Review of literature – current updates and management of retinitis pigmentosa By V.K.Sharma MS,FICS; Subodh Saraf,MS

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Editor                                   Dr Sudhir Singh   Advisors Prof. P.K Mathur Dr  Pavan Shorey   Editorial Board Dr Anshoo Choudhary Dr Arun Kshetrapal Dr L S Jhala Dr Mayank Agrawal Dr Mukesh Sharma Dr Sandeep Arora Dr Sonu Goel Dr Subodh Saraf Dr Sukesh Tandon Dr Sunil Gupta Dr Suresh Kumar Pandey Dr Swati Tomar Dr Virendra Agrawal   Review of literature – current updates and management of retinitis pigmentosa   V.K.Sharma  MS,FICS; Subodh Saraf,MS Corresponding Author Dr.V.K.Sharma MS,FICS, Senior Consultant Global Hospital & Institute of Ophthalmlogy, Abu Road Dist. Sirohi Rajasthan 307510 Article Code RJO20110106 IntroductionThe family of diseases known as retinitis pigmentosa (RP) is the most common inherited retinal degeneration worldwide. The word “retinitis” is a misnomer because retinal inflammation does not play a prominent role in the disease's pathophysiology.1,2 RP is defined as a heterogeneous group of inherited retinal disorders characterized by progressive degeneration of the photoreceptors with subsequent degeneration of the retinal pigment epithelium (RPE).1The recent application of molecular genetic analyses has heralded the rapid elucidation of the underlying gene defects in many cases.3 In this article, the fundamental clinical and electroretinographic characteristics of retinitis pigmentosa will be recalled. Additionally, the current understanding of the genetic causes of retinitis pigmentosa will be reviewed Pathophysiology  The pathogenesis of RP can be considered a continuum of metabolic disorders that initially cause rod photoreceptor degeneration with accompanying associated retinal pigment epithelium degeneration, eventually leading to complete cell death.1 Rod degeneration may also promote secondary cone degeneration. Studies evaluating the function of the bipolar cells have uncovered that the bipolar pathway remains intact after rod cell apoptosis. However, John et al.4 postulate that healthy bipolar cells attempt to re-establish communication with other nerve cells, such as the cones. Regrettably, these new connections relay inappropriate signals, leading to cone degeneration and eventually apoptosis.4 Clinical Description The age of onset of RP can vary from infancy through late middle age.1,4 The age at which symptoms become clinically apparent is correlated with the mechanism of inheritance (see below): X-linked RP, autosomal recessive RP, and autosomal dominant RP generally have their onsets at successively greater ages, although the age ranges overlap considerably. In summary, a typical case of RP will show atrophy and pigmentary changes to the retina and RPE, early night blindness, loss of the visual fields, loss of central visual acuity, attenuation of the retinal vasculature, and changes to the optic nerve head during the course of the disease. In atypical cases of RP or in the closely related allied diseases, any combination of these symptoms may be altered to a greater or lesser extent. 3 Genetic Classification The inheritance modes of RP include autosomal dominant (adRP), autosomal recessive (arRP), X-linked (XLRP), digenic RP, and mitochondrial RP. The terms simplex andmultiplex are also used to describe pedigrees. Simplex refers to an isolated case with an absence of any family history, whereas the term multiplex describes 2 or more affected family members (typically siblings) who have no pre-existing family history.5 19 known RP genes are grouped into various functional categories. These genes include: RHO, PDE6A, PDE6B, CNGA1, SAG, RPE65, RLBP1, ABCA4, RGR, RDS,ROM1, PROML1, NRL, CRX, RP1, RP2, RPGR, CRB1, and TULP1. At least 17 additional uncharacterized RP genes are thought to exist by mapping data.3 Autosomal recessive RP (arRP) is the most frequently inherited type of RP, accounting for approximately 20% to 30% of cases with 18 arRP genes identified to date. Autosomal recessive RP affects men and women equally. For the recessive trait to be phenotypically apparent, both parents must contribute an abnormal gene. Children born of parents who are each a carrier of the same arRP gene will have a 25% chance of receiving 2 normal genes (therefore, be neither a carrier nor affected), a 25% chance of receiving 2 recessive RP genes “homozygous” (being affected), and a 50% chance of receiving 1 normal gene and 1 RP gene (making the offspring an asymptomatic carrier of the abnormal gene “heterozygous”). Consanguinity strengthens the likelihood that a recessive trait will be manifested. Parents and offspring of an affected individual typically do not show signs of the disease. Common mutations include the PDE6 gene and the gene encoding for myosin VIIa. Autosomal dominant RP (adRP) is the second most frequently inherited type of RP, accounting for approximately 15% to 20% of cases. Sixteen adRP genes have been identified to date. Among the most prevalent are rhodopsin and peripherin/RDS. There is a 50% chance of passing the defective gene to the offspring, with males and females having equal chances of being affected. Although it is believed that adRP has the slowest progression, controversy exists regarding the authenticity behind this statement. X-linked RP (XLRP) is the least frequently inherited type of RP, accounting for only 6% to 10% of cases. Six genes to date have been identified. The RPGR and RP2 genes are among the most commonly found in X-linked RP cases, estimated to account for 70% to 90% and 10% to 20% of XLRP, respectively. The phenotypical expression of the gene is related to gender, with the abnormal recessive gene residing on the X chromosome. Because males have 1 X chromosome and 1 Y chromosome, they typically manifest the disease. Females typically do not manifest the trait because, having 2 X chromosomes, the normal gene on 1 X chromosome compensates for the abnormal gene on the other X chromosome. The affected males tend to have a severe form of RP. Severe visual impairment with visual acuity of less than 20/200 is typically observed by age 30 to 40.1,6 Less common modes of inheritance include digenic and mitochondrial DNA. Digenic RP occurs when altered genes for RP occur on 2 different chromosomes in the same individual. The interaction of the 2 genes causes RP. Kearns-Sayre and an Usher-like syndrome are believed to be inherited as mitochondrial genes.6 Current management options  A key element to initial management is information gathering. Patients should be asked to provide a history of the age of onset of dark adaptation problems or night blindness, visual field loss, and loss of visual acuity, using as much detail as possible. Symptoms of night blindness often reflect problems under dimly lit conditions, such as night driving. Progressive visual field loss often is correlated to complaints of increased clumsiness. A full review of systems should include history of cardiac dysfunction, deafness, intestinal disease, renal problems, or liver disease. This can be valuable toward evaluation of the likelihood of syndromic RP. A detailed family history provides information with regard to modes of inheritance. Determination of consanguinity in the pedigree is important because it increases the likelihood of an autosomal recessive condition.1 Electroretinography ERG shows reduced scotopic rod and combined responses during the early stages of the disease in which fundus changes are minimal. Later photopic responses become reduced and eventually the ERG becomes extinguished.7 ERG can be used to tell the patient the future prognosis of his disease. b wave implicit time is not prolonged in a self limited sectoral RP cases. So the patients of RP should be advised to undergo ERG.8 Relatives of RP patients, aged 6 years or more with normal rod and cone ERG have not been observed to develop the disease.8 Visual field Visual field testing is the most commonly used clinical tool for evaluating and monitoring the functional status of RP patients. Visual field testing can be used to monitor the progression of the disease as well as evaluate the severity of the condition in newly diagnosed patients. Furthermore, individuals with RP may qualify as legally blind by visual field criteria before central visual acuity drops to established legal blindness levels (i.e., 20/200). Typical visual field defects include an enlarged blind spot, mid-equatorial visual field defect, and generalized constriction. Subtypes of RP may be associated with distinct visual field defect patterns. For example, sectoral RP is typically associated with arcuate or altitudinal visual field defects. Therefore, Goldmann kinetic perimetry is recommended because of its sensitivity, its ability to test the far periphery, and its reproducibility. In addition, patients' responses to standard automated perimetry may be poor and variable. FFA & OCT can be used to monitor retina status in detail.1   The role of counselling  Education and counselling is imperative in the management of RP. Counseling modalities include genetic counselling, psychological counselling, and low vision rehabilitation counseling.1 Genetic counselling  The aim of genetic counselling is to educate patients about the hereditary nature of their eye disease and the likely mode of inheritance based on pedigree analysis and genotype (if known) as well as the likelihood of the trait expressing itself in other family members or future generations. Counselling enables affected individuals to become prepared to make informed decisions regarding future plans, such as pregnancy, vocational choices, and medical intervention. Because risks are based on the mode of inheritance, a complete detailed pedigree (see Fig 1) with evaluation of affected and non affected family members is essential. Examination of non affected family members may assist with the establishment of the correct diagnosis and prognosis. The burden of recognizing the probability of carrying the defective gene can become a psychological encumbrance to a patient, especially because no cure exists at this time. Thus, genetic testing should be approached with sensitivity. Psychological counselling  Patients identified with progressive retinal degenerations (for which there are no curative treatments) might need psychological counselling. The education and support provided through counseling can help patients come to terms with their disease. Treatment modalities, such as low vision rehabilitation, are more successful once the patient is properly motivated to succeed. Low vision rehabilitation  Low vision rehabilitation for RP patients has progressed from an optical/medical model to a functional disability model. A careful history can help identify specific functional problems that patients may experience during daily activities. Eye care providers can provide or recommend appropriate low vision services, vocational guidance, mobility training, and techniques to help RP patients lead a more autonomous life style. Optical devices used by patients with RP include visual field awareness devices, high-intensity lamps, filters, and magnifiers (such as closed circuit televisions). Visual field awareness includes scanning training, minus lenses, reverse telescopes, and prisms. Fresnel prisms can be used to promote peripheral visual field awareness in RP patients.1 Current treatment modalities  Vitamin therapy  Currently, there are no established standard treatment modalities for patients with RP. The most widely recognized nutritional supplement for RP patients is vitamin A palmitate. Studies by Berson et al.9 indicate that the average patient taking 15,000 IU/d of vitamin A palmitate could experience a slower progression of the disease. Interestingly, Berson et al. also noted that vitamin E appeared to be associated with an increase in the deterioration rate of the ERG in RP patients. In the context of this treatment, a beta carotene supplement is not a suitable substitute for vitamin A in the palmitate form. However, this therapy is not without controversy. More recently, studies have investigated the role of docosahexaenoic acid (DHA) in the treatment of RP. DHA is a long-chain omega-3 fatty acid, which is commonly found in fish. Patients who had recently begun vitamin A palmitate therapy showed further reduction in the rate of retinal degeneration when placed on concurrent DHA (1200 mg/d) supplements. Unfortunately, benefits did not extend beyond 2 years; thus, it was recommended to cease the use of DHA after a 2-year course.10 Patients should be monitored every 6 months while on therapy to watch for potential signs of toxicity. Female patients should be advised to cease therapy if they are planning to or become pregnant. 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. Treating associated ocular manifestations  Although modification of the primary disorder may not be feasible, ophthalmic management includes treating the collateral consequences of the dystrophy, such as the development of cataracts(surgery) and CME(carbonic anhydrase inhibitors, intravitreal steroid injection or laser photocoagulation.)1 Investigational 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 is a process that replaces or turns off the mutated disease-causing gene to restore some normal protein function.In an inherited disease, like RP, there are a number of methods used to replace or correct “abnormal” genes: (1) insertion of a normal gene into the genome to replace nonviable or diseased genes using a carrier “vector,” (2) Ribozyme therapy- Ribozymes can be designed to cleave mutant mRNA molecules so that the detrimental protein is not produced, thereby rescuing the cells., and (3) RNA interference.Gene replacement is necessary in recessive conditions, whereas ribozyme therapy and RNA interference may be useful in autosomal dominant conditions. RNA interference works in a similar manner, causing destruction of the aberrant RNA by existing cell defense processes.1 Various experiments have shown some success in rat and dogs. Most recently, in one study,11 3 young patients with infantile rod-cone dystrophy (Leber congenital amaurosis) were given subretinal injections of recombinant adeno-associated virus vector 2/2 expressing RPE65 complementary DNA (cDNA) under the control of a human RPE65 promoter, with one of the 3 making positive changes both objectively and subjectively. Another study12 reported that the same method of gene transfer of 3 subjects showed some improvement of retinal function. However, factors such as long-term efficacy, immune response, and tribulations associated with vectors used are some of the complicating factors associated with genetic therapy.  Cell transplantation  It has been postulated that by replacing damaged photoreceptor cells, new connections can reform, thereby improving visual function. Future treatment options might someday include cell transplantation. Cell transplantation is the re-infusing of cells into a patient in hopes of producing more healthy cells, which may replace nonfunctional cells. The 2 main sources of cells for transplantation in use today are retinal and stem cells. Retinal cell transplantation is the introduction of healthy photoreceptor cells into the host. The advantages of retinal cell transplantation over stem cell transplantation is that retinal cells integrate well into the host retinal layers and express specific retinal cell markers. The use of retinal transplantation in small rodent models has been associated with restoration of photoreceptor function, as evidenced by normalization of the ERG responses. Despite this apparent physical improvement, restoration of vision has not been well established & immunologic rejection has been seen. Alternatives such as the use of donor cells from another region of the same eye have helped with some of the limitations related to retinal cell transplantation. Stem cell transplantation is the process whereby a patient receives healthy stem cells, which may in turn begin producing normal retinal cells. One of the key advantages is that stem cells have the potential to differentiate into any type of cells, including retinal neural cells, which may replace lost photoreceptors. Previous studies have indicated that stem cells integrate well into the retina and adopt the morphologies and positions of Muller, amacrine, bipolar, horizontal, photoreceptor, and glial cells in adult mice. Stem cells commonly used in transplantation include adult neural (retinal or RPE) progenitor cells, bone marrow–derived stem cells, and fetal stem cells. Fetal stem cell transplantation involves transplanting photoreceptor cells and the underlying retinal pigment epithelial cells from the retinas of aborted fetuses. Visual improvement (both subjective and objective) has been documented in a number of subjects following this cell transplantation form. Radtke and Norman13 demonstrated that fetal retina transplanted into an adRP patient can survive 1 year without apparent clinical evidence of rejection and that continued improvement in visual acuity could be achieved. Gouras et al.14published histologic evidence of cellular reconnection after fetal retinal stem cell transplantation in adult rats. Their studies documented safe parameters associated with the procedure and apparent high tolerance for graft transplantation. Fetal stem cells have a greater immunologic tolerance, reducing the chance of rejection by the host and eliminating the need for immunosuppressive drugs. Fetal stem cells can easily overcome the trauma related to transplantation, unlike adult cells, which depend heavily on oxygen.1 Pharmacologic options  Pharmacologic possibilities using neurotrophic factors include basic fibroblast growth factors (bFGF) and ciliary neurotrophic factors (CNTF). Although the treatment did not eliminate the genetic defect, it did ameliorate the resulting condition. Other pharmacologic options used in patients with RP include anti-Parkinson's drugs. The value of these pharmacologic options is based on their antiapoptotic properties. 1 Neuroprosthetic devices  In 1929, it was documented that stimulation of the brain led to the perception of phosphenes, an entoptic phenomena, described as the perception of lights without “light” stimulation. Current neuroprosthetic devices use optic nerve, retinal, or cortical stimulation. These approaches are being assessed in clinical trials, but so far no visual prosthesis has restored “normal” vision; patients have only a crude level of visual perception.1 We are providing key to understand pedigree diagram given in the article. Since we are looking forward to the genetic treartment of many disorders in future, so an ophthalmologist should be aware of the notations given below.15 REFERENCES Review and update: Current treatment trends for patients with retinitis pigmentosaKelly Shintani, Diana L. Shechtman, Andrew S. Gurwood Optometry - Journal of the American Optometric Association Volume 80, Issue 7 , Pages 384-401, July 2009 Weleber R. Retinitis pigmentosa and allied disorders. In:  Ryan S,  Ogden T,  Schachat A editor. Retina. 2nd ed. St. Louis: Mosby-Year Book, Inc; 1994;p. 334–340 A brief review of retinitis pigmentosa and the identified retinitis pigmentosa genesJames K. Phelan,1 Dean Bok Molecular Vision 2000; 6:116-124http://www.molvis.org/molvis/v6/a16/ John SK, Smith JE, Aguirre GD, et al. Loss of cone molecular markers in rhodopsin-mutant human retinas with retinitis pigmentosa. Molecular Vision.2000;6:204–215 Daiger SP, Sullivan LS, Bowne S. et al. Retnet. Available at:www.sph.uth.tmc.edu/Retnet. Phelan JK, Bok D. A brief review of RP and the identified RP genes. June 2000 Available at: http://www.molvis.org/molvis/v6/a16. Jack J Kanski Clinical Ophthalmology A Systemic approach 6th edition. Berson EL, Retinitis Pigmentosa & Allied Diseases. Albert and Jakobiec’s Principles and practice of Ophthalmology, 3rd edition 2008, Chap 177, Page 2225 Berson EL, Rosner B, Sandberg MA, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol.1993;111:761–772 Berson E, Rosner B, Sandberg M, et al. Further evaluation of DHA in patients with RP receiving vitamin A treatment. Arch Ophthalmol. 2004;122:1306–1314 Bainbridge JWB, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008;358:2231–2239 Maguire AM, Simonelli F, Pierce EA. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008;358:2240–2248 Radtke , Norman D. Transplantation of intact sheets of fetal neural retina with its retinal pigment epithelium in retinitis pigmentosa patients. Am J Ophthalmol.2002;133(4):544–550 Gouras P, Du J, Gelanze M, et al. Survival and synapse formation of transplanted rat rods. Journal of Neural Transplantation & Plasticity. 1991;2:91–100 http://web.udl.es/usuaris/e4650869/docencia/segoncicle/genclin98/temes_teoria/imatges_temes_teoria/image5.gif   Disclaimer Rajasthan Journal Of Ophthalmology An Official Journal Of The Rajasthan Ophthalmological Society
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