Retinitis Pigmentosa


Practice Essentials

Retinitis pigmentosa (RP) is a group of inherited disorders characterized by progressive peripheral vision loss and night vision difficulties (nyctalopia) that can lead to central vision loss. See the image below.

Gross pathology of an eye in a man with retinitis Gross pathology of an eye in a man with retinitis pigmentosa.

Signs and symptoms

Presenting signs and symptoms of RP vary, but the classic ones include the following:

  • Nyctalopia (night blindness): Hallmark; most commonly the earliest symptom in RP

  • Visual loss, usually peripheral; in advanced cases, central visual loss

  • Photopsia (seeing flashes of light)

A careful family history with pedigree and possible examination of family members can be useful. In addition, a drug history is essential to rule out phenothiazine/thioridazine toxicity.

See Clinical Presentation for more detail.

Diagnosis

Because RP is a collection of many inherited diseases, significant variability exists in the physical findings. Ocular examination involves assessment of visual acuity and pupillary reaction, as well as anterior segment, retinal, and funduscopic evaluation.

Systemic examination for RP can be helpful to rule out syndromic RP, which are conditions that have pigmentary retinopathy and mimic RP, such as the following:

  • Syndromes associated with RP and hearing loss: Usher syndrome, [2Waardenburg syndrome, Alport syndrome, Refsum disease

  • Kearns-Sayre syndrome: External ophthalmoplegia, lid ptosis, heart block, and pigmentary retinopathy

  • Abetalipoproteinemia: Fat malabsorption, fat-soluble vitamin deficiencies, spinocerebellar degeneration, and pigmentary retinal degeneration

  • Mucopolysaccharidoses (eg, Hurler syndrome, Scheie syndrome, Sanfilippo syndrome): Can be affected with pigmentary retinopathy

  • Bardet-Biedl syndrome: Polydactyly, truncal obesity, kidney dysfunction, short stature, and pigmentary retinopathy

  • Neuronal ceroid lipofuscinosis: Dementia, seizures, and pigmentary retinopathy; infantile form is known as Jansky-Bielschowsky disease, juvenile form is Vogt-Spielmeyer-Batten disease, and adult form is Kufs syndrome

Testing

The following laboratory tests are useful in excluding masquerading diseases or in detecting conditions that are associated with RP:

  • Infectious studies for syphilis (VDRL, FTA-ABS), toxoplasmosis (when suspected; serum IgG)

  • Inherited/syndromic disease studies for Refsum disease (serum phytanic acid in the presence of other neurologic abnormalities), gyrate atrophy (ornithine levels), Kearns-Sayre syndrome (ECG to help rule out heart block), and abetalipoproteinemia (lipid profile with possible protein electrophoresis)

  • Neoplasm related studies for antiretinal antibodies (particularly antirecoverin antibodies), especially in cancer-associated retinopathy (CAR) or in severe RP

Other studies that may be helpful include the following:

  • Electroretinogram (ERG): Most critical diagnostic test for RP

  • Electro-oculogram (EOG): Not helpful in diagnosing RP, but central macular changes, normal ERG findings, and abnormal EOG findings suggest Best vitelliform macular dystrophy (Best disease)

  • Formal visual field testing: Most useful measure for ongoing follow-up care of patients with RP; Goldmann (kinetic) perimetry is recommended

  • Color testing: Commonly, mild blue-yellow axis color defects, although most patients with RP do not clinically complain of major difficulty with color perception

  • Dark adaptation study: Disproportionately reduced contrast sensitivity relative to visual acuity in RP; bright-light sensitivity

  • Genetic subtyping: Definitive test for diagnosis to identify the particular defect

Imaging tests

Fluorescein angiography is rarely useful in diagnosing RP; however, the presence of cystoid macular edema can be confirmed by this test. Likewise, although optical coherence tomography (OCT) is not useful in helping to establish a diagnosis of RP, this imaging study can be helpful to document the extent and/or presence of cystoid macular edema.

Procedures

Biopsy for histologic examination in patients with RP is not clinically helpful, owing to the general good health of these patients and the chronic nature of the disease. Generally, specimens are obtained only on chronically atrophic retinas.

See Workup for more detail.

Management

There is currently no cure for RP; therefore, therapies are limited. Nonetheless, it is essential to help patients maximize the vision they do have with refraction and low-vision evaluation.

Pharmacotherapy

Medications used in the management of RP include the following:

  • Fat-soluble vitamins (eg, vitamin A, vitamin E, ascorbic acid)

  • Calcium-channel blockers (eg, diltiazem)

  • Carbonic anhydrase inhibitors (eg, acetazolamide, methazolamide)

The following are medications with potential adverse effects in RP:

  • Isotretinoin (Accutane)

  • Sildenafil (Viagra)

  • High-dose vitamin E

Surgery

Surgical management of RP generally involves cataract extraction. However, following FDA approval in February 2013 for the first retinal implant in adults with severe cases of RP, implantation of this device may become a viable treatment option. [1]

Investigational procedures with potential in managing RP include the following:

  • Surgical placement of growth factors

  • Transplantation of retinal or retinal pigment epithelial (RPE) tissue

  • Placement of retinal prosthesis or phototransducing chip

  • Subretinal gene therapy

See Treatment and Medication for more detail.

Background

Retinitis pigmentosa (RP) is a group of inherited disorders characterized by progressive peripheral vision loss and night vision difficulties (nyctalopia) that can lead to central vision loss.

Gross pathology of an eye in a man with retinitis Gross pathology of an eye in a man with retinitis pigmentosa.

With advances in molecular research, it is now known that RP constitutes many retinal dystrophies and retinal pigment epithelium (RPE) dystrophies caused by molecular defects in more than 40 different genes for isolated RP and more than 50 different genes for syndromic RP. Not only is the genotype heterogeneous, but patients with the same mutation can phenotypically have different disease manifestations. In this article, the clinical manifestations for diagnosis, the new molecular understandings of the pathogenesis, and the latest therapeutic options for patients are reviewed.

RP can be passed on by all types of inheritance: approximately 20% of RP is autosomal dominant (ADRP), 20% is autosomal recessive (ARRP), and 10% is X linked (XLRP), while the remaining 50% is found in patients without any known affected relatives. RP is most commonly found in isolation, but it can be associated with systemic disease. The most common systemic association is hearing loss (up to 30% of patients). Many of these patients are diagnosed with Usher syndrome. Other systemic conditions also demonstrate retinal changes identical to RP.

Usher syndrome with typical retinitis pigmentosa aUsher syndrome with typical retinitis pigmentosa appearance.

RP is a misnomer, as the word retinitis implies an inflammatory response, which has not been found to be a predominant feature of this condition. As molecular understanding increases, RP will be further characterized by the specific protein/genetic defect. This characterization will have increasing importance in the determination of a prognosis and will likely allow clinicians to use gene-targeted therapies.

Pathophysiology

RP is typically thought of as a rod-cone dystrophy in which the genetic defects cause cell death (apoptosis), predominantly in the rod photoreceptors; less commonly, the genetic defects affect the RPE and cone photoreceptors. [3RP has significant phenotypic variation, as there are many different genes that lead to a diagnosis of RP, and patients with the same genetic mutation can present with very different retinal findings.

Cone dystrophy. Cone dystrophy.
Cone dystrophy demonstrating typical central maculCone dystrophy demonstrating typical central macular atrophy found in this condition.

Histopathologic changes in RP have been well documented, and, more recently, specific histologic changes associated with certain gene mutations are being reported. The final common pathway remains photoreceptor cell death by apoptosis. The first histologic change found in the photoreceptors is shortening of the rod outer segments. The outer segments progressively shorten, followed by loss of the rod photoreceptor. This occurs most significantly in the mid periphery of the retina. These regions of the retina reflect the cell apoptosis by having decreased nuclei in the outer nuclear layer. In many cases, the degeneration tends to be worse in the inferior retina, thereby suggesting a role for light exposure.

The final common pathway in RP is typically death of the rod photoreceptors that leads to vision loss. As rods are most densely found in the midperipheral retina, cell loss in this area tends to lead to peripheral vision loss and night vision loss. How a gene mutation leads to slow progressive rod photoreceptor death can occur by many paths, as illustrated by the fact that so many different mutations can lead to a similar clinical picture.

Cone photoreceptor death occurs in a similar manner to rod apoptosis with shortening of the outer segments followed by cell loss. This can occur early or late in the various forms of RP.

Epidemiology

Frequency

United States

The prevalence of typical RP is reported to be approximately 1 in 4000 in the United States. The carrier state is believed to be approximately 1 in 100. The highest reported frequency of occurrence for RP is among the Navajo Indians at 1 in 1878.

International

Worldwide prevalence of RP is approximately 1 in 5000. The frequency of occurrence for RP has been reported to be as low as 1 in 7000 in Switzerland.

Mortality/Morbidity

A multicenter population study by Grover et al of patients with RP who were at least 45 years or older found the following findings: 52% had 20/40 or better vision in at least one eye, 25% had 20/200 or worse vision, and 0.5% had no light perception. [4]

Sex

Usually, no sexual predilection exists. X-linked RP is expressed only in males; therefore, because of these X-linked varieties, men may be affected slightly more than women.

Age

The age of onset can vary. RP usually is diagnosed in young adulthood, although it can present anywhere from infancy to the mid 30s to 50s.



History

Presenting symptoms of RP vary, but the classic symptoms are discussed below.

Nyctalopia

The earliest symptom in RP is most commonly night blindness and is considered a hallmark of the disease.

Patients might report difficulties with tasks at night or in dark places, such as trouble walking in dim lit rooms (eg, movie theaters). Patients may report difficulties driving in low light, at dusk, or in foggy conditions.

Patients may also report a prolonged period of time needed to adapt from light to dark.

Visual loss

Peripheral vision loss is often asymptomatic; however, some patients notice this vision loss and report it as tunnel vision.

Patients may report bumping into furniture or doorframes or difficulties with sports requiring peripheral vision (eg, tennis, basketball).

The loss of vision is painless and slow to progress.

Photopsia

Many patients with RP report seeing flashes of light (photopsia) and describe them as small, shimmering, blinking lights similar to the symptoms of an ophthalmic migraine. However, in contrast to the patient with an ophthalmic migraine, the photopsia may be continuous rather than episodic.

Other history considerations

A careful family history with pedigree and possible examination of family members can be useful.

Drug history is essential to rule out phenothiazine/thioridazine toxicity.

Physical

Ocular examination

Because RP is a collection of many inherited diseases, significant variability exists in the physical findings. Interestingly, even patients with the same genetic defect can have different clinical manifestations of the disease. The most common findings are described below.

Vision

Snelling visual acuity can vary from 20/20 to light perception, but it is usually preserved until late in the disease.

Pupils

Pupil reaction can be normal with or without afferent pupillary defect.

Anterior segment

Patients can develop posterior subcapsular cataracts; up to 50% of adult patients with RP develop this type of cataract.

Fundus

The retina can appear unaffected early in the disease. Typical key findings include the following:

  • Bone spicules - Midperipheral retinal hyperpigmentation in a characteristic pattern

  • Optic nerve waxy pallor

  • Atrophy of the RPE in the mid periphery of the retina

  • Retinal arteriolar attenuation

The presence of vitreous cells is common. Patients can have a loss of the foveolar reflex or an abnormal vitreoretinal interface. A subset of patients with RP develops cystoid macular edema with an associated more rapid and potentially reversible loss of vision.

Retinitis punctata albescens, a variant of RP, presents with yellow deposits deep in the retina rather the normal increased pigmentation of the peripheral retina.

Cone-rod retinal degenerations present with central macular pigmentary changes (bull's eye maculopathy). [5Choroideremia and gyrate atrophy typically present with large scalloped areas of peripheral retinal atrophy.

Bull's eye maculopathy seen in cone dystrophy. Bull's eye maculopathy seen in cone dystrophy.

Systemic evaluation

A physical examination can be helpful to rule out syndromic RP, which are conditions that have pigmentary retinopathy and mimic RP. There are many syndromes; the more common and severe types are described below.

Usher syndrome is a form of RP with hearing loss. [2As many as 10% of patients with RP can have hearing loss, and most of these patients have Usher syndrome. Hearing loss in this syndrome can be congenital with complete hearing loss or can occur in middle age with less profound changes in hearing. Most cases of Usher syndrome are autosomal recessive, and mutations have been found in more than 12 genetic loci and 8 identified genes.

RP and hearing loss are also associated with Waardenburg syndrome, Alport syndrome, and Refsum disease, all of which have their own systemic manifestations.

Kearns-Sayre syndrome consists of external ophthalmoplegia, lid ptosis, heart block, and pigmentary retinopathy. This syndrome is caused by a mitochondrial genetic defect, and vision loss tends to occur later in life with moderate visual field loss and night vision difficulties. The cardiac conduction block can be life-threatening; therefore, an electrocardiogram (ECG) is essential to help rule out this syndrome in patients.

Abetalipoproteinemia is a condition caused by the lack of apolipoprotein B, leading to fat malabsorption, fat-soluble vitamin deficiencies, spinocerebellar degeneration, and pigmentary retinal degeneration. High-dose therapy with vitamins A and E can prevent or limit the extent of the retinal degeneration.

The mucopolysaccharidoses (eg, Hurler syndrome, Scheie syndrome, Sanfilippo syndrome) can be affected with pigmentary retinopathy like RP.

Bardet-Biedl syndrome consists of polydactyly, truncal obesity, kidney dysfunction, short stature, and pigmentary retinopathy. In this autosomal recessive condition, intelligence is usually subnormal, and vision loss occurs in the second decade and progresses to severe vision loss by middle age. Renal dysfunction can be severe and life-threatening, requiring full evaluation with initial diagnosis.

Polydactyly seen in Bardet-Biedl syndrome (associaPolydactyly seen in Bardet-Biedl syndrome (associated with retinitis pigmentosa).

Neuronal ceroid lipofuscinosis is characterized by dementia, seizures, and pigmentary retinopathy. Progressive vision loss occurs in early-onset cases. These disorders have been categorized clinically in relation to the age of onset and the temporal relation of vision loss to neurologic symptoms.

Onset of the infantile form is at age 8-18 months. The infantile disease is characterized by optic atrophy, macular pigmentary changes with mottling of the periphery, and low or absent electrophysiologic findings (electroretinogram [ERG] and visual-evoked response [VER]). In the infantile forms, the retinal changes can lead to confusion with Leber congenital amaurosis.

Onset of the late infantile form (Jansky-Bielschowsky disease) is age 2-4 years, and onset of the juvenile form (Vogt-Spielmeyer-Batten disease) is age 4-8 years. These forms more prominently show macular granularity or bull's eye maculopathy, and the appearance can be mistaken for a primary retinal dystrophy, such as Stargardt disease.

The adult form is known as Kufs syndrome. This form often does not have ophthalmologic manifestations, but electrophysiologic changes that are indicative of inner retinal and RPE damage have been observed.

Causes

RP is a collection of many different genetic diseases that lead to progressive photoreceptor loss and associated vision loss; therefore, the etiology is remarkably variable. As discussed in Pathophysiology, the final common pathway of all these diseases is photoreceptor cell death (predominantly rod photoreceptors). Research has shown that photoreceptor death can be induced by different pathways.

There have been so many important contributions by so many groups around the world that even cataloging them is a formidable task. Fortunately, the authors can refer the reader to the online version of McKusick's classic Mendelian Inheritance of Man (OMIM). Dr. Stephen Daiger also maintains a superb up-to-date Web site called RetNet that is dedicated to the molecular genetics of inherited retinal diseases. As shown on these Web sites, over 196 different genes have been found that lead to retinal disease and vision loss.

This article will not discuss all the genetic defects; however, some of the main defects, including several examples of how characteristic protein defects lead to vision loss and photoreceptor death, are discussed below.

In the United States, about 30% of autosomal dominant RP cases are caused by a mutation of the gene for rhodopsin, and approximately 15% of these cases are from a single point mutation. This single amino acid alteration in the protein rhodopsin then leads to photoreceptor cell death.

The autosomal dominant form of RP (ADRP) is usually the mildest form of RP with later age of onset. ADRP can be caused by mutations in at least 12 different genes, whereas the autosomal recessive form of RP can be triggered by changes in more than 22 different genes. X-linked RP tends to present early and is caused by mutations in only 2 known genes, with 75% of cases caused by a mutation of the retinitis pigmentosa GTPase regulator (RPGR) gene. [6]

Hebrard et al studied autosomal recessive RP by combining gene mapping and phenotype assessment in small, nonconsanguineous families. Comparing whole-genome scans using single nucleotide polymorphisms (SNP) microchips on 2 unrelated sibships with arRP, the study found one candidate gene for each family, thereby determining that only 2 affected individuals in each sibship were sufficient to lead to mutation identification; this can serve to avoid the long process of systematic sequencing of 506 exons. [7]

Photoreceptors are sensitive to light and have been placed in a high oxygen environment. As such, they are sensitive to genetic changes in multiple pathways, which can lead to their demise.

For example, some mutations in genes that control phototransduction and vitamin A delivery are expressed in the RPE (eg, RPE65, RBP, RDH5), but these RPE mutations cause the photoreceptors to die as bystanders, while the RPE initially stays healthy. Alternatively, mutations of the rhodopsin gene are expressed in the photoreceptor itself, which then leads directly to its own death.

Another interesting example is the mutation of the ABCA4 gene, which can cause both RP and Stargardt disease. This mutation affects a membrane protein called a flippase, which is found in the photoreceptor outer segments, and, as it moves, phototransduction molecules (eg, all-trans retinaldehyde) throughout the membrane. Defects in this protein cause a buildup of a toxic molecule that the RPE cells ingest when they phagocytosize the photoreceptor's outer segment. This leads to the death of the RPE. Since the photoreceptor requires the RPE for survival, it then in turn dies as well.

Another major class of mutations in RP affects the RDS/peripherin gene, which is found on chromosome arm 6p. Mutations in this gene also are found in pseudo-RP diseases, such as Gass adult foveal macular dystrophy, pattern dystrophy, and Stargardt-like disease. Therefore, classifying pigmentary retinopathies and dystrophies of the RPE by clinical appearance is problematic.

Mutations in beta-phosphodiesterase, an important protein in the phototransduction cascade, also have been linked to some cases of autosomal recessive RP. Many animal models of RP in dogs and mice demonstrate these and other defects. Underscoring the dichotomy between clinical presentation and genetic defect, a beta-phosphodiesterase mutation also has been linked to a congenital stationary night blindness.

Each syndromic form of RP has genetic defects that lead to photoreceptor death in addition to systemic complications. Over 45 genes have been found to cause these syndromic conditions, including 9 that cause Usher syndrome.

Differential Diagnoses


Laboratory Studies

The tests described below are useful in excluding masquerading diseases or in detecting conditions that are associated with retinitis pigmentosa (RP).

Infectious laboratory tests include the following:

  • Syphilis: Venereal Disease Research Laboratory (VDRL) test; fluorescent treponemal antibody absorption (FTA-ABS) test

  • Toxoplasmosis (when suspected): Serum immunoglobulin G (IgG)

Inherited/syndromic disease laboratory tests include the following:

  • Refsum disease: Serum phytanic acid in the presence of other neurologic abnormalities

  • Gyrate atrophy: Ornithine levels

  • Kearns-Sayre syndrome: ECG to help rule out heart block

  • Abetalipoproteinemia: Lipid profile with possible protein electrophoresis

Neoplasm related laboratory tests: Antiretinal antibodies, particularly antirecoverin antibodies, may be observed, especially in CAR or in severe cases of RP. Commercial tests are available.

Imaging Studies

Although fluorescein angiography is rarely useful to the clinician in diagnosing RP, the presence of cystoid macular edema can be confirmed by this test.

Optical coherence tomography (OCT) can be helpful to document the extent and/or presence of cystoid macular edema. OCT is not useful in helping to establish a diagnosis of RP.

Other Tests

Electroretinogram

ERG is the most critical diagnostic test for RP because it provides an objective measure of rod and cone function across the retina and is sensitive to even mild photoreceptor impairment.

The full-field ERG in RP typically shows a marked reduction of both rod and cone signals, although rod loss generally predominates.

A and b waves are reduced since the primary site of disease is at the photoreceptors or RPE.

The ERG is usually abnormal by early childhood, except for some of the very mild and regional forms of RP.

By contrast, the diagnosis for cone dystrophies is aided in part by clinical findings but more definitively by the ERG. Severe and selective loss of cone function occurs with varying degrees of rod abnormality.

In fundus albipunctatus, ERG recordings have absent rod function; after 3-4 hours of dark adaptation, ERG findings may be normal.

Congenital stationary night blindness displays a negative waveform on ERG.

Electro-oculogram

Electro-oculogram (EOG) fndings are always abnormal when ERG findings are abnormal; therefore, EOG is not helpful to the clinician in diagnosing RP.

Central macular changes, normal ERG findings, and abnormal EOG findings suggest Best vitelliform macular dystrophy.

Visually evoked cortical potentials

Visually evoked cortical potentials (VECPs) rarely provide additional information to the clinician when diagnosing RP.

Formal visual field

Progressive loss of peripheral vision is a major symptom along with visual acuity changes; therefore, this test is the most useful measure for ongoing follow-up care of patients with RP.

Goldmann (kinetic) perimetry is recommended, as it can more easily detect progressive visual field changes.

Midperipheral scotomas develop early in RP. These visual field defects can join together to form a ring scotoma. Patients can go on to develop constricted visual fields or tunnel vision. Some patients progress to being legally blind with central vision intact, but peripheral vision is limited to less than 20°.

Color testing

Mild blue-yellow axis color defects are common, although most patients with RP do not clinically complain of major difficulty with color perception.

Dark adaptation

Contrast sensitivity often is reduced out of proportion to visual acuity in patients with RP. Patients are usually sensitive to bright light.

Patients with fundus albipunctatus have poor dark adaptation but may have normal results after 3-4 hours of adaptation.

Genetic testing

Because of the wide variety of subtypes of so-called RP or related pigmentary retinopathies, the definitive test for diagnosis is identifying the particular genetic defect. RP including rod dystrophies and rod-cone dystrophies are often monogenetic conditions in which change in one genetic locus is the cause of the retinal pathology.

Genetic subtyping will become more useful as therapies begin to target specific genetic subtypes. In addition, identifying the gene may prove helpful in determining the prognosis and in providing genetic counseling. Genetic testing will be essential for gene therapy, and many gene therapy clinical trials are already underway for the treatment for retinal dystrophies such as Leber congenital amaurosis, Usher syndrome, Stargardt disease, and RP due to mutations in MERTK gene (see Gene therapy).

Medical insurance will not always cover the costs of genetic testing; however, the cost of these tests continues to decrease.

Histologic Findings

Histology is not clinically helpful. Because of the general good health of patients with RP and the chronic nature of the disease, histology usually has been obtained only on chronically atrophic retinas. Nonspecific atrophy of the sensory retina with hyperplastic changes in the RPE is observed. Animal studies of experimental RP models show cellular apoptosis in some varieties; in others, abnormalities of the rod outer segments are observed.


Medical Care

The diagnosis of retinitis pigmentosa (RP) can be overwhelming to many patients. While therapies are limited, physicians should emphasize the therapies that are available to help patients. Perhaps, most importantly, it is essential to help patients maximize the vision they do have with refraction and low-vision evaluation. Many devices are available to help patients with night vision difficulties, and most low-vision clinics are aware of these devices.

The authors believe that patients should have annual examinations, including visual field testing and periodic (every 5 y) ERG evaluations. Changes in examination findings can help guide patients in their activities and can help with prognosis. Often, these examinations can provide reassurance that the changes are slow. In addition, regular examinations can ensure patients have appropriate community and legal assistance. Finally, as new therapies emerge, routine evaluation can keep patients informed of clinical trials and new treatments.

Vitamin A/beta-carotene

Antioxidants may be useful in treating patients with RP, but no clear, prospective evidence in favor of vitamin supplementation yet exists.

A recent comprehensive epidemiologic study concluded that very high daily doses of vitamin A palmitate (15,000 U/d) slow the progress of RP by about 2% per year. The effects are modest; therefore, this treatment must be weighed against the uncertain risk of long-term adverse effects from large chronic doses of vitamin A.

Annually check liver enzymes and vitamin A levels. Beta-carotene doses of 25,000 IU have been recommended.

Docosahexaenoic acid (DHA)

DHA is an omega-3 polyunsaturated fatty acid and antioxidant.

Studies have shown a correlation of ERG amplitudes with patients' erythrocyte-DHA concentration. Others studies reported trends of less ERG change in patients with higher levels of DHA. Nutritional intake of omega-3 fatty acids may affect the rate of decline of visual acuity (see Diet), although further clinical trials must be done to determine DHA benefit.

Acetazolamide

Macular edema can reduce vision in the later stages of RP. Of the many therapies tried, oral acetazolamide has shown the most encouraging results with some improvement in visual function. Studies by Fishman et al and Cox et al have demonstrated improvement in Snelling visual acuity with oral acetazolamide for patients who have RP with macular edema. [8]

Topical acetazolamide can be effective but has not been found to be as effective as oral therapy.

Adverse effects, including fatigue, renal stones, loss of appetite, hand tingling, and anemia, may limit its use.

The use of corticosteroids for macular edema may be useful but has not been well studied.

Calcium channel blockers

Calcium channel blockers, such as diltiazem, are medications commonly used in cardiac disease.

Calcium channel blockers have shown some benefit in some animal models of RP, but they have been ineffective in other models.

No current recommendations exist regarding the use of calcium channel blockers in patients with RP.

Lutein/zeaxanthin

Lutein and zeaxanthin are macular pigments that the body cannot make but instead come from dietary sources.

Lutein is thought to protect the macula from oxidative damage, and oral supplementation has been shown to increase the macular pigment.

A National Institutes of Health (NIH) clinical trial, the Age-Related Eye Disease Study II (AREDS II), is beginning to test the effectiveness of lutein and zeaxanthin to slow age-related macular degeneration. Their ability to prevent cone photoreceptor cell death (such as what occurs in RP) has not been shown.

Doses from 6-20 mg per day have been recommended.

Valproic acid

Oral valproic acid has shown benefit in small clinical trials, and larger clinical trials are underway.

Medications with potential adverse effects in RP

Isotretinoin (Accutane): A medication used to treat acne has been reported to worsen night vision, ERG response, and dark adaptation. As its safety in patients with RP is not known, many physicians do not recommend isotretinoin use for their patients.

Sildenafil (Viagra): A medication to treat erectile dysfunction has been shown to cause reversible ERG and vision changes. Sildenafil is an inhibitor of PDE5 and less so PDE6. Mutations of the PDE6 gene are known to cause autosomal recessive RP. Therefore, physicians have suggested that this medication may not be safe for patients with RP, including carriers of the PDE6B gene mutation. Some users of sildenafil have experienced blue photopsias, suggesting that the drug is active in the retina at a physiological level.

Vitamin E: Reports have suggested that high doses of vitamin E (400 U/d) may be modestly deleterious in patients with RP. While doses as high as 800 IU/d have been recommended by some authors, the authors of this article recommend avoiding additional supplementation with vitamin E until further studies are conducted.

Other medications

Although doses of 1000 mg/d ascorbic acid have been recommended, no evidence exists that ascorbic acid is helpful.

Although bilberry is recommended by some practitioners of alternative medicine in doses of 80 mg, no controlled studies exist that document its safety or efficacy in treating patients with RP.

In patients who present with antiretinal antibodies, immunosuppressive agents (including steroids) have been used with anecdotal success.

Surgical Care

Cataract extraction

Cataract surgery can often be beneficial in the later stages of RP. Bastek et al studied 30 patients with RP; 83% of them improved by 2 lines on the Snellen visual acuity chart with cataract surgery. [9]

Perioperative use of corticosteroids is recommended to prevent postoperative cystoid macular edema.

Educating patients about reasonable expectations of cataract surgery is essential.

Growth factors

Ciliary neurotrophic factor (CNTF) has been shown to slow retinal degeneration in a number of animal models.

Phase II clinical trials have been conducted using an encapsulated form of RPE cells producing CNTF (Neurotech) for patients with Usher syndrome and RP. These encapsulated cells must be surgically placed into the eye.

In May 2009, Neurotech released results from this study, showing evidence of retinal thickening after 1 year of treatment. [10Visual improvement was not seen at this time point, but researchers believe more time may be needed to show preservation of function as compared to the untreated eye. [10Interestingly, patients with atrophic age-related macular degeneration treated with the same growth factor did have a measurable visual improvement after 1 year. [10]

Transplantation

Cell transplantation to treat retinal disease (including cells derived from stem cells) is being actively investigated as a potential way to replace damaged RPE or photoreceptor cells. Both adult bone marrow–derived stem cells and embryonic stem cells are being used in clinical trials in patients with RP.

In 2011, Advanced Cell Technology (ACT) launched a human trial of a stem-cell–derived therapy for people with age-related macular degeneration and Stargardt disease. In this study, the cells derived from stem cells are differentiated into cells with an RPE phenotype and then injected under the retina during vitrectomy surgery. Initial results demonstrated safety and a trend toward visual improvement in 18 patients over 3-12 months. [11Hopefully, this technology will also prove to be effective and helpful in patients with RP.

RPE cell transplants (not derived from stem cells) have been placed into the subretinal space to rescue photoreceptors in animal models of RP. One approach that may prove useful is ex vivo modification of these cells to provide trophic factors.

Transplantation of adult retinal tissue has also been studied in clinical trials without successfully or reproducibly improving patients’ vision. Small patches of retinal or RPE tissue have been transplanted, and this technique could be helpful in the following RP forms: when RP is based on an RPE defect, when RP with primary defects exists in the outer segments, if the disease is driven by an overload of the phagocytic activity of the RPE, or if the RPE cannot provide sufficient nutritional support to the outer segments.

Retinal prosthesis

Artificial vision for patients without any vision has only recently become a reality after years of research and investment. One effective approach uses a retinal prosthesis or phototransducing chip placed on the retinal surface. A digital camera placed in glasses can then transmit a stimulus to the intraocular chip, which electrically stimulates the retina in a pattern mimicking the image transmitted from the glasses, thereby giving the patient an electrically produced image to the ganglion cell layer of the retina. Preclinical trials in animal models have shown long-term stability. [12]

The US Food and Drug Administration (FDA) has approved the first retinal implant, the Argus II Retinal Prosthesis System, for adults aged 25 years or older with advanced RP. [1 Although this device will not restore vision to patients, it replaces the function of degenerated cells in the retina and may improve a patient’s performance of basic activities by improving their ability to perceive images and movement. [1]

The implant includes a small video camera, transmitter mounted on a pair of eyeglasses, video processing unit (VPU), and an implanted retinal prosthesis (artificial retina). The VPU transforms images from the video camera into electronic data that are wirelessly transmitted to the retinal prosthesis. About two thirds of patients had no adverse events related to the device or the procedure; however, over one third of patients had a total of 23 serious adverse events, including conjunctival erosion, dehiscence, retinal detachment, inflammation, and hypotony. [1]

Chow et al placed subretinal microphotodiodes (prosthesis) in patients with severe RP. [16These patients had subjective improvement; however, the improvement was delayed and occurred in retinal areas outside of where the chip was placed. Therefore, the effect was thought to be an indirect benefit to adjacent cells.

Gene therapy

Gene therapy is under investigation, with the hope to replace the defective protein by using DNA vector (eg, adenovirus, lentivirus). [17]

Gene therapy was successful in providing the missing protein to a dog with Leger congenital amaurosis (LCA). Using adeno-associated virus (AAV), the Briard dog with RPE65 mutations after treatment had 20% of its RPE cells express the functional protein, thereby allowing the dog to see. This was also effective in a mouse model of Leber congenital amaurosis.

Leber congenital amaurosis. Leber congenital amaurosis.

Gene therapy is now in human clinical trials for LCA, with promising results. In fact, 8 trials referring to gene therapy and RPE65 mutations are being conducted and listed on the clinicaltrials.gov Web site. Trials have also begun for RP, although currently only for MERTK gene mutation.

Because of the wide heterogeneity of defects in RP, gene therapy must be targeted specifically to each mutation.

Jacobson et al found that gene therapy is acceptably safe and effective in the extrafoveal retina for LCA caused by RPE65 mutations; however, no benefit and some risk was noted in treating the fovea. Age-dependent effects were not evident. [18]

It is not known which, if any, of the RP forms will show reversibility (even with a nondestructive reinsertion of the appropriate gene in the appropriate locus with appropriate regulation).

Consultations

Clearly, RP is associated with several systemic diseases. Because of the severity of the systemic illness and its early presentation in most patients, the ophthalmologist may act as the consultant to an internist.

Low-vision specialists can provide magnifying devices and field-expanding lenses for patients with RP who have poor central vision.

Audiology consults should be considered for patients with hearing loss or for those patients with known Usher syndrome.

Genetic testing and counseling is becoming increasingly valuable as the understanding of RP increases. Identification of the patient’s genotype offers several advantages. First, it confirms the genetic cause of the condition. In addition, it can occasionally help determine prognosis and may likely prove to be important for future therapy choices. Genetic counseling is very helpful to guide patients on the hereditary nature of their disease and the mode of inheritance. This counseling can help the patients with their future plans, such as pregnancy, job choices, and medical treatments.

Moreoever, psychological counseling should be made available to those patients when appropriate.

Diet

Many practitioners recommend a well-balanced diet with adequate leafy green vegetables that contain the aforementioned supplements in nontoxic doses.

For patients receiving vitamin A palmitate, a diet rich in omega-3 fatty acids may slow the rate of decline of visual acuity. [19]

Activity

Light exposure

Stressful light exposure, which generates free radicals and strains the regenerative capacity of the eye, might put dystrophic retinas at a disadvantage. However, little direct or epidemiologic evidence exists that the disease is modified by light.

A specific form of RP, the Pro23His mutation in rhodopsin, has been shown to have increased retinal damage with increased light exposure.

UV-absorbing lenses are recommended, particularly in rhodopsin mutation varieties of RP, and patients with cone degeneration frequently benefit from tinted lenses.



Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. In addition to the medications listed below, the use of lutein to human disease(s) is uncertain, although lutein apparently may slow retinal degeneration, according to Glickman et al. Doses of 20 mg/d have been recommended.

Although bilberry is recommended by some practitioners of alternative medicine in doses of 80 mg/day, no controlled studies exist documenting its safety or efficacy in treating RP.

Vitamins, Fat-Soluble

Class Summary

May delay RPE degeneration.

Vitamin A (Aquasol A, A-Natural, A-25)

Use of antioxidants in treating RP might be beneficial, but no evidence exists in favor of vitamin supplementation and possibly some slight evidence to the contrary. A comprehensive epidemiologic study by Norton et al concluded that very high daily doses of vitamin A palmitate (15,000 U/d) slow the progress of RP by about 2% per year. The effects are also modest, and the use of such treatment must be weighed against the uncertain risk of long-term adverse effects from large chronic doses of vitamin A. Yearly checks of liver enzymes and vitamin A levels are recommended.

While vitamin A is found almost exclusively in animals (eg, fish oil, liver), beta-carotene is found predominantly in leafy green vegetables. Beta-carotene has about one-sixth the bioavailability of vitamin A and is cleaved by the intestinal mucosa using the enzyme dioxygenase. It is reduced with 2 NADPH into retinol or vitamin A. Because of the body's limited ability to generate vitamin A from beta-carotene, it is nontoxic, even in amounts 6 times more than the US RDA.

Vitamin E (Aquasol E, Alph-E, Aqua Gem-E)

High doses of vitamin E (400 U/d) were modestly deleterious, according to Berson et al, nevertheless, doses as high as 800 IU/d have been recommended.

Ascorbic acid (Acerola, C-Gel, Ascocid, Vita-C)

Although doses of 1000 mg/d are recommended anecdotally, according to Naka et al, no evidence exists that ascorbic acid is helpful in RP.

Calcium channel blockers

Class Summary

Reduce toxic levels of cyclic GMP in the RPE.

Diltiazem (Cardizem, Diltzac, Tiazac)

Experimental therapy. A recent study by Frasson showed decreased degeneration of the retina in rd mutant mice. Homologous mutations in humans represent about 4% of patients with RP. No current recommendations exist regarding the use of diltiazem, a calcium channel blocker commonly used in cardiac disease, in any patients with RP, including those with the homologous mutation.

Carbonic anhydrase inhibitors

Class Summary

Reduce cystoid macular edema associated visual loss from RP.

Acetazolamide (Diamox Sequels)

In a small percentage of patients with RP, cystoid edema may respond to oral carbonic anhydrase inhibitors, such as acetazolamide, with some subjective improvement in visual function, according to Fishman et al. These may be patients in whom the macular RPE is relatively uninvolved by disease, since carbonic anhydrase inhibitors must act upon functional RPE to enhance water transport, according to Marmor. Topical CAIs have not been evaluated.

Methazolamide (Neptazane)

Reduces aqueous humor formation by inhibiting enzyme carbonic anhydrase, which results in decreased IOP.



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