations for this apparent fluorescence include reflected vitreous fluorescence from the surface of the lesion, improperly matched exciting and barrier filters, and autofluorescence of the yellow lesion. As the yellow pigment gravitates inferiorly, angiography in the area vacated by the yellow material reveals evidence of early fluorescence secondary to depigmentation and late staining of the altered RPE ( Figure 5.03 E). Often there is a narrow zone of hypofluorescence surrounding the atrophic lesion. Angiography permits detection of choroidal neovascularization and shows evidence of staining of fibrous tissue present in the subretinal space ( Figure 5.03 C). It is probable that occult choroidal neovascularization is present within some of the subretinal plaques of fibrous tissue.

Peripheral visual fields, electroretinographic findings, and dark adaptation in these patients are normal. Color vision in the late stages of the disease may be mildly disturbed. The EOG is markedly abnormal with the light to dark ratio usually being below 1.55. EOGs of carriers of the disease usually yield a subnormal result. Patients who are both homozygous and heterozygous for the Best1 gene show low Arden ratio, thus making this feature most characteristic of the condition. Vitreous fluorophotometry shows no evidence of breakdown in the outer blood–retinal barrier with few exceptions in patients with advanced macular degeneration. The disease is inherited as an autosomal-dominant trait. Best’s disease usually occurs in Caucasian patients but may occur occasionally in Africans and Asians ( Figure 5.03 A–C).

Visual prognosis is good for at least the first six decades of life. Most patients retain reading vision in at least one eye throughout life. The progression of visual loss is slow and occurs for the most part beyond the age of 40 years. Acute and permanent loss of central vision may occur in association with bleeding from subretinal new vessels ( Figure 5.01 E). A macular hole may occasionally occur in patients with Best’s disease as well as in patients with adult-onset foveomacular dystrophy or pattern dystrophy.

The histopathology of the vitelliform or pseudohypopyon stage of the disease is unknown. One histopathologic report concerned a relatively early scrambled-egg phase of the disease. One report concerned one eye with mild pigment macular changes in a 69-year-old man with advanced degeneration in the fellow eye. Findings in these reports were consistent in their demonstration of a generalized RPE abnormality that was associated with an abnormal accumulation of lipofuscin granules in the RPE and within macrophages in the subretinal space. None of these studies, however, showed the extensive lipofuscin storage characteristic of Stargardt’s disease, a finding in keeping with the absence of a dark choroid angiographically outside the area of the vitelliform lesion in patients with Best’s disease.

Other histopathologic findings in Best’s disease included a periodic acid–Schiff (PAS)-positive, acid mucopolysaccharide-negative, electron-dense, finely granular material in the inner segments of the degenerating photoreceptors and Müller cells recently identified predominantly as A2E ; an abnormal fibrillar material beneath the RPE cells in the region of photoreceptor cell loss, and normal choriocapillaris. Breaks in Bruch’s membrane and choroidal neovascularization have been demonstrated. One group of authors concluded that the sensory retinal changes were probably primary and the RPE changes secondary. These studies, together with the in vivo demonstration of autofluorescence of vitelliform lesions in Best’s disease by Miller, suggest that the yellow pigment may at least in part be caused by lipofuscin. There is no fluorescein angiographic evidence in this disease, however, for a diffuse marked lipofuscin storage disease such as occurs in Stargardt’s disease (see pp. 278–284). Histopathologic examination of a 86-year-old homozygous for BEST1 gene showed accumulation of lipofuscin, a large component of it made up of A2E, within the RPE cells. Other RPE granules were melanoliposomes. Extraction of the granules in this eye and another 81-year-old’s eye heterozygous for the gene showed the lipofuscin to be mostly made up of A2E similar to that found in diseases caused by the ABCR transport gene abnormality.

The vitelliform stage of Best’s disease should be differentiated from other diseases that cause solitary yellowish macular lesions; for example, dominantly inherited, adult-onset vitelliform foveomacular dystrophy (pattern dystrophy) (see Figure 5.06–5.08 ), basal laminar drusen (Figure 3.29), acute exudative vitelliform maculopathy (Figures 11.30 and 11.31), and fundus flavimaculatus (Stargardt’s disease) with large central flecks. The early age of development of the yellow lesion and the progressive vitelliruptiform changes are essential findings to differentiate patients with Best’s disease from those with adult-onset vitelliform foveomacular dystrophy (pattern dystrophy), because the latter disease may be associated with subnormal EOGs in one-third of cases and because both are dominantly inherited. Four other yellow lesions that may simulate Best’s disease include focal serous RPE detachments containing dehemoglobinized blood pigment, some cases of central serous retinopathy with subretinal fibrin, resolving subretinal hematomas, and unusually large acute solar maculopathy lesions. To be confident that one is dealing with Best’s vitelliform dystrophy rather than some other type of dystrophy, the following are required: (1) the presence of one of the recognized polymorphous lesions typical of Best’s disease; (2) dominant mode of inheritance; (3) moderate to severely subnormal EOG findings; and (4) onset and natural course of the disease typical for Best’s disease. Without this documentation the diagnosis of Best’s disease is open to question. Gene testing for the BEST1 gene with the presence of the above features confirms the diagnosis. Future identification of specific gene defects and the nature of the vitelliform material will help elucidate the pathogenic relationship of the various disorders that demonstrate similar yellow lesions in the macula.

Multifocal vitelliform lesions may occur in patients with Best’s disease ( Figure 5.04 ). Most patients with multifocal vitelliform lesions, however, have no other evidence of Best’s disease (see next section). The lesions may vary in size. Some may be several disc diameters or larger in size and often have some irregularity to their contour ( Figure 5.04 G–I). These larger lesions frequently demonstrate partial resolution or disruption. Multiple round flecks of yellow pigment may be arranged in a circular or oval distribution near the periphery of the partly disrupted lesions ( Figure 5.04 G).

Best1 gene has also been implicated in autosomal-dominant vitreoretinochoroidopathy (ADVIRC), autosomal-dominant microcornea rod–cone degeneration syndrome (ADMRCS), and autosomal-recessive bestrophinopathy (ARB), all with extraretinal features implicating the gene that may be involved in ocular development.

Group 1: Adult-Onset Foveomacular Vitelliform Dystrophy

Patients with adult-onset foveomacular vitelliform dystrophy share the following clinical features: (1) visually asymptomatic or mild visual blurring and metamorphopsia in one or both eyes, usually with the onset between ages 30 and 50 years; (2) symmetric, solitary, usually 1/3–1 disc diameter-size, round or oval, slightly elevated, yellow subretinal lesions, often with a central pigmented spot in each eye ( Figures 5.08–5.10 ); and (3) small yellow flecks that may or may not be present in the paracentral region. The symptoms of blurring and metamorphopsia are often unilateral despite the frequent presence of bilaterally symmetric lesions. The symptoms may improve spontaneously. Initially, the yellow lesion may be present in only one eye. Although most of the foveal lesions are approximately 1/3 disc diameter in size, occasionally they may be larger and misdiagnosed as the “sunny-side-up” stage of Best’s vitelliform macular dystrophy or as bilateral serous detachment of the RPE ( Figure 5.09 ). The yellow foveal lesions often develop a central gray or orange clump of pigment that biomicroscopically may show evidence of the pigment extending into the posterior retinal layers ( Figures 5.08A and B , 5.09D , and 5.10A and B). Later the foveal lesions may fade and leave an irregular oval or round area of depigmentation of the RPE ( Figure 5.08E ). Some patients eventually develop additional paracentral yellow deposits, often in a triradiate pattern ( Figure 5.08D–F ). Fluorescein angiography during the early stages of the disease shows either a nonfluorescent lesion ( Figure 5.09C ) or, more typically, a small irregular ring of hyperfluorescence surrounding a central nonfluorescent spot (halo) ( Figures 5.08C and I and 5.09F ). Some of the extrafoveal small yellow lesions show discrete staining, such as drusen ( Figure 5.10 C), and others, similar to the foveal lesions, are either nonfluorescent or have a halo of fluorescence surrounding them. The yellow and gray components of the lesions are brightly autofluorescent and the depigmented RPE in late lesions are hypoautofluorescent ( Figure 5.11K and L ).

Adult-onset foveomacular vitelliform pattern dystrophy.

A–C: This 30-year-old white woman developed metamorphopsia and a positive scotoma in the right eye 6 weeks before examination. The symptoms had improved by the time of examination. Visual acuity in the right eye was 20/25-1 and J-1 and in the left eye was 20/50 and J-1. Symmetric, slightly elevated, oval, discrete, one-third disc diameter size, yellow lesions with a central pigment clump were present in the foveolar areas (A and B). There were several small yellow deposits in the paracentral area of the left eye (arrows). Her electro-oculographic findings were subnormal (1.4 in both eyes). Angiography showed a fluorescent ring centered in the fovea of each eye (C). Yellow lesions in the midperiphery fluoresced (arrows).

D: Right eye of the 54-year-old mother of the patient illustrated in A–C. She noted mild distortion of vision in her left eye 10 years previously. Visual acuity in the right eye was 20/40 and J-2 and in the left eye was 20/30 and J-2. In the center of the fovea is an irregular, round area of depigmentation surrounded by multiple yellowish deposits. A few deposits (arrow) are present in the extramacular area. Her electro-oculographic findings were subnormal (1.22 in the right eye and 1.40 in the left eye). The angiographic pattern was similar to that in C.

E and F: The 70-year-old maternal grandmother of the patient illustrated in A–C had noted mild difficulty with reading in her left eye for the first time 30 years previously. This remained unchanged since that time. She was asymptomatic in her right eye. Her visual acuity in both eyes was 20/40. Note the central area of depigmentation of the retinal pigment epithelium (arrow, E) and faintly visible peripheral flecks. Angiography showed a reticular pattern of irregular hyperfluorescence (F). Her electro-oculographic findings were subnormal (1.0 in both eyes).

G–L: Central yellow lesions resembling inanimate and animate objects, e.g., spaceship (G), chicken (H and I), sunfish (J), airplane (K), and hobbyhorse (L). Note the yellow paracentral flecks.

Large vitelliform lesions associated with adult-onset vitelliform foveomacular pattern dystrophy.

A–F: This 51-year-old woman’s visual acuity was 20/80 bilaterally. She had discrete slightly elevated, yellowish lesions in the center of both maculae (A and B). Angiography revealed the lesions to be nonfluorescent (C). Same patient 3 years later (D and E). Note the pigment in the center of the lesion. Visual acuity was 20/60. The angiogram now showed an irregular hyperfluorescent ring centered in the fovea (F). Similar changes took place in the left macula during this same period of time. The patient gave no family history of macular degeneration. Her electro-oculographic findings were normal.

G–L: This 68-year-old woman’s visual acuity was 20/50 bilaterally. Note the large vitelliform lesions (G and H). Her electro-oculographic findings were normal (2.8 in the right eye and 3.5 in the left eye). The lesion in the left eye was nonfluorescent initially (I). Later phases (J and K, stereo, and L), however, suggested possible underlying choroidal neovascularization.

(A–F from Gass. )

Clinicopathologic findings in adult-onset vitelliform foveomacular pattern dystrophy.

A–F: This 66-year-old woman had a 4-month history of gradual decrease of vision in both eyes. Her visual acuity was 20/30 and J-1 in the right eye and 20/40 and J-2 in the left eye. Note the central foveal yellowish lesions with central black dots and the scattered, small, yellowish lesions in the paracentral area (A and B). Angiography revealed a fluorescent ring in the central macular area and hyperfluorescence of the small paracentral lesions (C.) One year later the patient’s vision had deteriorated slightly secondary to cataracts. The fundi were unchanged. The patient died soon after of carcinoma of the liver and the eyes were obtained for pathologic examination. Histopathologic findings in the right macula (D) showed focal loss of retinal receptor elements and pigment migration into the retina in the foveal area (arrow 1), clumping of cells laden with pigment and chorioretinal adhesion in the foveal area (arrow 2), a paracentral zone of thinning of the retinal pigment epithelium (arrows 3 and 4), and focal drusen (arrow 5). High-power view of the foveolar area (E) showed clumps of pigment-laden cells and calcific body (arrow). Note preservation of the choriocapillaris and slight thickening of the intercapillary pillars. High-power view of typical drusen (F) corresponding with one of the small yellow paracentral lesions.

G–J: Small partly faded central lesion (G and H) in the 57-year-old daughter of an 81-year-old mother with bilateral butterfly pattern of yellow flecks (I and J). The daughter’s visual acuity was 20/40 in the right eye and 20/50 in the left eye and the mother’s was 20/70 in both eyes.

(A–F from Gass. )

Variations in pattern dystrophy.

A–C: Family with adult vitelliform foveomacular dystrophy. The 28-year-old son (A) had mild blurring of vision in the right eye and bilateral, small, focal vitelliform lesions in the macula. Visual acuity was 20/20 in the right eye and 20/15 in the left eye. Electro-oculographic ratios were 1.6 in both eyes. The 51-year-old mother had bilateral butterfly dystrophy (B and C). Her visual acuity was 20/25 in the right eye and 20/30 in the left eye. The 81-year-old maternal grandfather had bilateral geographic atrophy of the RPE and less than 20/200 vision.

D and E: Fundus pulverulentus type of pattern dystrophy in a 73-year-old man with mild visual loss of 3 years’ duration. Visual acuity was 20/25. He had prominent reticular pigmentary changes in the periphery.

F–H: Reticular dystrophy in a young girl with visual acuity of 20/20 in both eyes. Her electro-oculogram and electroretinogram were normal. Two siblings had similar findings.

I–L: This 10-year-old male complained of difficulty seeing the blackboard. His visual acuity was 20/15 and 20/20 uncorrected. Both retinas show symmetrical appearance of honeycomb or chicken wire-like reticular pattern dystrophy (I and J). The hyperpigmented retinal pigment epithelium showed increased autofluorescence (K). The fovea had a normal contour with intact inner segment–outer segment junction (L, right eye).

(F–H, courtesy of Dr. Lee S. Anderson; I–L, courtesy of Dr. Scott Brodie.)

This form of pattern dystrophy was observed in females in three successive generations in one family ( Figure 5.08A–F ) at the Bascom Palmer Eye Institute. This family was originally reported in 1974 by this author (Gass) as having a peculiar foveomacular dystrophy, later referred to as adult-onset vitelliform foveomacular dystrophy. Recently a mutation of the peripherin RDS gene has been demonstrated in two of these patients. The mothers of two unrelated patients with adult-onset foveomacular vitelliform lesions showed evidence of butterfly dystrophy ( Figure 5.12A–G ).

Pattern dystrophy simulating fundus flavimaculatus.

A–C: This 53-year-old woman had 20/20 visual acuity bilaterally. Her electroretinographic and electro-oculographic findings were normal. There was no family history for eye disease. Angiograms of both eyes (B and C) showed multifocal stellate hypofluorescent lesions surrounded by hyperfluorescence and no evidence of diffuse dampening of the background fluorescence.

D–H: Clinicopathologic findings in a 51-year-old man with normal visual acuity and a fundus picture simulating fundus flavimaculatus. Note the peripheral flecks and the normal appearance of the central macular area (D–F). Light and electron microscopy revealed subtle and focal distension and minor variations in pigmentation of the retinal pigment epithelium (RPE). Occasional cells showed distended, relatively nonpigmented, dome-shaped apices extending above the adjacent RPE (G and H). The RPE did not stain with periodic acid–Schiff or for acid mucopolysaccharides. Electron microscopy showed that those RPE cells with distended cytoplasm contained tubulovesicular membranous material (H).

I–L: A 55-year-old woman from Trinidad with mixed heritage of African, East Indian, and French presented with decreased vision in her left eye to 20/100. Both fundi showed extensive fundus flavimaculatus type of pattern dystrophy extending beyond the arcades and loss of the vitelliform material in much of the lesions. Both maculas showed geographic atrophy and the left, a choroidal neovascularization in addition (I). A fluorescein angiogram confirmed the subfoveal choroidal neovascular membrane in the center of the geographic atrophy, with increasing fluorescence in the late frames (J and K). Note the absence of a dark choroid and halo of hyperfluorescence around central blockage from pigment, typical of fundus flavimaculatus type of pattern dystrophy. The right eye had a similar appearance without the choroidal neovascular membrane. She received intravitreal injections of bevacizumab every month for 4 months followed by every 2 months for a total of 8 injections. Her vision in the left eye improved to 20/40 and continued to remain stable at last follow-up 3 years later. An autofluorescence imaging shows increased autofluorescence of the yellow flecks and decreased autofluorescence of the atrophic flecks (L).

Unlike those in Best’s vitelliform macular dystrophy, the vitelliform lesions in patients with pattern dystrophy usually first appear in the fourth decade or beyond, are generally smaller, and do not show disruption and layering of the yellow pigment in the dependent portion of the lesions. In some families there is an overlap in the features of Best’s disease and pattern dystrophy.

Group 2: Butterfly-Shaped Pigment Dystrophy

When the gray or yellow pigment is arranged in a well-organized triradiate pattern confined to the center of the macula in a symmetric fashion, it has been likened to the shape of a butterfly ( Figure 5.12 A–C). A zone of depigmentation occurs around the pigment figure. The optic disc and vessels are normal. Some patients have a reticular pigmentary pattern of drusen in the periphery. The early phases of angiography show hyperfluorescence that outlines the nonfluorescent pigment figures in the macula ( Figure 5.12 C). The shapes of the central yellow lesions in pattern dystrophies vary considerably and may simulate a variety of inanimate or animate objects ( Figure 5.08G–L ).

Group 3: Reticular Dystrophy of the RPE

In patients with reticular dystrophy the pattern of yellow pigment extends into the periphery of the macula in a highly organized pattern that has been likened to coarse, knotted fishnet or chicken wire ( Figure 5.12J–L ). Its development usually begins in the foveal area. The network gradually extends four or five disc diameters from the macula in all directions. The net meshes are usually less than one disc diameter in size. The midperiphery and the periphery of the fundus are unaffected early in the disease. The network may be more apparent angiographically than ophthalmoscopically ( Figure 5.12H ). It usually fades with age and may be replaced by extensive atrophic changes in the RPE in later life. A similar but coarser pigmentary network has been reported by Mesker and associates. Patients with reticular dystrophy may show an autosomal-recessive as well as autosomal-dominant inheritance.

Group 4: Multifocal Pattern Dystrophy Simulating Fundus Flavimaculatus

Some patients develop multiple irregular or triradiate yellow lesions centrally or eccentrically, and in some cases these are widely scattered and partly interconnected in a triradiate fashion that may simulate that in fundus flavimaculatus (Stargardt’s disease) ( Figure 5.13A–H ). These patients, who do not show fluorescein angiographic evidence of a dark choroid suggesting lipofuscin storage, have been recently reported as examples of dominantly inherited fundus flavimaculatus (see p. 284). Unlike most patients with fundus flavimaculatus, these patients have good visual acuity and a more favorable visual prognosis. However, some of these patients with an exaggerated phenotype can show progressive loss of the yellow material and RPE/photoreceptor thinning and atrophy resulting in islands of, or confluent, geographic atrophy ( Figure 5.13 ). Choroidal neovascular membranes can rarely occur ( Figure 5.13 ). Histopathologic and electron microscopic studies of the eye of a patient with this type of pattern dystrophy have demonstrated that the flecks are not caused by abnormal lipofuscin storage ( Figure 5.13 G and H).

Complications of pattern dystrophy.

Choroidal neovascular membrane (CNVM).

A–H: This 75-year-old woman had a history of solitary vitelliform lesions in both eyes and presented with a choroidal neovascular membrane in her left eye and a visual decline to 20/100 (A, B). She underwent photodynamic therapy to the left eye, which resulted in a disciform scar. Fifteen months later the vision in the right eye dropped to 20/40 with increase in the size of the vitelliform lesion and reorganization of the central pigment (C). An angiogram showed staining of the yellow material (D and E). Four months later her vision dropped to 20/100; she now showed evidence of a CNVM with subretinal fluid and blood (F). An angiogram showed a classic CNVM with lacy appearance early and late leakage (G and H). The right eye also underwent photodynamic therapy with limited success.

Geographic atrophy.

I–L: This 65-year-old male presented with a vision of 20/70 in the right and 20/20 in the left eye. There was a small island of geographic atrophy corresponding to the loss of the yellow pigment in the foveal lesion (I and J). Autofluorescence shows decreased autofluorescence consistent with loss of retinal pigment epithelium (K). The left vitelliform lesion showed hyperautofluorescence (L).

Group 5: Coarse Pigment Mottling in the Macula (Fundus Pulverulentus)

Patients with fundus pulverulentus typically display mild visual loss associated with a prominent, coarse, punctiform mottling of the pigment epithelium in the central macular area ( Figure 5.12 D–G). This pattern is most often seen in patients with pseudoxanthoma elasticum in the author’s experience.

Although it is convenient to subdivide patients with pattern dystrophy into these five groups, it is important to realize that the fundus findings in some patients do not fall precisely into one group. Some may show one pattern in one eye and another pattern in the fellow eye. Others may show one or more eccentric triradiate yellow or darkly pigmented lesions. Some may have one or more lesions in only one eye early in their course. The fundus findings in patients with pattern dystrophy and an asymmetric distribution of triradiate pigment figures must be differentiated from similar findings that may develop in some patients with recurrent idiopathic central serous chorioretinopathy/organ transplant retinopathy, and in patients with Elschnig spots caused by hypertensive choroidopathy, e.g., in a patient with toxemia of pregnancy. (See Figure 3.57 , Figure 3.58 .)

The visual prognosis is good in all subgroups of dominantly inherited pattern dystrophy. Late geographic atrophy ( Figure 5.11 I and K) and choroidal neovascularization may occur in any of the subgroups and are responsible for visual loss. Choroidal neovascularization occurs only infrequently. Gass observed it most frequently in patients with the solitary vitelliform, butterfly pattern, and the exaggerated pattern simulating fundus flavimaculatus ( Figures 5.11 A–H and 5.12 I–L). Some, if not most, of the reports of subretinal neovascularization in fundus flavimaculatus probably concern patients with pattern dystrophy. Absence of a dark choroid angiographically and good visual function suggest pattern dystrophy rather than fundus flavimaculatus. An occasional cause of loss of vision in these patients is the development of a macular hole. Gass has observed the development of a macular hole in both eyes of a patient who some years previously presented with adult-onset foveomacular dystrophy.

Histopathologic examination of two eyes of a patient with a solitary yellow foveal lesion bilaterally ( Figure 5.10 A–F) showed focal loss of the retinal receptor elements and atrophy and partial loss of the RPE in the foveal area of both eyes. The central pigmented spots seen biomicroscopically were caused by a clump of large pigment-laden cells and extracellular melanin pigment lying between the retina and Bruch’s membrane with some extension into the outer retinal layers. In a ringlike zone surrounding this central pigment clump was a thick layer of slightly granular, eosinophilic, PAS-positive material lying between the thinned atrophic RPE and Bruch’s membrane. Fluorescent microscopy showed no unusual amount of lipofuscin present within the RPE cells in this lesion. Bruch’s membrane, the choriocapillaris, and the large choroidal blood vessels underlying the lesion were within normal limits. The paracentral yellow spots seen ophthalmoscopically proved to be typical drusen histopathologically ( Figure 5.10 F).

Histopathologic examination of the eyes of two other patients with almost identical lesions revealed similar findings. In one case, however, the eye showed evidence of a high concentration of lipofuscin, which may be responsible for the central yellow lesion. A report of the histopathologic and ultrastructural findings in two eyes of a 51-year-old man with a pattern of flecks suggesting fundus flavimaculatus and normal macula and visual acuity found no evidence of lipofuscin storage or acid mucopolysaccharide accumulation in the RPE – these are characteristic findings in fundus flavimaculatus ( Figure 5.13 D–H). Elevated aggregates of enlarged RPE cells with apices distended by accumulated lipid membranes with a tubulovesicular appearance were responsible for the flecks ( Figure 5.13 G and H). The findings in this patient suggest that the yellow flecks in the pattern dystrophies, although they clinically appear similar to those in Stargardt’s disease and fundus flavimaculatus, are not caused by focal lipofuscin storage in the RPE. The same may prove true in the case of vitelliform lesions in Best’s disease. Unlike patients with Stargardt’s disease, patients with Best’s disease and adult-onset vitelliform foveomacular dystrophy do not show the angiographic feature of obstruction of the normal background choroidal fluorescence (silent choroid) that is caused by diffuse heavy deposition of lipofuscin material in the RPE.

Group 1: Vermillion Fundi and Hidden Choroidal Fluorescence

Some patients with subnormal visual acuity have relatively normal-appearing fundi except for the easy-to-overlook heavily pigmented RPE that in most white patients imparts a vermillion color and that obscures most of the details of the choroid from view ( Figures 5.18 A and B and 5.19 A and B). Angiographically the retinal vessels are displayed prominently on a dark background of minimal choroidal fluorescence. In some cases the retinal capillaries appear to be more dilated than normal.

Group 2: Atrophic Maculopathy with or without Flecks

In some patients the loss of pigment in the macula may be so minimal that only with angiography can this be demonstrated with certainty ( Figure 5.18 E). These patients and those in group 1 may be misdiagnosed either as having functional complaints or as having a lesion involving the optic pathways. Particularly in young children, the flecks may not be present or may be quite small and limited in number ( Figure 5.18 F). Likewise the vermillion fundus and dark choroid angiographically may not be present in early life ( Figure 5.18 D and E). On subsequent follow-up, flecks as well as evidence of diffuse lipofuscin storage in the RPE occur ( Figure 5.18 F and G). The flecks may be confined to the macula or may extend into the midperiphery of the fundi. The degree and pattern of atrophy of the RPE in the central macular area vary and do not always correlate with the degree of visual loss. The RPE may show only mild loss of its normal color, a beaten-metal appearance, or marked geographic atrophy. A diffuse oval or bull’s-eye pattern of atrophy occurs commonly ( Figures 5.18 H and I and 5.19 J–L). The lipofuscin within the flecks accounts for the increased autofluorescence, which may be surrounded by regions of decreased autofluorescence from the adjacent atrophic RPE. The autofluorescence pattern can resemble chronic idiopathic central serous chorioretinopathy, mitochondrial myopathies, and flecks of pattern dystrophy. Patients with fundus flavimaculatus show a ring of decreased autofluorescence around the disc and in the fovea, unlike those with mitochondrial myopathies where this pattern is absent ( Figure 5.18 J and K). Patients with the bull’s-eye change may initially be seen with normal visual acuity and a ring scotoma. A few such patients retain 20/20 visual acuity until 40 years of age or beyond ( Figure 5.20 G–L). Varying degrees of atrophy of the RPE surround and extend between the flecks. This is always more evident angiographically than biomicroscopically ( Figure 5.19 H). If the number of flecks and amount of RPE atrophy are great, the angiographic dark choroid sign typical of Stargardt’s disease may not be evident in the posterior fundus, although it is often preserved in the peripapillary area. The optic disc and retinal vessels in patients in groups 1 and 2 are normal.

Extensive flecks of fundus flavimaculatus.

A–F: This 30-year-old male had extensive involvement of the fundus in both eyes extending almost to the equator (A–D). Note the decreased autofluorescence in most of the lesions except the very anterior ones that show increased autofluorescence, signifying progressive atrophy of the retinal pigment epithelium cells and loss of their lipofuscin content (E and F). His visual acuity was count fingers in the right and 20/30 in the left eye.

Evolution of flecks in fundus flavimaculatus and normal vision.

G–L: This 21-year-old young male was asymptomatic in 2004 and the flecks were discovered on a routine examination for glasses. He had a vermillion fundus without visible choroidal vessels in the posterior pole and yellow flecks, some with central pigmentation in the superior macula and superior to the disc (G and H). The red-free images better delineate the flecks.

I and J: Five years later there was a significant increase in the flecks now distributed all over the posterior pole and nasal to the disc in both eyes (K and L). His visual acuity was still 20/20 in each eye.

(A–F, courtesy of Dr. Franco Recchia and Dr. Brad Kehler.)

Patients with widespread flecks may develop in one or occasionally both eyes an eccentric well-defined zone of reactive RPE changes that includes hypertrophy, hyperplasia, fibrous metaplasia, and atrophy ( Figure 5.19 D). Patients with many flecks occasionally develop subretinal neovascularization and disciform detachment of the macula.

Color vision testing usually shows a mild red–green dyschromatopsia. Many patients show a prolongation in rod dark adaptation and selective prolongation of the later segment of rod recovery. Electroretinographic findings are usually normal or slightly disturbed. The EOG is subnormal in some cases. Some patients may develop photophobia, loss of color vision, and electroretinographic evidence of a cone dystrophy.

Group 3: Atrophic Maculopathy with Late Signs and Symptoms of Retinitis Pigmentosa

Patients in group 3 are similar to those in group 2 but in addition show signs and symptoms of retinitis pigmentosa, including nyctalopia, diffuse loss of pigment from the RPE, narrowing of the retinal vessels, and abnormalities of both the scotopic and photopic ERG.

Group 4: Flecks not Associated with Macular Atrophy

Patients may have paracentral and central flecks associated with minimal biomicroscopic and angiographic evidence of atrophy of the RPE between the flecks. Visual acuity may be normal if the center of the fovea is not involved by a fleck. Most patients with a large fleck in the foveola have subnormal acuity. Fluorescein angiography shows a dark choroid, obstruction of the background fluorescence by the flecks with minimal hyperfluorescence in a small area immediately surrounding the flecks. In the absence of information concerning other family members, and in eyes showing borderline evidence of a dark choroid, it may be difficult or impossible to differentiate some patients in group 4 from patients with dominantly inherited pattern dystrophy.

Whereas the fundus findings and the degree and rate of visual loss are usually symmetric, the atrophic changes and visual loss in some patients may be more advanced in one eye. In general, the onset, rate, and severity of visual loss are similar in family members, but notable exceptions to this rule occur. In an appraisal of visual loss with age by both life-table analysis and cross-sectional procedures in 95 patients with Stargardt’s disease, Fishman and associates found the probability of maintaining a visual acuity of 20/40 or better in at least one eye was 52% by age 19 years, 32% by age 29 years, and 22% by age 39 years. The visual acuity after reaching a level of 20/40 tended to decrease rapidly and stabilize at 20/200. Low-vision correction in these patients is highly successful.

There is considerable evidence that Stargardt’s disease and fundus flavimaculatus are the same disease and that the latter probably represents a more advanced and widespread stage of lipofuscin storage and RPE damage ( Figure 5.14 A–F). The age of onset of visual loss and the severity of visual loss are generally greater in patients with widespread flecks (fundus flavimaculatus). The electro-oculographic and electroretinographic findings are more likely to be subnormal in patients who either have or are destined to develop widespread flecks in the fundi and other signs and symptoms of a more widespread tapetoretinal dystrophy. The electrophysiologic studies therefore are probably of some prognostic value, particularly in younger patients who have only minimal flecks.

Histopathologic examination reveals that the RPE cells posterior to the equator are enlarged and densely packed with an intensely PAS-positive substance with ultrastructural, autofluorescent, and histochemical properties consistent with an abnormal form of lipofuscin ( Figure 5.21 ). The greatest concentration of this lipopigment is located in the posterior fundus. Scanning electron microscopy has shown evidence that focal areas of marked hypertrophy of RPE cells, as well as aggregates of cells containing lipofuscin, are responsible for the nonfluorescent yellow flecks ( Figure 5.21 I and J). Figure 5.21 (E–G) illustrates the typical light microscopic changes that occurred in one eye in each of two sisters with identical changes of geographic atrophy of the RPE associated with macular flecks characteristic of Stargardt’s disease. In an eye of a 16-month-old boy with incipient Stargardt’s disease the RPE cells were less distended with lipofuscin and at 9 years of age his remaining eye showed angiographically a dark choroid that was confined to the posterior fundus. This observation and the angiographic changes in the child illustrated in Figure 5.18 (D–G) are in keeping with the concept that the lipofuscin storage disorder of the RPE is an ongoing process and may not be clinically detectable in the early years of life. Birnbach et al. have suggested that all-trans retinol dehydrogenase, a photoreceptor outer-segment enzyme, may be defective in these patients.

Clinicopathologic findings in Stargardt’s disease.

A and B: Progression of geographic atrophy over a 9-year period in a patient with Stargardt’s disease.

C: Young woman with Stargardt’s disease and large area of geographic atrophy of the retinal pigment epithelium (RPE). Note flecks near the edge of the central lesion. Her sister, who had identical findings, died of cancer and her eyes were obtained at autopsy.

D–G: Histopathology of Stargardt’s disease in the sister of the patient illustrated in C. Both sisters had geographic atrophy of the RPE with surrounding flecks in the macular area ophthalmoscopically (C). Note the enlarged RPE cells engorged with lipofuscin pigment in the posterior fundus (D); the positive staining of the RPE with periodic acid–Schiff (PAS) (E); the loss of the outer retinal layers and RPE (arrows) in the central macular area (H); and the near-normal appearance of the RPE near the equator (G).

H–J: Scanning electron microscopy (I) and light microscopy (J) of the eye removed from a 24-year-old man with widespread flecks (fundus flavimaculatus) in the fundi (H) revealed that the flecks were caused by focal hypertrophy of the RPE cells that are distended with an intensely PAS-positive, granular, autofluorescent substance with the properties of an abnormal form of lipofuscin.

K: Diffusely hypertrophic RPE with PAS-positive granules, in the posterior pole (above), where there are more RPE melanosomes, compared to the periphery with fewer RPE melanosomes.

(C–G, courtesy of Dr. Robert P. Shaver; H–J, from Eagle et al. ; K, courtesy of Dr. Ralph C. Eagle Jr.)

The marked engorgement and hypertrophy of the RPE cells with lipofuscin in patients with widespread flecks appear to predispose them to development of one or more local patches of reactive and hypertrophic changes in the RPE ( Figure 5.19 D). The author has seen these RPE lesions in association with fundus flavimaculatus in eight patients. In at least one patient they were observed to develop following a blow to the head with a dodgeball ( Figure 5.19 D). Thus RPE engorgement with lipofuscin may predispose patients with fundus flavimaculatus to outer retinal damage in the event of a contusion injury. At the 1995 Retinal Society Meeting Dr. Richard Ober reported a patient with fundus flavimaculatus who sustained blunt trauma and Berlin’s edema that was confined to the macular region in an eye with the typical appearance of fundus flavimaculatus. Several weeks later the patient developed widespread degenerative changes of the RPE and subretinal fibrosis in the injured eye. Del Buey et al. have reported similar severe degenerative changes developing rapidly in association with fundus flavimaculatus in a young girl struck in the eye with a cork.

In most patients who show clinical evidence of lipofuscin storage fundus flavimaculatus is inherited as an autosomal-recessive trait. A similar phenotype, however, occurs in some families showing evidence of dominant inheritance ( Figure 5.19 A–G). The author has seen only one such family, and because only involvement of two successive generations was demonstrated, the inheritance may be recessive rather than dominant ( Figure 5.19 A–G). In families with dominantly inherited fundus flavimaculatus, gene mutations have been mapped to the short arm of chromosome 1 and to chromosome 13q34. Linkage to chromosome 6q has also been established. The patients in this latter family did not show angiographic evidence of lipofuscin storage. The author believes that patients with a fundus flavimaculatus-like distribution of flecks, absence of a dark choroid, autosomal-dominant inheritance, and generally a more favorable visual prognosis are more appropriately classified as having pattern dystrophy rather than Stargardt’s disease. Likewise, the author prefers to classify recessively inherited atrophic macular dystrophies in patients without flecks and without a dark choroid as “unclassified” rather than Stargardt’s disease.

Pattern dystrophy is not the only disorder that may simulate fundus flavimaculatus. A similar pattern of flecks may develop within weeks or several months in one or both eyes of patients with idiopathic uveal effusion (see Chapter 3 ), diffuse bilateral uveal melanocytic proliferation (see chapter 13 ), renal or other organ transplantation and chronic central serous chorioretinopathy (see Chapter 3 ), collagen vascular disease (see Chapter 3 ), and large cell lymphoma (see chapter 13 ).

North Carolina-Like Dominant Macular Dystrophy

Three other families with autosomal-dominant drusen and early-onset macular dystrophy resembling North Carolina macular dystrophy have been described recently with loci different from 6q14-q16.2. One is a four-generation British family localized to chromosome 5, region p13.1-p15.33, MCDR3 ; second, an English family with associated progressive sensorineural deafness to chromosome 14q ; and the third, a North American family mapped to 6q14 between loci for cone–rod dystrophy 7 ( CORD7 ) and North Carolina macular dystrophy ( MCDR1 ).

Chorioretinal Coloboma

Patients with typical inferotemporal chorioretinal colobomas that extend into the macula may occasionally develop loss of central vision because of choroidal neovascularization developing at the margin of the coloboma (Figure 3.31K and L).

Parametric linkage analysis originally localized the SFD gene to chromosome 22q13-qter. Subsequently, five different missense mutations and a splice site mutation have been identified in TIMP3 (tissue inhibitor of metalloproteinases 3). In the UK, all SFD families carry the same Ser181Cys TIMP3 mutation and it has been suggested that all cases relate to one single ancestor. TIMP3 encodes an RPE-expressed member of a group of zinc-binding endopeptidases involved in retinal extracellular matrix remodeling. Most recently a susceptibility locus near TIMP3 has been found to be associated with age-related macular degeneration, suggesting overlap of some disease mechanisms between the two conditions.

Nonprogressive Cone Dysgenesis

X-Linked Blue Cone Monochromatism

Patients with X-linked blue cone monochromatism are males having subnormal visual acuity, pendular nystagmus, photophobia, myopia, minimal fundus changes, and psychophysical and electrophysiologic evidence of both normal rod and blue cone functions. Neither red cone nor green cone function can be demonstrated psychophysically. Mutations in the L- and M-opsin gene array that result in the lack of functional L- and M-pigments, and thus inactivate the corresponding cones, have been identified in the majority of cases with blue cone monochromatism. Provisional assignment of the gene locus for blue cone monochromasy is in the vicinity of Xq28.

Congenital Color Blindness

Deuteranomaly results when a normal middle-wavelength (M) cone pigment is replaced by one that has a peak sensitivity at a longer wavelength (L). Protanomaly results when the normal long-wavelength pigment is replaced by one that has a peak sensitivity at a shorter midrange wavelength. Protanopia is caused by lack of a red cone pigment and deuteranopia by lack of green cone pigment. Visual acuity and the ocular fundi are normal. They are also inherited as an X-linked disorder and the gene defect is at Xq28. Congenital tritanopia, if it exists, is rare.

Goldmann–Favre Syndrome

There is increasing evidence to suggest that Goldmann–Favre syndrome may be a genetically determined retinal receptor dysgenesis primarily affecting the cone system in which an overabundance of S-cones partly replaces the other cone types. (See p364, ch 5.)

Late-Onset Sporadic Cone Dystrophy

Patients with late-onset sporadic cone dystrophy, who are often older than 50 years of age at the onset, develop slowly progressive loss of central or paracentral vision usually in the absence of any fundoscopic abnormalities. Visual acuity is often normal or near normal at presentation. Detection of color vision dysfunction is an important clue to early diagnosis because initially full-field ERG findings may be normal. These patients are often subjected to extensive neurologic investigations. The differential diagnosis in patients, particularly if they present with asymmetric paracentral field defects, or with a history of rapid onset of visual loss that may be associated with photopsia, includes acute zonal occult outer retinopathy (see Chapter 11 ) and occult macular dystrophy. Drug toxicity has been implicated in acute cone degeneration.

A subgroup of patients with Stargardt’s disease (atrophic maculopathy, flecks, and a dark choroid on fluorescein angiography) present with hemeralopia and ERG changes typical for a cone dystrophy. The disorder is recessively inherited in these patients with few exceptions.

The retinal dystrophy associated with autosomal-dominant cerebellar ataxia may affect primarily the cone system (spinocerebellar ataxia 7: SCA 7, see later section). Two of the four patients described with this association showed, in addition to the typical ERG findings of a cone dystrophy, a supernormal dark-adapted b-wave.

Some patients with cone and cone–rod dystrophies may exhibit a bright tapeto-like retinal reflex. Heckinlively and Weleber reported a late-onset cone dystrophy with X-linked recessive inheritance in patients with a greenish-golden iridescent RPE change in the posterior pole ( Figure 5.32 J–L). These patients demonstrated the Mizuo–Nakamura phenomenon and were prone to development of rhegmatogenous retinal detachment (see Oguchi’s disease, Figure 5.37 ). In a family with dominant cone dystrophy, Noble et al. observed a scintillating golden reflex, identical to that seen in female carriers of X-linked retinitis pigmentosa in the son and a diffuse golden-gray sheen similar to that of Oguchi’s disease in his mother. A golden sheen and pigment disturbance may also occur in families with progressive visual loss, normal ERG findings, and absence of the Mizuo–Nakamura phenomenon.

Analysis of genomic DNA isolated from affected members of a family of X-linked cone degeneration revealed a 6.5-kilobase deletion in the red cone pigment gene. Reduced levels of alpha-l-fucosidase activity in leukocytes was found in two patients with sporadic cone dystrophy. Screening of 24 patients with several forms of cone dystrophy failed to find this abnormality. Antibodies against human retinal proteins have been identified in the serum of some patients with cone dystrophy.

Heavily tinted glasses or miotics may be helpful in alleviating photophobia in patients with cone dystrophy.

Occult Hereditary Macular Dystrophy

Miyake et al. described three patients in two generations with progressive central visual loss, normal fundus and fluorescein angiographic findings, mild or moderate color vision defects, normal full-field ERG, and severely affected macular ERG. It is an autosomal-dominant disorder with age of presentation between 20 and 45 years, though an 11- and a 16-year-old patient have been described. Since the original description, the spectrum of visual loss and progression has widened. The presenting visual acuity is from 20/20 to 20/200. Color vision is variably affected. Some patients may show no progression of visual loss or change in their central scotoma, while the majority show worsening central vision. Multifocal ERG and more recently OCT have been useful in confirming the findings. All patients show foveal cone involvement; some show variable involvement of foveal rods. The characterisitic multifocal ERG finding is decreased amplitudes in the central ring or hexagons, with amplitudes returning to the control values as one moves eccentrically towards the peripheral hexagons. Implicit times, in addition, have been found to be delayed in some studies, suggesting involvement of more anterior retinal elements than cones alone. OCT shows variable thinning of the outer nuclear layer in most eyes, though some eyes with poor cone function have normal outer nuclear thickness, suggesting functional rather than structural loss. Though the early reports were from Japan, case series have been described in Italy, the rest of Europe, and the USA. No specific gene defect has so far been implicated.

Sporadic Occult Macular Dystrophy

A clinical and electrophysiologic appearance identical to the hereditary form of occult macular dystrophy has been seen in patients with no family history suggesting the disorder may have multiple etiologies or has variable penetrance. Patients with autoimmune antibodies to enolase or other retinal elements can present with central scotoma, cone dysfunction, and normal fundus and fluorescein appearance. A careful history of the age at onset of symptoms, progression, and any associated autoimmune disease may help differentiate these patients from occult macular dystrophy.

Normal Fundus

Autosomal-dominant (absent scotopic ERG, Riggs type; type I)

• 1.
  

  rhodopsin mutation ( RHO )

  
  
• 2.
  

  α subunit of rod transducin ( GNAT1 , Nougaret)

  
  
• 3.
  

  β subunit of rod cGMP phosphodiesterase ( PDE 6B )

X-linked (negative ERG, Schubert–Bornshein, type II)

• 1.
  

  L-type calcium channel ( CACNA1F ) incomplete X-linked stationary night blindness

  
  
• 2.
  

  Unidentified gene Xp11.4-11.3 complete X-linked stationary night blindness.

Abnormal Fundus

Autosomal-recessive

• 1.
  

  Arrestin ( SAG : Oguchi)

  
  
• 2.
  

  Rhodopsin kinase ( RHOK : Oguchi)

  
  
• 3.
  

  11- cis retinol dehydrogenase ( RDH5 : fundus albipunctatus).

Autosomal-Dominant Congenital Stationary Night Blindness

Autosomal-dominant patients have normal visual acuity and classically show a reduced but normal-appearing photopic response, and poor or absent amplitudes under scotopic conditions. This type of ERG response in congenital stationary night blindness is referred to as the Riggs response. Prolonged dark adaptation does not improve the scotopic ERG amplitudes. Some pedigrees, however, may show a Schubert–Bornschein-type response (electronegative ERG) that is more frequently observed in recessive and X-linked pedigrees of congenital stationary night blindness.

Autosomal-Recessive and Simplex Congenital Stationary Night Blindness

Autosomal-recessive and simplex patients may have normal or moderately reduced visual acuity and most are myopic. The ERG typically shows a progressive increase in the negative response (a-wave) during dark adaptation, but no similar increase in the positive response (b-wave). This electronegative ERG in congenital stationary night blindness is referred to as the Schubert–Bornschein type and it may occur in X-linked as well as recessive pedigrees. Miyake et al. further subdivided this group of patients based on the evaluation of the rod ERG and/or psychophysical dark adaptation: one group (complete type) lacked rod function, and the other group (incomplete type) showed evidence of rod function.

X-Linked Congenital Stationary Night Blindness

These patients are usually myopic and most have subnormal visual acuity. The fundi are unremarkable other than for myopic changes. Electroretinographic changes include normal to near-normal photopic responses and a barely recordable or unrecordable scotopic response. Dark adaptation studies typically show elevated rod thresholds. Reduced amplitude of oscillatory potentials of the ERG occurs in most patients as well as in female carriers of the X-linked form. Most heterozygous (carrier) females in families with X-linked congenital stationary night blindness are asymptomatic. Those with symptoms and electrophysiologic evidence of the disorder are nearly all daughters of asymptomatic carrier mothers. Daughters of affected males rarely show signs or symptoms of congenital stationary night blindness. Uneven X-chromosomal lionization is the most likely reason for females manifesting this disorder. The gene locus of this disorder has been found on the short arm of the X chromosome proximal to the DXS7 locus, the region between OTC and TIMP on the short arm of the X chromosome, and distal to Li.28 at Xp21.

Patients with congenital stationary night blindness may present with infantile blindness with a markedly subnormal photopic and scotopic ERG. This may incorrectly suggest the diagnosis of Leber’s congenital amaurosis. Visual responsiveness as measured by ERG takes 6–12 months to mature fully. In congenital stationary night blindness visual improvement during photopic conditions in these patients may be dramatic during the first year of life. Serial ERGs to detect evidence of this improvement may be helpful in some cases.

Oguchi’s disease, fundus albipunctatus, and Kandori’s disease are disorders in which congenital stationary night blindness is associated with fundus changes.

Oguchi’s Disease

Oguchi’s disease is one form of congenital stationary night blindness in patients with normal visual acuity, visual fields, and color vision. Ophthalmoscopy in the light-adapted state reveals either a greenish-white or a golden-yellow color to the fundus ( Figure 5.37 A and B). It may be confined to the posterior pole or to the periphery, or it may involve both. The density of these RPE changes obscures the details of the choroidal vasculature. The retinal vessels stand out in bold relief, and the color of the arteries and veins may be similar. The fundus achieves a normal color in from 30 minutes to several hours after dark adaptation (Mizuo phenomenon) ( Figure 5.37 F). Fluorescein angiography yields normal results ( Figure 5.37 E). Dark adaptation shows a delayed secondary adaptation (type I) or, rarely, absence of secondary adaptation (type II). The ERG shows subnormal rod responses that usually persist after prolonged adaptation. Oguchi’s disease is similar to fundus albipunctate dystrophy in that there is reversibility of the psychophysical function following prolonged dark adaptation, but it is different from X-linked congenital stationary night blindness associated with myopia, in which this adaptation does not occur. Histopathologic studies have revealed abnormally large cones in an area that extends 20° temporal from the optic disc and an additional layer of granular pigment between the photoreceptors and the true RPE. Yamanaka failed to find evidence of a distinct layer between the RPE and the receptors. De Jong et al. in four patients with X-linked retinoschisis postulated that the Mizuo–Nakamura phenomenon may be caused by an excess of extracellular potassium in the retina as a result of a decreased potassium-scavenging capacity of retinal Müller cells.

Oguchi’s disease.

A–F: This 46-year-old black woman had normal visual acuity. Note the golden color of the fundus in the light-adapted state (A–D). Her electro-oculographic findings were normal. The electroretinogram showed depression of the b-wave and reduced rod function. Angiography (E) was normal. Fundus photographs (F) of the right eye following 1 hour of dark adaptation. Note the color of the retinal pigment epithelium is normal.

This disease is inherited as an autosomal-recessive trait and mutations have been identified mostly in the arrestin gene and occasionally in the rhodopsin kinase gene.

A golden sheen confined to the macular area and the Mizuo phenomenon may occur in some patients with progressive, late-onset X-linked cone dystrophy ( Figure 5.32 J–L) and X-linked retinoschisis.

Nonprogressive Albipunctate Dystrophy (Fundus Albipunctatus)

Patients with nonprogressive albipunctate dystrophy complain of night blindness. Visual acuity, visual fields, and color vision are normal. Fundoscopic examination reveals a large number of discrete, small, punctate, white spots at the level of the RPE ( Figure 5.38 ). These lesions have their maximum density in the postequatorial region, but the center of the macula is usually spared ( Figure 5.38 ). The spots generally increase in number over the years but some spots can disappear over time in older people. The disc and retinal vessels are normal. The ERG is usually normal, but when it is abnormal, it usually improves toward normal levels after prolonged adaptation. The EOG may be subnormal but becomes normal after prolonged dark adaptation. The dark adaptation thresholds are markedly elevated but return to normal absolute threshold levels if the test is continued for several hours or longer. Overnight patching of the eyes prior to electrophysiological tests is a useful way to achieve prolonged dark adaptation. Fluorescein angiography reveals a mottled pattern of fluorescence throughout the midperiphery of the fundus. In general there is no correlation between the areas of hyperfluorescence and the white spots. Angiography may demonstrate changes in the RPE in the macular area, and occasionally a few patients may lose central vision because of a cone dystrophy or atrophic maculopathy ( Figure 5.38 B and C). The flecks are not hyperautofluorescent suggesting that these changes may not be at the pigment epithelial level but rather in the outer part of the photoreceptor layer. High-definition OCT confirms that the flecks correspond to dome-shaped opacifications at the photoreceptor outer-segment layer and continuous with the RPE cells. The disease demonstrates an autosomal-recessive inheritance with the gene defect in 11- cis retinol dehydrogenase (RDH5), the enzyme found in the RPE cells responsible for the production of 11- cis retinal, which is transported to the rods and cones to act as the chromophore in rhodopsin and cone opsins. A total of 19 different mutations have been found thus far in patients with fundus albipunctatus.

Fundus albipunctatus.

A and B: This 14-year-old female had normal vision, normal electroretinogram, and an abnormal electro-oculogram. The central and peripheral visual fields were normal. Dark adaptation studies revealed absence of rod vision. Small punctate opacities extended almost to the ora serrata (A and B). Two brothers, 15 and 17 years of age, had similar findings. All the patients were night-blind. A 12-year-old sister had normal eyes. Angiography revealed a mottled pattern of hyperfluorescence indicative of depigmentation of the retinal pigment epithelium (RPE) everywhere except in the macular area. Some of the punctate spots obscured choroidal fluorescence, whereas others did not.

C: Fundus albipunctatus in a 33-year-old man with bilateral macular dystrophy. His visual acuity was 20/40 in both eyes. His electro-oculographic findings were normal. His electroretinogram showed moderately abnormal rod and normal cone function. After 50 minutes of dark adaptation the electroretinogram was normal. His Farnsworth-Munsell 100-hue test revealed a blue-yellow defect. Angiography showed evidence of RPE atrophy in the macula.

Hereditary stationary night blindness with polymorphous flecked retina.

D: Large white flecks confined to the peripheral fundi of an 11-year-old girl with familial stationary night blindness. Note similarity to Figure 5.36 E–L.

E to K: The parents of this now 33 year old woman, (second of 3 siblings) noted a visual behavior in the dark different from her older sister when she was 3-5 years of age. Her vision was 20/20 in each eye at age 33, fundus showed symmetric appearance of several punctate white dots distributed up to the periphery and a bull’s eye maculopathy (E to I). The visual function with stationary night blindness and fundus appearance was unchanged 6 years later (J and K).

(D, from Miyake and Harada. )

This typically nonprogressive form of the disease is more common than its counterpart, RPA (see Figure 5.38 B–D) and Bothnia (Figure 5.44) and Newfoundland rod–cone dystrophy (Figure 5.45). Differentiation of these two diseases in younger patients may be difficult. Occasionally both forms of the disease may occur in the same family. RPA shows progressive nyctalopia, bone corpuscular pigment change, and vascular narrowing beginning by the third decade. Some patients, especially from Japan (38–43%), have a macular or cone dystrophy in addition to the flecks of fundus albipunctatus, all of whom have mutations in the RDH5 gene of fundus albipunctatus. Most, but not all, patients with macular involvement were older; whether this is a function of longer duration of disorder or a common Japanese ancestor in these various families remains to be determined. This macular change associated with decreased cone ERG amplitudes resembles the macular change seen in patients with Bothnia dystrophy; however the gene defects in the two conditions are different (see section on Bothnia dystrophy, below). It is conceivable the metabolic derangements caused by the two mutations have some similarity or overlap, given that they are both involved in the metabolism of 11- cis retinol.

Fundus albipunctatus should be differentiated from acquired nyctalopia associated with vitamin A deficiency (Figure 9.12A–F) as well as crystalline retinal dystrophy (see Figure 5.46 ), oxalosis (see Figure 5.67 ), cystinosis (see Figure 5.64 ), canthaxanthine retinopathy (see Figure 9.10), basal laminar drusen (see Figure 3.31 and 3.32), and Alport’s syndrome ( Figure 5.35 ). Pedigrees with larger “scale” or “silkworm-shaped” flecks with or without similar electrophysiologic findings may represent variants of albipunctate dystrophy ( Figure 5.38 D). Hayashi et al. found compound heterozygous mutations p.V177G and p.L310delinsEV in the RDH5 gene in a 3-year-old proband with night blindness and fundus changes similar to benign fleck retina. His asymptomatic parents and one of the grandparents each carried one of the mutations, explaining the autosomal-recessive inheritance.

Kandori’s Flecked Retina

Kandori’s flecked retina is an apparently rare, atypical type of congenital nonprogressive night blindness; it was described in four patients with sharply defined, dirty yellow, irregular relatively large flecks or patches of RPE atrophy distributed in the equatorial region between the macula and the equator. The macula was uninvolved. The retinal vessels and optic nerve were normal. Dark adaptation was delayed but returned to normal in 30–40 minutes. Visual acuity, visual fields, EOG, ERG, and visual evoked potentials were normal. Fluorescein angiography showed evidence of focal depigmentation of the RPE corresponding with the peripheral lesions. None of the four patients was from the same family. The flecks in these patients appear similar to, if not identical to, congenital grouped albinotic RPE spots. This is believed to be a congenital anomaly of the RPE that is usually unassociated with night blindness (see Figure 12.05).

Typical Retinitis Pigmentosa

“Typical retinitis pigmentosa” is used to refer to those patients with a hereditary dystrophy characterized by the onset of night blindness in childhood or young adulthood, progressive contraction of the peripheral visual field beginning as a mid zonal ring scotoma with preservation of central vision, and frequently profound visual loss or blindness in middle or later life ( Figures 5.39–5.41 ). Early in the course of the disease the most common presenting complaints are headache (53%) and photopsias (35%). Photopsias are spontaneous impulses exhibited by dying or disintegrating photoreceptors. Patients describe them as tiny blinking or shimmering lights or gold sparkles. A total of 10–15% of patients may not be aware of symptoms until central vision is affected. They experience variability in their visual function and may note worsening of vision during stress. There is a high incidence of relative myopia. The earliest fundoscopic changes consist of gray-green discoloration of the RPE giving a tapetal-like reflex, depigmentation of the RPE, mild narrowing of the peripheral retinal blood vessels, and migration of pigment into the overlying retina in a bone spicule pattern in a mid peripheral annular zone of both eyes. This annular zone progressively enlarges in an anterior and posterior direction and is associated with further attenuation of the retinal blood vessels, waxy pallor of the optic disc, and the development of a glistening reflex and crinkling of the inner retinal surface secondary to an epiretinal membrane. The pallor of the optic disc is due to astroglial proliferation on the surface of the optic disc. Retinal arterial and venular narrowing is a secondary phenomenon from retinal autoregulation. Loss of photoreceptors, the highest metabolically active cells in the retina, results in diffusion of nutrients from the choroidal capillary circulation into the inner retina reducing the metabolic demand on the inner retina and consecutively narrowing the retinal arteries and veins. Posterior polar cataract and fine vitreous opacities or cells often develop. This adds to visual loss. Classically, the macula has been described as being relatively normal and visual acuity is excellent until the later stages of the disease. Recent investigation has revealed that 50% or more of patients at the time of initial presentation will have biomicroscopic and angiographic evidence of macular changes, including cystoid macular edema ( Figure 5.42 A–D), epiretinal membrane, and atrophic changes in the RPE. Some degree of epiretinal membrane change in the macula is evident in most patients with retinitis pigmentosa. Cystoid macular edema is visible biomicroscopically in fewer than 10% of patients, in the author’s experience. The high incidence of 70% in 58 patients studied retrospectively by Fetkenhour and associates probably reflects the fact that patients with central visual loss are more likely to be referred for photographic studies. Those with cystoid macular edema often have more cells than usual in the vitreous. Although the incidence of cystoid macular edema probably is higher in younger patients showing minimal pigment migration into the retina, it may occur in all age groups and in patients with typical pigmentary changes. In most patients with subtle macular edema that is evident only angiographically in the paracentral area, visual acuity is good. By the time cysts become visible biomicroscopically, the patients are complaining of loss of central vision and the acuity is usually 20/40 or less. Some patients with chronic macular edema may retain good visual acuity for many years ( Figure 5.42 A–D). Most patients with macular edema have 1+ or 2+ vitreous cells. Loss of Snellen acuity in some patients is associated with atrophic RPE changes in the macula. This appears to occur more often in black patients than white patients.

Retinitis pigmentosa.

A–D: Cystoid macular edema in an 8-year-old boy with nyctalopia. Note the narrowing of the retinal arterioles (A). Visual acuity was 20/30. His electroretinogram was extinguished. The periphery of the fundus (B) showed mild bone corpuscular pigmentary changes. Early angiography (C) revealed evidence of generalized depigmentation of the retinal pigment epithelium. Note the nonfluorescent cross in the foveolar area. This is probably caused by central compression of the retinal xanthophyllic pigment by the large central retinal cysts. One-hour angiogram (D) revealed minimal evidence of fluorescein staining in the macula.

E and F: Widespread retinal edema and cystoid macular edema in a 42-year-old woman with night blindness, moderate number of vitreous cells, and minimal intraretinal pigment migration. Her electroretinogram was severely abnormal but not extinguished. Her sister had similar findings.

G–I: This 37-year-old man with an 8-year history of nyctalopia developed evidence of retinal telangiectasis inferiorly in the right eye in 1984 (H and I). Note narrowing of the retinal vessels (G). Because of progressive exudation he was treated with transscleral cryopexy in 1990.

J–L: Development of peripheral retinal telangiectasis and subretinal exudation occurred in the right eye of this patient during observation for typical retinitis pigmentosa, 2+ vitreous cells, and cystoid macular edema. The retinal telangiectasis was not present at the time of initial examination at age 14 but developed at age 18 years (K). There was extensive leakage of fluorescein from retinal vessels in macular and paramacular retina. The exudation seen in K cleared spontaneously over a period of 3 years (L). In spite of chronic cystoid macular edema she maintained 20/40 visual acuity during the 18 years of observation. She experienced gradual loss of peripheral vision. Her electroretinogram was extinguished at the time of initial examination.

Retinitis pigmentosa with Coats’-type response.

A and B: This 40-year-old woman from Iraq complained of difficulty seeing at night for more than 5 years. Her visual acuity was 20/20 in each eye. Visual fields were narrowed to central 20° in each eye. Both optic nerves were pale, the vessels were diffusely narrowed, the retinal pigment epithelium was atrophic everywhere except the macula and bone spicule pigment migration spared the macula, typical of retinitis pigmentosa (A and B).

C and D: This 37-year-old man with an 8-year history of nyctalopia developed evidence of retinal telangiectasis inferiorly in the right eye in 1984 (C and D). Note narrowing of the retinal vessels. Because of progressive exudation he was treated with transscleral cryopexy in 1990.

E and F: Development of peripheral retinal telangiectasis and subretinal exudation occurred in the right eye of this patient during observation for typical retinitis pigmentosa, 2+ vitreous cells, and cystoid macular edema. The retinal telangiectasis was not present at the time of initial examination at age 14 but developed at age 18 years (E). There was extensive leakage of fluorescein from retinal vessels in macular and paramacular retina. The exudation seen in E cleared spontaneously over a period of 3 years (F). In spite of chronic cystoid macular edema she maintained 20/40 visual acuity during the 18 years of observation. She experienced gradual loss of peripheral vision. Her electroretinogram was extinguished at the time of initial examination.

G–L: This 22-year-old woman was a member of a family with autosomal-dominant retinitis pigmentosa. She had moderately severe changes of retinitis pigmentosa in both eyes (G), with cystoid macular edema, demonstrated on the angiogram (H). Optical coherence tomography confirmed the presence of cysts in both macula (I1 and I2). The inferior fundus showed telangiectatic changes in the vessels with lipid exudation and retinal detachment (J–L). Laser was applied in several sessions to both eyes; the right eye responded with resolution of almost all the lipid; however the left eye continued to leak and the lipid exudation reached the fovea in spite of multiple laser treatments. Her vision remained at 20/100 on the right and 20/400 on the left.

Retinitis pigmentosa and central serous chorioretinopathy.

A–C: Recurrent episodes of idiopathic central serous retinopathy associated with multiple serous detachments of the retinal pigment epithelium (RPE: arrows, A and C) in both eyes occurred in this 30-year-old woman with retinitis pigmentosa sine pigmenti and an extinguished electroretinogram.

Late onset retinitis pigmentosa.

D–F: Long-standing “late-onset” retinitis pigmentosa occurred in this 66-year-old woman who was asymptomatic until 3 months prior to these pictures. Her family history was negative. Her visual acuity was 20/25 right eye and 20/80 left eye. She had marked concentric constriction of the visual fields bilaterally. Angiography revealed relative preservation of the RPE centrally and mild intraretinal staining in the central macular area of both eyes (E and F).

G–J: Histopathology of retinitis pigmentosa. Macular area (G) showing extensive atrophy of the receptor cell layer that is thinned to one cell thickness (arrows), and mild degeneration of the RPE and slight attenuation of the choriocapillaris. Mid peripheral fundus (H and I) showing extensive gliosis and atrophy of the retina, intraretinal migration of RPE around sclerosed retinal blood vessels, atrophy of the RPE and choriocapillaris (lower arrow), and cellular epiretinal membrane (upper arrow, I). High-power view showing vitreous cell filled with melanin pigment (J).

(A–C: from Lewis .)

Retinitis pigmentosa: response of cystoid macular edema (CME) to acetazolamide.

A–F: This 35-year-old African American male had a best-corrected visual acuity of 20/80 and 20/70. In addition to the peripheral pigmentary retinopathy, a large central cyst surrounded by a few small cysts were present in both maculas (A and B). Optical coherence tomography documented the cystoid macular edema in each eye (C and D). He was treated with oral acetazolamide 250 mg three times a day, which he tolerated well. Eight weeks later his vision had improved to 20/40 and 20/30 respectively; the cysts had decreased significantly in both eyes (E and F). Acetazolamide was continued at the same dose for 2 more months and slowly tapered off over the next 3 months. The CME recurred once he came off the acetazolamide and he was kept on maintenance dose of it from then onwards. The cyst in the right eye persisted, but the left eye remained resolved.

Usher’s syndrome.

G–J: A 68-year-old older brother has been followed for Usher’s syndrome for more than 20 years. His visual acuity has remained at hand motions for the past 20 years. Both eyes had extensive retinal atrophy, including the macula with bone corpuscles retinal pigment epithelium (RPE) migration (G and H). His 64-year-old younger brother had 20/400 vision in each eye. The optic nerves were pale bilaterally; vessels were narrowed with extensive pigment migration in each eye (I and J). The macula had some preservation of RPE that accounted for the 20/400 vision.

Fluorescein angiography often shows evidence of retinal and optic nerve capillary dilation; angiographic evidence of retinal capillary leakage may be confined to the macular area or the paracentral area in the vicinity of the vascular arcades, or it may involve the entire fundus. In those patients with visible cysts in the macula, most show a polycystic pattern of staining typical of cystoid macular edema. In some, however, no staining, minimal staining, or intermittent staining may occur ( Figure 5.42 ). It is difficult to determine whether most of the fluorescein staining is derived from dye leaking from retinal capillaries or from the choriocapillaris through abnormal RPE. Fluorescein angiography usually shows an increase in the retinal circulation time and sharply outlined zones of hyperfluorescence corresponding to the areas of atrophy of the RPE. In some patients there may be a delay in the development of choroidal hyperfluorescence in the area of RPE atrophy, indicating some atrophy of the underlying choriocapillaris. In others, the rapid development of the diffuse background choroidal fluorescence suggests the underlying choriocapillaris is intact. Autofluorescence studies show decreased autofluorescence corresponding to the involved RPE and periphery, and a ring of increased autofluorescence in the macula suggesting increased metabolic activity and lipofuscin accumulation in the macular RPE cells ( Figure 5.39 G, H, K, and L).

Recurrent serous detachment of the pigment epithelium and retina, identical to that occurring in idiopathic central serous chorioretinopathy, occurs as an infrequent complication in patients with retinitis pigmentosa. Dr. Gass has seen two such patients ( Figure 5.41A–C ). These patients should be distinguished from patients with chronic idiopathic central serous chorioretinopathy, who occasionally develop pigmentary changes that resemble sector retinitis pigmentosa but that are caused by long-standing dependent peripheral zones of serous retinal detachment (see Figure 3.06 and 3.07).

Histopathologic examination of eyes of patients with retinitis pigmentosa have shown degeneration of the retinal receptor elements, depigmentation of the RPE, migration of RPE cells into the overlying retina, particularly in the perivascular areas, hyalinization and thickening of the retinal vessel walls, diffuse atrophy of the whole retina, and gliosis ( Figure 5.41 G–J). These changes are usually most prominent in the mid peripheral fundus. The RPE and choriocapillaris are preserved during the early course of these changes. Later the RPE becomes atrophic and there may be partial obliteration of the choriocapillaris. Degeneration in the pigment epithelium and retina are probably of primary importance in causing the atrophy of the choriocapillaris. As the disease spreads posteriorly there is gliosis of the optic disc with extension of a fibrocellular glial membrane on to the anterior surface of the retina ( Figure 5.41 H). In the atrophic macular region, there is focal loss of the receptor cells, the outer limiting membrane, followed by degeneration of the RPE and attenuation of the underlying choriocapillaris ( Figure 5.41 G).

Large cystic spaces in the outer nuclear and outer plexiform layers and smaller cysts lying in the inner nuclear layer encircling the central area similar to that seen in aphakic cystoid macular edema have been described in one patient with retinitis pigmentosa. In a study of the maculas of 41 patients with all genetic types of retinitis pigmentosa, Stone et al. found evidence of some loss of ganglion cells as well as the underlying receptor cells (suggesting transsynaptic degeneration) but demonstrated that many eyes, particularly those with dominantly inherited retinitis pigmentosa, retain many ganglion cells even in the presence of marked loss of the underlying receptor cells ( Figure 5.41 J). Ultrastructural studies of the vitreous of patients with retinitis pigmentosa have revealed the presence of RPE cells, uveal melanocytes, retinal astrocytes, lymphocytes, and macrophage-like cells.

Kolb and Gouras on the basis of electron microscopic studies suggested that the melanocytes collecting around retinal blood vessel in retinitis pigmentosa may be uveal melanocytes. It is difficult, however, to explain why uveal melanocytes, which are poorly reactive cells, would migrate into the retina and vitreous. It is more likely that these are RPE cells that undergo a metamorphosis that simulates uveal melanocytes. The predilection for these RPE cells to accumulate around the retinal blood vessels accounts for the bone corpuscular patterns of pigment seen ophthalmoscopically. Newsome and Michels found that the predominant vitreous cell type in retinitis pigmentosa was the lymphocyte, most of which were T cells. They were unable to determine whether the vitreous cells played an active role in the pathogenesis of the retinitis pigmentosa. The presence of T cells in the vitreous may be largely the result of breakdown in the blood–ocular barrier that occurs in retinitis pigmentosa.

Several subtypes of retinitis pigmentosa due to various gene defects can show a variable appearance of the RPE change. A type of retinitis pigmentosa with RPE preservation is seen in patients with Crumbs homolog 1 ( CRB1 ) or CRUMB gene defect (See Figure 5.43G and H). Some patients show very little migration of pigment epithelial cells, called retinitis pigmentosa sine pigmenti. Those patients with autosomal-recessive retinitis pigmentosa have earlier onset of symptoms and findings. Women, who are X-linked carriers, can show a variable amount of involvement. Sometimes involvement is sectoral and occasionally it is extensive. Irregular lyonization of cells is responsible for the varying degrees of symptoms in female carriers of X-linked recessive retinitis pigmentosa. Pericentral retinitis pigmentosa patients have most of the findings related to the mid peripheral fundus around the arcades. Sectoral retinitis pigmentosa was first described in 1937. These patients generally have fine shiny crystals in addition to the sectoral consideration of the photoreceptor loss. Several of the patients can progress from cone to cone–rod degeneration.

Associated findings in typical retinitis pigmentosa include congenital deafness (Usher’s syndrome) that may or may not be associated with other evidence of central nervous system abnormalities, vitiligo, and calcific nodular drusen within the optic nerve head.

Calcified bodies on the optic nerve head in patients with retinitis pigmentosa have been attributed to hyaline bodies (drusen) by some and to astrocytic hamartomas by others. The evidence in favor of the former is more convincing.

Retinitis pigmentosa may be inherited in any one of the three classic modes. There is a general tendency for earlier and more severe involvement in those showing X-linked recessive and autosomal-recessive modes of inheritance. There are notable exceptions to the general rule that the disease in families with dominant inheritance is milder. Patients with X-linked disease are usually almost blind by the age of 30–40 years, whereas many affected patients with autosomal-recessive disease or no family history of disease retain central vision until they are 45–60 years old. An alteration in sperm axoneme is present in patients with X-linked retinitis pigmentosa. Almost 100% of the female carriers of X-linked retinitis pigmentosa can be identified on the basis of either or both fundus and ERG changes. The fundus changes include tapeto-like reflex in the macula, isolated regions of peripheral retinal degeneration, and occasionally widespread retinal degeneration.

Some authors have subdivided patients with dominantly inherited retinitis pigmentosa into two primary subgroups: one having diffuse pigmentation, concentric visual field loss, and no recordable ERG, the other with regionalized pigmentation, sectoral field loss, and some recordable ERG. The cumulative probability of maintaining a visual acuity of 20/40 or better over each decade of life decreased rapidly in the former type and remained above 90% through the fifth decade in the latter type. Patients with dominant disease can retain central vision beyond the age of 60 years.

A number of distinct mutations in the rhodopsin gene have been identified in different families with autosomal-dominant retinitis pigmentosa. There is evidence that some cases of dominant retinitis pigmentosa are the result of mutations in the retinal degeneration slow ( RDS ) gene on chromosome 6. Rosenfeld et al. reported a rhodopsin gene defect in one family with autosomal-recessive retinitis pigmentosa. Distinct mutations have not been identified in patients with X-linked retinitis pigmentosa. Jacobson et al. found discernible differences in the pattern of retinal dysfunction in patients with different rhodopsin mutations.

A natural course study of retinitis pigmentosa unassociated with systemic disease showed significant decline of full-field ERG amplitudes over a 3-year period in 77% of patients with detectable levels at baseline. Patients lost an average of 16–18.5% of remaining ERG amplitudes per year and 4.6% of remaining visual field per year.

Most patients with retinitis pigmentosa have myopia except for those with early-onset autosomal-dominant retinitis pigmentosa with nanophthalmos, Leber’s congenital amaurosis, and preserved para-arterial RPE ( Figure 5.43 G and H).

Retinitis pigmentosa with unusual peripheral retinal changes.

A–C: Retinitis punctata albescens in a 32-year-old man with nyctalopia, progressive loss of peripheral vision, and multiple, discrete, round, white flecks at the level of the retinal pigment epithelium (RPE) in the pericentral area (A). These flecks were more numerous and smaller in the mid peripheral area where there were more advanced atrophic changes in the RPE and retina. Note the narrowing of the retinal vessels (B). Angiography revealed widespread depigmentation of the RPE that was more marked peripherally (C).

D–F: Peculiar perivascular and geographic distribution of subretinal white lesions (F–H) in a woman with nyctalopia and evidence of a tapetoretinal degeneration.

G and H: Periarterial sparing of the pigment epithelium and an Oguchi-like metallic reflex in the periphery of a healthy 8-year-old boy with nyctalopia, onset of progressive visual loss at age 5 years, and an extinguished electroretinogram. His visual acuity was 20/200 bilaterally. There was no nystagmus. He had three normal siblings. There was no history of consanguinity.

I–L: Three-dimensional lacelike network of white retinal capillaries (J–L) in a 34-year-old woman with a lifelong history of nyctalopia, severe loss of peripheral visual field, and an extinguished electroretinogram. She had a sister with the same ocular disorder. Her visual acuity was 20/60 in the right eye and 20/50 left eye. Her electroretinogram was extinguished bilaterally.

Autoimmune responses have been detected in many degenerative ocular diseases, including retinitis pigmentosa, but their role in the pathogenesis of retinitis pigmentosa is unknown.

There is no proven effective treatment to slow the loss of visual function in patients with retinitis pigmentosa. A randomized trial of vitamin A (15 000 IU/day) and vitamin E (400 IU/day) supplementation for retinitis pigmentosa showed a beneficial effect of vitamin A in regard to inhibiting decline of ERG amplitudes, but it failed to demonstrate any benefit in slowing the course of loss of visual field. The results of the trial suggest an adverse effect of vitamin E on the course of retinitis pigmentosa. Use of oral acetazolamide and methazolamide and topical dorzolamide for the treatment of chronic cystoid macular edema in patients with retinitis pigmentosa has been beneficial in some cases. In some cases acuity improves without demonstrable improvement in the degree of angiographic fluorescein leakage. The mechanism seems to be via stimulation of the pump function of the RPE. Results of a scatter pattern of grid laser treatment for cystoid macular edema in a small series of patients with retinitis pigmentosa are unimpressive, and risks of this treatment in patients with only a limited peripheral field are high. There is some hope for the therapeutic value of transplantation of retinal tissues and gene therapy for retinitis pigmentosa and macular degenerative disorders. Transscleral transplantation of RPE into the subretinal space of animals has retarded photoreceptor degeneration in the vicinity of the transplant. Transfer of corrective genes into the subretinal space by the use of viral vectors is another possible strategy for therapy. Tissue growth factors appear to inhibit or slow the rate of hereditary retinal degeneration in animals. Although studies of patients with diabetes and retinitis pigmentosa have shown a protective effect of the latter in regard to the development of diabetic proliferative retinopathy, optic disc and retinal neovascularization does occasionally occur. When retinal neovascularization occurs in diabetics with retinitis pigmentosa, it usually develops in the periphery at the junction of perfused and nonperfused retina. There is a negative association of rhegmatogenous retinal detachment in patients with retinitis pigmentosa. Recent studies with implantable chips that function as retinal receptors are in progress. Rapid and extensive expanse in genotyping and genetherapy processes is likely to result in novel therapeutic approaches for these patients in the near future.

Electroretinography, dark-adaptation studies, and automated light- and dark-adapted perimetry are useful in the diagnosis, classification, and follow-up of patients with retinitis pigmentosa.

Usher Syndrome

Usher syndrome is an autosomal-recessive disorder of deafness, often congenital, combined with features typical of retinitis pigmentosa ( Figure 5.42 G to J). Cystic or atrophic macular changes are seen earlier in patients with Usher’s than typical retinitis pigmentosa, and are more prevalent in type I (62%) than type II (32%), most likely due to the more severe and earlier involvement in the former. Though von Graefe first described the condition in 1858, Charles Usher, a British ophthalmologist, noticed the hereditary nature of the disorder.

Usher syndrome can be divided into three major groups. The two most frequent forms are types I and II. In type I there is profound congenital sensorineural deafness resulting in prelingual deafness and speech impairment. Vestibular symptoms and childhood-onset retinopathy accompany the deafness. Type II is characterized by partial or profound, but nonprogressive, deafness, absence of vestibular symptoms and milder, later-onset retinopathy. The least common is type III, in which there is progressive deafness starting late in the second to fourth decade of life, onset of retinopathy in adult life, and hypermetropic astigmatism. Type III resembles type II except for progressive worsening of hearing.

Approximately 3–6% of persons have profound prelingual deafness of type I Usher syndrome. Type II Usher is more common and accounts for about two-thirds of patients. Type III constitutes less than 20%. The ERG is nondetectable in all groups early on in life. Occasionally, a type II Usher can have cerebellar atrophy resulting in ataxia. Type III has been associated with psychotic symptoms and magnetic resonance imaging (MRI) changes associated with this. The disorder is genetically and clinically heterogeneous and at least nine genetic loci have been identified. Usher type I has six different gene loci, mapping to 14q32, 11q13, 11p15, 10q, 21q21 and chromosome 10. Usher type II has been mapped to 1q41, 3p, and 5q, and others have been postulated.

Cochlear implants can be placed in profoundly deaf children and this has helped their speech. Usher syndrome can be mistaken for rubella retinopathy due to the deafness and pigmentary changes. However, an ERG will be useful in confirming the diagnosis of Usher’s. Other syndromes that can be associated with deafness and pigmentary retinopathy include infantile Refsum disease, adult Refsum disease, Cocayne syndrome, Bardet–Biedl syndrome, Alstrom disease, Flynn–Aird syndrome, Friedreich’s ataxia, and Kearns–Sayre syndrome.

Typical Pigmentary Retinal Dystrophy with Coats’ Syndrome

Some patients with typical sporadic or familial retinitis pigmentosa, usually during adulthood, may develop yellowish subretinal exudation derived primarily from the peripheral retinal vessels and present with a Coats’ syndrome picture ( Figure 5.40 C–F and G–L). The exudative detachment may be confined to the peripheral fundus, or it may be massive and extend into the posterior pole. Total retinal detachment may occasionally occur. Focal areas of irregular telangiectatic dilation of the retinal blood vessels, and occasionally angiomatous proliferation of retinal capillaries, occur usually in the peripheral fundus on a background of the typical findings of retinitis pigmentosa. Fluorescein angiography may show widespread evidence of capillary leakage in the retina in areas outside as well as within the area of exudative retinal detachment. Cystoid macular edema is usually present. The exudation may be self-limited ( Figure 5.40 E and F), or it may be progressive and result in extensive loss of vision. These patients require photocoagulation and cryotherapy to control the exudation ( Figure 5.40 J–L). This exudative response may also be the cause of massive segmental retinal gliosis in these patients. Histopathologic findings in one case revealed evidence of communication of choroidal blood vessels with the overlying exudative retinal mass. It is uncertain whether this communication is of primary importance in causing retinal exudation or occurs only secondarily after a long-standing exudative retinal detachment.

Angiographic evidence of retinal vascular leakage, either confined to the macular area or involving the entire fundus, has been frequently observed in retinitis pigmentosa, as well as a variety of other atypical tapetoretinal dystrophies, cone dystrophy, rod–cone dystrophy, Stargardt’s macular dystrophy, and familial exudative vitreoretinopathy. It is probable that massive yellowish exudative detachment in patients with retinitis pigmentosa represents an unusually severe alteration in the retinal vascular permeability that can probably occur in any of the inheritance patterns of retinitis pigmentosa. The frequency of bilaterality, adult onset, and absence of sex predilection suggest strongly that this exudative response in patients with retinitis pigmentosa is unrelated to congenital retinal telangiectasia, the most frequent cause of Coats’ syndrome. Dr. Gass has observed it developing in one patient during follow-up for a unilateral localized area of pseudoretinitis pigmentosa change caused by trauma. Mutations in the CRB1 gene have been found in 65% of patients with Coats’-type retinitis pigmentosa. The condition has been seen in patients as young as 4 years and in patients with Usher syndrome type II.

Leigh Syndrome (NARP Syndrome)

Leigh syndrome is a hereditary neurodegenerative disorder of infancy or childhood, and is characterized by developmental delay, psychomotor regression, signs of brainstem dysfunction, lactic acidosis, and symmetrical necrotizing lesions in the basal ganglia on the brainstem. The clinical course is variable with most cases of a poor outcome with progressive neurological deterioration leading to death within months or years. The definitive diagnosis depends on MRI changes, described as hyperintense lesions of the putamen and the brainstem.

NARP syndrome is typically caused by defects of the mitochondrial enzymes including pyruvate dehydrogenase and complexes 1, 2, and 4 of the respiratory chain. In most cases, the deficiencies are due to mutations in the nuclear genes and coding subunits of the complexes PDHA1, and SDHA, proteins implicated with assembly of complexes such as SURF1 and LRPPRC. In addition, mitochondrial DNA mutations are important causes of Leigh syndrome. A T8993C mitochondrial DNA mutation is a cause of Leigh syndrome.

The clinical picture is variable, and some patients have a milder phenotype. These patients who do not fulfill all the criteria for Leigh syndrome, are classified as Leigh-like syndrome, and they have a better prognosis but a lower biochemical and molecular diagnostic yield than patients with Leigh syndrome. The phenotypic variation in the mitochondrial DNA mutation is due to heteroplasmy or variable affection of the mitochondrial DNA mutations. The MT-ATP6 gene encoding to subunit 6 of the adenosine triphosphate synthase complex 5 is the commonest DNA gene mutation seen in cases with NARP. The T8993 gene mutation is the commonest mutation seen.

Some patients are known to improve significantly after 16–18 years of age. This may be due to the decrease in the mutational load with age that has been observed in some patients. The ocular changes that have been seen in these patients can be variable, bull’s-eye maculopathy has been discovered in an infant with Leigh’s disease noted at the age of 8 months. In addition, the retinal arterioles are diffusely narrowed with consecutive pallor of the optic disc, consistent with diffuse loss of photoreceptors. Optic atrophy, nystagmus, strabismus, ophthalmoplegia along with developmental delay, hypotonia, seizures, and psychomotor regressions are all features of Leigh’s disease. Leigh’s disease should be considered in the differential diagnosis of neurologically impaired infants presenting with a bull’s-eye maculopathy.

Retinitis Pigmentosa Sine Pigmenti

Patients with otherwise typical retinitis pigmentosa may show minimal or no evidence of pigment migration into the retina ( Figure 5.39 E–J). Pearlman and associates have presented evidence to suggest that the absence of pigment migration represents an initial stage of typical retinitis pigmentosa and is manifested by shorter duration of symptoms, less severe night blindness, and less impairment of the electroretinographic b-wave. Because some patients may initially be seen with visual loss secondary to cystoid macular edema or with field defects simulating arcuate scotomata, these patients may be misdiagnosed as having a neurologic disease or glaucoma. The ophthalmoscopic findings of waxy pallor of the optic disc, a glistening reflex secondary to epiretinal membrane change, a greenish or gray tapeto-like reflex from the altered RPE, and slight narrowing of the retinal arterioles should alert the clinician to inquire concerning symptoms of night blindness and to obtain electrophysiologic studies. Fluorescein angiography is helpful in detecting zones of depigmentation of the RPE not readily apparent ophthalmoscopically. Histopathologically, the changes are similar but less severe than those in typical retinitis pigmentosa. There is evidence of pigment migration into the retina but in amounts insufficient to be detected ophthalmoscopically.

Preserved Para-arterial RPE in Retinitis Pigmentosa

Heckenlively reported five patients with retinitis pigmentosa, probable autosomal-recessive inheritance, hypermetropia, and preservation of the RPE beneath the retinal arteries in areas of otherwise severe pigment epithelial and retinal atrophy ( Figure 5.43 G and H). Mutations in the CRB1 gene have been reported in a variety of autosomal-recessive retinal dystrophies, including retinitis pigmentosa with preserved para-arteriolar RPE, retinitis pigmentosa with Coats’-like exudative vasculopathy, early-onset RPE with preserved para-arterial RPE (PPRPE), and Leber’s congenital amaurosis. It appears that loss of function of members of the CRB/CRB complex in Drosophila and vertebrate retina results in typical architectural disorganization and light-induced degeneration. The alterations occur at the RPE photoreceptor level and also at the Müller cells.

Retinitis Punctata Albescens (RPA)

RPA is mostly an autosomal-recessive condition (rarely dominant) with multiple small gray or white dots that resemble the flecks of fundus albipunctatus. Confinement of the flecks to the region just outside the macula (not reaching the periphery), progressive night blindness, narrowing of retinal vessels, loss of peripheral field, and appearance of pigment spicules differentiate it from fundus albipunctatus ( Figure 5.43 A–C). Intermediate forms of these disorders exist.

RPA is mostly associated with mutations in RLBP1 , and occasionally in RHO, RDS , and RDH5 genes. There is a wide genetic heterogeneity amongst a reasonable phenotypic uniformity in this condition. Various mutations in the RLBP1 gene have been found, and in some cases none of the known mutations is positive. Bothnia dystrophy and NFRCD closely resemble RPA in many features and the gene affected is RLBP1 ; however the mutations are different from those known for RPA.

The differential diagnosis includes basal laminar drusen, fundus flavimaculatus, abetalipoproteinemia, oxalosis, cystinosis, talc emboli, Alport’s syndrome, canthaxanthine retinopathy, and fundus xerophthalmicus. Other types of flecks and peculiar color changes of the peripheral retina occasionally occur in patients with retinitis pigmentosa ( Figure 5.43 D–L).

Bothnia Dystrophy

The onset is in early childhood with symptoms of night blindness when the retina appears normal. Punctate white dots of RPA appear in teenage and young adults ( Figure 5.44 A). Macular pigment deposits ( Figure 5.44 B, C) followed by macular atrophic changes occur next ( Figure 5.44 D, H). This is followed by paracentral and mid peripheral round chorioretinal atrophic lesions resembling gyrate atrophy ( Figure 5.44 E) and narrowing of retinal vessels. Widespread pigment epithelial migration in the form of bone spicules occurs occasionally. Visual acuity progressively declines with age, leading to legal blindness by the fourth decade of life. Those whose vision never develops beyond 20/80 show nystagmus. Premature cataract has not been a feature. Fluorescein angiography shows mottled transmission defects from RPE atrophy.

Bothnia dystrophy.

A: A 15-year-old male with night blindness since early childhood, with 20/20 vision in both eyes. Visual fields were full bilaterally, rod responses were undetectable, mixed rod and cone responses were poor, and the cone response was subnormal. Left eye shows uniform white dots resembling flecks of fundus albipunctatus (A). The severely diminished scotopic and photopic amplitudes differentiate it from fundus albipunctatus.

B and C: This 16-year-old female with a visual acuity of 20/30 both eyes had a relative ring scotoma and suffered night blindness since early childhood. Her rod and mixed rod and cone responses were undetectable and the cone responses were subnormal. The right fundus shows diffuse glistening punctuate white dots interspersed with hyperpigmented dots (B and C).

D and E: This 26-year-old female with history of night blindness since early childhood and progressive loss of central vision had a visual acuity of 20/200 both eyes. She shows an older phenotype of Bothnia dystrophy with diffusely altered pigmentation of her fundus (D) and peripheral islands of geographic atrophy resembling gyrate atrophy (E). Her visual fields showed relative central and paracentral scotomas. The rod and mixed responses were undetectable and the cone responses were low.

F and G: A 36-year-old woman with distinct punctate white dots in the macula and diffusely mottled pigment epithelium outside the macula (F and G). Her vision was 20/100 right eye and count fingers left eye. She had bilateral central scotomas and undetectable rod and cone responses.

H: A 42-year-old female with 20/200 vision in both eyes, undetectable rod and cone electroretinograms with white dots all over the fundus and foveal atrophy (H).

(Courtesy of Dr. Ola Sandgren and Dr. Marie Burstedt.)

Visual fields are normal in young patients; gradually increasing central scotomas develop in the teens or in young adults, eventually leaving only peripheral islands of visual field. Color vision is affected early and worsens with age. Dark adaptation studies show abnormalities of both rod and cone function that progressively worsen. Electroretinography shows decreased amplitudes and increased implicit times for rod and rod–cone function early, and progressive cone dysfunction later on. Individuals heterozygous for the mutation show near-normal ERG amplitudes and implicit times. EOG is subnormal in all patients.

It is a unique autosomal-recessive rod–cone retinal dystrophy first described in the Bothnia Occidentalis region of Västerbotten county of northern Sweden, with a high prevalence of 1 per 4500 population. The disorder is caused by a mutation in the RLBP1 gene mapped to chromosome 15q26, encoding the human cellular retinaldehyde-binding protein (CRALBP). Patients affected by Bothnia dystrophy are homozygous for a C-to-T transition in exon 7 of the RLBP1 gene, leading to an arginine to tryptophan substitution at position 234 of the protein (R234W). CRALBP is located in the RPE, Müller cells, ciliary body pigment epithelium, outer epithelium of the iris, cornea, the optic nerve, and pineal gland. In the RPE it functions as the carrier protein for endogenous retinoids such as 11- cis -retinol involved in the visual cycle. Defect in the RLBP1 gene leads to defective binding of 11- cis retinaldehyde, thus preventing its regeneration, and subsequently loss of rod function. He et al. found R234W displays fivefold increased resistance to light-induced photoisomerization relative to wild-type CRALBP, caused by unanticipated domino-like structural rearrangements causing Bothnia-type retinal dystrophy by the impaired release of 11- cis -retinal from R234W.

Other mutations in the RLBP1 gene have been described: R150Q in exon 5 in three patients from India and in patients from Saudi Arabia, three additional mutations in a small family of European ancestry and two splice junction mutations, one of which causes NFRCD. Most of these patients present with white flecks, peripheral degenerative changes, and maculopathy and resemble the phenotype of Bothnia dystrophy, except NFRCD, which has an earlier onset and more rapid progression and so far has not developed the macular areolar atrophy.

Newfoundland Rod–Cone Dystrophy

Symptoms begin in infancy with night blindness, followed by progressive loss of peripheral, central, and color vision in childhood, resulting in severe visual loss by the second to fourth decade of life. Several white dots similar to fundus punctata albescens/fundus albipunctatus and Bothnia dystrophy may be seen in the posterior pole and midperiphery in some patients. In contrast to Bothnia dystrophy, where macular involvement occurs early, the macula in NFRCD is normal or exhibits a “beaten-bronze” atrophy. A perimacular ring of white stippling similar to that in RPA is observed in young patients, and a scallop-bordered geographic atrophy of the mid peripheral RPE develops over time ( Figure 5.45 A and B). This is similar in appearance to early gyrate atrophy, choroideremia, and Bothnia dystrophy; however, plasma ornithine levels are normal. Cataracts have not been documented, myopia is not seen consistently, and glaucoma has not been identified. Bone spicule pigmentation is not seen, optic discs are either normal or show trace pallor until late stage, and only mild attenuation of retinal vessels is seen in advanced disease ( Figure 5.45 G–K).

Newfoundland rod–cone degeneration (NFRCD).

A and B: This 47-year-old male was investigated for hyperreflexia and abnormal gait in 1993. In 2000, gait disturbance worsened and a retinal degeneration was noted. Cerebellar and cerebral atrophy was found on magnetic resonance imaging in 2001, and by 2007, the spasticity confined him to a wheelchair. He was found to have punctate white dots all over the fundus (early stage) with some patches of retinal pigment epithelium/choriocapillary atrophy (A and B). One sister had similar history and findings and two other siblings and parents were unaffected. His rod electroretinogram was flat and cone responses were diminished.

C–L: This patient with NFRCD had confluent peripheral and mid peripheral lacunar atrophy in both eyes (midstage, C and D). Angiogram showing “moth-eaten” retinal pigment epithelium in the macula and loss of choriocapillaris in the areas of lacunar atrophy. Composite images show the extent and distribution of the atrophy in the midperiphery in both eyes (G–I). Five years later, the lacunar atrophy appears stable without progression into the macula in both eyes (J and K). Visual field defects correspond to the lacunar atrophy with ring scotomas early in the disease, but only remaining temporal field when the disease is advanced and extends to the macula (L).

(Courtesy of Dr. James Whelan.)

The ERG rod responses are selectively reduced early, and the ERG rod and cone responses are both extinguished in advanced disease. The early visual field defect is a ring scotoma close to fixation rather than in the mid peripheral field seen in classic retinitis pigmentosa ( Figure 5.45 L). Central visual acuity may be as good as 20/20–20/60, although the central field may be less than 5°. The rate at which the ring scotoma widens and becomes a complete central scotoma is an indicator of the rate of progression of the disease. Color vision defects are initially mild red/green with or without blue/yellow defects, but this progresses rapidly to eventual loss of color perception. There are however exceptions where patients in their 30 s or 40 s have only mild to moderate color vision defects.

The area in Newfoundland in which the majority of affected patients reside is within a 10-mile (16-km) radius. Most inhabitants here migrated from southwestern England in the mid 18th century, and the population has remained fairly isolated till recently. A single common ancestor has not been identified. Two RLBP1 splice junction mutations are responsible for NFRCD, whereas missense mutations of RLBP1 are responsible for RPA, Bothnia dystrophy, and autosomal-recessive RP.

Bietti’s Crystalline Tapetoretinal Dystrophy

Patients with Bietti’s crystalline tapetoretinal dystrophy, usually males, are initially seen in middle age because of slowly progressive loss of vision frequently unassociated with nyctalopia. In the early stages of the disease fundoscopic examination reveals a striking fundoscopic picture characterized by the presence of glittering crystals scattered throughout the posterior fundus ( Figure 5.46 A, B, H, and I). These are located in all layers of the retina and can be confirmed on OCT.

Bietti’s crystalline tapetoretinal dystrophy.

A–D: Atypical pigmentary retinal dystrophy associated with widespread subretinal crystalline deposits in a 54-year-old man of Italian descent who had recently noted paracentral scotomas in both eyes. His visual acuity was normal. Note the relative paucity of crystalline deposits in those areas of geographic atrophy of the retinal pigment epithelium (RPE) (A and B). Visual field defects corresponded with the areas of RPE depigmentation. The corneas and conjunctivae were normal. His electro-oculogram was normal. Electroretinography showed subnormal rod and cone responses in both eyes. His past medical history was unremarkable. He had normal levels of serum ornithine and urine oxalates. There was no family history of consanguinity or visual loss.

E and G: This 34-year-old Lebanese man noted slow loss of central vision for several years. His family history was negative. His visual acuity was 20/70 right eye and 20/50 left eye. He had many retinal crystals in the posterior fundi (E) and subtle crystals in the corneas. There was evidence of early geographic atrophy of the RPE in the right eye (E–G). Note evidence of nonperfusion of the choriocapillaris paracentrally (arrows) and depigmentation of the RPE throughout the macula (F and G). An electroretinogram revealed mild decrease in cone amplitudes.

H–L: This 15-year-old female had many variably sized crystalline deposits throughout the postequatorial fundi (H and I). Three and one-half years later, she had severe visual loss, atrophy of the pigment epithelium, loss of the crystalline material, and sheathing of the choroidal vessels (J). Note the extensive loss of the choriocapillaris evident in the angiograms (K and L).

There are often multiple areas of geographic atrophy of the RPE in the posterior fundus ( Figures 5.46 and 5.47 ). Autofluorescence imaging shows decreased autofluorescence corresponding to the areas of RPE loss, punctate increased autofluorescence corresponding to pigment dots, possibly RPE hyperplasia, and very little hyperautofluorescence of the crystals. The crystals are less apparent in the areas of pigment epithelial atrophy. The optic disc and retinal vessels are typically normal. There may or may not be marginal crystalline dystrophy of the cornea characterized by the presence of sparkling yellow or white, round, polygonal, or needlelike crystals located in the anterior stroma of the perilimbal region. These crystals may become more prominent late in the disease and biopsy of the limbal conjunctiva and cornea has shown these crystals to be complex lipid inclusions within fibroblasts. The electroretinographic and electro-oculographic findings are usually subnormal. Fluorescein angiography reveals atrophy of the choriocapillaris in the zones of pigment epithelial atrophy. These zones progressively enlarge, become confluent, and extend into the periphery of the fundus. The rate of progression and severity of the disease are variable. Figure 5.46 (H–L) illustrates a black woman who had rapid progression of the disease. Most cases have been reported in patients of Italian or oriental extraction, in particular Chinese and Japanese.

Bietti’s crystalline dystrophy.

A–D: This 47-year-old woman of German descent complained of night blindness for more than 10 years. Her visual acuity was 20/40 on the right and 20/100 on the left. Diffuse atrophy of the retinal pigment epithelium (RPE) and choriocapillaris was seen in the posterior pole with shiny yellow white crystals all over in both eyes. Fluorescein angiography showed diffuse chorioretinal atrophy with patch preservation of RPE and choriocapillaris (B–D).

E–I: A 50-year-old Hispanic woman with complaints of photophobia and nycatalopia had a visual decline to 20/40 and 20/100. Color vision was diminished to 2/12 on the right and 0/12 on the left by Ishihara testing. Both eyes showed central RPE/choriocapillary atrophy with shiny crystals throughout the fundus (E and F). Choriocapillary and RPE loss were seen on angiography (G–I).

(Courtesy of Dr. Brian Berger.)

The hereditary pattern is autosomal-recessive and the causative gene is CYP4V2 , which belongs to the cytochrome P450 hemithiolate protein superfamily and is responsible for oxidizing various substrates in the metabolic pathway. Several mutations in the CYP4V2 gene have been described. Cultured cells and peripheral lymphocytes from patients with Bietti’s crystalline tapetoretinal dystrophy are found to have abnormally high triglycerides and cholesterol storage, and reduced metabolism of labeled fatty acid precursors, suggesting that Bietti’s crystalline dystrophy may result from abnormality of lipid metabolism. The nature of the crystals within the retina is unknown, but is presumed to be similar or related to the inclusions in the corneal and dermal fibroblasts and peripheral blood lymphocytes.

Leber’s Amaurosis (Infantile Tapetoretinal Dystrophy, Retinal Neuroepithelial Dysgenesis)

Leber used the name “congenital amaurosis” to describe an autosomal-recessively inherited disorder characterized by blindness or very low vision at birth, failure to fix, nystagmus, sluggish pupillary reaction, occasional photophobia, a positive oculodigital sign, and hyperopia in patients who later developed evidence of retinitis pigmentosa. Patients with Leber’s amaurosis are usually hyperopic, unlike patients with retinitis pigmentosa, who are typically myopic. Because there is accumulating evidence that many patients with congenital amaurosis have a retinal dysgenesis associated with minimal evidence of progressive visual loss, it is useful to group these patients, who are otherwise normal, apart from those with congenital blindness associated with a host of systemic disorders, including psychomotor retardation, mental retardation, hydrocephaly, deafness, epilepsy, cardiomyopathy, myopathy, dyscephaly, dwarfism, and other skeletal anomalies. It is possible that some of these latter patients may have an infantile-onset progressive tapetoretinal dystrophy.

At birth the fundi of most patients with Leber’s amaurosis are normal. Some patients, however, may show dysplastic fundus changes, including pseudopapilledema ( Figure 5.48 A), optic disc pallor ( Figure 5.48 D), optic disc hypoplasia ( Figure 5.48 D), macular coloboma, and chorioretinal coloboma ( Figure 5.48 E and F). A variety of pigment epithelial and retinal changes develop in early childhood and continue into adulthood. These include salt-and-pepper pigmentation, yellowish flecks, “marbleized” fundus with mosaic pattern ( Figure 5.48 C and I), periarteriolar distribution of well-demarcated yellow lesions located external to the retinal vessels, nummular pigmented lesions ( Figure 5.48 C), retinitis pigmentosa, choroideremia, gyrate atrophy, macular colobomata, and bull’s-eye maculopathy. A variety of progressive chorioretinal degenerative changes associated with narrowing of the retinal vessels and optic atrophy eventually develop ( Figure 5.48 B and C). Only occasionally does the typical bone spicule pattern of retinitis pigmentosa occur. Cataract and keratoconus are late complications.

Leber’s congenital amaurosis.

A: This 2-year-old girl had only light perception in both eyes. Note the anomaly of the optic disc. The electroretinogram was extinguished. Her refractive error was +4.50.

B and C: This 8-year-old boy had hand movements vision in the right eye and 20/70 in the left eye. Note the extensive geographic areas of atrophy of the retinal pigment epithelium (RPE) posteriorly and the round clumping of pigment in the periphery of the fundus. His electroretinogram was extinguished.

D: Optic disc hypoplasia, and marked narrowing of the retinal vessels in this boy with nystagmus, night blindness, and an extinguished electroretinogram.

E and F: This 14-year-old boy had poor vision since birth, nyctalopia, marked narrowing of the retinal vessels, pigmentary mottling in the macula (E), marked constriction of the visual fields, an extinguished electroretinogram, and an inferior colobomata of the choroid and retina bilaterally (F). His visual acuity was 20/40 right eye and 20/50 left eye. A first cousin had poor vision of uncertain cause. At age 25 years his findings were similar but his visual acuity was 20/200 bilaterally.

G–I: Coats’ syndrome in the left eye of this woman with nystagmus and marked loss of vision since birth. She had marked narrowing of the retinal vessels and extensive degeneration of the RPE with punctate RPE hyperplasia (H and I) in both eyes. In the left eye inferiorly there was extensive yellowish exudative detachment of the retina and retinal telangiectasis (G and H). Arrows in G and H indicate optic disc.

J: Histopathology of the eye of a 12-year-old boy with Leber’s amaurosis and xeroderma pigmentosa. Note monolayer of retinal receptors and absence of cone outer segments (arrow) in the macula, which was otherwise unremarkable. The mid peripheral retina showed disruption of the normal retinal architecture by gliosis.

K: Histopathology of the eye of another patient with Leber’s amaurosis who developed spontaneous rupture of the cornea that had severe keratoconus. Note in this section of the peripheral retina the marked degeneration and gliosis, the migration of RPE (left arrow) into the retina, and the focal areas of subretinal RPE hyperplasia beneath the retina (right arrow).

The ERG is extinguished in approximately 75% of patients and is markedly abnormal in the remainder. For infants with unexplained visual loss, an ERG is essential in differentiating Leber’s amaurosis from other causes of congenital blindness. Fluorescein angiography may show evidence of RPE atrophy not appreciated ophthalmoscopically as well as evidence of papilledema.

LCA is usually inherited as an autosomal recessive trait, although dominant inheritance has also been reported. Mutations in 10 retinal genes have so far been shown to cause LCA, namely AIPL1, CRB1, CRX, GUCY2D, RDH, RPE65, RPGRIP1, TULP1, IMPDH1 and, more recently, CEP290 . Because of the increasing number of LCA-causing genes, it is difficult to classify patients with LCA on a molecular basis and consequently to evaluate phenotype–genotype correlations. Gene therapy trials are underway in RPE65 involved patients.

LCA is usually inherited as an autosomal recessive trait, although dominant inheritance has also been reported. Mutations in 10 retinal genes have so far been shown to cause LCA, namely AIPL1 , CRB1 , CRX , GUCY2D , RDH , RPE65 , RPGRIP1 , TULP1 , IMPDH1 and, more recently, CEP290 . Because of the increasing number of LCA-causing genes, it is difficult to classify patients with LCA on a molecular basis and consequently to evaluate phenotype–genotype correlations. Gene therapy trials are underway in RPE 65 involved patients. Long-term follow-up studies of patients with Leber’s amaurosis reveal that, although there is a progression of the fundus changes throughout life, the visual function remains relatively stable in most patients. Loss of function is most likely to occur in those with macular colobomas and those who in later life develop keratoconus and cataracts. Most patients with Leber’s congenital amaurosis have the capability of normal cognitive function, but most perform poorly on standard IQ tests.

In childhood, histopathologic changes consist primarily of failure of development or loss of the rods and cones ( Figure 5.48 J). These changes are followed by progressive degenerative changes involving all of the retinal layers and RPE similar to that seen in retinitis pigmentosa ( Figure 5.48 K).

The natural course of most patients with Leber’s congenital amaurosis suggests that it is a retinal dysgenesis and not a progressive tapetoretinal degeneration. The progressive fundoscopic and histopathologic changes observed in these patients can all be explained on the basis of reactive changes occurring in the retina and pigment epithelium in response to the widespread absence at birth of the retinal receptor cells. These reactive changes include degeneration, proliferation, and intraretinal migration of the pigment epithelium; narrowing of the retinal blood vessels; proliferation of retinal glial cells; and transsynaptic degeneration of the ganglion cells.

The differential diagnosis of Leber’s congenital amaurosis includes cortical blindness, achromatopsia, congenital stationary night blindness, infantile-onset retinitis pigmentosa, and infantile ceroid lipofuscinoses. Electroretinography is important in establishing whether the retina is affected, and to what degree it is affected. Although the ERG may be severely abnormal or extinguished in Leber’s amaurosis, it is not affected in cortical blindness, and only mildly or moderately affected in congenital stationary night blindness. It may be severely affected early in infantile-onset tapetoretinal dystrophies. Absence of searching nystagmus, relatively good visual acuity, and absence of high hyperopia in these latter patients are features atypical for Leber’s amaurosis.

Neonatal Retinal Dysgenesis and Dystrophies Associated with Systemic Diseases

Several well-defined single-gene defects and other less well-defined disorders occur in which retinal dysfunction is one aspect of a generalized disease affecting other organ systems. These include Zellweger’s cerebrohepatorenal syndrome (see p. 397), Saldino–Mainzer syndrome, Senior–Loken syndrome (see p. 390), Joubert syndrome (see p. 398), and Arima’s syndrome (see p. 398). Unlike Leber’s congenital amaurosis, hyperopia is not characteristic of these disorders. Russell-Eggitt et al. have reported seven members of four families with neonatal nystagmus, poor vision, photophobia, severely abnormal or extinguished ERG responses, cardiomyopathy, and short obese habitus. Six had a life-threatening episode of cardiac failure and two died. Examination of muscle obtained at autopsy was unremarkable. Mrak et al. reported a congenital myopathy associated with congenital features of Leber’s amaurosis, hypotonia, delayed motor development, and histologic evidence of broadened or smeared A bands.

Stationary or Slowly Progressive Dominantly Inherited Tapetoretinal Dystrophy

Three successive generations of a black family seen at the Bascom Palmer Eye Institute demonstrated an early-onset, slowly progressive, atypical tapetoretinal dystrophy of variable severity associated with S-shaped deformity of the upper eyelid, microcornea, and angle closure glaucoma ( Figure 5.49 ). Some of the family members showed only mild RPE and retinal degenerative changes without visual loss. Others had more severe loss of central as well as peripheral vision. This family shares some features with a dominantly inherited RPE dystrophy with variable expressivity and complete penetrance characterized by myopia, nystagmus, and an RPE dystrophy of varying severity reported by Noble and associates. In some patients the fundus changes were mild and confined to the macula. The severity of the changes was not related to the extent of involvement or to the degree of myopia. Visual acuity varied from near normal to 20/200 or worse. The pendular nystagmus was not related to the visual function. Electroretinographic changes were present in all patients but varied from mild to severe. These families might be considered as having a dominant, less severe form of Leber’s amaurosis.

Slowly progressive dominantly inherited dystrophy in a family with nystagmus, myopia, microcornea, S-shaped lower-lid deformity, variable degrees of visual acuity loss, field loss, retinal degeneration, optic disc pallor, and electroretinographic abnormalities.

A–C: Ten-year-old black girl with lid deformity, optic disc pallor, and juxtapapillary and peripheral retinal pigment epithelium and retinal atrophy. Her electroretinographic study was normal.

D and E: Brother, 28 years old, of patient in A. Electroretinography revealed severely abnormal rod and cone function.

F: Father, 51 years old, of patient in A. His electroretinogram was nonrecordable.

G: Paternal aunt, 56 years old, of patient in A. Electroretinography revealed moderately abnormal rod and cone functions.

H and I: Eight-year-old grandson of patient in G.

Late-Onset Retinal Macular Degeneration (LORMD)

Patients with Scottish ancestry were first described with this autosomal-dominant condition. They are asymptomatic and have normal fundus till their fifth decade. Symptoms of night blindness begin in the fifth to sixth decade and progress rapidly over a few years. Early retinal changes include “drusenlike” yellow spots throughout the fundus that represent sub-RPE deposits ( Figure 5.50 C). Soon islands of RPE atrophy ensue, leaving intervening spaces of RPE that have scalloped edges ( Figure 5.50 D, E, J–L). The photoreceptor function rapidly worsens over an average of 5 years to leave the patient with severely constricted visual fields; central vision is lost later with further geographic atrophy of the macular RPE. There may be patchy involvement with preservation of the RPE in some parts of the fundus ( Figure 5.50 D, E, K, and L). Early in the course of the disease dark adaptation is affected. The retinal appearance resembles gyrate atrophy; however in patients with gyrate atrophy, the islands of geographic atrophy begin in the periphery and slowly progress towards the posterior pole, whereas those in LORMD are present early in the posterior retina, and ornithine and other amino acids are normal.

Late-onset retinal macular degeneration (LORMD).

A–H: This 62-year-old woman of German descent complained of difficulty with night vision for the past 5 years. Her optometrist noted retinal changes that were not seen 5 years before when he had last examined her. She was amblyopic in her right eye since early childhood and read 20/200 right eye and 20/50 left eye. Several nummular atrophic patches that became larger towards the periphery were seen in the posterior pole (A and B) and temporal fundus (D and E). The nasal retina showed fine drusen. Window defects were seen on angiography and the lesions were hypoautofluorescent. Visual fields showed peripheral constriction and electroretinogram revealed severely depressed rod and cone amplitudes in both eyes. Her father was known to have developed poor vision in his later life; she had two living siblings with no visual dysfunction. Two sons aged 32 and 34 were also asymptomatic.

I–L: This 60-year-old Hispanic male complained of nyctalopia and reduced central vision for 5 years. Several of his cousins had poor vision; no history was available about his own siblings. His vision was 20/100 and 20/80. Round patches of retinal pigment epithelium (RPE)/choriocapillaris atrophy were seen around the fovea and diffusely in the inferior fundus of both eyes (I–L). Patchy pigment migration and clumping were seen; there were intervening scalloped areas of RPE preservation typical of LORMD (J).

Some patients with abnormally long and anterior-attached lens zonules have been described. Histology, electron microscopy, and immunohistochemistry show deposition of material made up of components similar to deposits in age-related macular degeneration and SFD under the RPE. In addition there is accumulation of esterified (stains with oil red O) and unesterified cholesterol similar to contents of atheromatous plaques. The gene defect has been localized to CTRP5 .

Extensive Macular Atrophy with Pseudo Drusenlike Appearance

Hamel et al. described 18 patients with an onset before age 50 of a rapidly increasing atrophic macular lesion that involves the entire posterior pole up to the arcades, resembling geographic atrophy of age-related macular degeneration ( Figure 5.51 ). This vertically oriented atrophic macular lesion is surrounded by numerous drusenlike deposits (resembling reticular pseudodrusen) found throughout the posterior pole and the midperiphery in all cases ( Figure 5.51 A–C). All patients also had paving-stone degeneration in the far inferior periphery. No patient developed choroidal neovascularization and the disorder is not familial.

Macular atrophy with pseudodrusen.

A–F: This 54-year-old white woman had a family history of blindness in the elderly. Onset of symptoms started at age 50 with night blindness, marked photophobia, and difficulty in reading and face recognition at distance. Her visual acuity was right eye: 20/40 with −3.25 sph −1.25×170° and left eye: 20/400 with −4.00 sph −1.25×180°. Intraocular pressure was 13 mmHg right eye and 12 mmHg left eye. On Goldmann perimetry she had bilateral absolute central scotomas (E, F), and dark adaptation was delayed. Bilateral large macular atrophy with the largest diameter in the vertical axis, and numerous pseudodrusen were seen in the midperiphery (A, B). Optical coherence tomography showed the atrophy of the outer layers of the retina (D). Pseudodrusen were not autofluorescent (C) and were not visible on angiography or on optical coherence tomography.

(Courtesy of Dr. Christian Hamel. )

West Indies Crinkled Retinal Pigment Epitheliopathy

Recently, a novel retinal dystrophy ( Figure 5.52 ) was reported by Cohen et al. (presented at the Macula society annual meeting, February, 2010). All reported patients were black or from black ancestry, and originated in Martinique, a French West Indies island. The disease affected a whole family of an 86-year-old mother and her four children. Two other patients were diagnosed with the condition, one related (cousin) to this family, and one unrelated, but originating from the same geographic area.

West Indies crinkled retinal pigment epitheliopathy.

A and B: Composite of right and left eye of a patient with crinkled corrugations of the retinal pigment epithelium appearing as a white reticular net more densely packed in the macular area but extending to the midperiphery, resembling a crackled dry land. Mild pigmentation of the corrugations in the fovea and periphery.

C–I: Left eye of a second patient showing the distinct crinkling (C). The autofluorescence is variable,; most of the wrinkles correspond to hypoautofluorescence suggesting displacement of retinal pigment epithelium (RPE) pigment away from the wrinkles (similar to that seen in chorioretinal folds) (D). Fluorescein angiography revealed the wrinkle to be hyperfluorescent, again suggesting relative lack of pigment within the RPE (E) with late staining (F). Right eye of the same patient showed evidence of choroidal neovascularization with subretinal hemorrhage (G and H). Indocyanine green angiography showed a reticular pattern on late frames, but less distinctly (I). Optical coherence tomography showed that the RPE was thrown into ripples, giving the crinkled appearance (J). Electrophysiology and genetic testing is ongoing.

(Courtesy of Drs. SY Cohen, A Jean-Charles, and H Merle.)

The main fundus feature is the presence of a white reticular net located at the level of the RPE, dense in the macular area, but also present in the midperiphery, resembling crackled dry mud ( Figure 5.52 A–C). Some pigment may be observed within the reticular pattern either in the macula or the periphery. Autofluorescence pattern is variable, with hypoautofluorescence of the white lines ( Figure 5.52 D). Fluorescein angiography reveals a hyperfluorescent network pattern in the early frames, with late staining ( Figure 5.52 E–H). Indocyanine green angiography also displays the reticular pattern on late frames ( Figure 5.52 I). On OCT the RPE appears rippled, giving the crinkled appearance ( Figure 5.52 J). The etiopathogenesis of the disorder is unclear, be it an acquired or a dystrophic condition. Two patients developed subretinal hemorrhages related to possible polypoidal choroidal vasculopathy. Two patients also had disciform macular scarring which may have been secondary to hemorrhages and/or choroidal neovascularization. Electrophysiology and genetic testing are ongoing.

Non X-linked Choroideremia

Several women have been seen with diffuse chorioretinal atrophy (Fig. 5.55) without a family history of X-linked choroideremia. They do not have Turner’s syndrome(XO) or be a product of an affected father and a choroideremia carrier mother. It is likely that they have a disease different from choroideremia, and future genetic analysis is likely to yield a cause.

Goldmann–Favre Syndrome (Enhanced S-Cone Syndrome)

Goldmann–Favre syndrome (hyaloideotapetoretinal degeneration) is an autosomal-recessive disease characterized by night blindness, atypical peripheral pigmentary dystrophy, central and peripheral retinoschisis, complicated cataract at an early age, optically empty vitreous with an occasional vitreous band, and a markedly abnormal, often nonrecordable, ERG. In addition to narrowing of the retinal vessels and waxy pallor of the disc, the macula appears diffusely thickened by prominent superficially located macrocysts that fail to stain on fluorescein angiographic study ( Figure 5.57 C, E, and F). Giant macular schisis and cyst formation can be confirmed on OCT testing ( Figure 5.57 J–L). There have been reports of benefit with oral acetazolamide in decreasing the macular thickness in patients with enhanced S-cone syndrome.

Goldmann–Favre syndrome (enhanced S-cone syndrome).

A–C: This 19-year-old boy’s visual acuity in the right eye was 20/50 and J-1 and in the left eye was 10/200. He had a mid zonal scotoma. There were extensive schisis and large cystoid changes of the entire macular region (A). There was a broad mid zonal area of atrophy of the retinal pigment epithelium associated with some migration of pigment and narrowing of the retinal vessels (B). There was no peripheral retinoschisis. Fluorescein angiography (C) was within normal limits. There was no leakage of dye in the late stages of angiography. His electroretinogram showed absent photopic responses and markedly abnormal scotopic responses. His color vision was normal (Farnsworth D-15).

D–F: Goldmann–Favre disease in a 12-year-old boy complaining of mild loss of vision. His family history was negative. Visual acuity was 20/40 in the right eye and 20/100 in the left eye. He had retinal thickening and cystic changes throughout the macular areas (D). There were ill-defined subretinal white flecks (arrows, D and E) in the perimacular area. Angiography revealed focal areas of hyperfluorescence corresponding with the flecks (arrow, E and F). There was no evidence of intraretinal staining. An electroretinogram showed severely abnormal rod and cone function. The electro-oculographic findings were markedly abnormal. Eight years later the fundi were unchanged. Visual acuity was 20/400 and J-3 in the right eye and 20/300 and J-2 in the left eye.

G–L: This present 30-year-old male was examined by Dr. Gass at age 19 with a history of running into bushes when the child got out of the car in the dark for the previous 10 years. At that time he carried a diagnosis of juvenile macular schisis in both eyes. He was found to have a disciform scar in the macula of the right eye and extensive schisis in the macula of the left eye rephotographed at age 30 (G and H). He also had pigmented nummular lesions (arrow) sourrounding the arcades in each eye (I and J). The retinal vessels were of reasonable caliber and no bone spicule pigment migration was visible in either eye. A diagnosis of Goldmann–Favre (enhanced S-cone dystrophy) disease was made by Dr. Gass. Optical coherence tomography shows a scar from involuted choroidal neovascular membrane in the right eye with collapsed schisis and extensive schisis of the left macula extending up to the arcades (K and L).

Cases of night blindness and peripheral retinoschisis without macular schisis occur. Histopathologic examination of a peripheral biopsy specimen in one case showed nonspecific degeneration of the sensory retinal layers, thickened retinal vessel basement membranes, areas of retinal vascular occlusion, preretinal glial membranes, and choroidal vascular changes. Some patients with Goldmann–Favre syndrome demonstrate relatively enhanced S-cone function electrophysiologically identical to that found in the enhanced S-cone syndrome. These latter patients have night blindness, maculopathy (often cystoid), degenerative changes with partly pigmented yellow flecks in the region of the major vascular arcades, relatively mild visual field loss, slow progression, and a characteristic ERG. The dark-adapted ERG shows no response to low-intensity stimuli that normally activate the rods but large, slow responses to high-intensity stimuli. The large, slow waveforms persist without change under light adaptation and show a striking mismatch to photopically balanced short- and long-wavelength stimuli, with sensitivity much greater to short than to long wavelengths. It is possible that patients with Goldmann–Favre syndrome and those with enhanced S-cone syndrome, some of whom do not have macular schisis, are not distinct entities but are simply two identifiable phenotypes of clinical expression of a retinal degenerative disease with a single pattern of retinal dysfunction. Patients with both syndromes have been observed in the same family. There is evidence that patients with the enhanced S-cone syndrome have a retinal dysgenesis that probably occurs during the early development of the retina and results in many more S-cones that form in the place of many L/M-cones and rods. Many of the clinical and functional characteristics of enhanced S-cone syndrome, e.g., the negative waveform, reduced oscillatory potentials, retinoschisis, and vitreous changes, may be consequences of this early abnormality in the complex development sequence of the retina. Both patients illustrated in Figure 5.57 (A–F) reported in previous editions of this atlas as examples of Goldmann–Favre syndrome were recalled and both have enhanced S-cone syndrome.

Mutations in NR2E3 which encodes a photoreceptor nuclear receptor are responsible for enhanced S-cone syndrome, Goldmann–Favre syndrome, and clumped pigmentary retinopathy.

Familial Foveal Retinoschisis

Foveal retinoschisis, which is characterized by a delicate network of radiating cystic changes in the superficial retina and confined generally to the foveal area, is the hallmark of X-linked juvenile retinoschisis and should be differentiated from macular schisis, which is composed of a more coarse pattern of larger cystoid spaces that may extend throughout most of the macular area and is the hallmark of Goldmann–Favre syndrome. With rare exceptions, familial foveal retinoschisis is found only in males. The macula is involved in all cases, and many patients demonstrate evidence of widespread changes in the retina and RPE.

X-Linked Juvenile Retinoschisis

A constant diagnostic feature of X-linked juvenile retinoschisis, which is present at birth or soon afterward in all affected males, is a characteristic macular lesion referred to as “foveal schisis” ( Figure 5.58 A, C, G, J, and L and 5.59 A–C, E–G). Only 50% of patients will have evidence of peripheral retinoschisis or related findings, mostly in the inferotemporal quadrant ( Figure 5.58 A, B, J, and K). There may be large oval or round holes in the inner retinal layers creating “vitreous veils” ( Figure 5.58 B). Retinal blood vessels may or may not accompany the inner retinal layer. Unsupported retinal vessels may course into the vitreous cavity. Semitranslucent gray-white arborescent scrolls, a dendriform pattern of occluded retinal vessels ( Figure 5.58 H), silver-gray glistening patches on the retinal surface, perivascular cuffing, chorioretinal scars, vitreous detachment, intraretinal gray-white spots ( Figure 5.58 G), intraretinal blood cysts, and evidence of recent or old vitreous hemorrhage are other findings that may be present. Nasal dragging of the retina may be present in infancy and is presumed to be related to temporal dehiscence of the nerve fiber layer. Retinal and optic disc neovascularization may occur. Usually these patients are initially seen during the early school years, either because of reading difficulty or because of symptoms of vitreous hemorrhage. An occasional patient may be seen early in life because of a massive area of schisis that partly or completely obstructs the pupillary space.

X-linked juvenile retinoschisis.

A and B: Typical radiating inner retinal cysts associated with foveal schisis in a boy with peripheral retinoschisis and large holes in the inner retinal layers.

C and D: Foveomacular schisis in a 24-year-old man who first noted decreased vision at age 5 years. Visual acuity was 20/30. Angiography showed minimal changes in the retinal pigment epithelium.

E and F: Cystic changes simulating foveal retinoschisis in a 7-year-old boy with a rhegmatogenous retinal detachment. These disappeared after a scleral buckling procedure.

G–I: Foveal and peripheral retinoschisis in a 14-year-old boy with widespread intraretinal gray-white spots and sheathed and occluded peripheral retinal vessels. There were large holes in the inner retinal layers temporally in the right eye.

J–L: Twenty-two-year follow-up of X-linked juvenile retinoschisis in a patient who was age 15 years with visual acuity of 20/60 bilaterally when first seen with foveomacular schisis (J and K). Visual acuity at last examination was 20/200 right eye and 20/80 left eye. There was minimal change in the fundi (L).

Biomicroscopically, foveal schisis presents a characteristic picture of small superficially located cysts arranged in a stellate pattern and radial striae centered in the foveal area ( Figures 5.58 A, C, G, J, and L and 5.59 C, E, F, and G). The central cysts often have a fusiform shape. Additional cysts become evident more peripherally. This is associated with some elevation of the inner portion of the retina. A peculiar sheen develops on the retinal surface. This occasionally may present a golden tapetal reflex and the Mizuo–Nakamura phenomenon. Eventually the cyst walls may coalesce and form a large central schisis cavity. This is followed in some cases in adulthood by disappearance of the cystic changes, alterations in the underlying RPE, and finally development of a nonspecific atrophic macular lesion. Some patients demonstrate corrugations of the outer retina either in the temporal macula, or more extensively throughout the fundus. These corrugations appear to be at the photoreceptor and outer plexiform layers and are known to change in orientation and shape over time, and sometimes may disappear altogether. Two brothers are shown in Figure 5.59 . The younger sibling, who became symptomatic first, lost the corrugations over 5 years ( Figure 5.59 B and K). Whether the change in height and tautness of the schisis cavity impart forces to the temporal retinal to cause these corrugations is a hypothesis.

X-linked juvenile retinoschisis and outer retinal corrugations.

This 12-year-old male (sibling A) had a best-corrected visual acuity of 20/60 in each eye. There were cystic changes in the fovea in both eyes, more prominent on the right (A) than the left. In addition corrugations of the outer retina were likened to “flying seagulls” temporal to the schisis cavity in his left eye (B). His mother’s eye examination was normal. His vision gradually worsened over 5 years to the 20/200 level. Five years later his brother older by 2 years (sibling B) noted a rapid change in vision and could not be corrected with his contact lenses beyond 20/40. He had foveal schisis in both eyes associated with similar outer retinal corrugations, in his right eye (C and E). The schisis cavity was not detected by fluorescein angiography, while the corrugations were mildly fluorescent (D, arrow). Over the next year the corrugations changed in shape in his right eye and appeared in the left eye (arrows, F and G). Optical coherence tomography (OCT) of both maculas showed schisis cavity in multiple layers (H1 and H2). OCT through the corrugations showed them to be in the outer retina with processes of the photoreceptors and external limiting membrane (arrows, I1 and I2). Sibling A now had lost the retinal corrugations in his left eye, the schisis was more widespread in both eyes (J and K), and the OCT showed schisis cavity on the left was larger (L).

Some patients show progressive narrowing of the retinal vessels and develop peripheral changes of pigmentary retinal dystrophy. In childhood the RPE may be normal ( Figure 5.58 C and D) or may be diffusely or irregularly depigmented ( Figure 5.58 J and K). Rhegmatogenous detachment infrequently occurs, and spontaneous reattachment may occur. Rupture of a superficial retinal neovascular tuft within the area of schisis may cause either vitreous hemorrhage or bleeding into a peripheral retinal cyst. Most vitreous hemorrhages resolve spontaneously. Anomalous vascular looping or branching on the optic disc is common.

Most of the changes occurring in X-linked juvenile retinoschisis occur during the first two decades of life. Visual acuity often stabilizes at 20/50–20/100. The peripheral visual field is affected only when peripheral schisis is present.

On fluorescein angiography the posterior fundus is frequently normal ( Figure 5.58 D). In some patients there may be diffuse mottled hyperfluorescence indicative of extensive pigmentary changes present throughout the retina ( Figure 5.32 J and K). Patients with evidence of peripheral schisis may show leakage of dye from the retinal vessels within the area of schisis, as well as adjacent areas ( Figure 5.58 I). Evidence of nonperfusion of segments of the retina may be present. OCT demonstrates the cavities with vertical pillars separating them from each other ( Figure 5.59 H1 and H2). Dark adaptation is usually normal or minimally affected. Electroretinography typically shows abnormal b-wave and normal a-wave amplitudes, prolonged b-wave latencies and implicit times, reduced oscillatory potential generated by either rods or cones, and reduced 30-Hz flicker response. The findings are probably partly dependent upon the severity of the retinoschisis and the age of the patient. Electro-oculographic studies are usually normal in young patients.They may be subnormal in patients with severe involvement of the RPE.

Histopathologically, the splitting in juvenile retinoschisis occurs in the nerve fiber layer and ganglion cell layers. The internal limiting membrane of the retina is thinned over the area of schisis. The inner layer may or may not contain retinal blood vessels. To date no histopathology is available concerning the typical early stages of foveal schisis. The histopathologic findings and ERG abnormalities affecting the b-wave implicate the Müller cells at the primary cell involved in this disorder. (See p. 506 for the histopathologic findings of infantile cystoid maculopathy that macroscopically resemble foveal retinoschisis.) Unlike senile schisis, where retinal splitting occurs predominantly in the outer plexiform layer and adjacent nuclear layers, the superficial juvenile retinoschisis cavities do not contain acid mucopolysaccharides.

Progression of visual loss is usually slow and may be associated with minimal changes in the appearance of the fundi ( Figure 5.58 J and L). Peripheral schisis usually does not progress, and in some cases spontaneous reapposition of the inner and outer layers occurs.

There are no fundus changes in the female carriers. Arden et al. reported identification of obligate heterozygous X-linked juvenile retinoschisis: all patients demonstrated a lack of rod–cone interaction electroretinographically. Linked DNA probes have been used for carrier detection and diagnosis of X-linked juvenile retinoschisis.

Mutations including deletions, missense mutations, and null mutations in the Retinoschisin gene XRLS1 are responsible for the condition.

Foveal schisis may be simulated by focal contraction of the internal limiting membrane caused by contracted prefoveolar vitreous cortex following an aborted macular hole (see Figure 12.14J–L), by changes occurring in the inner retina in patients with a rhegmatogenous retinal detachment ( Figure 5.32 E and F), and by infantile cystoid maculopathy (see p. 506).

Bullous peripheral retinoschisis affecting the macula is seen mainly in infants and children and there is a marked tendency for spontaneous resolution. Prophylactic treatment to prevent spread of the schisis or to reattach the inner retina is generally unnecessary and may lead to severe complications.

Non X-Linked Foveal Retinoschisis

Typical foveal schisis has been reported in females with peripheral schisis, and in families showing evidence of autosomal-dominant inheritance ( Figure 5.60 ). The pattern of the foveal cystic changes is variable ( Figure 5.60 A, B, G, and H); some resemble cystoid edema in patients with retinitis pigmentosa whereas others have more vertically oriented columns of tissue between lucent spaces ( Figure 5.61 ). Lewis and associates have reported typical foveal schisis in three daughters of a nonconsanguineous marriage. Yamaguchi and Hara have reported a family of probable autosomal-recessively inherited peripheral retinoschisis without foveal schisis.

Non X-linked foveomacular schisis.

A–C: Foveomacular schisis in a 19-year-old woman with visual acuity 20/20 right eye, and 20/40 left eye. Angiography was normal (C). Her family history was negative. Her electroretinographic study was normal.

D–I: Familial foveomacular schisis in a brother and sister. Macular lesions were first noted in the sister at age 6 years. At age 15 years her acuity in the right eye was 20/30 bilaterally. She had mild epiretinal membrane changes and cystic foveal changes bilaterally that were associated with a yellowish change at the level of the retinal pigment epithelium (RPE) in the right eye (D and E). A few vitreous cells were present. There were no pars plana exudates. Fluorescein angiography in the left eye was normal (F). An electroretinogram was normal. The brother presented at age 21 years complaining of gradual visual loss for 5 years. He denied nyctalopia or hemeralopia. His visual acuity was 20/60 bilaterally. There were minimal vitreous cells present bilaterally, mild epiretinal membrane changes, and a large central cyst surrounded by smaller cysts in the center of the macula bilaterally (G and H). There was no peripheral retinoschisis. Angiography revealed a focal window defect hyperfluorescence centrally in both eyes (I). The retinal vessels and RPE appeared normal. An electroretinogram revealed some reduction of rod and cone amplitudes.

J–L: This 63-year-old woman had bilateral foveomacular schisis (J and K) and peripheral retinal schisis. Angiography was unremarkable (L). Her family history was negative.

Non-X-linked macular schisis.

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