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Important Note: The following information
is provided for your education. It should not be relied upon for
personal diagnosis or treatment. If you believe that a
particular therapy applies to you or someone you care about, be
sure to consult a doctor before trying it.
Retinitis Pigmentosa
Research: 2002-2006
Orphanet J Rare Dis. 2006 Oct 11;1(1):40 [Epub ahead of print]
Retinitis pigmentosa.
Hamel CP.
ABSTRACT: Retinitis pigmentosa (RP) is an inherited retinal dystrophy caused by
the loss of photoreceptors and characterized by retinal pigment deposits visible
on fundus examination. Prevalence of non syndromic RP is approximately 1/4,000.
The most common form of RP is a rod-cone dystrophy, in which the first symptom
is night blindness, followed by the progressive loss in the peripheral visual
field in daylight, and eventually leading to blindness after several decades.
Some extreme cases may have a rapid evolution over two decades or a slow
progression that never leads to blindness. In some cases, the clinical
presentation is a cone-rod dystrophy, in which the decrease in visual acuity
predominates over the visual field loss. RP is usually non syndromic but there
are also many syndromic forms, the most frequent being Usher syndrome. To date,
45 causative genes/loci have been identified in non syndromic RP (for the
autosomal dominant, autosomal recessive, X-linked, and digenic forms). Clinical
diagnosis is based on the presence of night blindness and peripheral visual
field defects, lesions in the fundus, hypovolted electroretinogram traces, and
progressive worsening of these signs. Molecular diagnosis can be made for some
genes, but is not usually performed due to the tremendous genetic heterogeneity
of the disease. Genetic counseling is always advised. Currently, there is no
therapy that stops the evolution of the disease or restores the vision, so the
visual prognosis is poor. The therapeutic approach is restricted to slowing down
the degenerative process by sunlight protection and vitaminotherapy, treating
the complications (cataract and macular edema), and helping patients to cope
with the social and psychological impact of blindness. However, new therapeutic
strategies are emerging from intensive research (gene therapy, neuroprotection,
retinal prosthesis).
-----
Curr Neurol Neurosci Rep. 2006 Sep;6(5):403-13.
Retinitis pigmentosa, pigmentary retinopathies, and neurologic
diseases.
Bhatti MT.
Department of Ophthalmology, University of FloridaCollege of Medicine, Box
100284 JHMHSC, Gainesville, FL 32610-0284, USA. tbhatti@eye.ufl.edu
Retinitis pigmentosa (RP) refers to a group of inherited retinal diseases with
phenotypic and genetic heterogeneity. The pathophysiologic basis of the
progressive visual loss in patients with RP is not completely understood but is
felt to be due to a primary retinal photoreceptor cell degenerative process
mainly affecting the rods of the peripheral retina. In most cases RP is seen in
isolation (nonsyndromic), but in some other cases it may be a part of a genetic,
metabolic, or neurologic syndrome or disorder. Nyctalopia, or night blindness,
is the most common symptom of RP. The classic fundus appearance of RP includes
retinal pigment epithelial cell changes resulting in retinal hypo- or
hyperpigmentation ("salt-and-pepper"), retinal granularity, and bone spicule
formation. The retinal vessels are often narrowed or attenuated and there is a
waxy pallor appearance of the optic nerve head. Electroretinography will
demonstrate rod and cone photoreceptor cell dysfunction and is a helpful test in
the diagnosis and monitoring of patients with RP. A detailed history with
pedigree analysis, a complete ocular examination, and the appropriate
paraclinical testing should be performed in patients complaining of visual
difficulties at night or in dim light. This review discusses the clinical
manifestations of RP as well as describing the various systemic diseases, with a
special emphasis on neurologic diseases, associated with a pigmentary
retinopathy.
-----
Ophthalmic Physiol Opt. 2006 Sep;26(5):490-6.
Night-vision goggles for night-blind subjects: subjective
evaluation after 2 years of use.
Hartong DT, Kooijman AC.
Laboratory of Experimental Ophthalmology, School of Behavioural and Cognitive
Neurosciences, University of Groningen, 9700 RB Groningen, the Netherlands.
d.t.hartong@ohk.umcg.nl
PURPOSE: To evaluate the usefulness of night-vision goggles (NVG) for
night-blind subjects after 1 and 2 years of use. METHODS: Eleven night-blind
subjects with retinitis pigmentosa used NVG for a 2-year period. At the end of
each year, they were requested to fill-in two questionnaires regarding their use
of the instrument. RESULTS: At both the 1- and 2-year evaluations, the subjects
reported fewer problems with mobility in the dark when they used the goggles. At
the 2-year evaluation, two individuals stated that they had stopped using the
instrument, while seven used it at least twice a week. The nine subjects still
using the instrument after 2 years reported an increase in their sense of
independence and an increase in their potential for activities. The instrument
was used most often during the dark winter season and for purposes such as
visiting friends and family, travelling to work or sports, attending meetings
and strolling. CONCLUSION: At the 2-year follow-up, NVG were still being used by
most of the night-blind subjects. Moreover, the device had a positive effect on
the subjects' experienced opportunities and sense of independence. The
instrument was considered useful in the daily lives of our subjects.
-----
Can J Ophthalmol. 2006 Aug;41(4):481-90.
The evidence for efficacy of omega-3 fatty acids in preventing or
slowing the progression of retinitis pigmentosa: a systematic review.
Hodge WG, Barnes D, Schachter HM, Pan YI, Lowcock EC, Zhang L, Sampson M,
Morrison A, Tran K, Miguelez M, Lewin G.
Department of Opthalmology, Ottawa Hospital Eye Institute, University of Ottawa,
Ont., Canada. whodge@ottawahospital.on.ca
BACKGROUND: Studies in preterm and term human infants have suggested that a
dietary supply of omega-3 fatty acids is essential for optimal visual
development. Several basic science studies support the hypothesis that omega-3
fatty acids may be useful therapeutic agents for pathologies of the retina and
lens. As part of a systematic review of the effect of omega-3 fatty acids on eye
health, the purpose of this study was to conduct a systematic review of the
scientific-medical literature to appraise and synthesize the evidence for the
effects of omega-3 fatty acids in preventing the development or progression of
retinitis pigmentosa. METHODS: A comprehensive search was undertaken in MEDLINE,
PREMEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Global
Health, and Dissertation Abstracts. Unpublished literature was sought through
manual searches of reference lists of included studies and key review articles
and from the files of content experts. Searches were not restricted by language
of publication, publication type, or study design. Eligibility criteria were
applied to screen eligible studies on two levels. Data extraction and quality
assessment were performed. RESULTS: Six studies published between 1995 and 2004
met eligibility criteria in investigating the question of the possible value of
omega-3 fatty acids in slowing the progression of retinitis pigmentosa.
Meta-analysis was not performed because there was not enough available
information for formal quantitative analysis. INTERPRETATION: There are trends
in improvement of some retinitis pigmentosa outcomes with omega-3 fatty acids in
the higher quality studies. Clinical research is preliminary in this field,
however. Accordingly, definitive answers will require significantly more
observational and interventional clinical research.
-----
BMC Ophthalmol. 2006 Jun 7;6:23.
Lutein supplementation in retinitis pigmentosa: PC-based vision
assessment in a randomized double-masked placebo-controlled clinical trial
[NCT00029289].
Bahrami H, Melia M, Dagnelie G.
The Wilmer Eye Institute, Department of Ophthalmology, School of Medicine, Johns
Hopkins University, Baltimore, MD, USA. hbahram2@jhmi.edu
BACKGROUND: There is no generally accepted medical or surgical treatment to stop
the progressive course of retinitis pigmentosa. Previous studies have suggested
lutein as a potential treatment with positive effects on macular pigment
density. The objective of this study was to examine the effect of lutein
supplementation on preservation of visual function in patients with retinitis
pigmentosa (RP) METHODS: In a double-masked randomized placebo-controlled phase
I/II clinical trial with a cross-over design, 34 adult patients with RP were
randomized to two groups. One group, consisted of 16 participants, received
lutein supplementation (10 mg/d for 12 wks followed by 30 mg/d) for the first 24
weeks and then placebo for the following 24 weeks, while the other group
included 18 participants for whom placebo (24 weeks) was administered prior to
lutein. Visual acuity, contrast sensitivity, and central visual field were
measured at different illumination levels at baseline and every week using a
PC-based test at home. RESULTS: For visual acuity (VA) at normal illumination
level, treatment with lutein reduced logMAR, i.e. improved VA, but this effect
was not statistically significant. The changes in normal (100%), low (4%), and
very low (0.1%) illumination log CS were not statistically significant
(p-values: 0.34, 0.23, and 0.32, respectively). Lutein had a statistically
significant effect on visual field (p-value: 0.038) and this effect increased in
the model assuming a 6-week delay in effect of lutein. Comparing the development
of vision measures against the natural loss expected to occur over the course of
48 weeks, most measures showed reduced decline, and these reductions were
significant for normal illumination VA and CS. CONCLUSION: These results suggest
that lutein supplementation improves visual field and also might improve visual
acuity slightly, although these results should be interpreted cautiously. As a
combined phase I and II clinical trial, this study demonstrated the efficacy and
safety of lutein supplementation.
-----
Am J Ophthalmol. 2006 May;141(5):850-8. Epub 2006 Mar 20.
Topical dorzolamide for the treatment of cystoid macular edema in
patients with retinitis pigmentosa.
Grover S, Apushkin MA, Fishman GA.
Department of Ophthalmology and Visual Sciences, University of Illinois at
Chicago, Chicago, Illinois.
PURPOSE: To determine if topical dorzolamide, as observed with the use of
systemic acetazolamide and methazolamide, would be effective in treating cystoid
macular edema (CME) in patients with retinitis pigmentosa (RP). DESIGN:
Prospective, nonrandomized clinical trial. METHODS: setting: Institutional.
patients: Fifteen patients with CME and RP. intervention: A baseline visual
acuity and optical coherence tomography (OCT) measurements were obtained in all
patients. Each one of them was then treated with topical dorzolamide, three
times a day, for at least four weeks in both eyes. main outcome measures:
Significant decrease in "foveal thickness" (more than 16%) and "foveal zone
thickness" (more than 11%), as measured by OCT. RESULTS: Thirteen (87%) of 15
patients showed a significant decrease in retinal thickness in at least one eye
after use of topical dorzolamide for at least four weeks. Five patients (33%)
demonstrated improvement in both eyes. All patients, except one, who responded
showed the effect within four weeks, but were monitored for a period of two to
nine months (average 4.5 months). Four patients (31%) who showed an initial
improvement in macular edema showed worsening with continued treatment.
CONCLUSIONS: The present study documents the potential efficacy of topical
dorzolamide for treating CME in patients with RP. We observed that some patients
may show a "rebound phenomenon" with continued use of the medication; hence,
there is a need for careful follow-up in patients being treated.
-----
Bioessays. 2006 Apr;28(4):344-54.
Why photoreceptors die (and why they don't).
Fain GL.
Department of Physiological Science, Life Science 3836, University of
California, Los Angeles, 90095-1606, USA. gfain@ucla.edu
Light can kill the photoreceptors of the eye, not only very bright direct
sunlight, but more moderate illumination if the light is present continuously.
Recent experiments show that rod apoptosis can be triggered by strong and
constant activation of transduction, and that death can be prevented if
transduction is inhibited even though the eye is illuminated. Vitamin A
deficiency and genetically inherited diseases, such as some forms of retinitis
pigmentosa and Leber congenital amaurosis, appear to kill like this:
transduction is activated at a high rate and continuously, and this causes the
rods to die. Why does transduction kill? Our best guess is that continuous
activation produces a prolonged lowering of the Ca(2+) concentration, which is
also thought to kill neurons in tissue culture and during the development of the
nervous system. To prevent death in constant light, rods have evolved protective
mechanisms including modulation of channels and ion transport to keep the Ca(2+)
from going too low. Prolonged light exposure also causes migration of
transduction proteins from one part of the cell to another and a reversible
shortening of the rod outer segments, the part of the cell that contains the
pigment rhodopsin. All of these mechanisms are at work in the normal eye to
reduce transduction and prevent the Ca(2+) concentration from dropping too low
for too long a time. That most of us retain our vision our entire lives is a
testament to their effectiveness.
-----
Ann Acad Med Singapore. 2006 Mar;35(3):137-8.
Retinal prostheses for the blind.
Javaheri M, Hahn DS, Lakhanpal RR, Weiland JD, Humayun MS.
Doheny Retina Institute, Doheny Eye Institute, Department of Ophthalmology, Keck
School of Medicine.
Using artificial means to treat extreme vision impairment has come closer to
reality during the past few decades. The goal of this research has been to
create an implantable medical device that provides useful vision for those
patients who are left with no alternatives. Analogous to the cochlear implants
for some forms of hearing loss, these devices could restore useful vision by
converting visual information into patterns of electrical stimulation that
excite the remaining viable inner retinal neurons in patients with retinitis
pigmentosa or age-related macular degeneration. Methods: Data for this review
were selected through a comprehensive literature search. Results: Advances in
microtechnology have facilitated the development of a variety of prostheses that
can be implanted in the visual cortex, around the optic nerve, or in the eye.
Some of these approaches have shown the promise of providing useful visual input
to patients with visual impairments. Conclusion: While the development of
various retinal prostheses have shown promise in limited clinical trials, there
are distinct advantages and disadvantages for each type of prosthesis. This
review will focus primarily on the Epiretinal Intraocular Retinal Prosthesis,
studied by our group, but will also briefly review other modalities: the
subretinal prosthesis, cortical prosthesis, and optic nerve prosthesis.
-----
Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3896-901. Epub 2006 Feb 27.
Ciliary neurotrophic factor (CNTF) for human retinal
degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular
implants.
Sieving PA, Caruso RC, Tao W, Coleman HR, Thompson DJ, Fullmer KR, Bush RA.
National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
paulsieving@nei.nih.gov
Full article: http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=16505355
Neurotrophic factors are agents with a promising ability to retard progression
of neurodegenerative diseases and are effective in slowing photoreceptor
degeneration in animal models of retinitis pigmentosa. Here we report a human
clinical trial of a neurotrophic factor for retinal neurodegeneration. In this
Phase I safety trial, human ciliary neurotrophic factor (CNTF) was delivered by
cells transfected with the human CNTF gene and sequestered within capsules that
were surgically implanted into the vitreous of the eye. The outer membrane of
the encapsulated cell implant is semipermeable to allow CNTF to reach the
retina. Ten participants received CNTF implants in one eye. When the implants
were removed after 6 months, they contained viable cells with minimal cell loss
and gave CNTF output at levels previously shown to be therapeutic for retinal
degeneration in rcd1 dogs. Although the trial was not powered to form a judgment
as to clinical efficacy, of seven eyes for which visual acuity could be tracked
by conventional reading charts, three eyes reached and maintained improved
acuities of 10-15 letters, equivalent to two- to three-line improvement on
standard Snellen acuity charts. A surgically related choroidal detachment in one
eye resulted in a transient acuity decrease that resolved with conservative
management. This Phase I trial indicated that CNTF is safe for the human retina
even with severely compromised photoreceptors. The approach to delivering
therapeutic proteins to degenerating retinas using encapsulated cell implants
may have application beyond disease caused by genetic mutations.
-----
Can J Ophthalmol. 2006 Feb;41(1):27-33.
Visual field expansion in patients with retinitis pigmentosa.
Somani S, Brent MH, Markowitz SN.
Background: To determine the effectiveness of using spectacle-mounted prisms for
field expansion in patients with retinitis pigmentosa (RP).Methods:
Vision-related activities of daily living (V-ADL) questionnaire scores and
functional visual field score (FFS) measurements were conducted before and after
a one-month trial of spectacle-mounted prisms in those patients with RP who had
residual central visual fields of less than 10 degrees. Results: 16 patients
were recruited who met study inclusion criteria. Mean V-ADL and FFS at baseline
were 67.6 (73%) and 22.9 (46%), respectively. After a 1-month trial using
spectacle-mounted prisms, V-ADL and FFS demonstrated significant improvement to
73.4 (80%, p < 0.05) and 27.0 (54%, p < 0.001), respectively. Interpretation:
Spectacle-mounted prisms effectively create visual field expansion and
noticeable spatial orientation benefits in patients with RP. This may provide an
adjunctive tool in low vision rehabilitation and should be considered in all
cases with RP with less than 10 degrees of visual field.
-----
Otol Neurotol. 2006 Feb;27(2 Suppl 1):S1-24, discussion S20.
Evidence-based overview of ophthalmic disorders in deaf children:
a literature update.
Nikolopoulos TP, Lioumi D, Stamataki S, O'Donoghue GM.
Department of Otorhinolaryngology, Athens University, Ippokration Hospital, 116
George Papandreou Street, Nea Philadelphia, Athens 143-42, Greece.
thomas.nikolopoulos@nottingham.ac.uk
BACKGROUND: Deaf children are heavily reliant on the sense of vision in order to
develop efficient communication skills and explore the world around them. Any
ophthalmic disorder may thus negatively impact on this process, especially if it
is unrecognised in the early years of life. These disorders may be correctable
(such as myopia) or treatable (such as cataract), and their early identification
is of the utmost importance to optimise language development (spoken or sign, or
both) and develop social cognition. Those children with non-correctable and
non-treatable visual disorders, like retinitis pigmentosa in Usher syndrome,
require multiple environmental adaptations and appropriate support services and
information. AIM:: To review the accumulated scientific knowledge on ophthalmic
disorders in deaf children and assess the quality of evidence published in the
literature in order to contribute to better diagnosis and management of these
conditions. MATERIAL AND METHODS: The project reviewed more than 1000 published
papers and other sources. 191 papers complied with the aims of the study and
were used in the project. From these studies, 95% were based on type III or IV
evidence (mainly descriptive studies or case reports). Only 3% were based on
type II evidence and 2% on type I evidence. RESULTS-CONCLUSIONS: The main
conclusions of this project are: a) the overall quality of evidence in the
literature concerning deaf children and their ophthalmic problems is very low,
b) the prevalence of ophthalmic problems in deaf children is very high
(approximately 40% to 60%) and these problems may remain undetected for years
although they may have a serious impact on children's acquisition of
communication skills, c) screening for ophthalmic problems in deaf children
should be encouraged and specialist ophthalmic examination should be carried out
as soon as the diagnosis of deafness is confirmed irrespective of age, and may
need to be repeated at intervals following diagnosis, d) families should be
informed about the nature of the screening process in discussion with the
relevant professionals and appropriate information should be available in a
range of formats and in different community languages, e) professionals
administering the tests should be familiar with the needs of deaf children with
ophthalmic problems and should be sensitive to the communication needs of the
child, especially undertaking behavioural testing where their collaboration is
needed, f) while orthoptists can perform the majority of psychophysical tests
(visual and stereo acuity tests, ocular motility tests, etc.) a comprehensive
opthalmologic assessment by slit lamp biomicroscopy, streak retinoscopy, direct
and indirect ophthalmoscopy, intraocular pressure measurement etc is required.
Electrophysiologic testing to help identification of Usher syndrome may also be
required, and finally g) serial hearing assessments of children with dual
sensory deficits are needed to monitor hearing thresholds, to optimise hearing
aid use and to ensure timely referral for cochlear implantation for those who
need it.
-----
Clin Exp Optom. 2006 Jan;89(1):10-7.
Mobility performance of low-vision adults using an electronic
mobility aid.
Jones T, Troscianko T.
Centre for Transport and Society, University of the West of England, Bristol,
United Kingdom.
Visually impaired people rank obstacle location and identification as two of the
most important mobility problems faced. Traditional mobility aids (the long
cane) provide information about where an object is located but only within their
limited (one metre) range. Although objects are located when traditional aids
are used, it is unlikely that they are identified. The Bristol Mobility Aid (BMA)
is an electronic travel aid that presents scene images to remaining residual
vision in a number of view formats. Previous work has suggested visually
impaired observers have better static object recognition using this aid. We
investigated the mobility performance of subjects with retinitis pigmentosa
using the BMA by determining the percentage preferred walking speed (PPWS), and
the number of errors made with three different BMA headset views on an indoor
mobility course. We found low-vision subjects had significantly reduced PPWS in
two of the three headset views and interestingly, sighted subjects had
significantly reduced PPWS when using the BMA in all three views. The numbers of
errors made were significantly higher across all vision groups when the BMA was
worn. We found that the BMA does not currently increase mobility in the visually
impaired. Results are discussed in terms of modifications that could be made to
the aid and methodological limitations.
-----
Adv Drug Deliv Rev. 2005 Oct 28; [Epub ahead of print]
Intraocular sustained drug delivery using implantable polymeric
devices.
Yasukawa T, Ogura Y, Sakurai E, Tabata Y, Kimura H.
Kurashiki Central Hospital, Kurashiki 710-8602, Japan; Department of
Ophthalmology, Nagoya City University Medical School, Aichi 467-8601, Japan.
Vitreoretinal diseases involving age-related macular degeneration (AMD) are
refractory to most topical or systemic drugs. The retina and the vitreous cavity
have a unique position regarding pharmacokinetics in that the inner and outer
blood retinal barriers separate the retina and vitreous from the systemic
circulation. Eye drops achieve minimal therapeutic concentrations in the
vitreoretinal tissue. Drug delivery systems are a strategy to address this.
Intraocular sustained drug release using implantable devices has been
investigated to treat vitreoretinal diseases. Possible targeted diseases include
those in which repeated intraocular injections are effective (cytomegalovirus
retinitis, uveitis), diseases requiring surgery (proliferative vitreoretinopathy),
and chronic diseases (AMD, macular edema, retinitis pigmentosa). Hydrophobic or
hydrophilic polymers shaped into a sheet, disc, rod, plug, or a larger device
can be implanted into the subretinal space, intrascleral space, vitreous space,
peribulbar space, or at the pars plana. Many researchers suggest the feasibility
of these implants to treat AMD.
-----
Clin Exp Optom. 2005 Sep;88(5):335-50.
Retinitis pigmentosa: visual function and multidisciplinary
management.
Herse P.
School of Optometry and Vision Science, University of New South Wales, Sydney,
NSW, 2052, Australia. p.herse@unsw.edu.au
Retinitis pigmentosa (RP) is a leading cause of blindness and visual disability
in younger people. Optometrists have a major role in detecting RP and in
reducing the visual disability associated with RP. This review summarises the
literature relating to visual function in people with RP, with particular
attention given to night-blindness, visual acuity decrease and visual field
contraction. The range of low vision aids available for people with RP is
reviewed and suggestions given on aids that have been found to be most
successful. Most importantly, this review overviews the range of services
available to people with RP and emphasises how optometrists need to work with a
network of professionals to ensure the best possible visual outcomes for people
with RP. Particular mention is made of current findings relating to orientation
and mobility training, driving, sensory substitution and adaptive technology.
The modern optometrist needs to be aware of the multiple needs of people with RP
and have the ability to link them with the professionals best able to help them.
-----
Hong Kong Med J. 2005 Aug;11(4):281-8.
Genetic markers for retinitis pigmentosa.
Wang DY, Chan WM, Tam PO, Chiang SW, Lam DS, Chong KK, Pang CP.
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong
Kong, Hong Kong Eye Hospital, 147K Argyle Street, Hong Kong.
OBJECTIVE. To review recent advances in the molecular genetics of retinitis
pigmentosa with emphasis on the development of genetic markers that aids
diagnosis and prognosis. DATA SOURCES AND EXTRACTION. Literature search of
MEDLINE from 1988 to 2005 using the following key words: 'retinitis pigmentosa',
'rhodopsin', 'RP1', 'RPGR', and 'genetic counseling'. References of two genes--RHO
and RP1--causing retinitis pigmentosa in the Chinese population were reviewed.
STUDY SELECTION. Literature and data related to genetic markers for retinitis
pigmentosa. DATA SYNTHESIS. The genetics of retinitis pigmentosa is complex. It
can be sporadic or familial, with heterogeneous transmission modes. Retinitis
pigmentosa is associated with nearly 40 chromosomal loci, where 32 candidate
genes have been identified. A large number of mutations are known to cause
retinitis pigmentosa. But no single mutation alone accounts for more than 10% of
unrelated retinitis pigmentosa patients. Genetic tests for retinitis pigmentosa
require screening for a consort of mutations in a large number of genes. High
throughput screening technology such as denaturing high performance liquid
chromatography and automated DNA sequencing should make such tests feasible.
CONCLUSIONS. Rapid developments in the understanding of the genetics of
retinitis pigmentosa have helped to establish genetic tests of clinical value.
The complex mode of inheritance nonetheless makes genetic counselling difficult,
even in the presence of positive genetic screening results.
-----
Optometry. 2005 May;76(5):309-17.
Sector retinitis pigmentosa.
Van Woerkom C, Ferrucci S.
Pasadena Optometry Center, Pasadena, California, USA.
BACKGROUND: Retinitis pigmentosa (RP) is one of the most common hereditary
retinal dystrophies and causes of visual impairment affecting all age groups.
The reported incidence varies, but is considered to be between 1 in 3,000 to 1
in 7,000. Sector retinitis pigmentosa is an atypical form of RP that is
characterized by regionalized areas of bone spicule pigmentation, usually in the
inferior quadrants of the retina. CASE REPORT: A 57-year-old Hispanic man with a
history of previously diagnosed retinitis pigmentosa came to the clinic with a
longstanding symptom of decreased vision at night. Bone spicule pigmentation was
found in the nasal and inferior quadrants in each eye. He demonstrated superior
and temporal visual-field loss corresponding to the areas of the affected
retina. Clinical measurements of visual-field loss, best-corrected visual
acuity, and ophthalmoscopic appearance have remained stable during the five
years the patient has been followed. DISCUSSION: Sector retinitis pigmentosa is
an atypical form of RP that is characterized by bilateral pigmentary
retinopathy, usually isolated to the inferior quadrants. The remainder of the
retina appears clinically normal, although studies have found functional
abnormalities in these areas as well. Sector RP is generally considered a
stationary to slowly progressive disease, with subnormal electro-retinogram
findings and visual-field defects corresponding to the involved retinal sectors.
CONCLUSION: Management of RP is very difficult because there are no proven
methods of treatment. Studies have shown 15,000 IU of vitamin A palmitate per
day may slow the progression, though this result is controversial. Low vision
rehabilitation, long wavelength pass filters, and pedigree counseling remain the
mainstay of management.
-----
Acta Ophthalmol Scand. 2005 Apr;83(2):248-51.
Intravitreal triamcinolone acetonide for treatment of cystoid
macular oedema in patients with retinitis pigmentosa.
Ozdemir H, Karacorlu M, Karacorlu S.
Istanbul Retina Institute Inc., Istanbul, Turkey.
PURPOSE: To evaluate the anatomic and visual outcomes of intravitreal
triamcinolone acetonide injection in patients with cystoid macular oedema (CMO)
secondary to retinitis pigmentosa (RP). METHODS: Five eyes of five patients with
CMO secondary to RP, aged 25-41 years (mean 33.2 years) made up the study
population. All eyes had persistent CMO despite medical treatment with 250 mg of
oral acetazolamide twice daily for 1 month. Intravitreal injection of 4 mg (0.1
ml) triamcinolone acetonide was offered to treat macular oedema. The visual and
anatomic responses were observed, as well as complications related to the
injection procedure and corticosteroid medication. RESULTS: Follow-up periods
varied between 6 and 8 months (mean 6.8 months); all patients completed 6 months
of follow-up. After intravitreal triamcinolone acetonide injection all patients
showed good anatomic response. The baseline median central macular thickness was
418 microm (range 376-626 microm). At 1 month, the median central macular
thickness had decreased to 224 microm (range 214-326 microm). At 3 and 6 months,
the median central macular thicknesses were 275 microm (range 215-584 microm)
and 312 microm (range 239-521 microm), respectively. Recurrent CMO was found in
one patient at the 3-month follow-up and in two patients at the 6-month
follow-up. Retreatment was performed in these patients. At the 1-month
follow-up, no patient was found to have lost vision and two patients showed
improvement. At the 3- and 6-month follow-ups, no patient had lost vision from
baseline but no patient had maintained their improved visual acuity (VA).
CONCLUSIONS: In our small series, all patients showed an anatomic improvement in
CMO after intravitreal injection of triamcinolone acetonide. However, in three
out of five patients, despite good anatomic results, no improvement in VA was
achieved. Because of the limitations of this pilot study, it is difficult to
explain why no improvement in VA was achieved despite good anatomic results in
some patients. Further study with longer follow-up periods and larger series is
warranted to assess the efficacy of the treatment.
-----
J Neural Eng. 2005 Mar;2(1):S105-20. Epub 2005 Feb 22.
Design of a high-resolution optoelectronic retinal prosthesis.
Palanker D, Vankov A, Huie P, Baccus S.
Department of Ophthalmology and Hansen Experimental Physics Laboratory, Stanford
University, Stanford, CA 94305-4085, USA.
It has been demonstrated that electrical stimulation of the retina can produce
visual percepts in blind patients suffering from macular degeneration and
retinitis pigmentosa. However, current retinal implants provide very low
resolution (just a few electrodes), whereas at least several thousand pixels
would be required for functional restoration of sight. This paper presents the
design of an optoelectronic retinal prosthetic system with a stimulating pixel
density of up to 2500 pix mm(-2) (corresponding geometrically to a maximum
visual acuity of 20/80). Requirements on proximity of neural cells to the
stimulation electrodes are described as a function of the desired resolution.
Two basic geometries of sub-retinal implants providing required proximity are
presented: perforated membranes and protruding electrode arrays. To provide for
natural eye scanning of the scene, rather than scanning with a head-mounted
camera, the system operates similar to 'virtual reality' devices. An image from
a video camera is projected by a goggle-mounted collimated infrared LED-LCD
display onto the retina, activating an array of powered photodiodes in the
retinal implant. The goggles are transparent to visible light, thus allowing for
the simultaneous use of remaining natural vision along with prosthetic
stimulation. Optical delivery of visual information to the implant allows for
real-time image processing adjustable to retinal architecture, as well as
flexible control of image processing algorithms and stimulation parameters.
-----
Semin Ophthalmol. 2005 Jan-Mar;20(1):17-23.
Embryonic stem cells: potential source for ocular repair.
Haruta M.
Department of Ophthalmology and Visual Sciences, Graduate School of Medicine,
Kyoto University, Japan. haruta@kuhp.kyoto-u.ac.jp
Many ocular diseases, such as retinitis pigmentosa and age-related macular
degeneration, reflect damage to specific cells that are not normally repaired or
replaced. Preliminary results of animal studies suggest that these degenerative
diseases may be treatable by transplantation of healthy fetal cells. However,
obtaining a sufficient number of suitable donor cells remains a problem. The
isolation of human embryonic stem (ES) cells has drawn much attention because of
their potential clinical application for patients with these degenerative
diseases. Because ES cells have the potential to generate all adult cell types,
ocular diseases resulting from the failure of specific cell types would be
potentially treatable through the transplantation of differentiated cells
derived from ES cells. In addition, because ES cells can proliferate
indefinitely in their undifferentiated state, they are expected to alleviate the
problem of the shortage of donor cells for cell-replacement therapy. Recently,
reproducible and efficient differentiation methods for the generation of lens
cells, retinal neurons, and retinal pigment epithelial (RPE) cells from ES cells
have been developed. This review focuses especially on these ocular cells
differentiated from ES cells. We will also discuss the potential therapeutic
uses of ES cells for the treatment of ocular diseases.
-----
Dev Ophthalmol. 2005;38:120-47.
Nutrition and retina.
Schmidt-Erfurth U.
Universitatsklinik der Augenheilkunde und Optometrie, Vienna, Austria.
ursula.schmidt-erfurth@akhwien.at
The impact of nutrition on manifestation and progression of retinal diseases has
become an important, controversial topic within recent years. The awareness of
this topic in the general population has increased partially due strong
commercial advertisements of supplements and diets. However, many potentially
beneficial nutritional effects on retinal diseases have not been proven in
prospective clinical trials. It is only for a few relatively rare diseases, such
as retinitis pigmentosa or gyrate atrophy, that adjustments in nutrition have
been proven effective and widely accepted. However, for the majority of patients
with retinal diseases the impact of nutritional factors is still insufficiently
understood. Theoretically, supplementation of antioxidants could have a
beneficial impact on a wide variety of retinal diseases or as a preventive
measure by limiting the degree of oxidative damage. The only prospective,
controlled, clinical trial providing proven benefit of antioxidant
supplementation for a retinal disease is the Age-Related Eye Disease Study (AREDS).
Patients with at least intermediate age-related macular degeneration (AMD) were
shown to have a significant benefit with regard to disease progression by
supplementing with high-dose antioxidants and zinc. It is however unclear
whether other antioxidants, such as lutein or zeaxanthin, may be better and
whether a preventive supplementation is useful. Especially studies on patients
with diabetic retinopathy have implicated an impact of higher cholesterol levels
on the progression of the disease. High-fat diets have been overall associated
to a number of retinal diseases. With the current knowledge it seems prudent to
advise everyone a balanced, low-fat diet as well as vitamin supplementation
within the recommended daily allowance. Smoking is an essential factor for
oxidative stress, and its cessation should be recommended to everybody in order
to prevent or slow down progression of retinal disease. High-dose antioxidant
supplementation according to the AREDS trial should currently only be
recommended to non-smokers with at least intermediate AMD. Based on results from
experimental studies, further prospective clinical studies are warranted on the
prevention and inhibition of disease progression in the most common retinal
diseases by nutritional means.
-----
Clin Chim Acta. 2005 Jan;351(1-2):5-16.
Gene mutations in retinitis pigmentosa and their clinical
implications.
Wang DY, Chan WM, Tam PO, Baum L, Lam DS, Chong KK, Fan BJ, Pang CP.
Department of Ophthalmology and Visual Sciences, Hong Kong Eye Hospital, The
Chinese University of Hong Kong, 147K Argyle Street, Kowloon, Hong Kong, China.
Retinitis pigmentosa (RP) is a group of inherited progressive retinal diseases
affecting about 1 in 3500 people worldwide. So far, there is no prevention or
cure, with permanent visual loss or even blindness the ultimate consequence
usually after midlife. The genetics of RP are complex. It can be sporadic,
autosomal dominant, autosomal recessive, or X-linked. Thirty-two genes are known
to be associated with RP, sometimes the same gene gets involved in different
inheritance traits. Some RP cases have a digenic cause. About 60% RP cases still
have no known genetic cause. A large number of mutations cause RP, and they can
be deletions, insertions, or substitutions that cause missense mutations or
truncations. The RHO, RP1, and RPGR genes contribute the greatest number of
known mutations causative of RP. But there is no single mutation that alone
accounts for more than 10% of unrelated patients. Genetic testing for RP
therefore requires screening for a group of genes. High-throughput and automated
sequence detection technologies are essential. Due to the complexity in
phenotype and genetics, and the fact that RP is untreatable, genetic testing for
presymptomatic diagnosis of RP is controversial. Meanwhile, new genes are still
to be identified, mostly by family linkage and sib-pair analysis. Research on
gene therapy for RP requires information on gene mutations causative of RP.
-----
Clin Ter. 2004 Jul-Aug;155(7-8):347-51.
[Diet and management of degenerative diseases of the retina
(retinitis pigmentosa)]
[Article in Italian]
Miggiano GA, Falsini B.
Centro di Ricerca in Nutrizione Umana, Istituto di Biochimica Clinica, Italia.
Considerable progress has been made in the understanding and management of
degenerative diseases of the retina. The dietetic intervention has been
favourably proposed in the most common forms of retinitis pigmentosa, a
condition potentially leading to blindness. Vitamin A has been shown to be
effective in delaying progression of the disease. In these patients such
treatment is the only possible therapy, to date, and a lifetime generous
supplementation of retinol is advisable, together with a vitamin A-rich diet
and/or a dietary supplement (e.g. carrot flour) or pharmacologic supplement of
vitamin A. Supply of vitamin A in doses up to 25000 IU (7500 igr/day), even for
several years, has so far proved safe from risk of occurrence of liver disease.
A possible effect on hypercholesterolemia related to a very prolonged treatment
in predisposed individuals can be avoided by using a special diet, particularly
enriched with beta-carotene. Guidelines for preparing a diet, specially
formulated to provide an elevated weekly supply of vitamin and/or its precursor
(equal to 15000 IU or 5000 microg of RE, retinol equivalent) and to control
possible risk factors related to dietetic manipulation (supply of fat lower than
30% of total calories, variable levels of cholesterol and polyunsaturated fatty
acids n-3, n-6) are presented. As long as resolutive therapy is lacking,
dietetic intervention plays a primary role, although underestimated, in the
management of the patients suffering from retinitis pigmentosa. The diet is
specifically characterized by presence of food with a high content of
carotenoids, substances with a favourable and additive effect.
-----
Arch Ophthalmol. 2004 Sep;122(9):1297-305.
Clinical trial of docosahexaenoic acid in patients with retinitis
pigmentosa receiving vitamin A treatment.
Berson EL, Rosner B, Sandberg MA, Weigel-DiFranco C, Moser A, Brockhurst RJ,
Hayes KC, Johnson CA, Anderson EJ, Gaudio AR, Willett WC, Schaefer EJ.
Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical
School, 243 Charles Street, Boston, MA 02114, USA.
OBJECTIVE: To determine whether a therapeutic dose of docosahexaenoic acid (DHA),
an omega-3 fatty acid, will slow the course of retinal degeneration in adult
patients with retinitis pigmentosa who are also receiving vitamin A. DESIGN:
Randomized, controlled, double-masked trial of 221 patients, aged 18 to 55
years, evaluated over a 4-year interval. Patients were given either 1200 mg/d of
docosahexaenoic acid or control capsules. All were given 15 000 IU/d of vitamin
A (given as retinyl palmitate). Randomization considered genetic type and
baseline dietary omega-3 fatty acid intake. MAIN OUTCOME MEASURES: The primary
outcome measure was the total point score for the 30-2 program of the Humphrey
field analyzer; secondary outcome measures were the total point score for the
30-2 and 30/60-1 programs combined, 30-Hz electroretinogram amplitude, and Early
Treatment Diabetic Rentinopathy Study visual acuity. RESULTS: No significant
differences in decline in ocular function were found between the docosahexaenoic
acid plus vitamin A (DHA + A) group and control plus vitamin A (control + A)
group over a 4-year interval among all 221 randomized patients or among the 208
patients who completed all 4 follow-up visits. The mean annual rate of loss of
sensitivity for the Humphrey Field Analyzer 30-2 program was 37 dB for the DHA +
A group and 38 dB for the control + A group (P =.88). For the Humphrey Field
Analyzer 30-2 and 30/60-1 programs combined, the mean annual rates of loss of
field sensitivity were 57 dB for the DHA + A group and 60 dB (P =.73) for
control + A group. No toxic adverse effects were observed. No significant
differences by treatment group assignment were observed within genetic types or
within the category of baseline omega-3 fatty acid intake. CONCLUSION: In
patients assigned to receive 15 000 IU/d of vitamin A, this randomized trial
showed that 1200 mg/d of docosahexaenoic acid supplementation over a 4-year
interval did not, on average, slow the course of disease in patients with
retinitis pigmentosa.
-----
Arch Ophthalmol. 2004 Sep;122(9):1306-14.
Further evaluation of docosahexaenoic acid in patients with
retinitis pigmentosa receiving vitamin A treatment: subgroup analyses.
Berson EL, Rosner B, Sandberg MA, Weigel-DiFranco C, Moser A, Brockhurst RJ,
Hayes KC, Johnson CA, Anderson EJ, Gaudio AR, Willett WC, Schaefer EJ.
Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical
School, 243 Charles Street, Boston, MA 02114, USA.
OBJECTIVE: To determine whether docosahexaenoic acid will slow the course of
retinal degeneration in subgroups of patients with retinitis pigmentosa who are
receiving vitamin A. DESIGN: A cohort of 208 patients with retinitis pigmentosa,
aged 18 to 55 years, were randomly assigned to 1200 mg of docosahexaenoic acid
plus 15 000 IU/d of vitamin A given as retinyl palmitate (DHA + A group) or
control fatty acid plus 15 000 IU/d of vitamin A (control + A group) and
followed up over 4 years. Seventy percent of the patients in each group were
taking vitamin A, 15 000 IU/d, prior to entry. We compared rates of decline in
ocular function in the DHA + A vs control + A groups among the subgroups defined
by use or nonuse of vitamin A prior to entry. We also determined whether decline
in ocular function was related to red blood cell phosphatidylethanolamine
docosahexaenoic acid level, dietary omega-3 fatty acid intake, or duration of
vitamin A use. Main outcome measures were Humphrey Field Analyzer visual field
sensitivity, 30-Hz electroretinogram amplitude, and visual acuity. RESULTS:
Among patients not taking vitamin A prior to entry, those in the DHA + A group
had a slower decline in field sensitivity and electroretinogram amplitude than
those in the control + A group over the first 2 years (P =.01 and P =.03,
respectively); these differences were not observed in years 3 and 4 of follow-up
or among patients taking vitamin A prior to entry. In the entire cohort, red
blood cell phosphatidylethanolamine docosahexaenoic acid level was inversely
related to rate of decline in total field sensitivity over 4 years (test for
trend, P =.05). This was particularly evident over the first 2 years among those
not on vitamin A prior to entry (test for trend, P =.003). In the entire control
+ A group, dietary omega-3 fatty acid intake was inversely related to loss of
total field sensitivity over 4 years (intake, <0.20 vs > or =0.20 g/d; P =.02).
The duration of vitamin A supplementation prior to entry was inversely related
to rate of decline in electroretinogram amplitude (P =.008). CONCLUSIONS: For
patients with retinitis pigmentosa beginning vitamin A therapy, addition of
docosahexaenoic acid, 1200 mg/d, slowed the course of disease for 2 years. Among
patients on vitamin A for at least 2 years, a diet rich in omega-3 fatty acids
(> or =0.20 g/d) slowed the decline in visual field sensitivity.
-----
Bull Acad Natl Med. 2003;187(9):1685-92; discussion 1692-4.
[Early therapeutic trials for retinitis pigmentosa]
[Article in French]
Dufier JL.
Service d'Ophtalmologie-Hopital Necker Enfants-Malades, 149, rue de Sevre, 75743
Paris cedex 15.
Non syndromic forms of Retinitis Pigmentosa (RP) constitute a collection of
clinically and genetically heterogeneous inherited retinal degenerative
diseases. They are characterized by a bilateral progressive visual loss
susceptible to cause blindness. These diseases are transmitted through pedigrees
according to all known modes of inheritance. They are bilateral and usually
start during infancy. However, very early clinical presentations exist, such as
those observed in children affected by Leber Congenital Amaurosis, as well as
late onset autosomal dominant forms of retinitis pigmentosa. The characteristic
clinical aspect of the rod-cone RP dystrophies is marked by alterations of the
peripheral retina associated with a night blindness and a progressive narrowing
of the visual field. The ophthalmoscopic examination of RP patients commonly
reveals thin retinal arteries and scattered pigmentary accumulations. In
contrast, there are cone rod retinal dystrophies whose onset is marked by a
decreased visual acuity before the appearance of any visual field alteration.
Some forms of RPs display an ocular fundus devoid of any pigmentary alteration.
Syndromic forms of RPs are not uncommon. The association of deafness with RP is
detected in nearly 30% of the patients. Other associations with RP can include
mental deficiency, facial dysmorphy, microcephaly, obesity, kidney deficiency,
immune deficiencies, metabolic disorders. The existence of such syndromic forms
of RP localizes RPs at the crossroad of several medical specialties. A long
lasting collaboration between our department of ophthalmology and the department
of medical genetics of the Necker-Sick Children Hospital has allowed us to
establish numerous genotype-phenotype correlations, especially in LCA and
Stargardt's disease. ABCR gene mutations cause Stargardt disease. ABCR mutations
may also cause some types of Ages Related Macular Degenerations (AMD). Nowadays,
there is no known efficient therapy available for patients affected by RP. Gene
therapies hold promises of treatment for patients affected by some of these
diseases for the next decade. In a not too far future, the use of
pharmacological drugs increasing a better intracellular oxygen availability,
without triggering any harmful production of free radical oxygen species (ROS),
while exerting an anti-apoptotic effect within photoreceptor cells, appears to
be a therapeutical strategy deserving to be tested in an appropriately designed
clinical trial. For the present time, optical and electronical devices as well
as night-vision glasses are the only possible tools allowing to improve the
quality of life of some patients.
-----
Graefes Arch Clin Exp Ophthalmol. 2004 Aug 10 [Epub ahead of print]
Retinal replacement-the development of microelectronic retinal
prostheses-experience with subretinal implants and new aspects.
Sachs HG, Gabel VP.
University Eye Clinic, University of Regensburg, Franz Josef Strauss Allee 11,
93042, Regensburg, Germany.
BACKGROUND. Progress in the field of microelectronics has led to the development
of visual prostheses for the treatment of blinding diseases. Different concepts
of retinal replacement are currently under investigation. The aim of the retinal
prostheses is to replace the function of lost photoreceptors in degenerative
diseases, such as retinitis pigmentosa. METHODS. Within the field of visual
prosthetic developments mainly two retinal based concepts are under
investigation. One of the concepts is the epiretinal implant which acquires
images of an external camera and after preprocessing by a computer reading this
visual information into the human visual system. In the subretinal prosthesis
design concept an array of stimulation electrodes is placed in the subretinal
space. True to the concept the image falling on the retina and its light
impulses are converted into electrical currents by microphotodiodes and the
retina is stimulated with these locally. To test the feasibility of the concepts
the biocompatibility and to determine basic stimulation parameters a lot of
animal experiments and first human experiments were carried out RESULTS.
Currently the research conducted by teams in Germany, the USA and Japan into
epiretinal and subretinal implants has reached the stage where clinical trials
can now be performed. Individual pilot studies were carried out for both the
epiretinal and the subretinal implant by different research groups DISCUSSION.
The results achieved by the researchers indicate that cortical action potentials
can be triggered by electric retinal stimulation with both concepts. The
experimental work has highlighted a whole range of obstacles, not all of which
have yet been fully resolved. These findings offer hope that coarse restoration
of vision may be feasible by electrical stimulation.
-----
Biomed Tech (Berl). 2004 Apr;49(4):99-103.
The retina implant--new approach to a visual prosthesis.
Alteheld N, Roessler G, Vobig M, Walter P.
Technical University Aachen, Dept. of Ophthalmology, Aachen, Germany. NAlteheld@ukaachen.de
Currently, no treatment is available for degenerative diseases of retinal
photoreceptors. The patients are faced with a high risk of blindness. Biological
approaches failed to prove efficacy. A new concept for the treatment of
disorders like retinitis pigmentosa is electrical stimulation at various levels
of the visual system. Therefore, devices were fabricated with stimulating
electrodes contacting retinal or central neurons to elicit biological activity
in these cells. It became possible to fabricate even complex devices with an
external power supply encapsulated within biocompatible materials. Animal
experiments showed that with implanted prototypes cortical activation could be
achieved and first experiments in blind human subject also suggest that vision
can be restored, however at present in a very low range of simply identifying
spots of light. Further developments and also the continuation of animal
experiments are necessary before the clinical application will become a standard
procedure.
-----
Arch Ophthalmol. 2004 Apr;122(4):587-96.
Outer retinal degeneration: an electronic retinal prosthesis as a
treatment strategy.
Loewenstein JI, Montezuma SR, Rizzo JF 3rd.
Retina Service, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston,
MA 02114, USA. john_loewenstein@meei.harvard.edu
OBJECTIVE: To review progress toward an electronic retinal prosthesis for outer
retinal degeneration. METHOD: Literature review. RESULTS: Retinal degenerations
such as retinitis pigmentosa result in a loss of photoreceptors. There is a
secondary loss of inner retinal cells, but significant numbers of bipolar and
ganglion cells remain for many years. Electrical stimulation can produce
phosphenes in the eyes of individuals who are blind as a result of retinitis
pigmentosa. Several research groups are trying to exploit this phenomenon to
produce artificial vision with electronic retinal prostheses. Two groups, with
private company sponsorship, have recently implanted first-generation devices in
subjects with advanced retinitis pigmentosa. They have reported limited
preliminary results. This article seeks to put these results in a broader
context and review potential obstacles to successful prosthesis development.
These include inner retinal cell viability, high thresholds, signal encoding,
power requirements, biocompatibility, and device encapsulation. CONCLUSION:
There has been substantial progress toward an electronic retinal prosthesis, but
fully functional, long-lasting devices are not on the immediate horizon.
-----
Arch Ophthalmol. 2004 Apr;122(4):460-9.
The artificial silicon retina microchip for the treatment of
vision loss from retinitis pigmentosa.
Chow AY, Chow VY, Packo KH, Pollack JS, Peyman GA, Schuchard R.
Optobionics Corporation, Naperville, Illinois, USA. alanykc@aol.com
OBJECTIVE: To determine the safety and efficacy of the artificial silicon retina
(ASR) microchip implanted in the subretinal space to treat vision loss from
retinitis pigmentosa. METHODS: 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.
RESULTS: During follow-up that ranged from 6 to 18 months, all ASRs functioned
electrically. No patient showed signs of implant rejection, infection,
inflammation, erosion, neovascularization, retinal detachment, or migration.
Visual function improvements occurred in all patients and included unexpected
improvements in retinal areas distant from the implant. MAIN OUTCOME MEASURES:
Subjective improvements included improved perception of brightness, contrast,
color, movement, shape, resolution, and visual field size. CONCLUSIONS: No
significant safety-related adverse effects were observed. 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.
-----
Arch Ophthalmol. 2004 Apr;122(4):587-96.
Outer retinal degeneration: an electronic retinal
prosthesis as a treatment strategy.
Loewenstein JI, Montezuma SR, Rizzo JF 3rd.
Massachusetts Eye and Ear Infirmary, Boston, Mass, and the Veterans'
Administration Center for Innovative Rehabilitation, Boston.
OBJECTIVE: To review progress toward an electronic retinal
prosthesis for outer retinal degeneration. Method. Literature
review. RESULTS: Retinal degenerations such as retinitis pigmentosa
result in a loss of photoreceptors. There is a secondary loss
of inner retinal cells, but significant numbers of bipolar and
ganglion cells remain for many years. Electrical stimulation can
produce phosphenes in the eyes of individuals who are blind as
a result of retinitis pigmentosa. Several research groups are
trying to exploit this phenomenon to produce artificial vision
with electronic retinal prostheses. Two groups, with private company
sponsorship, have recently implanted first-generation devices
in subjects with advanced retinitis pigmentosa. They have reported
limited preliminary results. This article seeks to put these results
in a broader context and review potential obstacles to successful
prosthesis development. These include inner retinal cell viability,
high thresholds, signal encoding, power requirements, biocompatibility,
and device encapsulation. CONCLUSION: There has been substantial
progress toward an electronic retinal prosthesis, but fully functional,
long-lasting devices are not on the immediate horizon.
-----
Arch Ophthalmol. 2004 Apr;122(4):460-9.
The artificial silicon retina microchip for the
treatment of vision loss from retinitis pigmentosa.
Chow AY, Chow VY, Packo KH, Pollack JS, Peyman GA, Schuchard
R.
Optobionics Corporation, Naperville, Ill.
OBJECTIVE: To determine the safety and efficacy of the artificial
silicon retina (ASR) microchip implanted in the subretinal space
to treat vision loss from retinitis pigmentosa. METHODS: 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. RESULTS: During follow-up that ranged from 6 to
18 months, all ASRs functioned electrically. No patient showed
signs of implant rejection, infection, inflammation, erosion,
neovascularization, retinal detachment, or migration. Visual function
improvements occurred in all patients and included unexpected
improvements in retinal areas distant from the implant. MAIN OUTCOME
MEASURES: Subjective improvements included improved perception
of brightness, contrast, color, movement, shape, resolution, and
visual field size. CONCLUSIONS: No significant safety-related
adverse effects were observed. 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.
----
Methods Mol Biol. 2004;246:439-49.
Delivery of genes to the eye using lentiviral
vectors.
Takahashi M.
Department of Experimental Therapeutics, Transitional Research
Center, Kyoto University Hospital, Kyoto, Japan.
The primary aim of gene transfer into the retinal cells has
been to investigate the developmental mechanisms of the retinal
cells or to reverse retinal diseases. Retroviruses have been used
to investigate the differentiation of retinal cells, to study
the embryonic retina in vivo or explant organ culture, and to
trace the fate of the cells that were dividing at the time of
gene transfer. Using adenovirus, Bennett et al. showed the possibility
of using gene therapy to correct degenerative diseases of the
central nervous system (CNS) (6). However, owing to the short
duration of the gene expression, adenovirus is not suitable for
correcting chronic diseases. Currently, lentivirus (7-9) and adenoassociated
virus vectors (10-14) are being used for studying and correcting
gene therapy of retinal degenerative diseases. Using an HIV vector
carrying the green fluorescent protein (GFP) gene expressed from
the cytomegalovirus (CMV) promoter, we showed that efficient and
long-lasting gene expression could be obtained in the retina (7,8).
Moreover, gene expression was restricted to the photoreceptor
cells and was more efficient with the rhodopsin promoter. Similar
results were reported using adeno-associated virus (AAV) vector.
Using a lentivirus vector carrying the phosphodiesterase beta
subunit (PDEbeta) gene, the mutation of which causes retinal degeneration
called retinitis pigmentosa in rd mice, photoreceptor cells were
rescued from degeneration in rd mice for at least 6 mo by PDEbeta
transduction using HIV-based lentivirus vector (9).
-----
Novartis Found Symp. 2004;255:17-27; discussion 27-36, 177-8.
Identifying retinal disease genes: how far have
we come, how far do we have to go?
Daiger SP.
Human Genetics Center, School of Public Health, Department of
Ophthalmology and Visual Science, The University of Texas Health
Science Center, Houston, TX 77030, USA.
One of the great success stories in retinal disease (RD) research
in the past decade has been identification of many of the genes
and mutations causing inherited retinal degeneration. To date,
more than 133 RD genes have been identified, encompassing many
disorders such as retinitis pigmentosa, Leber congenital amaurosis,
Usher syndrome and macular dystrophy. The most striking outcome
of these findings is the exceptional heterogeneity involved: dozens
of disease-causing mutations have been detected in most RD genes;
mutations in many different genes can cause the same disease;
and different mutations in the same gene may cause different diseases.
Superimposed on this genetic heterogeneity is substantial clinical
variability, even among family members with the same mutation.
The RD genes involve many different pathways, and expression ranges
from very limited (e.g. expressed in rod photoreceptors only)
to ubiquitous. These findings raise several general questions--in
addition to the extraordinary number of specific, biological problems
revealed. What fraction of the patient population can now be accounted
for by the known RD genes? How many more RD genes will be found,
and how should we find them? Are we dealing with just a handful
of disease mechanisms or are there many different routes to retinal
degeneration? How will this extreme heterogeneity affect our ability
to diagnose and treat patients? These questions are considered
in this summary.
-----
Invest Ophthalmol Vis Sci. 2003 Dec;44(12):5362-9.
Perceptual efficacy of electrical stimulation
of human retina with a microelectrode array during
short-term surgical trials.
Rizzo JF 3rd, Wyatt J, Loewenstein J, Kelly S, Shire D.
Department of Ophthalmology, Harvard Medical School and the Massachusetts
Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA.
joseph_rizzo@meei.harvard.edu
PURPOSE: This work is part of a feasibility assessment of a
retinal prosthesis as a means to restore vision to patients with
blindness caused by retinitis pigmentosa. The primary goal was
to assess the concordance of the form of induced perception and
the pattern of electrical stimulation of the retina, and the reproducibility
of the responses. METHODS: Five volunteers with severe retinitis
pigmentosa and one with normal vision were studied. A companion
paper in this issue provides details on demographics, visual function,
surgical methods, general stimulation strategy, and data analysis.
Volunteers were awake during surgery while a 10-microm-thick,
microfabricated electrode array was placed on the retina. The
array was connected to extraocular current sources that delivered
charges to 50-, 100-, and 400-microm-diameter electrodes. Negative
control trials were randomly included. Perceptual quality was
judged by the similarity between the form of stimulation and perception
(i.e., accuracy) and the reproducibility of responses. RESULTS:
Only 1 of 40 control tests yielded a false-positive result. On
average, volunteers 3, 5, and 6 reported percepts that matched
the stimulation pattern 48% and 32% of the time for single- and
multiple-electrode trials, respectively. Two-point discrimination
in the best cases may have been achieved in two blind subjects
using (center-to-center) electrode separation of 600 and 1960
microm. Reproducibility was achieved 66% of the time in the blind
subjects. By comparison, in the normal-sighted subject, perceptual
form was reported accurately 57% of the time, with 82% reproducibility,
and two-point discrimination may have been achieved in one trial
with 620-microm electrode spacing and in two trials each with
1860- and 2480-microm electrode spacing. In subjects 5 and 6,
perceptual size was inconsistently related to the charge, although
relatively large differences in charge (median: 0.55 microcoulombs
[microC]) between two trials produced differently sized percepts.
Longer stimuli did not produce rounder percepts. CONCLUSIONS:
Single percepts induced by single-electrode stimulation were relatively
small, but the form of percepts, especially after multielectrode
stimulation, often did not match the stimulation pattern, even
in a normal-sighted volunteer. Reproducible percepts were more
easily generated than those that matched the stimulation pattern.
-----
Artif Organs. 2003 Nov;27(11):986-95.
Electronic visual prosthesis.
Liu W, Sivaprakasam M, Singh PR, Bashirullah R, Wang G.
Department of Electrical Engineering, University of California
at Santa Cruz, CA 95064-1077, USA. wentai@soe.ucsc.edu
Retinitis pigmentosa (RP) and age-related macular degeneration
(AMD) are incurable diseases that result in profound vision loss
due to degeneration of the light sensing photoreceptors. However,
the discovery that direct electrical stimulation of the retinal
neurons creates visual sensation has inspired prosthetic devices
aimed to restore useful vision in RP/AMD patients. The approach
to one such electronic visual prosthesis is described in this
article. The prosthesis consists of an external unit and an internal
unit. The communication link has three components--power and data
transfer from the external to the internal unit, and data transfer
from the internal to the external unit. A novel method of integrating
power transfer and back telemetry is described here. The goal
is to design a stimulator chip with a small area with low power
consumption. This chip, capable of stimulating 60 dedicated electrodes,
is fabricated using AMI 1.2 microm process technology and the
results are presented. Improvements in the design to increase
the number of outputs to 1,000 have been discussed. The new circuit
is aimed at increasing the circuit density, reducing power per
stimulus, and meeting the requirements more closely than the previous
designs. The results of the designed chip are presented.
-----
Artif Organs. 2003 Nov;27(11):963-74.
Retinal and optic nerve diseases.
Margalit E, Sadda SR.
Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD,
USA.
A variety of disease processes can affect the retina and/or
the optic nerve, including vascular or ischemic disease, inflammatory
or infectious disease, and degenerative disease. These disease
processes may selectively damage certain parts of the retina or
optic nerve, and the specific areas that are damaged may have
implications for the design of potential therapeutic visual prosthetic
devices. Outer retinal diseases include age-related macular degeneration,
pathologic myopia, and retinitis pigmentosa. Although the retinal
photoreceptors may be lost, the inner retina is relatively well-preserved
in these diseases and may be a target for retinal prosthetic devices.
Inner retinal diseases include retinal vascular diseases such
as diabetic retinopathy, retinal venous occlusive disease, and
retinopathy of prematurity. Other retinal diseases such as ocular
infections (retinitis, endophthalmitis) may affect all retinal
layers. Because the inner retinal cells, including the retinal
ganglion cells, may be destroyed in these diseases (inner retinal
or whole retinal), prosthetic devices that stimulate the inner
retina may not be effective. Common optic nerve diseases include
glaucoma, optic neuritis, and ischemic optic neuropathy. Because
the ganglion cell nerve fibers themselves are damaged, visual
prosthetics for these diseases will need to target more distal
portions of the visual pathway, such as the visual cortex. Clearly,
a sound understanding of retinal and optic nerve disease pathophysiology
is critical for designing and choosing the optimal visual prosthetic
device.
-----
Mol Neurobiol. 2003 Oct;28(2):149-58.
The nature of dominant mutations of rhodopsin
and implications for gene therapy.
Wilson JH, Wensel TG.
Verna and Marrs McLean Department of Biochemistry and Molecular
Biology, Baylor College of Medicine, Houston, TX 77030.
Mutations in the rhodopsin gene are the most common cause of
retinitis pigmentosa (RP) among human patients. The nature of
the rhodopsin mutations has critical implications for the design
of strategies for gene therapy. Nearly all rhodopsin mutations
are dominant. Although dominance does not arise because of haploinsufficiency,
it is unclear whether it is caused by gainof- function or dominant-negative
mutations. Current strategies for gene therapy have been devised
to deal with toxic, gain-of-function mutations. However, analysis
of results of transgenic and targeted expression of various rhodopsin
genes in mice suggests that dominance may arise as a result of
dominant-negative mutations. This has important consequences for
gene therapy. The effects of dominant-negative mutations can be
alleviated, in principle, by supplementation with additional wild-type
rhodopsin. If added wild-type rhodopsin could slow retinal degeneration
in human patients, as it does in mice, it would represent a valuable
new strategy for gene therapy of RP caused by dominant rhodopsin
mutations.
-----
Ophthalmic Surg Lasers Imaging. 2003 Sep-Oct;34(5):398-400.
Treatment of cystoid macular edema related to
retinitis pigmentosa with intravitreal
triamcinolone acetonide.
Saraiva VS, Sallum JM, Farah ME.
Department of Ophthalmology, Federal University of Sao Paulo,
Sao Paulo, Brazil.
A case of cystoid macular edema related to retinitis pigmentosa
treated with intravitreal injection of triamcinolone acetonide
is described. A 30-year-old white man with retinitis pigmentosa
and progressive visual loss presented with a best-corrected visual
acuity of 20/40 in the right eye and 20/80 in the left eye. Examination
revealed cystoid macular edema in both eyes. After failure of
treatment with oral acetazolamide, intravitreal injection of 0.1
mL of triamcinolone acetonide 0.4% solution was performed in both
eyes. In the left eye, macular edema resorbed and visual acuity
improved to 20/50. However, 6 months after injection, visual acuity
worsened because of recurrence of cystoid macular edema. In the
right eye, cystoid macular edema also resorbed, but visual acuity
was unchanged. Intravitreal triamcinolone acetonide may be useful
for selected cases of cystoid macular edema related to retinitis
pigmentosa.
-----
Arch Ophthalmol. 2003 Sep;121(9):1269-78.
Biological safety assessment of docosahexaenoic
acid supplementation in a randomized clinical trial for X-linked
retinitis pigmentosa.
Wheaton DH, Hoffman DR, Locke KG, Watkins RB, Birch DG.
Retina Foundation of the Southwest, Dallas, TX 75231, USA. dwheaton@retinafoundation.org
BACKGROUND: In a 4-year placebo-controlled trial to elevate
blood docosahexaenoic acid levels in patients with X-linked retinitis
pigmentosa (XLRP), the goal was to assess the potential benefit
of docosahexaenoic acid supplementation in altering disease progression.
However, docosahexaenoic acid (22:6omega3) is a highly unsaturated
fatty acid and considered a target molecule for free-radical oxidative
damage. Thus, nutritional provision of docosahexaenoic acid might
lead to an increase in antioxidant stress. Additional concerns,
such as decreased platelet aggregation, increased bleeding time,
and alterations in lipoprotein cholesterol levels, have been reported
in supplementation studies with long-chain polyunsaturates. OBJECTIVE:
To assess the biological safety of long-term docosahexaenoic acid
supplementation. DESIGN: Forty-four male patients (mean age, 16
years) enrolled in a randomized, double-masked, clinical trial
and received docosahexaenoic acid, 400 mg/d, or placebo. Blood
samples were collected every 6 months. Biological safety analysis
included fatty acids, vitamin A and E concentrations, antioxidant
capacity, platelet aggregation, alanine aminotransferase activity,
and lipoprotein cholesterol and triglyceride profiles. RESULTS:
Mean plasma docosahexaenoic acid levels were elevated 2.5-fold
by supplementation compared with baseline. Patients receiving
placebo capsules exhibited no change (P =.35) in plasma docosahexaenoic
acid content. All adverse events reported were minor and equivalently
distributed between groups. Plasma vitamin A concentrations remained
unchanged during the trial. Mean plasma vitamin E concentrations
were correlated with age (P =.005), such that as patients with
XLRP matured, plasma vitamin E concentrations increased to approach
normal values. There was a trend (P =.10) toward lower mean vitamin
E concentrations in the docosahexaenoic acid-supplemented group
after 4 years. Docosahexaenoic acid supplementation did not compromise
plasma antioxidant capacity, platelet aggregation, liver function
enzyme activity, or plasma lipoprotein lipid content in patients
with XLRP. CONCLUSION: Long-term docosahexaenoic acid supplementation
to patients with XLRP was associated with no identifiable safety
risks in this 4-year clinical trial.
-----
Dev Ophthalmol. 2003;37:109-25.
Retinitis pigmentosa: genes, proteins and prospects.
Hims MM, Diager SP, Inglehearn CF.
Molecular Medicine Unit, St James's University Hospital, Leeds,
UK.
The name retinitis pigmentosa (RP) describes a heterogeneous
group of inherited progressive retinal dystrophies, primarily
affecting the peripheral retina. Patients experience night blindness
and visual field loss, often leading to complete blindness. RP
can be inherited in autosomal dominant, autosomal recessive, X-linked,
mitochondrial and genetically more complex modes. To date, 39
loci have been implicated in non-syndromic RP, for which 30 of
the genes are known. Many of these can be grouped by function,
giving insights into the disease process. These include components
of the phototransduction cascade, proteins involved in retinol
metabolism and cell-cell interaction, photoreceptor structural
proteins and transcription factors, intracellular transport proteins
and splicing factors. Current knowledge of each grouping is reviewed
briefly herein and consistent patterns of inheritance, which may
have functional significance, are noted. The complexity of these
diseases has in the past made it difficult to counsel patients
or to envisage widely applicable therapies. As a more complete
picture is emerging however, possibilities exist for streamlining
screening services and a number of avenues for possible therapy
are being investigated.
-----
J Leukoc Biol. 2003 Aug;74(2):151-60.
Retinal transplantation: progress and problems
in clinical application.
Lund RD, Ono SJ, Keegan DJ, Lawrence JM.
Moran Eye Center, University of Utah, Salt Lake City, UT 84132,
USA. raymond.lund@hsc.utah.edu
There is currently no real treatment for blinding disorders
that stem from the degeneration of cells in the retina and affect
at least 50 million individuals worldwide. The excitement that
accompanied the first studies showing the potential of retinal
cell transplantation to alleviate the progress of blindness in
such diseases as retinitis pigmentosa and age-related macular
degeneration has lost some of its momentum, as attempts to apply
research to the clinic have failed so far to provide effective
treatments. What these studies have shown, however, is not that
the approach is flawed but rather that the steps that need to
be taken to achieve a viable, clinical treatment are many. This
review summarizes the course of retinal transplant studies and
points to obstacles that still need to be overcome to improve
graft survival and efficacy and to develop a protocol that is
effective in a clinical setting. Emphasis is given particularly
to the consequences of introducing transplants to sites that have
been considered immunologically privileged and to the role of
the major histocompatibility complex classes I and II molecules
in graft survival and rejection.
-----
Curr Opin Ophthalmol. 2003 Jun;14(3):122-7.
Advances in the development of visual prostheses.
Lakhanpal RR, Yanai D, Weiland JD, Fujii GY, Caffey S,
Greenberg RJ, de Juan E Jr, Humayun MS.
Intraocular Retinal Prosthesis (IRP) Group, Doheny Retina Institute,
Doheny Eye Institute, Keck School of Medicine, University of Southern
California, Los Angeles, California 90033, USA.
Visual prostheses are based on neuronal electrical stimulation
at different locations along the visual pathway (ie, cortical,
optic nerve, epiretinal, subretinal). In terms of retinal prostheses,
advances in microtechnology have allowed for the development of
sophisticated, high-density integrated circuit devices that may
be implanted either in the subretinal or epiretinal space. Analogous
to the cochlear implants for some forms of deafness, these devices
could restore useful vision by converting visual information into
patterns of electrical stimulation that would excite the remaining
spared inner retinal neurons in patients with diseases such as
retinitis pigmentosa and age-related macular degeneration. The
different types of implants and recent results are discussed,
but special emphasis is given to retinal implants.
-----
Ophthalmology. 2003 Jun;110(6):1164-9.
Vitreoretinal surgery for cystoid macular edema
associated with retinitis pigmentosa.
Garcia-Arumi J, Martinez V, Sararols L, Corcostegui B.
Hospital Vall d'Hebron, Universidad Autonoma de Barcelona, Spain.
17215jga@comb.es
PURPOSE: To evaluate the anatomic and functional outcome of
vitreoretinal surgery in eyes with retinitis pigmentosa (RP) and
macular edema. DESIGN: Prospective noncomparative case series.
PARTICIPANTS: Twelve consecutive eyes of eight patients with RP
and a documented decrease in visual acuity (VA) to 20/60 or worse
caused by macular edema refractory to medical therapy. METHODS:
Pars plana vitrectomy was performed in the 12 eyes, followed by
posterior hyaloid dissection, removal of the posterior inner limiting
membrane after staining with indocyanine green, and gas tamponade.
Preoperative best-corrected VAs ranged from 20/60 to 20/400 (mean,
20/115). MAIN OUTCOME MEASURES: Changes in VA and foveal thickness
as determined by optical coherence tomography (OCT). RESULTS:
The mean preoperative retinal thickness at the fovea was 477 micro
m. Optical coherence tomography showed a decrease in macular thickness
of >40% in 10 eyes (83.3%), with a mean postoperative foveal
thickness of 260 micro m. The mean VA increased from 20/115 to
20/45, with an average of three lines of improvement. CONCLUSIONS:
Our results suggest that vitreoretinal surgery may effectively
manage macular edema in RP.
-----
Eur J Ophthalmol. 2003 Apr;13 Suppl 3:S5-10.
Introduction to apoptosis in ophthalmology.
Carella G.
Department of Ophthalmology and Visual Sciences, University Hospital
San Raffaele, National Study Group on Apoptosis in Ophthalmology,
Milano, Italy. g.carella@agonet.it
Apoptosis represents a mode of cellular death genetically programmed
to maintain homeostasis of tissues. In specific pathologic circumstances,
the death program may be activated by various environmental factors
such as exposure to toxic substances or bacteria or deprivation
of nutrients. From this point of view, apoptosis is considered
the final event in several pathologies. In ophthalmology, experimental
evidence has confirmed that apoptosis is a type of cellular death
involved in various pathologic processes including glaucoma, retinitis
pigmentosa, ischemic retinopathy, corneal reparative processes,
cataract, and retinoblastoma. The aim of this article is to review
the most recent results published in this field and to describe
some of the molecular mechanisms responsible for the activation
of the apoptotic program in some important ocular disorders. The
understanding of such mechanisms could outline new therapeutic
strategies for the prevention of cellular death in ophthalmology.
-----
Vision Res. 2003 Apr;43(9):1091-102.
Position, size and luminosity of phosphenes generated
by direct optic nerve stimulation.
Delbeke J, Oozeer M, Veraart C.
Neural Rehabilitation Engineering Laboratory, Universite Catholique
de Louvain, 54, Avenue Hippocrate, Box UCL 54.46, B-1200, Brussels,
Belgium.
Pulses of low intensity current, delivered through a cuff electrode
chronically implanted around the optic nerve of a blind retinitis
pigmentosa patient generate visual sensations. These phosphenes
are obtained at lower thresholds for a train of stimuli than for
single pulses, which suggests the existence of a spatial and temporal
integrating mechanism. The perceptions are much smaller than those
predicted from model simulations. A set of equations are derived
which show the effect of pulse current, duration, number and frequency
on the position, size and, to some extent, luminosity of the resulting
phosphenes.
-----
Doc Ophthalmol 2003 Jan;106(1):31-5
Prevention and therapy in hereditary retinal degenerations.
Besch D, Zrenner E.
Department of Pathophysiology of Vision and Neuro-Ophthalmology,
University Eye Hospital, Schleichstr. 12-16, D-72076 Tubingen,
Germany.
A survey of the present state of developments concerning prevention
and therapy of hereditary retinal diseases is given. In recent
years the techniques of molecular genetics have led to a rapid
identification of a great number of cloned or mapped genes responsible
for such diseases. Moreover, further progress has been made in
the understanding of disease mechanisms by describing the defective
proteins and their altered metabolism. The most recent preventive
and therapeutic strategies including gene therapy, dietary regimens,
anti-apoptotic agents, transplantation and retinal prosthesis
are discussed.
-----
Ophthalmology 2003 Feb;110(2):383-91
Photoreceptor transplantation in retinitis pigmentosa:
short-term follow-up.
Berger AS, Tezel TH, Del Priore LV, Kaplan HJ.
Department of Ophthalmology and Visual Sciences, Washington University
School of Medicine, St. Louis, Missouri, USA.
PURPOSE: To explore the use of adult human photoreceptor transplantation
as a treatment for advanced retinitis pigmentosa (RP). DESIGN:
Prospective noncomparative case series. PARTICIPANTS: Eight patients
with advanced RP. INTERVENTION: Transplantation of adult human
cadaver photoreceptor sheets harvested with the excimer laser.
No immunosuppression was used postoperatively. Patients were followed
for 12 months postoperatively. MAIN OUTCOME MEASURE: Visual acuity
and retinal function measured by psychophysical, electrophysiologic,
and clinical testing. RESULTS: Best-corrected visual acuity (Bailey-Lovie
chart), median reading speed, contrast sensitivity, and visual
fields for the operated eye were not statistically significantly
improved postoperatively. The amplitude and latency of the maculoscope
electroretinogram, as well as the log threshold for dark adaptation,
did not change between the operated and control (unoperated) eye.
There was no detectable homograft reaction on slit-lamp biomicroscopy
or fluorescein angiography. The only adverse effect observed was
one patient who complained of monocular diplopia after retinal
transplantation and subsequent cataract surgery. CONCLUSIONS:
Allogeneic adult human photoreceptor transplantation is feasible
in RP but was not associated with rescue of central vision or
a delay in visual loss. However, any possible slowing in the rate
of retinal degeneration will take many years to determine.
-----
Metab Brain Dis 2002 Sep;17(3):183-97
Treatment with taurine, diltiazem, and vitamin
E retards the progressive visual field reduction in retinitis
pigmentosa: a 3-year follow-up study.
Pasantes-Morales H, Quiroz H, Quesada O.
Institute of Cell Physiology, National University of Mexico, Mexico
City. hpasante@ifisol.unam.mx
The purpose of this study to assess the effect of the formula
taurine/diltiazem/vitamin E on the progression of visual field
loss in retinitis pigmentosa. A double blind, placebo controlled
study in 62 patients: visual field threshold values were obtained
in a Humphrey Field Analyzer from center (30 degrees) and periphery
(30-60 degrees), every 4 months during 3-year follow-up. Data
were analyzed by univariate regression, with slopes obtained from
the best fit lines. Based on slope values, three groups of patients
were identified as those showing negative, positive, or zero slope:
> or = 1 to < or = +1. In controls (32 patients), at central
area, the distribution in negative, zero, or positive slope was,
respectively, 16 (50%), 11 (35%), and 5 (15%). In the treated
group (30 patients) this distribution was 6 (20%) negative, 17
(53%) zero, and 7 (23%) positive slope. In periphery, 16 control
patients were distributed as 11 (69%) negative, 4 (25%) zero,
and 1 (6%) positive slope. In the treated group (17 patients),
the distribution was opposite: 1 (6%) negative, 7 (41%) zero,
and 9 (53%) positive slope. Nineteen patients receiving treatment
up to 6 years showed similar distribution by slope values. Eight
out of 9 patients switched from placebo (2 years) to treatment
(2-3 years), showed improving changes in their slope values. A
beneficial effect of the treatment decreasing the rate of visual
field loss was observed, likely through a protective action from
free radical reactions in affected photoreceptors.
-----
Neuroendocrinol Lett 2002 Aug;23(4):365-8
Pineal-regulating tetrapeptide epitalon improves
eye retina condition in retinitis pigmentosa.
Khavinson V, Razumovsky M, Trofimova S, Grigorian R, Razumovskaya
A.
St. Petersburg Institute of Bioregulation and Gerontology, North-Western
Branch of the Russian Academy of Medical Sciences, 3 Dynamo Project,
197110 St. Petersburg, Russia. ibg@medport.ru
We have studied the effect of tetrapeptide Epitalon (Ala-Glu-Asp-Gly)
on the course of congenital pigmented degeneration of the retina.
The application of Epitalon in Campbell rats is found to intensify
the bioelectric and functional activity of the retina due to the
preservation of its morphological structure. Epitalon therapy
in patients with degenerative retinal lesions results in a positive
clinical effect in 90% of the cases. The analysis of Epitalon
effects suggests that the tetrapeptide participates in the mechanisms
of transcription common for the epiphysis and retina.
-----
J Rehabil Res Dev 2002 May-Jun;39(3):313-21
Subretinal implantation of semiconductor-based
photodiodes: durability of novel implant designs.
Chow AY, Pardue MT, Perlman JI, Ball SL, Chow VY, Hetling JR,
Peyman GA, Liang C, Stubbs EB Jr, Peachey NS.
Optobionics Corporation, Wheaton, IL 60187, USA. alanykc@aol.com
Selective degeneration of the retinal photoreceptor layers
underlies blindness in retinitis pigmentosa (RP) and other inherited
retinal disorders. Because there are no therapies for these patients,
we are evaluating the possibility that electrical stimulation
delivered to the subretinal space by a microphotodiode array (MPA)
could replace, in some aspect, the function of diseased photoreceptors.
Early MPA prototypes utilized gold as the electrode material,
which gradually dissolved during the postoperative period following
subretinal implantation. Here we present the results obtained
when different MPA materials were used. Semiconductor-based silicon
MPAs (2 mm in diameter; 50 microm in thickness), incorporating
iridium/iridium oxide (IrOx) or platinum (Pt) electrodes, were
implanted into the subretinal space of the right eye of normal
cats with the use of vitreoretinal surgical techniques. Indirect
ophthalmoscopy, fundus photography, ganzfeld electroretinography,
and histology were used for the evaluation of the implanted retinas
postoperatively. Infrared (IR) stimulation was used to isolate
electrical responses generated by the MPA. The unimplanted left
eyes were used for control purposes. After the implantation surgery,
subretinal MPAs retained a stable position in the subretinal space.
Up to 12 months after surgery, there was little change in the
magnitude of the electrical response of IrOx- and Pt-based MPAs
to a standard IR light stimulus. Overlying the implant, there
was a near-complete loss of the outer retinal layer, which is
likely to reflect obstruction of choroidal nourishment to these
layers by the solid disk implant. In addition, the inner retinal
layers showed variable disorganization. Away from the implant,
the retina displayed a normal appearance. In comparison to electroretinograms
(ERGs) obtained from unimplanted eyes, responses recorded from
implanted eyes had a normal waveform but were slightly smaller
in amplitude. These results indicate that IrOx and Pt improve
implant electrode durability and that implants incorporating these
materials into the electrode layer do not induce panretinal abnormalities.
-----
Am J Ophthalmol 2002 Apr;133(4):544-50
Transplantation of intact sheets of fetal neural
retina with its retinal pigment epithelium in retinitis pigmentosa
patients.
Radtke ND, Seiler MJ, Aramant RB, Petry HM, Pidwell DJ.
Retina Vitreous Resource Center, Norton Audubon Hospital, Louisville,
Kentucky 40217, USA. ret.vit-resource.ctr@prodigy.net
PURPOSE: To show the safety of transplanting sheets of fetal
neural retina together with its retinal pigment epithelium (RPE)
to patients with retinitis pigmentosa. DESIGN: Interventional
case series. METHODS: Sheets of fetal neural retina and RPE were
transplanted together into the subretinal space near the fovea
unilaterally in the eyes of five patients with retinitis pigmentosa
who had only light perception in both eyes. The patients were
followed for 6 months. The main outcome measures were tissue typing
of both donors and recipients, fluorescein angiography, multifocal
electroretinogram (mfERG) testing, and clinical examination. No
immunosuppressive medications were given. RESULTS: No evidence
of rejection was observed. Up to 6 months there was no evidence
of tissue disintegration, retinal edema, or scarring. There was
no change in vision both by Snellen acuity and with mfERGs. Growth
of the transplant was noted in two of five patients at 6 months
vs. 2 weeks. All patients typed were HLA mismatched with donor
tissue. CONCLUSIONS: This study indicates that fetal retina can
be transplanted together with its RPE and survive for at least
6 months without evidence of rejection. However, no improvements
in vision were observed, possibly due to the severe retinal degeneration
of the patients.
-----
Eur Rev Med Pharmacol Sci 2002 Jan-Feb;6(1):1-8
Deflazacort treatment of cystoid macular edema
in patients affected by Retinitis Pigmentosa: a pilot study.
Giusti C, Forte R, Vingolo EM.
Institute of Ophthalmology, University La Sapienza, Rome, Italy.
BACKGROUND: To investigate the efficacy of a long-term treatment
with Deflazacort (DFZ), a third generation synthetic glucocorticoid,
in patients affected by Retinitis Pigmentosa (RP) complicated
by Cystoid Macular Edema (CME). METHODS: A randomized group of
10 RP subjects were selected for this pilot study and treated
with DFZ for one year according to a standard protocol. Far and
near Best Corrected Visual Acuity (BCVA), fluorescein angiography
(Heidelberg Retina Angiograph) and computerized perimetry (Humphrey
Visual Field Analyzer) were statistically assessed. RESULTS: Near
visual acuities, fluorescein angiographic findings and perimetric
data improved significantly (p < 0.01) while far BCVA varied
only slightly (p < 0.05). No ocular or systemic side effects
were recorded. CONCLUSIONS: Further case-control studies, also
involving a larger number of patients, are required to confirm
these preliminary results. However, the present investigation
seem to suggest that DFZ could be effective in reducing fluorescein
angiographic findings and improving perimetric data and near visual
acuities in RP patients, even though the pathogenesis of CME remains
poorly understood.
-----
Klin Oczna 2002;104(3-4):289-92
[Gene therapy prospects in ophthalmology]
[Article in Polish]
Stopa M.
Katedry i Kliniki Okulistyki Akademii Medycznej im. Karola Marcinkowskiego
w Poznaniu.
PURPOSE: Presentation of newest achievements from borderland
of ophthalmology and molecular biology and their clinical employment
areas in the therapy of eye diseases. MATERIAL AND METHODS: MEDLINE
database has been searched for terms gene, gene therapy, ocular,
eye in title and summary fields. RESULTS: Based on the latest
literature eye disorders have been selected that are currently
in focus of gene therapy. Experimental approaches in vitro as
well as in vivo have been reviewed. CONCLUSIONS: Modern ophthalmology
profits more and more from newest achievements in molecular biology
such as gene therapy. Transfer of additional genes to selected
target cells within eye is able to change function and allows
to achieve required effects. It is performed through employment
of so called vectors, small particles allowing the gene to be
transferred. Presently most often used vectors are derived from
viruses (retrovirus, adenovirus, viruses AAV). Experimental studies
have been performed in following eye diseases: retinitis pigmentosa,
Leber congenital amaurosis, glaucoma, retinoblastoma, postoperative
posterior capsule opacification, corneal diseases, age related
macular degeneration, uveal melanoma. In each case the experimental
results were promising. However, possible side effects of such
therapy are not sufficiently known. There have been no clinical
gene therapy studies in ophthalmology so far.
-----
Mol Ther 2002 Dec;6(6):813-23
Intercellular Trafficking of Adenovirus-Delivered
HSV VP22 from the Retinal Pigment Epithelium to the Photoreceptors-Implications
for Gene Therapy.
Cashman SM, Sadowski SL, Morris DJ, Frederick J, Kumar-Singh R.
Adenovirus (Ad)-mediated gene transfer is a promising technology
for therapy of a wide variety of genetic disorders of the retina.
The tropism of Ad vectors limits their utility to cells that express
the coxsackie-adenovirus receptor. Upon ocular delivery, Ad vectors
primarily infect the retinal pigment epithelium (RPE) and the
Muller cells of the retina. However, the most frequent blinding
diseases such as retinitis pigmentosa and age-related macular
degeneration are associated with the expression of mutant proteins
in the photoreceptors. In this study we demonstrate that adenovirus-delivered
heterologous proteins fused to the herpes simplex virus tegument
protein VP22 can translocate from infected cells to uninfected
cells in culture and in vivo. We tested three different ocular
cell lines, specifically Y79, RPE-J, and Chang C. We show that
there is a 3.25-fold increase in the number of Y79 cells that
take up GFP mediated by the intercellular trafficking properties
of VP22. Our data are based on FACS analysis of living cells and
there was no need for cell fixation for the effect to be observed.
When adenovirus expressing a VP22-GFP fusion was injected into
the subretinal space of adult mice, the VP22-GFP fusion peptides
translocated from the RPE to all of the other layers of the retina,
including the outer nuclear layer, which contains the photoreceptor
cell bodies. Our study has significant implications for a wide
variety of diseases of the retina and other organ systems.
-----
Biomed Tech (Berl) 2002;47 Suppl 1 Pt 1:158-60
[Medical aspects of active implants in the eye]
[Article in German]
Walter P.
Zentrum fur Augenheilkunde, Universitat zu Koln, Deutschland.
peter.walter@uni-koeln.de
Due to progress in miniaturizing complex electronic systems
the development of intraocular sensors and stimulators is feasible.
The Retina Implant will restore vision in patients with progressive
retinal degenerations by means of electrical stimulation of retinal
neurons, e.g. in Retinitis pigmentosa. After severe destructions
of the anterior segment with intact retina, e.g. after explosion
trauma an intraocular display will restore vision. In glaucoma
patients the implantation of a telemetric pressure sensor will
help to optimise the management of each individual patient. Pressure
profiles under everyday conditions will become available. These
active implants will open new perspectives in treatment and diagnostics
in ophthalmology.
-----
Curr Opin Ophthalmol 2002 Dec;13(6):387-392
Atypical presentations of ocular toxoplasmosis.
Smith JR, Cunningham Jr ET.
*Casey Eye Institute, Oregon Health & Science University,
Portland, Oregon, and the Department of Ophthalmology, New York
University School of Medicine, New York, New York, U.S.A. Dr.
Smith is the recipient of a Career Development Award from Research
to Prevent Blindness. Dr. Cunningham is an employee of Eyetech
Pharmaceuticals, Inc.
The diagnosis of ocular toxoplasmosis is based most often on
the presence of characteristic clinical findings, which include
focal retinochoroiditis, an adjacent or nearby retinochoroidal
scar, and moderate to severe vitreous inflammation. However, a
variety of less common, "atypical" presentations may
be unfamiliar to clinicians, delaying both diagnosis and treatment.
Patients who are immunocompromised or elderly may, for example,
present with large, multiple and/or bilateral lesions. Other unusual
manifestations include punctate outer retinal toxoplasmosis, retinal
vasculitis, retinal vascular occlusions, rhegmatogenous and serous
retinal detachments, a unilateral pigmentary retinopathy mimicking
retinitis pigmentosa, neuroretinitis and other forms of optic
neuropathy, and scleritis. Although in the past most cases of
ocular toxoplasmosis were considered to result from reactivation
of a congenital infection, it is now believed that postnatally
acquired infection accounts for many cases of this disease. With
appropriate use of antiparasitic therapy, the visual prognosis
for patients with both typical and atypical forms of ocular toxoplasmosis
may be good.
-----
Indian J Ophthalmol 2002 Sep;50(3):173-81
Gene therapy in ocular diseases.
Singh VK, Tripathi P.
Department of Immunology, Sanjay Gandhi Post-Graduate Institute
of Medical Sciences, Lucknow, India. singh@afrri.usuhs.mil
Gene therapy is a novel form of drug delivery that enlists
the synthetic machinery of the patient's cells to produce a therapeutic
agent. Genes may be delivered into cells in vitro or in vivo utilising
viral or non-viral vectors. Recent technical advances have led
to the demonstration of the molecular basis of various ocular
diseases. Ocular disorders with the greatest potential for benefit
of gene therapy include hereditary diseases such as retinitis
pigmentosa, tumours such as retinoblastoma or melanoma, and acquired
proliferative and neovascular retinal disorders. Gene transfer
into ocular tissues has been demonstrated with growing functional
success and may develop into a new therapeutic tool for clinical
ophthalmology in future.
-----
Surv Ophthalmol 2002 Jul-Aug;47(4):335-56
Retinal prosthesis for the blind.
Margalit E, Maia M, Weiland JD, Greenberg RJ, Fujii GY, Torres
G, Piyathaisere DV, O'Hearn TM, Liu W, Lazzi G, Dagnelie G, Scribner
DA, de Juan E Jr, Humayun MS.
Intraocular Prosthesis Group, Wilmer Eye Institute, Johns Hopkins,
Baltimore, MD 21287-9277, USA.
Most of current concepts for a visual prosthesis are based
on neuronal electrical stimulation at different locations along
the visual pathways within the central nervous system. The different
designs of visual prostheses are named according to their locations
(i.e., cortical, optic nerve, subretinal, and epiretinal). Visual
loss caused by outer retinal degeneration in diseases such as
retinitis pigmentosa or age-related macular degeneration can be
reversed by electrical stimulation of the retina or the optic
nerve (retinal or optic nerve prostheses, respectively). On the
other hand, visual loss caused by inner or whole thickness retinal
diseases, eye loss, optic nerve diseases (tumors, ischemia, inflammatory
processes etc.), or diseases of the central nervous system (not
including diseases of the primary and secondary visual cortices)
can be reversed by a cortical visual prosthesis. The intent of
this article is to provide an overview of current and future concepts
of retinal and optic nerve prostheses. This article will begin
with general considerations that are related to all or most of
visual prostheses and then concentrate on the retinal and optic
nerve designs. The authors believe that the field has grown beyond
the scope of a single article so cortical prostheses will be described
only because of their direct effect on the concept and technical
development of the other prostheses, and this will be done in
a more general and historic perspective.
-----
J Fr Ophtalmol 2001 Oct;24(8):854-9
[Optical coherence tomography in the follow up
of macular edema treatment in retinitis pigmentosa]
[Article in French]
Rumen F, Souied E, Oubraham H, Coscas G, Soubrane G.
Clinique ophtalmologique universitaire de Creteil, Centre Hospitalier
Intercommunal, 40, avenue de Verdun, 94010 Creteil.
Macular edema is frequently responsible for loss of central
vision in patients affected with retinitis pigmentosa (RP). This
macular edema can be treated with acetazolamide. Our purpose was
to evaluate optical coherence tomography (OCT) examination in
the follow-up of macular edema in RP. In addition, we tried to
evaluate the minimal efficient dose of acetazolamide, using means
other than fundus examination or fluorescein angiography. We report
the cases of 5 patients affected with typical retinitis pigmentosa
and fundus appearance of macular edema. These patients received
oral acetazolamide treatment (500 mg/d). The OCT examinations
were performed before and during treatment, which allowed us to
demonstrate, quantify and monitor the progression of macular edema
during treatment. OCT appears to be a useful tool in the follow-up
of patients affected with macular edema and RP. This noninvasive
examination contributes to improving our strategy in treating
patients.
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