Some of the heredodystrophic disorders appear to affect primarily the retinal pigment epithelium (RPE) and only secondarily the retina (e.g., Best’s disease). Others, such as retinitis pigmentosa, appear to affect both layers equally; still others affect primarily the sensory retina (e.g., cone dystrophies and the sphingolipidoses). Some affect primarily central vision, whereas others may affect most of the visual field. Several heredodystrophic diseases that may prove to affect primarily the RPE and retina are frequently associated with drusen and disciform detachment (dominantly inherited exudative drusen; basal laminar drusen; North Carolina dystrophy and macular staphyloma).
Best’s disease (vitelliform macular dystrophy) is an autosomal-dominantly inherited disorder with variable penetrance and expressivity. Linkage analysis has mapped the gene for Best’s disease for pedigrees in Sweden and Iowa to chromosome 11q13. The gene responsible for BVMD was cloned by Petrukhin and colleagues in 1998 and named the Bestrophin1 ( BEST1 ) gene. It consisits of 11 exons and 585 amino acids and spans 15 kilobases of genomic DNA. The gene is expressed predominantly in the RPE cells and the bestrophin protein is located mainly on the basolateral plasma membrane of the RPE and to a small extent within the RPE cells. The protein is believed to function as an intracellular Ca 2+ -dependent Cl − channel and an HCO 3 − channel. Disruption of the ion conductance across the RPE by abnormal bestrophin1 is likely responsible for the absence of light peak response in the electro-oculogram (EOG) in both patients and unaffected carriers of Best’s disease. The disease appears to affect primarily the RPE.
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.
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.
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.
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.
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.
ADVIRC is a hereditary pigmentary dystrophy described in 1982 by Kaufman and associates. It has an autosomal-dominant inheritance pattern and is characterized by peripheral pigmentary retinopathy for 360° with a discrete posterior boundary near the equator ( Figure 5.05 C–E) associated with punctate whitish opacities in the superficial retina along with vitreous cells and fibrillary condensation. Frequently, peripheral retinal arteriolar narrowing and occlusion, evidence of retinal neovascularization, choroidal atrophy, and presenile cataracts are present. Evidence of blood–retinal barrier breakdown is seen by cystoid macular edema.
These patients usually do not have symptoms of night blindness. The electroretinogram (ERG) is normal or only slightly reduced. The EOG is variably affected, with Arden ratio ranging from normal to subnormal. There have been a few cases with late cone dystrophy. The gene defect has been localized to the BEST1 gene with missense mutations and exon skipping on the long arm of chromosome 11.
Autosomal-Dominant Microcornea Rod–Cone Dystrophy, Cataract with Staphyloma
A subgroup of patients who have all or some features of ADVIRC may also have microcornea and shallow anterior chamber with evidence of subacute or acute angle closure glaucoma. Some of these patients show posterior staphyloma and some of them are myopic. The inheritance pattern is autosomal-dominant, and the gene again has been ascribed to the BEST1 mutation. The EOG is abnormal in all patients with ADMRCS syndrome. A full-field ERG may show subnormal photopic and scotopic responses. With time, these patients show progressive ERG changes with severe rod and cone photoreceptor dysfunction, unlike patients with ADVIRC who are relatively stable. The ADMRCS syndrome is generally more severe than ADVIRC. However, there are family members who have overlapping findings of the two conditions.
This condition was described by Burgess et al. in 2008. It usually starts with central visual loss at an age of onset ranging from 4 to 40 years, and the mean age of onset is approximately 25 years. The visual acuity often deteriorates to less than 20/60 in both eyes within a few years. Patients are generally hyperopic and show shallow anterior chambers and may present with subacute or acute angle closure glaucoma. Fundus examination shows irregular RPE alterations with whitish subretinal deposits that are seen throughout the retina, preferentially in the macula and midperiphery ( Figure 5.05 I–L). Retinal edema with neurosensory retinal detachment and subretinal fluid may be observed in the macula occasionally; this can be confirmed by optical coherence tomography (OCT). Patients may not show the vitelliform lesions that are characteristic of Best’s disease. The macular lesions may evolve into atrophic scars causing a further decline in vision. The EOG is severely reduced or absent to light rise. The focal pattern ERG in the macula is markedly abnormal, indicating severe macular dysfunction. The full-field ERG shows reduced and delayed rod and cone responses indicating panretinal photoreceptor dysfunction. On angiography, there is widespread patchy hyperfluorescence due to RPE atrophy and retinal edema. These areas correspond to areas of increased fundus autofluorescence (Figure 5.05L), suggesting lipofuscin accumulation in the pigment epithelium. The areas of RPE loss show decreased fundus autofluorescence. High-resolution OCT of the macula shows photoreceptor detachment from the pigment epithelium, disruption of the photoreceptor layer but persevered inner retinal layers (Figure 5.05M). Those patients who are heterozygous to the mutation are entirely normal clinically and electrophysiologically.
All the three conditions described above are caused by mutations in the BEST1 gene, the same gene that causes Best’s vitelliform macular dystrophy. Whereas Best’s, ADVIRC, and ADMRCS syndromes are autosomal-dominant, ARB occurs in the presence of homozygous or compound hetereozygous BEST1 mutation.
Nearly all mutations identified in Best’s vitelliform macular dystrophy and adult-onset foveal macular vitelliform dystrophy, a type of pattern dystrophy, are missense mutations. Those mutations causing ADVIRC and the MRCS syndrome are splice mutations, leading to in-frame deletions or duplications. The null phenotype of ARB is caused by homozygous or compound heterozygous nonsense or missense BEST1 mutation. The variable expressivity and penetrance probably account for the wide variation in the phenotype of these conditions. It is likely they are also dependent on other genetic or environmental modifiers to manifest all features of the condition.
Multifocal Vitelliform Lesions in Patients Without Evidence of Best’s Disease
Multifocal vitelliform lesions with the same features as those occurring in Best’s disease, in Dr. Gass’ experience, occur most frequently in patients with normal EOG findings and a normal family history ( Figures 5.06 and 5.07 ). Fluorescein angiography typically demonstrates nonfluorescence of the yellow lesions ( Figures 5.06 C and L, and 5.07 H). Occasionally, however, the yellow lesions demonstrate early hyperfluorescence ( Figure 5.07 J). As in the case of Best’s disease, the yellow lesions may disappear ( Figure 5.07 A–D). The frequency of normal EOG findings and a negative family history in patients with multifocal vitelliform lesions suggest that most of these patients do not have either Best’s disease or pattern dystrophy. The absence of a family history alone does not entirely exclude these diagnoses, since many affected persons with Best’s disease and pattern dystrophy are asymptomatic. This condition should be differentiated from acute exudative multifocal vitelliform maculopathy, an acute-onset inflammatory disorder of so far unknown cause, ARB, and paraneoplastic vitelliform maculopathy. Deutman reported a patient with loss of central vision for many years associated with peripheral and macular vitelliform lesions together with electroretinographic changes compatible with a rod–cone dystrophy. It is possible Deutman’s patient had autosomal recessive bestrophinopathy.
Autosomal-Dominant Pattern Dystrophies of the RPE
Autosomal-dominant pattern dystrophies are characterized by the development, usually in midlife, of mild disturbances of central vision associated with a variety of patterns of deposits of yellow, orange, or gray pigment in the macular area. The prognosis for retention of good central vision in at least one eye until late adulthood is good. The EOG may be slightly or moderately subnormal. The ERG is typically normal. These dystrophies are usually inherited as an autosomal-dominant trait. Mutations of the peripherin/ RDS and slow gene (Pro 210 ARG) and codon 167 of the RDS gene were first demonstrated in family members of patients with dominantly inherited pattern dystrophy. Since then several other mutations of the peripherin/ RDS gene have been found in families and sporadic cases of pattern dystrophy. Of importance are the various phenotypes, often within families seen with the same genetic mutation. In addition to the association with different phenotypes of pattern dystrophy, peripherin/ RDS gene mutations are associated with central areolar choroidal dystrophy, autosomal-dominant retinitis pigmentosa, autosomal-dominant cone and cone–rod dystrophy, retinitis punctate albescens, and digenic retinitis pigmentosa. One family demonstrated phenotypic variation, including retinitis pigmentosa and fundus flavimaculatus. The peripherin/ RDS gene localizes to chromosome 6p21.2, spans 26 kilobases of genomic DNA, and contains three exons. The gene product of peripherin/ RDS is an integral membrane protein peripherin/ RDS within rods and cones, and plays an important role in the photoreceptor outer-segment morphogenesis by managing disc formation, alignment, and shedding.
Based on the pattern of pigment distribution, pattern dystrophies have been subdivided into at least five principal groups. A few patients will show different patterns in the two eyes. A patient may show progression from one pattern to another over a period of years. Some pedigrees will show any combination or all four of the patterns of fundus change described in the succeeding sections. For these reasons it is probable that these are closely related, if not expressions of the same disorder.
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 ).
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 ).
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).
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.
Systemic Diseases Associated with Pattern Dystrophy
Macular changes typical of pattern dystrophy occur in 70% of patients with pseudoxanthoma elasticum (see Figure 3.38G–L and Chapter 3 ). The fundus pulverulentus pattern is most frequently observed, though all five types of pattern are seen (Figure 3.40.) Pattern dystrophy has also been observed in patients with myotonic dystrophy ( Figure 5.14 ), Kjellin’s syndrome (hereditary spastic paraplegia) ( Figure 5.15 ) maternally inherited mitochondrial myopathies, and one patient with McArdle’s disease, a glycogen storage disease in which a deficiency of myophosphorylase inhibits the ability of striated muscle to use its stored glycogen.
Myotonic dystrophia (myotonia atrophica) is a heredofamilial disorder characterized by myotonia, with selective muscle atrophy, baldness, testicular and ovarian atrophy, premature senility, and cataracts; it is also associated in at least 20–25% of patients with some evidence of retinal degeneration. A variety of funduscopic pictures have been described, most of which involve the various forms of the pattern dystrophies, including dark and yellow spots; stellate ( Figure 5.14 A–F), butterfly, and reticular patterns of pigmentation; and drusen (see Figure 5.13 I–K). Most patients have minimal loss of visual acuity. Pigment clumping and yellow flecks in a triradiate or stonewall configuration have been described in the peripheral fundus. Narrowing of the arterioles may occur. Burian and Burns found remarkably low voltage b-waves and subnormal a-waves in these patients, even when unassociated with any ophthalmoscopically visible changes. They also demonstrated dark adaptation abnormalities. Foveal densitometry changes are frequent early in asymptomatic patients. There is histopathologic evidence of degeneration of the peripheral retina with migration of pigment into the retina and some migration of pigment into the outer plexiform layer in the macular area. Melanosis and microthrombosis of the peripheral retinal vessels, together with pigmentary degeneration, have been described by other authors. Some authors have implicated quinine therapy in these patients as the cause of the fundus changes.
Kjellin’s Syndrome (Hereditary Spastic Paraplegia)
Kjellin’s syndrome is an autosomal-recessive syndrome characterized by slowly progressive spastic paraparesis and dementia. Some of these patients may show evidence of pattern dystrophy of the retina, most often the fundus flavimaculatus type ( Figure 5.15 ). The flecks seem to be stationary or very slowly progressive with no change noted over 5 years in a patient followed by the author ( Figure 5.15 A, B, K, and L). The fluorescein angiogram shows central blockage from the yellow material with halo of hyperfluorescence surrounding this, quite typical of the appearance in isolated pattern dystrophy. Autofluorescence study shows brilliant fluorescence of the material in the macula (Figure 5.15H and I) ; in addition the pigment epithelium shows widespread reticular type of hyperautofluorescence outside the macula (Figure 5.15 H and I), the significance of which is still unknown. The OCT suggests accumulation of the material within and just anterior to the RPE ( Figure 5.15 J1 and J2). The flecks and the RPE changes are not associated with significant visual morbidity, suggesting very slow breakdown of the cells that may be contributing towards the accumulation of the yellow material.
Vitelliform lesions similar to pattern dystrophy have been seen in a variety of maternally inherited mitochondrial diseases, including maternally inherited diabetes and deafness (MIDD), mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), myoclonic epilepsy, red ragged fibers (MERRF), and more widespread pigmentary changes in Kearns–Sayre, neurogenic muscle weakness, ataxia retinitis pigmentosa (NARP), and Danon disease (see later sections).
Macular Pattern Dystrophy in MIDD, MELAS, and MERRF
Mitochondrial DNA is inherited from the mother. Mitochondrial defects affect high-energy-utilizing organs such as the central nervous system, eye, inner ear, skeletal, and cardiac muscle. A point mutation A3243G in the mitochondrial DNA causes both MIDD and MELAS. The exact reason why the same mutation causes a different phenotype is not completely understood, though there can be an overlap of findings in some patients with MIDD and MELAS to a variable extent. Affected individuals can fall anywhere in the wide spectrum of clinical features. The disease can vary greatly in severity and features within a family. The degree of heteroplasmy (cells contain both mutated and normal mitochondrial DNA) likely determines the phenotypic variability between the three syndromes and in individuals within the same family.
A3243G mitochondrial mutation in individuals is seen with a wide range of mitochondrial encephalomyopathies, including MELAS or MELAS/MERRF overlap syndrome. It has been postulated that mitochondrial dysfunction causes a reduction in adenosine triphosphate, which in turn leads to an ion imbalance that results in death of hair cell and stria vascularis in the inner ear. Postmortem histopathologic examination of the temporal bone of a woman with MIDD due to the A3243G mutation has identified diffuse outer hair cell loss, severe degeneration of the stria vascularis, as well as a reduction in spiral ganglion cells. Similar histopathologic findings have been reported in association with the A3243G mutation in MELAS, though marked loss of neurons and gliosis in the ventral cochlear nuclei were also noted.
Macular pattern dystrophy seen in this disease spectrum has a variable phenotype ( Figures 5.16 and 5.17 ). The manifestations can be: grade I: several punctate pigment dots in the macula; grade II: a butterfly or reticular pattern that on fluorescein angiography shows the typical hyperfluorescent halo around an area of decreased fluorescence; grade III: in some eyes multifocal or a continuous perifoveal atrophy of the RPE. The flecks show increased autofluorescence ( Figure 5.17 E) (resembling the pattern seen in fundus flavimaculatus) while the areas of RPE atrophy show decreased autofluorescence ( Figure 5.17J and L ).
Rath et al. classified MIDD A3243G mutation-associated macular dystrophy into:
Type 1: continuous or discontinuous perifoveal geographic atrophy
Type 2: pattern dystrophy with flecks and variable RPE atrophy.
It appears that the phenotype changes with age, with increasing geographic atrophy over time.
Stargardt’s Disease (Fundus Flavimaculatus)
In 1909 Stargardt described an apparently autosomal-recessive disorder in seven patients from two families, with visual loss beginning in the first two decades of life, often with a normal fundus, and later associated with macular atrophy and yellowish deep retinal flecks. Rosehr examined two of Stargardt’s original patients 50 years later and found that they had good peripheral function. In 1965 Franceschetti described similar patients but with flecks that extended into the peripheral fundus. Histopathologic and histochemical studies in recent years have demonstrated evidence that these patients have a diffuse lipofuscin storage disease affecting the RPE. Stargardt’s disease and fundus flavimaculatus are names now used interchangeably in the literature for what the author believes are a heterogeneous group of disorders. Most authors do not restrict the diagnosis of Stargardt’s disease and fundus flavimaculatus to patients with fluorescein angiographic evidence of lipofuscin storage in the RPE, although most agree that the majority of patients show evidence of it. This author prefers to restrict the diagnosis of Stargardt’s disease and fundus flavimaculatus to describe different stages of the same disease in patients who, early in life, develop a vermillion or darkly colored fundus caused by excessive storage of lipofuscin within the RPE that prevents visualization of choroidal details (“dark” choroid).
Patients with Stargardt’s disease, usually during childhood or early adulthood, develop visual loss that may be unassociated with any evidence of flecks or RPE atrophy initially ( Figures 5.18 A and B and 5.19 A and B) but soon afterward is associated with atrophic macular changes and the appearance of peculiar yellowish RPE flecks ( Figure 5.18 C, F, H, and I). They appear somewhat similar to, but should be differentiated from, drusen. These flecks are variable in size, shape, and distribution. Unlike drusen, they are less often discretely round, oval, and dome-shaped. When located in the midperiphery, they are often arranged in a triradiate or reticular pattern that has been likened to a forked fishtail. As they begin to fade, their color changes from yellow to gray, partly due to loss of RPE substance, and they may appear larger and less discrete. Fluorescein angiography is important in differentiating the flecks in Stargardt’s disease (fundus flavimaculatus) from drusen. Whereas drusen show a pattern of hyperfluorescence corresponding precisely with their size, the yellow flecks in fundus flavimaculatus either appear nonfluorescent when the lipofuscin is intracellular or show an irregular pattern of fluorescence with disruption or atrophy of RPE cells ( Figures 5.18 G and 5.19 H).
Most patients with this disease experience loss of central vision first in childhood or young adulthood. Some, however, first become symptomatic in midlife or beyond. Loss of central vision may be accompanied by symptomatic as well as electrophysiologic evidence of significant cone dysfunction. Likewise some patients, particularly those who develop widespread flecks extending into the periphery, may develop evidence of rod as well as cone dysfunction. On the basis of the fundus and fluorescein angiographic findings at the time of presentation, patients with Stargardt’s disease can be subdivided into the following groups.
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.
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.
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 ).
Autosomal-Dominant Central Areolar Chorioretinal Dystrophy Unassociated with Drusen or Flecks
This dystrophy is characterized by the development of fine, mottled depigmentation in the macular region, usually in late childhood or early adulthood in the absence of any symptoms ( Figure 5.22 A, B, G, and H). Visual acuity, visual fields, ERG, and dark adaptation are normal early in the course. Multifocal ERG shows abnormal central function and late stages may sometimes show more widespread cone and rod dysfunction. The EOG may be subnormal. Fluorescein angiography is helpful in detecting the earliest pigmentary changes of the macular region that may eventually have a bull’s-eye configuration ( Figure 5.22 B, I, and J). Associated with the gradual development of symmetric, sharply outlined, bull’s-eye oval or round areas of geographic atrophy of the RPE in the macula in the absence of any flecks or drusen there is slow, mild deterioration of visual acuity during the fourth and fifth decades of life ( Figure 5.22 C, F, G, and H). The findings can be staged from 1 to 4 ( Figure 5.23 ). Families with earlier age of onset of visual acuity changes ( Figure 5.22 G–J) are known. The area of geographic depigmentation of the RPE enlarges concentrically but usually does not exceed three to four disc diameters. In some patients geographic atrophy of the RPE in the peripapillary region accompanies the macular changes. As the patient lives beyond the fifth decade, the reddish orange color of the large choroidal vessels within the area of RPE atrophy is replaced by a yellow-white color ( Figure 5.22 F, K, and L). Serous and hemorrhagic disciform detachment occurs rarely, if at all. Visual acuity in the range of 20/100–20/200 may be retained even during the seventh and eighth decades of life. The optic disc, retinal vessels, and RPE outside the macular area are usually normal in appearance.
Initially, a relative (but later an absolute) central scotoma corresponding to the area of RPE atrophy can be demonstrated. Peripheral fields are normal. Fluorescein angiography demonstrates varying degrees of loss of the choriocapillaris within the area of RPE atrophy that correlates well with the degree of loss of visual function. There usually is minimal evidence of atrophy of the large choroidal vessels throughout the course of the disease.
Dominantly inherited central areolar chorioretinal dystrophy unassociated with flecks occurs infrequently and has been confused in the literature with a variety of other more prevalent diseases associated with geographic atrophy of the RPE. Central areolar or geographic atrophy of the RPE and choroid is a nonspecific change that may occur in association with other diseases, including: (1) familial macular dystrophies associated with macular coloboma; (2) central areolar RPE dystrophy that may be the same disease as (1); (3) dominant macular drusen associated with senile macular degeneration and disciform detachment (see Figure 3.46); (4) basal laminar drusen; (5) autosomal-recessive macular dystrophy associated with Stargardt’s disease or fundus flavimaculatus ( Figures 5.13 and 5.14 ); (6) central areolar atrophy in the cone and rod–cone dystrophies ( Figure 5.16 ); (7) central areolar atrophy secondary to myopic degeneration (see Figure 3.34); and (8) central areolar choroidal and RPE atrophy secondary to serous or hemorrhagic disciform detachment of the RPE and retina from a variety of causes, such as idiopathic central serous chorioretinopathy or choroiditis. Autosomal-dominant central areolar choroidal dystrophy may also be confused with other disorders that cause a bull’s-eye pattern of pigment epithelial atrophy (see benign concentric annular macular dystrophy, p. 300, and chloroquine and hydroxychloroquine toxicity).
In 1953 Sorsby and Crick described five pedigrees of patients with “central areolar choroidal sclerosis.” Only one or possibly two families had evidence of dominant inheritance. Several patients showed evidence of flecks or drusen and may have had either Stargardt’s disease or senile macular degeneration. Histopathologic examination of one patient showed evidence of choroidal and RPE atrophy but no evidence of sclerosis of the choroidal vessels.
A family of three successive generations of patients with central areolar macular dystrophy seen in Miami also have autosomally dominantly inherited von Hippel–Lindau disease ( Figure 5.22 A–F). Mansour reported three brothers, each affected with central areolar choroidal dystrophy and pseudochondroplastic spondyloepiphyseal dysplasia, both of which are heterogeneous disorders with autosomal transmission. The association of two rare diseases having an autosomal-dominant inheritance (germ cell mosaicism in one parent) or autosomal-recessive inheritance resulting from parental or grandparental consanguinity (new syndrome) is more likely to be a true association than a simple coincidence. Mutation in the peripherin/ RDS gene on chromosome 6 is the most common cause of autosomal-dominant central areolar choroidal dystrophy, though the disease is genetically heterogeneous. Five different mutations have so far been found, the commonest being arginine 195 leucine mutation.
Basal Laminar Drusen Associated with Type II Mesangiocapillary (Membranoproliferative) Glomerulonephritis
Mesangiocapillary glomerulonephritis (MCGN, MPGN) is a renal disorder characterized by proliferation of mesangial cells and alterations in the basement membrane of the glomerulus. MCGN has been classified on the basis of the localization and composition of the glomerular deposits: type I with subendothelial electron-dense deposits along the glomerular basement membrane with presence of complement and immunoglobulin within the glomerulus, type II with electron-dense ribbon like deposits of C3 in the lamina densa of the glomerular basement membrane without the presence of immunoglobulin (also called dense deposit disease), and type III with deposits like those of both types I and II, and both subepithelial and subendothelial location. Other associated features of the disease include chronic hypocomplementemia, partial lipodystrophy, and a higher incidence of diabetes. Type I is twice as common as type II and is less severe. Type II usually begins in childhood or early adulthood and tends to be a progressive unremitting disease, often recurring even after renal transplantation. MPGN comprises approximately 4–7% of patients with idiopathic nephrotic syndrome. Basal laminar drusen and larger more typical drusen occur frequently in the macular region of patients with type II MCGN ( Figure 5.24 A–F). The number of deposits increases in number and size with age and duration of the disorder. Although most patients are visually asymptomatic, some may develop choroidal neovascularization at an early age. The fundus findings occur more frequently in those patients with type II MCGN who have in addition partial lipodystrophy. Those patients who have undergone renal transplant may develop signs of organ transplant retinopathy with exudative retinal detachment, retinal pigment epithelial mottling, or serous pigment epithelial detachments which may alter the fundus appearance. Light and electron microscopic study in one patient with drusen revealed diffuse and focal deposits in the basement membrane of the RPE similar to those found in the glomerulus. The nature of these deposits was not determined.
A variety of mutations in the complement factor H (CFH) gene are seen in a minority of patients with MPGN II. Homozygous or compound heterozygous CFH mutations result in lack of plasma CFH, causing uncontrolled alternate complement pathway activation resulting in ubiquitous C3 deposition in the Bruch’s membrane and glomerulus.
Dominantly Inherited Radial Basal Laminar Drusen (Malattia Levantinese, Doyne’s Honeycomb Macular Dystrophy)
A dominantly inherited disorder characterized by a radial pattern of innumerable, small, elongated basal laminar drusen was initially reported in a family from the Levantine valley in Switzerland. It was later found that the condition is the same as the dominantly inherited honeycomb retinal dystrophy described by Doyne in 1899. Typically the radiating pattern is most prominent in the temporal macular area and is often accompanied by larger nodular, and at times papillary, drusen and variable amounts of irregular subretinal fibrous metaplasia and hyperplasia of the RPE ( Figure 5.24 G–J). This subretinal scar tissue may or may not be vascularized. The visual acuity is often excellent in spite of the fibrous metaplastic changes. The radial drusen demonstrate early discrete fluorescence similar to that of basal laminar drusen ( Figure 5.25 B, C, F, and I). On indocyanine green angiography the lesions mask the fluorescence early, and the central drusen stains late with hypofluorescence of its edge. High-resolution OCT shows conical deposits between the RPE and the Bruch’s membrane, and late stages secondary disruption of the outer nuclear layer. Choroidal neovascularization is known to occur and responds to surgical removal, photodynamic therapy, and antivascular endothelial growth factor antibodies. Streicher and Krcméry and Dusek and associates have reported a dominantly inherited pedigree of patients with radial basal laminar drusen. Even though the typical appearance is of nodular drusen that fill the macula and often the area nasal to the disc, phenotypic heterogeneity is seen in some families, showing less extensive drusen or predominant fibrous change rather than drusen ( Figure 5.26 E and F). Mutation in the EFEMP1 gene (Arg345Trp) is responsible for the condition. There has been a family diagnosed clinically as malattia levantinese, without the Arg345Trp mutation, suggesting other gene defects may also cause this phenotype. Light and electron microscopic findings in one patient demonstrated evidence that these drusen are caused by thickening of the basement membrane of the RPE (see Figure 3.29J and K). Dr. Gass has seen one member of a family with North Carolina dystrophy who had a small zone of radial drusen (see next section). It is of interest that only one of the half-dozen patients with prominent radial basal laminar drusen examined in Miami had a family history of macular degeneration ( Figure 5.25 D–F).
North Carolina Macular Dystrophy and other Hereditary Macular Staphylomata (Colobomata)
North Carolina macular dystrophy is an autosomal-dominantly inherited disorder with complete penetrance. Its onset is in infancy and perhaps prenatally, its course is generally stable, and its phenotype is highly variable and includes drusenlike changes, disciform lesions with choroidal neovascularization, macular staphylomata, and peripheral drusen. Electroretinography, electro-oculography, and color vision are normal. Lefler et al. and Frank et al. reported a large pedigree from western North Carolina consisting of 545 family members in seven generations with a dominantly inherited macular dystrophy that they characterized as progressive, usually commencing in infancy and reaching its maximum severity in the early teenage years. Scattered lesions that they believed were drusen and pigmentary changes in the macula with normal visual acuity were the earliest fundoscopic changes (stage 1) ( Figures 5.27 A and B, 5.28 B, E–L). As the vision declined to the 20/50 range, there was an increase in the number as well as the confluence of the drusenlike changes (stage 2). In many patients the fundus changes did not progress beyond the drusen stage and visual acuity may have remained normal. Other family members showed a progressive decrease in the acuity to the 20/200 level concomitant with the development in some cases of almost total atrophy of the choroid, RPE, and retina in the macular area (stage 3). Although Lefler’s and Frank’s photographs appeared to show evidence of staphylomatous outpouching in association with these severe changes, they did not mention that change. Neither did they describe peripheral drusenlike changes or evidence of choroidal neovascularization and disciform detachment, although one of the patients depicted in their report as well as one of our patients showed evidence of this complication. The retinal vessels, peripheral fields, color vision, ERG, and EOG were normal. The general medical examination was typically normal except for a transport type of aminoaciduria that segregated independently of the foveal dystrophy, but which was also dominantly inherited. Small et al. studied 15 of the original Lefler’s and Frank’s patients over 10 years and noted stable vision and fundus appearance in all but one eye of one patient, thus confirming the relatively nonprogressive nature of the condition. Additionally, they noted peripheral yellow drusenlike changes in some of them.
Gass has seen members of three families from western North Carolina who demonstrated all of the clinical features reported by Lefler and associates and Frank and associates ( Figure 5.27 ). The yellow spots in the macula appeared biomicroscopically to be caused by focal areas of depigmentation of the RPE in the absence of nodular elevation, as observed in more typical drusen ( Figure 5.27 A, B, F, and L). In one patient there was a radial pattern of drusen in the paracentral region ( Figure 5.27 A). All of the drusen as well as the central spots showed prompt fluorescence ( Figure 5.27 C). In one family the mother showed evidence of disciform macular scarring in one eye ( Figure 5.27 D). In the other family the grandmother and her sister showed large, deep, circumscribed, staphylomatous or colobomatous areas of marked atrophy of the choroid and retina, absence of high myopia, and remarkably good visual acuity ( Figure 5.27 G, H, J, and K). The son and the grandchildren showed varying degrees of drusenlike changes in the macula. Unlike the cases reported by the previous authors, some of our patients have shown drusen in the peripheral fundus. The radial pattern ( Figures 5.03 B and F and 5.28 G and H) has also been seen in Small’s group of patients. Patients with drusen are largely asymptomatic unless they develop choroidal neovascularization. Often the parents are completely asymptomatic and have been incidentally discovered when the child developed symptoms ( Figure 5.28 ).
The North Carolina Macular dystrophy gene ( MCDR1 ) is mapped to the 6q14-q16.2 region, though the disease causing gene is yet to be identified. Though initially described in inhabitants of North Carolina with their descendancy traced to three Irish brothers, the phenotype has been found in Caucasian patients outside North Carolina and the USA, in African American ( Figure 5.29 ), Belize, and Korean patients. A black family in Chicago where three generations are affected is described in Figure 5.29 .
The presumably congenital staphylomatous macular lesions (referred to by some as macular colobomas, more recently as macular caldera by Goldberg et al. ), similar to that illustrated in this large pedigree, may occur in families that may show other features including Leber’s congenital blindness, progressive cone–rod dystrophy, and skeletal abnormalities. Pedigrees with fundus findings similar to North Carolina dystrophy include those of Leveille and associates in a black family, Fetkenhour and associates, and Miller and Bresnick. Small and associates have recently established that the cases reported from North Carolina and those by Hermsen and Judisch and Fetkenhour and associates are descendants of three Irish brothers who settled in the North Carolina mountains in the 1830s.
Gass has seen a 38-year-old mother and her 16-year-old son, both with moderate loss of central vision and large macular staphylomata unassociated with high myopia ( Figure 5.30 A–F). ERG, EOG, and color vision testing were normal in the mother. The son had a markedly abnormal rod ERG. They had no known relatives from North Carolina. Satorre and colleagues reported a Spanish family with autosomal-dominant bilateral macular colobomata. Gass has seen one patient with cone dystrophy and congenital macular staphyloma (see Figure 5.32 E and F). Heckenlively et al. reported macular colobomas in families with Leber’s congenital amaurosis and progressive cone–rod dystrophy. Dr. Gass has seen another young woman who, over a period of 13 years, developed progressive macular degeneration that was accompanied by the development of a large macular staphyloma in one eye ( Figure 5.30 G–J). Her family history was negative.
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 ).
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.
“Benign” Concentric Annular Macular Dystrophy
In 1974 Deutman described benign, concentric, annular macular dystrophy in patients who develop a paracentral ring scotoma associated with a bull’s-eye pattern of perifoveal atrophy of the RPE and variable degrees of hyperpigmentation of the central macular region. Slight narrowing of the retinal vessels may be present. The optic discs are normal. The visual acuity is either normal or near normal. The ERG may be normal or slightly abnormal. The EOG may be subnormal. There may be a mild to moderate color vision defect. The disease is inherited as an autosomal-dominant trait. Although initially termed “benign,” a recent 10-year follow-up of the pedigree described by Deutman revealed evidence of progression of benign, concentric, annular macular dystrophy into a more generalized tapetoretinal dystrophy involving both rod and cone function. A progressive decrease in visual acuity, nyctalopia, and dyschromatopsia were found in some members of the pedigree as well as an increase in the pigmentary maculopathy and peripheral bone corpuscular changes. Electrophysiology confirmed equal involvement of the rod and cone systems. This progression of the phenotype is indicative of retinitis pigmentosa with bull’s-eye appearance, since rod dysfunction and nyctalopia may be seen early. Photophobia and early loss of central vision, features of cone–rod degeneration, are not typical findings. Benign concentric annular macular dystrophy maps to 6p12.3-q16 in the vicinity of the interphotoreceptor matrix proteoglycan1 ( IMPG1 ) gene. The disease is autosomal-dominantly inherited. Miyake et al. described a bull’s-eye maculopathy and a negative ERG (b-wave smaller than a-wave) in four unrelated males with initially normal vision, progressive decrease in visual acuity, preserved cone ERG, and mild to moderate deficiency in color vision. They believed that these patients had a disease similar to benign concentric annular dystrophy, although none of their patients had evidence of dominant inheritance. EOG is almost always subnormal or abnormal and deteriorates with age. Dark adaptation also decreases with time. Visual fields may be normal early on and show a ringlike zone of decreased sensitivity around a small central island. Blue-yellow color vision may be deficient.
The differential diagnosis of concentric, annular, macular dystrophy includes cone dystrophy, rod cone dystrophy, lipofuscinosis, chloroquine retinopathy, bull’s-eye maculopathy associated with Stargardt’s disease (fundus flavimaculatus), sporadic progressive loss of visual acuity secondary to bull’s-eye macular atrophy without cone dystrophy, fenestrated sheen macular dystrophy, parafoveal atrophy of the RPE secondary to drusen, and autosomal-dominant central areolar chorioretinal dystrophy unassociated with flecks ( Figure 5.22 G–J).
Juvenile Hereditary Disciform Macular Degeneration
Disciform macular detachment occurs infrequently in children. When it occurs unilaterally in the absence of abnormalities in the opposite eye, it is usually attributed to an inflammatory lesion such as Toxocara canis , diffuse unilateral subacute neuroretinitis, and toxoplasmosis, or to a posttraumatic choroidal rupture. Occasionally, a child with rubella retinopathy (see Figure 7.27), pars planitis (see Figure 7.75), and multifocal choroiditis and panuveitis (the pseudo-presumed ocular histoplasmosis syndrome) may develop a disciform macular detachment. Some patients with Best’s vitelliform macular dystrophy may develop choroidal neovascularization and the various stages of serous and hemorrhagic disciform detachment (see Figures 5.01 E and 5.03 C). Choroidal neovascularization has occurred in two sibling children with juxtafoveolar retinal telangiectasis. In general, however, disciform macular detachment in children secondary to hereditary disease apparently occurs rarely. At the 1979 International Fluorescein Angiographic Meeting at Bath, Drs. Alan Bird and Steven Ryan briefly presented two families with multiple children with bilateral disciform macular lesions of unclassified type. In Miami we have observed bilateral disciform detachment of unknown causes in several children without a family history of macular degeneration, and in two sisters. The findings by Bird and Ryan suggest that the clinician should be cautious in making a diagnosis of bilateral disciform detachment secondary to an inflammatory cause without carefully examining other family members.
Pseudoinflammatory Sorsby’s Fundus Dystrophy (SFD)
In 1949 Sorsby and associates described five families with dominantly inherited macular dystrophy that was characterized by the development, usually during the fifth decade of life, of choroidal neovascularization, subretinal hemorrhage, and changes suggestive of disciform degeneration ( Figure 5.31 A–F). Progressive atrophy of the peripheral choroid and RPE occurs later in life and in some cases causes loss of ambulatory vision. Unfortunately the loss of peripheral function has generally been overlooked, as indicated by the name pseudoinflammatory macular dystrophy. This name was chosen because the extensive macular and paramacular changes have suggested to some a postinflammatory change. The term “pseudoinflammatory” is perhaps unfortunate for other reasons: (1) many of the patients have a disciform scar that is indistinguishable from that seen in a host of diseases, including senile macular degeneration and angioid streaks; (2) the fact that the scar extends away from the macula is a nonspecific change that may occur in patients with senile macular degeneration and angioid streaks; and (3) some patients with typical dominantly inherited macular drusen may develop disciform detachment in the fourth decade or earlier. Ashton and Sorsby studied the eyes of two sisters with this condition and noted histopathologic changes similar to those of senile macular degeneration and angioid streaks in patients with pseudoxanthoma elasticum. At least three of the original families reported by Sorsby and associates showed some evidence of drusen deposits at the level of Bruch’s membrane. One of his families (Kempster pedigree) had peripheral retinal dysfunction (progressive loss of night vision for up to 25 years before loss of central vision), a deposit of yellow subretinal material throughout the fundus, a tritan color defect, and loss of vision occurring because of choroidal neovascularization by the fifth decade of life. Some patients lost central vision because of geographic atrophy. The yellow material tended to become less apparent with age. Light and electron microscopic examination of the eyes of a 63-year-old descendant of the Kempster family demonstrated a thick deposit within Bruch’s membrane that stained positive for lipids, gross loss of the outer retina and RPE, and atrophy of the choriocapillaris. Although no yellow change in the fundus was apparent just prior to death the thickened layer of material between the basement membrane of the RPE and the inner collagenous zone of Bruch’s membrane may be the homolog of the yellow material seen clinically earlier in life. These changes were not noted in the histopathologic study of the eyes of one of two sisters described by Ashton and Sorsby.
Dreyer and Hidayat described the clinical and histopathologic findings in a family with dominantly inherited early-onset peripheral and central visual loss with marked EOG changes. The histopathologic changes were similar to those seen by Capon et al., except no thick sub-RPE deposit was described. Hoskin et al. noted a confluent yellow deposit confined to the macula and angioid streaks in another of Sorsby’s pedigrees (Ewbank). The yellow material in both families was associated with some delay in the appearance of fluorescence angiographically that was interpreted as evidence of delayed choriocapillary perfusion.
It is of interest that in a follow-up report of the original five families of Sorsby and associates, two patients were found with a typical fundoscopic picture of angioid streaks and multiple fine drusenlike deposits that appear identical to the peau d’orange change occurring in patients with pseudoxanthoma elasticum. There was no mention in the report as to the presence or absence of the skin lesion. Forsius and associates have reported a Finnish pedigree with a recessively inherited pseudoinflammatory dystrophy characterized by colloid bodies deep within the retina that they likened to those occurring in retinitis punctata albescens (RPA), angioid streaks, and widespread areas of choroidal atrophy and pigment derangement as the disease progressed. A four-generation pedigree characterized by submacular neovascularization in the third to fourth decade, yellow punctate deposits at the level of the pigment epithelium, myopia, nyctalopia beginning in childhood, mid peripheral equatorial pigment clumping and migration, and electrophysiologic abnormalities was reported from Oklahoma. Hamilton et al. reported a seven-generation pedigree with loss of central vision between the second and fourth decades. White to yellow fundus spots, atypical for drusen, accompanied a disciform degeneration in many patients. Some had atrophic maculopathy and others showed no spots. Atrophy of retina and RPE spread to the periphery. Wu et al. studied two brothers of family with dominant inheritance. They described generalized fine RPE granularity, iris transillumination defects, ERG changes, disciform lesions, and angiographic evidence of delay in choroidal perfusion in two brothers aged 28 and 34 years. Balyeat and colleagues described a dominantly inherited pedigree characterized by onset of nyctalopia beginning in childhood, myopia, subretinal neovascular membranes and yellow punctate deposits at the level of the RPE, mid peripheral and equatorial pigment clumping and migration, and ERG abnormalities. Steinmetz et al. studied a family with poor night vision and diffuse yellow deposit at the level of Bruch’s membrane in the posterior pole. There was minimal change in dark adaptation in the region of ophthalmoscopically normal fundus.
The term “pseudoinflammatory fundus dystrophy” should probably be confined to dominantly inherited pedigrees, who in the fourth and fifth decades of life or earlier lose peripheral as well as central visual function associated with serous and hemorrhagic disciform detachment unassociated with macular drusen ( Figure 5.31 A–F).
Helicoid Peripapillary Chorioretinal Dystrophy (“Choroiditis Areata,” Sveinsson’s Chorioretinal Atrophy)
This is a rare, distinct bilateral autosomal-dominant fundus disorder characterized by sharply demarcated, wing- or propellerlike atrophic chorioretinal lesions radiating away from the optic disc, in the absence of evidence of inflammation (serpiginous choroiditis), angioid streaks, myopic degeneration, and paravenous retinochoroidal atrophy. Mild astigmatism is common. It was first described in Iceland in 1939 by Sveinsson who named it “choroiditis areata”; Franceschetti in 1962 renamed it helicoid peripapillary chorioretinal degeneration due to the lack of inflammation, and Sveinsson redescribed four affected successive generations in 1979 demonstrating dominant inheritance and progression with age. The lesions can be seen at birth and progress slowly with late macular involvement. The topography of the lesions suggests that they may result from tearing of Bruch’s membrane and RPE. All cases so far have been described from Iceland, and the ones seen in Canada, Denmark, Faroes, Germany, Norway, Sweden, Switzerland, the UK, and the USA all have ancestors in Iceland who are members of the extended Icelandic pedigree. In order to prevent ambiguity associated with the term helicoid peripapillary chorioretinal dystrophy, the name Sveinsson’s chorioretinal atrophy has been proposed. The defect has been mapped to the 11p15 region by linkage analysis.
Cone Dystrophy (Cone Dysgenesis)
Cone dysfunction may occur as a result of either a maldevelopment of the cone system that is associated either with no or minimal progressive deterioration of the retina (nonprogressive cone dysgenesis), or with enzymatic defects that lead to progressive deterioration of the cone system (cone dystrophy).
Nonprogressive Cone Dysgenesis
Congenital achromatopsia is relatively rare and patients present with poor vision from birth, nystagmus, varying degrees of color vision loss, and photophobia. The condition is usually nonprogressive. The nystagmus may improve and become less prominent over time. The fundus examination is usually normal but occasionally peripheral pigment alteration or bull’s-eye maculopathy will be seen. Most patients are hypermetropic. ERG shows normal rod function but no cone function.
Complete Achromatopsia (Typical Achromatopsia or Rod Monochromatism)
Complete achromatopsia has an incidence of about 1 in 30 000. It is a recessively inherited disorder characterized by either complete absence of or severely limited color vision, reduced visual acuity, nystagmus, and photophobia. The visual acuity is usually in the 20/200 or worse range with debilitating aversion to light. Full-field cone ERG responses are either absent or severely reduced. The fundi may show absence of the foveal reflex and mild disturbances of the pigmentation in the macula. Histopathologic examination of eyes with complete monochromatism has shown 5–10% reduction in the normal number of extrafoveal cones and abnormal structure of the foveal cones. They have normal rods. These patients show no perception of color and all colors can be matched to various shades of gray. The Sloan achromatopsia test allows these patients to make matches of various colors to shades of gray that is not possible in patients with normal vision or a more benign congenital color vision deficiency. Three genes have been implicated so far. About one-quarter of the patients are associated with CNGA3 mutation, about 45–50% with CNGB3 mutation, and the third gene responsible, GNAT2, is found in less than 2% of patients.
Incomplete Achromatopsia (Atypical Achromatopsia)
These patients have a mild ability to discern color though abnormal, and have somewhat better visual acuity as compared to the complete achromats. The condition is also inherited as an autosomal-recessive inheritance where mid- and long-wavelength cones are probably present to a small extent. Mutations in CNGA3 have been found in patients with incomplete achromatopsia. The photophobia is more severe than the loss of vision. These patients often wear more than one pair of sunglasses due to extreme photophobia. Red contact lenses help alleviate some of the photophobia.
Two of the three cone systems (S small, M medium, and L long) are absent or nearly absent in these patients. The more common forms of cone monochromatism are those that have either the red or the green cones, as compared to blue monochromats.
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.
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.)
Progressive Cone Dystrophy
The term “cone dystrophy” is used to describe those patients with a heritable dystrophy in which predominantly the cone system is affected. It includes some patients in whom no evidence of rod dysfunction develops as well as those in whom rod deficiency later develops but cone deficiency predominates. Both types may be seen in the same pedigree. Most cases are sporadic, but when they are familial, most are autosomal-dominant or X-linked cone dystrophy. In X-linked cone dystrophy, pseudoprotanomaly and abnormal foveal densitometry findings have been identified in female carriers. In other families fundus changes and abnormalities in color vision, ERG, and visual evoked potential were found in female carriers. The age of onset, severity, and rate of progression vary from family to family and within the same family. The age of onset varies from childhood to midlife or beyond. The clinical features, all of which or only some of which may be present, initially include: (1) onset of progressive visual loss; (2) impairment of color vision even with minimal acuity loss; (3) impaired visual function in brightly illuminated situations and better vision in twilight or dim illumination and day blindness (hemeralopia); (4) normal or near-normal fundi initially and, later, RPE atrophy in the macula often progressing to a bull’s-eye pattern; (5) temporal pallor of the optic disc in some patients; (6) fluorescein angiographic evidence of depigmentation of the RPE in the macula (often antedating visible alterations in the fundi); (7) central scotoma with normal peripheral fields; and (8) reduced or nondetectable photopic as well as abnormal flicker response ERG. Some patients may demonstrate a supernormal scotopic ERG. Early selective involvement of the blue cone system may occur in some families with autosomal-dominant inheritance. Visual acuity varies from 20/20 early to 20/200 or less later. The macula may be normal ( Figure 5.32 H), or it may show a variety of changes, including mottling and clumping of the pigment epithelium, a bull’s-eye pattern of depigmentation, focal chorioretinal atrophy, and a macular staphyloma ( Figure 5.32 E and F). The bull’s-eye pattern of RPE atrophy and a corresponding zone of hyperfluorescence surrounding a central nonfluorescent spot similar to that seen in chloroquine retinopathy are the most commonly described biomicroscopic and angiographic changes in these patients ( Figures 5.31 G and H, 5.32 A, C, and D). Occasionally temporal pallor of the optic disc may be the only fundus change. Autofluorescence testing can show increased autofluorescence in a ring around the fovea surrounding an area of central hypoautofluorescence that corresponds to the bull’s-eye atrophy ( Figure 5.31 I and J). An acquired fixation nystagmus may be present. A few patients with predominantly the peripheral portion of the cone system affected may have normal color vision performance in the presence of a subnormal photopic ERG ( Figure 5.32 A).
Some of these patients may present with complaints of progressive day blindness yet have normal visual acuity. Conversely, if the central portion of the cone system is primarily affected, patients may have subnormal visual acuity, abnormal color vision, and a normal photopic ERG. As the disease progresses, they will develop abnormal photopic ERG findings. Many patients eventually develop some electroretinographic evidence of abnormal rod function. This varies in severity. When severe, it is associated with varying degrees of optic disc pallor, narrowing of the retinal vessels, and peripheral field loss. Often there is no or only minimal evidence of pigment migration. The EOG may be normal or abnormal. Patients with cone dystrophy and fundi resembling retinitis pigmentosa rarely complain of night blindness. Despite an extinguished ERG, they may show either a normal or mildly abnormal dark adaptation curve. This discrepancy is seen also in chloroquine retinopathy. The earliest histological changes seen are distortion and kinking of the foveal receptor segments followed by loss of nucleus and the rest of the cell bodies. Histopathologic and ultrastructural findings in an eye removed after development of ERG changes of rod involvement showed changes in the peripheral retina similar to that of mild retinitis pigmentosa. The differential diagnosis of a bull’s-eye maculopathy has been discussed elsewhere (see p. 300).
The progression of cone dystrophy is usually more rapid in patients with early onset of visual symptoms. Visual loss is usually, but not always, symmetric. The acuity usually does not decrease much below 20/200.
Some patients with cone dystrophy will show, in addition to reduced or missing potentials at light-adapted conditions and reduced photopic flicker frequencies, a supernormal dark-adapted b-wave amplitude (supernormal rod ERG). Some patients showing this latter ERG finding have a congenital stationary cone dysgenesis, whereas others demonstrate evidence of a progressive cone dystrophy. Most show pigmentary changes in the macula that in some patients has a bull’s-eye pattern. Mutations in KCNV2 which encodes a subunit of a voltage-gated potassium channel in both rods and cones has been found recently.
An X-linked form of cone dystrophy may have a golden sheen that disappears on dark adaptation; this is known as the Mizuo-Nakamura phenomenon ( Figure 5.32 J–L). Female carriers can have a wide spectrum of findings, some appearing relatively normal to those having bull’s-eye change in the macula. X-linked cone dystrophy has been mapped to three loci on the X chromosome.
Autosomal-dominant cone dystrophy or cone–rod dystrophy has been associated with several mutations that include mutations of the peripherin/ RDS gene, the CRX gene, the retinal guanylate cyclase gene ( RET-GC1 ), the guanylyl cyclase-activating protein 1 ( GCAP1 ) gene, AIPL1, GUCY2D, PITPNM3, PROM1, RIMS1, SEMA4A , and UNC11 gene. Peripherin RDS is present on both rod and cone segments. CRX codes for a photoreceptor-specific domain transcription factor. The RET-GC1 and GCAP1 gene are involved in cyclic guanosine monophosphate (cGMP) production. Different mutations within the same gene and mutations of several genes result in variable severity of the cone dystrophy.
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.
Fenestrated Sheen Macular Dystrophy
Fenestrated sheen macular dystrophy is an autosomal-dominant macular disorder characterized in young patients by tiny red fenestrations occurring in a central macular zone of a golden sheen ( Figure 5.33 A–C). Multifocal areas of hypopigmentation of the RPE become manifest in the paracentral area in young adulthood, and this may progress to an annular zone of depigmentation by the fourth decade. Fluorescein angiography shows window defects corresponding to the RPE changes and not related to the red fenestrations. The visual acuity may be mildly affected in late adulthood and ranges from 20/20 to 20/30. Mild changes in the ERG and EOG and color vision abnormalities may develop. The sheen reflex that appears to lie between the level of the RPE and retinal vessels persists, but the central fenestrations disappear as more changes in the RPE occur. Daily and Mets suggested that this disorder may be related to a defect or abnormality in macular xanthophyll. This disease should be added to the list of bull’s-eye maculopathies.
Dominantly Inherited Müller Cell Sheen Dystrophy (Familial Internal Limiting Membrane Retinal Dystrophy)
Dominantly inherited Müller cell sheen dystrophy is a rare, previously unreported disorder characterized biomicroscopically by prominent glistening light reflections emanating from the inner retinal surface that appears to be thickened, yet translucent, and thrown into a pattern of railroad track-like folds ( Figure 5.33 D–L). These changes are most prominent but are not limited to the posterior fundus. This dominantly inherited disorder is apparently associated with minimal visual morbidity prior to midlife, when patients may experience visual loss in one or both eyes as the result of biomicroscopic and angiographic evidence of widespread intraretinal edema ( Figure 5.33 D–H). In addition to typical cystoid macular edema, there is a pattern of superficial microcystic changes that extend throughout the posterior fundus. Vitrectomy in three eyes of two members of the same family has failed to improve the visual function ( Figure 5.33 D–I). One family member developed monocular loss of central vision that was attributed to vitreomacular traction. Pars plana vitrectomy failed to change either the visual function or the appearance of the fundus ( Figure 5.33 D–H). Histopathologically, these fundus changes are caused by thickening and undulation of the internal limiting membrane of the retina, superficial retinal schisis, and cystic spaces in the inner nuclear layer. All of these changes suggest a primary defect in the Müller cells ( Figure 5.33 J–L).
Asteroid Macular Dystrophy
Figure 5.34 (A–C), depicts the ophthalmoscopic and angiographic findings in a young woman with a striking seven-point dark stellate figure centered in the fovea of both eyes. Her visual acuity was 20/20. Her family history was normal. No family members were available for examination. It is probable, however, that this is a foveomacular dystrophy or dysgenesis with a good visual prognosis.
Sjögren–Larsson syndrome, an autosomal-recessive neurocutaneous syndrome, is characterized by the following clinical features: (1) congenital ichthyosis; (2) congenital low-grade stationary mental deficiency; (3) symmetric spastic paresis with maximum involvement of the legs; (4) convulsions; (5) dental and osseous dysplasia; (6) defective sweating; (7) hypertelorism; (8) reduced life expectancy; and (9) ophthalmoscopic changes in the macula, characterized by the presence of white glistening flecks and yellowish pigmentary changes that may simulate Best’s vitelliform dystrophy ( Figure 5.34 D and E). These macular changes are present in a majority of patients and considered pathognomonic. The glistening dots are believed to be located in the inner retina (ganglion cells and inner plexiform layer), may appear by age 1–2 years, and increase with age. Photophobia is often present. On fluorescein angiography the foveal and perifoveal areas show hyperfluorescence. The crystals do not block fluorescence, and are hyperautofluorescent. In addition to the crystals in inner retina, microcystoid spaces may be seen on OCT, a feature somewhat similar to idiopathic juxtafoveal telangiectasia type 2. Macular pigment levels were found to be reduced by macular pigment and autofluorescent reflectometer testing by van der Veen et al. ERG and EOG done in a few of these patients are usually normal. Patients with this syndrome are specifically deficient in the fatty aldehyde dehydrogenase component of the fatty alcohol oxidoreductase that catalyzes the oxidation of medium- and long-chain fatty aldehydes to corresponding fatty acids. This deficiency may be detected in the skin fibroblasts of patients and in carriers of the disorder.
The cardinal features of Aicardi’s syndrome are infantile spasms, agenesis of the corpus callosum, and a characteristic chorioretinopathy that may occur in association with other ocular abnormalities, including microphthalmia, colobomas of the optic nerve and choroid, scleral ectasia, persistent pupillary membrane, and glial tissue extending from the optic disc. Other associated findings are mental retardation, generalized seizures, hypotonia, cerebral malformations including microcephaly, polymicrogyria, periventricular and intracortical gray-matter heterotopias, interventricular cysts, choroid plexus papillomas and cysts, asymmetry of cerebral hemispheres, cortical atrophy, pineal gland cysts, vermian anomalies, and cerebellar hypoplasia. Costovertebral defects such as scoliosis, hemivertebrae, block vertebrae, fused vertebrae, and missing or bifurcated ribs and craniosyostosis are common findings. Characteristic fundus lesions are well-defined, circular, white lacunae with minimal pigmentation at their borders varying in size from one-tenth disc diameter to twice the normal size of the optic disc ( Figure 5.34 F–H). They are usually bilateral and are often symmetrically distributed. In general the lesions are clustered around the optic disc and decrease in size and number as they extend into the periphery of the fundus. Electroretinography may be normal or minimally disturbed. Histopathologically these lesions have been shown to correspond to areas of depigmentation and deficiency in the RPE as well as gross choroidal atrophy. It is probable that the chorioretinal lesions represent a dysgenesis and not a progressive dystrophic disorder since new lesions do not occur. Progressive pigmentation of the lesions has been documented. Aicardi’s syndrome occurs only in females, and no familial cases have been reported except for one report of discordance in monozygotic twins. It has been reported rarely in Klinefelter’s 47,XXY males, except for one report in a 46,XY male. No study so far has been able to demonstrate a defect in the X chromosome, hence it appears that the change occurs after fertilization. Attempts to find the mutation in the Xp22 and the Xq28 regions have been unsuccessful.
Alport syndrome is associated with genetic abnormality involving the COL4A3, COL4A4 , and COL4A5 genes that encode the production of type IV collagen. This protein is common to the basement membrane of the glomerulus, cochlea, retina, lens capsule, and cornea. The glomerular basement membrane is irregularly thickened and splinted and stretched. The immunohistochemical stain shows absence of A5 chain. Carrier females may have variable inactivation of the X chromosome in different tissues and may manifest some of the features. These patients present with hematuria, deafness, and progressive renal dysfunction. The condition was first described by Cecil Alport in 1927. The frequency is 1:5000. It accounts for 2.1% of end-stage renal disease in pediatric patients: 85% of affected patients are male. Affected males are more likely to be deaf and develop renal failure than females.
It is associated with the following ocular findings: microspherophakia; lenticonus ( Figure 5.35 E and F); anterior or posterior subcapsular cataracts; posterior polymorphous corneal dystrophy; multiple, small (20–50 μm in diameter), punctate, yellow-white lesions in the superficial pericentral retina in the macula ( Figures 5.34 J, K and 5.35 A and C, G and H); and confluent and clustered, punctate, yellow-white lesions located deep to the retinal vessels in the midperiphery of the fundi. The macular lesions may be present in early childhood but probably become more apparent with age and are seen in 35% of patients. They are not associated with angiographic or electrophysiologic changes other than that which may occur as a result of hypertension and renal failure. There may be spotty areas of window defects in the RPE associated with the peripheral lesions. The nature of these lesions is unknown. These patients are known to develop giant macular holes likely due to defective Müller cell basement membrane ( Figure 5.35 A–D). The anterior lenticonus is pathognomonic for Alport syndrome. Posterior polymorphous corneal dystrophy due to defect in the Descemet’s membrane occurs infrequently. Drusen in Bruch’s membrane, degeneration of the RPE in the macular area, and serous retinal detachments occurring in the terminal stage of renal insufficiency have also been reported in these patients.
Because these patients have abnormalities affecting basement membranes elsewhere, particularly that of the renal glomeruli, it is possible that the mid peripheral lesions may represent nodular thickening of the basement membrane of the RPE (basal laminar drusen; see Chapter 3 ), and that the superficial lesions in the macula are related to abnormalities of the basement membrane of the Müller cells or retinal astrocytes. Gehrs et al. have suggested that the retinal flecks may consist of an abnormal subtype alpha 5 of type IV collagen, which is a major structural component of the glomerulus basement membrane. The gene encoding for this protein has been localized to the same locus ( COL45A ) at Xq22, where genetic linkage studies have placed the defect in patients with X-linked Alport syndrome. Mutations in collagen type IV genes have been described to be responsible for X-linked ( COL4A5 ), autosomal-recessive, and autosomal-dominant Alport syndrome ( COL4A3/COL4A4 ). A related disorder, benign familial hematuria, is an autosomal-dominant disorder; about 40% of these cases cosegregate with the COL4A3/COL4A4 loci, the same site for autosomal-dominant Alport syndrome. It is likely that some cases of benign familial hematuria may represent the carrier state for autosomal-recessive Alport syndrome. Collagen type IV nephropathy is an entity in itself, and phenotypic manifestations of COL4A3/COL4A4 mutations may range from monosymptomatic hematuria (benign familial hematuria) to severe renal failure (Alport syndrome), depending on the gene dosage.
Retinal Dystrophy in Duchenne and Becker Muscular Dystrophy
Duchenne muscular dystrophy is a lethal X-linked recessive disorder characterized by progressive proximal muscular weakness, loss of ambulation, and early death. Ninety-five percent of patients are wheelchair-bound by age 12 years and the mortality rate is 95% by age 20 years. The dystrophin gene for the disorder is mapped to Xp21. Dystrophin, the gene product of Duchenne muscular dystrophy, is a 427-kDa submembranous cytoskeletal protein and many dystrophin-associated proteins, such as utrophin, dystroglycans, sarcoglycans, syntrophins and dystrobrevins, have been identified. Dystrophin and dystrophin-associated proteins are very important proteins for skeletal, cardiac, and smooth muscles and also for the peripheral and central nervous system, including the retina. Dystrophin and beta-dystroglycan localize at the retinal photoreceptor terminal; their deficiency results in abnormal neurotransmission between photoreceptor cells and ON bipolar cells. Dystrophin has seven isoforms in variable tissues, and the retina contains full-length dystrophin (Dp427), Dp260, and Dp71. Dp71 localizes in the inner limiting membrane and around the blood vessels, and Dp260 is expressed in the outer plexiform layer. It is generally assumed that dystrophin functions to stabilize muscle fibers with dystrophin-associated proteins by linking the sarcolemma to the basement membrane in muscles, but its function in the retina is unknown so far. Patients with Duchenne muscular dystrophy have subnormal scotopic ERG amplitudes in the form of electronegative b-waves; the extent is likely determined by the presence of, and location of, the gene deletion. Focal hyperpigmentation of the macula may be seen, but color vision, photopic ERGs, visual acuity, and extraocular muscle function remain normal, distinguishing Duchenne muscular dystrophy from other X-linked disorders with electronegative ERGs.
Occult Macular 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.
Unclassified Macular Dystrophies
Patients with a variety of nonspecific patterns of atrophic macular dystrophy unassociated with flecks, angiographic evidence of lipofuscin storage, or other electrophysiologic or systemic manifestations are occasionally encountered. In such patients the author prefers to label their macular dystrophy as “unclassified” rather than Stargardt’s disease.
Flecked Retina Associated with Café-Au-Lait Spots, Microcephaly, Epilepsy, Short Stature, and Ring 17 Chromosome
A ring chromosome is a type of deletion that results from breakage and loss in the terminal ends of each arm of a chromosome, followed by union of the broken ends ( Figure 5.36 D). Patients with ring 17 chromosome may have mental deficiency, seizures, short stature, microcephaly, and café-au-lait spots and demonstrate a striking pattern of yellow flecks at the level of the RPE throughout the posterior fundus ( Figure 5.36 A and B). None of these patients has cutaneous neurofibromas, Lisch iris nodules, or a family history of neurofibromatosis. Their chromosome diagnosis is 46,XY,r(17) (p13q25). Although the NF-1 gene has been mapped to chromosome 17, it is unlikely that these patients have NF-1 . The fluorescein angiographic findings in one case suggest that the flecks are associated with irregular depigmentation or thinning of the RPE as well as focal obstruction of the background fluorescence by some of the flecks ( Figure 5.36 C). Charles et al. found some evidence of blockage of choroidal fluorescence by the flecks, which were believed to be at the level of the pigment epithelium. Although the flecks resemble drusen, their poor correlation with foci of discrete hyperfluorescence suggests they have a different morphology.
Benign Familial Fleck Retina
Sabel Aish and Dajani and later, McAllister et al. and Audo et al., reported a beautiful pattern of somewhat polymorphous white flecks scattered widely throughout the fundi unassociated with any visual deficit or electrophysiologic deficits ( Figure 5.36 E–L). The flecks appear round posteriorly but become more polygonal towards the equator and periphery ( Figure 5.36 K and L). There is a suggestion the shape follows the choroidal venous lobular pattern especially beyond the arcades ( Figure 5.36 H and I). The flecks are hyperautofluorescent, suggesting accumulation of fluorphores within the RPE. No progressive changes in the flecks, the RPE, or photoreceptor function have been described to date and the condition remains benign. The pattern of flecks appears similar to that reported by Miyake and Harada in three patients in two families with congenital stationary night blindness. Two of their patients had absent scotopic ERG responses, subnormal EOG responses, and delayed dark adaptation.
Congenital Stationary Night-Blinding Diseases
Congenital, nonprogressive, night-blinding diseases are characterized by infantile onset of nyctalopia without progression and good visual acuity. These patients can be subdivided into two groups: those with normal-appearing fundi and those of a distinctive fundus abnormality.
Autosomal-dominant (absent scotopic ERG, Riggs type; type I)
rhodopsin mutation ( RHO )
α subunit of rod transducin ( GNAT1 , Nougaret)
β subunit of rod cGMP phosphodiesterase ( PDE 6B )
X-linked (negative ERG, Schubert–Bornshein, type II)
L-type calcium channel ( CACNA1F ) incomplete X-linked stationary night blindness
Unidentified gene Xp11.4-11.3 complete X-linked stationary night blindness.
Arrestin ( SAG : Oguchi)
Rhodopsin kinase ( RHOK : Oguchi)
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.
Three different missense changes have been found in the rhodopsin gene so far: Gly90Asp, Thr94Ile, and Ala292Glu. The night blindness remains stationary in most patients, but some with Gly90Asp mutation may develop a few bone spicule pigmentary change, mild vascular attenuation, and constriction of their peripheral visual field after age 35. Mild late cone dysfunction may also occur.
Alpha Subunit of Transducin Mutation: Nougaret Type
Transducin mediates the second step in the phototransduction cascade; photoactivated rhodopsin interacts with the alpha subunit of transducin. The only known disease causing mutation is Gly38Asp change. The cones have subnormal sensitivity and need 10 times more intense stimulation, there is a rod–cone break in dark adaptation, and the rods show a mild response under very bright flashes. The mechanism for this response is not understood. These patients have a normal fundus appearance throughout life.
Beta Subunit of Rod cGMP Phosphodiesterase: Rambusch Type
Rod cGMP phosphodiesterase, the third member of the phototransduction cascade, is composed of one α, one β, and two γ subunits. The change in the β subunit is a His258Asp, which results in alteration of cGMP concentration affecting impulse transmission. Their fundi remain normal.
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 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.
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.
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).
Retinitis Pigmentosa (Rod–Cone Dystrophies)
Retinitis pigmentosa, tapetoretinal dystrophy, and primary pigmentary retinal dystrophy are names used interchangeably to refer to a large spectrum of disorders of variable age of onset, rate of progression, severity, and mode of inheritance. These can be subdivided into two broad categories: typical and atypical.
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.
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).
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 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.
Atypical forms of Retinitis Pigmentosa
“Atypical pigmentary retinal dystrophy” is a term applied to retinal dystrophies that are closely related to typical retinitis pigmentosa and in some cases are incomplete forms of the disease.
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).
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
Choroideremia is a X-linked recessive chorioretinal dystrophy. It probably is the same disorder reported previously by some authors as X-linked choroidal sclerosis. Affected males usually note the onset of night blindness between 10 and 30 years of age. Some years later they become aware of loss of peripheral fields. Central vision is affected only in middle or later life. Mottled depigmentation of the RPE may be the only finding initially. Large patches of RPE and choroidal atrophy, however, develop in the midperiphery of the fundus and spread gradually in anterior and posterior directions. Eventually the patient is left with only a small island of relatively normal choroid and RPE in the macular area ( Figure 5.53 I and J, and 5.54 F and L). Choroidal neovascularization may rarely occur. Narrowing of the retinal vessels and optic atrophy accompany the later stages of the disease. Fluorescein angiography during the late stages of the disease demonstrates slowing of the retinal and choroidal circulation, marked loss of the RPE, and choroidal vasculature, but relative preservation of the RPE and the choroidal vessels, including the choriocapillaris in the central macular area ( Figure 5.53 E). Angiography usually demonstrates the presence of many choroidal vessels that may be difficult to see ophthalmoscopically. Some patients show severe impairment of the photopic functions in dark adaptation. Color vision is essentially normal. The ERG is abnormal early and becomes extinguished usually by midlife.
The female carrier demonstrates normal visual acuity, visual fields, dark adaptation studies, and electroretinographic findings and, with few exceptions, shows characteristic RPE mottling and depigmentation that is most marked in the midperiphery ( Figure 5.53 B and C, G and H, 5.54 E and K). The pigment granules in carriers have been described as being irregularly square in appearance. The pigmentary changes are not associated with abnormalities of either the optic nerve head or retinal vessels. The fundi resemble those seen in rubella retinopathy (see Figure 7.27) and toxic retinopathy caused by thioridazine (see Figure 9.02A) but are different from the streaky iridescent changes in the fundi of some carriers of X-linked retinitis pigmentosa.
It is important to identify these carriers because their sons will have a 50% chance of having choroideremia and their daughters a 50% chance of being carriers of the disease. Some female carriers are known to manifest clinical features of choroideremia, especially later in life due to irregular inactivation of the X chromosome (lyonization).
No known systemic association has been described in patients with choroideremia, except for one male with polydactyly, which was caused by an autosomal-dominant inheritance of polydactyly on his paternal side. He had normal growth, normal mentation, and no evidence of hypogonadism.
Choroideremia is caused by mutations in the CHM gene localized to the long arm of X-chromosome (Xq21.2). The mutation affects the production of Rab escort protein isoform 1 (REP-1), previously known as component A of Rab geranylgeranyltransferase (GGTase), the enzyme that plays a key role in the activation of Rab proteins that are responsible for the regulation of exocytic and endocytic cellular pathways. They control the protein trafficking of secretory and endocytic pathways. A reduction in particular of activated Rab27a by preferential binding by REP-1 is implicated in choroideremia. Several types of mutation in the CHM gene, including point deletions, large basepair deletions, splice site substitutions, and translocations, have been associated with the clinical findings of choroideremia. Though these patients lack REP-1 in all other cells too, the retina and choroid are the only structures affected in choroideremia; it is believed that REP-2, that resembles REP-1 to about 75% is enough to activate Rab proteins in cells outside the retina and choroid.
DNA analysis of chorionic villi obtained during pregnancy permits prenatal exclusion of choroideremia.
Histopathologic examination during the late stages of the disease reveals atrophy of the choroid, RPE, and overlying retina with relative sparing of the macula and periphery. Ultrastructurally, the curvilinear trilaminar structures within macrophages in the RPE and outer retina are similar to those seen in abetalipoproteinemia.
The retina in a symptomatic female carrier displayed areas of severe degeneration, with complete loss of photoreceptor outer segments, photoreceptor nuclear atrophy, and atrophy of the inner retina interspersed with near-normal areas. In affected regions, the RPE showed severe degeneration, with thinning, pigment clumping, and deposition of subepithelial debris. The choroid was depigmented. Labeling with cone opsin and rhodopsin antibodies revealed that cones and rods were severely affected. Ultrastructurally, RPE apical microvilli and basal infoldings were absent in the macula and banded fibers composed of clumps of wide-spaced collagen were present on the RPE’s basal surface and choroid. Bruch’s membrane was filled with vesicular structures, some smooth and others with bristle-like projections.
The differential diagnosis of choroideremia includes diffuse choriocapillary atrophy, which in some cases is dominantly inherited, and gyrate atrophy of the choroid, which is associated with hyperornithemia and autosomal-recessive inheritance. Figure 5.55 illustrates a fundus picture simulating choroideremia in two unrelated women with late-onset visual loss and a history of sibling involvement. Amino acid analysis, mode of inheritance, and examination of the mother’s fundus are important if the diagnosis of choroideremia is uncertain.
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.
Cone–Rod Dystrophies (Inverse Pigmentary Retinal Dystrophy)
Loss of central and color vision and development of nyctalopia, usually early in life, are the hallmarks of cone–rod dystrophy. The onset of symptoms may not begin until adulthood ( Figure 5.56 A). Initially some patients may manifest only clinical and electrophysiologic evidence of cone dystrophy (see p. 306). In the beginning the RPE in the macular area may be normal ( Figure 5.56 F and G). Later, mottling of the pigment in the macula along with slight narrowing of the retinal vessels occur. The pigmentary changes progress and may or may not be associated with bone spicules in the periphery. A bull’s-eye-like pattern of pigmentary derangement frequently develops centrally followed later by temporal pallor and capillary telangiectasis of the optic disc ( Figure 5.56 A, B, E, and H). The ERG, however, usually reveals markedly abnormal or absent cone responses and reduced rod responses. It may become extinguished. The EOG is flat. These patients show severe abnormalities of color vision. There may be some value to subclassification of these patients into groups depending upon the relative severity of the reduction of cone versus rod ERG amplitudes. Vitreous fluorophotometry is less likely to be abnormal in these patients than those with typical retinitis pigmentosa.
Cone–rod dystrophies are a heterogeneous group of inherited disorders. They may be inherited by all three main modes. The four major causative genes in the pathogenesis of cone–rod dystrophies are ABCA4 (which causes Stargardt disease and also 30–60% of autosomal-recessive cone–rod dystrophies), CRX and GUCY2D (which are responsible for many reported cases of autosomal-dominant cone–rod dystrophies and cone dystrophies), and RPGR (which causes about two-thirds of X-linked retinitis pigmentosa and also an undetermined percentage of X-linked cone–rod dystrophies). It occasionally is associated with neurologic disease ( Figure 5.56 F–I). Rabb et al. reported the clinicopathologic findings in a patient with cone–rod dystrophy. They can also be part of a syndrome such as Bardet–Biedl and SCA 7. A similar disease in baboons and Rdy cats has been studied by light and electron microscopy. Deletion mapping of a cone–rod dystrophy resulted in assignment to 18q211.
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.
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.
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.
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.