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QUESTION
WHAT SHOULD I TELL A PATIENT WITH RETINITIS PIGMENTOSA ABOUT PROGNOSIS AND SHOULD I PRESCRIBE VITAMIN A OR OTHER SUPPLEMENTS?
Jackson Abou Chehade, MD
Raymond Iezzi, MD, MS
Retinitis pigmentosa (RP) describes a specific pattern of photoreceptor degeneration in which rod photoreceptors within the retina degenerate before cones. Consequently, patients with RP commonly present with a chief complaint of nyctalopia and visual field constriction associated with their rod loss; however, visual acuity may remain normal even though the visual field may be less than 30°. In more advanced cases of RP, in the absence of rods, cone loss may occur, resulting in decreased visual acuity, color vision abnormalities, and a visual field of less than 10°.
Evaluating the Patient With Presumed Retinitis Pigmentosa
The clinical approach to a patient with suspected RP should be focused on determining if the patient does, in fact, have RP and ruling out other diagnoses that may share visual symptoms and examination findings with RP, such as vitamin A deficiency, congenital stationary night blindness, some uveitides, and autoimmune retinopathy (AIR). Thus, a structured approach to the diagnosis of RP should be considered.
History
The history should include a detailed discussion of the chief complaint and specific visual deficits. If the patient reports nyctalopia, discuss the age of onset, severity, and degree of progression, if any. Often, close family members can assist the patient, because the progression of visual deficits may be so gradual that the patient may not be able to characterize them. Ask if the patient bumps into people when walking or if he or she has had any recent fall or accidents. Remember to ask the patient if he or she is currently driving. It may be best to counsel the patient about ambulation training and driving after you have completed your assessment as these discussions require dedicated time. Information related to the duration of symptoms and factors or circumstances that worsen or improve symptoms can be helpful. Patients will often describe difficulty in transitioning between light and dark environments. Further, a patient with cone dystrophy will state that he or she sees better in dim lighting, which would not be the case for a patient with RP.
The past medical history should include a review of systems with emphasis on autoimmune, gastrointestinal, musculoskeletal, cancer, hearing loss, and medication use. Patients with hearing loss and RP may have Usher syndrome; however, RP patients may have non-Usher hearing loss as well. Genetic testing for both RP and hearing loss may be required to differentiate Usher syndrome from other diagnoses. A history of autoimmune conditions within the patient and family should be documented, as AIR patients may sometimes be referred with presumed RP. Patients with AIR may have peripheral field loss in addition to central or paracentral scotomata. AIR may present as a paraneoplastic syndrome. It is important to note that the presence of anti-retinal antibodies does not make the diagnosis of AIR as many patients have anti-retinal antibodies, particularly those with RP. Any acute or chronic retinal injury, whether it is the result of trauma or a chronic retinopathy, may expose the immune system to retinal antigens, resulting in anti-retinal antibodies. Progression of visual field loss in AIR often occurs centrally. As pathologic anti-retinal antibodies often interfere with synaptic transmission, the scotopic bright flash electroretinogram (ERG) often shows an a-wave dominated b-wave in which the electronegative amplitude deflection of the a-wave is much greater than the positive amplitude deflection of the b-wave. In many cases, the b-wave does not rise above the 0 millivolts.
The past surgical history should be organized by organ systems, paying attention to prior gastrointestinal surgery that could lead to a malabsorption syndrome and vitamin A deficiency or a prior history of surgical removal of extra digits from the hands or feet, which could be associated with RP secondary to Bardet-Biedl syndrome.
A careful family history and pedigree chart can identify patterns of familial inheritance. While RP may be sporadic with no known family history, pedigree analysis may demonstrate an X-linked recessive, autosomal recessive, or autosomal dominant pattern of inheritance. A well-documented pedigree can also identify other family members who may play an important role during genetic testing.
Physical Examination
A complete ophthalmologic examination should be performed. Confrontational visual fields should be checked for field constriction. Other common findings in RP include posterior subcapsular cataract, waxy pallor of the optic nerve, attenuation of retinal vessels, cystoid macular edema (CME), and pigment changes in the retinal periphery. Only a subset of patients with RP demonstrate bony spicule-like pigmentation changes in the retinal periphery. Often patients present with retinal pigment epithelial (RPE) depigmentation. Younger patients may not demonstrate any of these findings, but if they do it may be subtle.
Psychophysical Testing
Consider 30-2 size V FASTPAC and 60-4 size V FASTPAC. If the 30-2 field is severely constricted, consider a 10-2 size III FASTPAC visual field. Test-retest variability is lower with larger, size V targets. Goldmann-Weekers dark adaptometry testing is useful for quantitatively assessing rod and cone function, particularly if ERG is not available. On a basic level, the most important role of ERG testing in establishing the diagnosis of RP is to determine the health of the rods vs the cones. RP manifests with rod loss before cone loss, whereas cone dystrophy presents with cone loss before rod loss. Cone dystrophy patients usually have more pronounced photophobia, decreased acuity on presentation, and early color vision abnormalities as compared to RP patients who usually have excellent visual acuity and less pronounced photophobia and less color vision abnormalities. In the absence of CME, RP patients manifest with retina-related decreases in visual acuity in the latest stages of their disease when the visual field is usually less than 10° or 15°.
Objective Testing
IMAGING
Optical coherence tomography (OCT) is the safest and most useful imaging modality for the evaluation of RP. It is very sensitive in demonstrating CME—the most treatable retina-related cause of decreased vision in RP patients. The invisible wavelengths used for OCT imaging pose no threat of inducing phototoxicity in susceptible patients. It has been shown that a single set of fundus photographs with a standard fundus camera induced irreversible light-induced retinal degeneration in an autosomal dominant canine RP model.1 Consequently, clinicians should consider whether or not color fundus photographs are required and if the findings they elucidate, above and beyond the physical examination, would alter treatment or not.
ELECTROPHYSIOLOGICAL TESTING
Electroretinography plays a key role in establishing the diagnosis of RP and in differentiating RP from cone-rod dystrophy, congenital stationary night blindness, and AIR. Typically, full-field scotopic and photopic ERG testing is performed. The International Society for Clinical Electrophysiology of Vision (ISCEV) has set standards for ERG testing. In addition to these, the scotopic 0.2 candela-sec/M2 is an averaged and highly amplified full-field flash ERG that provides recordable response amplitudes, often in the setting of abolished standard ISCEV ERG responses.2 The multifocal ERG is most useful in the evaluation of patients with cone dystrophy or AIR.
GENETIC TESTING
As gene therapy emerges for several forms of RP, a molecular diagnosis is required to determine if a patient is eligible for treatment, making genetic testing essential in the care and management. Over 150 genetic RP variants have been identified, and while classical first-generation Sanger sequencing is very effective at identifying specific mutations within a single gene, Next-Gen sequencing, organized into disease-specific targeted gene panels, is very useful in identifying genetic mutations that may not have been sequenced using a la carte Sanger sequencing testing.3 Prior to the availability of Next-Gen sequencing studies, clinicians ordered sequencing for individual genes or small groups of genes using Sanger sequencing. This experience is like trying to find a needle in a haystack. Often these tests reveal no clinically significant mutations. Consequently, they are most useful when the most likely clinical diagnosis includes very few differential diagnoses. Next-Gen sequencing provides the opposite experience in several ways. It is very useful in identifying clinically significant genetic mutations when the disease phenotype, such as RP, includes several possible genotypic forms of the disease. Because a typical retinal degeneration targeted gene panel reports on the sequences of over 200 genes, it can often be difficult to interpret the test results without the guidance of a genetic counselor. Often, after a genetic abnormality is found that is consistent with the suspected disease, or a variant of unknown significance is found, additional genetic testing must be performed either in the patient’s parents and siblings, or Sanger sequencing is needed to confirm the molecular diagnosis. Consequently, referral to a genetic counselor who has an interest in ophthalmologic diseases is strongly recommended. Consultation with the genetic counselor includes a pretesting history and pedigree analysis as well as counseling. Genetic testing is more efficiently directed and genetic testing results counselling is provided. In some markets, insurance providers deny payment for genetic testing unless ordered by a board-certified medical geneticist.
What to Tell Your Patients With Retinitis Pigmentosa
RESOURCES
Faced with the possibility of going completely blind (which is rather small), patients with RP are often seeking information about the availability of emerging treatments and what they can do to slow down the progression of their RP. Patients with RP are among the most informed about their condition, particularly because the condition may be inherited. Consequently, many patients with familial disease are concerned for their children and other family members. Consider providing your patients with quality informational resources, such as those available through Research to Prevent Blindness (www.rpbusa.org) and Foundation Fighting Blindness (www.blindness.org). Organizations such as these allow patients with retinal degenerations to meet others and encourage participation in awareness and fundraising activities.
NUTRITION
Up to 96% of patients with RP reported the use of complementary and alternative medicine, with 75% reporting nutritional or vitamin therapy.4 Prior prospective, randomized clinical trials in patients with RP showed that those taking 15,000 IU of vitamin A, in the difficult to find form, retinyl palmitate, had a slower decline in full-field ERG cone responses compared to controls.5 Psychophysical studies, however, did not differ between the treatment and control cohorts. Consequently, it remains unclear if high-dose vitamin A is clinically relevant in patients with RP. While there were no serious adverse events in the treatment cohort in this study, the long-term safety of such therapy remains a question. Vitamin A is contraindicated in pregnancy as it is a known teratogen. It also increased lung cancer risk in smokers and has been associated with osteopenia and hepatotoxicity. Therefore, patients on high-dose vitamin A therapy require regular liver function and medical evaluation.
In a 4-year prospective placebo-controlled trial of docosahexaenoic acid (DHA) in patients with X-linked RP, no difference in ERG function was noted between DHA and placebo groups. No severe adverse events were noted; however, gastrointestinal upset was observed in some. A second analysis of the data showed that DHA supplementation significantly reduced the rate of visual field loss and loss of sensitivity of dark adaptometry thresholds.6
GENE THERAPY
Several prospective clinical trials are studying the effects of adeno-associated virus (AAV)-assisted gene therapy. These include an AAV-RPGR that is designed to replace lost retinitis pigmentosa GTPase Regulator (RPGR) protein function for patients with X-linked RP (XLRP). The RPGR-mediated form of XLRP accounts for up to 70% of all cases.
While there are several forms of Leber congenital amaurosis, the RPE65 gene-mediated form can now be treated with the first FDA-approved AAV, containing RPE65 cDNA in the United States. In addition, there is a gene therapy trial for choroideremia in which AAV-REP1 is designed to replace the lost function of the Rab escort protein 1 (REP1). All of these treatments require an appropriate molecular diagnosis, demonstrating the importance of genetic testing at the present time.
SENSORY SUBSTITUTION TECHNOLOGY
For patients who have lost all of their sight due to advanced RP, several approaches to restore rudimentary forms of vision are either Food and Drug Administration (FDA)–approved or in clinical or preclinical trials. Optogenetics involves delivering a microbial rhodopsin into the retinal ganglion cells (RGCs) via an AAV. Currently in Phase I clinical trials, this treatment involves injecting a channelrhodopsin-AAV vector into the vitreous. Channelrhodopsin is a light-activated ion channel that once inserted into the RGC membrane renders the cell light-sensitive. Patients would wear a set of glasses with a camera and light projectors. A computer within the system converts processed images from the camera into a higher-intensity image, more akin to the type of input that ganglion cells would receive from the outer retina. This image is projected onto the retina to theoretically restore rudimentary vision. One of the benefits of such an approach is that if it works, it may restore widefield vision, leveraging all of the remaining RGC over the entire retina. While results of the Phase I trial are not available at this time, preclinical animal studies demonstrated restoration of light-mediated behaviors.7
Currently, the Argus II retinal prosthesis (Second Sight Medical Products) is the only FDA-approved visual prosthesis. The device employs a camera and a visual processing unit that converts visual scenes into a series of electrical stimulation pulses, delivered to the retina via an epiretinal electrode array. While the electrode array is implanted onto the retinal surface within the macula, the antenna and active electronics package is placed around the eye like a scleral buckle. Percepts are unlike any form of natural vision; however, patients report that the device provides enough of a visual percept to allow them to identify the edges and locations of objects. Patients experience the device like a visual aid that assists them in navigation and activities of daily living. The utility of the retinal prosthesis improves as patients become more experienced with its use.
Patients should be encouraged to seek occupational therapy for ambulation training. It is better for them to do this while their vision is still good. Use of a cane can improve a patient’s confidence in ambulation and may reduce some of the isolation that can come with severe vision loss. When others see the patient’s cane, her or she knows to navigate in a manner to avoid collisions while walking. If an RP patient ultimately goes on to require gene therapy, optogenetics, or retinal prosthesis treatment, experience with ambulation using a cane and a guide dog, if available, can greatly improve the response to treatment.
References
1. Sudharsan R, Simone KM, Anderson NP, Aguirre GD, Beltran WA. Acute and protracted cell death in light-induced retinal degeneration in the canine model of rhodopsin autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2017;58(1):270-281. doi: 10.1167/iovs.16-20749
2. Berson EL. Long-term visual prognoses in patients with retinitis pigmentosa: the Ludwig von Sallmann lecture. Exp Eye Res. 2007;85(1):7-14.
3. Retinal Information Network. http://www.sph.uth.tmc.edu/Retnet/. Accessed April 27, 2018.
4. Kiser AK, Dagnelie G. Reported effects of non-traditional treatments and complementary and alternative medicine by retinitis pigmentosa patients. Clin Exp Optom. 2008;91(2):166-76. doi: 10.1111/j.1444-0938.2007.00224.x
5. Berson EL, Rosner B, Sandberg MA, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993;111(6):761-72.
6. Hoffman DR, Hughbanks-Wheaton DK, Spencer R, et al. Docosahexaenoic acid slows visual field progression in X-linked retinitis pigmentosa: ancillary outcomes of the DHAX trial. Invest Ophthalmol Vis Sci. 2015;56(11):6646-53. doi: 10.1167/iovs.15-17786
7. Pan ZH, Lu Q, Bi A, Dizhoor AM, Abrams GW. Optogenetic approaches to restoring vision. Annu Rev Vis Sci. 2015;1:185-210. doi: 10.1146/annurev-vision-082114-035532
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