Dr.Giridhar.A Giridhar Eye Institute CochinGiridhar Eye Institute
Retinitis pigmentosa Retinitis pigmentosa is a clinically and genetically heterogeneous group of hereditary disorders in which there is progressive loss of photoreceptor and pigment epithelial function. The prevalence of retinitis pigmentosa is between l/3000 and 1/5000 making it one of the most common causes of visual impairment in all age groups.
Introduction Retinitis pigmentosa, the most frequent cause of inherited retinal degeneration in patients, is caused by mutations in a number of retina-specific genes. Patients with retinitis pigmentosa typically experience nyctalopia in adolescence or early adulthood because of primary degeneration of their rods, usually beginning in the midperipheral retina. As the disease progresses, death of both rods and cones gives rise to a characteristic ring-shaped scotoma that expands with time to involve the far periphery and maculaBerson EL. Retinitis pigmentosa: unfolding its mystery. ProcnatlacadSci U S A1996;93:4526–4528.
Introduction Essential diagnostic criteria include Bilateral involvement Peripheral visual field loss Rod-dominated photoreceptor dysfunction (documented by either an elevated dark adaptation threshold or electroretinogram amplitude reduction) Progression of the disease. Common eye findings are : Posterior subcapsular cataract Degeneration of the vitreous Waxy yellow optic disk atrophy Narrowed retinal vessels Irregular reflexes of the inner limiting membrane Midperipheral atrophy of the pigment epithelium Bone spicule pigmentation.
Macular changes Fishman et al”’ reported three types of macular lesions in retinitispigmentosa patients: Group 1 - 58%~ of patients had atrophy of the macular area with thinning of the retinal pigment epithelium and mottled transmission defects on fluorescein angiography. Group 2 - 19%’ showed cystic lesions or partial thickness holes within the macula with radial, inner retinal traction lines and/or various degrees of preretinal membranes causing a “surface wrinkling phenomenon”, among these patients the overall clinical severity of the retinal degeneration varied, but several had minimal retinal changes in the periphery. Group 3 - 23%) of patients had cystoid macular edema and evidence of increased capillary permeability on fluorescein angiography These patients, like those in Group 2, had minimal or no pigmentary changes in the midperiphery, suggesting more recent onset or less severe retinitis pigmentosa
Vitreous changes The great majority of retinitis pigmentosa patients have changes in the vitreous.Pruett et al has classified into four groups: Stage I - fine colorless dust-like particles evenly distributed throughout the vitreous Stage II - posterior vitreous detachment; Stage Ill - vitreous condensation with the appearance of a matrix or reticulum of spindle-shaped condensations and/or cotton ball-like opacities Stage IV - collapse of the vitreous with greatly reduced volume.
Introduction RP can be passed on by all types of inheritance: 20% of RP is autosomal dominant (ADRP), 20% is autosomal recessive (ARRP) 10% is X linked (XLRP), while the remaining 50% is found in patients without any known affected relatives Patients with RP who were at least 45 years or older found the following findings: 52% had 20/40 or better vision in at least one eye, 25% had 20/200 or worse vision 0.5% had no light perception.Grover S, Fishman GA, Anderson RJ, et al. Visual acuity impairment in patients withretinitis pigmentosa at age 45 years or older. Ophthalmology. Sep 1999;106(9):1780-5
The Pathology Earlier histologic studies of photoreceptors in retinitis pigmentosa retinas demonstrated outer segment shortening and progressive loss of these critical cells Milam AH, Li Z-Y, Fariss RN. Histopathology of the human retina in retinitis pigmentosa. ProgRetin Eye Res 1998;17:175–205 Recent studies revealed that peripheral rods in degenerating retinas with retinitis pigmentosa undergo a remarkable process of neurite sprouting, forming long axon-like processes that extend through the outer plexiform layer into the inner retina Li Z-Y, Kljavin IJ, Milam AH. Rod photoreceptor neurite sprouting in retinitis pigmentosa. J Neurosci1995;15:5429– 5438. Milam AH, Li Z-Y, Cideciyan AV, Jacobson SG. Clinicopathologic effects of the Q64ter rhodopsin mutation in retinitispigmentosa. InvestOphthalmol Vis Sci1996;37: 753–765.
Retinal layers(A) Normal human retina . RPE 5 retinal pigment (B)Retinitis pigmentosa retina. The retina is thinepithelium; OS 5 outer segments; ONL 5 outer nuclear because many photoreceptors have died and thelayer; OPL 5 outer plexiform layer; INL 5 inner nuclear remaining photoreceptors lack outer segments. Somelayer; IPL 5 inner plexiform layer; GCL 5 ganglion cell photoreceptor somata are retained in the outerlayer nuclear layer, adjacent to the retinal pigment epithelium..The outer plexiform layer is thinned but the inner nuclear layer, inner plexiform layer, and ganglion cell layer appear relatively normal.
Immunolabeling of Rod Photoreceptors With Anti-opsin (Green) In Normal and Retinitis Pigmentosa Retinas .(C) Opsinimmunolabeling (green) is strongest in the outer segments (OS) and weak in the plasma membranes ofrod somata in the outer nuclear layer and synapses in the outer plexiform layer. (D) Retinitis pigmentosa Thesurviving rods are opsin positive (green) but few retain outer segments. Rod neurites (arrows) extend past theinner nuclear layer, and some terminate in the ganglion cell layer
Neurite sprouting Rods, amacrine and horizontal cells undergo neurite sprouting in human retinas with retinitis pigmentosa. These changes in the retinal neurons may contribute to the electroretinographic abnormalities and progressive decline in vision noted by patients with retinitis pigmentosa. These alterations may also complicate strategies for treatment of retinitis pigmentosa.
ImmunolabelingRetinitis pigmentosa retina .Localization of opsin (green) in rods in the outernuclear layer (ONL) and glialfibrillary acid protein (red) in reactive Mullercells(red).
Investigations Conventional investigations: Electroretinography – ERG Dark Adaptation and Visual Sensitivity Visual Field Fundus Reflectometry Contrast Sensitivity The Electrooculogram – EOG The Visually Evoked Response Fluorescein Angiography Vitreous Fluorophotometry
SD OCT in RP The functional and morphologic data for the patients with classic RP and without macular complications were not significantly different from those for healthy patients. SD OCT enables to obtain more precise information about the changes in macular status.
SD OCT in RP 1 2 3 41. A retinitis pigmentosa (RP) patient with no abnormalities2. Macular edema3. Vitreomacular traction4. Retinal thinning
Microperimetry A picture of the fundus in a patient with retinitis pigmentosa is overlaid with microperimetry (MP-1) results, showing no retinal sensitivity in the peripheral visual field.
TheHyperautofluorescent Ring Progressive constriction of the hyperautofluorescent ring and a concordant decrease in IS/OS junction length are observed over time.
History of genetics in RP The striking pedigree by Franceschetti (1953) was reproduced in the book by Francois (1961). Boughman et al. (1980) estimated the overall frequency at about 1 in 3,700, whereas the incidence of the recessive type, with at least 2 genocopies, was estimated to be about 1 in 4,450. No evidence of ethnic heterogeneity was found. Heckenlively et al. (1981) identified 43 cases of autosomal recessive RP among the Navajo Indians. In Shanghai, Hu(1982) analyzed 151 pedigrees with 209 cases of RP. Of these cases, the proportions of autosomal recessive (AR), autosomal dominant (AD), X-linked recessive (XR), and simplex cases were 33.1, 11, 7.7 and 48.3%, respectively.
Genetics in RP The greatest roadblock to molecular diagnosis of RP is the availability of genetic testing. THE GOALS AHEAD IN MOLECULAR GENETICS :1. Most of the genes causing RP must be identified.2. It must be possible to detect nearly all of the disease- causing mutations within these genes.3. Mutation testing must become inexpensive, reliable, and widely available.4. We must be able to understand, interpret, and explain the molecular information.
The total prevalence is 1 case per 3100 persons (range, 1 case per 3000 persons to 1 case per 7000 persons), or 32.2 cases per 100 000 persons.Haim et al. Epidemiology of retinitis pigmentosain Denmark. ActaOphthalmol Scand Suppl.2002;233:1-34.
Why finding the underlying disease causingmutation should matter to the patient or theclinician? Identifying the underlying mutation(s) can establish the diagnosis Knowing the genetic cause is essential for family counseling and for predicting recurrence risk and prognosis. Each new mutation that is found contributes to a better understanding of ocular biology The era of gene-specific and mutation specific treatments for inherited retinal diseases is quickly approaching**Bennett J. Gene therapy for Leber congenital amaurosis. Novartis Found Symp.2004;255:195-202.Chader GJ. Beyond basic research for inherited and orphan retinal diseases: successesand challenges. Retina. 2005;25:S15-S17
Number of mapped and identified retinaldisease genes from 1980 to 2006.
Genes and Mapped Loci Causing Nonsyndromic, Nonsystemic Retinitis Pigmentosa
Genes and Mapped Loci Causing Nonsyndromic, Nonsystemic Retinitis Pigmentosa
Genes and Mapped Loci Causing Nonsyndromic, Nonsystemic Retinitis Pigmentosa
Mutations in Genes That Cause an Appreciable Fraction of Retinitis Pigmentosa CasesPerspective on Genes and Mutations Causing Retinitis PigmentosaStephen et al Arch Ophthalmol. 2007;125:151-158
Genetic testing At least 35 different genes or loci are known to cause "nonsyndromic RP“DNA testing is available on a clinical basis for: RLBP1 (autosomal recessive, Bothnia type RP) RP1 (autosomal dominant, RP1) RHO (autosomal dominant, RP4) RDS (autosomal dominant, RP7) PRPF8 (autosomal dominant, RP13) PRPF3 (autosomal dominant, RP18) CRB1 (autosomal recessive, RP12) ABCA4 (autosomal recessive, RP19) RPE65 (autosomal recessive, RP20)For all other genes, molecular genetic testing is available on a research basis only
RP2 Gene in X linked inheritance Researchers emphasis the screening of the RP2 gene in patients younger than 16 years characterized by X- linked inheritance, decreased best-corrected visual acuity, high myopia, and early-onset macular atrophy Patients exhibiting a choroideremia like fundus without choroideremia gene mutations should also be screened for RP2 mutations.RP2 Phenotype and Pathogenetic Correlations in X-Linked RetinitisPigmentosa Thiran et al Arch Ophthalmol. 2010;128(7):915-923
Management of RP (Current perspective ) Vitamin A/beta-carotene Antioxidants may be useful in treating patients with RP. A recent comprehensive epidemiologic study concluded that very high daily doses of vitamin A palmitate (15,000 U/d) slow the progress of RP by about 2% per year. The effects are modest; therefore, this treatment must be weighed against the uncertain risk of long-term adverse effects from large chronic doses of vitamin A.
Lutein supplement Recent studies shows Lutein supplementation of 12 mg/d slowed loss of midperipheralvisualfield on average among non smoking adults with retinitis pigmentosa taking vitamin A.Clinical Trial of Lutein in Patients With Retinitis Pigmentosa ReceivingVitamin A Eliot et al. Arch Ophthalmol. 2010;128(4):403-411
Management of RP (Current perspective ) DHA is an omega-3 polyunsaturated fatty acid and antioxidant. Studies reported trends of less ERG change in patients with higher levels of DHA. However, a recent study compared DHA plus vitamin A to vitamin A alone in patients with RP over 4 years. Benefit of DHA was not seen. Further clinical trials must be done to determine DHA benefit.
Management of RP (Current perspective )Acetazolamide Oral acetazolamide has shown the most encouraging results with some improvement in visual function. Studies by Fishman et al and Cox et al have demonstrated improvement in Snelling visual acuity with oral acetazolamide for patients who have RP with macular edema*. Adverse effects, including fatigue, renal stones, loss of appetite, hand tingling, and anemia, may limit its use.*Fishman GA, Gilbert LD, Fiscella RG, Kimura AE, Jampol LM. Acetazolamide for treatment of chronicmacular edema in retinitis pigmentosa. Arch Ophthalmol. Oct 1989;107(10):1445-52
Management of RP (Current perspective ) Ascorbic acid 1000 mg/d Intra vitreal Triamcinolone for macular edema in RP* Rehabilitation with Low vision aids*Treatment of Cystoid Macular Edema in Retinitis Pigmentosa WithIntravitrealTriamcinolone. Lucia et al Arch Ophthalmol. 2007;125:759-764
Recent advances Transplant of Rods in Mice Retina Mice receiving rod-rich transplants demonstrated statistically significant greater cone numbers, with rescue of 40% of host cones normally destined to die during this period. Such findings indicate that transplantation of rods could limit loss of cones, thus preserving useful vision in human retinitis pigmentosa.Selective Transplantation of Rods Delays Cone Loss in a Retinitis Pigmentosa Model.SaddekMohand-Said, MD Arch Ophthalmol. 2000;118:807-811
Recent advances Sheet Transplant of Fetal Retina With Retinal Pigment Epithelium in Retinitis Pigmentosa: Norman D. Radtke and co workers transplanted a sheet of fetal neural retina with its retinal pigment epithelium into the subretinal space under the fovea unilaterally in a patient with Retinitis Pigmentosa with visual acuity of 20/800 in the treated eye.Vision Change After Sheet Transplant of Fetal Retina With Retinal PigmentEpithelium to a Patient With Retinitis Pigmentosa Norman et al Arch Ophthalmol.2004;122:1159-1165
Fetal Retinal TransplantFundus images: Arrows indicate the same blood vessel landmark in all images. A, Three weeks prior totransplantation. B, Two weeks after transplantation, showing heavy pigmentation of the transplant. Thetransplant area is outlined by white dots. C, Six months after transplantation, there is a loss of pigment. Awhite scar is recognizable at the retinotomy site. White dots outline the same area as in B. D, Twelve monthsafter transplantation, there is no change compared with 6 months.
The Hope A change in visual acuity from 20/800 to 20/400 (7 months), 20/250 (9 months), and 20/160 (1 year) was observed by ETDRS visual acuity testing. At 2 years 2 months after the surgery, the patient noted that she could definitely see better with the eye that was operated on. She could also read the large-print Reader’s Digest and print on the computer with the eye that was operated on that she could not read with the other eye.
Artificial Silicon Retina Microchip The ASR microchip is a 2-mm-diameter silicon-based device that contains approximately 5000 microelectrode- tipped microphotodiodes and is powered by incident light. The right eyes of 6 patients with retinitis pigmentosa were implanted with the ASR microchip while the left eyes served as controls. Safety and visual function information was collected.The Artificial Silicon Retina Microchip for the Treatment of Vision LossFrom Retinitis Pigmentosa Alan Y. Chow, MD Arch Ophthalmol. 2004;122:460-469
ASR MICROCHIP B -The ASR microchipA -The ASR’s size relative to a penny. (original magnification ×36).C-The ASR pixels D -Subretinal location of the implanted ASR(original magnification 1400). microchip.
ASR Implant Fundus photographs and fluorescein angiograms of an implanted artificial silicon retina microchip in the superior temporal retina.
The Hope No significant safety-related adverse effects were observed. Subjective improvements included improved perception of brightness, contrast, color, movement, shape, resolution, a nd visual field size The observation of retinal visual improvement in areas far from the implant site suggests a possible generalized neurotrophic-type rescue effect on the damaged retina caused by the presence of the ASR. A larger clinical trial is indicated to further evaluate the safety and efficacy of a subretinally implanted ASR.
Stem Cells UK Researchers working with mice, transplanted mouse stem cells which were at an advanced stage of development, and already programmed to develop into photoreceptor cells, into mice that had been genetically induced to mimic the human conditions of retinitis pigmentosa. These transplanted cells integrate, differentiate into rod photoreceptors, form synaptic connections and improve visual function. This research may in the future lead to using transplants in humans to relieve blindness.Retinal repair by transplantation of photoreceptor precursorsR. E. MacLaren. Nature 444, 203-207 2006
“Pikachurin” The sight saving protein ? Pikachurin is a dystroglycan-interacting polysaccharide which has an essential role in the precise interactions between the photoreceptor ribbon synapse and the bipolar dendrites The protein localizes to the synaptic cleft in the photoreceptor ribbon synapse, which transmits signals from visual cells to the brain,"Pikachurin, a dystroglycan ligand, is essential for photoreceptor ribbon synapse formation". Sato (2008). Nat.Neurosci. 11 (8): 923–31
Gene Therapy Expression of archaebacterialhalorhodopsin in light-insensitive cones can substitute for the native phototransduction cascade and restore their light sensitivity in mouse models of retinitis pigmentosa. Using human ex vivo retinas, researchers shows that halorhodopsin can reactivate light- insensitive human photoreceptors.Genetic Reactivation of Cone Photoreceptors Restores Visual Responses in Retinitis pigmentosaVolker et al Science 23 July 2010
0.15% UF-021 (unoprostone isopropyl)(OCUSEVA) Phase 2 Clinical Trial Data of UF-021 in Retinitis Pigmentosa Patients Presented at ARVO 2011 The purpose of the phase 2 study was to test the effects of unoprostone isopropyl in protecting and improving the central vision in mid-stage to late-stage RP patients The primary efficacy endpoint was the change seen on the visual field analysis as checked by an instrument called the MP-1 microperimeter The results show promise, specifically with the advantage that it only requires instillation of drops, rather than a completed surgical intervention. BUT the group that was instilled with placebo drops still showed improvement in about 17 of the 112 patients in the trial (15.2%).
Tauroursodeoxycholic acid (TUDCA) Tauroursodeoxycholic acid (TUDCA) is an ambiphilic bile acid. Research had positive affects on the health of the mouse retina, including a reduced accumulation of superoxide radicals, rod cell death, and disruption of cone inner and outer segments. The findings of the study are elucidating optimized conditions for RP treatmentPhillips et al"Tauroursodeoxycholic acid preservation of photoreceptor structure and function in the rd10 mousethrough postnatal day 30". Invest Ophthalmol Vis Sci. 2008 May;49(5):2148-55