MICHAEL A. KLUFAS, MD,* IRENA TSUI, MD,*† SRINIVAS R. SADDA, MD,† HAMID HOSSEINI, MD,* STEVEN D. SCHWARTZ, MD*

Purpose: To report the ultrawidefield fundus autofluorescence (UWF-FAF) patterns in ABC4A Stargardt disease. Methods: A retrospective cohort study of patients with a clinical diagnosis of Stargardt disease, confirmed ABCA4 genotype, and ultrawidefield fundus autofluorescence imaging using an Optos P200Tx. Four independent graders evaluated the images. Ultrawidefield fundus autofluorescence images were evaluated for the presence of posterior pole and peripheral findings, and were classified into one of three types (Type I: lesions confined to the macula with no peripheral findings; Type II: macular atrophy with flecks only in the periphery; Type III: macular atrophy and varying degrees of peripheral atrophy).

Results: Ultrawidefield fundus autofluorescence was performed on 58 eyes of 29 patients. Reviews of images revealed the presence of peripheral (outside the 55° view of standard nonwidefield FAF imaging) alterations on UWF-FAF in 76% of eyes. Overall, the UWF-FAF pattern was classified as Type I in 24% eyes (14/58), Type II in 24% (14/58), and Type III in 52% (30/58). The most common genetic mutations were c.2588G.C (6/29 patients, 20.7%), and c.5882G.A (5/29 patients, 17.2%).

Conclusion: Ultrawidefield fundus autofluorescence reveals peripheral changes in the majority of patients with Stargardt disease. Peripheral FAF changes may have implications for diagnosis, prognosis, and management of individual patients with Stargardt disease.

RETINA 0:1–13, 2017

Stephen James Talks, FRCOphth, Akhunzada Muhammad Aftab, FCPS, Imran Ashfaq, FRCOphth, MRCS(Ed), and Taha Soomro, MBBS

Abstract:

The use of imaging for age-related macular degeneration (AMD) depends on how it benefits clinical management and on reimbursement. The latter should relate to the former. This review assesses how different forms of AMD can be imaged and what information this provides. For nonneovascular AMD high-resolution optical coherence tomography (OCT), autofluorescence, and near infrared imaging can identify the type of drusen, such as reticular pseudodrusen, which influences prognosis, and the amount of atrophy, for which phase 3 trials are underway. Clarifying the correct diagnosis for late-onset Stargardt and macular telangiectasia, if treatment becomes available, will be especially important. Choroidal thickness can be measured and changes with anti‒vascular endothelial growth factor treatment, but how this influences management is less clear. The finding of a thick choroid may alter the diagnosis to pachychoroid neovasculopathy, which may have a different treatment response. Peripheral retinal changes are commonly found on ultrawide-field imaging but their importance is not yet determined. The mainstay of imaging is OCT, which can detect neovascular AMD by detecting thickening and be used for follow-up, as the presence or absence of thickening is the main determinant of treatment. Higher resolution systems and now OCT angiography are able to distinguish neovascular type, especially type 2 choroidal neovascularization but also polypoidal choroidal vasculopathy and retinal angiomatous proliferation. Fundus fluorescein and indocyanine green angiographies still have a role, although that partly depends on whether photodynamic therapy is being considered. Automated image analysis and machine learning will be increasingly important in supporting clinician decisions.Key Words: age-related macular degeneration, imaging, optical coherence tomography, optical coherence tomography angiography, fundus autofluorescence(Asia-Pac J Ophthalmol 2017;6:498–507)

Rodolfo Mastropasqua1☯³, Lisa Toto2☯³*, Enrico Borrelli2, Luca Di Antonio2, Peter A. Mattei2, Alfonso Senatore2, Marta Di Nicola3, Cesare Mariotti4 1 Moorfields Eye Hospital, NHS Foundation Trust, London, United Kingdom, 2 Department of Medicine and Science of Ageing, Ophthalmology Clinic, University G. D'Annunzio Chieti-Pescara, Chieti, Italy, 3 Department of Experimental and Clinical Sciences, Laboratory of Biostatistics, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy, 4 Department

Abstract

Background to assess vessel density of superficial capillary plexus (SCP), deep capillary plexus (DCP) and choriocapillaris (CC) in advanced Stargardt disease (STGD) using optical coherence tomography angiography (OCTA) and correlate these findings with macular function using pattern electroretinogram (PERG) and multifocal electroretinogram (mfERG). Methods Twelve patients (24 eyes) with advanced STGD underwent vessel densities and macular thickness measurements using OCTA. A control group of 24 healthy controls (24 eyes) was chosen for comparison. In the STGD group correlation between vessel density and macular thickness and between macular function and morphologic parameters were evaluated.

Results Whole parafoveal vessel density (VD) of SCP was significantly lower in STGD group compared to the control group (p<0.05). Foveal VD and whole parafoveal VD of the DCP were significantly lower in STGD group compared to the controls (p<0.05). CC was significantly decreased in STGD compared to controls (p<0.05). Foveal macular thickness (MT), full parafoveal MT, and inner limiting membrane (ILM)-inner plexiform layer (IPL) parafoveal MT thickness were decreased in STGD eyes compared to controls (p<0.001). PERG and mfERG were both significantly reduced in STGD compared to controls (p<0.001). A direct correlation was found between full parafoveal MT and vessel density in the STGD group.

Conclusions Patients with advanced STGD showed a reduction of SCP, DCP and CC compared to healthy eyes related to a reduction of total and ILM-IPL macular thickness. These results

Tommaso Verdina1 & Vivienne C. Greenstein2 & Andrea Sodi3 & Stephen H. Tsang2,4 & Tomas R. Burke2 & Ilaria Passerini5 & Rando Allikmets2,4 & Gianni Virgili3 & Gian Maria Cavallini 1 & Stanislao Rizzo3

Abstract

Purpose The purpose of our study was to investigate morphofunctional features of the preferred retinal location (PRL) and the transition zone (TZ) in a series of patients with recessive Stargardt disease (STGD1). Methods Fifty-two STGD1 patients with at least one ABCA4 mutation, atrophy of the central macula (MA) and an eccentric PRL were recruited for the study. Microperimetry, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) were performed. The location and stability of the PRL along with the associated FAF pattern and visual sensitivities were determined and compared to the underlying retinal structure. Results The mean visual sensitivity of the PRLs for the 52 eyes was 10.76 +/- 3.70 dB. For the majority of eyes, PRLs were associated with intact ellipsoid zone (EZ) bands and qualitatively normal FAF patterns. In 17 eyes (32.7%) the eccentric PRL was located at the edge of the MA. In 35 eyes (67.3%) it was located at varying distances from the border of the MAwith a TZ between the PRL and the MA. The TZ was associated with decreased sensitivity values (5.92 +/- 4.69 dB) compared to PRLs (p<0.05), with absence/disruption of the EZ band and abnormal FAF patterns (hyper or hypoautofluorescence). Conclusions In STGD1 eccentric PRLs are located away from the border of MA and associated with intact EZ bands and normal FAF. The TZ is characterized by structural and functional abnormalities. The results of multimodal imaging of the PRL and TZ suggest a possible sequence of retinal and functional changes with disease progression that may help in the planning of future therapies; RPE dysfunction appears to be the primary event leading to photoreceptor degeneration and then to RPE loss.

Keywords

Fundus autofluorescence . Fundus flavimaculatus . Eccentric fixation . Microperimetry . Preferred retinal location . SD-OCT . Stargardt disease

Maurizio Battaglia Parodi,1 Pierluigi Iacono,2 Giacinto Triolo,1 Carlo La Spina,1 Ilaria Zucchiatti,1 Maria Vittoria Cicinelli,1 Enrico Borrelli,1 Maria Pia Manitto,1 Elisabetta Martina,1 Francesco Bandello1

ABSTRACT

Background To correlate patterns in short-wavelength (SW) and near-infrared (NIR) fundus autofluorescence (FAF) with morpho-functional outcomes in eyes affected by Stargardt disease. Methods Fifty-four eyes of 27 patients were prospectively enrolled. All patients underwent a complete ophthalmologic examination including SW-FAF, NIR-FAF, microperimetry and spectral-domain optical coherence tomography (SD-OCT). The main outcome measures were identification of a correlation between NIR-FAF and SW-FAF patterns within the foveal region and best corrected visual acuity (BCVA) values. Secondary outcome measures were correlation of FAF patterns with SD-OCT findings and retinal sensitivity on microperimetry.

Results

Eyes showing a pattern of foveal hyper-FAF on NIR-FAF had a higher BCVA than eyes with a reduced FAF signal (0.44±0.23 LogMAR vs 1.08±0.19, p<0.001). Similarly, mean sensitivity within 2° of the foveal region was significantly better (6.45±2.39 dB) in eyes with hyper-FAF than in eyes with hypo-FAF (0.23 ±0.45 dB, p<0.001). Moreover, eyes with hyper-FAF on SW-FAF did not present a significant difference in BCVA (0.73±0.31 vs 0.83±0.43, p=0.335) and mean retinal sensitivity (4.34±3.91 dB vs 2.33±2.96, p=0.07) compared with the subgroup with foveal hypo-FAF. The integrity of both the photoreceptor inner/outer segment junction and the photoreceptor outer segment/retinal pigmented epithelium junction was significantly correlated with a preserved BCVA and a foveal hyper- FAF pattern on NIR-FAF.

Conclusions

Our data suggest that NIR-FAF patterns correlate with morpho-functional outcomes in eyes affected by Stargardt disease. Longitudinal investigations are warranted to assess more precisely the actual contribution of NIR-FAF in the clinical characterisation of Stargardt disease.

Paola Sasso,MD,PhD,* Andrea Scupola,MD,† Valeria Silvestri,CO,* FilippoM.Amore,MD,PhD,* Edoardo Abed,MD,† Luigi Calandriello,MD,† Gabriela Grimaldi,MD,† Aldo Caporossi,MD

Vinod Kumar1

Abstract

Purpose To characterize autofluorescence (AF) patterns occurring in Stargardt macular dystrophy (STGD1) using ultrawide- field (UWF) imaging. Methods This paper is a cross-sectional observational study of 22 eyes of 11 patients (mean age 23.44 years) with Stargardt disease-fundus flavimaculatus who presented with decrease of vision at a tertiary eye care center. UWF short-wave AF images were obtained from all the patients using an Optos TX200 instrument. The main outcome measures were to assess patterns of AF changes seen on UWF AF imaging. Results All eyes showed a central area of hypoautofluorescence at the macula along with retinal flecks extending centrifugally as well as to the nasal side of the optic disc. Peripapillary sparing was seen in 100% of the eyes. Flecks were seen to be hypoautofluorescent in the center and hyperautofluorescent in the periphery in 77.8% eyes and were only hyperfluorescent in 27.2%. A background-increased fluorescence was visible in 100% of eyes, the outer boundary of which was marked by distribution of flecks in 81.9% eyes. A characteristic inferonasal vertical line was seen separating the nasal hypoautofluorescent area from the temporal hyperautofluorescent area in all the eyes. Conclusions UWF AF changes in STGD1 are not limited to the posterior pole and may extend more peripherally. UWF imaging is a useful tool for the assessment of patients with Stargardt macular dystrophy.

Keywords

Autofluorescence . Fundus flavimaculatus . Stargardt disease . Ultra-wide field

AnnaM. Tracewska 1,*, Beata Kocyła-Karczmarewicz 2, Agnieszka Rafalska 3, JoannaMurawska 4, Joanna Jakubaszko-Jablonska 3,5,6,Małgorzata Rydzanicz 7, Piotr Stawi ´nski 7, El˙zbieta Ciara 2 , Muhammad Imran Khan 8,9, Arjen Henkes 8,9, Alexander Hoischen 8,10, Christian Gilissen 9,10, Maartje van de Vorst 8,9, Frans P.M. Cremers 8,9, Rafał Płoski 7,y and Krystyna H. Chrzanowska 2,y

Abstract:

Mutations in retina-specific ATP-binding cassette transporter 4 (ABCA4) are responsible for over 95% of cases of Stargardt disease (STGD), as well as a minor proportion of retinitis pigmentosa (RP) and cone-rod dystrophy cases (CRD). Since the knowledge of the genetic causes of inherited retinal diseases (IRDs) in Poland is still scarce, the purpose of this study was to identify pathogenic ABCA4 variants in a subgroup of Polish IRD patients. We recruited 67 families with IRDs as a part of a larger study. The patients were screened with next generation sequencing using a molecular inversion probes (MIPs)-based technique targeting 108 genes involved in the pathogenesis of IRDs. All identified mutations were validated and their familial segregation was tested using Sanger sequencing. In the case of the most frequent complex allele, consisting of two variants in exon 12 and 21, familial segregation was tested using restriction fragment length polymorphism (RFLP). The most prevalent variant, a complex change c.[1622T>C;3113C>T], p.[Leu541Pro;Ala1038Val], was found in this cohort in 54% of all solved ABCA4-associated disorder cases, which is the highest frequency reported thus far. Additionally, we identified nine families displaying a pseudo-dominant mode of inheritance, indicating a high frequency of pathogenic variants within this population.

Keywords: ABCA4; Stargardt disease; cone-rod dystrophy; retinitis pigmentosa; inherited retinal disorders

Chantal Dysli,1 Sebastian Wolf,1 Katja Hatz,2,3 and Martin S. Zinkernagel1

1Department of Ophthalmology and Department of Clinical Research, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland 2Vista Klinik, Binningen, Switzerland 3University Hospital Basel, Basel, Switzerland

PURPOSE.

The purpose of this study was to describe autofluorescence lifetime characteristics in Stargardt disease (STGD) using fluorescence lifetime imaging ophthalmoscopy (FLIO) and to investigate potential prognostic markers for disease activity and progression. METHODS. Fluorescence lifetime data of 16 patients with STGD (mean age, 40 years; range, 22– 56 years) and 15 age-matched controls were acquired using a fluorescence lifetime imaging ophthalmoscope based on a Heidelberg Engineering Spectralis system. Autofluorescence was excited with a 473-nm laser, and decay times were measured in a short (498–560 nm) and long (560–720 nm) spectral channel. Clinical features, autofluorescence lifetimes and intensity, and corresponding optical coherence tomography images were analyzed. One-year follow-up examination was performed in eight STGD patients. Acquired data were correlated with in vitro measured decay times of all-trans retinal and N-retinylidene-N-retinylethanolamine.

RESULTS. Patients with STGD displayed characteristic autofluorescence lifetimes within yellow flecks (446 ps) compared with 297 ps in unaffected areas. In 15% of the STGD eyes, some flecks showed very short fluorescence lifetimes (242 ps). Atrophic areas were characterized by long lifetimes (474 ps), with some remaining areas of normal to short lifetimes (322 ps) toward the macular center.

CONCLUSIONS.

Patients with recent disease onset showed flecks with very short autofluorescence lifetimes, which is possible evidence of accumulation of retinoids deriving from the visual cycle. During the study period, many of these flecks changed to longer lifetimes, possibly due to accumulation of lipofuscin. Therefore, FLIO might serve as a useful tool for monitoring of disease progression. (ClinicalTrials.gov number, NCT01981148.)

Keywords: fluorescence lifetimes, fundus autofluorescence, ophthalmic imaging, Stargardt disease, STGD, fundus flavimaculatus, retinal dystrophies, FLIO

Marco Nassisi 1,2 ID , Saddek Mohand-Saïd 1,3, Claire-Marie Dhaenens 4, Fiona Boyard 1, Vanessa Démontant 1, Camille Andrieu 3, Aline Antonio 1, Christel Condroyer 1, Marine Foussard 1, CécileMéjécase 1, Chiara Maria Eandi 2, José-Alain Sahel 1,3,5,6,7, Christina Zeitz 1,* ID and Isabelle Audo 1,3,8,* ID

Abstract:

Here we report novel mutations in ABCA4 with the underlying phenotype in a large French cohort with autosomal recessive Stargardt disease. The DNA samples of 397 index subjects were analyzed in exons and flanking intronic regions of ABCA4 (NM_000350.2) by microarray analysis and direct Sanger sequencing. At the end of the screening, at least two likely pathogenic mutations were found in 302 patients (76.1%) while 95 remained unsolved: 40 (10.1%) with no variants identified, 52 (13.1%) with one heterozygous mutation, and 3 (0.7%) with at least one variant of uncertain significance (VUS). Sixty-three novel variants were identified in the cohort. Three of them were variants of uncertain significance. The other 60 mutations were classified as likely pathogenic or pathogenic, and were identified in 61 patients (15.4%). The majority of those were missense (55%) followed by frameshift and nonsense (30%), intronic (11.7%) variants, and in-frame deletions (3.3%). Only patients with variants never reported in literature were further analyzed herein. Recruited subjects underwent complete ophthalmic examination including best corrected visual acuity, kinetic and static perimetry, color vision test, full-field and multifocal electroretinography, color fundus photography, short-wavelength and near-infrared fundus autofluorescence imaging, and spectral domain optical coherence tomography. Clinical evaluation of each subject confirms the tendency that truncating mutations lead to a more severe phenotype with electroretinogram (ERG) impairment (p = 0.002) and an earlier age of onset (p = 0.037). Our study further expands the mutation spectrum in the exonic and flanking regions of ABCA4 underlying Stargardt disease.

Keywords: ABCA4; Stargardt disease; phenotype-genotype correlation

Andrea Sodi1 & Dario Pasquale Mucciolo1 & Francesca Cipollini 1 & Vittoria Murro1 & Orsola Caporossi1 & Gianni Virgili1 & Stanislao Rizzo1

Abstract

Purpose To evaluate the structural features of the macular region by enface OCT imaging in patients with clinical diagnosis of Stargardt disease, confirmed by the detection of ABCA4 mutations. Methods Thirty-two STGD patients were included in the study for a total of 64 eyes. All patients received a comprehensive ophthalmological examination, color fundus photography, fundus auto-fluorescence imaging and OCT. Five OCT scans were considered: ILM and RPE scans (both automatically obtained from the instrument), above-RPE slab, photoreceptor slab and sub-RPE slab (these last three manually obtained). Results ILM scans showed evident radial folds on the retinal surface in 8/64 eyes (12.5 %). In 6 of the 7 patients, these vitreo–retinal interface abnormalities were unilateral. The photoreceptor slab showed some macular alterations ranging from dis-homogeneous, hypo-reflective abnormalities (7/64 eyes, 11 %) to a homogeneous, well-defined, roundish, hypo-reflective area (17/64 eyes, 27 %) in all the eyes. The sub-RPE slab showed a centrally evident, hyper-reflective abnormality in 58/64 eyes (90.6 %). Superimposing the sub- RPE slab over the images corresponding to the photoreceptor slab, the area of the photoreceptor atrophy sharply exceeded that of the RPE atrophy (44/46 eyes, 96 %). Conclusion Enface OCT proved to be a clinically useful tool for the management of STGD patients, illustrating in vivo the structural abnormalities of the different retinal layers.

Keyword Maculopathy . Stargardt . OCT . Photoreceptors . Retina . Dystrophy

SRUTHI AREPALLI, MD,* ELIAS I. TRABOULSI, MD, MED,* JUSTIS P. EHLERS, MD*†

Purpose:

To quantify and correlate ellipsoid zone and photoreceptor outer segment changes with visual acuity in Stargardt disease. Methods: An institutional review board–approved study of 32 eyes with Stargardt disease was performed. After spectral domain optical coherence tomography, the macular cube was exported into a novel analysis tool and volumetric assessment from the ellipsoid zone to the retinal pigment epithelium was performed. Using this information, mapping was completed with en face representation of the height between the ellipsoid zone and retinal pigment epithelium. This analysis provided quantification of ellipsoid zone and photoreceptor outer segments, including atrophy (ellipsoid zone to retinal pigment epithelium thickness = 0 mm) and attenuation (ellipsoid zone to retinal pigment epithelium thickness ,20 mm). These parameters were compared with visual acuity and controls (n = 12 eyes).

Results:

Visual acuity ranged from 20/30 to 20/250. The central foveal B-scan area of ellipsoid and photoreceptor outer segments was significantly less than controls (0.13 ± 0.05 mm2 vs. 0.17 ± 0.03 mm2, respectively, P = 0.0074). The central foveal B-scan mean thickness measured 22.52 ± 9.0 mm in Stargardt versus 30.0 ± 5.08 mm (P = 0.0096). Atrophy and attenuation were significantly higher in Stargardt patients (22% vs. 1%, P = 0.005 and 43% vs. 1%, P = 0.0002). Visual acuity directly correlated with ellipsoid zone/ outer segment volume (R = 0.57, P , 0.005) and inversely correlated with attenuation and atrophy (R = 20.53 and 20.57; P , 0.005 for all).

Conclusion:

Eyes with Stargardt disease frequently have significant disruption of the ellipsoid zone and outer segments. This degenerative change was successfully quantified with a novel assessment platform and identified correlates with visual function. This software provides the opportunity for quantitative assessment and possible longitudinal surveillance.

RETINA 0:1–5, 2017

DHANASHREE RATRA, MS,* ROY TAN, MMED,† DURGASRI JAISHANKAR, BSC,* NEHA KHANDELWAL, MS,† ARUSHI GUPTA, DOMS,‡ JAY CHHABLANI, MS,‡ RUPESH AGRAWAL, MD*§

Purpose:

To evaluate structural changes in the choroid of patients with Stargardt disease using swept source optical coherence tomography scans.

Methods:

A retrospective comparison cohort study was conducted on 39 patients with Stargardt disease, and on 25 age and gender matched-healthy controls. Subfoveal choroidal thickness (SFCT) was computed from the swept source optical coherence tomography machine, and the scans were binarized into luminal area and stromal areas, which were then used to derive choroidal vascularity index (CVI). Choroidal vascularity index and SFCT were analyzed independently using linear mixed effects model.

Results:

There was no significant difference in SFCT between the 2 groups (347.20 ± 13.61 mm in Stargardt disease vs. 333.09 ± 18.96 mm in the control group, P = 0.548). There was a significant decrease in the CVI among eyes with Stargardt disease as compared with the normal eyes (62.51 ± 0.25% vs. 65.45 ± 0.29%, P , 0.001). There was a negative association between visual acuity and CVI (correlation coefficient = 20.75, P , 0.001) and a positive association between visual acuity and SFCT (correlation coefficient = 0.21, P = 0.035).

Conclusion:

Choroidal vascularity index appears to be a more robust tool compared with SFCT for choroidal changes in Stargardt disease. Choroidal vascularity index can possibly be used as a surrogate marker for disease monitoring. A decrease in CVI was associated with a decrease in visual function in eyes with Stargardt disease. RETINA 0:1–6, 2017