Retinitis pigmentosa: Treatment

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]. The clinical manifestations of RP include night blindness, loss of peripheral vision from progressive loss of photoreceptors, and variably loss of central vision due to cataracts and macular edema.

Although there is no cure for RP, treatments are available for managing some aspects of its clinical manifestations [2]. New treatments involving gene therapy, transplantation, and implanted electrical devices, are in active development.

This topic addresses available treatment options as well as review therapeutic strategies that remain experimental. The clinical manifestations and diagnosis of retinitis pigmentosa are discussed separately. (See "Retinitis pigmentosa: Clinical presentation and diagnosis".)

MANAGEMENT — Vitamin and nutritional supplementation therapy is beneficial only for a limited group of patients with some forms of retinitis pigmentosa (RP). Several new treatments are on the horizon to slow or possibly even reverse the retinal degeneration caused by photoreceptor loss.

Vitamin and nutritional supplementation — A role for vitamin therapy in RP was originally suggested by an observational study in which patients with RP who were taking vitamins A and E appeared to have slower decline in electroretinography (ERG) measurements than those not taking vitamin supplements [3].

Dietary modification is the definitive therapy for three rare forms of retinitis pigmentosa:

●Abetalipoproteinemia (Bassen-Kornzweig syndrome) – Abetalipoproteinemia is a genetic disorder that causes defective intestinal absorption of lipids, including fat soluble vitamins. Ophthalmologic and neurologic manifestations of abetalipoproteinemia include RP, peripheral neuropathy, ataxia, and, in up to one-third of patients, intellectual and developmental disabilities. Treatment with fat soluble vitamins (E, A, and K) can modify manifestations of the disease. In early stages of disease, vitamin A and E supplementation may restore retinal function, improving dark adaptation and reversing ERG abnormalities [4-6]. (See "Neuroacanthocytosis", section on 'Abetalipoproteinemia'.)

●Phytanic acid oxidase deficiency (Refsum disease) – Refsum disease is the result of a genetic abnormality in which the enzyme that breaks down phytanic acid is absent. Patients develop RP, cerebellar ataxia, and peripheral polyneuropathy. Severely reducing intake of foods containing phytanic acid, such as dairy products, certain types of meat, and seafood, can slow or stop progression of the disease. (See "Neuropathies associated with hereditary disorders", section on 'Refsum disease'.)

●Alpha-tocopherol transport protein deficiency (ataxia with vitamin E deficiency) – Alpha-tocopherol transport protein deficiency is a hereditary syndrome with RP, ataxia, and vitamin E deficiency. Treatment with vitamin E may halt progression. (See "Overview of the hereditary ataxias", section on 'Treatable diseases'.)

Vitamin A — The role for vitamin A in the treatment for RP, outside of its well-established indication in patients with abetalipoproteinemia, remains controversial. It is unclear if small potential benefits of vitamin A supplementation outweigh the potential risks. Therefore, we do not recommend high-dose vitamin A for patients with RP.

In a randomized controlled trial, 601 patients aged 18 to 49 years with RP (including autosomal dominant, autosomal recessive, X-linked non-syndromic and Usher syndrome) were randomly assigned to one of four treatment groups: vitamin A (15,000 international units/day); vitamin E (400 international units/day); both vitamin A and E at these doses; or trace amounts of vitamin A and E [7]. Cone ERG amplitudes were measured. At four- to six-year follow-up, patients taking supplemental vitamin A had a slightly lower rate of decline of ERG amplitudes. Results suggested that vitamin E had a negative impact, accelerating the decline of ERG amplitudes in a subset of patients with the highest initial cone ERG results. No significant effect on visual field or visual acuity was noted for either vitamin supplement. There are several limitations in drawing conclusions about the beneficial effects of vitamin A. Positive response to treatment was seen only on the ERG, and no effect was seen on clinically relevant measures of visual function.

There is a theoretical risk of toxicity from long-term high-dose vitamin A. The toxic effects of high-dose vitamin A include hepatomegaly, bone changes such as osteoporosis, elevated blood lipid levels, increased intracranial pressure, and teratogenicity. Although the daily intake of the dose of vitamin A palmitate suggested as treatment for RP (15,000 international units, equivalent to three times the daily allowance) was not shown to be harmful in adults in this study, there are no well-controlled studies on the effect of vitamin A at this dose when taken longer term, such as over decades. (See "Overview of vitamin A".)

While we do not recommend vitamin A supplementation for RP, we do suggest that adults with early to middle stages of RP avoid vitamin E supplements. Patients who have been advised to take vitamin A should have annual fasting vitamin A levels and liver function tests; older patients should be monitored for osteoporosis. High-dose vitamin A supplementation is contraindicated during pregnancy or for those planning to become pregnant, due to teratogenicity.

Marine omega-3 fatty acids — Docosahexaenoic acid (DHA), an omega-3 fatty acid found naturally in fish, is a major structural lipid of retinal photoreceptor outer segment membranes [8] and may be involved in rhodopsin regeneration [9]. The long-term effectiveness of DHA on the progression of RP is uncertain. We suggest that patients with RP consume a diet high in omega-3 fatty acids, but we do not suggest that patients take supplemental DHA.

Although observational studies and subgroup analyses from trial have shown possible benefit of a diet high in omega-3 fatty acids [10-13], no benefit of DHA supplementation was demonstrated in randomized trials:

●A 2013 systematic review involving three randomized trials (one of vitamin A alone, one of DHA alone, and one comparing DHA plus vitamin A with vitamin A alone) found no effect on the progression of visual field or visual acuity loss, although an effect on ERG amplitudes was demonstrated in some subgroups [14]. A subsequent randomized trial in patients with X-linked RP found that long-term DHA supplementation did not slow loss of cone or rod ERG [15].

Gene therapy — Remarkable progress has been made in the identification of the genes involved in RP and in gene therapy targeting the RPE65 gene.

Mutations in the RPE65 gene are one of the causes of RP and Leber congenital amaurosis (LCA), a form of RP present at birth [16]. This gene encodes for a protein involved in the visual cycle, which converts light entering the eye into electrical signals transmitted to the brain. Mutations lead to reduced or absent levels of RPE65 activity, with resultant blocking of the visual cycle and impaired vision.

In cases such as this, where a genetic defect leads to the loss of an encoded protein, gene-replacement therapy can provide a healthy copy of the defective gene, thus allowing the cell to produce the protein. However, timing of gene replacement in the progression of RP is critical, as adequate numbers of viable photoreceptor cells must still be present to produce enough of the missing protein to restore visual function. This is because mutations in retinitis pigmentosa cause the death of rod photoreceptors through apoptosis. In late stages of the condition when most of the rods have been eliminated, cones secondarily slowly degenerate due to progressive oxidative damage [17].

In 2017, the US Food and Drug Administration (FDA) approved voretigene neparvovec-rzyl (Luxturna), the first directly administered gene therapy that targets RPE65. Voretigene neparvovec-rzyl uses an adeno-associated virus using recombinant DNA techniques and is delivered by a single subretinal injection by a retina specialist. The retinal cells then produce the protein that converts light to an electrical signal in the retina [18].

This treatment is approved for patients with biallelic (having both a paternal and a maternal mutation) RPE65 mutation-associated retinal dystrophy (chronic, bilateral, and progressive disorders of visual function, including RP). This condition affects approximately 1000 to 2000 patients in the United States and is associated with progressive vision loss. This loss of vision can begin as early as the first few months of life (LCA), or during childhood or adolescence, and ultimately progresses to complete blindness.

Voretigene neparvovec-rzyl represents a significant therapeutic advance which may provide improvement in vision and prevent further deterioration. However, cautious optimism is necessary, as the drug is not expected to restore normal vision, and only about half of treated patients had minimally meaningful improvement in short-term studies [19]. Long-term clinical evidence is pending.

In the United Kingdom, the National Institute for Health and Care Excellence (NICE) has recommended voretigene neparvovec-rzyl for eligible patients who have enough viable retinal cells. In England, an estimated 86 people will be eligible for treatment [20].

Experimental therapies

Retinal cell transplantation — The potential for transplanted retinas, retinal sheets, and clumps of retinal neurons to restore vision in mice and humans with RP has been under investigation since the 1980s. Until recently, transplanted tissue or cells have not developed synaptic connections with host cells and thus have not had functional impact [21,22].

The potential for transplantation of fetal retinal pigment epithelium to rescue abnormal photoreceptors in RP is being investigated. After fetal retinal implantation into six patients with RP, slight improvement in visual acuity was seen in three patients (one patient with bilateral improvement including the eye that did not receive the transplant) although the extent of improvement was not clinically significant [23]. Integration of donor cells into the host retina is dependent upon the stage of cell differentiation at the time of donor harvest [24]. Successful integration of committed fetal progenitor cells that developed into functional rod photoreceptors was demonstrated in a mouse model of RP [24]. Transplanted cells did not integrate into the retina in mice with more active disease and more rapid retinal degeneration.

Regulatory and ethical issues with use of human fetal retinal cells has led to exploration of human embryonic stem cells that might be induced to differentiate into photoreceptor progenitor cells [25]. Such stem cells may also produce factors that enhance survival of host photoreceptors, as demonstrated in mouse models [26,27]. In addition, mouse embryonic stem cells can be used to create a complex three-dimensional array of retinal cells [28].

A human clinical trial, the Safety Study in Retinal Transplantation for Retinitis Pigmentosa, has completed enrollment [29]. Its long-term goal is to determine if transplantation can prevent blindness or restore eyesight in patients with RP.

Retinal prosthesis devices — Devices are being tested that transduce light into electrical signals and transmit this information directly to the inner retina (bypassing the diseased outer retina of RP), optic nerve, or occipital visual cortex. Patients involved in studies of these devices have reported seeing flashes of light and have been able to sense motion, locate large objects, and recognize large letters [30-32]. There are multiple retinal prostheses in clinical trials.

One retinal prosthesis system (Argus II) converts video images captured from a very small camera housed in the patient’s glasses into a series of small electrical impulses that are wirelessly transmitted to an array of 60 electrodes on the retina [33]. The Argus II was the first artificial retina to receive widespread commercial approval. Second Sight has discontinued new implants of the Argus II system. Vision restoration is theoretically correlated with the number of electrodes. Newer generations of prostheses have increasingly more electrodes, with one in the development phase with over 1000 electrodes [34]. Retinal prostheses have the potential to enhance the quality of life of RP patients by aiding in object recognition, mobility, and independent living.

OTHER INTERVENTIONS

Treatment of macular edema — Cystoid macular edema can reduce central vision in later stages of retinitis pigmentosa (RP). The most successful treatment thus far is the oral carbonic anhydrase inhibitor acetazolamide. Acetazolamide increases fluid absorption across the retinal pigment epithelium. In the absence of macular edema, carbonic anhydrase inhibitors do not improve vision or alter the course of electroretinography (ERG) degradation in patients with RP [35].

In a small crossover trial, 10 of 12 patients with RP and chronic macular edema demonstrated objective and subjective improvement in visual acuity when treated with acetazolamide 500 mg/day [36]. Side effects include peripheral paresthesias, loss of appetite, fatigue, renal stones, and anemia. Methazolamide has fewer side effects but may be less effective [37]. Rebound edema has been reported due to tachyphylaxis to oral carbonic anhydrases [38,39].

Dorzolamide, a topical carbonic anhydrase inhibitor, may be effective for patients who cannot tolerate the systemic effects of oral carbonic anhydrases [40]. In a retrospective cohort study of 32 patients with cystoid macular edema from RP and Usher syndrome who received dorzolamide, 10 patients (31 percent) had improved visual acuity by ≥7 letters [41].

Case reports of the use of intravitreal triamcinolone in patients with RP and macular edema describe a limited and transient response [42,43]. Large randomized trials have not been conducted.

Cataract extraction — Posterior subcapsular cataracts develop in 35 to 51 percent of adult patients with RP [44-46]. Central vision may improve with cataract extraction. However, patients must be counseled that there will be no improvement in their visual field and no impact on progression of disease.

Light restriction — Although reduced light exposure decreased the rate of photoreceptor loss in two animal models of RP [47,48], there are no data in humans to support advising patients to limit their exposure to light. Two case studies, involving patients with RP who had restricted light exposure to one eye but not the other, found no difference in ERG results or ophthalmoscopic appearance between the eyes [49,50].

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 5^th to 6^th 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 10^th to 12^th 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 AND RECOMMENDATIONS

●There is no cure for the photoreceptor loss or retinal epithelial damage associated with simple retinitis pigmentosa (RP). Some rare forms of RP, associated with multiorgan involvement, are due to specific nutritional deficiencies and may respond to dietary modification or vitamin supplementation. (See 'Vitamin and nutritional supplementation' above.)

●High-dose vitamin A supplementation may slow the rate of decline of the amplitude of the cone photoreceptor electroretinography (ERG) response but has not been shown to slow loss of vision. Except for patients with abetalipoproteinemia, we suggest not treating patients with high-dose vitamin A (Grade 2B). Except for patients with rare syndromes of RP related to vitamin E deficiency, we suggest patients with RP not take supplemental vitamin E (Grade 2B). (See 'Vitamin A' above.)

●The long-term effectiveness of docosahexaenoic acid (DHA), an omega-3 fatty acid, on progression of RP is uncertain. No benefit of DHA supplementation was demonstrated in randomized trials, although observational studies have shown possible benefit of a diet high in omega-3 fatty acids. Until results are available from additional trials, we suggest that patients with RP consume a diet high in omega-3 fatty acids, but we suggest that patients not take supplemental DHA (Grade 2C). (See 'Marine omega-3 fatty acids' above.)

●New or experimental approaches to treatment for RP include gene therapy, transplantation of fetal retinal cells or stem cells, and electronic retinal prostheses. (See 'Gene therapy' above and 'Experimental therapies' above.)

●We recommend that patients with macular edema and RP be treated with an oral carbonic anhydrase inhibitor (Grade 1B) (see 'Treatment of macular edema' above). A topical carbonic anhydrase inhibitor is an alternative in patients who do not tolerate the oral formulation.

●Patients with RP and posterior cataracts will likely benefit from cataract extraction. There is no evidence that reduced light exposure provides benefit for RP patients. (See 'Other interventions' above.)