Download ARVO 2016 Annual Meeting Abstracts 282 Macular diseases

ARVO 2016 Annual Meeting Abstracts
282 Macular diseases/dystrophy
Monday, May 02, 2016 3:45 PM–5:30 PM
Exhibit/Poster Hall Poster Session
Program #/Board # Range: 2677–2704/C0128–C0155
Organizing Section: Retina
Program Number: 2677 Poster Board Number: C0128
Presentation Time: 3:45 PM–5:30 PM
Comparison of Microperimetry and Humphrey Perimetry for
Hydroxychloroquine Toxicity Screening
Sophia Wong, Eric Chin, Susanna S. Park. University of California
Davis, Sacramento, CA.
Purpose: Humphrey perimetry (HP) is the most widely used
functional test for hydroxychloroquine toxicity screening.
Microperimetry (MP) is an alternative that tests macular sensitivity
and correlates functional deficits with anatomical location and has
the advantage of fixation tracking. In this prospective study, we
compared Humphrey 10-2 perimetry and microperimetry in normal
subjects and those on hydroxychloroquine (HCQ) therapy to assess
their relative sensitivity.
Methods: Patients on chronic HCQ therapy for an autoimmune
condition and normal subjects were included in this study. HP
(Zeiss HFA) and MP (CenterVue MAIA) were performed in the
same visit. Tests with poor reliability (greater than 10% fixation
loss, false positives or negatives) and poor fixation stability
were excluded. Normal HP was defined as zero depressions on
the pattern deviation map. Normal MP was defined as normal
sensitivity at all test points (compared to normative data provided
by the manufacturer: average threshold greater than 26 dB and
percent reduced thresholds less than 8%).
Results: A total of 4 normal subjects (8 eyes) and 11 subjects on
HCQ (22 eyes) were enrolled. One eye from a normal subject
and 4 eyes of 3 HCQ subjects were excluded from analysis
due to unreliable testing (3 eyes with poor HP reliability and 2
eyes with poor HP reliability and poor MP fixation). Qualitative
analysis was carried out on 14 subjects (25 eyes). Among 7 eyes
(4 subjects) studied in the normal group, only 4 eyes were normal
in both HP and MP. Among 18 eyes (10 subjects) tested in the
HCQ group, 5 eyes (27.8%) showed abnormality on HP only, 8
eyes (44.4%) showed abnormality on HP and MP, and 5 (27.8%)
showed no abnormality with either method. Four eyes (2 subjects)
were diagnosed with toxic maculopathy based on concurrent
abnormality on OCT or mfERG. Among these 4 eyes diagnosed
with toxic maculopathy, 3 eyes had both abnormal HP and MP and
1 eye had abnormal HP and normal MP.
Conclusions: In this small pilot exploratory study, we note that
MP with fixation tracking may provide a more reliable method
of testing macular function. However, results on HP and MP may
not be interchangeable as abnormalities noted with one method
were not always reproduced with the other method. Further study
with a larger sample is needed to determine the relative sensitivity
and specificity of HP versus MP in diagnosing toxic maculopathy
secondary to HCQ use.
Commercial Relationships: Sophia Wong, None; Eric Chin;
Susanna S. Park, None
Program Number: 2678 Poster Board Number: C0129
Presentation Time: 3:45 PM–5:30 PM
Exacerbation of Macular Edema Associated with Hyperbaric
Oxygen Therapy
Stephen M. Hypes1, 2, Ashkan Abbey3, 4, Yoshihiro Yonekawa3, 4,
Jeremy D. Wolfe3, 4. 1Neurology & Ophthalmology, Michigan State
University COM, Dearborn, MI; 2Ophthalmology, Beaumont Health
- Southshore Campus, Trenton, MI; 3Associated Retina Consultants,
Royal Oak, MI; 4Ophthalmology, William Beaumont Hospital, Royal
Oak, MI.
Purpose: Hyperbaric oxygen therapy (HBOT) is being marketed as
a treatment for retinovascular diseases without scientific evidence.
HBOT has been shown to increase VEGF levels in tissues; therefore,
we hypothesize HBOT may in fact worsen the vascular permeability
of diseased retinal vasculature. We report a patient who developed
an abnormally acute and diffuse macular edema from a preexisting
retinal arterial macroaneurysm (RAM) following HBOT.
Methods: Retrospective clinical analysis of visual acuity (VA),
spectral domain optical coherence tomography (SD-OCT), and
fluorescein angiography (FA) before and after administration of
HBOT in a 71-year-old woman with a preexisting RAM.
Results: The patient presented with acute onset of blurry vision
OS. BCVA was 20/200, and examination revealed submacular
hemorrhage OS and a new RAM as seen on FA. The patient
underwent vitrectomy with subretinal tissue plasminogen activator
and pneumatic displacement. VA improved to 20/150 one week
after surgery. One week post-operative SD-OCT showed trace
residual subretinal fluid, and no intraretinal edema. In the following
weeks, the patient underwent 7 consecutive sessions of HBOT. At
post-operative week 5, VA OS had decreased to 20/200 and a new,
acute, diffuse, and severe macular edema was noted. Fluorescein
angiography demonstrated increased leakage from the RAM
and surrounding angiopathic vessels. The patient was directed to
discontinue HBOT, and the edema quickly resolved with intravitreal
ranibizumab treatment.
Conclusions: HBOT may exacerbate macular edema from
retinovascular diseases. We recommend that retinovascular disease
not be listed as an indication, but as a relative contraindication for
HBOT, until proven otherwise.
Commercial Relationships: Stephen M. Hypes, None;
Ashkan Abbey, None; Yoshihiro Yonekawa, None;
Jeremy D. Wolfe, None
Program Number: 2679 Poster Board Number: C0130
Presentation Time: 3:45 PM–5:30 PM
Drusen-like deposits in young adults affected by Systemic Lupus
Erythematosus
Alessandro Invernizzi1, 2, Laura Dell’Arti1, Elena Garoli1,
Gaia Leone1, Daniela Galimberti1, Alessandro Santaniello3,
Gabriella Moroni4, Francesco Viola1. 1Department of Clinical
Sciences and Community Health, University of Milan,
Ophthalmological Unit, IRCCS-Cà Granda Foundation – Ospedale
Maggiore Policlinico, Milan, Italy; 2Department of Biomedical
and Clinical Science - University of Milan, Eye Clinic - Luigi
Sacco Hospital, Milan, Italy; 3Department of Clinical Sciences
and Community Health, University of Milan, Immunology Unit,
IRCCS-Cà Granda Foundation – Ospedale Maggiore Policlinico,
Milan, Italy; 4Department of Clinical Sciences and Community
Health, University of Milan, Nephrology Unit, IRCCS-Cà Granda
Foundation – Ospedale Maggiore Policlinico, Milan, Italy.
Purpose: To assess the prevalence of drusen-like deposits in eyes
of patients affected by Systemic Lupus Erythematosus (SLE) by
the use of a non invasive multimodal imaging approach, to study
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ARVO 2016 Annual Meeting Abstracts
their size and distribution throughout the fundus and to find possible
correlations between these alterations and systemic involvement.
Methods: 60 consecutive emmetropic eyes from 60 subjects
affected by SLE under 55 years of age, without visual symptoms,
and 60 emmetropic eyes from 60 healthy volunteers age and sex
matched were enrolled into the study. SLE patients medical history
was recorded with particular attention to the presence of SLE
American Rheumatology Association diagnostic criteria (ARA). All
the included eyes underwent a complete ocular examination and a
non invasive multi-imaging assessment including: spectral domain
optical coherence tomography (SD-OCT), infrared (IR), fundus
autofluorescence (FAF), red-free (RF) and fundus photography
(FP). The prevalence, distribution and size (small<63 microns,
medium=63-125, large>125) of drusen-like deposits identified by
each imaging technique were analyzed in both patients and controls.
Correlations between ARA criteria and funduscopic alterations
characteristics were studied.
Results: Drusen-like deposits were identified in 41.6% of SLE eyes
and in 3% of controls resulting in a statistically significant difference
(p<0.001) between the two groups. In SLE patients showing drusenlike defects small, medium and large deposits were present in 70.8%,
50% and 41,6% of the eyes respectively. Most involved posterior
pole quadrants were temporal (78%) and nasal (72%). Superior and
inferior areas were involved in 44% and 48% of cases respectively
whereas central field showed the lowest lesions prevalence (24%).
No significant correlations were found between the presence of
drusen-like deposits and any of the eleven ARA criteria. On the other
hand, large deposits and a wider distribution of the lesions (more
than 3 quadrants involved) correlated with the presence of SLE
glomerulonephritis (p=0.03 and p=0.02 respectively).
SD-OCT showed the highest sensitivity (96%) in detecting drusenlike deposits as compared to the other imaging techniques performed
in the study.
Conclusions: SLE correlates with the presence of drusen-like
deposits in young adults. SLE glomerulonephritis correlates with
deposits size and distribution.
Commercial Relationships: Alessandro Invernizzi;
Laura Dell'Arti, None; Elena Garoli, None; Gaia Leone, None;
Daniela Galimberti, None; Alessandro Santaniello, None;
Gabriella Moroni, None; Francesco Viola, None
Program Number: 2680 Poster Board Number: C0131
Presentation Time: 3:45 PM–5:30 PM
Macular function assessment with microperimetry in patients
with macular dystrophy
Jung Lo, Jong-Jer Lee, Wei-Yu Chiang,
Hsi-Kung Kuo, Pei-Chang Wu. Ophthalmology, Kaohsiung Chang
Gung Memorial Hospital, Taiwan, Kaohsiung, Taiwan.
Purpose: The shift of fixation in patient with macular degeneration
may impair visual acuity (VA) and daily life. The aim of this study
is to assess correlation between fixation shift in microperimetry and
visual function in patients with macular dystrophy (MD).
Methods: Nineteen patients (age 24-76, mean 56.7 ± 12.2 years)
with MD, including 14 females and 5 males, were enrolled in this
retrospective study. One eye from each patient with a better VA was
analyzed. Fixation shift (FS), defined as the direction and distance
between location of fovea and preferred retinal locus (PRL), was
determined by superposition of images of microperimetry-1 (MP-1)
and spectral domain optical coherence tomography (SD-OCT). The
alignment of MP-1 and SD-OCT images based on vascular landmarks
was conducted with Photoshop. Pearson’s correlation test (r) was
used for analyzing the correlations of parameters.
Results: The mean sensitivity (MS) in MP-1 was 8.94 ± 6.18 dB,
and the best corrected visual acuity (BCVA) ranged from 20/800
to 20/20. FS was observed in 14 (73.7%) patients, mostly to the
supero-nasal quadrant of macula (11/14, 78.5%), and two patients
presenting inferior FS had low percentage of fixation points within 2
degree in MP-1 (32 - 33%) and poor BCVA (20/800 - 20/200). Five
eyes without FS presented BCVA 20/25 to 20/20 while MS ranging
from 1.4 to 17.8 dB. The mean distance of FS was 1080 ± 818
micrometers in patient with FS. The distance of FS was correlated
to the logarithm of the minimum angle of resolution (logMAR) VA
(r = 0.765, P = 0.001), and the percentage of fixation points within
2 degree in MP-1 (r = -0.586, P = 0.027), but not correlated to MS
in MP-1 (r = -0.151, P = 0.606). The percentage of fixation location
in MP-1 was correlated to the distance of FS (r = -0.521, P = 0.022),
and the central macular thickness in SD-OCT (r = 0.673, P= 0.008).
Superimposed fovea and PRL was observed if the ellipsoid zone in
fovea was spared without complete degeneration in SD-OCT.
Conclusions: The presenting VA is correlated to FS in MD patients.
The MS in MP-1 may be reduced before VA and FS deteriorates
when MD progresses, and the percentage of fixation location in MP-1
significantly correlates with FS. When compared to VA and SD-OCT,
MP-1 could be more sensitive to macular dysfunction when fovea is
preserved anatomically, and suitable for early detection of the disease
progression.
Commercial Relationships: Jung Lo, None; Jong-Jer Lee, None;
Wei-Yu Chiang, None; Hsi-Kung Kuo, None; Pei-Chang Wu,
None
Program Number: 2681 Poster Board Number: C0132
Presentation Time: 3:45 PM–5:30 PM
Risk factors of the antimalarial drug’s maculopathy:
retrospective study in 3580 patients’ cohort
Clémentine David2, Christine Fardeau2, Claude Simon1,
Bahram Bodaghi2, Phuc Lehoang2, Juliette Knoeri2,
Benedicte Lebrun-vignes3. 1Fédération Electrophysiologie, Hôpital
Pitié-Salpétrière, Université Paris VI, Paris, PARIS, France; 2Service
d’Ophtalmologie, Centre de Référence en Maladies Rares, Hôpital
Ptié-Salpétrière, Université Paris VI, DHU Vision et Handicap,
PARIS, France; 3Department Pharmacovigilance, Hôpital PitiéSalpétrière, University Paris VI, Paris., PARIS, France.
Purpose: Antimalarial drug are widely prescribed to treat systemic
lupus erythematosus, rheumatoid arthritis and other connective tissue
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ARVO 2016 Annual Meeting Abstracts
disease, and also for the antimalarial prevention. The incidence of
the maculopathy is about 1% to 5 years. The main risk factor is
the cumulative dose. The daily overdose has also been involved.
Some risk factor are conventionally referred, including: age over 60
years, renal or hepatic failure, high body mass index (BMI), and a
preexisting retinopathy. The objective of this study is to analyze the
statistical value of theses classical risk factors.
Methods: This retrospective study was realized from 1.01.2009 to
1.01.2013, in cohort of 3580 patients treated by antimalarial drug.
The diagnostic of toxic maculopathy was retained if at least two
exams among ocular fundus, macular autofluorescence, central
visual field, sd optical tomography, and multifocal electrophysiology,
showed compatible signs with the diagnosis. Correlations with the
molecule’s nature, and classical risk factors were analyzed.
Results: 55 patients had a toxic maculopathy after a treatment period
from 3 to 20 years. The cumulative dose differed statistically between
chloroquine (CQ) (633±198 grams) and hydroxychloroquine (HCQ)
(1681±413 grams, p=0.02). Daily overdose has been found for 2
patients with HCQ and one patient with CQ. High BMI has been
found for 3 patients(OR = 1,1). 4 patients had an elevated serum
creatinine, 2 patients had elevated serum transaminases(OR = 1,5).
3 patients had a preexisting retinopathy(OR = 1,4). Monitoring for 2
years didn’t showed a poor outcome for theses 3 patients.
Conclusions: Two thirds of the patients exhibiting a toxic
maculopathy didn’t have any classical risk factors. The presence of a
preexisting retinopathy, that can interfere with early diagnosis, didn’t
appear like an evolving risk factor.
Commercial Relationships: Clémentine David, None;
Christine Fardeau, None; Claude Simon, None; Bahram Bodaghi;
Phuc Lehoang, None; Juliette Knoeri, None; Benedicte Lebrunvignes, None
Program Number: 2682 Poster Board Number: C0133
Presentation Time: 3:45 PM–5:30 PM
Comparing macula thickness between sickle cell patients of HbSS
and HbSC genotype using spectral domain optical coherence
tomography
Wei Sing Lim1, Juliana Helou2, Tejal Magan2, Moin Mohamed2.
1
Ophthalmology, Princess Royal University Hospital, London, United
Kingdom; 2St Thomas Hospital, London, United Kingdom.
Purpose: HbSS patients have less severe proliferative retinopathy
but more severe systemic complications compared to HbSC patients.
We previously shown mean macula thickness to be lower in HbSS
patients compared to HbSC patients based on a small cohort of 41
eyes. We have extended the study here to include 380 eyes to confirm
if there is a real difference in macula thickness between HbSS and
HBSC patients.
Methods: A list of HbSC and HbSS patients seen in the eye clinic
at St Thomas Hospital was generated. 197 HbSC eyes and 183
HbSS eyes from 204 patients were included. Eyes with other ocular
pathologies that affected macula thickness were excluded. The
latest macula OCT were retrospectively analysed. Macula thickness
were recorded in all subfields of the ‘early treatment of diabetic
retinopathy study ‘ (ETDRS) grid for both right and left eyes. The
thickness measured were compared between HbSS and HbSC eyes.
99 HbSC right eyes were compared with 90 HbSS right eyes. 98
HBSC left eyes were compared with 93 HbSS left eyes. Analysis of
right and left eyes were not combined. Unpaired t-test was used to
verify the significance of the results.
Results: The mean age (SD) was 42 (13) and 36(11) for HbSC and
HBSS patients respectively. Macula thickness was lower in HBSS
eyes compared to HbSC eyes in all subfields of the EDTRS grid but
only reached significance at p value of <0.05 in the outer temporal
subfields. This statistically significant difference was found in both
right and left eyes. The mean outer temporal macula thickness (SD)
was 240 (23) microns in HbSC right eyes compared with 231 (26)
microns in HbSS right eyes and 242 (21) microns in HbSC left eyes
compared with 234 (26) microns in HbSS left eyes. Table 1 and
2 compared the macula thickness of all the other subfields on the
EDTRS grid.
Conclusions: HbSS eyes have thinner outer temporal macula
compared to HbSC eyes. This is likely due to greater retinal
ischaemia caused by sickling in HbSS eyes compared to HbSC eyes.
This is in contrast to more advanced proliferative sickle retinopathy
in HBSC eyes compared to HBSS shown in other studies.
Table 1 Macula thickness of HbSC and HbSS right eyes in all
subfields of the ETDRS grid
Table 2 Macula thickness of HbSC and HbSS left eyes in all subfields
of the ETDRS grid
Commercial Relationships: Wei Sing Lim, None; Juliana Helou,
None; Tejal Magan, None; Moin Mohamed, None
Program Number: 2683 Poster Board Number: C0134
Presentation Time: 3:45 PM–5:30 PM
Mapping metamorphopsia and central visual field loss in macular
disease patients
Niall C. Strang1, David B. Yorston2, McGowan Gerard5,
David Thomson4, Milena Mihaylova3. 1Life Sciences, Glasgow
Caledonian University, Glasgow, United Kingdom; 2Gartnavel
Hospital, Glasgow, United Kingdom; 3Sensory Neurobiology,
Institute of Neurobiology, Sofia, Bulgaria; 4City University, London,
United Kingdom; 5Ophthalmology, University Hospital Ayr, Ayr,
United Kingdom.
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ARVO 2016 Annual Meeting Abstracts
Purpose: The card version of D-Charts are effective at mapping
changes in metamorphopsia pre- and post-surgery within the central
visual field in patients with macular disease. Recently a software
version of the D-Charts has been developed to reduce recording time.
Here we measure metamorphopsia and central field loss using the
software version of the D-Chart and compare the results with the
Amsler chart. Furthermore we use the D-Charts to monitor changes
in the central visual field that occur during anti-VEGF treatment.
Methods: The D-Charts use octagonal grids, divided into eight
sectors, formed by black elements (squares) of various densities.
The grids are at varying eccentricities between 0.5 and 12 degrees
from fixation. Subjects fixate the centre of the D-charts and touch
the screen in the distorted sector. The metamorphopsia score (the
maximal element separation which produced distortion or field
loss) is determined for each ring and sector. The results provide
two dimensional maps of metamorphopsia severity and visual loss.
Twenty fully corrected subjects with macular disease were tested
using the software version of the D-Chart and the Amsler chart. In
the second part of the study a further seven subjects were measured
during a period of anti-VEGF treatment to examine changes in
central field occurring during treatment.
Results: The total metamorphopsia score (MTotal) did not correlate
with the area of distortion reported on the Amsler chart although the
size and location of the field plots using the two charts were similar.
The D-Chart provided greater detail relating to the distribution of
distortion and field loss and recording was completed in less than 2
minutes per eye. In the second part of the study the D-Chart plots
changed in line with the predicted effects of anti-VEGF treatment.
Conclusions: The increased information provided by the D-Chart
makes comparison with Amsler chart results difficult although
the size and location of the field plots were consistent. The
software version of the D-Chart is easy to use and maps changes in
metamorphopsia and central field loss that occur in patients with
macular disease.
Commercial Relationships: Niall C. Strang, None;
David B. Yorston, None; McGowan Gerard, None;
David Thomson, Thomson Software Solutions; Milena Mihaylova,
None
Program Number: 2684 Poster Board Number: C0135
Presentation Time: 3:45 PM–5:30 PM
Clinical and genetic study of late onset Stargardt disease
Ada Orrico, Paolo Melillo, Valentina Di Iorio, 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 provide a detailed phenotype characterization of late
onset Stargardt disease (STGD1) compared to the juvenile form.
Methods: We reviewed the medical charts of STGD1 patients, who
underwent best-corrected visual acuity (BCVA), fundus photography,
optical coherence tomography, full-field electroretinography, and
microperimetry. Statistical analysis of onset age was done to identify
a cut-off to discriminate between typical juvenile and late onset
forms. Regression models were fitted in order to evaluate the disease
progression. The study adhered to the tenets of the Declaration of
Helsinki and received approval by the Local Ethics Committee.
Results: The study cohort consisted of 205 patients with clinical
diagnosis of STGD1 and mutations on both ABCA4 alleles. The
onset age showed a bimodal distribution and the cut-off between
typical juvenile and late-onset forms was estimated as 30 years.
These findings led to the identification of a group of 56 patients with
the typical juvenile onset (group A) and 20 patients with onset age
over 30 years (group B), with at least one follow-up visit. The age of
patients at baseline in group A ranged from 11 to 52 years (29.9±1.4
years), the onset age from 4 to 27 years (17.0±0.7 years) and disease
duration from 1 to 46 (11.8±1.4 years). The age of patients at baseline
in group B ranged from 38 to 71 years (48.2±1.9 years), the onset
age from 32 to 48 years (38.5±1.1 years) and disease duration from
2 to 28 years (9.7±1.5 years). No significant differences (p>0.05)
were observed in the Fishman and Lois class distribution. Disease
progression was estimated in both groups, with reference to disease
length. The BCVA decreased with a rate of 0.093 (p<0.001) and
0.019 (p=0.111) logMAR per year in group A and B, respectively.
Both groups showed a significant decrease of MS (β=-0.028, p=0.001
in group A; β=-0.037, p=0.017 in group B), whereas the fixation
stability significantly worsened in group A (β=-0.010, p=0.014),
while appeared to be stable in group B (β=-0.007, p=0.302). Genetic
analysis revealed that missense mutations (particularly G1961E) were
more frequent in group B than group A.
Conclusions: The current study accurately describes a disease form
characterized by a later onset, enabling to estimate its prevalence as
10% of STGD1 population. The late onset form was associated with
a milder clinical phenotype and, genetically, more frequent missense
mutations compared to typical juvenile STGD1.
Commercial Relationships: Ada Orrico, None; Paolo Melillo,
None; Valentina Di Iorio, None; Settimio Rossi, None;
Michele Della Corte, None; Francesco Testa, None;
Francesca Simonelli, None
Support: NEY 1R24EY019861-01A1
Program Number: 2685 Poster Board Number: C0136
Presentation Time: 3:45 PM–5:30 PM
TEASE: a phase 2 clinical trial assessing the tolerability and
effects of oral once-a-day ALK-001 on Stargardt disease
Hendrik P. Scholl1, Syed M. Shah1, Christine N. Kay2,
Stephen H. Tsang7, Kimberly E. Stepien3, Paul S. Bernstein4,
Byron L. Lam5, Michael B. Gorin6, Ilyas Washington7, Leonide Saad8.
1
Ophthalmology, Johns Hopkins University, Baltimore, MD;
2
Vitreoretinal Associates, Gainesville, FL; 3Eye Institute, Medical
College of Wisconsin, Milwaukee, WI; 4Moran Eye Center,
University of Utah, Salt Lake City, UT; 5Bascom Palmer Eye
Institute, University of Miami, Miami, FL; 6Jules Stein Eye Institute,
University of California Los Angeles, Los Angeles, CA; 7Harkness
Eye Institute, Columbia University Medical Center, New York, NY;
8
Alkeus Pharmaceuticals, Boston, MA.
Purpose: Stargardt disease (STGD1) is the leading cause of inherited
juvenile macular degeneration. The disease stems from mutations
in ABCA4, a gene that encodes a vitamin A transport protein in the
retina. Defective vitamin A transport results in accelerated formation
of vitamin A dimers, thought to cause retinal degenerations including
STGD1. The tolerability and effects of ALK-001 in Stargardt disease
(“TEASE”) study is the first of several prospective clinical trials
to test the extent to which slowing the dimerization of vitamin A
prevents the progression of STGD1.
Methods: ALK-001 is a vitamin A replacement: the chemical
structure of ALK-001 is similar to that of vitamin A but 3 hydrogen
atoms have been exchanged by deuterium. This change prevents
ALK-001 from dimerizing. However, ALK-001 keeps all known
functions of vitamin A. In preclinical evaluation, ALK-001 slows
the rate of vitamin A dimerization approximately 4 to 5 fold but
does not affect the visual cycle. TEASE is a 24-month, multicenter,
randomized, double-masked, placebo-controlled study evaluating the
effects of ALK-001 in up to 50 patients diagnosed with molecularly
confirmed STGD1 aged between 12 and 60 years. Study subjects
may have any visual acuity to enroll and must have a lesion of welldefined decreased signal on fundus autofluorescence imaging (FAF).
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ARVO 2016 Annual Meeting Abstracts
TEASE subjects are randomly assigned to receive one of two doses
of ALK-001 (30 subjects) or placebo (20 subjects) for one year. After
one year, half of the subjects receiving placebo will be randomly
crossed over to receive ALK-001 for the following 12 months, while
all other subjects will continue receiving their initial treatment. A
Data Monitoring Committee (DMC) reviews safety and efficacy data
throughout the study.
Results: Enrollment is ongoing. As of late 2015, 15 subjects have
been enrolled, with the longest treatment duration of about 3 months.
The median best corrected visual acuity at baseline was 63 letters
(range, 26-85) in the best eye. Median age was 44 years (range, 2059) and median disease duration 8 years (range, 1-25). Median lesion
size in the best eye on FAF was 1.80 mm2 (range, 0.25-17.74).
Conclusions: The TEASE study is one of the first FDA-regulated
phase 2 clinical trials assessing a novel oral compound for retinal
degenerative disease secondary to vitamin A dimerization, including
STGD1.
TEASE trial design
Commercial Relationships: Hendrik P. Scholl, None;
Syed M. Shah, None; Christine N. Kay, None; Stephen H. Tsang;
Kimberly E. Stepien, None; Paul S. Bernstein, None;
Byron L. Lam, None; Michael B. Gorin, None; Ilyas Washington,
Alkeus Pharmaceuticals (C), Alkeus Pharmaceuticals (P);
Leonide Saad, Alkeus Pharmaceuticals, Alkeus Pharmaceuticals (S)
Clinical Trial: NCT02402660
Program Number: 2686 Poster Board Number: C0137
Presentation Time: 3:45 PM–5:30 PM
Clinical and genetic characteristics of intermediate-onset
Stargardt disease
Nathalie Bax, Stanley Lambertus, Cecile van der Poort,
B. Jeroen Klevering, Frans P. Cremers, Carel C. Hoyng.
Ophthalmology, Radboud UMC, Nijmegen, Netherlands.
Purpose: To describe the phenotypic and genotypic features in
intermediate-onset Stargardt patients. We already described the
phenotypes of early- and late-onset Stargardt disease.
Methods: Eighty-three Stargardt patients with an age at onset
between 11 and 44 years. We reviewed medical records and
ophthalmologic examinations for age at onset, best corrected
visual acuity (BCVA), ophthalmoscopy, color fundus photography,
fundus autofluorescence, fluorescein angiography (FA), spectraldomain optical coherence tomography (SD-OCT), full-field
and multifocal electroretinography (ffERG and mfERG), visual
field testing and color vision testing. The ABCA4 gene had been
analysed for mutations in the protein-coding exons and flanking
intronic sequences. A subset of these cases were also analyzed for
heterozygous deletions using the MLPA technique.
Results: The mean age at onset was 21.18±8.94 years. Mean duration
of follow-up was 17.7±13.9 years. BCVA at last recorded visit was
0.93 logMAR (20/170 Snellen). Irregular yellow-white fundus flecks
were present at 91% of the patients at first visit. FA showed a dark
choroid in 17 out of 58 patients (29.3%). Forty-nine of 50 patients
with SD-OCT images showed (central) retinal pigment epithelium
loss. On ffERG at first visit in 48 patients, 44 had normal amplitudes
(91.7%). mfERG in 23 patients showed reduced or extinguished
central responses. Central visual field loss occurred in 57 out of 68
patients (83.8%). Eight of 51 patients (15.7%) tested for color vision
defects had normal color vision. Genetic screening of 143 patients
revealed ≥2 ABCA4 mutations in 109 patients, single heterozygous
mutations in 29 patients, and no mutations in four patients. The
mild variant c.2588G>C was identified in a compound heterozygous
manner in 33% of the 143 patients, most frequently in combination
with the non-canonical splice variants c.768G>T (n= 13) or c.546110T>C (n=7). Based on other studies, both were deemed to be severe
variants.
Conclusions: We show that intermediate-onset Stargardt patients
also form a distinctive group. Patients have better visual acuity
than patients with early-onset Stargardt, but show a more severe
phenotype than late-onset Stargardt patients. Visual acuity declines
progressively in 5-10 years after age at onset. Yellowish fundus flecks
are present in the majority of the patients. This phenotype is often
caused by a combination of a mild with a severe ABCA4 mutation.
Commercial Relationships: Nathalie Bax, None;
Stanley Lambertus, None; Cecile van der Poort, None;
B. Jeroen Klevering, None; Frans P. Cremers, None;
Carel C. Hoyng, None
Program Number: 2687 Poster Board Number: C0138
Presentation Time: 3:45 PM–5:30 PM
Progression of visual acuity and fundus autofluorescence in
recent onset Stargardt disease: ProgStar study
Sheila K. West1, Xiangrong Kong1, Beatriz E. Munoz1,
Artur V. Cideciyan2, Michel Michaelides3, Ann-Margret Ervin4,
Srinivas R. Sadda5, 6, Hendrik P. Scholl1. 1Medicine, Johns Hopkins
Wilmer Eye Inst, Baltimore, MD; 2Ophthalmology, Scheie Eye
Institute, U Penn, Philadelphia, PA; 3Moorfields Eye Hospital,
University of London, London, United Kingdom; 4Bloomberg School
of Public Health, Johns Hopkins University, Baltimore, MD; 5Doheny
Eye Institute, Los Angeles, CA; 6David Geffen School of Medcine,
UCLA, Los Angeles, CA.
Purpose: The progression rates for functional loss (visual acuity,
VA) and structural change (fundus autofluorescence, AF) in Stargardt
patients appear to vary by the degree of loss at presentation. Amongst
participants of the Progstar study, we evaluated the progression rates
in patients who were recently symptomatic, defined as presenting
within 2 years of reported symptom onset.
Methods: 36 participants (71 eyes) of the 251 participants enrolled
in the retrospective study had onset of symptoms within 2 years
of their first visit, and had at least one visit with both VA and AF
reported. Among them, 65 eyes had ≥2 visits with both VA and AF.
VA was reported as best corrected/presenting acuity and converted to
LogMAR. Atrophic lesions identified from AF images were graded
using a standard protocol, and areas of decreased AF were reported
as follows: Definitely decreased AF (DDAF), poorly-demarcated
questionably decreased AF, and well–demarcated questionably
decreased AF. We used linear models with generalized estimating
equations to compare baseline VA and lesion areas, and linear mixed
effects models to estimate the yearly progression rate of VA and
lesion areas.
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ARVO 2016 Annual Meeting Abstracts
Results: The median age at first visit was 21 years (range, 7 to 63),
and 78% were within one year of symptom onset. At the first visit,
median LogMAR VA was 0.70 (IQR 0.3-0.9). The median DDAF
area was 0, (IQR 0-0.12), and the mean area in the 32% of eyes
with DDAF was 1.85mm2. The mean total area of decreased AF
was 1.51mm2 (SD=1.88). The median duration of follow-up was 3
years (IQR 2-4 years). In longitudinal analysis, the loss of VA was
0.05 LogMAR (95%CI 0.04-0.07) per year, and a greater rate of
VA loss was associated with better initial VA (p<.0001). The yearly
progression rate for total area of decreased AF was 0.50 (95%CI:
0.40-0.60)mm2. The yearly progression rate for DDAF was 0.38
(95%CI: 0.27-0.50) mm2. An increase in both DDAF and total lesion
area was associated with a loss of VA (p<.001).
Conclusions: This cohort of Stargardt participants who reported
onset of symptoms within two years had highly variable visual acuity
and lesion area, with slow progression per year. Increase in lesion
area over time was associated with loss of VA.
Commercial Relationships: Sheila K. West, None;
Xiangrong Kong, None; Beatriz E. Munoz, None;
Artur V. Cideciyan, None; Michel Michaelides, None; AnnMargret Ervin, None; Srinivas R. Sadda, Avalanche (C), Novartis
(C), Optos (C), Bayer (C), Allergan (F), Genetech (F), Carl Zeiss
Meditec (F), Genetech (C), Stem Cells, Inc (C), Thrombogenics
(C), Optos (F), Regeneron (C), Iconic (C), Allergan (C);
Hendrik P. Scholl, None
Support: Foundation Fighting Blindness Clinical Research Institute
(FFB CRI) and a grant to FFB CRI by the U.S. Department of
Defense USAMRMC TATRC, Fort Meade, Maryland (grant numbers
W81-XWH-07-1-0720 and W81XWH-09-2-0189).
Program Number: 2688 Poster Board Number: C0139
Presentation Time: 3:45 PM–5:30 PM
Biofeedback Rehabilitation in Patients with Stargardt disease: a
randomized controlled trial
Francesco Maria D’Alterio1, Paolo Melillo1, Valentina Di Iorio1,
Gaia Olivo2, Anna Prinster3, Arturo Brunetti2, Mario Quarantelli3,
Francesco Testa1, Francesca Simonelli1. 1Eye Clinic,
Multidisciplinary Department of Medical, Surgical and Dental
Sciences, Second University of Naples, Naples, Italy; 2Department
of Advanced Biomedical Sciences, University of Naples “Federico
II”, Naples, Italy; 3Institute of Biostructure and Bioimaging, National
Research Council, Naples, Italy.
Purpose: Few previous case series studies reported data on
microperimetry (MP1) biofeedback rehabilitation in macular
diseases, including Stargardt disease (STGD). We performed a
randomized clinical trial to evaluate the efficacy of biofeedback
rehabilitation of the extrafoveal Preferred Retinal Locus (PRL) of
fixation in STGD patients.
Methods: 24 patients (aged 29.2±11.8 years; 8F) with ABCA4 related
STGD were enrolled and randomized to treatment (TG) or control
(CG) group. Inclusion criteria were: best corrected visual acuity
(BCVA)≥ 1/20; age ≥8 years; no other ocular or systemic diseases.
Patients who underwent ocular surgery or experimental therapy in
the last 6 months were excluded. The 2 groups were homogeneous
for age (TG 29.66±12.9 years; CG 28,75±11.33 years) and for
disease severity (measured with Fishmann and Lois classifications).
At the baseline and after 3 months patients underwent an ocular
examination including: BCVA measured with ETDRS chart,
reading speed (RS) and minimum print size (MPS) measured with
Colenbrander Reading Chart and MP1 (NIDEK Technologies). TG
underwent 12 biofeedback rehabilitation sessions of 10 min for each
eye by the same operator, once a week. Outcome measures were
variations between the groups in BCVA and Reading Test parameters
(RS, MPS) in the dominant eye (determined by the Miles Test).
Measures are presented as mean±SD. Differences in the measures
were assessed by unpaired t-test (significant p-value <5%). The study
adhered to the tenets of the Declaration of Helsinki and received
approval by the Local Ethics Committee; each patient gave informed
consent.
Results: BCVA in TG improved (5-10 letters) in 8 patients, decreased
(10 letters) in 1 patient and remained stable in 3 patients, whereas
in CG remained stable in 8 patients and decreased (5-10 letters)
in 4 patients. The RS on average increased in the TG (13.4±17.4
words/min) whereas it remained stable in the CG (-0.6±4.0 words/
min). Moreover, after the rehabilitation patients were able to read
smaller size letters (-0.5±0.6), while patients in the CG showed no
improvement or worsening (-0.08±0.16). Statistical analysis showed
that variations of BCVA (p=0.014), RS (p=0.013) and MPS (p=0.005)
between the groups were significant.
Conclusions: Our findings confirm that MP1 biofeedback
rehabilitation improves visual function and reading abilities, thereby
ameliorating overall quality of vision in STGD patients.
Commercial Relationships: Francesco Maria D'Alterio;
Paolo Melillo, None; Valentina Di Iorio, None; Gaia Olivo, None;
Anna Prinster, None; Arturo Brunetti, None; Mario Quarantelli,
None; Francesco Testa, None; Francesca Simonelli, None
Program Number: 2689 Poster Board Number: C0140
Presentation Time: 3:45 PM–5:30 PM
Stargardt Disease Expression on a Background of Low
Lipofuscin: The Impact of the p.G1961E Mutation of ABCA4
Winston Lee1, Kalev Noupuu1, 3, Jana Zernant1, Kaspar Schuerch1,
Peter Gouras1, Stephen H. Tsang1, 2, Janet R. Sparrow1, 2,
Rando Allikmets1, 2. 1Ophthalmology, Columbia University, New
York, NY; 2Pathology & Cell Biology, Columbia University, New
York, NY; 3Ophthalmology, Tartu University, Tartu, Estonia.
Purpose: 488nm autofluorescence images and spectral domainoptical coherence tomography scans were analyzed in 195 patients
harboring two disease-causing ABCA4 mutations. The cohort was
divided into two groups: those with at least one p.G1961E allele
(G, n=61) and those with all other ABCA4 mutation combinations
(N, n=134).
Methods: A longitudinal and cross-sectional analysis of
autofluorescence images and spectral domain-optical coherence
tomography scans was conducted in 195 patients harboring two
disease-causing ABCA4 mutations. The cohort was divided into two
groups: those with at least one p.G1961E allele (G, n=61) and those
with all other ABCA4 mutation combinations (N, n=134).
Results: Groups were age-matched (G, mean=37.4, range=5-79;
N, mean=37.9, range=8-83). Fleck distributions were different
between groups. A proportion of group G patients exhibited no flecks
(28%) or flecks that were distributed and morphologically “lesioncentric” (confined to/and along the contour of the central lesion).
Flecks in group N were present in almost all patients (96%), were
comparatively more advanced and evenly distributed across the
posterior pole. Fleck severity and distribution in group G, but not N,
increased with age. Incidence of geographic atrophy (GA) was lower
in group G (26%) but measured area increased with fleck severity and
age, while GA was evident in a majority of group N (71%) to a more
varying extent. GA area never extended beyond the macula in group
G while 37% of group N exhibited extensive atrophy across the
posterior pole. Group N lesions were often multifocal or contained
small “satellite” lesions peripherally that expanded and coalesced at
differing rates (mean=1.84 mm2/yr, SD=1.84). Single, well-defined
lesions were observed in all group G patients which expanded at a
more consistent rate (mean=0.74 mm2/yr, SD=0.55).
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ARVO 2016 Annual Meeting Abstracts
Conclusions: STGD1 expression in patients with the p.G1961E
allele is characterized by a focal lesion that progresses to a single,
steadily expanding area of GA with lesion-centric flecks. Significant
lipofuscin accumulation in all other ABCA4 mutation combinations
results in the earlier widespread development of flecks which
resorb and progress as GA lesions. Over time, these non-central or
“satellite” lesions expand and coalesce across the posterior pole.
Commercial Relationships: Winston Lee; Kalev Noupuu, None;
Jana Zernant, None; Kaspar Schuerch, None; Peter Gouras,
None; Stephen H. Tsang, None; Janet R. Sparrow, None;
Rando Allikmets, None
Support: NEI EY021163; NEI EY019861
Program Number: 2690 Poster Board Number: C0141
Presentation Time: 3:45 PM–5:30 PM
Comparison of en-face Optical Coherence Tomography and
Fundus Autofluorescence for assessment of macular lesion area in
Stargardt disease
Paolo Melillo, Ada Orrico, Valentina Di Iorio, Anna Nesti,
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: This study compared the macular lesion area in Retinal
Pigmented Epithelium (RPE), computed by an automatic algorithm
(sub-RPE slab) from en-face Spectral Domain Optical Coherence
Tomography (SD-OCT), with the fundus lesion area, assessed
by Fundus Autofluorescence (FAF) imaging, in Stargardt disease
(STGD1). Moreover, the progression of RPE lesion area was
estimated over a multi-year follow-up in a large STGD1 patient
cohort.
Methods: We reviewed the medical records of STGD1 patients with
mutations in ABCA4 gene, who underwent best-corrected visual
acuity (BCVA), fundus photography, FAF, SD-OCT, and full-field
electroretinography. Linear models based on GEE were fitted in
order to evaluate the disease progression over a multi-year follow-up.
BCVA values were converted in LogMAR for statistical analysis.
The data are presented as mean ± standard error of mean. 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: We analyzed a subgroup of 25 patients (13 females;
aged: 37.1 ± 2.8 years), undergoing both OCT and FAF imaging,
to evaluate the correlation between the two parameters. The linear
regression model showed a significant correlations between the two
parameters (β=0.843; p-value <0.001; R2=0.947).
To assess the annual rate of disease progression, a cohort of 101
patients (aged: 30.0 ± 1.4 years), followed up for a mean time of
3.1 ± 0.1 years, was analyzed. Mean BCVA was 20/100 ± 20/1000
for both eyes. The mean RPE lesion area, measured by OCT, was
2.97 ± 0.39 mm2, in right eyes, and 3.16 ± 0.42 mm2, in left eyes.
Furthermore, RPE lesion area was significantly correlated with BCVA
(β=0.61, p=0.045). The longitudinal analysis revealed a significant
enlargement of RPE lesion area at a mean linear rate of 0.146 mm2/
year (p=0.021). Finally, the BCVA significantly worsened at a mean
rate of 0.065 logMar (≈3 ETDRS letters) / year (p<0.001).
Conclusions: The current study describes, for the first time in
literature, a longitudinal analysis of the macular lesion area assessed
by SD-OCT in a STGD1 disease cohort, showing a significant
progression over the follow-up. Our findings suggest that the
evaluation of lesion area by SD-OCT could be a useful measurement
of disease progression, in particular to design future clinical trials.
Commercial Relationships: Paolo Melillo, None; Ada Orrico,
None; Valentina Di Iorio, None; Anna Nesti, None; Settimio Rossi,
None; Michele Della Corte, None; Francesco Testa, None;
Francesca Simonelli, None
Support: NEI 1R24EY019861-01A1
Program Number: 2691 Poster Board Number: C0142
Presentation Time: 3:45 PM–5:30 PM
Impact of segmentation density on spectral domain optical
coherence tomography (SD-OCT) assessments in Stargardt
disease
Anamika Jha1, Alexander Ho1, Muneeswar G. Nittala1,
Rupert W. Strauss2, Hendrik P. Scholl2, Srinivas R. Sadda1, 3. 1Doheny
Eye Institute, Los Angeles, CA; 2Ophthalmology, Johns Hopkins
Wilmer Eye Institute, Baltimore, MD; 3David Geffen School of
Medicine, UCLA, Los Angeles, CA.
Purpose: SD-OCT segmentation algorithms currently do not perform
well in segmenting intraretinal layers in eyes with Stargardt disease.
These inaccuracies can be managed by tedious manual correction.
We compared selective B-scan segmentation strategies in generating
mean retinal layer thickness and preserved area data from SD-OCT
scans in patients with Stargardt disease (STGD1).
Methods: 13 eyes from 13 STGD1 patients were randomly selected
from the ongoing Natural History of the Progression of Atrophy
Secondary to Stargardt Disease (ProgStar) studies. For each eye,
a 49-section 20°x20° high resolution SD-OCT scan was collected.
The space between each B-scan was approximately 120-125 µm. All
49 B-scans were segmented manually to quantify retinal pigment
epithelium (RPE), photoreceptor outer segments (OS) and inner
segments (IS), outer nuclear complex (ONC), and inner retina (InR).
For each volume scan, mean thickness (MT) and total area (TA) were
generated with three different B-scan selection strategies, using:
all 49 B-scans; 1 of every 2 B-scans; and an “adaptive” method,
containing a subset of (or all) 49 B-scans that the grader deemed as
significantly different from adjacent B-scans. The Mann-WhitneyWilcoxon test was used to test for significant (α = 0.05) differences.
Results: No statistically significant (p < 0.05) differences were
detected between the three strategies (Table 1). For the adaptive
strategy, the average # of segmented B-scans was 35 (SD=10;
range=22-49).
Conclusions: These data suggest that a selective segmentation
strategy may be a viable alternative to exhaustive, comprehensive
manual segmentation in Stargardt disease. These results may have
implications for increasing the efficiency of SD-OCT grading
strategies in clinical trials for Stargardt disease and other related
macular degenerative disorders.
Table 1. Average MT (± SD; µm) and average TA (± SD; mm2) of
intraretinal layers quantified by 3 strategies.
Commercial Relationships: Anamika Jha, None; Alexander Ho,
None; Muneeswar G. Nittala, None; Rupert W. Strauss, None;
Hendrik P. Scholl, None; Srinivas R. Sadda, Carl Zeiss Meditec
(F), Optos (F)
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.
ARVO 2016 Annual Meeting Abstracts
Support: Supported by the Foundation Fighting Blindness Clinical
Research Institute (FFB CRI) and a grant to FFB CRI by the U.S.
Department of Defense USAMRMC TATRC, Fort Meade, Maryland
(grant numbers W81-XWH-07-1-0720 and W81XWH-09-2-0189).
Clinical Trial: NCT01977846
Program Number: 2692 Poster Board Number: C0143
Presentation Time: 3:45 PM–5:30 PM
Ellipsoid Zone Mapping and Outer Retinal Assessment in
Stargardt disease
Sruthi Arepalli, Elias I. Traboulsi, Justis P. Ehlers. Ophthalmology,
Cole Eye Institute, Cleveland, OH.
Purpose: Visual decline is a common occurrence in Stargardt
disease secondary to macular atrophy with associated ellipsoid
zone (EZ) loss. Reliable and objective measurement of the EZ is
difficult with conventional methods. This study utilizes a novel
EZ mapping analysis tool for en face visualization and volumetric
EZ-retinal pigment epithelium (RPE) assessment in eyes diagnosed
with Stargardt disease. The purpose of the study is to quantitatively
characterize the EZ status in Stargardt disease and correlate the
findings with clinical characteristics.
Methods: This is an IRB-approved retrospective case series
examining the OCT features of Stargardt disease. Macular cube scan
data was exported for analysis. A novel EZ mapping tool was utilized
to analyze volumetric measurements and en face characterization of
relative EZ volume and atrophy. En face characterization included
the percentage of macular scan area with total atrophy (EZ-RPE
thickness = 0 microns) and percentage of macular scan area with EZ
attenuation (EZ-RPE thickness < 20 microns). Clinical characteristics
were correlated with EZ mapping features. EZ mapping values were
compared to a normal cohort.
Results: Thirty-two eyes were included in the study with a diagnosis
of Stargardt disease. Clinical features included 20 eyes with macular
flecks and 17 eyes with clinical macular atrophy. Mean EZ volume
in Stargardt patients was 1.0 +/- 0.33 mm3. In normal eyes, the EZ
volume was 1.27 +/- .09 mm3. Mean percentage of macular EZ
attenuation area was 42% in Stargardt patients compared to < 1%
in normal eyes. Similarly, mean percentage of macular EZ atrophy
was 22% compared to < 1% in normal eyes. EZ maps demonstrated
variable levels of atrophy [e.g., moderate (Figure 1), severe (Figure
2)]. EZ volume was directly correlated with visual acuity. Conversely,
the percentage of EZ attenuation and EZ atrophy were negatively
correlated with visual acuity.
Conclusions: EZ mapping provided objective quantitative
assessment of outer retinal integrity in Stargardt disease. Multiple
EZ mapping parameters were correlated with visual acuity. Utilizing
EZ mapping may provide a unique opportunity for longitudinal
assessment in Stargardt disease and detect early features of macular
atrophy.
Blue demonstrating moderate EZ loss
Blue demonstrating severe EZ loss
Commercial Relationships: Sruthi Arepalli, None;
Elias I. Traboulsi, Sparks Therapeutics (C), Retrophin (C), Sanofi
(C); Justis P. Ehlers
Support: NIH/NEI K23-EY022947-01A1; Ohio Department of
Development TECH-13-059
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.
ARVO 2016 Annual Meeting Abstracts
Program Number: 2693 Poster Board Number: C0144
Presentation Time: 3:45 PM–5:30 PM
Progression of late-onset Stargardt disease
Stanley Lambertus1, Moritz Lindner2, Nathalie Bax1,
Matthias M. Mauschitz2, Matthias Schmid3,
Steffen Schmitz-Valckenberg5, Bernhard H. Weber4, Frank G. Holz2,
Gert Jan van der Wilt5, Monika Fleckenstein2, Carel C. Hoyng1.
1
Department of Ophthalmology, Radboud university medical center,
Nijmegen, Netherlands; 2Department of Ophthalmology and GRADE
Reading Center, University of Bonn, Bonn, Germany; 3Informatics
and Epidemiology, Institute for Medical Biometry, Bonn, Germany;
4
Institute of Human Genetics, University of Regensburg, Regensburg,
Germany; 5Department for Health Evidence, Radboud university
medical center, Nijmegen, Netherlands.
Purpose: Accurate biomarkers are crucial to determine potential
effects of emerging therapeutic trials for Stargardt disease. The
natural course of late-onset Stargardt includes a typical phenotype
of retinal pigment epithelium (RPE) atrophy that often spares the
fovea, and is surrounded by yellow-white flecks. To this end, areas of
RPE atrophy could serve as a sensitive monitor for this disease. We
therefore performed a retrospective cohort study to show the accuracy
of this outcome measure and calculated sample sizes for a simulated
trial.
Methods: We analyzed retinal features, visual acuity, and RPE
atrophy progression using fundus autofluorescence and near-infrared
reflectance imaging in 47 late-onset Stargardt patients (disease onset
≥45 years). Endpoints of visual acuity were observed using Turnbull’s
estimators. Progression of RPE atrophy was analyzed by a two-level
random effects linear mixed model. Sample size calculations were
performed for a 2-year study duration and a dropout rate of 15%.
Results: Survival analysis yielded a median interval between disease
onset and a decline in visual acuity to 20/32, 20/80, and 20/200 of
2.74 (95% confidence interval, 0.54-4.41), 10.15 (95% CI, 6.1311.38), and 11.38 (95% CI, 6.13-13.34) years, respectively. Over
time, progression of RPE atrophy was observed (mean, 0.22±0.02
mm/year; p<0.001). If only patients with bilateral RPE atrophy are
included in a 2-year study, 32 patients are needed to reach a power of
80% (95% CI, 79.3-82.4), assuming a fixed therapeutic effect size of
30%.
Conclusions: The development of RPE atrophy reflects the
most prominent feature of disease progression in late-onset
Stargardt. Expansion rates appeared to be fairly slow. Nonetheless,
measurements of RPE atrophy resulted in a robust biomarker for
disease progression.
Statistical power of a simulated 2-year interventional study in
late-onset Stargardt as a function of sample size. Calculations were
performed for an expected effect size of 50 % (red), 40 % (blue) and
30 % (green) reduction of atrophy progression. Shown are means
(±95% confidence intervals) of 10000 simulations per data point.
Commercial Relationships: Stanley Lambertus, None;
Moritz Lindner, Alimera Sciences (R), Carl Zeiss Meditec (F),
Heidelberg Engineering (F), Heidelberg Engineering (R), Optos
(F), Genentech (F); Nathalie Bax, None; Matthias M. Mauschitz,
None; Matthias Schmid, None; Steffen Schmitz-Valckenberg;
Bernhard H. Weber, None; Frank G. Holz, Genentech (R), Carl
Zeiss Meditec (F), Optos (F), Genentech (F), Heidelberg Engineering
(F), Novartis (C), Boehringer Ingelheim (C), Optos (C), Novartis
(R), Bayer (C), Bayer (R), Heidelberg Engineering (C), Novartis
(F), Merz (C), Genentech (C), Heidelberg Engineering (R), Acucela
(C), Bayer (F), Allergan (C); Gert Jan van der Wilt, None;
Monika Fleckenstein, Heidelberg Engineering (F), Novartis (R),
US20140303013 A1 pending (P), Bayer (R), Genentech (R), Carl
Zeiss Meditec (F), Merz (C), Optos (F), Heidelberg Engineering (R),
Genentech (F); Carel C. Hoyng, None
Support: This study was supported by the Stichting A.F. Deutman
Researchfonds Oogheelkunde, Nijmegen, The Netherlands; Deutsche
Forschungsgemeinschaft, Bonn, Germany, Grant No FL 658/4-1
and Ho1926/3-1; BONFOR GEROK Program, Faculty of Medicine,
University of Bonn, Grant No O-137.0020; and by the following
foundations that contributed through UitZicht: Stichting MD fonds,
Landelijke Stichting voor Blinden en Slechtzienden, and Oogfonds.
The funding organizations had no role in the design or conduct of this
research. They provided unrestricted grants.
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ARVO 2016 Annual Meeting Abstracts
Program Number: 2694 Poster Board Number: C0145
Presentation Time: 3:45 PM–5:30 PM
Cross-sectional evaluation of microperimetric fixation location
and stability in Stargardt disease in the ProgStar study
Etienne M. Schonbach1, Mohamed A. Ibrahim1, Rupert W. Strauss1, 2,
Xiangrong Kong1, Alexander Ho3, Paul S. Bernstein4,
Janet S. Sunness5, Eberhart Zrenner6, Srinivas R. Sadda3, 7,
Sheila K. West1, Hendrik P. Scholl1. 1Wilmer Eye Institute, Johns
Hopkins University School of Medicine, Baltimore, MD; 2Moorfields
Eye Hospital, London, United Kingdom; 3Doheny Eye Institute,
Los Angeles, CA; 4Moran Eye Center, University of Utah School of
Medicine, Salt Lake City, UT; 5Greater Baltimore Medical Center,
Baltimore, MD; 6Center for Ophthalmology, Institute for Ophthalmic
Research, Eberhard Karls Universität, Tübingen, Germany; 7David
Geffen School of Medicine, Los Angeles, CA.
Purpose: To investigate the relationship between microperimetric
fixation location (FL) and fixation stability (FS), demographic
features, and best-corrected visual acuity (BCVA) in Stargardt
disease (STGD1) as part of the multicenter ProgStar study (The
Natural History of the Progression of Atrophy Secondary to Stargardt
Disease).
Methods: We enrolled patients with ABCA4-related STGD1 in a
multicenter, prospective, cross-sectional, observational study. We
used MP1 data (Nidek Technologies): FL was expressed as the
eccentricity of the preferred retinal locus (PRL) from the anatomical
fovea, FS as the 95.4 %-bivariate contour ellipse area (BCEA),
and best- corrected visual acuity (BCVA) as ETDRS letters. Linear
models with generalized estimating equations were used for statistical
analysis while accounting for between-eye correlations.
Results: Of 238 patients, 105 (44 %) were males. Median age was 32
years (mean, 33.8 years; range, 7- 69 years) and the median duration
of symptoms was 9 years (mean, 11.8 years; range, 0- 55 years).
Median PRL eccentricity from the fovea was 6° (mean, 6.2°; range,
0°- 25°), median BCEA was 21.4 deg2 (mean, 31.1 deg2; range,
0.370 deg2- 267 deg2), median BCVA was 42 ETDRS letters (mean,
46.2 letters; range, 20- 88 letters). Each year of additional disease
duration was associated with 0.11° more eccentric FL (p =0.0008)
but not with FS (p =0.936). Each year of later onset of symptoms
of STGD1 was associated with 0.14° more central FL (p < 0.0001)
and 0.84 deg2 smaller BCEA (p <0.0001). Each year of additional
age was associated with 0.67° more central fixation (p =0.0007)
and 0.46 deg2 smaller BCEA (p =0.0014). A single linear model
best described the relationship between FL and BCVA: one degree
farther PRL eccentricity was associated with 2.3 letters loss of BCVA
(p <0.0001) and one additional letter of BCVA with 0.15° more
central FL (p <0.0001). The association of FL with BCVA was robust
after adjusting for BCEA. Pearson correlation coefficients between
patients’ right and left eyes were 0.892 (p <0.0001) for FL and 0.851
(p <0.0001) for FS. After 10 years of disease duration, 82 % of
patients had more than 2° PRL eccentricity in both eyes.
Conclusions: Longer disease duration is associated with an increase
of eccentricity and loss of stability of fixation in STGD1.
Commercial Relationships: Etienne M. Schonbach;
Mohamed A. Ibrahim, None; Rupert W. Strauss, None;
Xiangrong Kong, None; Alexander Ho, None; Paul S. Bernstein,
None; Janet S. Sunness, None; Eberhart Zrenner, None;
Srinivas R. Sadda, Novartis (C), Avalanche (C), Stem Cells Inc
(C), Optos (C), Bayer (C), Allergan (F), Carl Zeiss Meditec (F),
Genentech (C), Thrombogenics (C), Optos (F), Regeneron (C),
Genentech (F), Iconic (C), Allergan (C); Sheila K. West, None;
Hendrik P. Scholl, None
Support: Supported by the Foundation Fighting Blindness Clinical
Research Institute (FFB CRI) and a grant to FFB CRI by the U.S.
Department of Defense USAMRMC TATRC, Fort Meade, Maryland
(grant numbers W81-XWH-07-1-0720 and W81XWH-09-2-0189)
Clinical Trial: NCT01977846
Program Number: 2695 Poster Board Number: C0146
Presentation Time: 3:45 PM–5:30 PM
The natural history of the progression of atrophy secondary
to Stargardt disease type 4 (Progstar-4 Study): Baseline
demographics and ocular characteristics of patients with PROM1 related retinal dystrophy
Syed Mahmood A. Shah1, 2, Mohamed Ahmed1, 2, Nadia Junaid1, 2,
Saghar Bagheri1, 2, Beatriz E. Munoz2, Rupert W. Strauss2,
Etienne M. Schonbach1, 2, Michel Michaelides3, Ann-Margret Ervin2,
Hendrik P. Scholl2. 1Quantum Vision Reading Center, Baltimore, MD;
2
Wilmer Eye Institute, Johns Hopkins University, Batlimore, MD;
3
Moorfields Eye Hospital, London, United Kingdom.
Purpose: The longitudinal, multicenter ProgStar-4 study aims to
characterize the natural history of Prominin-1 (PROM1) related
retinal dystrophy (Stargardt disease type 4/STGD4; OMIM #603786).
The baseline characteristics of patients enrolled in the ProgStar-4
Study are described.
Methods: Patients with disease-causing mutations in the PROM1
gene and associated retinal dystrophy were enrolled. At baseline,
best corrected visual acuity (BCVA), fundus autofluorescence
(AF, Heidelberg Engineering), optical coherence tomography
(OCT, Heidelberg Engineering) and microperimetry (MP-1, Nidek
Technologies) were obtained and analyzed by the Quantum Vision
Reading Center (QVRC).
Results: Ten eyes from 5 patients with mean age of 38.2±7.6 years
have been enrolled to date into the study. The mean age at onset of
symptoms was 25.8±10.5 years with an average disease duration
of 12.4±12.4 years. Mean BCVA at baseline was 60.8±19.2 letters
(range: 38-91). All patients had areas of decreased AF with a mean
area of 6.2±2.2 mm2. Eight (80%) eyes had poorly demarcated
questionably decreased AF (PD-QDAF) and 2 (20%) had definitely
decreased AF (DDAF) with one multifocal subfoveal DDAF lesion.
Eight out of 10 eyes had an increased edge AF and none had any
flecks. Mean central subfield thickness was 181.7±42.0 µm, total
macular volume was 6.8 ± 0.6 mm2 and 6 eyes had loss of outer
retinal architecture involving the fovea. Mean sensitivity (MS) as
measured by MP-1 was 9.5±5.0 dB, with unstable fixation in 4 eyes
(40%) and an average 1 standard deviation bi-contour ellipse area
(BCEA) of 2.17±3.3 degrees2. Fixation was eccentric in 5 eyes (50%)
with an average PRL location of 3.9±3.5 degrees from the center of
the anatomic fovea.
Conclusions: Progstar-4 is the first multicenter study to prospectively
follow patients with STGD4 to characterize disease progression.
Our baseline characteristics show that the main AF lesion type was
PDQDAF. Four eyes from 2 patients showed preservation of the
sub-foveal outer retina, but only one of them had both preservation
on OCT and absence of AF lesions involving the fovea. Longitudinal
data will provide valuable insights into the natural history of STGD4
and will inform clinical trial design for interventional studies that aim
to slow down disease progression.
Commercial Relationships: Syed Mahmood A. Shah, None;
Mohamed Ahmed; Nadia Junaid, None; Saghar Bagheri,
None; Beatriz E. Munoz, None; Rupert W. Strauss, None;
Etienne M. Schonbach, None; Michel Michaelides, None; AnnMargret Ervin, None; Hendrik P. Scholl, None
Support: The Shulsky Foundation
Clinical Trial: NCT02410122
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to access the versions of record.
ARVO 2016 Annual Meeting Abstracts
Program Number: 2696 Poster Board Number: C0147
Presentation Time: 3:45 PM–5:30 PM
Scotopic and photopic macular functions as assessed with
microperimetry (MP1) in patients with Stargardt disease type 1 –
The SMART Study
Mohamed A. Ibrahim6, Rupert W. Strauss6, 1, Xiangrong Kong6,
Ann-Margret Ervin6, Alexander Ho2, Janet S. Sunness3,
Isabelle S. Audo4, David G. Birch5, Srinivas R. Sadda2, 7,
Millena G. Bittencourt6, Hendrik P. Scholl6. 1Moorfields Eye Hospital
and UCL Institute of Ophthalmology, London, United Kingdom;
2
Doheny Eye Institute, Los Angeles, CA; 3Greater Baltimore Medical
Center, Baltimore, MD; 4CHNO des Quinze-Vingts, DHU Sight
Restore, INSERM-DHOS CIC 1423, Sorbonne Universités, UPMC
Univ Paris 06, INSERM, CNRS, Institut de la Vision, Paris, France;
5
Retina Foundation of the Southwest, Dallas, TX; 6Wilmer Eye
Institute at the Johns Hopkins University, Baltimore, MD; 7David
Geffen School of Medicine, UCLA, Los Angeles, CA.
Purpose: To characterize scotopic and photopic macular function
with MP1S in patients with Stargardt disease type 1 (STGD1) in
the SMART Study (Scotopic Microperimetric Assessment of Rod
Function in Stargardt Disease)
Methods: Patients with confirmed mutations in the ABCA4 gene
and STGD1 phenotype were enrolled (sub-cohort of the ProgStar
Study). One eye from every patient (best eye) underwent testing
using a custom pattern on the MP1S system (Nidek Technologies),
before (mesopic; m) and after (scotopic; s) dark-adaptation. Mesopic
testing used a white stimulus; scotopic testing a blue stimulus with a
combined neutral density filter to align sensitivity with the dynamic
range of the MP1S and a 500nm short-pass filter. Tests were graded
at the Doheny Image Reading Center. Mean sensitivity (MS) in the
ring 4-10 degrees from the fovea was calculated for both the mesopic
(mMS) and scotopic (sMS) tests. The distance of center of gravity of
fixation points (preferred retinal locus or PRL) from the anatomical
fovea was measured along with the 2SD bivariate contour ellipse area
(BCEA). Descriptive statistics and correlation coefficients were used
to assess the relationship between photopic and scotopic outcome
variables.
Results: 136 patients from 7 centers were enrolled. 54% were
female, 82% were white, mean age was 34.5 (SD±14) years, mean
age of onset was 24.6 (SD±13.7) years, and mean disease duration
(DD) was 10 (SD±7.3) years. The mean BCVA was 53.4 letters
(SD±17.9). The mean mMS was 12.2 (SD±4.6) dB and the mean
sMS was 11.1 (SD±5.0) dB with the one-log unit filter. mMS and
sMS were highly correlated with Pearson correlation coefficient of
0.81 (p<0.0001). The mean mPRL was 4.9 (SD±3.9) degrees and
the mean sPRL was 5.34 (SD±3.8) degrees. mPRL and sPRL were
highly correlated with correlation coefficient of 0.77 (p<0.0001). The
mean 2SD mBCEA was 26.8 (SD±34.7) deg2 and the mean sBCEA
was 30.4 (SD±31) deg2. mBCEA and sBCEA were correlated with
correlation coefficients of 0.68 (p<0.0001).
Conclusions: In our cohort of patients with STGD1, photopic and
scotopic macular performance were highly correlated when assessed
using mean macular sensitivity in the perifoveal area. There were no
significant differences in the distance of PRL from fovea or the 2SD
BCEA of fixation.
Commercial Relationships: Mohamed A. Ibrahim, None;
Rupert W. Strauss, None; Xiangrong Kong, None; AnnMargret Ervin, None; Alexander Ho, None; Janet S. Sunness,
None; Isabelle S. Audo, None; David G. Birch, None;
Srinivas R. Sadda, Avalanche (C), Novartis (C), Optos (C),
Stem Cell Inc (C), Bayer (C), Thrombogenetics (C), Allergan (F),
Carl Zeiss Meditec (F), Genetech (C), Optos (F), Regeneron (C),
Genentech (F), Iconic (C), Allergan (C); Millena G. Bittencourt,
None; Hendrik P. Scholl, None
Support: Supported by the Foundation Fighting Blindness Clinical
Research Institute (FFB CRI) and a grant to FFB CRI by the U.S.
Department of Defense USAMRMC TATRC, Fort Meade, Maryland
(grant numbers W81-XWH-07-1-0720 and W81XWH-09-2-0189).
Clinical Trial: NCT01977846
Program Number: 2697 Poster Board Number: C0148
Presentation Time: 3:45 PM–5:30 PM
Results from spectral-domain optical coherence tomography (SDOCT) at baseline compared with normative data: The Natural
History of the Progression of Atrophy Secondary to Stargardt
Disease (ProgStar) Study
Alexander Ho1, Beatriz E. Munoz2, Rupert W. Strauss2, 6,
Anamika Jha1, Ngoc Lam1, Zhihong Hu5, David G. Birch3,
Eberhart Zrenner4, Sheila K. West2, Srinivas R. Sadda1, 7,
Hendrik P. Scholl2. 1Doheny Eye Institute, Los Angeles, CA;
2
Ophthalmology, Johns Hopkins Wilmer Eye Institute, Baltimore,
MD; 3Retina Foundation of the Southwest, Dallas, TX; 4Institute
for Ophthalmic Research, Centre for Ophthalmology, University of
Tübingen, Tübingen, Germany; 5Doheny Image Analysis Laboratory,
Doheny Eye Institute, Los Angeles, CA; 6Moorfields Eye Hospital
and UCL Institute of Ophthalmology, London, United Kingdom;
7
David Geffen School of Medicine, UCLA, Los Angeles, CA.
Purpose: The multicenter observational ProgStar studies aim to
characterize the natural history of Stargardt disease (STGD1). Retinal
architecture metrics derived from SD-OCT in a subset of patients
enrolled into the prospective ProgStar study at baseline visit are
compared to those of normal subjects.
Methods: Baseline visit SD-OCT images for 113 genetically
confirmed, randomly-selected STGD1 participants enrolled at 9 sites
into ProgStar were evaluated at a central reading center (Doheny
Image Reading Center/DIRC). SD-OCT images from both eyes
were graded, when available. 20 eyes from 20 normal subjects were
also evaluated. If thickness data were available for both eyes in the
STGD1 data subset, one eye was randomly selected for inclusion in
the analysis. Proprietary DIRC software was used to generate mean
thicknesses in the central subfield and inner ring of the ETDRSgrid for the retinal pigment epithelium (RPE), photoreceptor outer
segments (OS) and inner segments (IS), outer nuclear complex
(ONC), and inner retina (InR) layers. ProgStar eye data were
normalized using Z-scores.
Results: The mean age for ProgStar subjects was 33 years (SD=15).
The mean age of the normal subjects was 29 years (SD=8). RPE, OS,
IS, and ONC thickness measures collected from the STGD1 subset
were outside 2 SDs of the normal eye data (Table 1).
Conclusions: Outer retinal layers (RPE, OS, IS, ONC) in the
STGD1 data subset have statistically significantly less thickness as
compared to normals. These differences are important for the design
of interventional clinical trials in STGD1.
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.
ARVO 2016 Annual Meeting Abstracts
& RPE as well as intense SHRM in the SRS corresponding to the
fibrosis
Conclusions: Classical clinical/FP stages of BVMD have
characteristic corresponding OCT findings. In the previtelliform
stage, OCT can reveal SHRM not evident on clinical exam. Early
stages VA can be normal, but deteriorates as atrophy & fibrosis
appear on exam, and photoreceptor & RPE loss are seen on OCT.
OCT appears to be an essential tool for more precise staging of
BVMD
Table 1. Intraretinal layer metrics (average and SD of mean
thickness) for normal eyes and ProgStar baseline visit eyes.
Commercial Relationships: Alexander Ho, None;
Beatriz E. Munoz, None; Rupert W. Strauss, None; Anamika Jha,
None; Ngoc Lam, None; Zhihong Hu, None; David G. Birch, None;
Eberhart Zrenner, None; Sheila K. West; Srinivas R. Sadda, Carl
Zeiss Meditec (F), Optos (F); Hendrik P. Scholl, None
Support: Supported by the Foundation Fighting Blindness Clinical
Research Institute (FFB CRI) and a grant to FFB CRI by the U.S.
Department of Defense USAMRMC TATRC, Fort Meade, Maryland
(grant numbers W81-XWH-07-1-0720 and W81XWH-09-2-0189).
Clinical Trial: NCT01977846
Program Number: 2698 Poster Board Number: C0149
Presentation Time: 3:45 PM–5:30 PM
Characterization of Best’s Vitelliform Macular Dystrophy
(BVMD) on Multimodal Imaging
Nizar S. Abdelfattah1, David S. Boyer2, Srinivas R. Sadda1.
1
Ophthalmology, Doheny Eye Institute, South Gate, CA; 2Retina
Vitreous Associated Medical Group, Beverly Hills, CA.
Purpose: To describe a comprehensive range of BVMD phenotypic
features on multimodal imaging in a large cohort & to correlate these
features with visual acuity
Methods: Cases were identified from the records of a large private
practice retina group. Diagnosis was based on clinical exam & EOG.
Patients were evaluated by a complete exam, biomicroscopy, color
fundus photography (FP), fluorescein angiography & spectral domain
OCT. Demographic data, visual function data & imaging findings
were recorded for 1 random eye of each subject
Results: Fifty eyes were included (69±17 years old, 68% female)
in this study. FP analysis revealed eyes in all stages of BVMD.
Previtelliform stage (n=12) mean BCVA (mBCVA) was 0.65±0.33,
and FPs were normal. OCT showed normal retina or a characteristic
vitelliform lesion (subfoveal hyperreflective material (SHRM)
between the ellipsoid zone & the retinal pigment epithelium (RPE).
Vitelliform stage (n=20) mBCVA was 0.46±0.2. FPs showed yellow
and/or mottled lesions, sometimes multifocal. Vitelliform material
was evident on OCT, but in 3 cases was located in the sub-RPE
space. Pseudohypopyon stage (n=3) mBCVA was 0.1. FPs showed a
vitelliform lesion with a horizontally oriented fluid-level separating
an upper serous component from a yellowish lower component.
OCT through serous areas showed a hyporeflective accumulation in
the subretinal space (SRS) with variable RPE atrophy. The inferior
yellowish component corresponded to SHRM on OCT. Vitelliruptive
stage (n=8) mBCVA was 0.5±0.17. FP images showed a disrupted
yellow lesion with a ring of yellowish material. OCT showed
multiple vitelliform accumulations in the SRS. Atrophic stage (n=4)
mBCVA was 0.19±0.1. FPs showed a vitelliform lesion with atrophy
without fibrosis. Corresponding OCT showed residual SHRM in
some areas but loss of the overlying retinal bands as well as RPE
atrophy. In the cicatricial stage (n=2), mBCVA was 0.2±0.06. FP
showed atrophy & definite fibrosis. OCT showed atrophy of the ONL
Commercial Relationships: Nizar S. Abdelfattah, None;
David S. Boyer, Alcon (R), bayer (C), Santaris (C), KalVista
(C), GS (C), genetech (C), Genentech (R), Santen (C), Alcon (C),
Aerpio (C), Allergan (R), Ohr (C), Regeneron (C), Regeneron (R),
Novartis (C), allergan (C), Novartis (R), Neurotech (C), Nicox (C),
ThromboGenics (C); Srinivas R. Sadda, Avalanche (C), Novartis
(C), Optos (C), Bayer (C), Allergan (F), Carl Zeiss Meditec (F),
Genetech (C), Stem Cells (C), Thrombogenics (C), OPtos (F),
Regeneron (C), Genentech (F), Iconic (C), Allergan (C)
Program Number: 2699 Poster Board Number: C0150
Presentation Time: 3:45 PM–5:30 PM
Acetazolamide for the treatment of cystic macular lesions in
children and young adults with hereditary macular dystrophies
Sanne K. Verbakel1, John van de Ven1, Linda M.P. Le Blanc1,
Joannes M.M. Groenewoud2, Eiko de Jong1, Carel C. Hoyng1.
1
Ophthalmology, Radboud University Medical Center, Nijmegen,
Netherlands; 2Epidemiology, Biostatistics, and HTA, Radboud
University Medical Center, Nijmegen, Netherlands.
Purpose: Little is known regarding the therapeutic effect of oral
acetazolamide in the management of cystic macular lesions in
children and young adults with hereditary macular dystrophies,
despite that this group is of special interest in view of the age of
onset of most hereditary macular dystrophies. Therefore, the aim
of this retrospective, observational clinical study was to determine
the efficacy of oral acetazolamide in the treatment of cystic macular
lesions in children and young adults with hereditary macular
dystrophies.
Methods: We studied a total of 17 children and young-adults
with X-linked retinoschisis (XLRS) or dominant cystoid macular
dystrophy (DCMD), treated with oral acetazolamide for cystic
macular lesions. All patients were assessed for best-corrected visual
acuity and foveal zone thickness (FZT) with spectral-domain optical
coherence tomography before and during treatment. A reduction of
more than 21,7% or 43,8% in FZT, equal to exceeding normal FZT
variability, was considered significant in patients with XLRS and
DCMD, respectively.
Results: Overall, mean FZT decreased from 435,7 µm at baseline
to 312,0 µm at the most recent visit while receiving treatment
(p<0.001). 5 of 7 (71,4%) XLRS patients and 4 of 10 (40,0%) DCMD
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.
ARVO 2016 Annual Meeting Abstracts
patients showed a significant reduction of FZT in at least one eye.
4 of 7 (57,1%) XLRS patients and 2 of 10 (20,0%) DCMD patients
showed a reduction in both eyes over a median treatment interval of
14,4 (range; 1-54) months. In 8 of 9 (88,9%) patients, this reduction
was already present after one month of treatment. An improvement
of visual acuity in one eye was observed in 4 of 17 patients (2 XLRS
patients; 2 DCMD patients), but none of the patients showed an
improvement of visual acuity in both eyes. Reported minor side
effects were limb paresthesias, hypokalemia or fatigue in 10 patients
(58,9%) and one patient suffered from the major side effect of kidney
stones.
Conclusions: We showed that treatment with oral acetazolamide
decreases FZT in up to half of the children and young-adults with
XLRS or DCMD, and that this effect is already visible within one
month in the majority of patients. Further examination will be
necessary to study long-term benefit in preserving and restoring
normal retinal anatomy in relation to side effects.
Commercial Relationships: Sanne K. Verbakel, None;
John van de Ven, None; Linda M.P. Le Blanc, None; Joannes
M.M. Groenewoud, None; Eiko de Jong, None; Carel C. Hoyng,
None
Program Number: 2700 Poster Board Number: C0151
Presentation Time: 3:45 PM–5:30 PM
Multimodal imaging evaluation of the pseudohypopyon stage in
Adult-Onset Foveomacular Vitelliform Dystrophy
Liran Tiosano, Edward Averbukh, Itay Chowers. Department of
Ophthalmology, Hadassah-Hebrew University Medical Center,
Jerusalem, Israel.
Purpose: A pseudohypopyon stage (PHS) was described in AdultOnset Foveomacular Vitelliform Dystrophy (AFVD). At this stage,
optical coherence tomography (OCT) demonstrate a lesion that is
composed of hyperreflective material that was described to settle
in the inferior part of the lesion and a hyporeflective material at the
superior part. We sought to characterize this stage of the disease.
Methods: Clinical and multimodal imaging database including
126 AFVD eyes (n= 68 patients) was evaluated to identify the
PHS. All patients in the database were previously genotyped
negative for mutations in genes previously associated with AFVD
(PRPH2, BEST1, IMPG-1, and IMPG-2). Demographics, clinical
characteristics, SD-OCT findings, color and fundus autofluorescence
findings and microperimetry studies were retrospectively analyzed.
Results: Seven eyes (6 patients; male/female=3/3) harboring PHS,
follow-up was 27±7.2 months (range: 18-32). All eyes remained
in the PHS during the follow-up. In SD-OCT, hyperreflective
material was demonstrated between the retinal pigmented epithelium
and the ellipsoid zone in the temporal aspect of the lesion while
hyporeflective material was evident nasally in six eyes; one eye
had hyporeflective material in the superior lesion portion (P=0.01
for vertical vs. lateral distribution of lesion material). Ellipsoid
zone remained intact above the hyperreflective area in 6 eyes, and
disrupted above the hyporeflective area in 6 eyes. Mean±SD lesion
size (width and height) at baseline were 1518±498 and 212±60
micron, respectively, and 1404±364 and 172±52 micron at the last
visit (P=NS). The mean best corrected visual acuity (BCVA) at
presentation and at last follow-up was 0.20±0.25 LogMAR and
0.26±0.19 LogMAR, respectively (P=0.014). Microperimetry
demonstrated better retinal sensitivity over the hyperreflective
compared with the hyporeflective lesion area. FAF demonstrated
intense hyperautofluorescence over the hyperreflective area.
Conclusions: PHS in AFVD is uncommon. It composes a relatively
large lesion where the degenerative process is usually initiated at the
nasal side, and does not respect gravity. This process is accompanied
by altered retinal function manifested by decreased sensitivity and
progressive visual loss at a mean the rate of less than one ETDRS
line during 2 years.
Commercial Relationships: Liran Tiosano, None;
Edward Averbukh, None; Itay Chowers, None
Program Number: 2701 Poster Board Number: C0152
Presentation Time: 3:45 PM–5:30 PM
Multimodal Imaging Analysis of Cone Photoreceptors Mosaic in
Human Juvenile X-linked Retinoschisis
Lucia Ambrosio1, 2, James D. Akula1, 2, Tara L. Favazza1,
Emily A. Swanson1, Robert J. Munro1, Matthew Swanson1,
Anne Moskowitz1, 2, Ronald M. Hansen1, 2, Anne B. Fulton1, 2.
1
Ophthalmology, Boston Children’s Hospital, Boston, MA;
2
Ophthalmology, Harvard Medical School, Boston, MA.
Purpose: Juvenile X-linked retinoschisis (XLRS) is characterized
by the formation of schitic cavities within the retinal layers. XLRS
is a monogenic disease caused by mutation in the RS1 gene.
Retinoschisin (RS) is an extracellular binding protein secreted
from retinal cells as a disulphide-linked octamer. Although most
classes of adult retinal neurons express RS, it is most abundant in
photoreceptors. One putative mechanism in XLRS is the failure of
RS to cross the photoreceptor membrane to the extracellular space,
causing it to accumulate in photoreceptors which become swollen and
sick. We studied the cone mosaic in adaptive optics (AO) scanning
light ophthalmographic (SLO) images of XLRS retinae.
Methods: A 17 year old boy with a Trp96Arg missense mutation in
the RS1 gene and a 12 year old boy with an unspecified mutation
were studied. Following a standard clinical examination, images
of the macula from 2°-10° eccentric along the horizontal meridian
were obtained using our multimodal adaptive optics retinal imager
(MAORI). Cones were identified in these images using a semiautomated routine. The diameter of every identified cone was
measured by calculating the number of pixels at the half-height of
the intensity distribution of the cone 2(pixels/π)½. To convert pixels
to degrees to microns, the ‘angular subtense’ of 1° of retina was
estimated using the parameters of Gullstrand’s Schematic Eye No. 2.
Results: The 17 year old XLRS subject presented with Snellen visual
acuity 20/38 (1.91 minutes of arc) in the imaged eye. His spherical
equivalent was -0.75 D. Central macular thickness was 296 µm;
the AO-SLO also showed apparent swelling of the inner segments.
Patchy views of the photoreceptors were obtained, between the
schitic cavities, in the AO-SLO. Cone diameter was 4.2 µm. In the
12 year old subject, Snellen acuity was 20/100 (5.01 minutes of arc);
spherical equivalent was 1.13 D, central macular thickness was 335
µm and cone diameter was 3.5 µm. In contrast, in control subjects
(n=7), cone diameter is 3.1±0.45 µm.
Conclusions: The diameters of the cones displayed in AO-SLOs
were larger in XLRS than normal subjects, consistent with putative
swelling. Conceivably the abnormal protein is trapped in the inner
segment. However, poor fixation XLRS subjects may have led to
more eccentric scans, or, perhaps, only the largest and brightest cones
were visible due to disease.
Commercial Relationships: Lucia Ambrosio, None;
James D. Akula, None; Tara L. Favazza, None; Emily A. Swanson,
None; Robert J. Munro, None; Matthew Swanson, None;
Anne Moskowitz, None; Ronald M. Hansen, None;
Anne B. Fulton, None
Support: EY010597 (ABF)
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.
ARVO 2016 Annual Meeting Abstracts
Program Number: 2702 Poster Board Number: C0153
Presentation Time: 3:45 PM–5:30 PM
Long term visual and anatomic outcomes of Type 1 Macular
Telangiectasia
Bish Pal1, Celine Sys2, Maria Gkika1. 1Medical Retina, Moorfields
Eye Hospital, London, United Kingdom; 2AZ Sint-Lucas, Bruges,
Belgium.
Purpose:
To report visual and anatomic outcomes of different management
options in eyes with Type 1 idiopathic Macular Telangiectasia
(MacTel)
Methods:
A retrospective review of patients with symptomatic MacTel Type 1
seen at Moorfields Eye Hospital was performed. Eyes with diabetic
retinopathy, age-related macular degeneration, or any other macular
pathology were excluded. Demographic data, medical and ocular
history, best-corrected visual acuity (BCVA) and central retinal
thickness (CRT) measured by optical coherence tomography (OCT)
were recorded
Results:
12 eyes were included in this study. 6 eyes were treated with macular
laser (Group1) and 4 eyes with a combination of treatment (macular
laser±intravitreal antivascular endothelial growth factor±intravitreal
steroids) (Group2). 2 patients were just observed (Group3). In all
treated eyes treatment was initiated if BCVA was less than 6/9
Snellen. Mean age was 48.3±15.3 years. At the last follow-up,
there was a mean±SD decrease in BCVA of 1±1.3 lines in Group1,
0.8±1.7 lines in Group2 and 0.5±0.7 lines in Group3. In 5 eyes
BCVA was stable. These were eyes that either left untreated because
BCVA was better than 6/9 Snellen or their treatment was initiated
when BCVA was better than 6/18 Snellen. In 1 eye (Group2) there
was an improvement of 1 line. However, BCVA changes are not
at a statistically significant level (p=0.105, Wilcoxon Singed Rank
Test). Also, CRT changes are not statistically significant (p=0.638,
Wilcoxon Singed Rank Test). OCT revealed intraretinal cysts and
exudates in all eyes, however their presence is not correlated to
BCVA (p=0.777, Spearman Test). BCVA preservation is related to
extrafoveal disease manifestation. Disruption of the photoreceptor
layer is related to worse initial and final BCVA.
Conclusions:
Macular laser alone or in combination with other treatments
stabilised, but did not improve the BCVA or CRT significantly in
eyes with Type 1 MacTel. The suboptimal outcomes may be related
to the retrospective nature of the study with small sample size. If the
treatment is initiated early in the disease the outcomes maybe better.
Commercial Relationships: Bish Pal, Novartis (R); Celine Sys,
None; Maria Gkika, None
Support: Moorfields Eye Hospital and National Institute of Health
Research Grant
Program Number: 2703 Poster Board Number: C0154
Presentation Time: 3:45 PM–5:30 PM
Comparsion of autofluorescence patterns in patients with myopic
neovascular membrane with BCVA
Ali Hadi AlHassany, Manju Chandran, Geeta Menon. Retina, Frimley
Health NHS Foundation Trust, Swindon, United Kingdom.
Purpose: It has been well known that metabolic activity of the
photoreceptor- RPE complex can be reflected in distinguished
autofluorescence patterns of different pathologies of the retina. These
patterns can help early disease detection and monitoring of its activity
where conventional colour fundus photographs show little if any
of these changes. The current study is to correlate visual outcome
with pre-treatment fundus autofluorescence in myopic choroidal
neovascular membrane.
Methods: 11 eyes from 11 patients were involved in this study with
diagnosis of myopic CNV that has been confirmed at the initial visit.
Patients’ age range was 23-69 with mean age of 47. Patients’ baseline
BCVA was recorded and FAF were recorded and follow up was four
weekly.
Results: There was an average gain of 19 lettres in patients
whether receiving Ranibizumab or Bevacizumab for myopic CNV.
The median BCVA for patients before treatment was 64, and the
median was 82.75 after first treatment. Subfoveal hypoflourescence
on autoflourescence was associated with thickness of more than
300microns in 8 patients, less than 300microns in 2 patients.
Hyperflourescence was associated with thickness of less than 300
microns in 1 patient.
Conclusions: We tried to correlate the autofluorescence patterns in
a group of patients with myopic CNV, before and soon after starting
first treatment, with BCVA and OCT images. From our findings, we
can notice there is improvement in the majority of patients gaining
an average of 19 letters whether those received Bevacizumab or
Ranibizumab. We can also notice that there is hypofluorescnence
on FAF associated with thickness of more than 300 microns in 8
patients, less than 300 microns in 2 patients. Hyperfluorescence
was noticed in 1 patient associated with thickness of less than 300
microns. Using a paired t-test, The two-tailed P value equals 0.0009,
the difference is considered statistically very significant. We can
conclude, therefore, in the majority of patients there is a gain of
average of 19 letters on vision chart associated with hypofluorescence
on FAF and thickness of more than 300 microns on OCT. Therefore,
patients receiving anti-VEGF treatment for myopic CNV could be
followed up and visual prognosis could be anticipated from this
association.
Commercial Relationships: Ali Hadi AlHassany, None;
Manju Chandran, None; Geeta Menon, None
Program Number: 2704 Poster Board Number: C0155
Presentation Time: 3:45 PM–5:30 PM
OCT Angiography in Adult Onset Foveomacular Vitelliform
Dystrophy
Komal Joshi, Peter L. Nesper, Amani A. Fawzi, Rukhsana Mirza.
Ophthalmology, Northwestern University, Chicago, IL.
Purpose: To describe findings of Adult-Onset Foveomacular
Vitelliform Dystrophy (AOFVD) on Optical Coherence Tomography
Angiography.
Methods: Case series of eight consecutive patients (14 eyes) with
AOFVD. Patients were studied with Spectral Domain Optical
Coherence Tomography (SD-OCT) and OCT Angiography. OCT
Angiography images were obtained using the RTVue-XR Avanti
system (Optovue Inc., Femont, California) with split-spectrum
amplitude-decorrelation angiography (SSADA) software. Main
Outcome measures were presence or absence of choroidal
neovascularization and any unifying patterns that could be identified
on OCT angiography for AOFVD.
Results: Eight consecutive patients (14 eyes) were studied with
SD-OCT and OCT angiography. Patients with clinical exam findings
consistent with AOFVD received SD-OCT. Eyes with hyperreflective material above the RPE and below the Inner Segment/
Outer Segment layer, consistent with vitelliform lesion on SD-OCT
were further analyzed with OCT angiography. 1 of 14 eyes (7%) had
Choroidal Neovascularization under the vitelliform lesion on OCT
angiography. 9 of 14 eyes (64%) had shadowing of superficial/deep
capillary plexus onto the outer retina giving the false appearance of
choroidal neovasculariztion in the region of the vitelliform lesion.
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.
ARVO 2016 Annual Meeting Abstracts
All 14 eyes (100%) had blockage of flow signal under the vitelliform
lesion that presented as artifactual loss of choriocapillaris under the
vitelliform lesion.
Conclusions: OCT angiography can be used as a non-invasive
imaging modality to visualize choroidal neovascularization in
AOFVD. There are common artifacts that must be considered when
analyzing OCT angiography with vitelliform lesions, including
shadowing of superficial retinal vessels onto the outer retina and
blockage of signal giving the appearance of lost choriocapillaris
under the vitelliform lesion.
Commercial Relationships: Komal Joshi, None; Peter L. Nesper,
None; Amani A. Fawzi, None; Rukhsana Mirza, 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.