1. Dr.Giridhar.A
Giridhar Eye Institute
Cochin
Giridhar Eye Institute

2. 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.

3. 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 macula
Berson EL. Retinitis pigmentosa: unfolding its mystery. ProcnatlacadSci U S A
1996;93:4526–4528.

4. 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.

5. 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

6. 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.

7. 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 with
retinitis pigmentosa at age 45 years or older. Ophthalmology. Sep 1999;106(9):1780-5

8. 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.

9. Retinal layers
(A) Normal human retina . RPE 5 retinal pigment
(B)Retinitis pigmentosa retina. The retina is thin
epithelium; OS 5 outer segments; ONL 5 outer nuclear because many photoreceptors have died and the
layer; OPL 5 outer plexiform layer; INL 5 inner nuclear remaining photoreceptors lack outer segments. Some
layer; IPL 5 inner plexiform layer; GCL 5 ganglion cell photoreceptor somata are retained in the outer
layer 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.

10. 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 of
rod somata in the outer nuclear layer and synapses in the outer plexiform layer. (D) Retinitis pigmentosa The
surviving rods are opsin positive (green) but few retain outer segments. Rod neurites (arrows) extend past the
inner nuclear layer, and some terminate in the ganglion cell layer

11. 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.

12. Immunolabeling
Retinitis pigmentosa retina .Localization of opsin (green) in rods in the outer
nuclear layer (ONL) and glialfibrillary acid protein (red) in reactive Muller
cells(red).

13. 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

14. Newer Clinical Investigations
 Spectral domain OCT
 Micro perimetry
 Fundus Auto fluorescence
 Genetic subtyping

15. 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.

16. SD OCT in RP
1 2
3 4
1. A retinitis pigmentosa (RP) patient with no abnormalities
2. Macular edema
3. Vitreomacular traction
4. Retinal thinning

17. 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.

18. Fundus Autofluorescence

19. TheHyperautofluorescent Ring
 Progressive constriction of the hyperautofluorescent
ring and a concordant decrease in IS/OS junction
length are observed over time.

20. 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.

21. 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.

22. 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 pigmentosa
in Denmark. ActaOphthalmol Scand Suppl.
2002;233:1-34.

23. Why finding the underlying disease causing
mutation should matter to the patient or the
clinician?
 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: successes
and challenges. Retina. 2005;25:S15-S17

24. Number of mapped and identified retinal
disease genes from 1980 to 2006.

25. Genes and Mapped Loci Causing Nonsyndromic, Nonsystemic
Retinitis Pigmentosa

26. Genes and Mapped Loci Causing Nonsyndromic, Nonsystemic
Retinitis Pigmentosa

27. Genes and Mapped Loci Causing Nonsyndromic, Nonsystemic
Retinitis Pigmentosa

28. Mutations in Genes That Cause an Appreciable Fraction of Retinitis
Pigmentosa Cases
Perspective on Genes and Mutations Causing Retinitis Pigmentosa
Stephen et al Arch Ophthalmol. 2007;125:151-158

29. 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

30. 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 Retinitis
Pigmentosa Thiran et al Arch Ophthalmol. 2010;128(7):915-923

31. 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.

32. 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 Receiving
Vitamin A Eliot et al. Arch Ophthalmol. 2010;128(4):403-411

33. 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.

34. 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 chronic
macular edema in retinitis pigmentosa. Arch Ophthalmol. Oct 1989;107(10):1445-52

35. 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 With
IntravitrealTriamcinolone. Lucia et al Arch Ophthalmol. 2007;125:759-764

36. 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

37. 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 Pigment
Epithelium to a Patient With Retinitis Pigmentosa Norman et al Arch Ophthalmol.
2004;122:1159-1165

38. Fetal Retinal Transplant
Fundus images: Arrows indicate the same blood vessel landmark in all images. A, Three weeks prior to
transplantation. B, Two weeks after transplantation, showing heavy pigmentation of the transplant. The
transplant area is outlined by white dots. C, Six months after transplantation, there is a loss of pigment. A
white scar is recognizable at the retinotomy site. White dots outline the same area as in B. D, Twelve months
after transplantation, there is no change compared with 6 months.

39. 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.

40. 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 Loss
From Retinitis Pigmentosa Alan Y. Chow, MD Arch Ophthalmol. 2004;122:460-469

41. ASR MICROCHIP
B -The ASR microchip
A -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.

42. ASR Implant
Fundus
photographs and
fluorescein
angiograms of an
implanted
artificial silicon
retina microchip
in the superior
temporal retina.

43. 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.

44. 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 precursors
R. E. MacLaren. Nature 444, 203-207 2006

45. “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

46. 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 pigmentosa
Volker et al Science 23 July 2010

47. 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%).

48. 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
treatment
Phillips et al"Tauroursodeoxycholic acid preservation of photoreceptor structure and function in the rd10 mouse
through postnatal day 30". Invest Ophthalmol Vis Sci. 2008 May;49(5):2148-55

49. Is there hope?