Associated Features
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Poor correlation between acuity and extent of “tunnel vision”.
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Retinal arteriolar narrowing.
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“Waxy nerve pallor” from reactive gliosis.
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Posterior subcapsular cataracts in middle age.
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Progressive chorioretinal atrophy.
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Frequently, but not always, a family history.
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Associated systemic abnormalities uncommon but important.
“Stationary” retinal degenerations are stable in comparison with, and less progressive than, most forms of retinitis pigmentosa (RP), even though there is often some change over time.
Progressive Diffuse/Panretinal Degenerations
Introduction
The term retinitis pigmentosa (RP) encompasses a set of diverse hereditary disorders that affect the photoreceptors and retinal pigment epithelium (RPE) diffusely across the entire fundus but begin with initial geographical involvement in either the periphery or the macula. These conditions typically, but not always, progress over many years to an advanced stage and result in global reduction or loss of vision. As a group, the majority of forms of RP lead initially to death of the rod photoreceptors, which impairs vision in dim light and causes loss of peripheral vision, and later involves cones as the symptoms progress leading to “tunnel vision.” However, some of the allied forms primarily cause cone photoreceptor loss and initially manifest with a reduction in central visual acuity.
Such conditions are determined genetically, and all genetic patterns of inheritance are represented. In many cases, a patient represents an isolated case with no known affected relatives, which makes a genetic etiology less obvious and must be differentiated from acquired etiologies, such as inflammatory or infectious retinal insults. The possibility and availability of genetic diagnosis is much higher than ever before, and identification of the various defects within the abnormal genes that result in these conditions is possible. New treatment options are being tested, and others are anticipated in the years ahead because of a new understanding of the pathophysiology of the disease.
The approach to the patient involves initial categorization of the degeneration into either a rod-cone disease or cone-rod disease, two conditions that carry different prognoses. Further subtyping of the disease provides even better information about prognosis. Rod-cone degeneration is typically more severe—the long-term prognosis is loss of most or all vision by later years. Cone-rod degeneration affects central vision quite early and peripheral vision only later. Because the human retina has 120 million rods and only 6 million cones, it may function well without cones, as exemplified by achromatopsia. The prognosis in cone-rod dystrophy is good for at least some future vision, even though central vision is jeopardized. A review of the patient’s symptoms and retinal function studies, particularly visual field testing and electroretinography (ERG), are required to differentiate rod-cone from cone-rod degenerations.
Epidemiology and Pathogenesis
Familial retinal degeneration with intraneural retinal pigmentation was described as early as 1855 by Donders. It is now understood that most cases have a genetic basis and involve photoreceptor cell death through apoptosis. No racial or ethnic predisposition exists. Men may be affected slightly more than women because of X-linked conditions.
The term retinitis pigmentosa refers to a broad category of genetically heterogeneous diseases, which includes many different forms of primary photoreceptor abnormalities—some affect rods first and cones later (termed rod-cone dystrophy ) or the reverse (termed cone-rod dystrophy ). The prevalence of primary photoreceptor degeneration is in the range 1 : 3000–1 : 5000. The carrier state for recessive retinitis pigmentosa is approximately 1 : 100, based on the prevalence of recessive retinitis pigmentosa. These numbers are approximate because of the complexity of the many different forms of RP now identified by gene cloning. In most cases, these diseases are thought to be simple Mendelian traits that result from DNA alteration in single genes.
Rod-Cone Dystrophy
Rod-cone dystrophy manifests clinically with typical RP and affects the rod photoreceptors earlier and more severely than it does the cone photoreceptors. Severe cone involvement occurs in the end stage of the disease, when total vision loss ensues. The key features of the rod-cone type of disease are progressive night blindness and visual field constriction, which become more severe as more rods die, leading to cone loss. The appearance of midperipheral ring scotomas during progressive stages of visual field loss is not uncommon. Typically, both eyes are affected similarly.
Visual acuity is initially affected minimally and typically remains near to 20/20 (6/6) for many years despite progressive field loss to severe tunnel vision. Careful history taking frequently reveals some night blindness, even in early-stage rod-cone disease. Symptoms of typical RP include prolonged dark adaptation. However, many patients with RP are able to drive at night on well-lit streets. Patients complain of problems in dimly lit restaurants and theaters and are symptomatic when they come indoors from bright sunlight. By the midstage of the disease, visual field constriction occurs. Patients may appear clumsy because they collide with a door frame or a friend who walks alongside because of unrecognized tunnel vision. End-stage rod-cone disease results in loss of both peripheral vision and central vision. Many patients have only barely functional central vision by late middle age and lose all vision later. However, the changes occur slowly, and the young patient may be reassured that some vision is most likely to remain for many years or decades, even though the long-term prognosis is grim. Glare sensitivity to bright light occurs in end-stage rod-cone dystrophy, when the diseased cones saturate in bright light.
The functional profile of early-stage rod-cone dystrophy is shown in Fig. 6.14.1 . The rod ERG amplitude loss is worse than that for cones (light-adapted: single flash and 30 Hz flicker). Goldmann visual fields are still relatively large with the large V4e target but considerably constricted to the small I4e target—such disparity between the ratio of field area with the V4e versus I4e targets is typical for rod-cone dystrophy. Tests of dark-adapted thresholds show 1–3 log units of rod sensitivity loss, which equates with 10–1000 times more light required to see at night. The disease does not act uniformly across the retina, and rod threshold should be tested at multiple points of vision to give a sensitivity profile across the central and peripheral vision.
As visual fields constrict further, even to the large V4e target, dark-adapted thresholds become worse because only cones remain to mediate vision, even in dim light. At this stage, the patient suffers from severe night blindness. With time, the cone ERG responses deteriorate further until eventually both the rod and cone responses are reduced profoundly, and all ERG responses are termed “nonrecordable.” By this time, visual acuity is typically less than 20/40 (6/12), color discrimination is impaired, and fields are greatly constricted.
Cone-Rod Dystrophy
Patients with cone-rod dystrophy complain of poor acuity, reduced color vision, and glare sensitivity to bright sunlight.
Particularly in the early stages, the fundus may appear normal, with minimal diffuse retinopathy and normal vessels and disc. Visual fields initially remain full with the Goldmann V4e target but may be constricted slightly with the I4e target. It is more likely that at least some peripheral vision is retained in patients who have cone-rod dystrophy as opposed to those who have rod-cone dystrophy. ERG shows that cone-mediated responses (30 Hz flicker and photopic single flash responses) are reduced proportionally more than the dark-adapted rod b-wave (see Fig. 6.14.1 ). Although the rod b-wave amplitudes may be subnormal technically, rod dark-adapted threshold sensitivity remains nearly normal when tested using a Goldmann-Weekers dark adaptometer after 45 minutes in the dark. The combination of ERG and psychophysical rod threshold tests is the best way to diagnose cone-rod dystrophy. Patients who have the least rod involvement carry the best prognosis for intermediate-term vision. At the other end of the prognosis spectrum are rare patients who develop a central scotoma early in life; the field defect enlarges gradually but relentlessly toward the periphery, with practically total visual loss by late middle age. These patients usually receive the diagnosis of “macular degeneration” in childhood; the condition has been termed “inverse retinitis pigmentosa” because pigment spicules are more abundant in the central retina than in the midperiphery. Infrequently, a patient with cone-rod dystrophy has an essentially normal rod but a very reduced cone on ERG and is considered to have “cone dystrophy.” Such patients have a good prognosis for vision into later age. Some patients with cone-rod dystrophy are first symptomatic after age ≥50 years and may progress quickly to considerable vision loss. Such patients are a diagnostic challenge because of the later age at presentation; initially, ERG results may be marginally normal, but the results of repeat ERGs after 6–12 months progress to subnormal.
Diagnosis and Ancillary Testing
For diagnosis, visual function tests are an important adjunct to retinal examination. Tests may also help identify correctly the clinical subtype of the disease. Accurate subtyping provides the basis for counseling about expectations for school and career choices, for the provision of genetic information to the extended family, and for potential treatment.
The history can be helpful. Complaints of “night blindness” may indicate total lack of vision in very dim light or diminished acuity as ambient light dims. Tunnel vision may be suggested by recent automobile accidents or clumsiness in the narrow spaces of elevators or doorways. Any family history of slowly progressive unexplained vision loss must be sought.
Electroretinography
Full-field (Ganzfeld) electroretinography (ERG) is quite sensitive to even mild photoreceptor impairment. Rod b-wave amplitudes are reduced in the earliest stages of disease when the retina may appear clinically normal and vision complaints are minimal. For the diagnosis of genetically at-risk younger patients who have otherwise minimal retinal findings, ERG is essential. ERG helps in the diagnosis of the disease in relatives when a retinitis pigmentosa pedigree is established.
Initially, ERG is used to test the rod system by testing with a dim flash after 30 or more minutes in the dark (“scotopic ERG”). The cone system is tested by using single, bright flashes superimposed on a bright background that suppresses activity of rods (“photopic ERG”) and also using a 30-Hz flicker to which cones respond but rods do not. Many complex and analytical schemes of ERG analysis are employed in special circumstances, but the most useful initial measures of ERG abnormality will be discussed below. Scotopic (dark-adapted condition, rod-driven) and photopic (light-adapted, cone-driven) b-wave amplitudes are key in that they provide the first index of disease severity and help differentiate rod-cone from cone-rod disease.
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Scotopic b-waves reduced by 50% or more—this indicates progressive disease rather than a variant of “stationary” disease.
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Early cone system disease—this frequently reduces the amplitudes of 30-Hz flicker before photopic b-wave responses to single flashes.
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Delayed flicker implicit time (from flash to response peak)—this is a highly sensitive measure of abnormality, and implicit times may be prolonged even with normal flicker amplitude; implicit times are very robust and relatively immune to artifacts caused when the patient squeezes on the ERG contact lens electrode (which reduces flicker amplitude but does not change timing).
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Photopic oscillatory potentials (high-frequency wavelets of small amplitude that originate in the proximal retina)—these are generally reduced earlier or to a greater degree than the photopic, single-flash b-wave, and oscillatory potentials may be reduced in retinal vascular diseases.
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Relative preservation of the scotopic a-wave amplitude (from rod photoreceptors) but reduced scotopic b-wave (from signaling by second-order bipolar cells)—this is called an “electronegative” ERG wave-form and is highly suggestive of congenital stationary night blindness (CSNB) or X-linked juvenile retinoschisis. In these cases, the ERG change indicates faulty synaptic signaling from rods to bipolar cells, deficient bipolar responsivity, or Müller cell disease.
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Broad and flat bottom trough to the photopic a-wave—this is highly suggestive of CSNB.
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The full-field ERG reflects global retinal activity and is insensitive to macular scars; thus, it does not correlate with visual acuity determined solely by foveal function.
Monitoring Disease Progression
After some time, the ERG is repeated for the following reasons:
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Confirmation of the diagnosis.
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Determination of the rate of progression.
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Monitoring of the effects of therapy, such as vitamin A administration or other.
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Provision of objective information about progression, to help the patient cope with a disease that causes vision loss.
ERG may be repeated 1–2 years after the first test just to confirm the findings, or serial yearly tests may be used to estimate progression. Exceptionally rapid cone ERG loss in a child may raise suspicion of atypical forms of RP, which include neuronal ceroid lipofuscinosis and indicate the need for a neurological evaluation, particularly if seizure activity is reported.
Visual Field Testing
Goldmann perimetry is preferable for initial RP visual field testing out to 90° in the far temporal periphery because the midperipheral retina is involved first in the rod-cone type of disease. The recent introduction of semi-automated kinetic perimetry might prove a valuable alternative. Even moderate stages of rod disease typically show extensive peripheral field loss to the small, I4e Goldmann target, whereas cone-rod disease leaves peripheral fields more intact. Subjects with RP may respond poorly to automated perimeters—careful studies using a Goldmann perimeter are more successful for obtaining representative fields. Macular dysfunction may be well followed by testing the central field by using automated static perimeters (e.g., Humphrey Visual Field Analyzer 24–2 or 10–2 programs). Many patients with RP are unaware of lost peripheral vision or a ring scotoma even after several suggestive events (i.e., recent automobile accidents). The patient will appreciate the physician who simply takes the time to explain visual field test results and may immediately recall instances of previous problems with everyday activities.
Dark Adaptation Testing
Night vision symptoms occur early in the course of RP disease and must be evaluated by using dark adaptation studies. One of the instruments to do this is the Goldmann-Weekers dark adaptometer. The patient is placed in darkness and asked to detect the dimmest possible (threshold) light, which becomes progressively dimmer as time proceeds. Final absolute threshold sensitivity is normally reached after 30–40 minutes in the dark. An alternative test strategy is to determine only the final thresholds after 45–60 minutes in the dark. Thresholds are tested in several different retinal locations to sample the distribution of disease. Some patients who complain of difficulty seeing at night are found to have normal dark-adapted thresholds. Such patients may have under corrected myopia, and the complaint is really of blurred vision in dimmer light. Other patients may have maculopathy and notice worse acuity in dimmer light, even though normal rod-mediated, absolute dark sensitivity is maintained.
Color Vision Tests
In degenerative retinopathy, color testing is a useful adjunct to visual acuity tests because it provides additional information about the condition of the macular cones. Patients with RP rarely volunteer information about problems with color vision because nearly all can readily differentiate the major colors of red, green, and blue. However, in rod-cone dystrophies, tritan (“blue-yellow”) color discrimination loss on the Farnsworth D-15 panel is a sensitive index of early foveal cone involvement and may presage acuity loss within the next few years. In cone dystrophies, loss of color discrimination normally parallels visual acuity loss. The D-15 test, which consists of 15 color chips that must be arranged in color sequence, is simple, is rapid, does not tire the patient, and is easy to score. In the D-15 test, >2 minor neighbor errors indicate pathology. The Farnsworth 100 Hue test is more elaborate but seems to be no more sensitive for detecting maculopathy. The Ishihara and American Optical color plates were designed specifically to identify individuals with congenital red–green abnormality and are less useful than the D-15 test for the evaluation of early macular dysfunction that results from a retinal dystrophy.
Fluorescein Angiography
Fluorescein angiography (FA) is sometimes used for hereditary maculopathies, such as Stargardt disease and Best disease, or in suspected toxic maculopathy from hydroxychloroquine, chloroquine, or psychotropic agents, but in many cases, the information can be gained from less invasive modalities, such as fundus autofluorescence.
Fundus Autofluorescence
Fundus autofluorescence with excitation at 488 nm is increasingly recognized to demonstrate characteristic, and in some cases pathognomonic, changes in many retinal diseases especially inherited retinal degenerations. It is thought to elicit the autofluorescence of lipofuscin primarily and, as such, demonstrates distinctive patterns in Stargardt, Best, and bull’s-eye maculopathies. Even in RP, characteristic autofluorescence patterns of a hyperautofluorescence ring have been observed to correlate with retinal sensitivity and optical coherence tomography (OCT) and may reflect progression of RP.
Optical Coherence Tomography
In vivo high-resolution cross-sectional images of the central retina can be obtained using OCT. In RP, OCT abnormalities range from reduction in retinal thickness caused by photoreceptor loss, to increase in retinal thickness caused by macular edema. Structural changes measured by OCT correlate with functional changes, as measured by visual fields and multifocal ERG, and can also be used to monitor disease progression in RP.
Electro-oculography
Electro-oculography (EOG) result is abnormal whenever the ERG result is abnormal, and thus it provides useful information only when the ERG result is normal. Therefore, EOG is not performed automatically with every ERG examination. One of the very few current uses for EOG is to track the genetic pattern in Best vitelliform macular dystrophy, in which the expressivity is highly variable.
Multifocal Electroretinography
In contrast to full-field (Ganzfeld) ERG, in which a global response is elicited by stimulation of all the retina by a single light stimulus, in multifocal ERG (mfERG) a localized response is elicited by simultaneous stimulation of multiple discrete areas of the central retina. The local responses may be extracted by correlating the recorded response with the stimulus sequence. In a diffuse retinal disease, such as RP, Ganzfeld ERG is a more useful overall estimator of retinal function. However, mfERG can be used to explore the local aspects of cone function. Diagnostically, it is perhaps most useful in the determination of chloroquine and hydroxychloroquine toxic maculopathies, as well as occult maculopathy and for the differentiation of macular versus optic nerve related central scotomas.
Visual Evoked Cortical Potential
Visual evoked cortical potential (VECP) monitors visual signals that reach the cortex and is dominated heavily by macular function, with a far smaller contribution from the peripheral retina. Any disturbance of retinal function, altered optic nerve conduction, or visual cortex processing alters the VECP. Retinal, and particularly macular, dystrophies affect the VECP, but these conditions are nearly always identified and monitored better by using other visual function tests.
Retinal function tests have value beyond simple diagnosis because they give insight into the nature of the disease, inform about the severity or stage, and provide information for genetic counseling. Results of the examination must be communicated to the patient because subtyping and staging the disease provide information about expectations for the course of future vision and the genetic implications for the patient’s family.
Genetic Testing
As clinical examination and testing lead physicians to a clinical diagnosis, new advances in understanding the genetic basis for disease now support genetic testing to confirm clinical diagnoses and provide additional information about familial risk. In conjunction with genetic counseling, genetic information can be informative for prognosis, as well as providing risk information to family members. From a research perspective, genetic testing improves the understanding of the pathophysiology of the disease and is also a prerequisite before contemplating any gene-based therapies. The speed of identification of genes involved in various retinal degenerations far outpaces the rate of publications produced, and any attempt to enumerate them would be obsolete far before this ever gets to print. The RetNet retinal information network database ( http://www.sph.uth.tmc.edu/Retnet ) provides an updated catalog of genes associated with RP and other inherited retinal diseases. Many of these genes are available for sequencing through commercial enterprises as well as through research institutions. As the number of genes identified as being associated with RP and other retinal degenerations increases, the development of screening systems, such as high-throughput arrays, has made genetic testing feasible in these genetically heterogeneous diseases. Efforts using whole exome sequencing or even whole genome sequencing have also led to the identification of genes involved in retinal degenerations.
The National Eye Institute at the National Institutes of Health is working with the vision community in creating the eyeGENE (National Ophthalmic Disease Genotyping and Phenotyping) Network. This genetic repository allows patients to harness an organization of existing research laboratories within the vision community that have been certified by the Clinical Laboratory Improvement Amendments, and to develop a database of genotypes and phenotypes. The Network will assist in developing public and professional awareness of genotype/phenotype resources that are available to people with various ocular genetic diseases, their clinicians, and scientists studying these diseases. Ultimately, the eyeGENE Network will enhance our understanding of genotype–phenotype correlations and aid in the recruitment of patients interested in participating in future clinical trials related to genetic eye diseases.
Ocular Findings/Manifestations
Typical Retinitis Pigmentosa
The key features of typical RP normally found are as follows:
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“Bone-spicule” intraneural retinal pigment.
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Thinning and atrophy of the RPE in the mid- and far-peripheral retina.
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Relative preservation of the RPE in the macula.
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Gliotic “waxy pallor” of the optic nerve head.
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Attenuation of retinal arterioles.
The extent of bone-spicule pigmentation is quite variable—many involved retinas have some, even if very little, of this pigment. This is particularly true in children in whom more subtle abnormalities of RPE pigmentation are more common than are typical spicules. The severity of the features increases with age, such as the amount of pigment, the extent of disc gliosis, and the degree of arteriolar narrowing. Major deviations from this clinical picture suggest atypical RP. In particular, several of the X-chromosome retinal dystrophies (described subsequently) deviate widely from this standard picture. The identification of typical RP is particularly important for clinical trials because diagnosis implies the exclusion of other RP subtypes that may have unusual rates of progression.
Typically, both eyes are affected to a comparable extent, although some degree of difference between each eye is expected normally. Highly asymmetric differences are described as “unilateral retinitis pigmentosa,” in which one eye lags in degeneration by the equivalent of many years, although both eyes invariably show involvement on careful testing. Such apparent unilateral retinitis pigmentosa cases may also result from post infectious causes or blunt trauma to one eye.
Other manifestations of the disease include cataracts, especially of the posterior subcapsular variety, and cystoid macular edema (CME). Both of these complications may reduce the central acuity, even when the underlying disease process affects the peripheral retina only.
Careful clinical examination, careful taking of family history, and diagnostic testing may lead the clinician to suspicion of a certain genetic involvement. Molecular identification of the causative gene is possible in some cases (e.g., pro-23-his rhodopsin mutation) ( Fig. 6.14.2 ). A long-sought goal is to correlate a specific gene with a specific phenotype, but this is accomplished rarely because most retinitis pigmentosa mutations result in a similar phenotype. Some unique conditions exist, such as the mutations in RDS/peripherin gene, which may cause a peculiar maculopathy in addition to peripheral retinal degeneration. In general, however, it is not yet possible to predict the specific causative gene from the clinical presentation.
Further, even within the RP cases attributed to a particular gene, such as that which codes for rhodopsin, major variations in the clinical features and disease severity are caused by mutations at different positions within the gene. In rhodopsin RP, the pro-23-his mutation causes fairly typical retinitis pigmentosa ; the cys-187-tyr mutation results in a rapid course of degeneration ; and the thr-58-arg mutation results in sectoral involvement. The clinical course may vary even within a single family with a single genotype. Consequently, it is impossible to summarize retinitis pigmentosa as a single definition or clinical picture. In general, however, typical RP progresses slowly, such that a period of 1–3 years is needed to document changes.
X-Linked Retinitis Pigmentosa
X-linked retinitis pigmentosa (XLRP) has features of typical retinitis pigmentosa, although prominent parafoveal atrophy may be present. Affected boys show subtle or modest RPE granularity, but frank, intraneural retinal bone-spicule pigment typically does not appear until the teenage years. Acuity is good during childhood, but by age 20 years, acuity loss and field constriction rule out the acquisition of a driver’s license, and dark-adapted thresholds are elevated by as much as 3 log units (1000-fold sensitivity loss). Night blindness is severe by the mid-teenage years. Rate of vision decline is rapid, and major functional loss is expected by age 30 years; blindness by age 40 years is common.
The clinical features of two different forms of XLRP (RP2 and RP3, the latter caused by mutations in the RPGR gene) overlap extensively, and both progress to severe vision disability by young adulthood. All those affected show typical characteristics of RP, although cone vision is affected to a greater degree than in many autosomal forms of RP, particularly in those who have RP3. ERG reveals a major reduction of both the rod and cone responses even in young boys and is essential to stage the disease.
Leber’s Congenital Amaurosis
The term Leber’s congenital amaurosis (LCA) describes a group of retinal dystrophies characterized by very early onset of severe disease. The first sign noticed by the child’s parents is usually nystagmus, a common finding in children who have never developed good central vision. The severity of visual loss can range from moderate to very marked (light perception) and is usually progressive. Children with severe visual loss may self-elicit phosphenes by rubbing their eyes through their eyelids (the oculodigital sign). Fundus findings are variable. They can be limited to moderate pigmentation abnormalities, but frank atrophic retinal changes are common; marked attenuation of retinal vessel diameter is the norm. The amplitude of all ERG responses is markedly reduced; this test is therefore essential for the differential diagnosis with other ophthalmic diseases associated with congenital visual loss and nystagmus. LCA is usually inherited as an autosomal recessive trait. Mutations of more than a dozen genes can cause LCA; about half of them are also implicated in adult-onset retinitis pigmentosa.
Cone Dystrophy
Fundus changes are quite variable, with the classic fundus finding being described as a “bull’s-eye” maculopathy ( Fig. 6.14.3 ). Particularly in the early stages, the fundus may appear benign, with minimal diffuse retinopathy and normal vessels and disc. At the other end of the prognosis spectrum are rare patients who develop a central scotoma early in life; the field defect enlarges gradually but relentlessly toward the periphery, with practically total visual loss by late middle age. These patients usually receive the diagnosis of “macular degeneration” in childhood; the condition has been termed “inverse retinitis pigmentosa” because pigment spicules are more abundant in the central retina than in the midperiphery. Typically, ERG findings indicate that cone function (photopic responses) is more affected than rod function (scotopic responses), but both are abnormal. Infrequently, a patient with cone-rod dystrophy has an essentially normal rod but a very reduced cone on ERG and is considered to have “cone dystrophy.”
Genetics and Pathology
RP can be inherited in an autosomal dominant, autosomal recessive, or X-linked fashion. Frequently, no other family members are known to be affected, a condition known as “sporadic,” “isolated,” or “simplex” RP. According to different surveys, up to 50% of patients with RP are in this category. Many, but not all, of these patients have autosomal recessive RP, and others may be caused by new mutations. Pedigree analysis shows evidence of autosomal dominant inheritance in about 25%, of autosomal recessive inheritance in about 25%, and of X-linked inheritance in about 10% of patients.
RP can be caused by mutations in multiple genes, many of which encode proteins essential for photoreceptor structure and function. To date, the field has identified more than 20 genes which cause autosomal dominant RP, more than 30 genes which cause autosomal recessive RP, and more than 2 genes which cause X-linked RP. More have been located but not identified, and these numbers are expected to increase in the future ( Table 6.14.1 ). The RetNet retinal information network database ( http://www.sph.uth.tmc.edu/Retnet ) provides an updated catalog of genes associated with RP and other inherited retinal diseases.
| Autosomal Dominant (AD) Conditions | Autosomal Recessive (AR) Conditions | X-linked (XL) Conditions | Systemic Diseases with Retinal Degeneration Component | Acquired Conditions |
|---|---|---|---|---|
AD retinitis pigmentosa (RP)
| AR RP
| XL RP
| Usher’s syndrome
| Toxic retinopathy
|
AD cone-rod dystrophy
| AR cone-rod dystrophy
| XL cone-rod dystrophy
| Bardet–Biedl syndrome
| Postinfectious retinopathy
|
AD Leber’s congenital amaurosis
| AR Leber’s congenital amaurosis
| Choroideremia
| Refsum’s disease
| Pigmentary retinopathy secondary to trauma |
AD congenital stationary night blindness
| Achromatopsia
| Juvenile retinoschisis
| Kearns–Sayre syndrome
| Melanoma-associated retinopathy
|
Best disease
| AR congenital stationary night blindness
| XL congenital stationary night blindness
| Joubert’s / Senior–Loken syndrome
| Cancer-associated retinopathy
|
XL blue cone monochromatism
|
The identified RP-associated genes may be grouped into mainly five categories:
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Phototransduction.
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Retinal metabolism.
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Tissue development and maintenance.
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Cellular structure.
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Splicing.
Rhodopsin was the first major retinitis pigmentosa gene to be identified. As with rhodopsin, the majority of the RP genes identified thus far involve components of the phototransduction cascade within the rod photoreceptor, which include transducin, phosphodiesterase (α- and β-subunits of PDE), arrestin, recoverin, and the G protein–coupled Na+/K+ light-activated channel on the rod membrane. Another set of genes code for structural proteins in rod cells and include RDS/peripherin and ROM1. Developmental genes, such as the homeobox gene CRX, are also implicated in the development of cone-rod degeneration. More recently, genes involved in the spliceosomal protein complex, which catalyzes the removal of intronic sequences, such as PRPF3, PRPF8, and PRPF31, have been identified and found to comprise ≈10% of the RP-associated genes.
The molecular mechanisms by which these genetic mutations eventually cause rod-cell death are unclear, although ample evidence indicates that apoptosis is involved in the final pathway of cell death.
That the cone photoreceptors ultimately die from a disease that begins with rod-cell disease remains a puzzle. One hypothesis invokes common elements of the RPE that are involved intimately in the diurnal cycle of phagocytosis of the outer-segment discs shed daily by both rods and cones. In the case of rhodopsin mutation RP, rhodopsin is the major protein in the rod outer segments and the diurnal process of phagocytosis of the shed rod-disc membrane by the RPE may eventually result in secondary RPE pathology. With time, the RPE cannot properly service the cone photoreceptors, which subsequently die as “innocent bystanders.” Alternative explanations are that cone viability depends on the existence of a rod-derived factor and that the mechanical scaffold provided by rods is required for cone survival.
Clinical examination of the retina from a 73-year-old woman who had autosomal dominant RP from a pro-23-his rhodopsin mutation revealed that she had 20/50 (6/15) visual acuity several months before her death, and her fields were only 17°. Her fundus had typical RP changes of heavy bone-spicule pigmentation across the entire 360° periphery, and the underlying RPE was atrophic (see Fig. 6.14.2 ). After her death, histological examination of her eye showed major loss of the photoreceptors ( Fig. 6.14.4 ). Tissue from the parafoveal region of the left eye in the region of relative preserved retina showed the following:
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Photoreceptor outer segments shortened greatly, such that they are nearly absent, and the inner segments shortened.
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Number of photoreceptor nuclei (outer nuclear layer) decreased greatly, the majority of those left being cone nuclei—virtually no rod photoreceptors remain in this end-stage RP.
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RPE swollen grossly by intraretinal debris, with loss of melanosomes and dispersion of pigment granules.
Systemic Associations and Differential Diagnosis of Pigmentary Retinopathy
RP is associated with many systemic conditions, of which the following warrant particular attention either because of their incidence (e.g., Usher syndromes, in which early-onset hearing loss is associated with RP) or because the diagnosis, which may be recognized by the ophthalmologist first, has major medical implications. At other times, diagnosis can be important for early treatment with subsequent long-term positive health and vision effects (e.g., Refsum’s disease, abetalipoproteinemia). Secondary causes of RP-like disease should be entertained in the absence of family history of the disease; the differential diagnosis of pigmentary retinopathy includes multiple nonhereditary conditions. Table 6.14.1 lists the main features of many retinal degenerations and associated systemic conditions, with a brief updated list of associated genes as well as acquired conditions that are part of the differential diagnosis.
Course and Outcomes
Projections about future vision are always difficult in degenerative disease, particularly because the RP subtypes do not have a single clinical course. XLRP typically affects visual acuity by young adulthood, and visual acuity of some XLRP female carriers also becomes severely impaired. Thus a simple summary of vision loss in the various forms of retinal degeneration is not possible, particularly for visual acuity. In all cases, functional tests using ERG and visual thresholds best establish the current stage of retinal cell function in aggregate and thus provide an initial basis for any prognostic statement. Prognostic statements depend on careful disease subtyping. When subtyping is elusive, analysis of whether the patient has rod-cone disease or cone-rod disease provides vision estimates that may be used for general prognosis.
Introduction
The term retinitis pigmentosa (RP) encompasses a set of diverse hereditary disorders that affect the photoreceptors and retinal pigment epithelium (RPE) diffusely across the entire fundus but begin with initial geographical involvement in either the periphery or the macula. These conditions typically, but not always, progress over many years to an advanced stage and result in global reduction or loss of vision. As a group, the majority of forms of RP lead initially to death of the rod photoreceptors, which impairs vision in dim light and causes loss of peripheral vision, and later involves cones as the symptoms progress leading to “tunnel vision.” However, some of the allied forms primarily cause cone photoreceptor loss and initially manifest with a reduction in central visual acuity.
Such conditions are determined genetically, and all genetic patterns of inheritance are represented. In many cases, a patient represents an isolated case with no known affected relatives, which makes a genetic etiology less obvious and must be differentiated from acquired etiologies, such as inflammatory or infectious retinal insults. The possibility and availability of genetic diagnosis is much higher than ever before, and identification of the various defects within the abnormal genes that result in these conditions is possible. New treatment options are being tested, and others are anticipated in the years ahead because of a new understanding of the pathophysiology of the disease.
The approach to the patient involves initial categorization of the degeneration into either a rod-cone disease or cone-rod disease, two conditions that carry different prognoses. Further subtyping of the disease provides even better information about prognosis. Rod-cone degeneration is typically more severe—the long-term prognosis is loss of most or all vision by later years. Cone-rod degeneration affects central vision quite early and peripheral vision only later. Because the human retina has 120 million rods and only 6 million cones, it may function well without cones, as exemplified by achromatopsia. The prognosis in cone-rod dystrophy is good for at least some future vision, even though central vision is jeopardized. A review of the patient’s symptoms and retinal function studies, particularly visual field testing and electroretinography (ERG), are required to differentiate rod-cone from cone-rod degenerations.
Epidemiology and Pathogenesis
Familial retinal degeneration with intraneural retinal pigmentation was described as early as 1855 by Donders. It is now understood that most cases have a genetic basis and involve photoreceptor cell death through apoptosis. No racial or ethnic predisposition exists. Men may be affected slightly more than women because of X-linked conditions.
The term retinitis pigmentosa refers to a broad category of genetically heterogeneous diseases, which includes many different forms of primary photoreceptor abnormalities—some affect rods first and cones later (termed rod-cone dystrophy ) or the reverse (termed cone-rod dystrophy ). The prevalence of primary photoreceptor degeneration is in the range 1 : 3000–1 : 5000. The carrier state for recessive retinitis pigmentosa is approximately 1 : 100, based on the prevalence of recessive retinitis pigmentosa. These numbers are approximate because of the complexity of the many different forms of RP now identified by gene cloning. In most cases, these diseases are thought to be simple Mendelian traits that result from DNA alteration in single genes.
Rod-Cone Dystrophy
Rod-cone dystrophy manifests clinically with typical RP and affects the rod photoreceptors earlier and more severely than it does the cone photoreceptors. Severe cone involvement occurs in the end stage of the disease, when total vision loss ensues. The key features of the rod-cone type of disease are progressive night blindness and visual field constriction, which become more severe as more rods die, leading to cone loss. The appearance of midperipheral ring scotomas during progressive stages of visual field loss is not uncommon. Typically, both eyes are affected similarly.
Visual acuity is initially affected minimally and typically remains near to 20/20 (6/6) for many years despite progressive field loss to severe tunnel vision. Careful history taking frequently reveals some night blindness, even in early-stage rod-cone disease. Symptoms of typical RP include prolonged dark adaptation. However, many patients with RP are able to drive at night on well-lit streets. Patients complain of problems in dimly lit restaurants and theaters and are symptomatic when they come indoors from bright sunlight. By the midstage of the disease, visual field constriction occurs. Patients may appear clumsy because they collide with a door frame or a friend who walks alongside because of unrecognized tunnel vision. End-stage rod-cone disease results in loss of both peripheral vision and central vision. Many patients have only barely functional central vision by late middle age and lose all vision later. However, the changes occur slowly, and the young patient may be reassured that some vision is most likely to remain for many years or decades, even though the long-term prognosis is grim. Glare sensitivity to bright light occurs in end-stage rod-cone dystrophy, when the diseased cones saturate in bright light.
The functional profile of early-stage rod-cone dystrophy is shown in Fig. 6.14.1 . The rod ERG amplitude loss is worse than that for cones (light-adapted: single flash and 30 Hz flicker). Goldmann visual fields are still relatively large with the large V4e target but considerably constricted to the small I4e target—such disparity between the ratio of field area with the V4e versus I4e targets is typical for rod-cone dystrophy. Tests of dark-adapted thresholds show 1–3 log units of rod sensitivity loss, which equates with 10–1000 times more light required to see at night. The disease does not act uniformly across the retina, and rod threshold should be tested at multiple points of vision to give a sensitivity profile across the central and peripheral vision.
As visual fields constrict further, even to the large V4e target, dark-adapted thresholds become worse because only cones remain to mediate vision, even in dim light. At this stage, the patient suffers from severe night blindness. With time, the cone ERG responses deteriorate further until eventually both the rod and cone responses are reduced profoundly, and all ERG responses are termed “nonrecordable.” By this time, visual acuity is typically less than 20/40 (6/12), color discrimination is impaired, and fields are greatly constricted.
Cone-Rod Dystrophy
Patients with cone-rod dystrophy complain of poor acuity, reduced color vision, and glare sensitivity to bright sunlight.
Particularly in the early stages, the fundus may appear normal, with minimal diffuse retinopathy and normal vessels and disc. Visual fields initially remain full with the Goldmann V4e target but may be constricted slightly with the I4e target. It is more likely that at least some peripheral vision is retained in patients who have cone-rod dystrophy as opposed to those who have rod-cone dystrophy. ERG shows that cone-mediated responses (30 Hz flicker and photopic single flash responses) are reduced proportionally more than the dark-adapted rod b-wave (see Fig. 6.14.1 ). Although the rod b-wave amplitudes may be subnormal technically, rod dark-adapted threshold sensitivity remains nearly normal when tested using a Goldmann-Weekers dark adaptometer after 45 minutes in the dark. The combination of ERG and psychophysical rod threshold tests is the best way to diagnose cone-rod dystrophy. Patients who have the least rod involvement carry the best prognosis for intermediate-term vision. At the other end of the prognosis spectrum are rare patients who develop a central scotoma early in life; the field defect enlarges gradually but relentlessly toward the periphery, with practically total visual loss by late middle age. These patients usually receive the diagnosis of “macular degeneration” in childhood; the condition has been termed “inverse retinitis pigmentosa” because pigment spicules are more abundant in the central retina than in the midperiphery. Infrequently, a patient with cone-rod dystrophy has an essentially normal rod but a very reduced cone on ERG and is considered to have “cone dystrophy.” Such patients have a good prognosis for vision into later age. Some patients with cone-rod dystrophy are first symptomatic after age ≥50 years and may progress quickly to considerable vision loss. Such patients are a diagnostic challenge because of the later age at presentation; initially, ERG results may be marginally normal, but the results of repeat ERGs after 6–12 months progress to subnormal.
Rod-Cone Dystrophy
Rod-cone dystrophy manifests clinically with typical RP and affects the rod photoreceptors earlier and more severely than it does the cone photoreceptors. Severe cone involvement occurs in the end stage of the disease, when total vision loss ensues. The key features of the rod-cone type of disease are progressive night blindness and visual field constriction, which become more severe as more rods die, leading to cone loss. The appearance of midperipheral ring scotomas during progressive stages of visual field loss is not uncommon. Typically, both eyes are affected similarly.
Visual acuity is initially affected minimally and typically remains near to 20/20 (6/6) for many years despite progressive field loss to severe tunnel vision. Careful history taking frequently reveals some night blindness, even in early-stage rod-cone disease. Symptoms of typical RP include prolonged dark adaptation. However, many patients with RP are able to drive at night on well-lit streets. Patients complain of problems in dimly lit restaurants and theaters and are symptomatic when they come indoors from bright sunlight. By the midstage of the disease, visual field constriction occurs. Patients may appear clumsy because they collide with a door frame or a friend who walks alongside because of unrecognized tunnel vision. End-stage rod-cone disease results in loss of both peripheral vision and central vision. Many patients have only barely functional central vision by late middle age and lose all vision later. However, the changes occur slowly, and the young patient may be reassured that some vision is most likely to remain for many years or decades, even though the long-term prognosis is grim. Glare sensitivity to bright light occurs in end-stage rod-cone dystrophy, when the diseased cones saturate in bright light.
The functional profile of early-stage rod-cone dystrophy is shown in Fig. 6.14.1 . The rod ERG amplitude loss is worse than that for cones (light-adapted: single flash and 30 Hz flicker). Goldmann visual fields are still relatively large with the large V4e target but considerably constricted to the small I4e target—such disparity between the ratio of field area with the V4e versus I4e targets is typical for rod-cone dystrophy. Tests of dark-adapted thresholds show 1–3 log units of rod sensitivity loss, which equates with 10–1000 times more light required to see at night. The disease does not act uniformly across the retina, and rod threshold should be tested at multiple points of vision to give a sensitivity profile across the central and peripheral vision.
As visual fields constrict further, even to the large V4e target, dark-adapted thresholds become worse because only cones remain to mediate vision, even in dim light. At this stage, the patient suffers from severe night blindness. With time, the cone ERG responses deteriorate further until eventually both the rod and cone responses are reduced profoundly, and all ERG responses are termed “nonrecordable.” By this time, visual acuity is typically less than 20/40 (6/12), color discrimination is impaired, and fields are greatly constricted.
Cone-Rod Dystrophy
Patients with cone-rod dystrophy complain of poor acuity, reduced color vision, and glare sensitivity to bright sunlight.
Particularly in the early stages, the fundus may appear normal, with minimal diffuse retinopathy and normal vessels and disc. Visual fields initially remain full with the Goldmann V4e target but may be constricted slightly with the I4e target. It is more likely that at least some peripheral vision is retained in patients who have cone-rod dystrophy as opposed to those who have rod-cone dystrophy. ERG shows that cone-mediated responses (30 Hz flicker and photopic single flash responses) are reduced proportionally more than the dark-adapted rod b-wave (see Fig. 6.14.1 ). Although the rod b-wave amplitudes may be subnormal technically, rod dark-adapted threshold sensitivity remains nearly normal when tested using a Goldmann-Weekers dark adaptometer after 45 minutes in the dark. The combination of ERG and psychophysical rod threshold tests is the best way to diagnose cone-rod dystrophy. Patients who have the least rod involvement carry the best prognosis for intermediate-term vision. At the other end of the prognosis spectrum are rare patients who develop a central scotoma early in life; the field defect enlarges gradually but relentlessly toward the periphery, with practically total visual loss by late middle age. These patients usually receive the diagnosis of “macular degeneration” in childhood; the condition has been termed “inverse retinitis pigmentosa” because pigment spicules are more abundant in the central retina than in the midperiphery. Infrequently, a patient with cone-rod dystrophy has an essentially normal rod but a very reduced cone on ERG and is considered to have “cone dystrophy.” Such patients have a good prognosis for vision into later age. Some patients with cone-rod dystrophy are first symptomatic after age ≥50 years and may progress quickly to considerable vision loss. Such patients are a diagnostic challenge because of the later age at presentation; initially, ERG results may be marginally normal, but the results of repeat ERGs after 6–12 months progress to subnormal.
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