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Track No. 1: Strategies for the diagnosis and management of retinitis pigmentosa

BY RON P. GALLEMORE, MD, PHD; ANDREW SHYU, MD; and JOHN R. HECKENLIVELY, MD

RETINITIS PIGMENTOSA: OPTIMIZING CARE FOR YOUR PATIENTS

Retinitis pigmentosa (RP) is diagnosed in approximately one in every 4000 people, and it is one of the most common inherited retinal diseases

in the world. It is characterized by the degeneration of rod photoreceptors.

Although most patients with end-stage RP are legally blind, the disease progresses to varying degrees of vision loss depending on genetics, penetrance, associated conditions, secondary involvement of the cone photoreceptors, and treatment. With the US Food and Drug Administration (FDA) approval of the Argus II Retinal Prosthesis (Second Sight) for the management of advanced cases, it is appropriate to review the latest strategies for the diagnosis and management of RP.

DIAGNOSISThe diagnosis of RP begins with the clinical history

and an examination. Typically, patients present with a complaint of night vision loss, although decreased visual acuity, bumping into objects, or glare are also common. RP is genetically linked, with 20% of cases being autosomal dominant (18 genes identified to date), 13% autosomal recessive (23 genes), and 8% X-linked recessive (2 genes).1 In dominant RP, some patients may ignore their symptoms, as they often observe them in other family members.

A clinical examination usually reveals the classic bone spicule pigmentary degeneration in the far periphery along with arterial attenuation and waxy pallor of the optic nerve.2 Sectoral RP (usually inferonasal), unilateral

RP, nonpigmented RP (sine pigmento), and limited pigmentation can also occur.3-5

ASSOCIATED CONDITIONSPatients with RP have associated treatable ocular

disorders, and these should not be overlooked. RP may be associated with cystoid macular edema (CME), Fuchs heterochromic uveitis, posterior subcapsular (PSC) lens

Figure 1. Red-free (A) and autofluorescent (B) images in a patient

with advanced retinitis pigmentosa (RP) with visual acuity of

20/25 OD, 20/40 OS. Autofluorescence is used to help quantify

the macular damage in RP.

A

B

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TABLE 1. RECOMMENDED DIAGNOSTIC TESTS FOR PATIENTS WITH RP.Diagnostic Test Purpose

Montage fundus photos (FF) Characterize phenotype; monitor progression

Fluorescein angiography (FA) Identify CME and vascular leakage

Optical coherence tomography (OCT) Quantify macular edema, assess retinal nerve fiber layer

Goldmann visual field (GVF) Quantify field loss over time

Retinal acuity meter (RAM) Quantify visual potential

ffERG Assess functional retinal activity, identify combined rod-cone dystrophy

mfERG Quantify macular function

Specific serum antiretinal antibodies Identify presence of antiretinal autoantibodies

Microperimetry Assess macular function

Autofluorescence Quantify macular damage, monitor progression

Genetic testing Identify genotype, monitor progression

FTA-abs, RPR Rule out pseudo-RP

LFTs, vitamin A and DHA levels Quantify baseline values before starting supplements

Figure 2. Pre- and post-dexamethasone intravitreal implant OS of a patient with vitreous inflammation, cystoid macular edema (CME),

and retinitis pigmentosa (RP). Optical coherence tomography (OCT) studies showed a decrease in macular thickness, and fluorescein

angiography (FA) studies showed a decrease in hyperfluorescence in late studies. The patient noted an improvement in corrected visual

acuity from 20/50+1 to 20/30-2 OS. This is the same patient as in Figure 1.

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opacities, primary angle closure glaucoma, choroidal neovascularization, macular hole, and Coats disease.6-13

DIAGNOSTIC TESTINGSome specialists advise limited testing for patients with

RP because it may not affect management. There is also

the concern that bright-flash photography may accelerate retinal degeneration.14,15 Ancillary testing, however, provides support for the diagnosis and can affect disease management. As shown in Table 1, we recommend a full spectrum of baseline tests, including fundus photography and fluorescein angiography (FF/FA), optical coherence

TABLE 2. ASSOCIATED CONDITIONS AND CORRESPONDING TREATMENT PLANS FOR RP PATIENTSDiagnosis Treatment

Posterior subcapsular cataract Cataract extraction and intraocular lens

Cystoid macular edema Steroid (drop, injection, implant), carbonic anhydrase inhibitor (CAI; topical or pill), NSAID (drops), anti-VEGF (injection)

Vitreomacular traction, macular hole Vitrectomy

Retinal degeneration Vitamin A, lutein, zeaxanthin, DHA; avoid vitamin E

Glaucoma Topical CAI, avoid prostanoids

Choroidal neovascularization Anti-VEGF injections

Uveitis Steroid (drop, injection, implant), CAI (topical or pill), NSAID (drops), anti-VEGF (injection)

Figure 3. A patient with epiretinal membrane (ERM) and associated vitreomacular traction (VMT) underwent pars plana vitrectomy (PPV) and

membrane peeling OS. The fovea remained intact with corrected VA improved from 20/70-2 to 20/60 OS. The patient subsequently developed

a macular hole associated with cystoid macular edema (CME) OS and underwent PPV, membrane peeling, posterior sub-Tenon (PST) injection,

and gas. The hole closed with a decrease in macular thickness and an improved corrected visual acuity from 20/60-1 to 20/50-2 OS.

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tomography (OCT), Goldmann visual field (GVF), full-field electroretinogram (ffERG), and multifocal ERG (mfERG).

In select cases, microperimetry and autofluorescence images (Figure 1) are also obtained. Liver function tests (LFTs) and vitamin A baseline levels are also advised before considering vitamin A therapy. Rapid plasma reagin (RPR) and fluorescent treponemal antibody absorption (FTA-abs) tests are also necessary to rule out pseudo-RP from syphilis. Additionally, blood serum tests for antiretinal antibodies and genetic mutations should be considered.

Some clinicians recommend OCT testing alone to rule out CME, as OCT studies have been shown to be useful for both the diagnosis of CME and treatment response monitoring.16 Because there are cases of CME in the absence of frank cystic changes on the OCT, we advise that FA studies be performed in all cases. Montage fundus photos can document the distribution of phenotypic changes, and an FA will reveal CME as well as vasculitis, if present. Furthermore, it has been noted that 37% of RP patients and 90% of RP patients with CME have an autoimmune condition with autoantibodies to retinal cells, and a blood serum test for antiretinal antibodies can detect this.17,18

ERG testing is often underutilized. While the scotopic and photopic systems may be extinguished in advanced RP, ERG can be very useful in testing patients who are young, have incomplete penetrance, or have fundus changes, as well as for monitoring changes over time. Some patients do not exhibit frank changes of RP, in which case the suppressed scotopic response will support the diagnosis, particularly a decrease in amplitude and delayed b-wave

response.19 An mfERG may also be used to assess periph-eral macular function in cases where the ffERG amplitudes may be equivocal as the central-to-peripheral response difference can help in the diagnosis.20

Retinal acuity meter (RAM) testing is a critical aspect of evaluating retinal function in RP patients with cataract. PSC cataracts are often underdiagnosed and undertreated in patients with RP.8 Some clinicians assume that cataract extraction would be of limited benefit and may not carefully examine the lens with retroillumination for opacities. When an early PSC cataract is noted, they may assume that the retinal problem outweighs the cataract noted on examination. Although RAM testing can under- or overestimate the visual potential, it is still a useful tool that can estimate potential visual acuity following cataract surgery.

TREATMENTThere are a number of recommended treatment options

for RP patients with associated conditions, as shown in Table 2. Randomized controlled studies have shown that high-dose vitamin A (retinyl palmitate, 15000 U/d) slows the rate of vision field loss, and patients are 32% less likely to have a 50% or more decrease in ERG baseline amplitude per year.

On the other hand, high-dose vitamin E (400 U/d) may accelerate field loss, with a 42% increased chance of having a 50% or more decrease in patients’ ERG baseline amplitude per year.21 Patients with X-linked RP have significantly lower docosahexaenoic acid (DHA) levels than control subjects, and the administration of

Figure 4. In the Argus II system, a receiver in the glasses captures images and wirelessly transmits these signals to a 60-electrode diode

array. This epiretinal implant stimulates the healthy ganglion cells to send signals to the optic nerve and brain for image interpretation

(A). A fundus photo of the Argus II Retinal Implant placed epiretinally (B).

(Courtesy of Lawrence Livermore National Laboratory; Elaine Leibenbaum

, Carl Regillo, MD, and Sunir Garg, M

D.)A B

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DHA (1200 mg/d) has been shown to lessen the rate of RP when given for 2 years with vitamin A.22-25 Lutein (12 mg/d), when supplemented with vitamin A, has lessened the rate of midperipheral visual field loss in nonsmoking adults with RP.26 Additionally, lutein and zeaxanthin may improve the macular pigment and reduce central vision loss.27

CME is prevalent in 70% of RP patients,6 and there are several treatment options. Oral carbonic anhydrase inhibitors (CAIs), such as acetazolamide and methazolamide, have been clinically shown to improve visual acuity, perhaps by stimulating fluid transport across the RPE.28-30

Both CAIs and intravitreal triamcinolone acetonide (IVTA) injections may improve macular edema and visual acuity in RP patients,31,32 but they can also result in rebound macular edema with continued use.31-33 In addition, topical CAIs, such as dorzolamide and brinzolamide, may reduce CME and be efficient. CAIs may also prevent apoptosis from carbonic anhydrase IV gene mutations.34 Some patients with RP appear to have vitreous inflammation with CME.32 The vitreous cells may be cell fragments from degenerative rods, but we

believe there can be inflammation as well. In such cases, the sustained release of the dexamethasone intravitreal implant (Ozurdex, Allergan) has shown success (Figure 2).35

An alternative is an IVTA injection, although this may be associated with a more severe pressure response and faster cataract formation as well as the potential for greater toxicity. Topical antiinflammatory drops, such as steroids and nonsteroidal drugs, may be beneficial, but controlled studies have not been performed. Although further research is needed, immunosuppressive therapy has shown long-term benefits for patients with autoimmune retinopathies and could be considered for RP patients with antiretinal antibodies.36

Anti-VEGF injections should be administered for RP patients with choroidal neovascularization. However, the usage of bevacizumab (Avastin, Genentech) is controversial for the treatment of CME. There is one negative report37 and one positive report38 demonstrating a decrease in macular thickness and improvement in visual acuity in RP patients.

Although there are limited positive results, anti-VEGF drugs could reduce macular edema without the risks

Figure 5. An overview of the Alpha IMS subretinal implant with a cable that extends from the eye to the ear (A). Location of the implant

in the eye (B). Location of the photodiodes within the retinal layers (C). Patient with implant and wireless control unit (D). Placement of

the polyimide foil and cable in orbit (E). Location of subretinal implant (F).

(Cou

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of Zr

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r, 20

11.)

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of steroids, including cataract and glaucoma. They may also be useful for patients who do not fully respond to CAIs. We have found short-term but limited long-term benefits for those patients receiving sequential injections. Vitreomacular traction (VMT) and macular holes may develop in RP patients, and standard pars plana vitrectomy with membrane peeling may be used to restore vision (Figure 3).12

Other surgical options include growth factor implants and a retinal prosthesis. Treatment with ciliary neurotrophic factor (CNTF) has been demonstrated to preserve central vision in rat models,39,40 and surgical implementations of encapsulated cell intraocular implants releasing CNTF have improved visual acuity in some RP patients.41 Further phase 2 clinical study data are still under review.

The FDA approved the Argus II for RP. The system utilizes glasses that capture images and wirelessly transmit the signals to the implant on the surface of the retina (Figure 4). This epiretinal implant contains a 60-electrode diode array, which transmits an electrical signal via contact to the retinal ganglion cells, which are relatively healthy in RP patients. The signals then travel to the optic nerve and the brain for conversion to an image. This product may only be used in advanced RP patients who are 25 years or older, have bare or no light perception in both eyes, and are pseudophakic or aphakic.

The surgery takes approximately 4 hours and requires patients to return to the clinic for 2 months of training. Preliminary results from a phase 2/3 clinical trial by Second Sight gave light perception to no light perception patients and improved functional vision including door finding, object identification, and quality-of-life scores. The system will soon be available in select clinical centers in the United States in late 2013. The system is slated to cost more than $100,000, and Second Sight is currently working with Medicare and other companies for authorization approval.42-44

Another retinal implant has been developed by Eberhard Zrenner, MD, and colleagues at the University of Tubingen, Germany (Alpha IMS, Retinal Implant AG). A total of 21 people have received this subretinal implant, which contains 1500 photodiodes and the potential to see 20/1000 within an 11 x 11º field of vision. While a battery pack is needed, patients do not need to wear hardware; they see with their eyes and not through an external camera (Figure 5). The greater number of sensors carries the potential of improved visual acuity, but larger studies with longer follow-up are required.45

FUTURE DIRECTIONSModulating neurotrophic factors may play a critical role

in the treatment of RP patients. The loss of cones late in the disease, for example, may be due in part to the loss of growth factors released by the adjacent rods. Cones do not express the genetic defects seen in RP. Photoreceptor transplantation, gene transfection, stem cell implants, and immune modulation are all areas of active research. As we identify more of the genes involved, and how to regulate programmed cell death, we will see a brighter future for patients with this disease. n

1. Daiger SP, Bowne SJ, Sullivan LS. Perspective on genes and mutations causing retinitis pigmentosa. Arch Ophthalmol. 2007;125(2):151-158.2. Hamel, C. Retinitis pigmentosa. Orphanet J Rare Dis. 2006;1(1):40.3. Fahim AT, Daiger SP, Weleber RG. Nonsyndromic Retinitis Pigmentosa Overview. Seattle, Washington: GeneReviews [Internet]; 2000. https://www.ncbi.nlm.nih.gov/pubmed/20301590. Accessed December 14, 2017.4. Carr RE, Siegel IM. Unilateral retinitis pigmentosa. Arch Ophthalmol. 1973;90(1):21-26. 5. Pearlman JT, Flood TP, Seiff, SR. Retinitis pigmentosa without pigment. Am J Ophthalmol. 1976;81(4):417-419.6. Fetkenhour CL, Choromokos E, Weinstein J, Shoch, D. Cystoid macular edema in retinitis pigmentosa. Transactions. Section on Ophthalmology. American Academy of Ophthalmology and Otolaryngology. 1977;83(3 Pt 1).7. Chowers I, Zamir E, Banin E, Merin S. Retinitis pigmentosa associated with Fuchs’ heterochromic uveitis. Arch Ophthalmol. 2000;118(6):800-802.8. Heckenlively J. The frequency of posterior subcapsular cataract in the hereditary retinal degenerations. Am J Ophthalmol. 1982;93(6):733-738.9. Fishman GA, Anderson RJ, Lourenco P. Prevalence of posterior subcapsular lens opacities in patients with retinitis pigmentosa. Br J Ophthalmol. 1985;69(4):263-266.10. Badeeb O, Trope G, Musarella M. Primary angle closure glaucoma and retinitis pigmentosa. Acta Ophthalmol Scand. 1993;71(6):727-732.11. Iwakiri R, Okinami S, Hirata, A. Two cases of retinitis pigmentosa associated with choroidal neovascularization. Nippon Ganka Gakkai Zasshi. 2007;111(8):606-611.12. Jin ZB, Gan DK, Xu, GZ, Nao-i N. Macular hole formation in patients with retinitis pigmentosa and prognosis of pars plana vitrectomy. Retina. 2008;28(4):610-614.13. Ayesh I, Sanders MD, Friedmann AI. Retinitis pigmentosa and Coats’s disease. Br J Ophthalmol. 1976;60(11):775-777.14. Gawande AA, Donovan WJ, Ginsburg AP, Marmor MF. Photoaversion in retinitis pigmentosa. Br J Ophthalmol. 1989;73(2):115-120.15. Adrian W, Everson RW, Schmidt I. Protection against photic damage in retinitis pigmentosa. Adv Exp Med Biol. 1977;77:233-247.16. Chung H, Hwang JU, Kim JG, Yoon YH. Optical coherence tomography in the diagnosis and monitoring of cystoid macular edema in patients with retinitis pigmentosa. Retina. 2006;26(8):922-927.17. Hooks JJ, Tso MO, Detrick B. Retinopathies associated with antiretinal antibodies. Clin Diagn Lab Immunol. 2001;8(5):853-858.18. Heckenlively JR, Jordan BL, Aptsiauri N. Association of antiretinal antibodies and cystoid macular edema in patients with retinitis pigmentosa. Am J Ophthalmol. 1999;127(5):565-573.19. Berson, EL. Retinitis pigmentosa. The Friedenwald Lecture. Invest Ophthalmol Vis Sci. 1993;34(5):1659-1676.20. Dolan FM, Parks S, Hammer H, Keating D. The wide field multifocal electroretinogram reveals retinal dysfunction in early retinitis pigmentosa. Br J Ophthalmol. 2002;86(4):480-481.21. 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):761-772.22. Hoffman DR, Birch DG. Docosahexaenoic acid in red blood cells of patients with X-linked retinitis pigmentosa. Invest Ophthalmol Vis Sci. 1995;36(6):1009-1018.23. Berson, EL, Rosner B, Sandberg MA, et al. Further evaluation of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment: subgroup analyses. Arch Ophthalmol. 2004;122(9):1306-1314.24. Berson, EL, Rosner B, Sandberg MA, et al. Clinical trial of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment. Arch Ophthalmol. 2004;122(9):1297-1305.25. Berson, EL, Rosner B, Sandberg MA, et al. Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A. Arch Ophthalmol. 2010;128(4):403-411.26. Aleman TS, Duncan JL, Bieber ML, et al. Macular pigment and lutein supplementation in retinitis pigmentosa and Usher syndrome. Invest Ophthalmol Vis Sci. 2001;42(8):1873-1881.27. Fishman GA, Gilbert LD, Fiscella RG, Kimura AE, Jampol LM. Acetazolamide for treatment of chronic macular edema in retinitis pigmentosa. Arch Ophthalmol. 1989;107(10):1445-1452.

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28. Hughes BA, Gallemore RP, Miller SS. Transport mechanisms in the retinal pigment epithelium In: The Retinal Pigment Epithelium: Current Aspects of Function and Disease. Marmor MF, Wofensberger TJ, Eds. New York, NY: Oxford Univ. Press. 1998;103-134.29. Gallemore RP, Hughes BA, Miller SS. Retinal pigment epithelial transport mechanisms and their contributions to the electroretinogram. Prog Retin Eye Res. 1997;16(4):509-566.30. Fishman GA, Gilbert LD, Anderson RJ, Marmor MF, Weleber RG, Viana MA. Effect of methazolamide on chronic macular edema in patients with retinitis pigmentosa. Ophthalmology. 1994;101(4):687-693.31. Saraiva VS, Sallum JM, Farah ME. Treatment of cystoid macular edema related to retinitis pigmentosa with intravitreal triamcinolone acetonide. Ophthalmic Surg Lasers Imaging. 2003;34(5):398-400.32. Fishman GA, Glenn AM, Gilbert LD. Rebound of macular edema with continued use of methazolamide in patients with retinitis pigmentosa. Arch Ophthalmol. 1993;111(12):1640- 1646.33. Datta R, Waheed A, Bonapace G, Shah GN, Sly WS. Pathogenesis of retinitis pigmentosa associated with apoptosis-inducing mutations in carbonic anhydrase IV. Proc Natl Acad Sci USA. 2009;106(9):3437-3442.34. Spalton, DJ, Bird AC, Cleary PE. Retinitis pigmentosa and retinal oedema. Br J Ophthalmol. 1978;62(3):174-182.35. Srour M, Querques G, Leveziel N, et al. Intravitreal dexamethasone implant (Ozurdex) for macular edema secondary to retinitis pigmentosa. Graefes Arch Clin Exp Ophthalmol. 2013;251(6):1501-1506.36. Ferreyra HA, Jayasundera T, Khan NW, He S, Lu Y, Heckenlively JR. Management of autoimmune retinopathies with immunosuppression. Arch Ophthalmol. 2009;127(4):390-397.37. Melo GB, Farah ME, Aggio FB. Intravitreal injection of bevacizumab for cystoid macular edema in retinitis pigmentosa. Acta Ophthalmol Scand. 2007;85(4):461-463.38. Yuzbasioglu E, Artunay O, Rasier R, Sengul A, Bahcecioglu H. Intravitreal bevacizumab (Avastin) injection in retinitis pigmentosa. Curr Eye Res. 2009;34(3):231-237.39. Li Y, Tao W, Luo L, et al. CNTF induces regeneration of cone outer segments in a rat model of retinal degeneration. PLoS One. 2010;5(3): e9495.40. Tao W, Wen R, Goddard MB, et al. Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2002;43(10):3292-3298.41. Sieving PA, Caruso, RC, Tao W, et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci USA. 2006;103(10):3896-3901.42. Chaderà GJ, Weiland J, Humayun MS. Artificial vision: needs, functioning, and testing of a retinal electronic prosthesis. Prog Brain Res. 2009;175:317-332.43. Humayun MS, Dorn JD, Ahuja AK, et al. Preliminary 6 month results from the Argus II epiretinal prosthesis feasibility study. Conf Proc IEEE Eng Med Biol Soc. 2009;2009:4566- 4568.44. Humayun MS, Dorn JD, da Cruz, L, et al. Interim results from the international trial of Second Sight’s visual prosthesis. Ophthalmology. 2012;119(4):779-788.45. Zrenner E, Bartz-Schmidt KU, Benav H, et al. Subretinal electronic chips allow blind patients to read letters and combine them to words. Proc R Soc Lond B Biol Sci. 2011;278(1711):1489-1497.

Ron P. Gallemore, MD, PhDn founder and director of the Retina Macula Institute and Research

Center in Los Angeles, Calif., and an assistant professor at the Jules Stein Eye Institute, University of California, Los Angeles School of Medicine

n financial interest: none acknowledged n rongallemoremd@gmail.com

John R. Heckenlively, MD n the Paul R. Lichter professor of Ophthalmic Genetics and

Ophthalmology, and visual sciences director at the Center for Retinal and Macular Degeneration at the University of Michigan, Kellogg Eye Center in Ann Arbor, Mich.

n financial interest: none acknowledgedn jrheck@umich.edu

Andrew Shyu, MDn previously an ophthalmic technician with the Retina Macula

Institute and Research Center; currently a transitional year resident and prospective resident at Temple University Ophthalmology in Philadelphia, Pa..

n financial interest: none acknowledged n apshyu@gmail.com

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