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Retinitis pigmentosa: Clinical presentation and diagnosis

Retinitis pigmentosa: Clinical presentation and diagnosis
Author:
Seema Garg, MD, PhD
Section Editor:
Matthew F Gardiner, MD
Deputy Editor:
Jane Givens, MD, MSCE
Literature review current through: Jun 2022. | This topic last updated: Feb 01, 2022.

INTRODUCTION — Retinitis pigmentosa (RP) comprises a complex group of inherited dystrophies characterized by progressive degeneration and dysfunction of the retina, primarily affecting photoreceptor and pigment epithelial function [1]. RP may occur alone or as part of a syndrome and may be inherited as a dominant, recessive, or X-linked trait or occur sporadically. The same genetic mutation may cause different symptoms in different individuals, and the same syndrome may be caused by different mutations [2].

Night and peripheral vision are lost progressively, leading to a constricted visual field and markedly diminished vision in some patients. Retinal degeneration can be seen on ophthalmoscopy as typical bone-spicule deposits or attenuated retinal vessels, or detected in early stages by special tests of retinal function.

The term "retinitis" is a misnomer since the pathogenesis is not inflammatory. Other terms for RP include "rod-cone dystrophy," "tapetoretinal degeneration," and "pigmentary retinopathy."

A family history of RP is present in about 70 percent of patients. The worldwide prevalence of RP is estimated at 1 in 4000 to 5000 [3-7]. About 100,000 patients are affected in the United States.

This topic addresses the natural history, diagnosis, and genetics of RP. Treatment and prognosis are discussed separately. (See "Retinitis pigmentosa: Treatment".)

GENETICS

Inheritance — There are multiple patterns of inheritance, and underlying gene abnormalities, for disorders classified as retinitis pigmentosa (RP). The same genetic mutation may cause different phenotypic patterns in different patients (phenotypic pleiotropy), and multiple genetic abnormalities may give rise to the same syndrome (allelic heterogeneity). A list of identified genes causing RP is available at the RetNet website [8].

Determining the specific genetic abnormality underlying RP can serve several functions:

Confirm the diagnosis of RP in equivocal cases

Predict prognosis for patient and risk for other family members

Identify types of RP for clinical trial eligibility, as gene-specific prevention and treatment protocols become available.

Additionally, identifying the cause of the disease will contribute to a better understanding of the biology of the retina and its pathology.

The typical form of RP, in which clinical manifestations are restricted to the eye (non-syndromic RP), comprises approximately 65 percent of all cases in the United States [2]. The distribution of inheritance patterns for these cases is approximately 30 percent autosomal dominant, 20 percent autosomal recessive, 15 percent X-linked, and 5 percent recessive early-onset (Leber congenital amaurosis or LCA). The remaining 30 percent are sporadic.

Autosomal dominant RP confers a 50 percent risk to the offspring of affected individuals. In autosomal recessive RP, each child has a 25 percent risk of being affected if both parents are carriers. X-linked RP patients are typically male. However, female carriers of X-linked RP may have visual symptoms [9]. Affected males cannot transmit the abnormal gene to their sons, but all daughters will be carriers. Where there is no family history of RP and an abnormal gene cannot be determined, the risk of RP affecting offspring is less than 5 percent unless there is consanguinity in the family [3].

In addition to typical forms of RP, syndromic forms exist that involve multiple organs. The most common form of syndromic RP is Usher syndrome. Usher patients have congenital or early-onset hearing impairment followed by development of RP. Bardet-Biedl syndrome is the next most common syndromic form and is associated with polydactyly, obesity, renal abnormalities, and developmental delay. Mutations involving the nephronophthisis (NPHP) genes are well characterized and cause childhood end-stage kidney disease and RP. (See "Genetics and pathogenesis of nephronophthisis".)

Gene mutations — Linkage analyses in families with multiple affected individuals have resulted in the identification of numerous genomic regions that harbor mutations causing RP. The first RP mutation was identified in 1989 in the rhodopsin gene (RHO) on chromosome 3q21.3 [10]. Rhodopsin is a light-absorbing pigment in the membrane of the rod photoreceptor cell. A proline-to-histidine change at amino acid 23 in this gene was found in 1990 [11]. This mutation alone accounts for 10 percent of autosomal dominant RP in the United States White population.

The pace of discovery has been exponential, as more than 3000 genetic mutations in approximately 70 genes have been discovered [12]. Over 71 genes have been implicated in non-syndromic RP, 66 genes in syndromic RP, and 14 genes in LCA [8]. The protein products of these genes are involved in multiple pathways: the phototransduction cascade; vitamin A metabolism; cytoskeletal structures; signaling and cell to cell interactions; RNA intron splicing factors; regulation of intracellular protein traffic; and phagocytosis.

The three most common genes implicated in RP, accounting for approximately 30 percent of all RP in 2007, are [2]:

RHO (>26 percent of autosomal dominant RP).

USH2A, also known as Usherin (10 percent of autosomal recessive RP). USH 2A can be mutated to cause both nonsyndromic RP and syndromic RP as part of the Usher syndrome [13].

RP GTPase regulator (RPGR; ~75 percent of X-linked retinitis pigmentosa).

Another gene, EYS, a homolog of Drosophila eyes shut, was identified in 2008 as the gene responsible for autosomal recessive RP at the RP25 locus [14]. This gene may be involved in a significant proportion of patients with autosomal recessive RP from diverse geographic ancestries worldwide. This is the largest eye gene identified (spanning more than 2 million DNA base pairs), and it may be involved in production of a protein necessary for maintaining mechanical support and rigidity of the outer segment of the eye [15].

It is possible to detect disease-causing mutations in over 50 percent of patients with autosomal dominant RP, 30 percent of patients with recessive RP, 70 percent of patients with recessive LCA, and nearly 90 percent of patients with X-linked RP [16].

Genetic testing — With the first retinal gene therapy approved by the US Food and Drug Administration (FDA) in December 2017 for RPE65-associated LCA (voretigene neparvovec-rzyl) and a multitude of ongoing gene therapy trials, genetic testing has become a critical component in the diagnosis and management of retinitis pigmentosa. In 2006, the National Eye Institute sponsored eyeGENE, a program which provided genetic testing for patients with a variety of inherited eye diseases [17]. In 2016, the American Academy of Ophthalmology released a position statement on the role of genetic testing in inherited retinal disease management [16]. As treatment is available for a subtype of LCA/RP, it is essential that genetic testing be offered for patients with LCA and early-onset RP. In addition, a molecular diagnosis obtained from genetic testing allows patients to determine whether they are eligible for inclusion into clinical trials for RP.

Certification under the Clinical Laboratory Improvements Amendment (CLIA) is essential for clinical genetic testing in the United States. In addition, the genetic analysis provided by the laboratory should follow American College of Medical Genetics and Genomics standards. Skilled interpretation of the pathogenicity of identified variants (mutations) is important to sort out the clinical relevance of the results of genetic testing.

Several commercial ocular genetics laboratories offer large, comprehensive, next-generation sequencing retinal dystrophy panels with rapid turnaround of results. Nonprofit laboratories, such as the John and Marcia Carver Nonprofit Genetic Testing Laboratory at the University of Iowa, and Massachusetts Eye and Ear, also offer comprehensive testing.

The Foundation Fighting Blindness (FFB) is offering genetic testing and ocular genetic counseling as part of a research study available through the free online My Retina Tracker registry. Patients in the My Retina Tracker registry provide informed consent to share their deidentified data, which is accessible to researchers to help accelerate progress on RP and other inherited retinal diseases research. It is essential that a patient that has undergone genetic testing be referred for ocular genetic counseling, which can be provided by a geneticist or a certified genetic counselor.

CLINICAL MANIFESTATIONS

Symptoms — The visual symptoms of retinitis pigmentosa (RP) arise primarily from the loss of retinal photoreceptors, both rods and cones.

Night blindness (nyctalopia) is one of the earliest symptoms [3-7]. Patients may notice that they become disoriented in dim light, or that adaptation to dim light is slow, as in movie theaters. However, night blindness may go unrecognized until the disease is advanced, due to the insidious nature of RP and pervasive artificial light sources; some patients never recognize night blindness as a symptom [18]. Once a patient is suspected of having RP, he should be referred to an ophthalmologist who specializes in hereditary eye disease or to a genetics professional.

Progressive constriction of the visual field is another common feature. Patients may be considered "clumsy" before the diagnosis is made [6]. The most common early pattern of visual field loss is loss in the midperiphery of the visual field (between 30 to 50 degrees eccentric to fixation, as this is where the density of rods is greatest), followed by extension of the visual loss into the far periphery of the visual field [3]. Patients may experience no impact from a decrement in visual field until the central visual field is reduced to about 50 degrees in diameter (normal is 180 degrees with both eyes open) [7].

Visual acuity is variably affected. Patients may retain good visual acuity for years, despite extensive loss of peripheral vision. Eventually, most patients experience loss of visual acuity due to disease progression. In a study of 982 adult patients with RP, 52 percent had visual acuity of 20/40 or better in at least one eye and 25 percent had visual acuity of 20/200 or worse in both eyes. Only 5 percent had no light perception in both eyes. Patients with X-linked RP tend to have poorest visual acuity; those with autosomal dominant RP typically retain better visual acuity [19-21].

Cataracts and abnormalities in the central retina, such as macular edema or macular cysts, often contribute to deterioration in visual acuity [20,22,23].

The functional impact of RP, in terms of difficulty with activities of daily living, correlates most strongly with loss of visual acuity [24]. Loss of visual field has less impact, and decrements detected by electroretinographic data correlate least well with activity impairment. (See 'Full-field electroretinography' below.)

Other symptoms commonly reported by patients with RP include photopsias (sensations of sparkling lights) [3,18] and headache [18].

Ocular findings

Retina — The classic ophthalmoscopic findings in retinitis pigmentosa (RP) are described as a triad: attenuation of the retinal blood vessels, waxy pallor of the optic disc, and intraretinal pigmentation in a bone-spicule pattern (picture 1 and picture 2). Retinal vascular attenuation was found in 94 percent of 384 eyes and optic disc pallor in 52 percent in one series [25].

The optic disc has a waxy, pale appearance thought to be due to both optic disc atrophy and gliosis overlying the disc [3,4,6]. Drusen of the optic disc (hyaline-like, acellular, laminated globular excrescences) are due to aberrant axonal transport and are more common in patients with RP than in the general population [26,27].

The retina may appear normal in early states of RP, even though electrophysiologic testing reveals dysfunction of the photoreceptors (see 'Full-field electroretinography' below). This "early" stage may last for decades [3]. As the disease advances, the retinal vessels become more attenuated until they appear thread-like.

Abnormal retinal pigmentation develops when pigment migrates from disintegrating retinal pigment epithelial cells into the superficial ("inner") retina in response to photoreceptor cell death (figure 1) [3,6]. The pigmentary abnormality is visible initially as a dusting of fine pigment extending from the mid to far peripheral retina. Later, "bone-spicules" (accumulations of pigment along the interstitial spaces surrounding retinal blood vessels) form throughout the mid and far retinal periphery [28]. Atrophy of the choriocapillaris may be present in advanced RP, exposing the large choroidal vessels underneath [3,6].

The macula, or central retina, becomes affected in moderate or advanced disease, when photoreceptor degeneration advances and leads to retinal thinning and loss of visual acuity [6,22,25,29]. A central atrophic or bulls-eye lesion will be visible in some patients [3,25].

Patients may also develop cellophane maculopathy (also called "surface wrinkling retinopathy") and foveal cysts, with or without associated edema [22,23,25]. These problems compound the loss of visual acuity due to photoreceptor death.

Lens — Cataracts, especially posterior subcapsular cataracts, affect approximately 50 percent of patients with RP [3,4,6,25,30]. Cataract prevalence is higher in the autosomal dominant subtype [30].

Vitreous — The vitreous humor may contain a dust-like pigmented substance, comprised of pigment granules [18]. Complete posterior vitreous detachment is more common than in normal subjects [3,4,6,7,25,31].

Functional abnormalities — Abnormalities in refractive error, visual acuity and visual fields, contrast sensitivity, and color vision may occur in patients with retinitis pigmentosa (RP).

Refractive error — RP is associated with astigmatism and myopia [3,6,32]. In one study, myopia was present in 75 percent of 268 eyes of patients with RP and in only 12 percent of a normal population [32]. The prevalence of myopia is higher in patients with X-linked RP. (See "Visual impairment in adults: Refractive disorders and presbyopia".)

Visual acuity and visual fields — Visual loss in RP usually begins with mid-peripheral scotomata that progress over time to involve the entire periphery. Loss of photoreceptors in the macula in advanced disease leads to progressive constriction of the central visual field and worsening visual acuity. Patients are left with a central island of vision that gradually constricts over time.

Contrast sensitivity — Standard visual acuity is measured at high contrast. The ability to distinguish low-contrast objects is another measure of visual function that is diminished in patients with RP [33]. Loss of contrast sensitivity may contribute to patients' perception of decreased vision when standard visual acuity testing is normal.

Color vision — Color vision remains normal until the macula becomes involved and visual acuity is reduced. When color vision is affected, testing usually reveals a blue cone deficiency [3,5,7].

DIAGNOSIS — The diagnosis of retinosis pigmentosa (RP) is made by a combination of history (nyctalopia and peripheral vision loss), fundus exam (waxy pallor of the optic nerve, arterial attenuation, and pigmentary changes in the peripheral retina), and ancillary testing results (attenuation of the rods, and later cones, on the full-field electroretinogram [ERG] and constriction of the visual field on Goldmann perimetry).

Dark adaptometry — Dark adaptometry is a psychophysical measurement of the visual threshold to a light stimulus. After being exposed to a bright light stimulus, subjects are placed in the dark for 30 minutes, and the minimum intensity light that can be detected by the subject is measured at interval time points.

In normal subjects, there is an initial increase in sensitivity to low light, a phenomenon mediated by cone photoreceptors, that reaches a plateau within five minutes. Subsequently, the rod system progressively activates and sensitivity to light increases again until a second plateau is reached. Abnormalities of dark adaptometry in RP include loss of rod sensitivity, or loss of both rod and cone sensitivity [3,5,6,34].

Full-field electroretinography — The ERG, a mainstay in the diagnosis of RP since the early 1950s, measures the electrical response of the retina to light stimuli [35]. Full-field electroretinography, the traditional standard, activates the entire retina simultaneously. An electrode is placed on the cornea or on the skin of the eyelid and the color and the intensity of a light stimulus are manipulated to activate the cones or rods, separately or together.

RP causes a reduction in the amplitude and a delay in the timing of the electrical signal produced by retinal stimulation [36]. The amplitude of the ERG correlates well with the size of the remaining visual field [37]. Patients with moderate or advanced RP have a non-recordable (extinguished) ERG.

The ERG may be abnormal even in early stages of the disease, when the retina appears normal. Full-field electroretinography is invaluable in detecting RP in patients at risk for the disease (eg, family members of diagnosed patients) who have normal-appearing retinas.

Multifocal electroretinography — Focal electroretinography records the local electrical signal generated by the stimulation of a discrete portion of the retina. Multifocal electroretinography, another technique, permits the recording of many focal electroretinograms simultaneously and represents central cone function [38].

The multifocal ERG is useful in monitoring patients with RP in later stages of the disease. This technique can record electroretinographic responses generated within the functioning maculae in patients who have nearly extinguished full-field ERGs [39-41].

DIFFERENTIAL DIAGNOSIS — Several acquired conditions cause extensive chorioretinopathy and may be confused with retinitis pigmentosa (RP). These include traumatic retinopathy, retinal inflammatory diseases, paraneoplastic retinopathy, drug toxicity, and rare conditions such as diffuse unilateral subacute neuroretinitis.

Traumatic retinopathy — Traumatic retinopathy is the most common masquerader of RP [42]. Several months after blunt or penetrating injury to the eye, the retina may assume an appearance similar to that of RP [43]. The retinal pigment epithelium becomes atrophic and dark retinal pigment migrates into the superficial retina, especially along retinal vessels. This bone-spicule pattern is sometimes indistinguishable from that seen in RP. These changes do result in visual loss but, in contrast to RP, the loss is not progressive over time and the electroretinogram (ERG) may even be normal.

Retinal inflammatory diseases — Pigmentary retinopathies may occur in rubella, syphilis, toxoplasmosis, and herpesvirus infection of the retina. Rubella retinopathy is the most common ocular manifestation of congenital rubella [44]. If a child has congenital hearing loss secondary to rubella infection and concurrent rubella retinopathy, the child may be mistakenly diagnosed with Usher syndrome, a genetic disorder affecting the cochlea and retina (see 'Genetics' above). Electroretinography may facilitate the correct diagnosis, as the ERG is only mildly abnormal in rubella but severely abnormal in Usher syndrome.

Congenital or acquired syphilis may mimic advanced RP [45]. However, unlike RP, syphilis produces patchy pigmentary retinal changes and chorioretinal scars.

Toxoplasmosis or herpes infections of the retina may also produce a pigmentary retinopathy. Random patches of severe retinopathy occur with these infections, similar to syphilis retinopathy. The ERG is usually only mildly abnormal in inflammatory pigmentary retinopathies but markedly abnormal in RP.

Autoimmune paraneoplastic retinopathy — Although rare, panretinal degeneration can accompany certain cancers, particularly small-cell lung and cervical carcinoma. The ERG is usually severely abnormal. Cancer-associated retinopathy (CAR) is thought to be due to anti-retinal autoantibodies [46]. Melanoma-associated retinopathy (MAR) presents with night blindness but has a unique ERG pattern distinguishable from that of RP. (See "Paraneoplastic visual syndromes".)

Drug toxicity — Phenothiazines and chloroquine bind to melanin and concentrate in the retinal pigment epithelium. Thioridazine in doses higher than 800 mg/day can cause severe retinal toxicity. This toxicity may manifest as a pigmentary retinopathy that mimics early RP [47].

Chloroquine retinopathy may develop when total doses exceed 300 g [48]. Bone-spicules may develop in the peripheral retina but, unlike retinitis pigmentosa, dark adaptometry is usually normal. Hydroxychloroquine retinopathy, which is less common than chloroquine retinopathy, may develop after medication use for longer than five years and at a dose of greater than 6.5 mg/kg/day. The retinopathy is typically milder than chloroquine retinopathy.

Diffuse unilateral subacute neuroretinitis — Diffuse unilateral subacute neuroretinitis (DUSN) is a rare panretinal degeneration secondary to infection with the worms Baylisascaris procyonis and Toxocara canis. In the late stages, the fundus appearance resembles that of advanced RP, but unlike RP the abnormalities are typically restricted to one eye. (See "Toxocariasis: Visceral and ocular larva migrans" and "Anthelminthic therapies".)

NATURAL HISTORY — The presentation of retinitis pigmentosa (RP) is variable, affecting some patients with visual loss in childhood while others are asymptomatic well into adulthood. The typical course of RP is gradual loss of visual field, visual acuity and electroretinographic activity over time. Central retinal function declines more slowly than more peripheral retinal function [19,49]. Most patients meet criteria for legal blindness by age 40 due to narrowing of visual fields [7].

In two longitudinal studies of patients with RP, followed for three and nine years, the visual field diminished at a rate of 4.6 to 12 percent per year [19,49]. Three distinct patterns of visual field loss were identified in another longitudinal study: progressive, generalized constriction; expansion from a midperipheral ring scotoma; or loss beginning superiorly and expanding nasally or temporally [50]. The patterns of visual field loss within a particular family did not vary.

Visual acuity declines more slowly than loss of visual fields [19,49]. The presence of macular lesions on initial presentation is associated with greater loss of visual acuity [51]. Patients with a normal macula lost on average one line of visual acuity over five years while patients with a macular lesion lost an average of three to four lines over five years.

Measurement of cone electroretinograms may help estimate the long-term visual prognosis for a given patient, and serial measurements can help refine this prediction [52] (see 'Full-field electroretinography' above). In one report, an estimated 25 percent of patients with typical RP at initial presentation were over 40 years old and had a cone amplitude ≥3.5 microV; on average, such patients would be expected to retain some vision throughout their lifespan without treatment [52].

The age of symptom onset, ranging from childhood to adulthood, does not correlate well with the onset of photoreceptor degeneration [53].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topic (see "Patient education: Retinitis pigmentosa (The Basics)")

SUMMARY

Retinitis pigmentosa (RP) comprises a group of inherited conditions that cause progressive retinal degeneration and affect the photoreceptors and retinal pigment epithelium. A family history is identified in about 70 percent of patients; there are multiple inheritance patterns. (See 'Introduction' above.)

Approximately 70 genes have been implicated in RP. RP occurs in a simple form in the majority of patients but may also occur as part of a syndrome involving other organs. There is variability of the phenotype depending on the specific gene mutation. Compared with other inherited types of RP, X-linked RP is generally more severe. (See 'Genetics' above.)

Night blindness is one of the earliest symptoms but can be so gradual that it may go unnoticed by patients. Loss of visual field is progressive, starting in the midperiphery and progressing more peripherally, resulting in a constricted visual field. (See 'Symptoms' above.)

Changes in the ocular fundus seen on ophthalmoscopy include optic disc pallor, attenuated vessels, and pigment deposits in a bone-spicule pattern. The macula may be affected in advanced disease. Cataracts may further compromise central vision. (See 'Ocular findings' above.)

Abnormalities in refractive error, visual acuity and visual fields, contrast sensitivity, and color vision may occur in patients with RP. (See 'Functional abnormalities' above.)

The diagnosis of RP is made by a combination of history (nyctalopia and peripheral vision loss), fundus exam (waxy pallor of the optic nerve, arterial attenuation, and pigmentary changes in the peripheral retina), and ancillary testing results (attenuation of the rods, and later cones, on the full-field electroretinogram [ERG] and constriction of the visual field on Goldmann perimetry). (See 'Diagnosis' above.)

Acquired conditions resulting in ophthalmoscopic findings resembling RP include ocular trauma, ocular inflammation associated with infection (rubella, syphilis, toxoplasmosis, herpesvirus), paraneoplastic retinopathy, drug toxicity (phenothiazines and chloroquine), and diffuse unilateral subacute neuroretinitis. (See 'Differential diagnosis' above.)

Age of symptom onset ranges from childhood to adulthood, but photoreceptor degeneration can be detected many years before affected individuals are aware of vision problems. (See 'Natural history' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Syndee Givre, MD, PhD, who contributed to an earlier version of this topic review.

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