Session 107 Retinal Degeneration

Transcription

ARVO 2016 Annual Meeting Abstracts
107 Retinal Degeneration
Sunday, May 01, 2016 8:30 AM–10:15 AM
Exhibit/Poster Hall Poster Session
Program #/Board # Range: 124–163/A0319–A0358
Organizing Section: Retina
Program Number: 124 Poster Board Number: A0319
Presentation Time: 8:30 AM–10:15 AM
Evaluation of demographical, clinical and imaging characteristics
of 304 retinitis pigmentosa (RP) patients screened for retinal
prosthesis candidacy
Dilek Güven, Mehmet Demir, Erdem Ergen, Semra Tiryaki Demir,
Atilla Demir, Hakan Kacar. Ophthalmology Department, Sisli
Hamidiye Etfal Teaching and Research Hospital, ISTANBUL,
Turkey.
Purpose: To evaluate the demographical and clinical characteristics
of RP patients applied between June 2014-October 2015
Methods: Personal-family history of the patients were recorded.
Ophthalmological examination included visual acuity(VA) testing,
biomicroscopy, fundoscopy, spectral-domain optical coherence
tomography(OCT) and fundus autofluorescence(FAF) imaging
Results: Out of 304 RP patients 36.2% was female, mean age
was 43.8±14.6 years.(8-76 years) Consanguinity rate was 57.8%,
sporadic cases constituted 38.7%. There was no coexisting systemic
disorder in 51% of the patients and no additional ocular pathology
in 80% of 608 eyes. Cataract surgery was performed in 24.5% of
the eyes, 28 % of the eyes had posterior-subcapsular, 8.6% had
nuclear cataract. Nystagmus was seen in 24.9 %, orthophoria in
54.5% and exophoria in 41.7%. VA categories and corresponding
percentages were; no light perception 6.5%, only light perception
34.1%, seeing hand movements 31.2%, counting fingers at 1meter
to 10/100 (12.8%) and ≥10/100 (15.4%). Fundus examination
revealed end-stage RP in 69.5%, severe macular atrophy in 7.4% of
the eyes. Mean foveal thickness was 126.41±68.89um. There was a
positive correlation between VA and foveal thickness and a negative
correlation between age and both VA and foveal thickness. ILM and/
or ERM thickening(41.9%), presence of micropseudocyst(19.2%),
cystoid macular edema(3.5%) were among the mostly seen retinal
abnormalities. The rate of choroidal thinning, which was excepted
as subfoveal thickness <250umwas 61.9%. As the patient was older
or axial length was longer, choroidal thinning was more. Foveal
thickness and choroidal thinning showed a negative, foveal thickness
and presence of IS/OS line integrity showed a positive correlation.
There was presence of hyper-autofluorescent ring in 25.7%, abnormal
hyper-autofluorescent patterns at the macula in 44%, absence of
fundus autofluorencence (outer retinal atrophy) in 59% and decreased
FAF at the periphery in 81% of the eyes. In the presence of FAF loss,
VA was significantly less. Mean axial length was 22.98 mm.
Conclusions: Screening RP patients using OCT, FAF and biometry
is advised both at the time of diagnosis and follow-up. These findings
are believed to be very useful both for documenting the course of
the disease as well as selecting candidates for innovative treatment
modalities.
Commercial Relationships: Dilek Güven, None; Mehmet Demir;
Erdem Ergen, None; Semra Tiryaki Demir, None; Atilla Demir,
None; hakan kacar, None
Japan Occult Macular Dystrophy Project: Association of
Genotype and Photoreceptor Architecture
Kaoru Fujinami1, 2, Shuhei Kameya3, Shinji Ueno4, Mineo Kondo5,
Takaaki Hayashi6, Kei Shinoda7, Shigeki Machida8, 9, Yozo Miyake10, 1,
Takeshi Iwata11, Kazushige Tsunoda1. 1Laboratory of Visual
Physiology, Division of Vision Research, National Institute of
Sensory Organs, National Hospital Organization, Tokyo Medical
Center, Meguro-ku, Japan; 2Department of Ophthalmology,
Keio University, School of Medicine, Shinjuku-ku, Japan;
3
Department of Ophthalmology, Nippon Medical School Chiba
Hokusoh Hospital, Inzai, Japan; 4Department of Ophthalmology,
Nagoya University Graduate School of Medicine, Nagoya, Japan;
5
Department of Ophthalmology, Mie University Graduate School
of Medicine, Tsu, Japan; 6Department of Ophthalmology, The Jikei
University School of Medicine, Minato-ku, Japan; 7Department of
Ophthalmology, Teikyo University School of Medicine, Itabashiku, Japan; 8Department of Ophthalmology, Dokkyo Medical
University Koshigaya Hospital, Koshigaya, Japan; 9Department
of Ophthalmology, Iwate Medical University School of Medicine,
Morioka, Japan; 10Aichi Medical University, Nagakute, Japan;
11
Division of Molecular and Cellular Biology, National Institute of
Sensory Organs, National Hospital Organization, Tokyo Medical
Center, Meguro-ku, Japan.
Purpose: To determine the clinical and molecular genetic
characteristics of Japanese cohort with occult macular dystrophy
(OMD) in a multi-central study.
Methods: Twenty-three patients from 21 families with the clinical
diagnosis with OMD were recruited from ten institutes over Japan.
Full medical history and clinical examinations including spectraldomain optic coherence tomography (SD-OCT) were undertaken.
Patients were classified into one of the two groups based on
the SD-OCT findings; classical group showing both blurring of
photoreceptor ellipsoid zone and absence of interdigitation zone;
and non-classical group lacking at least one of these two features.
Primal exome sequencing with targeted analysis and in silico
pathogenicity evaluation were performed for mutation detection.
Statistical association between architectural phenotype classification
and genotype classification (presence of pathogenic RP1L1 variants)
was investigated.
Results: There were 12 families with the classical SD-OCT
findings and 9 with non-classical findings. Nine pathogenic RP1L1
missense variants were identified in 12 families (57%) including
three previously reported variants (p.R45W, p.S1199C, p.G1200A)
and six novel variants (p.G221R, p.T1194M, p.T1196I, p.G1200D,
p.G1200V, p.V1201G). A novel homozygous frameshift variant with
premature termination (c.6063delC, p.D2021EfsX3) was found in
a patient. Statistically significant association between architectural
phenotype and genotype was revealed.
Conclusions: The spectrum of morphologic phenotype and
pathogenic RP1L1 variants was documented in a nation-wide
Japanese cohort with OMD. Association of the architectural
phenotype and genotype indicates two types of pathophysiology
underlying the clinical presentation of OMD; “hereditary” OMD
including RP1L1-retinopathy with the classical phenotype and OMDlike syndrome (progressive occult maculopathy).
Commercial Relationships: Kaoru Fujinami; Shuhei Kameya,
None; Shinji Ueno, None; Mineo Kondo, None; Takaaki Hayashi,
None; Kei Shinoda, None; Shigeki Machida, None; Yozo Miyake,
None; Takeshi Iwata, None; Kazushige Tsunoda, None
These abstracts are licensed under a Creative Commons Attribution-NonCommercial-No Derivatives 4.0 International License. Go to http://iovs.arvojournals.org/
to access the versions of record.
Novel Autosomal Dominant Retinitis Pigmentosa (adrP)
Mutation with Features of Gyrate Atrophy
James Kasenchak1, Tamara Vrabec2. 1Ophthalmology, Geisinger
Health System, Danville, PA; 2Ophthalmology, Geisinger Health
System, Danville, PA.
Purpose: To report a new mutation of autosomal dominant retinitis
pigmentosa with fundus findings suggestive of gyrate atrophy (GA)
and equivocal serum amino acid levels. Genetic testing identified a
novel mutation in the RHO gene consistent with adRP. adRP should
be included in the differential diagnosis of gyrate atrophy.
Methods: Multimodal imaging including SD-OCT and fundus
photos. ERG and visual field testing were obtained. Urine and
serum biochemical profiles and targeted genetic screening were also
performed.
Results: A 66-year-old man with a past ocular history of myopia
presented with constricted visual fields and night blindness. Exam
was significant for cystoid macular edema, pallor of the optic discs,
and lacunar chorioretinal atrophy. Subtle bone spicule pigmentation
was present in intervening areas. Serum analysis revealed mild
hyperornithinemia. Ornithine aminotransferase enzyme levels were
normal. ERG rod and cone signals were extinguished. Genetic
testing identified a novel mutation in the RHO gene consistent with
autosomal dominant retinitis pigmentosa (adRP).
Conclusions: We describe ocular and genetic features of a patient
with a novel mutation for adRP. Usually lacunar chorioretinal atrophy
would be indicative of gyrate atrophy, but in this case the diagnosis of
GA was ruled out with normal ornithine aminotransferase levels and
a RHO mutation confirmed the diagnosis of RP. Patients who present
with lacunar chorioretinal atrophy are investigated to rule out GA.
This case underscores the importance of genetic testing for adRP in
these patients. Clinicians should be aware of this new form of adRP
that shares clinical characteristics with GA
Figure 1a. Wide-field fundus photographs show round regions of
chorioretinal atrophy located predominantly in the superonasal
periphery. Less well-defined depigmentation is present inferiorly. The
retinal vessels are attenuated and discs are pale.
Figure 1b: 50 degree magnified image of superonasal fundus OD
demonstrates pigment clumps in association with and remote from
round lesions.
Commercial Relationships: James Kasenchak, None;
Tamara Vrabec, None
A novel heterozygous mutation in PRPH2/RDS gene causing
a spectrum of phenotypic manifestations in a family with
autosomal dominant retinitis pigmentosa (adRP)
Fares Antaki1, Razek Georges Coussa1, Christina Chakarova2,
Susan Wakil1, Vincent Sun1, Pierre Lachapelle4, Allison Dorfman1,
Irma Lopez1, Kunka Kamenarova3, Shomi S. Bhattacharya2,
Robert K. Koenekoop1. 1McGill University Health Center, The
McGill Ocular Genetics Laboratory, Montreal, QC, Canada; 2UCLInstitute of Ophthalmology, London, United Kingdom; 3Department
of Cellular Therapy and Regenerative Medicine, Andalusian
Molecular Biology and Regenerative Medicine Centre, Sevilla,
Spain; 4Department of Ophthalmology and Neurology-Neurosurgery,
Montréal Children’s Hospital-Research Institute, McGill University,
Montreal, QC, Canada.
Purpose: Retinitis pigmentosa (RP) is a hereditary group of clinically
and genetically heterogeneous retinal dystrophies that eventually lead
to blindness. The genetics of RP are still incomplete despite intense
studies. Currently, about 50 genes explain ~50% of cases. We studied
a Canadian family of Syrian origin with adRP and aimed to identify
the causal gene.
Methods: Next generation sequencing, family linkage analysis using
Affymetrix Human Map 250K Nsp Array and exome capture (AROS,
Denmark) were sequentially performed on selected patients. The
disease locus was mapped to chromosome 6p, close to the PRPH2/
RDS gene. PCR based Sanquer sequencing of the PRPH2/RDS gene
was performed in order to identify the novel mutation. Phenotypes
were characterized by visual acuity, funduscopy, Goldmann visual
fields, OCT (Heidelberg Engineering Inc, Germany), fundus
autofluorescence and ERG.
Results: A novel heterozygous mutation in PRPH2/RDS
(del352_356TGCTGinsCT) in all affected individuals was identified.
The mutation was associated with a wide spectrum of phenotypic
manifestations. In particular, the initial proband (MOGL 322) showed
severe progressive disease with non-recordable ERGs as well as
typical tunnel vision constriction while other patients showed normal
fundi and FAF and abnormal ERGs.
Conclusions: We have successfully identified a novel mutation
in PRPH2/RDS leading to adRP. The full extent of the mutation
spectrum and severity is currently being investigated. Our findings
are crucial in expanding the current understanding of inherited retinal
blinding diseases in order to provide new avenues for therapeutic
interventions and help in patients’ counselling.
Commercial Relationships: Fares Antaki, None; Razek
Georges Coussa, None; Christina Chakarova, None; Susan Wakil,
None; Vincent Sun, None; Pierre Lachapelle; Allison Dorfman,
None; Irma Lopez, None; Kunka Kamenarova, None;
Shomi S. Bhattacharya, None; Robert K. Koenekoop, None
Support: FFB-Canada, CIHR, FRSQ and NIH
A new syndromic form of retinal degeneration due to mutations
in the PCYT1A gene
Mariaelena Filippelli1, Rosa Boccia1, Raffaella Colucci1,
Valentina Di Iorio1, Anna Nesti1, Maria Rosaria Barillari2,
Nicola Brunetti Pierri3, 4, Francesco Testa1, Sandro Banfi4, 5,
Francesca Simonelli1. 1Eye Clinic, Multidisciplinary Department
of Medical, Surgical and Dental Sciences, Second University of
Naples, Naples, Italy; 2Department of Mental and Physical Health
and Preventive Medicine, Second University of Naples, Naples,
Italy; 3Department of Translational Medicine, University of Naples
Federico II, Naples, Italy; 4Telethon Institute of Genetics and
Medicine, Pozzuoli, Italy; 5Department of Biochemistry, Biophysics
and General Pathology, Second University of Naples, Naples, Italy.
Purpose: Mutations in PCYT1A have recently been found in a
few patients presenting with two apparently different phenotypes:
one characterized by the association of spondylometaphyseal
dysplasia and cone-rod dystrophy (SMD-CRD) and the other with
congenital lipodystrophy, severe fatty liver disease, and reduced
HDL cholesterol but without ophthalmic or skeletal involvement.
Here, we present a 4-year-old Italian male harboring 2 mutations
in the PCYT1A gene and presenting with retinal degeneration, low
HDL cholesterol, and increased liver enzyme levels (AST and ALT)
without evidence of skeletal involvement.
Methods: The patient underwent ophthalmological, genetic, pediatric
and audiometric evaluations. The ophthalmological examination
included best corrected visual acuity (BCVA), color vision testing,
ocular motility examination, retinography, optical coherence
tomography (SD-OCT) and standard electroretinogram (ERG). Next
Generation Sequencing (NGS) for genes associated with inherited
retinal diseases was performed on DNA extracted from blood.
Results: The disease onset was referred at the age of 2 years with
night-blindness and reduced visual acuity. At the age of 4 years the
patient showed a BCVA 20/200 in both eyes, normal color vision
and ocular motility. Fundus examination revealed widespread “salt
and pepper” retinal degeneration. OCT examination showed reduced
macular thickness with retinal pigment epithelium dystrophy. ERG
recordings revealed scotopic responses below noise level and reduced
photopic tracings. He was non-dysmorphic (normal height, weight
and head circumference); audiometric evaluation was also normal.
Plasma biochemistry revealed low HDL cholesterol levels, increased
AST and ALT. A targeted NGS analysis for 150 genes responsible for
inherited retinal dystrophies showed two mutations in the PCYT1A
gene: a missense mutation (p.A93T) and a splice site mutation
(c.897+1G>A).
Conclusions: This is the first case in literature of a patient with
mutations in the gene PCYT1A displaying rod-cone retinal
degeneration, reduced HDL cholesterol, signs of fatty liver disease
without skeletal involvement or lipodystrophy. Therefore, the
phenotype of our patient includes a combination of features of the
two apparently distinct disorders that were previously associated
with PCYT1A mutations. So, our findings expands the spectrum of
phenotypic manifestations reported so far with PCYT1A mutations.
Commercial Relationships: Mariaelena Filippelli, None;
Rosa Boccia; Raffaella Colucci; Valentina Di Iorio, None;
Anna Nesti, None; Maria Rosaria Barillari, None; Nicola Brunetti
Pierri, None; Francesco Testa, None; Sandro Banfi, None;
Francesca Simonelli, None
Next generation sequencing-based comprehensive molecular
diagnosis of retinitis pigmentosa probands in Miami
Jennifer Verriotto1, Qi Zhang2, Mingchu Xu3, Yumei Li3, Hui Wang2,
Lin Gan2, Rui Chen3, Byron L. Lam1. 1Bascom Palmer Eye Institute,
University of Miami, Miami, FL; 2College of Life Sciences, Zhejiang
University, Hangzhou, Zhejiang, China; 3Human Genome Sequencing
Center, Baylor College of Medicine, Houston, TX.
Purpose: Retinitis pigmentosa (RP) is a group of heterogeneous
inherited retinal diseases, and the prevalence of RP and frequency of
RP genotypes vary across populations. To examine if the mutation
spectrum is distinct for patients with RP in the Miami area where
a significant portion of the population is Hispanic, we performed
targeted next-generation sequencing (NGS) for a cohort of unrelated
RP cases recruited from the area.
Methods: Comprehensive molecular screening was performed using
NGS approach targeting a panel of 186 known retinal human disease
genes. Putative pathogenic mutations were identified and validated
by Sanger sequencing. Segregation testing was conducted when
additional family members are available.
Results: A total of 71 unrelated RP families were recruited, including
37 Hispanic families. Putative mutations (35 novel pathogenic
mutations) were identified in 46 families, achieving a solving rate
of 65%. In 9 families, the PRPF31 was mutant, making it the most
commonly genotype. Mutations in other retinal disease genes
(IMPG1, CDHR1) were observed in 2 families, providing potential
new phenotype-genotype RP links.
Conclusions: To our knowledge, this was the first NGS
comprehensive mutation screen for RP patients from the Miami area
where a significant portion of the population is Hispanic. Distinct
mutation spectrum has been observed with PRPF31 as the most
common geneotype. A novel PRPF31 mutation was shared by three
Cuba families, indicating a founder effect. Our results verified the
genotype differences in populations and underscored the importance
of a comprehensive, unbiased approach in clinical molecular
diagnosis.
Commercial Relationships: Jennifer Verriotto, None; Qi Zhang,
None; Mingchu Xu; Yumei Li, None; Hui Wang, None; Lin Gan,
None; Rui Chen, None; Byron L. Lam, None
Support: This work is supported by the National Eye Institute
[R01EY022356, R01EY018571, vision core grant P30EY002520],
the Retina Research Foundation, the Foundation Fighting Blindness
[grant number BR-GE-0613-0618-BCM] to R.C. B.L and J.V. are
supported by Department of Defense grant W81XWH-09-1-0674,
NEI core grant P30-EY14801, Adrienne Arsht Hope for Vision
Retinal Degeneration fund, and Research to Prevent Blindness. Q.Z.
and L.G. are supported by Zhejiang Province Science Grant No.
2012C13023-1. This work is supported by grant from the National
Natural Science Foundation of China to H.W. (31471196).
GENETIC BACKGROUND OF RETINITIS PIGMENTOSA IN
TURKISH PATIENTS
Gungor Sobaci. School of Medical Sciences, HACETTEPE, Ankara,
Turkey.
Purpose: Although more than 50 genes reported as causative to
retinitis pigmentosa (RP), there are still some challenges to make a
definite diagnosis; because, clinical severity and disease phenotype
are often differ among individuals with the same variant, most likely
as the result of genetic and/or environmental modifying factors.
Hence, there is still strong necessity to increase our knowledge about
genetic background of RP in different patient populations. This
study aims to elucidate the pathogenic variants in RP-related genes
using targeted next generation sequencing (NGS) for Turkish RP
population.
Methods: We have tested 150 Turkish patients with the diagnosis of
RP clinically for 57 RP-related genes via NGS (Ion PGMTM-Thermo
Fisher Scientific) and Sanger Sequencing (Thermo Fisher Scientific).
These were selected from RP registry in Ankara Research Group for
Inherited Disorders of Eye (ARGIDE). Ten syndromic RP patients
have also been tested with a gene panel involved in 350 genes to
find out disease mutations of known RP genes. Non-inherited causes
of retinal inflammation that presents with fundus findings similar
to retinitis pigmentosa, including trauma, infection, autoimmune
retinopathy, and drug toxicity were excluded.
Results: We validated the NGS with 57-gene and 350-gene
panel for elucidation of RP-related gene variants in syndromic
and nonsyndromic RP, including Usher syndrome, Bardett-Biedl
syndrome, the neuronal ceroid lipofuscinoses, and Refsum Disease in
Turkish population.
Conclusions: Targeted NGS-based sequencing with its costeffectiveness and power to demonstrate RP-related gene variants
seems to be suitable for the molecular diagnosis of RP in developing
countries.
Commercial Relationships: Gungor Sobaci, None
Comparative Measurements of Rod Function in Retinal
Degenerations with Two-color Dark-adapted Perimetry
Artur V. Cideciyan, Jason Charng, Malgorzata Swider,
Rebecca Sheplock, David B. McGuigan, Rodrigo Matsui,
Alejandro J. Roman, Sharon B. Schwartz, Samuel G. Jacobson.
Dept of Ophthalmology, Scheie Eye Institute, Univ of Pennsylvania,
Philadelphia, PA.
Purpose: Novel treatment strategies for inherited retinal
degenerations (IRD) are directed at either improving rod function
or arresting its progressive loss. Rod function can be measured with
two-color dark-adapted perimetry (TCDP). Modified Humphrey
Field Analyzers (mHFA) developed for TCDP (Jacobson et al., 1986;
Roman et al., 2005) have been established as the ‘standard’ with a
long-standing track record of published results in dozens of IRDs.
More recently, Nidek MP1-S and Medmont DAC systems have
become available for TCDP but their comparison to mHFA remains
unknown to date.
Methods: We performed TCDP with the MP1-S in 10 RP patients
and with the DAC in 10 RP patients; each patient also had TCDP
with mHFA. mHFA projects stimuli into a white bowl; DAC has
LEDs placed at specific loci within a black bowl. Both perimeters
perform under free viewing conditions. MP1-S presents filtered LCD
display to the central visual field under infrared retinal tracking.
The shorter wavelength stimuli were 500, 505, <505 nm, and longer
wavelength stimuli were 650, 620, >605 nm for the mHFA, DAC and
MP1-S, respectively. All stimuli were Goldman V sized (1.7deg in
diameter) and 200 ms in duration.
Results: MP1-S and mHFA comparison were performed along the
horizontal and vertical meridians between 4 and 14 deg eccentricity
with 2 deg spacing. Loci with rod-mediation based on previously
established mHFA criteria, demonstrated sensitivity difference
(blue minus red) for MP1-S stimuli of 16.7+/-3.9 dB (mean+/-sd;
when adjusted for ND filters used to extend the dynamic range of
the instrument). DAC and mHFA comparison were performed in
retina-wide testing extending to 72 deg eccentricity in temporal and
nasal fields on a 12 deg grid. Loci with mHFA-defined rod mediation
showed a sensitivity difference for DAC stimuli of 22.0+/-6.6 dB.
Available dynamic ranges for the shorter wavelength stimuli were 65
dB, 75 dB and 50 dB for the mHFA, DAC and MP1-S, respectively.
Conclusions: Rod function using TCDP can be measured with the
mHFA, Nidek MP1-S and Medmont DAC. The blue-red difference
cutoff corresponding to underlying rod function for both colors
of TCDP were 9 and 8.8 dB for MP1-S and DAC, respectively.
Strengths, weaknesses and availability should be considered carefully
in the decision to use a specific equipment for studies of natural
history and clinical trials involving measurement of rod function in
IRDs.
Commercial Relationships: Artur V. Cideciyan, None;
Jason Charng, None; Malgorzata Swider, None;
Rebecca Sheplock, None; David B. McGuigan, None;
Rodrigo Matsui, None; Alejandro J. Roman, None;
Sharon B. Schwartz, None; Samuel G. Jacobson
Support: FFB Center Grant, RPB
High symmetry of visual field loss in X-linked retinitis
pigmentosa
Julia-Sophia Bellingrath1, 2, Immanuel Philip Seitz1, 3, Susanne Kohl3,
Eberhart Zrenner1, 3, Nicola Gloeckle7, Holger Prokisch4,
Susan Downes5, 2, Simon Ramsden6, Robert E. MacLaren2, 5,
Dominik M. Fischer1, 2. 1University Eye Hospital, University
Hospital Tübingen, Tübingen, Germany; 2Nuffield Laboratory of
Ophthalmology, Nuffield Laboratory of Clinical Neuroscience,
University of Oxford, Oxford, United Kingdom; 3Institute for
Ophthalmic Research, University Hospital Tübingen, Tübingen,
Germany; 4Institute of Human Genetics, Helmholtz Centre
Munich, Munich, Germany; 5Oxford Eye Hospital, Oxford
University Hospitals, Oxford, United Kingdom; 6Manchester
Centre for Genomic Medicine, Central Manchester University
Hospitals, Manchester, United Kingdom; 7Centre for Genomics and
Transcriptomics, Tübingen, Germany.
Purpose: Mutations in RPGRORF15 cause 70 to 90% of X-linked
retinitis pigmentosa (XLRP), making this gene a high-yield target for
therapeutic intervention. By analyzing pre-treatment characteristics
in a cohort of 50 XLRP-RPGR patients, this study aims to assist
future interventional trials by analyzing symmetry of disease, rate of
progression and suitability of outcome measures.
Methods: A retrospective, cross-sectional analysis of 50 patients
extracted visual acuity, visual fields (I4e and III4e targets), foveal
thickness and ERG data points (ISCEV standard protocol) alongside
molecular genetic data. Symmetry and progression were assessed
using linear regression and cross-sectional analysis, respectively.
Kaplan-Meyer Curves were used to estimate cumulative ‘survival’ of
6/6 vision, reading ability and legal blindness at different ages.
Results: Of the observed phenotypes, 96% followed rod-cone
and 4% a cone-rod phenotype. 73% of exonic mutations occurred
in ORF15. 80% of missense mutations clustered in exons 1-14,
whereas 85% of nonsense mutations were present in ORF15.
No clear genotype-phenotype relationship could be established
between mutations located in exons 1-14 or ORF15. Patients with
ORF15 mutations did not have a significantly different visual acuity
(p = 0.9) or visual field (III4e; p = 0.6) than those with mutations in
exons 1-14. Comparison of both eyes revealed a strong symmetry
of degeneration in all outcome measures, with visual fields (I4e R2
= 0.99; III4e R2 = 0.9) and ERG (30 Hz flicker R2 = 0.9) exhibiting
the highest symmetry. Disease progression eluded description by a
simple function. Kaplan-Meier curve (KMC) estimates predicted a
loss of 6/6 vision at a mean of 34 years (± 2.9; Confidence Interval),
with a loss of reading ability occurring at 39 years (± 2.6) and a
complete loss of vision at 48 (± 1.6) years.
Conclusions: High symmetry in all outcome measures confirms that
the contralateral eye can be used as an internal control in an RPGRXLRP gene therapy trial. The variability between patients makes
an intra-individual control preferable to an inter-individual control.
According to these findings, the most sensitive parameter to measure
disease progression and treatment success in an interventional RPGRXLRP trial seems to be kinetic visual field using the III4e target.
KMC analysis predicts the most severe decline in vision between the
third and fourth decade of life.
Commercial Relationships: Julia-Sophia Bellingrath,
None; Immanuel Philip Seitz, None; Susanne Kohl, None;
Eberhart Zrenner, None; Nicola Gloeckle, None; Holger Prokisch,
None; Susan Downes, None; Simon Ramsden, None;
Robert E. MacLaren, None; Dominik M. Fischer, None
Support: Studienstiftung des deutschen Volkes, Claussen Simon
Stiftung
Detectable rod function in patients with retinitis pigmentosa (RP)
with or without a measureable rod electroretinogram (ERG)
response
Lea D. Bennett1, Martin Klein1, Kelly Kiser1, Donald C. Hood2,
David G. Birch1, 3. 1Retina Foundation of the Southwest, Dallas,
TX; 2Ophthalmology, Columbia University, New York, NY;
3
Ophthalmology, UT Southwestern Medical Center, Dallas, TX.
Purpose: Although it is known that rod photoreceptors are primarily
affected in RP, rod visual fields are not well characterized due to
the unavailability of commercial devices capable of detecting rod
sensitivity in the periphery. The current standard for measuring rod
function is the full-field ERG (ffERG), which, despite being the
summed electrical response to light from the remaining rods, is not
detected in patients with advanced RP. A new scotopic perimeter
designed to test rod function throughout the visual field was used in
order to determine if patients with RP had measurable rod function in
the absence of a rod ffERG response.
Methods: Normal controls (n=7; age 36.9 ± 18.8yrs) and patients
with RP (n=27; age 53.6 ± 14.4yrs) had one eye dilated and dark-
adapted for 45 minutes. Rod ffERG responses were elicited by
the ISCEV flash (0.01 cd.s/m2). Patients with RP were separated
into 2 groups, those with a rod ffERG response >3µV (n=17)
and without a rod ffERG response (<3µV; n=10). A DAC (darkadapted chromatic perimeter; Medmont International Pty Ltd;
Victoria, Australia) was used to test 164 points over 144° with short
(505 nm) and long (625 nm) wavelength stimuli. Thresholds to short
wavelength stimuli were considered rod-mediated if the sensitivity
was within 20 dB of the normal control rod threshold. In some
patients rod-mediation was further evaluated by determining the
difference in threshold between the 505 nm and 625 nm stimuli.
Results: The average sensitivity across all locations for normal
controls was 52.3 ± 4.1 dB, which was higher than for patients
with RP (22.1 ± 14.0 dB; p<0.0001). Patients had an average of
53.8 ± 48.2 test points that were rod-mediated. Patients with a rod
ffERG response had 80.3 ± 41.7 rod-mediated loci. For those without
a rod ffERG response, 4 patients with RP (40%) retained at least 5
rod-mediated loci.
Conclusions: Rod function can be quantified with the DAC perimeter
even when the rod ffERG response is non-detectable. This provides a
possible outcome measure of rod function for clinical trials involving
retinal degenerative diseases.
Commercial Relationships: Lea D. Bennett, None; Martin Klein,
None; Kelly Kiser, None; Donald C. Hood, None; David G. Birch,
None
Support: 5 RO1 EY009076-20
A Biomarker for Disease Course in Patients with Autosomal
Dominant Retinitis Pigmentosa due to RHO Mutations
Safa Rahmani1, Jason Comander1, Carol W. DiFranco1,
Bernard Rosner2, Michael A. Sandberg1. 1Berman-Gund
Laboratory for the Study of Retinal Degenerations, Department
of Ophthalmology, Massachusetts Eye & Ear Infirmary, Harvard
Medical School, Boston, MA; 2Department of Biostatistics, Channing
Laboratory, Harvard Medical School, Boston, MA.
Purpose: To determine whether the rate of decline of full-field cone
electroretinogram (ERG) amplitude is related to baseline cone ERG
amplitude or implicit time in patients with autosomal dominant
retinitis pigmentosa (RP) with a Rhodopsin (RHO) gene mutation.
Methods: ERG recordings to 30-Hz full-field white flashes from
54 patients with autosomal dominant RP due to RHO mutations
were analyzed retrospectively. Cone ERG responses were recorded
in consecutive examinations separated by at least one year from the
patient’s baseline (ages 8-66, 3-15 years of follow up). All had a
delayed cone ERG implicit time at baseline (i.e., ≥ 33 msec). We used
Stata 14 to perform repeated-measures longitudinal regression with
loge amplitude as the dependent variable and time, quintile median
loge baseline amplitude, quintile median baseline implicit time, and
the cross products of time x quintile median loge baseline amplitude
and time x quintile median baseline implicit time as the independent
variables.
Results: The mean exponential rate of amplitude decline over
follow up was not significantly related to baseline amplitude. In
contrast, for each increasing msec of baseline implicit time, the mean
rate of amplitude decline accelerated by an average of 1.3%/year
(p < 0.0001). The lowest quintile of baseline implicit time progressed
at an average of 4.4%/year, while the highest quintile progressed at
an average of 16.2%/year (Figure 1).
Conclusions: A more delayed baseline cone ERG implicit time
predicts a faster rate of loss of cone ERG amplitude in RP patients
with a RHO mutation. This finding may be useful to clinicians to help
them advise patients about their future mobility handicap. It can also
be useful for patient selection in clinical trials by limiting patients
to those likely to have faster rates of progression, which should
make it easier to detect a treatment difference over time and shorten
clinical trials. Findings for patients with RHO mutations will also be
compared with findings for patients with X-linked RP due to RPGR
mutations and with findings for patients with autosomal recessive RP
due to USH2A mutations.
Commercial Relationships: Safa Rahmani; Jason Comander,
None; Carol W. DiFranco, None; Bernard Rosner, None;
Michael A. Sandberg, None
Support: Foundation Fighting Blindness, Columbia, MD., Research
to Prevent Blindness, New York, New York
Treatment of retinitis pigmentosa by Lycium barbarum
Henry H. Chan1, Christie H. Lam1, Kwok-Fai So4,
Raymond C. Chang3, Jimmy S. Lai4, Chi-wai Do1, Iris F. Benzie2,
Serena Z. Li1, Kaiyip Choi1, Man Pan Chin1, Wing Yan Yu1.
1
Laboratory of Experimental Optometry (Neuroscience), School of
Optometry, The Hong Kong Polytechnic University, Hong Kong,
Hong Kong; 2Department of Health Technology and Informatics,
The Hong Kong Polytechnic University, Hong Kong, Hong Kong;
3
Laboratory of Neurodegenerative Diseases, School of Biomedical
Sciences, LKS Faculty of Medicine, The University of Hong Kong,
Hong Kong, Hong Kong; 4Department of Ophthalmology, LKS
Faculty of Medicine, The University of Hong Kong, Hong Kong,
Hong Kong.
Purpose: To study the immediate effect of Lycium barbarum (LB)
treatment on retinal functions, especially the cone function, in
patients with retinitis pigmentosa (RP).
Methods: The study is a double-masked randomized clinical
trial. RP subjects were recruited with eye examination including
ETDRS Visual Acuity, Humphrey Field Analysis and Multifocal
Electroretinogram. The RP subjects were randomly allocated to either
LB or placebo groups with daily treatment (10g/day) for 12 months
and had follow up in every 6 months.
Results: It is the report after the first 6 months of intervention. There
were 23 subjects in LB group (49.8±13.3yr) and 12 in placebo group
(46.5±10.2yr); p=0.43). The compliance rates for LB and placebo
groups were 89±8.2% and 85±11.1% respectively (p=0.30).
The changes of 90% contrast VA for LB and placebo groups were
-0.01±0.05 and 0.07±0.12 respectively (p=0.09). The changes of
10% contrast VA for LB and placebo groups were -0.05±0.08 and
0.06±0.07 respectively which were significantly different (p=0.047).
The changes of mean defect from HFA 30-2 full-threshold for LB and
placebo groups were -0.33±0.80dB and -0.06±0.63dB respectively
(p=0.50). The changes of mean defect from HFA 10-2 full-threshold
for LB and placebo groups were -0.13±1.10dB and -1.40±1.25dB
respectively which were significantly different (p=0.04).
The amplitude changes of direct component (DC) from global flash
mfERG for LB and placebo groups were: -2.44±4.25nV/°2 (Central,
C); -0.14±1.13nV/°2 (Paracentral, P) and 2.01±8.52nV/°2 (C);
0.03±0.83nV/°2 (P) respectively. The amplitude changes of induced
component (IC) from mfERG for LB and placebo groups were
-5.28±12.2nV/°2 (C); -0.23±1.30nV/°2 (P) and -0.73±4.71nV/°2 (C);
-0.33±0.58nV/°2 (P) respectively. The implicit time changes of DC
for LB and placebo groups were: 0.73±3.07msec (C); 0.64±4.71msec
(P) and 1.55±4.28 msec (C); -0.35±2.51msec (P) respectively.
The implicit time changes of IC for LB and placebo groups were:
1.41±2.52msec (C); 1.21±5.42msec (P) and 0.42±4.81msec (C);
-0.52±4.82msec (P) respectively. No significance were observed in all
mfERG parameters (p>0.05).
Conclusions: Our results confirm that the 6 months LB treatment for
RP patients had marginal significant improvement in low-contrast
VA and central visual sensitivity. The neuroprotective effect of LB
is believed to delay or minimize the deterioration of central visual
function in RP.
Commercial Relationships: Henry H. Chan; Christie H. Lam,
None; Kwok-Fai So, None; Raymond C. Chang, None;
Jimmy S. Lai, None; Chi-wai Do, None; Iris F. Benzie, None;
Serena Z. Li, None; Kaiyip Choi, None; Man Pan Chin, None;
Wing Yan Yu, None
Support: Health and Medical Research Fund (01121876), General
Research Funds (PolyU5605/13M), PolyU Internal Grants (G-YBBS,
G-YBGS, Z-0GF, G-UB83, G-YK88)
Clinical Trial: NCT02244996
The Impact of Exercise on Quality of Life and Progression of
Disease in Retinitis Pigmentosa
Joshua Levinson2, Ethan Joseph2, Joe Nocera1, Laura Ward2,
Machelle T. Pardue1, Beau B. Bruce2, Jiong Yan2. 1Center for Visual
and Neurocognitive Rehabilitation, Atlanta VA Medical Center,
Atlanta, GA; 2Emory University, Atlanta, GA.
Purpose: Exercise has been found to be neuroprotective in animal
models of retinal degeneration. This study aims to evaluate exercise
patterns in patients with retinitis pigmentosa (RP) and investigate the
effect of exercise on quality of life (QOL) and visual function.
Methods: Adult patients with RP seen at a single academic
center between 2005 - 2014 were identified. Exercise habits were
assessed using the Godin Leisure-time Exercise Questionnaire
via telephone survey. The SF-36 general health survey, National
Eye Institute Visual Function Questionaire-25 (NEI VFQ-25), and
Pepper Assessment Tool for Disability (PAT-D) were administered
to evaluate QOL. A retrospective chart review was conducted to
evaluate visual function including visual acuity, Goldmann visual
fields (GVF), and electroretinography. Clinical data was collected at
the initial and final visits.
Results: 142 of 496 patients participated in the phone survey
(28.6%). The mean age of study participants was 46.4 years.
For patients with multiple clinic visits, the median length of
follow-up was 4.3 years. The Godin exercise survey revealed
78 (56.1%) “active”, 26 (18.7%) “moderately active”, and
35 (25.2%) “insufficiently active” patients. “Active” patients
reported significantly less disability on PAT-D evaluation than
“insufficiently active” patients (24.6 vs 30.5, p=0.03). 67 patients
were employed (47.5%). Employed patients scored significantly
better on vision-related QOL testing (56.7 vs. 43.9, p<0.0001) and
the Pepper disability survey (24.2 vs. 29.4, p=0.01) than unemployed
patients. “Active” patients scored higher on the NEI VFQ-25 than
“insufficiently active” patients (52.8 vs. 45.5, p=0.08) though this did
not reach statistical significance. Mean initial best-corrected logMAR
visual acuity in the better-seeing eye was 0.66 (Snellen 20/91).
The mean combined initial horizontal-vertical III4e GVF score
was 56.9 degrees in the right eye and 62.9 degrees in the left eye.
“Active” patients had higher mean GVF scores than “insufficiently
active” patients for both right and left eye visual fields though these
differences did not reach statistical significance (Right 66.2 vs. 40.3,
p=0.17. Left 64.7 vs. 52.5, p=0.73).
Conclusions: More research is warranted to evaluate the influence of
exercise on QOL and progression of disease in RP.
Commercial Relationships: Joshua Levinson, None;
Ethan Joseph; Joe Nocera, None; Laura Ward, None;
Machelle T. Pardue, None; Beau B. Bruce, None; Jiong Yan, None
Support: NIH Core Grant EY006360, Research to Prevent
Blindness, Dept. of Veterans Affairs Rehabilitation R&D Service
Research Career Scientist Award C9257S (MTP)
Transcorneal electrical stimulation in patients with retinitis
pigmentosa: significant increase in photopic b-wave amplitude
after one year
Florian Gekeler1, 2, Mariya Gosheva2, Johanna Pach1,
Barbara Wilhelm2, Karl Ulrich Bartz-Schmidt2, Eberhart Zrenner2,
Andreas Schatz1, 2. 1Ophthalmology, Klinikum Stuttgart, Stuttgart,
Germany; 2Department of Ophthalmology, University of Tübingen,
Tübingen, Germany.
Purpose: Transcorneal electrical stimulation (TES) has shown
beneficial effects in patients with retinitis pigmentosa (RP) exerting
effects presumably through the release of neurotrophic factors. After
promising results of an exploratory study in 24 patients over 6 weeks
(Schatz et al., IOVS 2011) the here presented study assessed safety
and efficacy by subjective and objective parameters after 1 year in
a cohort of 60 patients. Here, we specifically report on results of the
ganzfeld ERG.
Methods: Fifty-two patients completed the prospective, randomized,
partially-blinded study with stimulation of 30 min. per week for
52 consecutive weeks in one eye. Patients were randomly assigned
to sham (n=20), 150% (n=15), or 200% (n=17) of their individual
electrical phosphene threshold. TES was applied by CE-marked
stimulator and electrodes (Okuvision GmbH, Reutlingen, Germany),
performed partially at home and in the study center. Ganzfeld
ERG was assessed 5 times in regular intervals according to ISCEV
standards (rod protocol: 4 steps with intensities from 0.16 to 3 phot
cd.s/m and 4 ms duration, a single flash of 3 cd.s/mwhite 6500 K,
and a 9 Hz flicker; cone protocol: a single-flash response of 3 phot
cd.s/m with a background illumination of 30 phot cd/m and a 30 Hz
flicker). Primary outcome measures were visual field area (Goldmann
III/4e), secondary measures the development of electroretinographic
parameters.
Results: The application of TES over the study period was tolerated
well. Kinetic visual field results did not reach statistical significance
but showed a positive trend. Tendencies of improved function were
also observed for scotopic ERG parameters: standard flash a-wave
amplitude P=0.60, b-wave amplitude P = 0.084, 9 Hz-flicker:
P=0.78 (assessed by a REML test). The photopic ERG standard
flash improved by 37% in the 200% group and by 17% in the 150%
group in comparison to sham (P<0.0001), implicit times did no show
a homogeneous picture; in the 30 Hz flicker changes did not reach
statistical significance (P=0.30).
Conclusions: While only a non-significant trend for improvement
was seen in the scotopic ERG and visual field area after 1 year
significant improvements of the photopic ERG underline the
potential of TES in the treatment of patients with RP. Even longer
studies in more patients could presumably clarifiy the definite role of
TES in RP.
Commercial Relationships: Florian Gekeler; Mariya Gosheva,
Okuvision GmbH, Reutlingen, Germany (F); Johanna Pach,
Okuvision GmbH, Reutlingen, Germany (F); Barbara Wilhelm,
Okuvision G,bH, Reutlingen, Germany (F); Karl Ulrich BartzSchmidt, Okuvision GmbH, Reutlingen, Germany (F);
Eberhart Zrenner, Okuvision GmbH, Reutlingen, Germany (F);
Andreas Schatz, Okuvision GmbH, Reutlingen, Germany (F),
Okuvision GmbH, Reutlingen, Germany (C)
Support: Okuvision GmbH, Reutlingen, Germany
Transcorneal electrical stimulation for patients with retinitis
pigmentosa – Safety and efficacy evidence from a multicentric
observation study – TESOLA
Andreas Schatz2, 1, Johanna Pach2, Mariya Gosheva1,
Barbara Wilhelm1, Tobias Peters1, Peter Martus3, Ida Zündorf4,
Karl-Ulrich Bartz-Schmidt1, Eberhart Zrenner1, Florian Gekeler2.
1
Centre for Ophthalmology, University of Tuebingen, Tuebingen,
Germany; 2Department of Ophthalmology, Stuttgart, Germany;
3
Department of Epidemiology and Biostatistics, Tuebingen,
Germany; 4Okuvision GmbH, Reutlingen, Germany.
Purpose: The multicentric observational study was performed to
verify the safety and efficacy of transcorneal electrical stimulation
(TES) in a large number of patients with retinitis pigmentosa (RP).
Methods: 105 patients (mean age 46 ± 15.9; 58 males) underwent
TES (5-ms biphasic pulses@20 Hz, 30 minutes/week for 6 months)
using the OkuStim®-system (Okuvision GmbH, Germany) and
finished the study per protocol. All patients were stimulated in one
eye with 150% stimulation current of their individual electrical
phosphene threshold. Patients were stimulated at home after a 4-week
training in the clinic (n=32) or in the clinic (n=73). Primary outcome
was safety; secondary endpoints were efficacy measurements via
visual field and visual acuity; additional intraocular pressure (IOP)
and optical coherence tomography (OCT) were performed. Patients
were examined at baseline (week 1), during weeks 12, and 24
(stimulation) as well as weeks 36 and 48 (follow up examinations
during stimulation free period).
Results: 97 patients completed the study per protocol. Most
adverse events (AE) were dry eye symptoms reported by patients
(37.5% of all AE). No serious AEs related to the treatment were
observed; no serious AEs related to the treatment were reported
during the follow up examinations. The efficacy analyses revealed
significant improvement in the BCVA in the stimulated eye
(MANOVA; p < 0.05), while no changes were observed in the
fellow eye (MANOVA; p > 0.05). Moreover positive trend showing
improvements in the visual fields of the stimulated eye as compared
to the fellow eye was observed (Ranks test; p = 0.084). No significant
effect on IOP or OCT were observed during stimulation.
Conclusions: TES was found to be safe; AEs were mainly dry eye
symptoms treatable by artificial tears. Significant improvements in
visual acuity and the positive tendency in visual fields observed in the
stimulated eyes demonstrate the efficacy of TES in RP patients. The
majority of patients reported to be satisfied with the therapy.
Commercial Relationships: Andreas Schatz, Okuvision
GmbH (F); Johanna Pach; Mariya Gosheva, Okuvision GmbH
(F); Barbara Wilhelm, Okuvision GmbH (F); Tobias Peters,
Okuvision GmbH (F); Peter Martus, Okuvision GmbH (F);
Ida Zündorf, Okuvision GmbH; Karl-Ulrich Bartz-Schmidt,
None; Eberhart Zrenner, Okuvision GmbH (F); Florian Gekeler,
Okuvision GmbH (F)
Gene Therapy Utilizing Short Hairpin RNAs for Autosomal
Dominant Retinitis Pigmentosa
Michael Massengill, William W. Hauswirth, Alfred S. Lewin.
University of Florida, Gainesville, FL.
Purpose: Autosomal dominant RP (adRP) caused by mutant
rhodopsin (RHO) is incurable. We previously showed that tandem
delivery of a short hairpin RNA (shRNA) to degrade endogenous
RHO and a hardened RHO cDNA with recombinant adeno-associated
virus (rAAV) preserves vision in a mouse model of adRP with P23H
mutant RHO. To date, our attempts to extend this methodology
to rapidly degenerating mouse models of adRP with either T17M
or I307N mutant RHO have been unsuccessful. The goal of this
study was to design rAAV vectors containing shRNAs with high
knockdown efficiency of RHO to extend our approach to other
models of adRP with mutant RHO.
Methods: We designed ten siRNAs to target both human and
dog RHO. Co-transfections of siRNAs or shRNA plasmids and
a plasmid expressing GFP-tagged human RHO were performed
with Lipofectamine in 293T cells. qRTPCR and flow cytometry
(n=3) 48 hours post-transfection were utilized to measure percent
knockdown of RHO. Non-targeting siRNAs or shRNA plasmids
served as controls. Statistical significance (p<0.05) was determined
via 1-way ANOVA followed by a Student-Newman-Keuls Test.
Experiment1: siRNAs were transfected at concentrations of 10, 20, &
40nM with a plasmid encoding GFP-tagged human RHO (500nM).
Experiment 2: Three siRNAs were selected and their sequences were
expressed as small hairpin RNA (shRNA) driven by the H1 promoter.
Each was transfected at 200, 400, and 800nM with GFP-tagged
human RHO (400nM). Experiment 3: The H1-shRNA cassettes were
cloned in rAAV plasmids and were transfected at 800nM with either
GFP-tagged WT, T17M or P23H human RHO.
Results: The ten siRNAs demonstrated knockdown efficiencies
that ranged between 0 and 70% at the protein level. Interestingly,
knockdown at the RNA level was similar among siRNAs.
We selected siRNAs 1, 13, and 15 for further analysis. When
incorporated in to a H1-shRNA cassette, shRNAs 1, 13, and 15
demonstrated statistically significant knockdown of 23.3% ± 10.1,
52.8% ± 9.7, and 73.9% ± 5.5, respectively, at 400nM when
compared to control. The H1-shRNA cassettes maintained their
biological activity when cloned in to rAAV2 and were effective at
targeting GFP-tagged human RHO with mutations causing adRP
(T17M, P23H).
Conclusions: We generated rAAV vectors containing shRNAs with
superior knockdown efficiency that will be tested in other animal
models of adRP, such as the T17M mouse and T4R dog.
Commercial Relationships: Michael Massengill, University of
Florida (P); William W. Hauswirth, University of Florida (P),
AGTC, Inc. (I); Alfred S. Lewin, University of Florida (P), AGTC,
Inc. (C)
Support: NIH grants: R24 EY022012-04 and P30-EY021721
The National Eye Institute Prospective ABCA4 Retinopathy
Natural History Study: Autofluorescence Imaging Analysis
Laryssa Huryn1, Brett G. Jeffrey1, Aarti Hinduja1,
Catherine A. Cukras1, Wadih M. Zein1, Robert B. Hufnagel1,
Yuri V. Sergeev1, Benedetto Falsini2, Amy Turriff1,
Denise Cunningham1, Brian P. Brooks1. 1Ophthalmic Genetics,
National Eye Institute, Bethesda, MD; 2Universita’ Cattolica, Rome,
Italy.
Purpose: The purpose of this study is to investigate the progression
of atrophy in ABCA4 retinopathy using imaging techniques.
Methods: Forty nine patients carrying at least one ABCA4
mutation and clinical diagnosis of Stargardt disease or cone-rod
dystrophy underwent comprehensive ophthalmic evaluations as
part of a prospective ABCA4 retinopathy natural history protocol
at the National Institutes of Health (NCT01736293). Color fundus
photos, short-wavelength autofluorescence (SW-AF) (Heidelberg
488/500nm), and spectral domain-optical coherence tomography
(SD-OCT) images were acquired and this data was used for analysis.
Genotype-phenotype correlation analysis of the nature of mutations
to the imaging findings was performed. One year follow-up data was
compared to baseline visits.
Results: Of the forty nine patients that were enrolled in this study,
to date, 29 patients had a complete data set spanning one year and
were included in this analysis. Age at baseline examination ranged
from 12 to 63 years and visual acuity ranged from 20/16 to 20/500.
Discrete areas of hypo-autofluorescence on SW-AF were delineated
using the Heidelberg Spectralis RegionFinder software and a withinsession repeatability coefficient of 0.07 log mm2 was found. Seven
patients (24%) were found to have progression in atrophy greater
than the variability determined by the repeatability coefficient over
this one year time span with a median rate of change of 0.114 log
mm2 per year in one eye (30% per year). Age of the patients that
progressed ranged from 16 to 61 years at baseline with visual acuity
that remained essentially stable (range=20/16-20/250). Five of these
seven patients that progressed had a phenotype of discrete central
atrophy with surrounding flecks and atrophic lesions.
Conclusions: Fundus imaging, specifically autofluorescence has
been instrumental in the diagnosis and monitoring of patients with
Stargardt disease. One year, prospective data supports SW-AF
as a reliable method to monitor change in patients with ABCA4
retinopathy. This study provides an opportunity to investigate the
association between fundus autofluorescence changes in Stargardt
disease with molecular genetics and other clinical findings that may
be used as outcome variables in future trials.
Commercial Relationships: Laryssa Huryn, None;
Brett G. Jeffrey, None; Aarti Hinduja, None;
Catherine A. Cukras, None; Wadih M. Zein, None;
Robert B. Hufnagel, None; Yuri V. Sergeev, None;
Benedetto Falsini, None; Amy Turriff, None; Denise Cunningham,
None; Brian P. Brooks, None
The National Eye Institute Prospective ABCA4 Retinopathy
Natural History Study: Fundus Guided Retinal Sensitivity Over
1 Year
Brett G. Jeffrey, Malika Nimmagadda, Aarti Hinduja, Amy Turriff,
Laryssa Huryn, Robert B. Hufnagel, Catherine A. Cukras,
Wadih M. Zein, Brian P. Brooks. Ophthalmic Genetics & Visual
Fundtion Branch, National Eye Institute/NIH, Bethesda, MD.
Purpose: To investigate retinal sensitivity measured with fundus
guided perimetry prospectively over a year, in patients with ABCA4
retinopathy.
Methods: Fundus guided measurements of retinal sensitivity
were recorded at baseline and then at 6 and 12 months from
48 patients with at least 1 mutation in ABCA4, and aged 12-63 yrs
(median = 38 yrs). Right eye mesopic retinal sensitivity was
measured to a 10-2 pattern. Left eye retinal sensitivity was measured
with 2-color dark-adapted perimetry to a reverse L-shape pattern,
centered on the fovea and extending 15o nasally and 11o superiorly.
Results: RIGHT EYE: Meaningful change in mesopic sensitivity for
the 10-2 pattern was taken to be a loss of >=8dB in at least 5 points.
Mesopic sensitivity measured to a 10-2 grid at baseline could be
classified into 3 groups: Group 1 (n=29), no continuous breaks in
outermost ring and >10 central points with reliable sensitivity (i.e.
>=8dB). Group 2 (n=4): most of the 10-2 outer ring remained, but
there were <5 central points with reliable sensitivity. Group 3 (n=12),
<5 points across the entire 10-2 grid had a reliable sensitivity. Fifteen
of the 20 Group 1 patients (75%) showed progression over 1 year. As
Groups 2 and 3 had insufficient numbers of reliable points to follow,
we trialed a modified extended pattern with 70 points extending 5
to 17 deg from the fovea along horizontal and vertical meridians.
Retinal sensitivity could be measured along at least 1 axis, beginning
7 to 11 deg from the fovea in all Group 2 patients, and 8 of 12 (66%)
Group 3 patients with a Goldman III (n=5) or V (n=3) stimulus.
LEFT EYE: The length of the non-seeing area along a meridian was
calculated as the distance (o) from the fovea to a where a criterion
threshold was reached. Repeatability coefficients (RCs) for the
length of the non-seeing area were <2.5o for the blue stimulus and
<4o deg for the red stimulus. Progression over 1 year was greater
than variability determined from the RC in 6 of 28 patients (22%)
recorded with the blue stimulus and 5 of 22 patients (22%) with the
red stimulus.
Conclusions: With one year of follow-up, meaningful changes in
both mesopic and scotopic retinal sensitivity could be documented in
15 and 6 ABCA4 patients respectively. The use of extended patterns
combined with larger Goldman V stimuli enabled measurement of
retinal sensitivity in advanced cases of ABCA4 retinopathy.
Commercial Relationships: Brett G. Jeffrey, None;
Malika Nimmagadda, None; Aarti Hinduja, None;
Amy Turriff; Laryssa Huryn, None; Robert B. Hufnagel,
None; Catherine A. Cukras, None; Wadih M. Zein, None;
Brian P. Brooks, None
Methods: Wide-field, ssOCT cube scans (9 x12 mm, 256 B-scans,
512 A-scans, DRI-OCT, Topcon, Inc) were obtained from 7 eyes of
6 patients with RP (autosomal recessive: 2, autosomal dominant: 2,
Usher syndrome type II: 2) aged 19 to 60 years with BCVAs ranging
from 20/20 to 20/25. OCT macular volume and averaged B-scans,
and SW-FAF images, were also obtained using Spectralis HRA+OCT
(Heidelberg Eng). Following manual correction of the automated
Topcon segmentation of the IS/OS band and OS/retinal pigment
epithelium (OS/RPE) layers, the average reflective intensity of enface slabs of varying thickness were generated with these borders as
references using special purpose software (ATL 3D-Suite).[1,2] For
each eye, the lateral extent of the intact IS/OS area was compared to
the width of the band measured on OCT B-scans and to the borders of
the hyperFAF ring/arc on the SW-FAF image following registration
of the images.
Results: For the en-face images (Fig. 1B), slabs (Fig. 1A), with the
IS/OS band as reference, optimized visualization of the boundary of
the intact IS/OS area for 6 eyes (Fig. 1B); for one eye, the reference
was the OS/RPE. For all 7 eyes, there was good agreement between
the lateral extent of the IS/OS area and width of the band measured
on the averaged B-scans (Fig.1B, C, solid vertical lines), as well
as with the locations of the terminations of the band on individual
ssOCT B-scans. In addition, all 7 eyes had a ring/arc of hyperFAF
(Fig. 1D). The inner border of the hyperFAF area (Fig. 1D)
corresponded to the en-face boundary of the IS/OS area (Fig. 1B).
Conclusions: En-face imaging has potential clinical value for
visualizing and tracking changes in the integrity of the IS/OS band in
patients with RP. 1. Fortune et al. IOVS 2014; 2. Hood, Fortune et al.
IOVS 2015.
En-face imaging as a method for monitoring changes in the inner
segment (IS)/outer segment (OS) band in retinitis pigmentosa
Jason Nunez1, Donald C. Hood1, 2, Daiyan Xin1, Stephen H. Tsang2, 3,
Juan Reynaud4, David G. Birch5, Brad Fortune4,
Vivienne C. Greenstein2. 1Psychology, Columbia University, New
York City, NY; 2Ophthalmology, Columbia University, New York,
NY; 3Pathology and Cell Biology, Columbia University, New York,
NY; 4Legacy Devers Eye Institute, Portland, OR; 5Retina Foundation
of the Southwest, Dallas, TX.
Purpose: To compare en-face imaging of the area of the intact IS/
OS band (aka EZ band) derived from wide-field swept-source
optical coherence tomography (ssOCT) volume scans to current
measurements of IS/OS band width on OCT averaged B-scans, and
measurements of the borders of rings/arcs seen on short-wavelength
fundus autofluorescent (SW-FAF) images in patients with retinitis
pigmentosa (RP).
Inner Retinal Thickness in Late Stage Retinitis Pigmentosa
Kirsten G. Locke1, Kelly I. Locke-Reddin1, Donald C. Hood3,
David G. Birch1, 2. 1Ophthalmology, Retina Foundation of the
Southwest, Dallas, TX; 2Ophthalmology, UT Southwestern
Medical Center, Dallas, TX; 3Psychology, Columbia University,
New York, NY.
Purpose: With emerging new technologies for vision restoration,
such as epiretinal implants and optogenetic approaches, the integrity
of the inner retinal [retinal nerve fiber layer (RNFL), ganglion
cell (GC) and inner plexiform (IP)] layers in patients with retinitis
pigmentosa (RP) is critical. Here we use SDOCT to assess GCIPL
(GC and IP layers combined) in patients with RP where the ellipsoid
zone (EZ) has disappeared and visual acuity is down to 20/400
(logMAR 1.3) or worse.
Methods: OCT 9x9 mm volume scans (Spectralis, Heidelberg,
Germany) consisting of 31 B-scans were collected from a single eye
in 25 patients (mean age: 48.6 ±15.7 yrs) with late stage RP. Using
manual correction of the segmentation lines within the Spectralis
software, the total retina (TR), RNFL and GCIPL mean thicknesses
were measured over the 9 ETDRS macula grid locations. All
measurements were compared to 25 age-similar normal subjects
(mean age: 45.4 ±19.5 yrs).
Results: The mean TR thickness was 229.7 ±20.3 microns (norm:
303.0 ±13.1 microns; p<0.0001). All but one patient was below
the normal 95% range (277-329 microns). The mean RNFL was
45.3 ±7.6 microns (norm: 28.6 ±3.0 microns; p<0.0001). All patients
but one were above the normal 95% range (23-34 microns). The
mean thickness of the GCIPL in patients was 68.2 ±10.1 microns,
comparable to normal (70.6 ±7.5 microns; p=0.26). Four patients
were outside the normal 95% range (56-85 microns); two thinner and
two thicker than normal.
Conclusions: The majority of patients with late-stage RP had reduced
TR due to loss of the outer retinal layers. As reported previously
(Hood et al., IOVS, 2009), most patients had thickened RNFL. The
mechanism of the RNFL thickening is unknown at this time and
may or may not pose a challenge for vision restoration. GCIPL for
most patients remained within normal limits in the central macula
regardless of visual acuity. Patients with preserved GCIPL may be
suitable candidates for vision restoration targeting the inner retina.
Commercial Relationships: Kirsten G. Locke, None;
Kelly I. Locke-Reddin, None; Donald C. Hood, Topcon Inc (F),
Heidelberg Engineering (F), Topcon Inc (C); David G. Birch, None
Support: EY09076
Fig. 1. A. B-scan from cube. B. En-face slab. C. Averaged B-scan. D.
SW-FAF.
Commercial Relationships: Jason Nunez, None; Donald C. Hood,
Heidelberg Engineering (F), Zeiss (C), Topcon, Inc. (C),
Topcon, Inc. (F); Daiyan Xin, None; Stephen H. Tsang, None;
Juan Reynaud; David G. Birch, None; Brad Fortune, None;
Vivienne C. Greenstein, None
Support: R01 EY009076
Increased Velocity of Retinal Blood Flow in RP subjects with
Significantly Improved Visual Function following Transcorneal
Electrical Stimulation in a Randomized Controlled Trial
Ava K. Bittner1, Kenneth R. Seger1, Samantha Kayser1,
J C. Ramella-Roman2. 1College of Optometry, Nova Southeastern
University, Ft. Lauderdale, FL; 2Florida International University,
Miami, FL.
Purpose: To examine the repeatability of and changes in retinal
blood velocity (RBV) in the macular capillaries of retinitis
pigmentosa (RP) participants in a randomized controlled trial
evaluating the efficacy of Transcorneal Electrical Stimulation (TES)
for improving visual function.
Methods: Four eyes of 3 TES subjects who developed significantly
improved visual function (i.e., >0.4 logMAR visual acuity or >100%
log retinal area of Goldmann visual fields) and six other eyes that
received TES but did not have a significant visual function change
were compared to 3 control subjects’ eyes that received placebo sham
intervention (inactive laser acupuncture). Coefficients of variation
(CoV) for RBV were measured at 2 baseline visits, as well as after
2 and 6 weeks of TES/intervention sessions. We used a retinal blood
cell tracking system similar to a speckle imaging system; it relies
on tracking the non-uniform distribution of red blood cells within
the capillary and is capable of dealing with very low signal-to-noise
ratios.
Results: CoV for RBV were 5% and 8% on average within a single
vessel location in an image for arteries and veins, respectively.
Test-retest CoV were 13% on average within a single artery or vein
location for 2 within-visit or between baseline visit images. The eyes
with and without visual improvements had a significant 32% and
19% increase in RBV on average in arteries, respectively, after 2 TES
sessions when compared to control eyes (95%CI:16-48%;p<0.001)
(95%CI:0.3-38%;p=0.047). The eyes with visual improvements had
a significant 31% increase in RBV in veins after 2 TES sessions
(95%CI:4-59%;p=0.02), but those without visual changes had no
significant RBV change in veins (p=0.70) compared to control eyes.
For eyes with improved vision, the increases in RBV were slightly
reduced after 6 TES sessions to 14% and 24% in arteries and veins
(p=0.18 and p=0.07), respectively, and RBV was not significantly
different than controls for eyes that did not improve post-TES after
6 weekly intervention sessions (p=0.68 and p=0.95).
Conclusions: RBV measurements in RP patients are reliable
outcomes supporting a physiological basis for visual function
improvements in RP subjects who received TES.
Commercial Relationships: Ava K. Bittner, None;
Kenneth R. Seger, None; Samantha Kayser;
J C. Ramella-Roman, None
Support: NIH Grant R21 EY023720
Reduced Central Retinal Artery Blood Flow is Related to
Decreased Central Visual Function in Retinitis Pigmentosa
Patients
Samantha Kayser1, Deborah Mendelsohn2, Jorge Han2,
Patricia Vargas2, Brennan Nelson1, Alexandra Benavente-Perez3,
Ava K. Bittner1. 1College of Optometry, Nova Southeastern
University, Fort Lauderdale, FL; 2Medical Sonography Program,
Nova Southeastern University, Fort Lauderdale, FL; 3College of
Optometry, State University of New York, New York City, NY.
Purpose: A previous study described how patients with retinitis
pigmentosa (RP) exhibited significantly reduced systolic and diastolic
blood flow velocities in the central retinal artery (CRA) compared
to normal controls using color Doppler imaging (CDI). We explored
whether such vascular abnormalities are related to level of vision loss
across RP patients with a wide range of disease severity.
Methods: We measured the CRA peak systolic velocity (PSV) and
end diastolic velocity (EDV) in 22 RP patients using CDI (GE Logiq
7 ultrasound) twice in each eye at each of two visits within a month.
At each of these two visits, ETDRS visual acuity (VA), Goldmann
visual fields (GVF), and 10-2 Humphrey visual fields (HVF) were
completed. PSV and EDV were used to calculate mean flow velocity
(MFV); correlations with visual function were adjusted for age and
gender.
Results: Mean within- and between-visit coefficients of variation
were 16-22% for PSV and EDV. In eyes with reduced mean VA >0.3
logMAR, MFV was significantly lower on average than in eyes with
better VA (p=0.037). Reduced MFV was also significantly associated
with lower HVF mean deviation scores using size III target
(p=0.007). Subjects with worse vision who completed the HVF with
the size V target had significantly reduced MFV that was significantly
correlated with decreased mean sensitivity at the 4 most central test
locations around fixation (p=0.004). GVF log retinal areas (V4e and
III4e) were not significantly related to MFV (p=0.79; p=0.78).
Conclusions: The PSV and EDV measures in the CRA of RP patients
were reliable and appeared reduced in cases of impaired central but
not peripheral visual function loss. These measures of retrobulbar
ocular blood flow are a promising outcome measure to determine the
potential physiological basis for visual function changes in clinical
trials for RP.
Commercial Relationships: Samantha Kayser, None;
Deborah Mendelsohn, None; Jorge Han, None; Patricia Vargas,
None; Brennan Nelson, None; Alexandra Benavente-Perez, None;
Ava K. Bittner, None
Support: NIH Grant R21 EY023720
Wide-field MultiColor Spectral Imaging and Wide-field Spectral
Domain Optical Coherence Tomography Imaging in Retinitis
Pigmentosa
Ulrich Kellner2, 1, Simone Kellner2, 1, Silke Weinitz2, 1,
Ghazaleh Farmand2, Birgit Lindau2, 1, Heidi B. Stoehr3,
Bernhard H. Weber3. 1RetinaScience, Bonn, Germany;
2
AugenZentrum Siegburg, MVZ ADTC Siegburg GmbH, Rare retinal
Disease Center, Siegburg, Germany; 3Institute for Human Genetics,
Regensburg, Germany.
Purpose: To evaluate the diagnostic value of wide-field MultiColor
spectral imaging (WF-MC) and wide-field spectral domain optical
coherence tomography (WF-SD-OCT) in patients with retinitis
pigmentosa.
Methods: Between November 2014 and November 2015 a
consecutive series of 42 patients with retinitis pigmentosa were
examined clinically and with WF-MC and WF-SD-OCT (55 degrees,
Spectralis MultiColor HRA & OCT, Heidelberg Engineering,
Germany)). Further retinal imaging in 30 or 55 degree mode
(fundus autofluorescence (FAF), near-infrared autofluorescence
(NIA), spectral domain OCT (SD-OCT) were performed with the
same system. DNA testing was performed via targeted gene panel
diagnostics.
Results: The series of patients included retinitis pigmentosa
associated with different disease genes and different inheritance
patterns. WF-MC provided a wide-angle view of retinal abnormalities
beyond the vascular arcades excluding the far periphery. The
evaluation of the three different monochromatic images (blue 486
nm, green 518 nm, near-infrared 815 nm) allowed a differentiation
in inner retinal or pigment epithelial and choroidal lesions. Retinal
thinning beyond the posterior pole can be visualized with WF-SDOCT with a good correlation to choroidal thinning within the same
image.
Conclusions: WF-MC and WF-SD-OCT provide the opportunity to
observe more details of retinal alterations in retinitis pigmentosa in
the midperipheral and peripheral retina area.
Commercial Relationships: Ulrich Kellner, None;
Simone Kellner, None; Silke Weinitz, None; Ghazaleh Farmand,
None; Birgit Lindau, None; Heidi B. Stoehr, None;
Bernhard H. Weber, None
Wide-field MultiColor Spectral Imaging and Wide-field Spectral
Domain Optical Coherence Tomography Imaging in ABCA4related retinal dystrophies
Simone Kellner1, 2, Silke Weinitz1, 2, Ghazaleh Farmand1,
Heidi B. Stoehr3, Bernhard H. Weber3, Ulrich Kellner1, 2.
1
AugenZentrum Siegburg. MVZ ADTC Siegburg GmbH, Rare retinal
Disease Center, Siegburg, Germany; 2RetinaScience, Bonn, Germany;
3
Institute for Human Genetics, Regensburg, Germany.
Purpose: To evaluate the diagnostic value of wide-field MultiColor
spectral imaging (WF-MC) and wide-field spectral domain optical
coherence tomography (WF-SD-OCT) in patients with ABCA4related retinal dystrophies.
Methods: Between November 2014 and November 2015 a
consecutive series of 23 patients with ABCA4-related retinal
dystrophies were examined clinically and with WF-MC and WF-SDOCT (55 degrees, Spectralis MultiColor HRA & OCT, Heidelberg
Engineering, Germany)). Further retinal imaging in 30 or 55 degree
mode (fundus autofluorescence (FAF), near-infrared autofluorescence
(NIA), spectral domain OCT (SD-OCT) were performed with the
same system. DNA testing was performed via targeted gene panel
diagnostics.
Results: The series of patients included ABCA4-related retinal
dystrophies. WF-MC provided a wide-angle view of retinal
abnormalities beyond the vascular arcades excluding the far
periphery. In the majority of patients lesions were confined to the
posterior pole, mid-peripheral lesions indicated progression from
macular dystrophy to cone-rod dystrophy. The evaluation of the
three different monochromatic images (blue 486 nm, green 518 nm,
near-infrared 815 nm) allowed a differentiation in inner retinal or
pigment epithelial and choroidal lesions. Subretinal lesions beyond
the posterior pole could be visualized with WF-SD-OCT as indicator
for cone-rod-dystophy.
Conclusions: WF-MC and WF-SD-OCT provide the opportunity
to observe more details of retinal alterations in ABCA4-related
retinal dystrophies at the posterior pole and in the peripheral retina
visualizing the continuous change of lesions from the fovea to the
periphery
Commercial Relationships: Simone Kellner, None; Silke Weinitz,
None; Ghazaleh Farmand, None; Heidi B. Stoehr, None;
Bernhard H. Weber, None; Ulrich Kellner, None
Quantifying Fundus Autofluorescence Rings in Patients with
Retinitis Pigmentosa
Kaspar Schürch1, Stephen H. Tsang1, Winston Lee1,
Katherine Boudreault1, Tobias Duncker1, Russell L. Woods2,
Francois C. Delori2, Janet R. Sparrow1. 1Ophthalmology, Columbia
University, New York, NY; 2Schepens Eye Research Institute, Boston,
MA.
Purpose: Quantitative fundus autofluorescence (qAF) enables
measurement of fundus AF intensities amongst groups of individuals.
We applied the qAF approach to study the high autofluorescent rings
that are often a feature of fundus autofluorescence (AF) images
obtained from patients with retinitis pigmentosa (RP).
Methods: Ten (10) RP patients (age 15 to 56 years; total 17 eyes)
having clearly defined autofluorescent rings, clear lenses and no
floaters were selected for study. Inheritance was autosomal dominant
in 3 patients and autosomal recessive in the others. AF images (30°,
488 nm excitation) were acquired with a confocal scanning laser
ophthalmoscope equipped with an internal fluorescent reference.
After exclusion of the vessels, gray level intensities in rectangular
regions of interest (ROI) (2395 ± 930 pixels) over and outside the
ring were obtained in the superior, temporal and inferior aspect of
each ring. qAF-units were calculated. Control values consisted of
previously published data from age-similar healthy subjects with no
family history of retinal dystrophy. qAF values are reported relative
to the 95% confidence interval (CI) for the same retinal location in
age-matched healthy eyes.
Results: qAF values outside and over the rings could be higher,
similar or lower than qAF values at the same position in age-similar
healthy eyes. Seven (7) eyes were found to have higher qAF-units
in all 3 quadrants over of the ring compared to qAF values at the
same location in healthy age-matched eyes. Additionally, in 2, 1 and
0 eyes qAF was only higher temporally, inferiorly and superiorly,
respectively. Thus in 24/51 eyes (47%) qAF in the ROI over the ring
was higher than in healthy eyes. One eye had qAF-units below the
95%CI outside the ring, with values over the ring being within the
normal range in all 3 quadrants.
Conclusions: Although the qAF values associated with AF rings
in the RP patients varied, in 47% of cases, qAF over the ring was
outside the 95% CI for age-matched healthy eyes. The high qAF
indicates that increased fluorophore production may be a factor in the
formation of the rings.
Commercial Relationships: Kaspar Schürch, None;
Stephen H. Tsang, None; Winston Lee; Katherine Boudreault,
None; Tobias Duncker, None; Russell L. Woods, None;
Francois C. Delori, None; Janet R. Sparrow, None
Support: NIH Grant EY024091, Research to Prevent Blindness
to the Department of Ophthalmology Grant, OPOS Foundation
Scholarship
Retinal and Choroidal Changes in Retinitis Pigmentosa Patients
with Severe Macular Degeneration, a Potential Candidate for
Retinal Implant
Yakup Çevik1, Ata Baytaroğlu2, Abdullah Agin2, Uğur Acar2,
Gungor Sobaci2. 1Ophthalmology, Ardahan State Hospital, Ardahan,
Turkey; 2Ophthalmology, Hacettepe University, Ankara, Turkey.
Purpose: Retinal implants are primarily designed for patients
suffering from degenerative retinal disease such as retinitis
pigmentosa (RP) where outer retinal cells deteriorate while inner
retinal cells stay intact. We investigated whether the inner retinal
layer (IRL) are preserved, or not and there are relations between the
choroidal thickness (ChT), IRL and retinal nerve fiber layer (RNFL)
thickness values in RP patients with severe macular degeneration
(MD).
Methods: We considered Spectral-Domain Optical Coherence
Tomography (SD-OCT, Spectralis, Heidelberg Engineering,
Germany) measurements of the right eyes of 40 RP patients (14
male, 26 female) with severe MD having LP to HM vision and 40
age- and sex-matched healthy controls. The built-in segmentation
analysis program with 1-3-6 mm ETDRS grid of Spectralis was used
for evaluation. The parafoveal ChT values were measured 1500 µm
away from the fovea centralis. We used parametric variants (t-tests
and Pearson Correlation test), p value of less than 0.05 for statistical
significance.
Results: The mean ages were 32.40 ± 2.87 years (19 - 51) in RP
patients and 31.60 ± 2.65 (20- 53) years in control group, respectively
(p=0.62). The mean ChT values were 174.80 ± 40.29 μm subfoveally,
166.80 ± 10.53 μm temporally, 144.40 ± 8.52 μm nasally (p=0.009),
152.14 ± 14.31 μm superiorly (p<0.001) and 164.20 ± 9.64 μm
inferiorly in RP patients and 278.42 ± 76.09 μm subfoveally,
245.23±83.24 μm temporally, 230.54 ± 54.12 μm nasally, 275.42
±72.16 μm superiorly and 267.23 ± 83.52 μm inferiorly in control
group. There were statistically significant thinner for all quadrants
compare to control group.(p<0.001 for each)
Conclusions: RP patient with severe MD seems to have significant
decrease in IRL which seems not to correlate to the other layers
including the ChT. Retinal implants needs to be customized for each
patients individually.
Commercial Relationships: Yakup Çevik, None; Ata Baytaroğlu,
None; Abdullah Agin, None; Uğur Acar, None; Gungor Sobaci,
None
Natural history study of RPE65 associated autosomal recessive
retinal dystrophies
Laurence Pierrache1, 8, Suzanne Yzer1,
Maria M. van Genderen2, José Schuil2, Nienke Boonstra2,
Jan-Willem R Pott3, Mary J. van Schooneveld6, 7, Frans P. Cremers4, 5,
Caroline C. Klaver8, 9, Ingeborgh Van Den Born1. 1The Rotterdam Eye
Hospital, Rotterdam, Netherlands; 2Bartiméus, Zeist, Netherlands;
3
Ophthalmology, University Medical Center Groningen, Groningen,
Netherlands; 4Department of Human Genetics, Radboud University
Medical Center, Nijmegen, Netherlands; 5Radboud Institute for
Molecular Life Sciences, Radboud University Medical Center,
Nijmegen, Netherlands; 6Ophthalmology, Academic Medical Center,
Amsterdam, Netherlands; 7Clinical Genetics, Academic Medical
Center, Amsterdam, Netherlands; 8Ophthalmology, Erasmus Medical
Center, Rotterdam, Netherlands; 9Epidemiology, Erasmus Medical
Center, Rotterdam, Netherlands.
Purpose: Gene augmentation therapy and pharmacological
substitution therapy for RPE65 associated autosomal recessive retinal
dystrophies (LCA2 and RP20) seem to be within reach for patients.
It is currently unclear whether the RPE65 genotype correlates with
phenotype and visual course, and if this knowledge would influence
the timing and type of therapy that needs to be considered. We
performed a longitudinal cohort study to gain insight into the natural
course of disease as a function of RPE65 genotype.
Methods: We collected retrospective and prospective data from
43 subjects with biallelic homozygous or compound heterozygous
RPE65 mutations, 30 originating from a genetic isolate. We studied
the course of visual acuity over time.
Results: The median age of patients in our cohort at recent
examination was 26.5 years, ranging from 8 months to 58 years. The
majority of subjects were diagnosed with RPE65 associated retinal
dystrophy within the first year of life, based on nystagmus, lack of
eye contact, night blindness, adoration to bright light, and severely
reduced electrographic responses. Visual acuity in early childhood
ranged from 1.3 to 0.1 logMAR at the age of 5, and remained
relatively stable the first three decades of life. In a subset of patients
perifoveal atrophy seemed the precursor of loss of central vision
during in the fourth decade.
Mutation analysis revealed 12 different disease causing variants
(Table). We found missense, nonsense, frame shift mutations and
mutations that altered splicing. The Y368H founder mutation was the
most observed mutation in our cohort, 20 patients (47%) carried this
mutation on both alleles.
We observed large differences in visual function between individuals
carrying the same RPE65 mutations, even in siblings from the same
genetic pool and exposed to similar environmental factors.
Conclusions: Genotype-phenotype correlations were not present in
our cohort of 43 subjects with retinal dystrophies caused by RPE65
mutations. Central visual function as measured in childhood varied
widely, subsequently remained stable for the first three decades of
life, but inevitable progressed towards blindness.
Frequency of RPE65 mutations
Commercial Relationships: Laurence Pierrache, None;
suzanne yzer, None; Maria M. van Genderen; José Schuil, None;
Nienke Boonstra, None; Jan-Willem R Pott, None; Mary J. van
Schooneveld, None; Frans P. Cremers, None; Caroline C. Klaver,
None; Ingeborgh Van Den Born, None
Support: Stichting Combined Ophthalmic Research Rotterdam
Clinical phenotype and progression of Usher syndrome related to
mutations in MYO7A or USH2A
Francesco Testa1, Raffaella Colucci1, Antonella De Benedictis1,
Vincenzo Marcelli2, Elio Marciano2, Alberto Auricchio3, 4,
Anne Kurtenbach5, Christine Petit6, Crystel Bonnet6,
Eberhart Zrenner5, Francesca Simonelli1. 1Eye Clinic,
Multidisciplinary Department of Medical, Surgical and
Dental Sciences, Second University of Naples, Naples, Italy;
2
Audiology Unit, Department of Neuroscience, Reproductive and
Odontostomatologic Science, University of Naples Federico II,
Naples, Italy; 3Medical Genetics, Department of Translational
Medicine, University of Naples Federico II, Naples, Italy; 4Telethon
Institute of Genetics and Medicine (TIGEM), Naples, Italy; 5Centre
for Ophthalmology, Institute for Ophthalmic Research, University of
Tuebingen, Tuebingen, Germany; 6Institut de la Vision, Paris, France.
Purpose: To compare the clinical phenotype and natural history of
retinitis pigmentosa (RP) in a large Italian cohort of patients affected
by Usher syndrome (USH) carrying mutations in MYO7A and
USH2A, the most common USH type 1 (USH1) and type 2 (USH2)
genes, respectively.
Methods: 88 patients with a clinical diagnosis of either USH1
(26 patients) or USH2 (62 patients) were genetically screened.
48 subjects had disease-causing mutations: 10 patients in MYO7A,
33 in USH2A, and 5 in other USH genes (CDH23, PDZD7 and
CDH23/USH2A). Clinical examination included best-corrected visual
acuity (BCVA), fundus examination, Goldmann visual field (GVF),
electroretinogram (ERG), audio-vestibular assessment. In order to
assess onset of visual, audio-vestibular disfunction, standardized
questionnaires were submitted to the patients or their parents. Finally,
longitudinal analysis was performed over a median follow-up time
of 3.5 years. Repeated-measure longitudinal regression analysis
was performed on log-transformed values to estimate the mean rate
of change. The study was approved by the local Ethics Committee,
and performed in compliance with the declaration of Helsinki and
international guidelines. All the patients provided a written informed
consent.
Results: The comparison between MYO7A and USH2A patients
showed an earlier onset of hearing impairment, vestibular dysfunction
and also of RP and visual symptoms (night blindness) in MYO7A
patients compared to those of USH2A. Moreover, the MYO7A
patients started to walk in older age than USH2A. BCVA and GVF
decreased faster in MYO7A than in USH2A patients (mean annual
exponential rates for BCVA: -3.92% vs -3.44%, p= 0.025 and for
GVF: -8.52% vs -4.97%, p= 0.005), whereas there was no significant
difference between the two groups of patients for ERG amplitudes
(8.06% vs 2.76%, p= 0.172). Finally, based on BCVA and GVF,
MYO7A patients reached legal blindness at a median age of 37 years,
compared to the 52 years of USH2A subjects.
Conclusions: Our data showed that MYO7A patients presented
an earlier disease onset and a more severe visual impairment
than USH2A patients. For the first time in literature, the current
longitudinal analysis demonstrated a faster progression of retinal
disease in MYO7A patients rather than in USH2A patients. Finally,
this information could be helpful for the clinical classification of the
disease and for the design of gene therapy clinical trials
Commercial Relationships: Francesco Testa, None;
Raffaella Colucci, None; Antonella De Benedictis;
Vincenzo Marcelli, None; Elio Marciano, None;
Alberto Auricchio, None; Anne Kurtenbach, None;
Christine Petit, None; Crystel Bonnet, None; Eberhart Zrenner,
None; Francesca Simonelli, None
Support: European Union - Seventh Framework Programme under
grant agreement HEALTH-F2-2010-242013 (TREATRUSH).
Clinical characterization and genotype-phenotype correlations in
PDE6A-related retinitis pigmentosa
Ditta Zobor1, Laura Kühlewein1, Nicole Weisschuh2,
Christian P. Hamel3, Bart P. Leroy4, Sten Andreasson5,
Ayuso Carmen6, Günther Rudolph7, Bernd Wissinger2, Susanne Kohl2,
Eberhart Zrenner1, 8. 1Institute for Ophthalmic Research, University
Tübingen, Germany, Tübingen, Germany; 2Molecular Genetics
Laboratory, Institute for Ophthalmic Research, University Tübingen,
Tübingen, Germany; 3Institute of Neurosciences of Montpellier,
Hôpital Saint Eloi Montpellier, Montpellier, France; 4Center for
Medical Genetics, Department of Ophthalmology, Ghent University
Hospital Ghent, Ghent, Belgium; 5Department of Ophthalmology,
Lund University, Lund, Sweden; 6Department of Genetics,
Instituto de Investigacion Sanitaria-University Hospital Fundacion
Jimenez Diaz (IIS - FJD, UAM), Madrid, Spain; 7Department of
Ophthalmology, Ludwig-Maximilians-University Munich, Munich,
Germany; 8Werner Reichardt Centre for Integrative Neuroscience
(CIN); University Tübingen, Tübingen, Germany.
Purpose: Mutations in the PDE6A gene - encoding the a-subunit
of the rod cGMP-phosphodiesterase - account for 1% of autosomal
recessive retinitis pigmentosa (arRP) through impaired regulation of
cGMP levels in the rod outer segment. This study aims for a detailed
clinical characterization of patients with PDE6A mutations.
Methods: Data from 28 patients (15 female, 13 male, age: 18 - 83y,
mean 39.3±13.3y) with genetically confirmed PDE6A mutations
were collected. Besides psychophysical tests (ETDRS visual acuity
(VA), kinetic visual field (VF), Roth Hue 28 color vision test, dark
adaptation), detailed electrophysiological examination was carried
out including Ganzfeld and multifocal ERG (mfERG). Furthermore,
fundus autofluorescence and spectral domain OCT imaging were
performed for an in-depth morphological characterization.
Results: disease varied considerably. The two siblings homozygous
for p.V685M showed markedly reduced visual function (mean VA:
0.9±0.1 logMAR; mean VF for target III4e: 187.5±68 deg2, mean
central retinal thickness (CRT): 118.25±16 µm) and no recordable
ERG responses. In comparison, most patients revealed significantly
better visual function (mean VA: 0.35±0.36 logMAR; mean VF:
3061.94±3643.2 deg2, mean CRT: 202.95±83.22 µm). Although
Ganzfeld ERGs were mostly non-recordable, mfERGs showed
residual responses in these cases. Significant heterogeneity was
observed in the rate of progression over age, in some cases with
a remarkably slow time course. The two siblings homozygous for
p.R102S presented with well-preserved function (mean VA: 0.0±0
logMAR, mean VF: 12304.8±854.8 deg2, mean CRT: 216.75±7.58
µm) and remaining ERG responses. For all patients, a high degree
of left to right eye symmetry was found with a higher correlation
efficient for CRT (r=0.87) than for VA (r=0.71).
Conclusions: Mutations in the PDE6A gene cause typical arRP, but
with highly heterogenous disease courses depending on the genotype.
The p.V685M mutation seemed to cause worse clinical outcome especially if patients were homozygous for this mutation, while the
p.R102S mutation was linked to milder diseases manifestation. These
findings will be useful for the identification of patients concerning
future therapeutic trials. The observed good intra-individual
symmetry is highly relevant for any interventional trial as the second
eye will be able to serve as an internal control.
Commercial Relationships: Ditta Zobor, None; Laura Kühlewein;
Nicole Weisschuh, None; Christian P. Hamel, None; Bart P. Leroy,
None; Sten Andreasson, None; Ayuso Carmen, None;
Günther Rudolph, None; Bernd Wissinger, None; Susanne Kohl,
None; Eberhart Zrenner, None
Support: Tistou & Charlotte Kerstan Stiftung
The prevalence of cystic macula lesions in genetically confirmed
Usher syndrome patients
Ieva Sliesoraityte1, Saddek Mohand-Said1, Larissa Moutsimilli1,
Tunde Peto2, Jose Sahel1. 1Ophthalmology Section, Centre Hospitalier
National d’Ophtalmologie, Paris, France; 2NIHR Biomedical Rsrch
Ctr for Ophthalmolog, London, United Kingdom.
Purpose: Usher syndrome (USH) is a rare autosomal recessive group
of disorders characterized by retinitis pigmentosa (RP), sensorineural
hearing loss and vestibular dysfunction. We aimed to investigate the
prevalence of cystic macula lesions (CML) in genetically confirmed
USH patients.
Methods: 76 patients (mean 42±14 years) were prospectively
observed at the Clinical Investigation Center, CHNO des QuinzeVingts, Paris, France. All patients were found to carry at least
one mutation, while 89% of them carried two mutations in USHassociated genes. High quality optical coherence tomography (OCT)
scans (Spectralis HRA + OCT, Heidelberg Engineering, Dossenheim,
Germany) were utilized to grade CML using a standard grading
system. Once the grading database was verified and closed, the
grading and clinical data were merged.
Results: In our patients’ cohort the prevalence of CML in USH
associated genes was the following: 5/11(45%) MYO7A, 1/3(33%)
CDH23, 0/1(0%) PCDH15, 0/1(0%) USH1C, 11/38(29%) USH2A,
3/6(50%) GPR98, 3/3(100%) CLRN1, and 0/1(0%) had mutations
in GPR98 and MYO7A genes. The inner nuclear layer (INL) was
affected in 8/16(50%), outer nuclear layer (ONL) in 7/16(44%),
and the retinal ganglion cell layer (RGC) in 1/16(6%) of the cases.
In USH2A cases, CML affinity was observed to INL layer, while in
CLRN1 and GPR98 to ONL layer, respectively.
Conclusions: CML is a common complication in patients with USH.
CML tend to have a high prevalence in INL and ONL retinal layers.
CML can potentially impact on future therapeutic trials where visual
acuity is used as an outcome measure.
Commercial Relationships: Ieva Sliesoraityte; Saddek MohandSaid, None; Larissa Moutsimilli, None; Tunde Peto, None;
Jose Sahel, None
Support: Diseases ERAREl N°58: Eur-USH, http://eur-ush.eu, http://
www.e-rare.eu
Correlation of Macular Thickness (Spectral-domain OCT) and
Retinal Vascular Perfusion Indices by the Novel Technology of
OCT-Angiography in Retinitis Pigmentosa
Sandeep Grover, Kumar Sambhav. Ophthalmology, University of
Florida College of Medicine, Jacksonville, FL.
Purpose: Retinitis pigmentosa (RP) is characterized by progressive
degeneration of photoreceptors, leading to thinning of the
‘photoreceptor layer’ and attenuation of retinal arterioles, presumed
to be due to vascular perfusion differential. Spectral-domain OCT
(SD-OCT) provides retinal thickness in various areas of retina. With
the advent of this novel technology of OCT angiography (OCTA),
it provides a 3D noninvasive vascular perfusion mapping of various
retinal layers and choriocapillaris. This study correlates the retinal
thickness by SD-OCT with the vascular perfusion indices, as
measured by OCTA in this cohort of patients with RP.
Methods: Patients with RP who had both SD-OCT (Spectralis,
Heidelberg) and OCTA (Avanti, Optovue) done (29 eyes of
16 patients) were included in this study. Retinal thickness was
measured in all 9 ETDRS subfields - central (CMT), inner ring
(parafoveal) and outer ring (perifoveal) in all eyes by SD-OCT. The
OCTA reported perfusion indices (vessel density and flow index)
in parafoveal and perifoveal areas for each of the 4 en-face layers
of the retina - superficial plexus, deep plexus, photoreceptors and
choriocapillaris. Correlation statistics were performed between the
central macular thickness (CMT) by SD-OCT and visual acuity;
perifoveal and parafoveal retinal thickness with perfusion indices in
each retinal layer in the same zones.
Results: The mean parafoveal retinal thickness was 301.36±47.69;
and mean perifoveal retinal thickness was 254.92±33.18. OCTA
showed that there was marked decrease in perfusion indices in
superficial and deep retinal plexus and marked increase in the
photoreceptor layer in patients with RP compared to normal
(p<0.001) with no significant change in choriocapillaris layer
(p>0.05). There was poor correlation of retinal thickness to perfusion
indices of superficial and deep plexus but better correlation was
noted with perfusion indices of that of photoreceptor layer and
choriocapillaris (r≥0.5).
Conclusions: The parafoveal and perifoveal retinal thickness did not
correlate well with the superficial and deep plexus vascular perfusion
indices but with the photoreceptor and choriocapillaris indices. This
new technology of OCTA gives an insight into the pathogenesis of
RP and may be of prognostic value as a marker for the severity of the
disease in the future.
Commercial Relationships: Sandeep Grover, None;
Kumar Sambhav, None
Structural loss precedes visual acuity loss in the fovea of patients
with retinal degeneration
Asma Saud1, Kavitha Ratnam2, Jia Qin2, Panagiota Loumou1,
Shane Griffin1, Austin Roorda2, Travis Porco3, Jacque L. Duncan1.
1
Ophthalmology, University Of California San Fransisco, San
Francisco, CA; 2School of Optometry and Vision Science Graduate
Group, University of California Berkeley, Berkeley, CA; 3Proctor
Foundation, University Of California San Fransisco, San Fransisco,
CA.
Purpose: To assess the relationship between cone spacing with
clinical measures of visual acuity over time in eyes with inherited
retinal degeneration (IRD).
Methods: High-resolution images of the retina were obtained using
adaptive optics scanning laser ophthalmoscopy from 19 eyes of 15
IRD patients: 12 with RP, 1 with Usher syndrome type 2, 1 with
Usher syndrome type 3 and 10 eyes of 5 normal subjects. These
images were taken at two time points separated by greater than 300
days (mean 557 days, range 311-1935 days). From these images,
cone spacing was measured from 0.02 to 0.19 degrees from the
preferred retinal locus (PRL), which indicates the anatomic fovea.
These values were used to compute cone spacing Z-scores, (based on
37 age-similar normal eyes). Z-scores were compared to log mean
angle of resolution (log MAR) best-corrected visual acuity at each of
the two time points for each subject.
Results: Cone spacing measured within 0.19 degrees from the PRL
was significantly correlated with logMAR at baseline (Spearman’s
rank correlation rho=0.56, 95% confidence interval (CI) 0.29-0.78,
P < 0.01, clustered bootstrap) and at follow-up (rho=0.50, 95% CI
0.09—0.77, P=0.03). Comparing longitudinal Z score values with
baseline, there was a small but significant increase in Z score during
follow up in the retinal degeneration patients of +0.56 (P=0.027),
but there was no significant change in logMAR in patients, and no
significant change in Z score or log MAR in normal eyes.
Conclusions: Cone spacing correlated with visual acuity in normal
subjects and patients with inherited retinal degeneration. In eyes with
retinal degeneration, cone spacing increased slightly but significantly
during 1-5 years of follow up, although logMAR did not change
significantly. These results suggest cone spacing Z score may be a
more sensitive measure of cone loss at the fovea than measures of
visual acuity in patients with inherited retinal degeneration.
Commercial Relationships: Asma Saud, None; Kavitha Ratnam,
None; Jia Qin, None; Panagiota Loumou, None; Shane Griffin,
None; Austin Roorda, University of Rochester and University
of Houston, US 7,118,216 (P), University of Rochester and
University of Houston, US 6,890,076 (P); Travis Porco, None;
Jacque L. Duncan, None
Support: NIH Grant EY002162, FDA R01-41001, Research to
Prevent Blindness, The Bernard A. Newcomb Macular Degeneration
Fund, That Man May See, Inc., Hope for Vision, NIH EY023591
Foundation Fighting Blindness, 2012 Beckman Initiative for Macular
Research Grant 1201
Fragile Maculas in Patients with Retinal Degeneration due to
RPGR-ORF15 Mutations: Spatio-temporal Models of Disease
Progression
Jason Charng1, Malgorzata Swider1, Rebecca Sheplock1,
Alexander Sumaroka1, Alejandro J. Roman1, Marc C. Peden2,
Elise Heon3, Sharon B. Schwartz1, Samuel G. Jacobson1,
Artur V. Cideciyan1. 1Dept of Ophthalmology, Scheie Eye Institute,
Univ of Pennsylvania, Philadelphia, PA; 2Retina Associates of
Florida, Tampa, FL; 3Ophthalmology and VisionSciences, The
Hospital for Sick Children, Toronto, ON, Canada.
Purpose: One of the most common molecular forms of retinitis
pigmentosa (RP) is an X-linked (XL) disease caused by RPGR
mutations in the ORF15 exon. Promising treatments include
gene augmentation therapy demonstrating arrest of photoreceptor
degeneration (Beltran et al. PNAS, 2012&2015). We measured
macular photoreceptor structure and RPE disease in patients to
evaluate retinal targets for eventual gene therapy trials.
Methods: We characterized RPGR-ORF15 patients (n=39, ages
10-51) with SD-OCT, autofluorescence, BCVA and foveal
sensitivities.
Results: Refractions tended to be myopic (range -14D to +3D,
median=-4D). 76% of patients had a BCVA of 20/32 or lower
(range 20/20 to LP). Across the macula, there was a spectrum of
disease severity and abnormalities were distributed across a range of
spatial patterns. All eyes had abnormal macular structure by OCT. In
32 eyes, a detectable EZ layer extended only to 1.1° on average from
the fovea along the horizontal and vertical meridians. Many eyes
demonstrated a partial or complete parafoveal degeneration. In the
perifovea, the majority of eyes showed no detectable EZ layer. In a
few cases, EZ layer could be measured perifoveally, with a tendency
of superior over inferior structural retention, which was also apparent
on autofluorescence imaging. Foveal structure was an excellent
predictor of foveal function. Macular imaging results were consistent
with the hypothesis that RPGR-ORF15 disease showed a progressive
spatio-temporal time course that could be described by the sum of
central and peripheral components, each with a different natural
history. Central disease would start parafoveally, encircle the fovea
and annular fronts would expand centrifugally and centripetally.
Peripheral disease would either start as a midperipheral annulus and
expand centripetally towards the macula, or start in the inferior retina
with a disease front sweeping across the macula from inferior to
superior retina.
Conclusions: In most ORF15 patients, the EZ layer is either
nondetectable or limited to the foveal region. Structural and
functional measures suggest fragile maculas are not targets of
experimental subretinal therapies. Future studies will evaluate
extramacular regions in search of retained rods and cones that could
be targeted with subretinal gene therapy.
Commercial Relationships: Jason Charng; Malgorzata Swider,
None; Rebecca Sheplock, None; Alexander Sumaroka, None;
Alejandro J. Roman, None; Marc C. Peden, None; Elise Heon,
None; Sharon B. Schwartz, None; Samuel G. Jacobson, AGTC (F),
AGTC (P); Artur V. Cideciyan, AGTC (F), AGTC (P)
Support: AGTC, The Chatlos Foundation, Inc., FFB, RPB.
Retinitis pigmentosa or severe hydroychloroquine retinopathy?
Michael Marmor1, 2. 1Byers Eye Institute, Palo Alto, CA;
2
Ophthalmology, Stanford University School of Medicine, Stanford,
CA.
Purpose: Late and severe hydroxychloroquine (HCQ) retinopathy
is known to mimic retinitis pigmentosa (RP) with diffuse retinal
degeneration and reduced full-field ERG. A series of patients
with high HCQ exposure and ERG changes compatible with RP
or cone-rod dystrophy is analyzed to seek factors that can help to
differentiate.
Methods: Records from 11 patients having long or excessive
exposure to HCQ were reviewed and compared. Nearly half were
of Asian origin. Clinical evaluations had raised the possibility of
underlying or concomitant dystrophy. All had ERG recordings with
significant amplitude reduction and marked delay in cone implicit
time. All had SD-OCT, and most had Goldmann fields (GVF) and/or
wide-field autofluorescence (FAF) images.
Results: None cited early visual symptoms or gave a family history.
ERG loss was sometimes severe, but most showed similar cone and
rod involvement. Retinal degeneration was most often pericentral,
but extended beyond the arcades with varying degrees of diffuse
peripheral damage (but no bone-spicule pigmentation). SD-OCT
was rarely useful since signs of parafoveal damage were obscured
by degeneration across the macula. Peripheral field (GVF) was more
preserved than might be expected from the ERG, and superior loss
sometimes extended down to the disk. FAF showed less peripheral
RPE loss than usual with RP and only one case showed a perifoveal
glow ring.
Conclusions: One case seemed typical of RP, although concomitant
HCQ toxicity could not be ruled out. Others showed atypical findings
such as cone>rod ERG loss, distinct pericentral degeneration,
surprising preservation of peripheral field and sometimes a distinct
incursion of superior field loss (inferior retinal degeneration) upon
the disk (which may be a useful sign). Dystrophy might in theory
predispose to toxic damage, but pericentral RP is rare and not likely
to explain all of these cases. The prevalence in Asian patients may
reflect the fact that toxicity in Asians often begins pericentrally, and
early damage may have been missed with parafoveal screening.
These cases suggest that most patients with severe late HCQ exposure
will show clues that implicate toxicity over dystrophy. Genetic testing
could resolve this ambiguity, but at present the positive yield is too
low. Occam’s razor favors one disease unless evidence for more is
definitive.
Commercial Relationships: Michael Marmor, None
Clinical presentation and management of Familial Exudative
Vitreoretinopathy
Ismaël Chehaibou, Ana Clément, Florence Metge, Catherine Edelson,
Aude Affortit, Pascal Dureau, Georges Caputo. 75019 Paris - France,
Fondation Ophtalmologique Adolphe De Rothschild, Paris, France.
Purpose: To report the clinical characteristics and surgical outcomes
of patients with familial exudative vitreoretinopathy (FEVR).
Methods: Retrospective interventional case series of patients
with FEVR. Data were collected from patient charts including
demographic features, clinical and angiographic findings, initial
and final best visual acuity. Depending on the severity of disease,
patients were treated either with peripheral laser photocoagulation,
cryotherapy or surgery (vitrectomy and/or scleral buckling). Inclusion
criteria included clinical diagnosis of FEVR. Primaries outcomes
were anatomic features: status of the macula and extent of retinal
detachment. The secondary outcome was the visual acuity.
Results: We included 85 eyes of 44 patients. Patients were
male predominant (68%) and the average age at presentation was
6,96 +/- 7,88 years (range 1month – 42 years). Stage 1 FEVR
was identified in 13 eyes (15%), stage 2 in 17 eyes (20%), stage
3 in 5 eyes (6%), stage 4 in 34 eyes (40%) and stage 5 in 16 eyes
(19%). Eighteen eyes didn’t require any treatment. Thirty three eyes
were treated only by peripheral laser coagulation or cryotherapy.
In this group the macula was attached in 25 eyes (75%) without
requiring further intervention. Thirty-four eyes underwent surgery:
15 vitrectomies, 18 vitrectomies and scleral buckling and 1 scleral
buckling alone. In this group, at the last examination, the macula was
completely attached in 16 eyes (47%). Visual acuity was assessable
for 30 eyes and it increased in 11 eyes (37%), remained stable in 15
eyes (50%) and decreased in 4 eyes (13%). Overall, among the 65
eyes with evaluable visual acuities, 25 eyes (38%) achieved Snellen
acuities of at least 20/100 and in two eyes acuities dropped to no light
perception.
Conclusions: Early diagnosis, based on wide-field fundus
examination with fluorescein angiography and prompt structured
management are beneficial in patients with FEVR. Peripheral laser
photocoagulation prevents from poor evolution in early stages and
contributes to reduce extraretinal vascularization and subretinal
exudate before surgery in selected cases of retinal detachment.
In advanced stages, surgical management improves the retinal
reattachment rate and allows preservation of functional visual acuity.
Commercial Relationships: Ismaël Chehaibou, None;
Ana Clément, None; Florence Metge, None; Catherine Edelson,
None; Aude Affortit, None; Pascal Dureau, None;
Georges Caputo, None
Clinical presentation and disease course in Choroideremia
patients
Raffaella Colucci, Rosa Boccia, Valentina Di Iorio, Ada Orrico,
Paolo Melillo, Settimio Rossi, Michele Della Corte, Francesco Testa,
Francesca Simonelli. Eye Clinic, Multidisciplinary Department of
Medical, Surgical and Dental Sciences, Second University of Naples,
Naples, Italy.
Purpose: To report the disease progression in patients with clinical
and genetic diagnosis of Choroideremia (CHM) over a long-term
follow-up.
Methods: A retrospective longitudinal study was performed in 30
subjects. Medical charts of the baseline and follow-up visits were
reviewed to extract the following ocular findings: Best-Corrected
Visual Acuity (BCVA), fundus examination, Goldmann Visual Field
(GVF), Optical Coherence Tomography (OCT), Microperimetry
(MP1) and standard full-field Electroretinogram (ERG). Baseline data
are presented as mean ± standard error of the mean. For the statistical
regression analysis, BCVA was converted in LogMAR. Repeated
measure regression models based on GEE were adopted to analyze
the change of the clinical variables over follow-up. A p-value less
than 5% was considered statistically significant. The study adhered
to the tenets of the Declaration of Helsinki and received approval by
the Local Ethics Committee. Moreover, each patient gave written
informed consent.
Results: The mean age at baseline was 34.7 ± 3.1 years (range:
7-65 years). The mean visual acuity (at first visit) in the cohort was
0.6 ± 0.2 LogMar in both eyes. Moreover, all the patients showed a
constricted GVF (mean: 4758 ± 1603°2 in right eyes; 5105 ± 1615°2
in left eyes). Dark-adapted ERG responses were below the noise level
in all the patients, while light-adapted ERG responses were detectable
in 8 patients, even if with a marked reduction of amplitude.
The patients were followed up for a mean time period of 6.7 years.
The analysis showed a significant reduction of BCVA with a mean
rate of 0.038 LogMar (about 2 ETDRS letters) per year (p<0.001),
associated with a decrease of GVF area with a mean exponential rate
of 6.4% per year (p<0.001), and of MS with a mean exponential rate
of 4.3% per year (p<0.001). Finally, the Mean Macular Thickness
significantly decreased with a mean exponential rate of 0.9% per year
(p=0.009).
Conclusions: Our longitudinal analysis showed a progressive decline
of visual functionality, although slow. Moreover, the function loss
was associated with progression of retinal degeneration, detectable
by OCT. Our longitudinal data about the natural disease course could
be helpful to identify patients most amenable for gene therapy and to
show efficacy in open label clinical trials.
Commercial Relationships: Raffaella Colucci, None; Rosa Boccia,
None; Valentina Di Iorio, None; Ada Orrico, None; Paolo Melillo,
None; Settimio Rossi, None; Michele Della Corte, None;
Francesco Testa, None; Francesca Simonelli, None
Extramacular fibrosis in Coats’ disease
Alejandra Daruich, Alexandre Matet, Marie-Claire Gaillard,
Hoai Viet Tran, Francis L. Munier. Department of ophthalmology,
University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile
des Aveugles, Lausanne, Switzerland.
Purpose: In Coats’ disease, the terms “vitreoretinal fibrosis”,
“proliferative vitreoretinopathy” or “fibrotic vitreoretinopathy have
been used to report extramacular fibrosis, a late complication that has
been so far poorly characterized but can lead to progressive tractional
detachment of the retina and ciliary body. The aim of this study
was to determine the rate, risk factors and outcome of extramacular
fibrosis in Coats’ disease.
Methods: Consecutive cases from a single center were
retrospectively reviewed. Clinical characteristics and treatments were
analyzed by comparative, multivariate and survival approaches.
Results: Among 69 patients with Coats’ disease, 28 (40.6%) showed
evidence of extramacular fibrosis (mean follow-up: 58.2 months).
Mean time of fibrosis onset was 17.4 months. Extent of retinal
exudation and rate of exudative retinal detachment at baseline were
significantly higher in eyes that developed extramacular fibrosis
compared to those that did not (P <0.001). Similarly, these parameters
showed significant differences using multivariate (p< 0.05) and
survival analysis (p<0.001). Extension of telangiectasia, number
of cryotherapy or laser sessions, and treatment by anti-VEGF were
not associated with extramacular fibrosis. Final visual acuity was
worse in patients with extramacular fibrosis (p<0.001). The rates
of tractional retinal detachment and macular fibrosis were higher in
patients with extramacular fibrosis (39.0% versus 0% and 60.7%
versus 19.5%, respectively, p<0.001).
Conclusions: Extramacular fibrosis led to a worse visual prognosis
and was associated with the extent of retinal exudation and the
presence of exudative retinal detachment at diagnosis. Treatment
should target a quick resolution of exudation to limit its development.
Commercial Relationships: Alejandra Daruich, None;
Alexandre Matet, None; Marie-Claire Gaillard, None; Hoai
Viet Tran, None; Francis L. Munier, None
Targeting retinal degeneration in ABCr -/- mice with dietary
saffron
Stefano Di Marco1, Darin Zerti1, Rita Maccarone1,
Benedetto Falsini2, Silvia Bisti1. 1DISCAB, University of L’Aquila,
L'Aquila, Italy; 2Ophthalmology, Catholic University, Rome, Italy.
Purpose: Stargardt disease/fundus flavimaculatus (STD/FF) retinal
dystrophy is thought to develop through oxidative damage as a
consequence of ABCA4 gene mutation. Recent findings indicate
that Saffron and its components may exert neuroprotection by
counteracting retinal oxidative damage. The aim of this study was to
investigate the effect of saffron supplementation on retinal function
and morphology in an animal model of STG/FF.
Methods: We analyzed ABCr -/- mice at three different time points: 2,
5 and 12 months of age in a) ABCr -/-Control group b) ABCr -/- treated
with saffron from birth. In addition, to speedup the apoptotic process
and to evaluate the effects of saffron on different severity stages of
the pathology, we exposed to bright continuous light (BCL), 3000
lux for 72 hours at 2, 5 and 12 months of age c) ABCr -/- untreated
animals and d) ABCr -/- treated with saffron from birth. To evaluate
retinal functionality, we recorded ERG responses from all groups. To
assess morphology we estimated the expression of Fibroblast growth
factor receptor 2, Glial fibrillary acidic protein (GFAP), apoptotic
cells by mean of TUNEL staining, activation of microglia by mean of
IBA-1 staining and lipofuscine deposits.
Results: ERG recordings: amplitude of both a- and b-waves are
significantly higher in both Control-treated and BCL-treated with
respect to untreated groups at all the tested time points. Neuronal
death, microglia activation, reactive gliosis and lipofuscine deposits
are reduced by saffron treatment in both experimental treated
groups while FGF expression is not modulated by saffron treatment
remaining high throughout the entire lifespan of ABCr -/- mice.
Conclusions: Saffron treatment preserves both morphology and
function in ABCr -/- mice suggesting the possibility to be used as
treatment for STD/FF.
Commercial Relationships: Stefano Di Marco, None; Darin Zerti,
None; Rita Maccarone, Hortus Novus (S); Benedetto Falsini;
Silvia Bisti, Hortus Novus (S)
Support: THELETHON GGP10149
Purpose: To evaluate the patterns and distribution of ocular
angiogenic complications in patients with inherited retinal
degenerations.
Methods: A clinic-based database composed of patients clinically
diagnosed as inherited retinal degenerations was reviewed and
those complicated with angiogenic changes including choroidal
neovascularization (CNV), non-CNV related macular edema (ME),
exudative retinal detachment (ERD) and retinal vasculitis-like
changes were further analyzed for fundus photography, spectrum
domain optical coherence tomography (SD-OCT) and fluorescein
angiography (FA).
Results: Totally 207 cases clinically dignosed as multiple types of
inherited retinal degenerations were included in our database, 47
patients were found to have angiogenic complications. CNV was
shown predominantly in patients with Bietti crystalline dystrophy
(BCD, 11 eyes, 8 out of 32 patients) and vitelliform macular
dystrophy (VMD, 5 eyes, 4 out of 18 patients). Non-CNV related ME
was presented in patients with BCD (24 eyes of 14 patients), VMD
(7 eyes of 4 patients), retinitis pigmentosa (RP, 17 eyes, 12 out of 50
patients), and more rarely cone dystrophy (CD, 1 eye of 1 patient).
Apart from attenuation of retinal vessels, novel vascular changes in
the peripheral retina, including vasculitis-like damages, ERD and
retinal neovascularization were also observed in patients with RP (7
eyes of 4 patients) and pigmented paravenous chorioretinal atrophy
(PPCRA, 1 eye, 1 patient out of 6 patients).
Conclusions: Various types of angiogenic pathology were displayed
in a considerable number of retinal dystrophic diseases. CNV is
a rather common complication among the patients with BCD and
VMD, cautions should be taken for further therapeutic process.
Occurrence of non-CNV related ME is more frequently seen
among cases with BCD, VMD and RP, while appeared as a novel
alteration in cases with CD. Other angiogenic complications such
as retinal vasculitis, ERD and peripheral retinal neovascularization
were also exhibited in individuals with RP as well as PPCRA, and
corresponding medical or surgical treatments should be warranted to
prevent further visual loss.
Angiogenic Complications Exhibited in Patients with Inherited
Retinal Degenerations
Qian LI1, 2, Xiaoyan Peng3, 1, Yang Li3, Xiaoqing Zhu1.
1
Ophthalmology, Beijing Tongren Eye Center, Beijing, China;
2
National Eye Institute, Bethesda, MD; 3Beijing Institute of
Ophthalmology, Beijing, China.
A patient genetically diagnosed as cone dystrophy was found to have
significant macular edema.
A patient with RP showed vasculitis changes by FFA and ERD by
SD-OCT.
Commercial Relationships: Qian LI, None; Xiaoyan Peng, None;
Yang Li, None; Xiaoqing Zhu, None
Support: Beijing Municipal Administration of Hospitals' Youth
Programm (QML20150205)
Progression of macular atrophy in pattern dystrophies
Céline Mebsout Pallado1, Anne Sikorav1, Oudy Semoun1,
Camille JUNG2, Eric H. Souied1. 1Department of Ophthalmology,
Centre Hospitalier Intercommunal de Creteil, Creteil, France, Paris,
France; 2Centre de Recherche Clinique – Centre de Ressources
Biologiques, Centre Hospitalier Intercommunal de Creteil, Creteil,
France.
Purpose: To quantify the progression of macular atrophy associated
with pattern dystrophies using a novel fundus autofluorescence semiautomated software and to analyze demographical and clinical data.
Methods: Patients diagnosed with pattern dystrophy followed in the
retina department of a single academic medical center during at least
2 years were included in this retrospective, observational study if they
had macular atrophy. Best-corrected visual acuity (BCVA), fundus
photographs, infrared reflectance, fundus autofluorescence (FAF)
imaging, and spectral-domain optical coherence tomography were
routinely performed associated with fluorescein and indocyanine
green angiographies when necessary. The progression of macular
atrophy areas was evaluated on FAF frames using Region Finder
Analyser®, a semi automated software embedded in Spectralis
device.
Results: We included 19 eyes of 12 patients. The median follow-up
was 4.5 years [Interquartile Range IQR 2.7 – 5.5]. 15.8% of affected
eyes (3/19) presented with choroidal neovascularization. Median
initial BCVA was 0.2 logMAR [IQR 0.05 – 0.4]. Median final BCVA
was 0.2 logMAR [IQR 0.1-0.4]. Decreased vision occurred in 15.8%
of cases (3/19). Atrophy involved foveal area in 68.4% of cases.
The median atrophy progression rate evaluated by Region Finder
Analyser® was 0.101mm2/year [IQR 0.054 – 0.257]. The median
initial atrophy area was 0.294mm2 [IQR 0.18 – 0.398], and the
median final atrophy area was 0.844 [IQR 0.06 – 1.4].
Conclusions: The progression of macular atrophy in pattern
dystrophies appears to be slow compared to age-related macular
degeneration. Visual acuity is usually preserved in most of cases.
Nevertheless, some patients had more severe forms in our study, with
choroidal neovascularization or large atrophy. Further studies are
necessary to confirm this trend and to correlate the progression of
atrophy in pattern dystrophies with genetic data.
Commercial Relationships: Céline Mebsout Pallado, None;
Anne Sikorav, None; Oudy Semoun, None; Camille JUNG, None;
Eric H. Souied, None

Session 107 Retinal Degeneration

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