Nicole Marie Psaltis, O.D. WJB Dorn VAMC, Columbia SC Residents Day Proposal August 30, 2010

• Abstract ‐ Retinitis pigmentosa (RP) is a group of inheritable eye conditions, constituting retinal and RPE dystrophies, which progress to vision loss. Patients with identical genetic mutations can manifest different phenotypic presentations. This case describes an atypical presentation of RP.

• Case History ‐ A 57‐year‐old Caucasian male veteran presented to the Wm. Jennings Bryan Dorn VA Eye Cinic in Columbia, South Carolina on June 23, 2009 ‐ Chief Complaint ƒ Decreasing peripheral field of vision ƒ The patient had a secondary complaint of painless blurred vision distance and near of gradual onset ‐ Ocular History ƒ Hyperopic astigmatism OU ƒ Unremarkable ocular health history per patient’s account ƒ Last eye exam was 2.5 years ago ‐ Medical History ƒ Alcohol abuse ƒ Esophageal reflux ƒ Hypercholesterolemia ƒ Hypothyroidism ƒ Depression ƒ PTSD ƒ Substance Abuse ‐ Medications ƒ Citalopram Hydrobromide ƒ Hydrochlorothiazide ƒ Nicotine Patch ƒ Omeprazole ƒ Simvastatin ƒ Trazodone ‐ Allergies ƒ Naproxen ‐ Family Ocular History ƒ Unremarkable ‐ Pertinent Findings ƒ Entering VA: 20/25+2 OD, 20/25 OS cc ƒ Pupils: PERRL (‐) APD ƒ EOM: FROM OU ƒ CVF: Constricted OU

ƒ Subjective Refraction: +2.00‐2.00x109 OD +2.25‐1.25x065 OS ƒ Anterior Segment Evaluation: WNL OU ƒ Tap: 13 mmHg OD, 14 mmHg OS @ 1109 AM ƒ DFE: Atrophic presentation with distinct cessation perifoveally OU. Coalesced hyperplastic lesions, rarely in bone spicule appearance, scattered throughout posterior pole OU. Scattered areas of atrophy of scalloped appearance in far periphery to ora serrata. Vessels are mildly narrow and attenuated OU. Maculae were flat and intact OU. The optic nerve cup‐to‐disc ratios are 0.10, round OU. The presentation is symmetrical. ƒ Diagnosis: Unspecified Bilateral Annular Chorioretinal Atrophy

‐ September 4, 2009 Follow‐up ƒ The patient now presents with a secondary complaint of distorted central vision as if he is “looking through a screen door”. He also complains of photopsias and chromatopsias yellow and blue in color ƒ When probed, the patient reports his grandfather having an unexplained loss of peripheral vision. ƒ BCVA: 20/25+2 OD, 20/25 OS cc ƒ DFE: Cotton wool spot along superior‐temporal vascular arcade OD Atrophic and pigmentary retinal presentation appears stable from 6/23/2009. ƒ Plan: Request fee‐basis ERG; refer to ophthalmology for further retinal evaluation

• Laboratory Studies: ‐ On September 4, 2009 a Humphrey Visual Field 30‐2 was attempted, however the patient was unable to complete the field due to excessive jaw movement secondary to denture plates. When probed regarding the HVF, the patient reported he was unable to “see peripheral lights”. ‐ Macular OCT September 4, 2009 ƒ OD: Foveal thickness 157 microns; radial analysis displays slight retinal elevation ƒ OS: Foveal thickeness 191 microns; radial analysis displays slight retinal elevation ‐ Full‐Field ERG November 9, 2009 ƒ Significant loss of rod function OU and borderline abnormality of cone function OU ‐ Goldmann Perimetry‐ pending ƒ Expect ring scotoma OU ‐ Serum ornithine ƒ WNL

• Differential Diagnoses ‐ Retinitis Pigmentosa ‐ Gyrate Atrophy ƒ However, patient’s plasma ornithine level normal ‐ Infectious processes ƒ Syphilis, Toxoplasmosis ƒ FTA‐ABS, serum IgG normal ‐ Paraneoplastic Retinopathy ‐ Cone‐Rod Dystrophy ‐ Drug Toxicity

• Diagnosis and Discussion:

‐ Retinitis Pigmentosa

Retinitis Pigmentosa (RP) is a group of interited retinal dystrophies differentiated by abnormalitiy of the photoreceptors and retinal pigment desposits detected by fundoscopy. Pigment deposits are predominant in the retinal periphery and the central retina is usually spared. The most common form is known as rod‐cone dystrophy, with night blindness as the primary symptom and progressing to peripheral vision loss under photopic conditions. The rods primarily degenerate while there is a secondary degeneration of cones. Cases have been known to progress rapidly over a few decades while others never result in blindness. Some cases present as a cone‐rod dystrophy and visual acuity loss dominates over peripheral vision loss. There are non‐syndromic and syndromic forms. As of 2006, 45 causative loci have been identified in the non‐syndromic form. Molecular diagnosis is difficult due to the mass heterogeneity of the disorder. There is a family history in approximately 50% of cases.

Typically, the earliest symptom of RP is nyctalopia (difficulty seeing under low light conditions) followed by photophobia and decreased visual acuity in later stages. Patchy mid peripheral field loss eventually evolves to form a ring scotoma and tunnel vision. Bone spicule deposits, attenuation of retinal vessels, retinal atrophy and waxy disc pallor are typical RP fundus findings. The ERG generally shows dramatic weakening of a‐wave and b‐wave amplitudes.

The traditional form of RP is divided into three stages. In the first stage, nyctalopia is the initial symptom and generally becomes apparent in the second decade of life. In this stage, peripheral visual field defects tend to only occur in dim light. The fundus appearance may be normal. The ERG is the key to diagnosis during this early stage, as there will be a decreased b‐wave under scotopic conditions. In the mid stage, nyctalopia is obvious and the patient is aware of peripheral vision loss under all lighting conditions. Patients also become photophobic on account of macular disruption due to mild atrophy or edema, however the foveomacular area and far periphery remain relatively spared. There is vessel attenuation and disc pallor. In the end stage, patients reach tunnel vision and are not able to get around autonomously. Pigment is now deposited in the foveomacular area. RP is further categorized into early and late onset. Early onset is diagnosed when symptoms of mid stage RP is present at two years of age. Late onset is diagnosed when early stage begins around mid life. Autosomal dominant forms are generally the mildest forms, and in some cases may start after age 50. Autosomal recessive forms typically begin in the first decade of life. X‐linked RP also tends to start early and is associated with myopia.

When there is rapid progression of symptoms later in life, ocular trauma, inflammation, infection, paraneoplastic syndromes and a spinocerebellar ataxia should be considered. The patient under investigation has no history of ocular trauma or signs of inflammation. CBC does not show any signs of underlying infection and there is no evidence of malignancy. Spinocerebellar ataxia is unlikely as patient’s gait and coordination are normal.

This case represents a unique presentation of what is likely RP. There is an annular chorioretinal atrophy which begins in the mid‐periphery and spares the foveomacular region. The pigment deposits are rarely of bone spicule formation and have the appearance of larger pigment clumps. The scalloped margins of atrophy resemble that consistent in gyrate atrophy, however, the patient’s ornithine levels are normal. The presentation is symmetrical. The patient has a chronic subtle macular edema, verified by OCT. FANG is still pending. Although the patient was unsure of details of his family’s ocular history, he did report his grandfather suffering from an unknown loss of peripheral vision. The patient’s retinal vascular was only minimally attenuated and optic discs did not have a pallor appearance. Bass et al described a family with a hereditary retinal disease consisting of retinal and choroidal atrophy with spared maculae and preserved visual acuity. While some of the family members were symptomatic with loss of visual field, others were asymptomatic and none reported nyctalopia. FANG on these patients revealed hyperfluorescence in areas of retinal atrophy and hypofluorescence in areas pertaining to choroidal atrophy. Although FANG has not yet been performed by the patient of interest, the fundus presentation is similar to those described by Bass et al, however the Bass et al patients did not experience nyctalopia and rods were spared on account of their normal ERGs. Interestingly, further genetic testing revealed the Thr17Met variant, a rhodopsin mutation associated with autosomal dominant RP.

• Treatment/Management

‐ There is no current therapy which can completely cease the progression of pigmentary retinopathies or will restore the loss of vision. The current management involves decelerating the degeneration, treating secondary complications, and helping the patient cope with blindness. Vitamins A and E have been shown to protect photoreceptors with trophic and anti‐oxidant effects. However, there is no conclusive evidence of the benefits of Vitamin A. Vitamin A has not yet been prescribed for this patient. If Vitamin A is prescribed, serum retinol, triglycerides and liver enzymes should be monitored regularly. Due to the clinical evidence that many forms of genetic pigmentary retinopathies are light‐ dependent, patients should be instructed to wear UV protection when outdoors. Yellow‐ orange shades reduce photophobia, a common symptom of RP. Sunglass recommendation was made to this patient.

The most frequent complications of RP include posterior subcapsular cataracts and macular edema. The patient of interest has visually insignificant nuclear sclerosis of the lens OU, but not the characteristic posterior capsular opacity of RP. A central posterior subcapsular cataract will blur the remaining central vision of an RP patient, and on account must be removed even though the patient may have, or is more at risk for, macular edema. Chronic macular edema occurs frequently in RP patients causing a decreased visual acuity. Acute episodes of macular edema may be successfully relieved with a carbonic anhydrase inhibitor at 500mg or less daily. However, the macular edema in RP tends to be chronic and this treatment is generally a waste of time.

Low vision aids are available to assist in maintaining the independence of the RP patient. The patient of interest was referred to the WJB Dorn Low Vision Specialty Clinic where optical and mechanical devices will be recommended and trialed. Due to the relative early stage of the vision loss, an occupational therapy referral will also be considered. A psychological consult should also be placed during phases of debilitation to assist in coping with the vision loss.

• The Future

‐ There is a vast amount of research on possible future treatment options of RP. In 2006, UK researchers successfully transplanted stem cells into mice. These stem cells were programmed to become photoreceptor cells. The mice had been genetically induced with the conditions of RP and age‐related macular degeneration. The success was the result of the photoreceptors making the connections to the retinal nerve cells. This was a breakthrough because it has been widely understood that the retina has no regenerative properties, as cells of the central nervous system do not have an intrinsic ability to regenerate. There has been research involving Pikachurin, a retinal protein which has an essential role in the interaction between photoreceptor synapse and bipolar cell dendrites. Deletion of Pikachurin causes an abnormal ERG. In 2010, there has been recent success with gene therapy in mice models. Gene therapy is the insertion of genes into an individual’s diseased cells or tissues and mutant alleles are replaced by functional alleles. Several growth factors are under investigation and have had some success in animal models. Vitreal encapsulated cells of ciliary neurotrophic growth factor (CNTF) is under Phase One of clinical investigation. In contrast to photoreceptors, RPE grafts have been shown to rescue sick RPE in rats in which a mutation causes a retinal dystrophy by lack of outer segment phagocytosis. This is the pathophysiology of certain rare cases of RP. This research has shown that RPE transplantation is possible in cases of RP due to RPE defects, but a method to relieve the immunogenic reaction has to be found. Microphotodiode arrays have been developed and trialed to replace degenerated photoreceptors and capture light while stimulating the retina. These retinal prosthetics are still under investigation.

• Take Home Points

‐ Retinitis Pigmentosa is a collection of retinal and rarely RPE dystrophies which, due to the vastness of possible genetic mutations, can present in various ways. Although there is no established treatment to slow down or halt the progression of the disease, diagnosis is critical for proper patient education and preparedness for what may be inevitable vision loss. Although these patients lose vision in the periphery, careful examinations must continue to be given to ensure there are no threats to the patients’ limited, remaining vision. Visual threats such as cataracts and corneal edema exist as consequences of RP and should be diagnosed and treated accordingly. There is much research effort geared towards preserving vision and even reversing detrimental loss of vision which has already occurred. Until this impending technology becomes a reality in clinical practice, it is important, as eye care providers, to act both as health care practitioners and those that can help ease the social and psychological well being for our patients.

• Works Cited

‐ Hamel, C. Retinitis pigmentosa. Orphanet Journal of Rare Diseases. 2006. 1:40.

‐ Retinitis Pigmentosa. https://health.google.com/health/ref/Retinitis+pigmentosa. August 28, 2010.

‐ Garg, SJ, M.D. The Merck Manuals. Online Medical Library. Retinitis Pigmentosa. November, 2008. http://www.merck.com/mmhe/sec20/ch234/ch234e.html . August 28, 2010.

‐ Telander, DG M.D., PhD. De Beus, A M.D., PhD. Small, K, M.D. Emedicine for WebMD. Retinitis Pigmentosa. August 19, 2009. http://emedicine.medscape.com/article/1227488‐ overview. August 28, 2010.

‐ Berson EL. Retinitis pigmentosa and allied retinal diseases. In: Tasman W, Jaeger EA, eds. Duane's Ophthalmology. 15th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2009:chap 24

‐ Fay A. Diseases of the visual system. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Philadelphia, Pa: Saunders Elsevier;2007:chap 449

‐ Sieving PA, Caruso RC. Retinitis pigmentosa and related disorders. In: Yanoff M, Duker JS, eds. Ophthalmology. 3rd ed. Maryland Heights, Mo: Mosby Elsevier;2008:chap 6.10

‐ American Optometric Association. Retinitis Pigmentosa. http://www.aoa.org/x4722.xml. August 28, 2010.

‐ Bass, SJ, King, Noble KG. Autosomal Dominant Pericentral Retinochoroidal Atrophy. Retina: 26:1. 2006 71‐79.

‐ Bass, SJ, King, Noble KG. The THR17MET Mutation is Associated with an Unusual Retinochoroidopathy in an Autosomal Dominant Pedigree. Retina. 28:7. 2008