DONATE MAINS

Retinitis pigmentosa

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disorders characterized by progressive bilateral degeneration of the rod and cone photoreceptors that leads to night blindness and progressive visual field defects.

RP belongs to the group of pigmentary retinopathies. Historically, classifications of RP have been based on either distribution of the retinal involvement (central, pericentral, sector or peripheral subtypes) or age of onset or modes of inheritance or predominant photoreceptors involved. At present, there is no uniformly accepted classification system of RP. Many authors divide RP either into two main groups: isolated (when the pathology is confined to the eye alone) and syndromic (when the ocular degeneration is associated with abnormalities in one or more organ systems) or three main groups: nonsyndromic, or "simple" (affecting the eye alone), syndromic (affecting other systems, such as hearing) or systemic (affecting multiple tissues and organs). It is generally considered that 70-80% of all RP cases fall in the category nonsyndromic rod-cone dystrophy.

The retina is the light-sensitive tissue lining the inner surface of the eye. It is a complex, layered structure with several layers of neurons interconnected by synapses (Figure 1).

63349 004 94FAF325
Figure 1. Structure of the retina - Origin: www.britannica.com

The only neurons directly sensitive to light are the photoreceptor cells that through a cascade of biochemical events convert the light into nerve impulses, which are then processed by the retina and sent through nerve fibers to the brain. There are mainly two photoreceptor types: the rods and cones. Rod photoreceptors are responsible for motion detection and vision in scotopic conditions (night vision). Cone photoreceptors provide trichromatic color and high contrast vision and operate in photopic conditions (i.e. normal daylight conditions). A third, much rarer type of photoreceptor, the photosensitive ganglion cell, is important for reflexive responses to bright daylight (nyctemeral cycle).

In RP, light-sensitive rods and cones are damaged and visual symptoms indicate the gradual loss of the photoreceptor function leading to irreversible visual loss. The outer nuclear layer of the retina (consisting of rod and cone photoreceptor nuclei) is severely attenuated in patients with RP. The inner nuclear layer (composed of nuclei from the amacrine cell, bipolar cell and horizontal cell neurons) and the ganglion-cell layer are fairly well preserved until late in the disease course. In most forms of typical RP (rod-cone RP), rods are affected more severely than the cones. In other RP types, rod and cone decline is similar. Occasionally, the deficit of cones far exceeds that of rods. In this case, the condition is termed cone-rod degeneration, a form of RP in which loss of visual acuity and defective color vision are the prominent early symptoms.


Prevalence

The prevalence of typical RP is estimated at approximately 1 in 3,000 to 1 in 5,000 individuals. RP affects about 1.5 million people worldwide and is the most common inherited retinal degenerations. The highest reported prevalence for RP, 1 in 1878, is among the Navajo Indians (Native American tribe of Northern America). A lifetime risk of developing RP in Denmark has been reported to be 1 in 2500. In Switzerland, the prevalence of RP has been reported to be as low as 1 in 7000. Sexual predilection has not been identified. However, as the expressivity of the X-linked RP is more severe in males, men may be affected slightly more than women. Ethnic preponderance has not been documented, but RP caused by mutations in particular genes may be more frequent in certain isolated or consanguineous populations.


Onset and clinical features

Onset

RP is typically diagnosed in young adulthood, but the age of onset may range from early childhood to the mid 30s to 50s. Photoreceptor degeneration has been detected as early as age of six years even in patients who remain asymptomatic until young adulthood.

    • Clinical features:

 

Since rod function is primarily affected, the most common initial symptoms of typical RP (rod-cone RP) include night blindness (nyctalopia), followed by visual field defects with preservation of central visual acuity until the late stages of the disease. Severe visual impairment occurs by ages 40 to 50 years.

    • Nyctalopia:

 

The earliest symptom in RP is most commonly night blindness, which is considered a hallmark of the disease. It is usually observed during childhood. Patients complain of defective dark adaptation: difficulty seeing in dim illumination (night, dusk or fog conditions), tendency to trip easily or bump into objects when in poor lighting.

    • Visual loss:

 

Progressive visual field constriction (typically presenting by the teenage age) is another hallmark of RP. The visual field defects may initially present as small asymptomatic scotomas that progress to form a "tunnel" configuration as the disease advances. The rate of progression is slow but relentless. The visual field loss is usually symmetric and expands more rapidly outward, with a slower progression inward toward the central field.

Typical rod-cone RP is associated with preservation of the central vision acuity until the later stages of the disease. In some cases, the onset of central visual impairment is earlier (e.g. atypical RP or presence of associated factors, such as cystoid macular edema and cataracts). Visual acuity can remain normal. Reading impairment and difficulties in undertaking daily activities are typically seen when visual acuity falls below 0.5 (20/40).

    • Color vision defects:

 

Color vision in patients with typical rod-cone RP remains good until the central vision is affected at a level of 20/40 or worse. A deficiency in blue cone function (acquired tritanopia) is characteristic of advanced RP. Mild blue-yellow axis color defects are common, however most patients do not complain of significant difficulties with color perception.

    • Photophobia:

 

Photophobia is common mostly in patients with cone-rod RP, especially in the later stage of the disease.

    • Photopsia:

 

RP patients report seeing flashes of light (photopsia) described as small, shimmering, blinking lights or coarse sparkling grains similar to the symptoms of an ophthalmic migraine. In contrast to ophthalmic migraine, the photopsia in RP is rather continuous than episodic. Photopsia is a common complain in patients with cone-rod RP in their mid-peripheral field of vision, adjacent to areas of scotoma. Photopsias may decrease over the years, as scotomas become denser.

    • Other clinical manifestations:

 

RP patients frequently develop a form of cataract (up to 50% of adult RP patients). It is typically observed between 20 and 39 years of age, and the incidence is increasing with age. Keratoconus is rare but it may reduce visual acuity and increase glare. Loss of contrast sensitivity and eye fatigue are frequently reported. Myopia varies among distinct subtypes of RP, an increased prevalence being noted in X-linked RP.

    • Fundus findings:

 

Fundus findings depend on the stage of retinal deterioration. The earliest observed changes in the fundus are fine dust-like granularity of the retinal pigment epithelium (RPE), with normal associated vasculature and pigmentary mottling ("moth-eaten" pattern). However, visible funduscopic changes may be absent in the initial stages. The middle stage shows a more patchy loss of the RPE and the beginning of retinal vessel attenuation. Arteriolar narrowing, waxy palor of the disc, cystoid macular edema and bone spicule-like pigment changes are consistent with long-standing retinal and RPE degeneration in advanced RP.

    • Syndromic RP:

 

Approximately 20-30% of RP patients have associated non-ocular disease that includes more than 30 different syndromes. Among the most common syndromic forms of RP are Usher syndrome, Refsum disease, Bassen-Kornzweig syndrome, Bardet-Biedl syndrome and Batten disease.


Diagnosis of RP

The diagnosis of RP is suspected in patients with poor night vision or a family history (more than 40% of RP cases in the US have no family history). It relies upon documentation of rod dysfunction as measured by dark adaptation or electroretinogram, progressive loss in photoreceptor function, loss of peripheral vision and bilateral involvement.

The most common findings on ocular examination are usually preserved visual acuity until late-stage disease and reduced visual fields. Most adult patients have posterior subcapsular cataracts and visual acuity that varies from 20/20 to near blindness late in the disease.

1. Fundus examination is one of the most informative diagnostic methods, helping to distinguish RP from other retinal dystrophies that have similar clinical findings but distinctive retinal changes. In individuals with advanced RP, ophthalmoscopy of the retina is characterized by the presence of intraretinal clumps of black pigment (abnormal fundus with bone-spicule deposits), markedly attenuated retinal vessels, loss of RPE, pallor of the optic nerve, posterior subcapsular cataracts (Figure 3). Cells in the vitreous are commonly seen.

2. Electroretinogram (ERG) is the most critical diagnostic test for RP. It determines objectively the functional status of the photoreceptors and is sensitive to even mild photoreceptor impairment. Responses obtained under dark-adapted conditions generally reflect rod function, and responses obtained under light-adapted conditions generally reflect cone function. Thus, rod responses can be separated from cone responses, permitting definition of the type and extent of rod and/or cone involvement.

3. The full-field ERG in RP typically shows a marked reduction of both rod and cone signals. Rod loss generally predominates. Amplitudes of the a- and b-waves can be either moderately reduced or almost non-detectable, depending on the stage of the disease and the genetic defect. Time intervals from stimuli to peak rod or cone isolated responses are prolonged in typical RP. The ERG is usually abnormal by early childhood, except for some of the very mild and regional forms of RP. An observation of early and severe impairment of pure rod responses occurs is critical to the diagnosis of RP in young individuals. Individuals with advanced RP have non-detectable rod and cone responses. Patients with cone ERG amplitudes as low as 1 μV or less can still have ambulatory vision and read newspapers.

4. Fundus autofluorescence (FAF) imaging is a relatively novel quick, simple, efficient and noninvasive imaging method for topographic mapping of lipofuscin changes in the RPE (and other fluorophores in the outer retina and subneurosensory space). It gives information above and beyond that obtained by conventional imaging methods, such as fundus photography, fluorescein angiography, and optical coherence tomography. Confocal scanning laser ophthalmoscopy (cSLO) is a useful technique for FAF imaging. It allows documentation of its spatial distribution over large retinal areas. FAF imaging became a very important diagnostic tool in a variety of retinal diseases. In RP, there is a loss of peripheral autofluorescence that corresponds to the loss of photoreceptors. Autofluorescence in the macular region is usually preserved until late stages of the disease. Rings of retinal foveal hyperautofluorescence is present in approximately 80% of patients with preserved central vision. The diameter of the ring directly correlates with the macular function (Figure 3). FAF is considered useful and sensitive non-invasive diagnostic tool to monitor retinal degeneration.

6. Optical coherence tomography (OCT) is usually not used to establish a diagnosis of RP but is especially useful for measurement of retina thickness, assessment of the status of the photoreceptor layer and determining the presence of cystoid macular edema. It is also used to evaluate the effects of therapy.

7. L'electro-oculogram (EOG) and visually evoked cortical potentials (VECPs).

8. Functional assessment of vision includes dark adaptation threshold examination of the visual field (Goldmann kinetic perimetry or a Humphrey field analyzer), color vision (assessed with Ishihara plates, the Farnsworth D15 or other tests), contrast sensitivity (measured with a contrast chart), visual acuity (using the Snellen charts for assessment of distance and central vision).

9. Genetic subtyping can be definitive test for diagnosis of RPGenetic subtyping can be definitive test for diagnosis of RP. Molecular genetic testing on a clinical basis may be available (depending on the local resources in the country) for some RP-causing genes, such as RLBP1, RP1, RP2, RHO, RDS, PRPF8, RPGR, PRPF3, CRB1, ABCA4 and RPE65. For all other genes, molecular genetic testing is available on a research basis only. Thus, it is possible now to detect disease-causing mutations in 40-50% of patients with autosomal dominant RP, roughly 30% of patients with autosomal recessive RP and nearly 90% of patients with X-linked RP. Determination of the exact inheritance pattern is critical for the genetic counseling and determining the prognosis.

Many different factors may affect the early diagnosis of RP and cause a significant delay in diagnosis. For example, reading impairment and difficulties in undertaking daily activities are typically seen later in the disease course, when the visual acuities fall below 0.5 (20/40). Electrically illuminated night-time environment permits the night-time activities to be typically done with sufficient light. As a consequence, by the time the patient recognizes the symptom of night blindness, a reduction in cone sensitivity can be significant. Thus, objective quantitative measures of retinal function are much more reliable than symptoms for diagnosis of RP and crucial to describe the degree of visual compromise and rate of its decline.

Differential diagnosis

Differential diagnosis should rule out acquired retinal degenerations (such as peripheral reticular pigmentary degeneration), infectious and inflammatory retinopathy (rubella, syphilis, cytomegalovirus infection, herpes simplex, posterior uveitis), retinopathies associated with cancer and trauma with intraocular foreign body, grouped pigmentation of the retina (bear-track), retinal detachment resolution, pigmented paravenous retinochoroidal atrophy and vitamin A deficiency should also be taken in consideration, as they manifest mainly with night blindness. Drug history is essential to rule out toxicity due to phenothiazines (chlorpromazine, thioridizine), chloroquine and deferoxamine.

Systemic evaluation should rule out conditions that present with pigmentary retinopathy and mimic RP, such as Usher syndrome, Waardenburg syndrome, Alport syndrome, Refsum disease, Leber congenital amaurosis (LCA), Senior-Loken syndrome, Bardet-Biedl syndrome, unilateral RP, abetalipoproteinemia, mucopolysaccharidoses, neuronal ceroid lipofuscinosis. Congenital stationary night blindness, dystrophies of the choroid and retina (gyrate atrophy, choroideremia).


Etiology

Causatives genes

RP is characterized by enormous genetic heterogeneity. At least 45 different genes and loci have been identified to cause nonsyndromic RP so far. Most mutations affect rods selectively and, through an unknown pathway, cause apoptotic death of the rod cells (clinically leading to night blindness and substantial defects in the peripheral visual field). Cones are seldom directly affected by the identified mutations, but in many cases they degenerate secondarily to rods (clinically leading to visual field constriction, loss of central vision and complete blindness).

Although the causative genetic mutations are often known, the mechanisms leading to photoreceptor degeneration remain poorly defined. Genes associated with RP encode proteins that are involved in phototransduction (the process by which the energy of a photon of light is converted in the photoreceptor cell outer segment into a neuronal signal), the visual cycle (production and recycling of the chromophore of rhodopsin), photoreceptor structure and photoreceptor cell transcription factors. However, the function of many genes associated with RP remains unknown. The involvement of apoptotic and multiple non-apoptotic mechanisms in the pathogenesis of RP has been suggested.

Though most cases of RP are monogenic, the disease is very heterogeneous genetically. Many different genes may cause the same disease, while different mutations in the same gene may cause different diseases. Clinical severity and disease phenotype often differ among individuals with the same mutation, most likely as a result of genetic and/or environmental factors. Genotype/phenotype correlations in RP will have to take into account these complexities.

Most genes for RP cause only a small proportion of cases, except for the rhodopsin gene (RHO), which leads to about 25% of dominant RP, the USH2A gene, which might cause about 20% of recessive RP (including many with Usher syndrome type II), and the RPGR gene that accounts for about 70% of X-linked RP. Altogether, mutations in RHO, USH2A and RPGR genes cause about 30% of all cases of RP.

Inheritance and genetic counseling

The inheritance modes of RP include autosomal dominant (ad), autosomal recessive (ar), X-linked (xl), digenic and mitochondrial patterns. Because of the variation in both the nature of the penetrance and expressivity of the genes coding for RP, ocular manifestations widely vary among the inherited modes and even among members within the same family.

Autosomal recessive RP (arRP) is the most frequently inherited type of RP, accounting for approximately 20-30 % of cases with approximately 25 arRP genes identified so far. Mutations in RPE65, PDE6A and PDE6B cause 2-5 % of arRP cases, while mutations in USH2A, which can also cause Usher syndrome, may account for up to 5% of arRP cases. Autosomal recessive RP occurs when both parents are unaffected carriers of the same defective gene. The chance of a child being affected is one in four.

Autosomal dominant RP (adRP) is the second most frequently inherited type of RP, accounting for approximately 15-20 % of cases. Twenty adRP genes have been identified to date (see http://www.sph.uth.tmc.edu/Retnet/). Three genes, RHO, RP1 and PRPH2, account for approximately 25-30 %, 5-10 % and 5-10 % of adRP cases, respectively. More than 100 RHO mutations have been reported so far, causing variation within the clinical presentations. In adRP, typically, one of the parents is affected by the disease. The chance is one in two of any given offspring being affected by the disease, if the affected parent has one normal and one defective gene.

X-linked RP (xlRP) is the least frequently inherited type of RP, accounting for 6-10 % of cases. Two genes and two additional loci have been identified to date. Mutations in RPGR (also called RP3) and RP2 are the most common causes of xlRP, accounting for 70-90% and 10-20%, respectively, of the xlRP cases. X-linked recessive RP may occur in offspring in two ways. The father can be affected or mother can be carrier of the defective gene. If the father is affected, all sons will be unaffected and all daughters will be carriers. If the mother is the carrier, one in two sons will be affected and one in two daughters will be carriers. In families with xlRP, males are affected; females carry the genetic trait and usually do not experience serious vision loss. However, they can manifest a milder form of the disease.

Very rare modes of inheritance include digenic and mitochondrial DNA patterns. Digenic RP is caused by the simultaneous presence of a mutation in the PRPH2/RDS gene and a mutation in the ROM1 gene.

Regarding family planning issues, the optimal time for determination of genetic risk is before pregnancy. Prenatal testing and preimplantation genetic diagnosis may be available for families in which the disease-causing mutation(s) has been identified in an affected family member


Management

Currently, there is no known effective treatment that can prevent or reverse the vision loss in RP. Standard treatment modalities remain to be established

1. General recommendations

Supportive measures to maintain and/or improve quality of life should be provided to all individuals affected by RP. Low vision rehabilitation and optical aids should be proposed, including high-intensity lamps, contrast enhancing filters, infrared blocking sun lenses, magnifiers (such as closed circuit televisions). Compensation of the restricted visual field could be achieved by scanning training, minus lenses, reverse telescopes and prisms. In case of profoundly constricted fields, mobility training should be advised.

Patients with RP are advised to wear low wave length blocking sunglasses (as dark as can be tolerated without compromising vision) with tinted side shields outdoors during the day. For example: CPF 550 lenses (Corning Photochromatic Filter manufactured by Corning Glass Works), which filter out 97-99% of the spectral and ultraviolet energy below 550 nm wavelength. Reduction in light exposure, especially stressful light exposure, is beneficial. Prolonged light deprivation, however, has little or no effect on the disease course.

Regular eye exams are necessary to track the rate and degree of deterioration. Assessment of visual fields, cataract or macular edema should be performed on annual basis. ERG evaluation is periodic, every 2-3 years.

Psychological counseling is appropriate as it provides education and support to patients and their families. Patients should understand the variable, slowly progressive course of the disease that leads to bilateral, initially peripheral and later central vision loss. Patients should be carefully advised about their ability to drive a motor vehicle, especially under dimly lit conditions, such as night driving.

2. Treatment modalities

Medication

Photoreceptor function can be potentially preserved by administration of vitamin A palmitate, lutein, docosohexanoic acid (DHA), calcium-channel blockers. The precise mechanism(s) of the possible supportive role of these medications in retinal degenerations remains unclear.

The most widely recognized nutritional supplement for RP patients is vitamin A palmitate, which has been shown to slow the rate of retinal degeneration. Currently, adult patients (over the age of 18) with common forms of RP and good general health are recommended to take vitamin A palmitate under medical supervision. The suggested dosage regimens vary (15,000 IU/day or 50,000 UI once a week or 50,000 UI every 2 weeks). Patients should avoid the concomitant use of high doses of vitamin E, as paradoxally it can increase the deterioration rate, probably due to reduced availability of other vitamins in the retina. Patients should be aware of the benefits/risks expectations associated with vitamin A treatment. On one hand, though vitamin A therapy may slow the progression of the disease, it has not been shown to improve the visual acuity or visual field. On the other hand, high doses of vitamin A may be teratogenic and can potentially cause liver damage. It also increases the risk of lung cancer in case of tobacco consumption. As a consequence, female patients should be advised to cease therapy if they are planning to or become pregnant. Regular check of liver enzymes should also be recommended. Beta-carotene alone can be used to replace vitamin A therapy. Patients should also be advised of the importance of a well-balanced diet including leafy green vegetables and omega-3 fatty acids for further benefits.

Recently, docosahexaenoic acid (DHA), a long-chain omega-3 fatty acid commonly found in fish, has been investigated in RP treatment. Further reduction in the rate of retinal degeneration has been shown upon DHA treatment (1200 mg/d) in patients recently placed on vitamin A palmitate therapy. However, the beneficial effects of DHA do not usually extend beyond a treatment period of two years.

Lutein and/or zeaxanthin (macular pigments from dietary sources), 20 mg/d for six months, have been shown to increase macular pigment in approximately 50% of individuals with RP, without change in central vision. The long-term effects of this supplementation have yet to be evaluated.

Some studies have demonstrated that calcium channel blockers (e.g. diltiazem) inhibit the photoreceptor degeneration. Neuroprotective effects of these drugs have been shown in several forms of RP only and seem to be restricted to certain mutations and/or model studied and/or the calcium channel blocker used.

Some anti-Parkinson's drugs with antiapoptotic properties have been included in the treatment of RP. The value of this option remains to be evaluated.

Cystoid macular edema that may cause significant additional loss of visual function in patients with RP have been shown to respond to oral or topical (less effective) carbonic anhydrase inhibitors, e.g. acetazolamid. If the macular edema is severe and unresponsive to acetazolamide, local injections of corticosteroids could be considered although their efficacy is still under discussion.

Cataract surgery

As a general guideline, cataract surgery should be performed as soon as it causes significant impairment of vision. It should not be deferred too long, thus the patient would benefit from the surgery before the evolution of the retinal disease limits the postoperative recovery. The surgical procedure itself is not more complicated than regular cataract removal from an eye with no retinal degeneration. One might be cautious in case of preexisting macular edema and the surgery should be postponed until resolution of the edema. There is no real evidence that retinal degeneration is hastened or macular edema triggered by the surgery but postoperative follow-up should detect such complications. Patients should be educated about reasonable expectations of cataract extraction, as cataract surgery in young adults and cataract surgery in both eyes in patients with advanced RP may be sometimes compromised.

The inheritance modes of RP include autosomal dominant (ad), autosomal recessive (ar), X-linked (xl), digenic and mitochondrial patterns. Because of the variation in both the nature of the penetrance and expressivity of the genes coding for RP, ocular manifestations widely vary among the inherited modes and even among members within the same family.

Autosomal recessive RP (arRP) is the most frequently inherited type of RP, accounting for approximately 20-30 % of cases with approximately 25 arRP genes identified so far. Mutations in RPE65, PDE6A and PDE6B cause 2-5 % of arRP cases, while mutations in USH2A, which can also cause Usher syndrome, may account for up to 5% of arRP cases. Autosomal recessive RP occurs when both parents are unaffected carriers of the same defective gene. The chance of a child being affected is one in four.

Autosomal dominant RP (adRP) is the second most frequently inherited type of RP, accounting for approximately 15-20 % of cases. Twenty adRP genes have been identified to date (see http://www.sph.uth.tmc.edu/Retnet/). Three genes, RHO, RP1 and PRPH2, account for approximately 25-30 %, 5-10 % and 5-10 % of adRP cases, respectively. More than 100 RHO mutations have been reported so far, causing variation within the clinical presentations. In adRP, typically, one of the parents is affected by the disease. The chance is one in two of any given offspring being affected by the disease, if the affected parent has one normal and one defective gene.

X-linked RP (xlRP) is the least frequently inherited type of RP, accounting for 6-10 % of cases. Two genes and two additional loci have been identified to date. Mutations in RPGR (also called RP3) and RP2 are the most common causes of xlRP, accounting for 70-90% and 10-20%, respectively, of the xlRP cases. X-linked recessive RP may occur in offspring in two ways. The father can be affected or mother can be carrier of the defective gene. If the father is affected, all sons will be unaffected and all daughters will be carriers. If the mother is the carrier, one in two sons will be affected and one in two daughters will be carriers. In families with xlRP, males are affected; females carry the genetic trait and usually do not experience serious vision loss. However, they can manifest a milder form of the disease.

Very rare modes of inheritance include digenic and mitochondrial DNA patterns. Digenic RP is caused by the simultaneous presence of a mutation in the PRPH2/RDS gene and a mutation in the ROM1 gene.

Regarding family planning issues, the optimal time for determination of genetic risk is before pregnancy. Prenatal testing and preimplantation genetic diagnosis may be available for families in which the disease-causing mutation(s) has been identified in an affected family member.


Treatment modalities

Recent developments include therapeutic modalities associated with gene therapy aimed at correcting various specific mutations, cell transplantation to replace lost cells, pharmacologic options to help preserve photoreceptors and the use of neuroprosthetic devices to generate visual perception.

Gene therapy

Gene therapy aims at correcting various specific disease-causing mutations. By replacing or turning off the mutated gene, healthy genes can be inserted into the retina to restore the protein function. Different gene-mediated therapeutic strategies have been developed using either viral or non-viral vectors. The large number of genes however and the dominant inheritance of many types of RP are major challenges for the corrective gene therapy.

In mutations leading to loss of function (arRP or X-linked recessive retinal degenerations), the principle of gene therapy is to correct the genetic defect by the introduction of a wild-type version of the mutated gene into the cells in which normal functioning of this gene is required (photoreceptors or RPE cells). One notable gene-replacement approach targets the RPE65 gene.

Dominantly inherited mutations typically alter the transcribed aminoacid sequence and result in toxic variants of the encoded protein (gain-of-function or dominant-negative mutations). One strategy to treat these alterations is to eliminate the mutant gene (gene silencing). The remaining normal copy of the gene is expected to provide sufficient functional protein. Current experimental approaches used in autosomal dominant conditions include ribozyme-based or interference RNA (RNAi)-based gene therapy.

Gene therapy approaches have experimentally been shown to delay and reverse the course of RP, with associated improvement of photoreceptor function in various animal models. Long-term efficacy and safety of the gene therapy still needs to be established

Trophic factors

Neurotrophic factors such as basic fibroblast growth factors (bFGF or FGF-2) and ciliary neurotrophic factors (CNTF) are currently under investigation as therapeutic modalities in RP. It has been shown that FGF-2 exerts both histologic and functional rescue on degenerating photoreceptors. However, it also triggers pathological retinal neovascularization, which makes it unacceptable for human therapy. CNTF has been found to slow retinal degeneration in a number of animal models. Clinical studies have reported evidence of retinal thickening and measurable visual improvement after one year of treatment with CNTF. However, paradoxical decrease in both scotopic and photopic responses in CNTF-treated retina has also been described, leading to evaluation of other trophic factors. Among them, glial cell line-derived neurotrophic factor (GDNF), has been found to slow down the rod degeneration and preserve visual function.

Prevention the secondary degeneration of cones in RP represents a very promising approach. This because such a therapy could be applied in a wide range of mutations expressed in rods, and even at late stages of the disease. Rod-derived cone viability factor (RdCVF) has recently been shown to induce cone survival directly and to increase the cone numbers. Functional rescue and increased ERG-wave amplitudes have been documented. RdCVF trophic effects appear independent from the mechanisms and extent of rod degeneration that is one of the main advantages of this approach.

Neuroprosthetic devices

In RP, prosthesis can be designed to take over the function of the lost photoreceptors by electrical stimulation of the remaining healthy cells of the retina. Current implanted neuroprosthetic devices use optic nerve, retinal and cortical stimulation.

Optic nerve stimulation involves electrodes placed around the optic nerve, resulting in colored phosphenes throughout the visual field. By changing the duration and amplitude of the electrical stimulus, RP patients can perceive different levels of brightness of the generated phosphene.

Retinal stimulation includes both subretinal and epiretinal prostheses (phototransducing chip placed on the retinal surface). It consists of electrical current passing from individual electrodes that stimulate cells in the appropriate areas of the retina. At present, retinal prosthetics are still under clinical investigation and not available commercially.

Cortical stimulation (surface or intracortical stimulation) uses visual images captured by a camera that are collected on a computer base stimulator mounted on a pair of glasses. The main advantage of the cortical visual prosthesis is that it bypasses the damaged retina and directly stimulates the primary visual cortex. However, it is associated with increased risk of seizures. Low-resolution imaging, craniotomy-associated risks and the cost should be considered.

Visual prosthetics

The BrainPort vision device is a non-surgical assistive visual prosthetic that translates information from a digital video camera to the tongue through gentle electrical stimulation. It consists of a base unit, a head-mounted camera, a hand-held controller, and an electrode array that sit on top of the tongue. The system collects visual information through the camera, send it instantaneously to the base unit, which converts it into an electrical pattern. The latter is then displayed on the tongue though the electrode array. A tactile "image" is then created using electrical stimulation.

Artificial human vision and other future modalities

Recently, technology transforming the auditory information into visual sensory information has been developed (vOICe). It uses an extraocular camera placed within sunglasses. Visual images from the camera are then mapped into sound, which the subject must decode into visual input (seeing with sound). Yet, no large clinical trials have been conducted to assess the capacities of this technology.

Speech recognition software, light-sensitive microchip implantation, wearable computers, satellite positioning and other emerging technologies have been invented and can help the individuals with RP in the future. It is still to be established whether patients with RP achieve useful vision with these devices. Since about 2001, people with vision impairment may have access to commercial GPS-based navigations systems.

Potential future therapies

Cell transplantation

Cell transplantation consists in re-infusing of healthy cells into a sick retina. It aims at producing more healthy cells to replace the nonfunctional cells. Two different strategies have been developed: RPE transplantation (that attempts to obtain beneficial effects upon the adjacent photoreceptors) and retinal neuronal transplantation (that attempts to replace lost photoreceptor cells). Today, two main sources of cells for transplantation are used, retinal and stem cells.

Retinal cell transplantation is the introduction of healthy photoreceptor cells into the host. The advantage of this method over stem cell transplantation is that the retinal cells integrate well into the retinal layers and express specific retinal cell markers. In stem cell transplantation, the patient receives healthy stem cells, which may begin producing normal retinal cells. The main advantage of the stem cells is that they have the potential to differentiate into any type of cells, including retinal neural cells. Both adult bone marrow-derived stem cells and embryonic stem cells are under investigation. Subjective and objective visual improvement has been documented in a number of subjects following this cell transplantation method

Channelrhodopsin

Some degree of vision may potentially be restored if remaining neurons could directly respond to light and transmit information to visual centers. Recently, light-sensitive cation channels (Channelrhodopsins) and anion pumps (Halorhodopsins) were shown to modulate the neural activity in response to visible light. All known Channelrhodopsins are unspecific cation channels, conducting H+, Na+, K+, and Ca2+ ions. By targeting these rhodopsins, a virtual ON or OFF signaling pathway may potentially be generated and a new technology for vision restoration proposed.


Prognosis

RP is a progressive disease with an exponential decline in remaining visual field area (estimated at 3-13% loss annually) and ERG amplitude (estimated at 9-19% loss annually). The rate of progression and degree of visual loss varies from person to person. Most individuals with RP are legally blind by age 40 due to severely constricted visual fields (central visual field of less than 20 degrees in diameter). Loss of vision eventually leads to bare or no light perception, posing a continuous threat to patients' independence.

According to some studies, individuals with adRP have the best prognosis, with the majority of those younger than age 30 years having a visual acuity of 20/30 or better. Males with xlRP have the worst prognosis, with all individuals older than age 50 years having a visual acuity lower than 20/200. Individuals with arRP and RP with a single occurrence in the family are intermediate in severity. Other investigators, however, do not confirm the correlation between visual impairment and genetic subtype.


References

Berson EL : Management of retinitis pigmentosa. Retinal Physician, Wolters Kluwer Pharma Solutions, Inc.: www.retinalphysician.com. Accessed October, 2008.

Daiger SP, Bowne SJ, Sullivan LS : Perspective on genes and mutations causing retinitis pigmentosa. Arch Ophthalmol. 2007 February;125(2):151-158.

Delyfer MN, Léveillard T, Mohand-Saïd S, Hicks D, Picaud S, Sahel JA: Inherited retinal degenerations: therapeutic prospects. Biology of the Cell. 2004 May; 96(4):261-269.

Hartong DT, Berson EL, Dryja TP : Retinitis pigmentosa. The Lancet. 2006 November 18-24; 368(9549):1795-1809.

Pagon RA, Daiger SP : Retinitis pigmentosa overview. GeneTests. University of Washington; Seattle: http://www.GeneTests.org. Accessed September 16, 2005.

RetNet : Genes and Mapped Loci Causing Retinal Diseases (http://www.sph.uth.tmc.edu/RetNet/)

Shintani K, Shechtman DL, Gurwood AS: Review and update : Current treatment trends for patients with retinitis pigmentosa. Optometry, 2009 July; 80(7):384-401.

Yang Y, Mohand-Said S, Danan A, Simonutti M, Fontaine V, Clerin E, Picaud S, Léveillard T, Sahel JA: Functional cone rescue by RdCVF protein in a dominant model of retinitis pigmentosa. Molecular Therapy. 2009 May; 17(5):787-795.

Robson AG, El-Amir A, Bailey C, Egan CA, Fitzke FW, Webster AR, Bird AC, Holder GE. Pattern ERG correlates of abnormal fundus autofluorescence in patients with retinitis pigmentosa and normal visual acuity. Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3544-3550.

Contributors: Katia Marazova, MD, PhD (février 2010), Pr José-Alain Sahel and Dr Isabelle Audo, MCU-PH

Disclaimer: This document contains information based on published scientific articles and is for educational purposes only. It is in no way intended as a substitute for qualified medical professional help, advice, diagnosis or treatment.

image_science