2. Isfahan University of Medical Sciences
S.Bakhtavar MD
Isfahan University of Medical Sciences

3. RP ( وراثت ؛ تشخیص ؛ درمان )

4. Retinitis pigmentos Definition: Rp defines a clinically & retinal
gentically diverse group of different retinal dystrophy initially affecting the rod photoreceptor cells with subsequent.
Degeneration of cones and pigment epithelial
function (rod-cone- dystrophy and RPE dys function)
It is the most commonly encountered

5. Hereditary fundos dystrophy with a prevalence of approximately

6. RP Definition
The pigmentary retinopathy can be divided into tow large group 1. primary RP in which the disease process in confined to the eye’s with no other systemic manifestation.

7. 2- Secondary pigmentary retinepathy in which the retinal degeneration is associated with single or multiple organ system

8. Inheritance
The age of onset, rate of progression eventual related to the mode of inheritamce RP may occur as an isolated sporadic disorder or be inherited as AD.AR or XL

9. Many cases are due to mutation of rhodopsine gene
Many cases are due to mutation of rhodopsine gene. XL is the least common but most severe form and may result in complete blindness by the third or four the decade. Female carriers may have normal fundos or show a golden – metal (tapetal) reflex at the macula and or small peripheral pathes of bone spicule pigmentation

12. RP often atypical may also be associated with systemic disorder which are usually AR.

13. Inheritance of RP AD There are currently at least 12 form (of ADRP)
ADRP accounts for %10 - %20 of RP cases depending on the country surveyed

14. AR autosomal recessive RP (ARRP) represent about %20 of RP cases At least 15 Genetic type of ARRP have been identified.

15. Xlinked RP account for about %10 of RP in USA and %25 in england¸up to %40 of case presenting in the USA have no family history.

16. Diagnose
The diagnosis criteria for RP comprise bilateral involvement with loss of peripheral and night vision. The classical triad of RP a ( arteriolar attenuation ) b) rtinal bone spicule pigmentation and ) c) ( waxy disc palor )

17. Presentation: Nyctalopia often during the 2nd – 3rd decade though may be earlier or later depending on the pedigree.

18. Sign in chronological order: A) Subtle mid-peripheral RPE atrophy associated with mild arteriolar narrowing and mid-peripheral intraretinal perivascular bone - spicule pigmentary change

20. B) Gradual increase in density of the pigmentary change with arteriolar and posterior spread.

22. C) Tesselated funus appearance
C) Tesselated funus appearance . Due to RPE atrophy and unmasking of large choroidal vessels.

24. D) Severe arteriolar narrowing and gliotie waxy pallor of the optic disc.

26. E) The macula may show atrophy, epiretinal membrane formation and CMO
E) The macula may show atrophy, epiretinal membrane formation and CMO. The latter may respond to systemic acetazolamide

27. ERG in early disease shows reduced Scotopic rod and combined responses¸ later photopie respone become reduced and eventually the ERG become extinguished uished.

29. ERG Both a and bwave are reduced
ERG Both a and bwave are reduced . bwave are characteristically prolonged in time as well as diminished in amplitude.
The carrier state of xlinked recessive RP often shows amild reduction or delay in bwave. An undectatable ERG is not diagnose of RP but simply document severe retinal degeneration.

30. EOG is subnormal with an absence of the light rise.

31. Perimetry initially demonstrate small mid peripheral scotoma that gradually.
Coalesce to form the classical annular scotoma. which expands both peripherally and centrally.
It ultimately leaves a tiny island of centeral vision which may eventually be extinguished.
Perimetry is useful in monitoring the progression of disease.

32. Prognosis is variable and tend to associated with the mode of inheritance follow.

33. XL disease has the worst prognosis with severe visual loss by the 4th decade.
AR disease and sporadie cases have a more favourable prognosis with retention of centeral version untile (the 5th -6th decade) on later.
AD disease generally has the best prognosis with retention of centeral virsion beyond the 6th decade.

34. 1- Ocular association. Posterior sub capsular cataract
1- Ocular association . Posterior sub capsular cataract. are common in all form of RP. surgery is often beneficial. 2- Open – angle – glaucoma occurs in 3% of cases. 3- Myopia is common. 4- Keratoconus is un common. 5- Vitreous change which are common consists of posterior Vitreous detachment and occcasionally in termediate uveitis

35. 6- Optie disc drusen. Occur more frequently in patients with RP
6- Optie disc drusen. Occur more frequently in patients with RP. 7- Coats like diseasewith’lipd deposition in the peripheral retina and exudative RD

37. Atypicad retinitis pigments Atypical RP describes conditions that are closely related to typical RP or represent in complete forms of the disease.

38. Atypical RP 1- Cone-rod dystrophy
In which the cone component is affected earlier and more severely then in typical RP presentation is with impairment of central vision and not with nyctolopia.
Examination may show a macular lesion with or without peripheral change

39. Atypical RP
2- RP sine pigment is characterized by absence or paucity of pigment accumulation which may subsequently appear with time

41. Atypical RP
3- Retinitis punctate albescens In an AR variant characterized by scattered whitish-yellow spot.
Most numerous at the equator.
Usually sparing the macular.
And associated with arteraiolar attenuation they are similar to the spot in fundous albipunctatus but often have a more radial pattern

43. Sector RP is an AD variant RP
Charac terized by involve ment of inferior quadrants :
Or 1 or 2 sector of the fundus
Progression is slow and many cases are stationary.
Many of there cases show an unusually deep demarcation between affected and unaffected area of the retina in contrast to the diffuse damage of more typical RP the
important of recognizing these forms is that some are either non progressive or very slowly progressive.

45. Sectoral RP is generally symmetric the 2 eyes which helps to r/o acquired damage. (From trauma, vascular insult or in flamation)

46. Sector RP
Carriers of x linked RP can have fundus finding that appear as a sectorial pigmentary retinpathy . because there is evidence that the sectorial loss in many cases is related to light toxicity in patients with rhodopsin mutations , UV light protection and anti oxidant vitamin are reasonable recommend for regional disease.

47. Atypical RP
Some patient with RP like disease present with macular involvement or markediy reduced V/A very early in the course of disease, which is unusual for RP.
Field loss may progress outward from center rather than in ward (central (RP) )

48. Atypral RP
Other patients show a tight ring scotoma within the central 20' or 30' (pericentral (RP))
This group of regional variants is probably heterogenous, because most of the caseses apper sporadic and few have been well
characterized clinically or generentally.

49. Atypical RP Unilateral RP is a rare disorder that is usually sporadic.
The vast majority of unilatrerad pigmentary retinal degeneration are likely to have an acquired origin. Such as
A) previus vascular occlusion.
B) prior RD .
C) trauma
D) uveitis,
E) infection,
F) or retained metallic intra ocular foreign body.

50. To make a diagnosis of true unilaleral RP.
The clinician must R/O such secondary causes, document a normal ERG in the unaffected eye and follow the patient for at least 5 years to R/O bilateral asymmetric disease.

51. Differential diagnosis of RP when evaluating suspected RP in a patients with a negative family history (simplex RP) It is important for the clinician to consider acquired cause of retinal degeneration that can mimic RP

52. Differential diagnosis of RP
Including : 1- previous ophtalmic artery occlusion. 2- diffuse uveitis 3- infection such as syphilis, 4- paraneoplastc syndrom and 5- retinal drug toxicity 6- Secondary forms of pigmentary retinpathy associated with metabolic or other organ system disease.

53. The DD of RP is important because the prognostic implication of the disease are serious and an error in diagnosis can be devastating in terms of psychological impact or failureto to recognize a treatable entity

54. Medical Care
The diagnosis of retinitis pigmentosa (RP) can be overwhelming to many patients. While therapies are limited, physicians should emphasize the therapies that are available to help patients.

55. Medical Care
Perhaps, most importantly, it is essential to help patients maximize the vision they do have with refraction and low-vision evaluation.
Many devices are available to help patients with night vision difficulties, and most low- vision clinics are aware of these devices.

56. The authors believe that patients should have annual examinations, including visual field testing and periodic (every 5 y) ERG evaluations.
Changes in examination findings can help guide patients in their activities and can help with prognosis.

57. Often, these examinations can provide reassurance that the changes are slow.
In addition, regular examinations can ensure patients have appropriate community and legal assistance.
Finally, as new therapies emerge, routine evaluation can keep patients informed of
clinical trials and new treatments.

58. Management of PR include regular ophtalmologist evaluation at inlerval of 1-2 years . With control of ERG and visual field

59. Vitamin A/beta-carotene
Antioxidants may be useful in treating patients with RP, but no clear, prospective evidence in favor of vitamin supplementation yet exists.
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.

60. The effects are modest; therefor this treatment must be weighed against the uncertain risk of long-term adverse effects from large chronic doses of vitamin A
Annually check liver enzymes and vitamin A levels .Beta- carotene doses of IU have been recommended.

61. Docosahexaenoic acid (DHA)
DHA is an omega-3 polyunsaturated fatty acid and antioxidant.
Studies have shown a correlation of ERG amplitudes with patients' erythrocyte-DHA concentration.

62. Others 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. In this study, the benefit of DHA was not seen. Further clinical trials must be done to determine DHA benefit.

63. Acetazolamide
Macular edema can reduce vision in the later stages of RP. Of the many therapies tried, oral _ acetazolamide has shown the most encouraging results with some improvement in visual function.

64. 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.

65. Topical acetazolamide can be effective but has not been found to be as effective as oral therapy.
Adverse effects, including fatigue, renal stones, loss of appetite, hand tingling, and anemia, may limi,ts use

66. The use of corticosteroids for macular edema may be useful but has not been well studied.
Calcium channel blockers
Calcium channel blockers, such as diltiazem, are medications commonly used in cardiac disease.

67. Calcium channel blockers have shown some benefit in some animal models of RP, but they have been ineffective in other models.
No current recommendations exist regarding the use of calcium channel blockers in patients with RP.

68. Lutein/zeaxanthin
Lutein and zeaxanthin are macular pigments that the body cannot make but instead come from dietary sources.
Lutein is thought to protect the macula from oxidative damage, and oral supplementation has been shown to increase the macular pigment.

69. A National Institutes of Health (NIH) clinical trial, the Age-Related Eye Disease Study II (AREDS II), is beginning to test the effectiveness of lutein and zeaxanthin to slow age-related macular degeneration.

70. Their ability to prevent cone photoreceptor cell death (such as what occurs in RP) has not been shown.
Doses of 20 mg/d have been recommended.

71. Surgical Care Cataract extraction
Cataract surgery can often be beneficial in the later stages of RP. Bastek et al studied 30 patients with RP; 83% of them improved by 2 lines on the Snellen visual acuity chart with cataract surgery.
Perioperative use of corticosteroids is recommended to prevent postoperative cystoid macular edema.
Educating patients about reasonable expectations of cataract surgery is essential.

72. Growth factors
Ciliary neurotrophic factor (CNTF) has been shown to slow retinal degeneration in a number of animal modeis

73. Transplantation
Small patches of retinal or RPE tissue have been transplanted, and this technique could be helpful in the following RP forms: when RP is based on an RPE defect, when RP with primary defects exists in the outer segments, if the disease is driven by an overload of the phagocytic activity of the RPE, or if the RPE cannot provide sufficient nutritional support to the outer segments.

74. RPE cell transplants have been placed into the subretinal space to rescue photoreceptors in animal models of RP. One approach that may prove useful is exvivo modification of these cells to provide trophic factors

75. Transplantation
Stem cells are being actively investigated as a potential source to replace damaged RPE or photoreceptor cells. Both adult bone marrow-derived stem cells and embryonic stem cells are being used in animal models with the goal to investigate how to induce appropriate cell integration and differentiation.

76. No current investigational protocols exist in humans for this type of intervention.

77. Retinal prosthesis
A retinal prosthesis or phototransducing chip placed on the retinal surface has been investigated for several years. The healthy ganglion cell layer of the retina can be stimulated, and implants in animal models have long-term stability .

78. In a study by Humayun et al, this has been shown to be beneficial in human subjects .
One patient who had no light perception from RP was able to see and localize a flashlight after the prosthesis. With this prosthesis, an external camera (placed in the patient's eyeglasses) transmits to the retinal prosthesis.
Additional clinical trials are underway

79. Retinal prosthesis
Chow et al placed subretinal microphotodiodes (prosthesis) in patients with severe RP.
These patients had subjective improvement; however, the improvement was delayed and occurred in retinal areas outside of where the chip was placed. Therefore, the effect was thought to be an indirect benefit to adjacent cells.
Currently, no retinal prosthesis is available for clinical use, and this technology remains investigational

80. Gene therapy
Gene therapy is under investigation, with the hope to replace the defective protein by using DNA vector
(eg, adenovirus, lentivirus).
Gene therapy was successful in providing the missing protein to a dog with Leber congenital amaurosis (LCA). Using adeno-associated virus (AAV), the Briard dog with RPE65 mutations after treatment had 20% of its RPE cells express the functional protein, thereby allowing the dog to see. This was also effective in a mouse model of Leber congenital amaurosis. Leber congenital amaurosis.

81. Gene therapy
Gene therapy is now in human clinical trials for LCA, with promising results. In fact, 8 trials referring to gene therapy and RPE65 mutations are open and listed on the clinicaltrials.gov Web site.
Because of the wide heterogeneity of defects in RP, gene therapy must be targeted specifically to each mutation.
It is not known which, if any, of the RP forms will show reversibility (even with a nondestructive reinsertion of the appropriate gene in the appropriate locus with appropriate regulation).

82. Consultations
Clearly, RP is associated with several systemic diseases. Because of the severity of the systemic illness and its early presentation in most patients, the ophthalmologist may act as the consultant to an internist.
Low-vision specialists can provide magnifying devices and field-expanding lenses for patients with RP who have poor central vision.

83. Audiology consults should be considered for patients with hearing loss or for those patients with known Usher syndrome.
Genetic testing and counseling is becoming increasingly valuable as the understanding of RP increases.

84. Consultations
Identification of the patient's genotype offers several advantages. First, it confirms the genetic cause of the condition. In addition, it can occasionally help determine prognosis and may likely prove to be important for future therapy choices. Genetic counseling is very helpful to guide patients on the hereditary nature of their disease and the mode of inheritance. This counseling can help the patients with their future plans, such as pregnancy, job choices, and medical treatments.
Moreoever, psychological counseling should be made available to those patients when appropriate.

85. Diet
Many practitioners recommend a well- balanced diet with adequate leafy green vegetables that contain the aforementioned supplements in nontoxic doses.
No evidence exists that particular foods in excess are helpful or harmful.

86. Activity Light exposure
Stressful light exposure, which generates free radicals and strains the regenerative capacity of the eye, might put dystrophic retinas at a disadvantage. However, little direct or epidemiologic evidence exists that the disease is modified by light.

87. A specific form of RP, the Pro23His mutation in rhodopsin, has been shown to have increased retinal damage with increased light exposure.
UV-absorbing lenses are recommended, particularly in rhodopsin mutation varieties of RP, and patients with cone degeneration frequently benefit from tinted lenses.