ART 2015 AdvAnced ReTinAl TheRApy

ART 2015
Advanced retinal Therapy
Vienna, December 5th, 2015
www.artvienna.eu
Advanced retinal Therapy
www.artvienna.eu
Vienna, December 5th, 2015
Dear colleagues, experts and friends,
it is a great privilege to have you with us at the 12th conference of advanced retinal teaching (ART) 2015.
The clear focus of these annual get-togethers is to present, discuss and understand novel and relevant perspectives in the
field of retina with the potential to induce paradigm shifts. This includes novel diagnostic technologies as well as cuttingedge therapies. Identification of such relevant novel tools and targets is key and requires setting priorities in the selection
process. The philosophy of ART is to focus on translation of scientific advances into accepted therapies.
Angiographic OCT in retinal diagnosis is a brilliant example of improving practicality for patients and knowledge for doctors.
The modality has therefore rapidly gained acceptance in the clinics. It is now the responsibility of ophthalmologists to
extract as much diagnostic features as possible, but at the same time identify the key parameters, which impact disease
management in an efficient way. This requires a steep and collaborative learning curve to convert a novelty into benefit.
In terms of advanced therapy, anti-VEGF substances are about to leave the macula as its classical target and provides unexpected
efficacy in pathologies affecting the entire retina. Whether this path towards all-retina therapy in one of the leading diseases of
modern times, diabetic retinopathy, can be followed, how this should be done and which consequences are to be considered
both medically and economically opens a completely new discussion of pathogenetic and practical paradigms.
Yet, the retina is the representative of the brain in the eye. While visual signals are perceived at the level of the retina, true
visual perception is the consequence of processing in multiple specified centers in the brain. The keynote lecture of ART 2015
is given by Nancy Kanwisher, the Ellen Swallow Richards Professor in the Department of Brain and Cognitive Sciences at MIT
and member of the National Academy. Her research goes even beyond visual performance by identifying the neural and
cognitive mechanisms underlying human visual cognition and behaviour. With this insight into the human “visual mind” she
will open a series of talks capturing the state-of-knowledge of visual processing from the photoreceptor to the cortex.
Experts are sharing their comprehensive knowledge among each other and the community with the aim to bring innovation
from bench to bedside and from doctors to patients.
We invite you to join and enjoy this collaborative process and wholeheartedly welcome you to ART 2015 in Vienna
Sincerely
Ursula Schmidt-Erfurth
Professor and Chair
Department of Ophthalmology and Optometry
Medical University of Vienna
Director Christian Doppler Laboratory
for Ophthalmic Image Analysis (OPTIMA)
Feinberg School of Medicine
Northwestern University Chicago
Advanced retinal Therapy
www.artvienna.eu
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0 7.30Registration – until 13.00
08.30 Welcome & Opening
Ursula Schmidt-Erfurth
Professor and Chair, Department of Ophthalmology and Optometry, Medical University of Vienna
Director Christian Doppler Laboratory for Ophthalmic Image Analysis (OPTIMA)
Feinberg School of Medicine, Northwestern University Chicago
09.00 Value and understanding of OCT angiography
Moderation: Andreas Pollreisz
Head Translational Research Group, Medical University of Vienna
09.00
Patricia A. D’Amore
Boston (USA)
The vascular landscape in macular disease
Schepens Eye Research Institute, Harvard Medical School
09.15
Ruikang K. Wang
Seattle (USA)
Vascular feature detection by OCT technology in 2015 and beyond
Department of Bioengineering and Ophthalmology, University of Washington
09.30
André Romano
São Paulo (BR)
Neovista Eye Center, Federal University of São Paulo
09.45
Amani A. Fawzi
Chicago (USA)
The forefront of novel OCT-based vascular imaging
Feinberg School of Medicine, Northwestern University Chicago
10.00
Bénédicte Dupas
Paris (FR)
Department of Ophthalmology, Lariboisière Hospital
Clinical state-of-the-art in angiographic OCT
OCT angiography in healthy retinal and various vascular retina diseases
10.15 EXPERT PANEL DISCUSSION: OCT angiography
10.45 Coffee Break
11.15 Anti-VEGF therapy in the management of proliferative retinopathy
Moderation: Ursula Schmidt-Erfurth
Professor and Chair, Department of Ophthalmology and Optometry, Medical University of Vienna
Director Christian Doppler Laboratory for Ophthalmic Image Analysis (OPTIMA)
Feinberg School of Medicine, Northwestern University Chicago
11.15
Reinier O. Schlingemann Amsterdam (NL)
Is there enough evidence to switch from laser to anti-VEGF therapy in diabetic retinopathy?
Department of Ophthalmology, University of Amsterdam
11.30
Mary Elizabeth Hartnett Salt Lake City (USA)
Rationale, evidence and safety concerns for anti-VEGF therapy in proliferative angiogenesis
Department of Ophthalmology & Visual Sciences, Hartnett Laboratory, Moran Eye Center, University of Utah
11.45
Robert L. Avery
Santa Barbara (USA)
California Retina Consultants, University of California
Management of proliferative retinopathy: Are drugs eliminating the laser forever?
Is there enough evidence for a paradigm shift?
12.00
Jennifer K. Sun
Boston (USA)
Beetham Eye Institute, Harvard Medical School
Disease-modifying perspectives in diabetic retinopathy by intravitreal pharmacotherapy
12.15
Simon Harding
Liverpool (UK)
A realistic scenario of drug therapy in the real world
Department of Eye and Vision Science, University of Liverpool
12.30 EXPERT PANEL DISCUSSION: Anti-VEGF in proliferative retinopathy
13.00 Lunch Break
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Advanced retinal Therapy
www.artvienna.eu
14.00 KEYNOTE LECTURE: Vision and behaviour:
Understanding the role of vision and hearing in the brain
Nancy Kanwisher
Cambridge (USA)
Department of Brain & Cognitive Sciences, Massachusetts Institute of Technology
14.45 Imaging vision between retina and brain
Moderation: Andreas Reitner
Head Neuroophthalmology, Medical University of Vienna
14.45
Alipasha Vaziri
Vienna (AUT)
The efficacy of retinal perception: From a single photon to visual perception
Research Institute of Molecular Pathology (IMP), University of Vienna
14.55
Sebastian M. Waldstein Vienna (AUT)
Structure-function correlation by computational retinal imaging
Department of Ophthalmology, Medical University of Vienna
15.05
National Eye Institute
15.15
Graham E. Holder
Moorfields Eye Hospital
15.25
Berthold Pemp
Vienna (AUT)
The role of the optic nerve in visual function
Department of Ophthalmology, Medical University of Vienna
15.35
Jody C. Culham
London (CAN)
The neuroscience of human vision for perception and action
Culham Lab, Brain and Mind Institute, Western University
15.45
Markus Ritter
Vienna (AUT)
Imaging retinal disease in the brain
Department of Ophthalmology, Medical University of Vienna
Catherine A. Cukras
Bethesda (USA)
State-of-the-art retinal function testing in macular disease
London (UK)
Methods and means to differentiate functional deficits in the clinics
Advanced retinal Therapy
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Faculty
Robert L. Avery
Graham E. Holder
Ursula Schmidt-Erfurth
California Retina Consultants and Research
Foundation
University of California
Santa Barbara (USA)
Department of Electrophysiology
Moorfields Eye Hospital and Institute of
Ophthalmology
London (UK)
Professor and Chair
Department of Ophthalmology and
Optometry
Medical University of Vienna
Director Christian Doppler Laboratory
for Ophthalmic Image Analysis (OPTIMA)
Vienna (AUT)
Feinberg School of Medicine
Northwestern University Chicago
Chicago (USA)
Catherine A. Cukras
Nancy Kanwisher
Department of Epidemiology and Clinical
Applications
National Eye Institute, NIH
Bethesda (USA)
Department of Brain & Cognitive Sciences
Massachusetts Institute of Technology
Cambridge (USA)
Jody C. Culham
Department of Ophthalmology and
Optometry
Medical University of Vienna
Vienna (AUT)
Department of Psychology, Culham Lab,
Brain and Mind Institute
University of Western Ontario
London (CAN)
Patricia A. D’Amore
Schepens Eye Research Institute Massachusetts Eye and Ear
Departments of Ophthalmology and
Pathology, Harvard Medical School
Boston (USA)
Bénédicte Dupas
Department of Ophthalmology
Lariboisière Hospital
Paris (FR)
Amani A. Fawzi
Department of Ophthalmology
Feinberg School of Medicine
Northwestern University Chicago
Chicago (USA)
Simon Harding
Department of Eye and Vision Science
University of Liverpool
Honorary Consultant Ophthalmologist
Royal Liverpool University Hospital
Liverpool (UK)
Berthold Pemp
Andreas Pollreisz
Head Translational Research Group, Medical
University of Vienna
Vienna (AUT)
Andreas Reitner
Head Neuroophthalmology, Medical
University of Vienna
Vienna (AUT)
Markus Ritter
Department of Ophthalmology and
Optometry
Medical University of Vienna
Vienna (AUT)
André Romano
Department of Ophthalmology, Beetham Eye
Institute
Joslin Diabetes Center, Harvard Medical
School
Boston (USA)
Alipasha Vaziri
Research Institute of Molecular Pathology
(IMP), University of Vienna
Vienna (AUT)
Sebastian M. Waldstein
Department of Ophthalmology and
Optometry
Christian Doppler Laboratory for Ophthalmic
Image Analysis (OPTIMA)
Medical University of Vienna
Vienna (AUT)
Ruikang K. Wang
Department of Bioengineering and
Neovista Eye Center, Federal University of São Ophthalmology
Paulo, Paulista School of Medicine
University of Washington
São Paulo (BR)
Seattle (USA)
Henry C. Witelson Ocular Pathology
Laboratory at McGill University
Montreal (CAN)
University of Miami, Miller School of Medicine
Miami (USA)
Mary Elizabeth Hartnett
Reinier O. Schlingemann
Department of Ophthalmology & Visual
Sciences, Hartnett Laboratory
Moran Eye Center, University of Utah
Salt Lake City (USA)
Department of Ophthalmology
University of Amsterdam
Amsterdam (NL)
Scientific Management
Ursula Schmidt-Erfurth
epartment of Ophthalmology and Optometry
D
Medical University of Vienna
Tel. +43 1 40 400-48470
Fax +43 1 40 400-78890
Email [email protected]
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Jennifer K. Sun
Advanced retinal Therapy
www.artvienna.eu
Dieses Arzneimittel unterliegt einer zusätzlichen Überwachung. Dies ermöglicht
eine schnelle Identifizierung neuer Erkenntnisse über die Sicherheit. Angehörige von Gesundheitsberufen sind aufgefordert, jeden Verdachtsfall einer Nebenwirkung
zu melden. Bezeichnung des Arzneimittels: EYLEA® 40 mg / ml Injektionslösung
in einer Durchstechflasche. (Vor Verschreibung bitte die Fachinformation beachten).
Qualitative und quantitative Zusammensetzung: Wirkstoff: 1 ml Injektionslösung
enthält 40 mg Aflibercept*. Jede Durchstechflasche enthält 100 μl, entsprechend 4 mg
Aflibercept. Diese Menge reicht aus, um eine Einzeldosis von 50 μl, in denen 2 mg
Aflibercept enthalten sind, anzuwenden. *Fusionsprotein aus Fragmenten der extrazellulären Domänen der humanen VEGF-Rezeptoren (vaskulärer endothelialer Wachstumsfaktor) 1 und 2 und dem Fc-Fragment des humanen IgG1, hergestellt in Ovarialzellen chinesischer Hamster (CHO) vom Typ K1 mit Hilfe rekombinanter DNA-Technologie.
Sonstige Bestandteile: Polysorbat 20, Natriumdihydrogenphosphat 1 H2O, Dinatriumhydrogenphosphat 7 H2O, Natriumchlorid, Sucrose, Wasser für Injektionszwecke.
Pharmakotherapeutische Gruppe: Ophthalmika / Antineovaskuläre Mittel. ATC-Code:
S01LA05. Anwendungsgebiete: EYLEA® wird angewendet bei Erwachsenen zur
Behandlung der neovaskulären (feuchten) altersabhängigen Makuladegeneration (AMD),
einer Visusbeeinträchtigung aufgrund eines Makulaödems infolge eines retinalen
Venenverschlusses (RVV) (Venenastverschluss [VAV] oder Zentralvenenverschluss [ZVV])
und einer Visusbeeinträchtigung aufgrund eines diabetischen Makulaödems (DMÖ).
Dosierung und Art der Anwendung: Nur zur intravitrealen Injektion. Applikation nur
von einem qualifizierten Arzt mit Erfahrung in der Durchführung intravitrealer Injektionen. Empfohlene Dosis: 2 mg Aflibercept (0,05 ml) entsprechend 50 Mikroliter. Feuchte AMD: Initialbehandlung: 3 Injektionen im monatlichen Abstand, gefolgt von 1 Injektion alle 2 Monate. Eine Verlaufskontrolle zwischen den Injektionen ist nicht notwendig.
Nach den ersten 12 Monaten der Behandlung kann das Behandlungsintervall basierend
auf dem funktionellen und / oder morphologischen Befund verlängert werden. In diesem
Fall sollte das Kontrollintervall durch den behandelnden Arzt festgelegt werden, dieses
kann häufiger sein als das Injektionsintervall. RVV (Venenastverschluss [VAV] oder
Zentralvenenverschluss [ZVV]): Nach der Initialinjektion wird die Behandlung monatlich
fortgeführt. Der Abstand zwischen zwei Dosierungen sollte nicht kürzer als ein Monat
sein. Wenn der funktionelle und morphologische Befund darauf hinweisen, dass der
Patient nicht von einer weiteren Behandlung profitiert, sollte die Behandlung mit EYLEA®
beendet werden. Die monatliche Behandlung wird fortgeführt bis der maximale Visus
erreicht ist und / oder keine Anzeichen von Krankheitsaktivität mehr zu erkennen sind.
Drei oder mehr aufeinanderfolgende monatliche Injektionen können notwendig sein.
Unter Aufrechterhaltung des funktionellen und / oder morphologischen Befundes kann
das Behandlungsintervall entsprechend einem „Treat and Extend“-Schema schrittweise verlängert werden, allerdings liegen zu wenige Daten vor, um auf die Länge dieser
Intervalle schließen zu können. Wenn sich der funktionelle und / oder morphologische
Befund verschlechtert, sollte das Behandlungsintervall entsprechend verkürzt werden.
Die Kontroll- und Behandlungstermine sollten durch den behandelnden Arzt basierend
auf dem individuellen Ansprechen des Patienten festgesetzt werden. Die Kontrolle der
Krankheitsaktivität kann eine klinische Untersuchung, eine funktionelle Untersuchung
oder bildgebende Verfahren (z. B. eine optische Kohärenztomographie oder eine Fluoreszenzangiographie) beinhalten. Diabetisches Makulaödem: Initialbehandlung: fünf
aufeinanderfolgenden monatlichen Injektionen, gefolgt von einer Injektion alle zwei
Monate. Eine Verlaufskontrolle zwischen den einzelnen Injektionen ist nicht notwendig.
Nach den ersten 12 Monaten der Behandlung mit EYLEA® kann das Behandlungsintervall basierend auf dem funktionellen und / oder morphologischen Befund verlängert
werden. Das Kontrollintervall sollte durch den behandelnden Arzt festgesetzt werden.
Wenn der funktionelle und morphologische Befund darauf hinweisen, dass der Patient
nicht von einer weiteren Behandlung profitiert, sollte die Behandlung mit EYLEA®
beendet werden. Gegenanzeigen: Überempfindlichkeit gegen Aflibercept oder einen
der sonstigen Bestandteile. Bestehende oder vermutete okulare oder periokulare Infektion. Bestehende schwere intraokulare Entzündung. Warnhinweise und Vorsichtsmaßnahmen: Intravitreale Injektionen können zu einer Endophthalmitis führen.
Wenden Sie immer angemessene aseptische Injektionsmethoden an. Zusätzlich
sollten die Patienten innerhalb der ersten Woche nach der Injektion überwacht werden,
um im Falle einer Infektion eine frühzeitige Behandlung zu ermöglichen. Die Patienten
müssen alle Symptome, die auf eine Endophthalmitis hinweisen, unverzüglich melden.
Anstiege des Augeninnendrucks (IOP) wurden innerhalb von 60 Minuten nach intravitrealen Injektionen beobachtet. Besondere Vorsicht ist bei schlecht eingestelltem
Glaukom geboten (keine Injektion solange IOP ≥ 30 mmHg). In allen Fällen müssen
sowohl IOP als auch die Perfusion des Sehnervenkopfes überwacht und angemessen
behandelt werden. Möglichkeit der Immunogenität. Weisen Sie die Patienten darauf
hin, alle Anzeichen oder Symptome einer intraokularen Entzündung, z. B. Schmerzen,
Photophobie oder Rötung, zu berichten, da diese klinische Anzeichen einer Überempfindlichkeit sein könnten. Systemische Nebenwirkungen inklusive nicht-okularer
Hämorrhagien und arterieller thromboembolischer Ereignisse wurden nach intravitrealer
Injektion von VEGF-Hemmern berichtet. Die Sicherheit und Wirksamkeit einer gleichzeitigen Behandlung beider Augen mit EYLEA® wurde nicht systematisch untersucht.
Es liegen keine Erfahrungen zur gleichzeitigen Behandlung von EYLEA® mit anderen
anti-VEGF Arzneimitteln (systemisch oder okular) vor. Zu den Risikofaktoren, die nach
einer anti-VEGF Therapie bei feuchter AMD zur Entwicklung eines retinalen Pigmentepitheleinrisses führen können, gehören großflächige und / oder hohe Abhebungen
des retinalen Pigmentepithels. Zu Therapiebeginn ist Vorsicht bei Patienten mit diesen
Risikofaktoren geboten. Aussetzen der Behandlung bei Patienten mit rhegmatogener
Netzhautablösung oder Makulalöchern Grad 3 oder 4. Aussetzen der Behandlung bei
Einriss der Retina, bis der Riss adäquat verheilt ist. Aussetzen der Behandlung und
nicht vor dem nächsten geplanten Termin fortsetzen bei: Verminderung der bestmöglich korrigierten Sehschärfe von ≥ 30 Buchstaben im Vergleich zur letzten Messung;
subretinale Blutung, mit betroffenem Zentrum der Fovea oder bei Größe der Blutung
≥ 50 % der gesamten betroffenen Läsion. Aussetzen der Behandlung 28 Tage vor oder
nach einem durchgeführten oder geplanten intraokularen Eingriff. EYLEA® sollte während der Schwangerschaft nicht verabreicht werden, es sei denn der mögliche Nutzen
überwiegt das potenzielle Risiko für den Fetus. Frauen im gebärfähigen Alter müssen
während der Behandlung und für mindestens 3 Monate nach der letzten intravitrealen
Injektion von Aflibercept eine zuverlässige Verhütungsmethode anwenden. Personengruppen mit begrenzten Daten: Es gibt begrenzte Erfahrung bei der Behandlung von
Patienten mit ischämischen ZVV und VAV. Bei Patienten mit den klinischen Anzeichen
eines irreversiblen, ischämischen Visusverlustes ist die Behandlung nicht empfohlen.
Es gibt nur begrenzte Erfahrungen bei der Behandlung von Personen mit einem aufgrund
eines Typ I-Diabetes verursachten DMÖ oder bei Diabetikern mit einem HbA1c über
12 % oder mit proliferativer diabetischer Retinopathie. EYLEA® wurde nicht untersucht
bei Patienten mit aktiven systemischen Infektionen oder bei Patienten, die gleichzeitig
andere Augenerkrankungen wie eine Netzhautablösung oder ein Makulaloch hatten.
Es gibt ebenfalls keine Erfahrungen bei der Behandlung mit EYLEA® bei Diabetikern
mit nicht eingestelltem Bluthochdruck. Das Fehlen dieser Information sollte bei der
Behandlung dieser Patienten berücksichtigt werden. Nebenwirkungen: Sehr häufig:
Bindehautblutung, verminderte Sehschärfe. Häufig: Einriss des retinalen Pigmentepithels, Abhebung des retinalen Pigmentepithels, Netzhautdegeneration, Glaskörperblutung, Katarakt, Kernkatarakt, Subkapsuläre Katarakt, Kortikale Katarakt, Hornhauterosion, Hornhautabrasion, IOP-Anstieg, verschwommenes Sehen, Glaskörpertrübung,
Hornhautödem, Glaskörperabhebung, Schmerzen an der Injektionsstelle, Augenschmerzen, Fremdkörpergefühl im Auge, erhöhter Tränenfluss, Augenlidödem, Blutung an der
Injektionsstelle, Keratitis punctata, Bindehauthyperämie, okuläre Hyperämie; Gelegentlich: Erblindung, Überempfindlichkeit (einschließlich allergischer Reaktionen), Endophthalmitis, Netzhautablösung, Netzhauteinriss, Uveitis, Linsentrübung, Hornhautepitheldefekt, Reizung an der Injektionsstelle, abnorme Empfindung im Auge, Reizung
des Augenlids, Iritis, Iridocyclitis, Schwebeteilchen in der Vorderkammer; Selten:
traumatische Katarakt, Vitritis, Hypopyon. Nebenwirkungen bezogen auf die Wirkstoffgruppe: erhöhte Inzidenz von Bindehautblutungen bei Patienten, die antithrombotische Arzneimittel erhielten. Möglichkeit der Immunogenität. Pharmazeutischer
Unternehmer: Bayer Pharma AG, D-13342 Berlin, Deutschland. Verschreibungs-/
Apothekenpflicht: Rezept- und apothekenpflichtig, wiederholte Abgabe verboten.
Weitere Angaben zu Warnhinweisen und Vorsichtsmaßnahmen für die Anwendung,
Wechselwirkungen mit anderen Arzneimitteln und sonstigen Wechselwirkungen,
Schwangerschaft und Stillzeit und Nebenwirkungen entnehmen Sie bitte der veröffentlichten Fachinformation. Stand der Information: Februar 2015
L.AT.03.2015.1880
Augenblicke
voller Leben
Visusverbesserung ist mehr als
reiner Buchstabengewinn.*
1 Visusbeeinträchtigung aufgrund eines Makulaödems infolge eines retinalen
Venenverschlusses (RVV) bei Erwachsenen. Hiervon erfasst ist sowohl der
Venenastverschluss (VAV, Zulassung seit 02/2015) als auch der Zentralvenenverschluss (ZVV, Zulassung seit 08/2013).
* Fachinformation EYLEA®, Stand: Februar 2015.
Value and understanding of
OCT angiography
THE VASCULAR LANDSCAPE IN MACULAR DISEASE
Patricia A. D’Amore
Schepens Eye Research Institute - Massachusetts Eye and Ear
Departments of Ophthalmology and Pathology, Harvard Medical School
Boston (USA)
Abstract
The retina is unusual in that it has two blood supplies for such a thin tissue: the retinal vasculature, which supports the inner retina, and the
choroidal vasculature, which supplies the outer retina – especially the photoreceptors. Moreover, these two vascular beds are distinct in
their structure and function. The inner retinal vasculature is the site of the inner blood retinal barrier and so is characterized by extensive
tight junctions, dramatically reduced transcytosis and specialized surface transporters. In contrast, the choroidal vasculature, which is comprised of feeder vessels and an apical capillary plexus, is highly fenestrated. In addition, the choroid receives about 80 % of the blood flow
while the remaining 20 % versus the inner retina. In the outer retina, the retinal pigment epithelium is the site of the barrier. Both of these
vascular beds are the sites of major complication: diabetic retinopathy in the inner retina, neovascular AMD and geographic atrophy in the
outer retina. Diabetic macular edema is believed to arise primarily from the microvasculature of the inner retina, although a role for RPE
barrier breakdown has not been systematically investigated. The choriocapillaris is the source of new blood vessels in exudative AMD. The
growth and permeability of these vessels is driven by VEGF, a fact demonstrated by the response in many patients to anti-VEGF therapies.
Ironically, experimental data have demonstrated that normal capillaries are dependent on RPE-secreted VEGF for the maintenance of their
fenestrations, integrity and survival. As a result, the RPE loss that characterizes geographic atrophy is closely associated with the regression
of the underlying choriocapillaris.
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Value and understanding of
OCT angiography
VASCULAR FEATURE DETECTION BY OCT TECHNOLOGY IN 2015 AND BEYOND
Ruikang K. Wang
Department of Bioengineering and Ophthalmology
University of Washington
Seattle (USA)
Background
Optical coherence tomography based microangiography (OMAG) is a new retinal imaging modality that can be used to provide 3D retinal
microvascular networks without a need for contrasting agents. The OMAG data processing is based on OCT-complex signals, rather than
its amplitude or phase information. The purpose of this talk is demonstrate the capability of OMAG to deliver higher sensitivity detection
of blood flow imaging, and to provide wide field imaging of retinal vasculature, upon which to detect the vascular features of age related
macular degeneration (AMD) at different stages.
Methods
Twenty AMD patients were recruited, including early stage AMD, geographic atrophy (GA), neovascular AMD and polypoidal choroidal
vasculopathy (PCV); and scanned by a Cirrus 5000 HD-OCT (SD-OCT) angiography prototype and a high-speed 1050 nm swept-source OCT
(SS-OCT) prototype system (both from Carl Zeiss Meditec Inc., USA). For SS-OCT prototype, a 3×3 mm scanning area centered on the fovea
was captured for OMAG images. For SD-OCT, motion tracking feature was implemented into the prototype, which enabled large field of
view (FOV) OMAG images (> 7 mm x 7 mm). For data processing, OCT-complex signal differentiation approach was employed to extract
the blood flow from static tissue. The bulk tissue motion was removed by cross-correlation method. The 3D angiography was segmented
into 5 layers including superficial (GCL+IPL), deep (INL+OPL), subretinal (ONL -> Bruchs membrane), and choriocapillaris (CC) and choroid
layers. The en face maximum projection was used to obtain 2-dimensional angiograms at different layers coded with different colors for
better visualization. Flow and structure images were combined for cross-sectional view.
Results
En face OMAG images of AMD patients showed a great agreement with fluorescein angiography (FA) and ICG angiography (ICGA). OMAG
gave more distinct vascular network visualizations that were less affected by subretinal hemorrhage. The small drusen was observed in the
early stage AMD patient; however, the retinal vessels were manifest as normal subjects. For GA patient, the abnormality of RPE layer was
discovered and the choriocapillaries and large choroidal vessel were detected and observed by OMAG angiograms. Feeding and draining
vessels were found in neovascular AMD and PCV patients. The CNV regions were highly demarcated compared with FA images, which were
obscured by the leakage in the late phases.
Conclusion
OMAG provides depth-resolved information and detailed vascular images of AMD patients. The segmentation helped us observe the location of abnormal vessel. The color-coded angiograms gave more visualized view of blood vessel in different layers. Further studies should
be done to quantify OCT angiography and the role in treatment of neovascular AMD.
Advanced retinal Therapy
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7
Value and understanding of
OCT angiography
Clinical state-of-the art in angiographic OCT
André Romano
Neovista Eye Center, Federal University of São Paulo, Paulista School of Medicine
São Paulo (BR)
Henry C. Witelson Ocular Pathology Laboratory at McGill University
Montreal (CAN)
University of Miami, Miller School of Medicine
Miami (USA)
Background
Optical coherence tomography angiography (OCTA) is quick and non-invasive, and provides volumetric data with the clinical capability of
specifically localizing and delineating pathology along with the ability to show both structural and blood flow information in tandem. The
purpose of this study is demonstrate the potential of its use in various retinal and choroidal vascular diseases.
Methods
Cross-sectional, observational study of healthy subjects as well as in various retinal and choroidal vascular diseases.
OCTA was performed on 2 x 2, 3 × 3, 6 x 6, 8 x 8 mm sections centered on the fovea, nasal macula, temporal macula and optic nerve. Retinal
vasculature was assessed within four horizontal slabs consisting of the inner, middle, outer retina and choroicapillaries. The vasculature within
each retinal slab was reconstructed using phase-based and intensity contrast-based algorithms and visualized as separate en face images.
Results
OCTA demonstrates capillary networks consistent with previous histological studies in healthy and vascular diseases. No retinal vessels
were found in the outer retina.
Optical coherence tomography angiography provided more distinct vascular network patterns compared to fluorescein angiography in
both retinal and choroidal diseases. Microaneurysms, retinal nonperfusion areas, neovascularization in the posterior pole at the optic disc
and choroidal neovascularization were clearly visualized on OCT angiograms. OCT angiography showed specific vascular patterns that
consistently documented qualitative findings from previous histological studies.
Conclusion
OCTA is a new technology that has great potential for use in the clinical setting. Compared with FA and ICGA, the current retinal angiographic
gold standards, OCTA advantages are that it is non-invasive, acquires volumetric scans that can be segmented to specific depths, uses
motion contrast instead of intravenous dye, can be obtained within seconds, provides accurate size and localization information, visualizes
both the retinal and choroidal vasculature, and shows structural and blood flow information in tandem. It is a great and useful imaging
modality for the evaluation of common ophthalmologic diseases such AMD, diabetic retinopathy, artery and vein occlusions, and glaucoma.
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Advanced retinal Therapy
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Value and understanding of
OCT angiography
THE FOREFRONT OF NOVEL OCT-BASED VASCULAR IMAGING
Amani A. Fawzi, MD, Brian Soetikno, BS, Ronil Shah, BS, Ji Y, PhD, Wenzhong Liu, BS, Patryk Purta, BS, Hao Zhang, PhD
Department of Ophthalmology
Feinberg School of Medicine, Northwestern University Chicago
Chicago (USA)
Background
This study was designed to validate the ability of combination of visible-light OCT and Doppler OCT to quantify the oxygen saturation of
hemoglobin and blood flow within inner retinal vessels, enabling us to quantify the inner retinal oxygen consumption and metabolic rate
of oxygen (MRO2) in vivo.
Methods
Using a combination of animal models and human retinal imaging, we used visible light (560–600 nm) as a source for OCT imaging. This
wavelength maximizes our ability to measure blood flow as well as retinal vascular oxygen saturation in vivo. We used this approach in an
animal model of retinal ischemia, the oxygen induced retinopathy (OiR), as well as in an animal model of laser-induced neovascularization.
Results
In the OIR model, we observed that the retinal oxygen delivery was decreased by 61 % in the OiR group compared to controls at postnatal
day 18, at the height of proliferative retinopathy in this model. Using confocal microscopy of isolectin-stained retinal vascular flat mounts
showed decreased vascular density in the superficial and deep inner retinal networks in OiR rats, suggesting that the abnormal vascular
network played an important role in decreased oxygen delivery. Similarly, retinal MRO2 was 59 % lower in the OiR group compared to
controls. Retinal morphometric measurements on histopathologic examination showed statistically significant decreased thickness of all
retinal sublayers in the OiR group, suggesting that decreased retinal MRO2 was due to decreased retinal neuronal thickness and therefore
decreased oxygen consumption. In the laser-induced CNV model, vis-OCT was able to detect perfusion in the CNV lesion by 4–5 days, the
time point at which histopathological evidence of perfusion is also evident.
Conclusion
Capitalizing on the unique ability of visible OCT to simultaneously measure retinal oxygen saturation of hemoglobin, retinal vessel diameter,
and blood flow, we have quantified the retinal MRO2 in healthy rats and OiR at P18.
In addition, we combined this new technology with histological and immunostaining analysis to gain an improved understanding of the
relevant pathologic changes. The findings in this study add new insights into the pathophysiology of oxygen demand and consumption
in rats with OiR, which can be extrapolated to retinal ischemic diseases including proliferative diabetic retinopathy. These results will be
discussed in context of their implications for human diabetic retinopathy and neovascular AMD.
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9
Value and understanding of
OCT angiography
OCT ANGIOGRAPHY IN HEALTHY RETINA AND VARIOUS VASCULAR RETINAL DISEASES
Bénédicte Dupas
Department of Ophthalmology
Lariboisière Hospital
Paris (FR)
Background
Optical Coherence Tomography Angiography (OCTA) allows to image separately the superficial and deep capillary plexus (SCP and DCP,
respectively).
Methods
The authors report their experience of AngioVue, Optovue RTVue XR Avanti (Optovue, Inc., Freemont, CA) for exploring capillary plexus in
healthy retina and various diseases.
Results
In normal subjects, OCTA showed that the deep capillary vortexes drain into the superficial venules.
In Diabetic Retinopathy: OCTA shows microvasculature anomalies in both capillary plexus in RD. The ability of OCTA to detected MAs seems
inferior to that of FA but its accuracy for the evaluation of capillary non-perfusion is superior.
In MacTel 2, capillaries proliferate in the outer retina where the EZ is disrupted.
Conclusion
OCTA gives new information on retinal circulation in healthy retina and disease.
10
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Andreas Pollreisz
H
ead Translational Research Group, Medical University of Vienna
Vienna (AUT)
Experts
EXPERT PANEL DISCUSSION:
OCT angiography
Patricia A. D’Amore, Boston (USA)
Ruikang K. Wang, Seattle (USA)
André Romano, São Paulo (BR)
Amani A. Fawzi, Chicago (USA)
Bénédicte Dupas, Paris (FR)
12
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IS THERE ENOUGH EVIDENCE TO SWITCH FROM LASER TO ANTI-VEGF THERAPY IN
DIABETIC RETINOPATHY?
Reinier O. Schlingemann
Department of Ophthalmology
University of Amsterdam
Amsterdam (NL)
Abstract
Pan-retinal photocoagulation is the standard treatment for high-risk proliferative diabetic retinopathy. If applied early in the disease, this
treatment has life-long efficacy with few side effects. Pars plana vitrectomy is indicated in advanced cases with fibrovascular membranes
and a threat of tractional macular detachment.
With regards to anti-VEGF therapy as an adjuvant treatment a recent Cochrane review concluded; ‘very low or low quality evidence from RCTs
for the efficacy and safety of anti-VEGF agents when used to treat PDR over and above current standard treatments. However, the results
suggest that anti-VEGFs can reduce the risk of intraocular bleeding in people with PDR. Further carefully designed clinical trials should be
able to improve this evidence’ (Cochrane Database Syst Rev. 2014 Nov 24;11: Martinez-Zapata MJ et al.). Another systematic review was more
optimistic: ‘The use of anti-VEGF agents before PRP results in superior functional and structural outcomes at 3 months to 4 months. The use
of anti-VEGF agents before PPV results in decreased duration of surgery, fewer breaks, and less intra-operative bleeding. Although there is
evidence for a decreased incidence of early postoperative vitreous hemorrhage, the quality of evidence is low. The available data therefore
support the use of anti-VEGF agents as adjuncts to PRP and PPV in patients with complicated proliferative diabetic retinopathy primarily as
a means of facilitating, and potentially minimizing the iatrogenic damage resulting from, these procedures’ (Retina. 2015 Oct;35(10):1931–42:
Simunovic MP and Maberley DA).
A possible disadvantage of anti-VEGF therapy in PDR is the acceleration by anti-VEGF agents of the angio-fibrotic switch, the transition of
the angiogenic phase in PDR to fibrosis and traction. It has been suggested that this phenomenon is mediated by connective tissue growth
factor which may act in a critical balance with VEGF.
The use of anti-VEGF therapy as an alternative for PDR has several major disadvantages and not been studied in RCTs.
In conclusion, anti-VEGF therapy may be useful as an adjuvant treatment in the course of PDR and before PPV, but is use as a long term
alternative to PDR remains unknown.
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Anti-VEGF therapy in the management
of proliferative retinopathy
In the last 10–15 years, ample evidence has become available indicating that VEGF-A produced by ischemic retina is the key mediator of
angiogenesis in proliferative diabetic retinopathy. What is the evidence that anti-VEGF therapy may be a good adjunctive treatment, or
even acquire a role as an alternative for PRP?
RATIONALE, EVIDENCE AND SAFETY CONCERNS FOR ANTI-VEGF THERAPY IN
PROLIFERATIVE ANGIOGENESIS
Mary Elizabeth Hartnett
Department of Ophthalmology & Visual Sciences, Hartnett Laboratory
Moran Eye Center, University of Utah
Salt Lake City (USA)
Background
Blinding retinal diseases are associated with damaged capillaries that leak fluid into the retina or no longer support the retina and cause
non-perfusion with subsequent blood vessel growth (angiogenesis) into the vitreous. Photocoagulation seeks to treat leaking capillaries
and hypoxic avascular retina to relieve the stimuli causing aberrant intravitreal angiogenesis. Anti-vascular endothelial growth factor (VEGF)
therapies inhibit angiogenesis by binding VEGF and/or inhibiting receptor activation. Anti-VEGF for diabetic macular edema (DME) was
found optimal to laser in visual acuity and OCT outcomes in several clinical trials, although anti-VEGF improved only about 40 % of DME
cases. This presentation focuses on the rationale for anti-VEGF therapies, current clinical evidence and concerns regarding safety in proliferative angiogenic diseases, i.e., proliferative diabetic retinopathy (PDR) and severe retinopathy of prematurity (ROP), and provides thought
regarding differences in outcomes seen between laser and anti-VEGF therapy.
Anti-VEGF therapy in the management
of proliferative retinopathy
Methods
Review of literature from 2012 to Sept 2015 focusing on major clinical trials and preclinical data.
Results VEGF is essential for viability, and the requirement wanes in adulthood but does not go away. VEGF signaling has crosstalk with other pathways involved in the pathogenesis of proliferative angiogenic retinal diseases, including inflammatory, oxidative, metabolic and hypoxic
mechanisms, and inhibiting VEGF can lead to compensatory activation of other pathways. VEGF is increased in models of aberrant intravitreal
angiogenesis and in patients with PDR or severe ROP. Activation of VEGF signaling causes disordered developmental angiogenesis, allowing blood vessels to grow outside the plane of the retina rather than into ischemic retina, and increased expression of adhesion molecules
within capillaries. Both mechanisms increase avascular retina, a hypoxic stimulus for VEGF and angiogenic factors. These preclinical studies
also help explain clinical observations of reduced capillary nonperfusion with anti-VEGF treatment.
In DR clinical trials, compared to laser, anti-VEGF reduced worsening of retinopathy and improved DR severity. However, sustained IOP
elevation and serious vascular events were reported following anti-VEGF treatment.
In severe ROP, compared to laser, anti-VEGF was effective in reducing intravitreal angiogenesis (stage 3) in severe ROP and improving
vascularity of the avascular retina in clinical studies and one trial. However, concerns exist in the developing preterm infant with reports of
reduced serum VEGF for 2 months, persistent avascular retina and recurrence of retinopathy. Controversy exists regarding anti-VEGF effects
on refractive error and IOP. Among clinical studies, there are differences in enrolled preterm infant age and weight/blood volume, prenatal
and perinatal oxygen and nutritional factors, and in types of anti-VEGF agents and doses, limiting comparability.
Conclusion
There is rationale to interfere with pathologic over-activation of VEGF signaling to reduce avascular retina and aberrant intravitreal angiogenesis, but other mechanisms may be in play. In PDR, evidence supports anti-VEGF therapy in not only preventing worsening of, but also
improving DR severity. In severe ROP, evidence supports VEGF over-activation as a mechanism. In both PDR and ROP, concerns of long-term
safety exist. More studies are needed, especially in ROP, and awareness of differences in ROP phenotype and prenatal, perinatal and potential
genetic/epigenetic influences must be considered when comparing and designing clinical trials.
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MANAGEMENT OF PROLIFERATIVE RETINOPATHY: ARE DRUGS ELIMINATING THE LASER
FOREVER? IS THERE ENOUGH EVIDENCE FOR A PARADIGM SHIFT?
Robert L. Avery
California Retina Consultants and Research Foundation
University of California
Santa Barbara (USA)
Background
Laser treatment of proliferative diabetic retinopathy (PDR) was shown to be effective in reducing visual loss in pioneering randomized
controlled clinical trials which not only saved many patients’ vision, but paved the way for similar randomized trials in ophthalmology as
well as other fields of medicine. For decades, panretinal photocoagulation (PRP) has been the gold standard for the treatment of PDR, but
about 10 years ago, anti-VEGF agents were shown to have a beneficial but transient effect on PDR. Subsequent trials have shown some
benefit to these injections, but controversy remains as to the role of anti-VEGF agents for PDR.
Methods
Published studies of anti-VEGF for PDR are reviewed.
Conclusion
There is increasing evidence for a beneficial role of anti-VEGF agents in the treatment of PDR. Controversy still remains as to whether this
role is best as an adjunct to PRP, or as a replacement for PRP.
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Anti-VEGF therapy in the management
of proliferative retinopathy
Results Following numerous anecdotal reports demonstrating a beneficial effect of anti-VEGF agents on PDR, randomized clinical trials have
evaluated this effect. A recent Cochrane analysis reviewed 18 diverse randomized trials and found treatment was associated with better
vision and less bleeding in some trials, but the quality of the evidence was deemed very low to low quality. A smaller Cochrane analysis
of studies of preoperative anti-VEGF found some evidence supporting a reduction in postoperative vitreous hemorrhage rates with treatment, but again with limits due to the quality of data. The DRCR.net will soon report results of a prospective trial comparing anti-VEGF
injections to PRP. However, even if this study demonstrates superior outcomes for injections over PRP, there are risks that are difficult to
assess in clinical trials. For instance, in clinical practice, an individual patient may be lost to follow-up due to either non-compliance or
an extended illness, and in the absence of continued anti-VEGF injections, PDR could progress and develop serious complications with a
higher likelihood than if PRP had been administered.
DISEASE-MODIFYING PERSPECTIVES IN DIABETIC RETINOPATHY BY INTRAVITREAL
PHARMACOTHERAPY
Jennifer K. Sun
Department of Ophthalmology, Beetham Eye Institute
Joslin Diabetes Center, Harvard Medical School
Boston (USA)
Background
The natural history of diabetic retinal vascular complications involves progressive worsening of retinopathy over time, with approximately
50–60 % of patients developing proliferative diabetic retinopathy after a few decades of diabetes. Nonetheless, recent clinical studies have
demonstrated that medical therapy with intravitreal agents such as anti-vascular endothelial growth factor (VEGF) can lead to substantial
improvements in both diabetic macular edema (DME) and nonproliferative diabetic retinopathy (NPDR). A key issue in understanding both
the potential clinical benefit of these treatments as well as possible mechanistic implications of their effects is how durable the improvements are in retinopathy severity after cessation of therapy or less frequent dosing.
Anti-VEGF therapy in the management
of proliferative retinopathy
Methods
Phase 3 clinical trials of anti-VEGF agents for DME, including the Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol I and
the RIDE/RISE and VIVD/VISTA trials have provided valuable data regarding treatments needed for a beneficial effect in DME and NPDR. In
addition, these studies have explored the long-term sustainability of optimal treatment effect on visual acuity and anatomic outcomes in
the setting of as needed treatment regimens and when intravitreous treatment is deferred.
Results
Data from both Protocol I and the RIDE/RISE studies demonstrate that visual improvements are maintained in eyes treated with intravitreous
anti-VEGF for DME once dosing is switched from continuous monthly treatments to a prn regimen. Although 8–10 treatments on average
are given over the first year of therapy for DME, injections in the 2nd through 5th years are dramatically reduced to an average of 0–3 injections. In these studies of eyes with DME, many patients treated with anti-VEGF also maintained stability or improvement of DR severity from
baseline with no treatment or reduced frequency dosing.
Conclusion
Intravitreous pharmacotherapy with anti-VEGF for DME provides excellent visual outcomes that are maintained in most patients with a “treat
and defer” regimen requiring only infrequent injections after the first year of therapy. Although large scale studies have not yet focused
specifically on NPDR as an indication for intravitreous therapy, results are promising based on DME studies that anti-VEGF treatment may
have a long-term disease modifying effect in many eyes that is sustained with less frequent dosing.
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A REALISTIC SCENARIO OF DRUG THERAPY IN THE REAL WORLD
Simon Harding
Department of Eye and Vision Science
University of Liverpool
Honorary Consultant Ophthalmologist
Royal Liverpool University Hospital
Liverpool (UK)
Widespread introduction of anti-VEGF therapy will have further impact on hard pressed services. Maintenance of clinical skills for delivery
of laser will be essential to limit this effect.
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Anti-VEGF therapy in the management
of proliferative retinopathy
Abstract
Scatter peripheral retinal laser photocoagulation (PRP) is established in and remains the mainstay of the treatment of proliferative diabetic
retinopathy (PDR, DR). Access, criteria for initiation of therapy and mode of delivery vary widely throughout the world. Wide angle imaging
and anti-VEGF therapy offer enhancements to the clinical management of retinopathy across the different clinical scenarios in PDR.
Anti-VEGF therapy provides early improvement prior to scatter PRP in florid retinopathy with or without new vessels, iris neovascularisation
(NV) and PDR with severe diffuse diabetic macular oedema and exudative maculopathy. In advanced DR, anti-VEGF therapy should be
used with caution in the presence of tractional retinal detachment. Further evidence is required to guide the management of peripheral
NV and peripheral non-perfusion seen on wide angle colour imaging/angiography. The role of anti-VEGF therapy in PDR without high risk
characteristics awaits further evidence while its use in pre-proliferative DR meeting the 4:2:1 rule and in pregnancy remains limited.
Expert PANEL DISCUSSION: Anti-VEGF in proliferative retinopathy
Moderation
Ursula Schmidt-Erfurth
Professor and Chair
Department of Ophthalmology and Optometry
Medical University of Vienna
Director Christian Doppler Laboratory for Ophthalmic Image Analysis (OTIMA)
Vienna (AUT)
Feinberg School of Medicine
Northwestern University Chicago
Chicago (USA)
Experts
EXPERT PANEL DISCUSSION:
Anti-VEGF in proliferative retinopathy
Reinier O. Schlingemann, Amsterdam (NL)
Mary Elizabeth Hartnett, Salt Lake City (USA)
Robert L. Avery, Santa Barbara (USA)
Jennifer K. Sun, Boston (USA)
Simon Harding, Liverpool (UK)
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KeyNote: FMRI OF THE HUMAN VISION SYSTEM: WHAT WE HAVE LEARNED AND WHAT IST NEXT
Nancy Kanwisher
Department of Brain & Cognitive Sciences
Massachusetts Institute of Technology
Cambridge (USA)
Abstract
Humans are highly visual animals. At least a third of our cortex is devoted to the problem of figuring out what we are looking at. The last 25
years of fMRI research have revealed the functional organization of this large swath of cortex in glorious detail. The first few studies identified cortical areas predicted by prior work in macaques, like V1, V2, and visual motion area MT/V5. Next came discoveries of new regions
not reported previously in animals, such as the fusiform face area, which responds selectively to faces, the parahippocampal place area,
which responds selectively to places, and the extra striate body area, which responds selectively to bodies. Each of these regions is found,
in approximately the same location, in every normal subject. Collectively, these and related findings constitute substantial scientific progress,
by revealing how the brain carves up the problem of vision. What matters is not where exactly each functional region lies in the brain, but
what the fundamental components are of the brain machinery for vision.
However, even a beautifully detailed functional map of human visual cortex is just the beginning. This map is not a completed scientific story,
but a roadmap for a future research program into the underlying neurobiological mechanisms. To understand the brain basis of vision we
ultimately need to understand the representations extracted and computations conducted in each region, the circuits that implement those
computations, and the connectivity and interactions between regions. Non-invasive methods in humans provide some clues into these
questions, but the most powerful methods are those available in other primates. Work by Tsao, Freiwald, and others on the cortical system
for face perception in macaques is a stunning example of the rich neurobiological understanding possible from animal models. Luckily,
extensive evidence suggests that the functional architecture of high-level vision between in humans is similar and indeed homologous to
macaques, suggesting that many of the insights from monkey research apply to humans. Interestingly, the same appears not to be the case
in audition. Our recent results indicate a functional organization in humans that appears to differ sharply with that of macaques, because
human auditory cortex is organized around uniquely human functions like speech perception and music.
Another fundamental question is how all this systematic structure gets wired up over development, and how each region “knows” where
in the cortex to arise. Our finding that the “visual word form area” responds to familiar but not unfamiliar orthographies shows that the
selectivity of at least one cortical region is based on the individuals’ experience. We are currently testing whether prior connectivity instructs
functional development, by asking if the location where the visual word form area arises can be predicted from patterns of cortical connectivity in the same child before she learned to read.
KEYNOTE LECTURE:
Vision and behaviour
Perhaps the deepest and hardest question about human visual cortex is why we have specialized neural machinery in the first place, and
why we apparently have it for some visual categories (like faces, places, and bodies), but apparently not others (like food, dangerous animals,
or weapons). Computational modelling may be able to illuminate this question, by testing whether we have specialized machinery only for
visual problems that pose unique computational challenges, or whether instead we simply develop cortical specializations for categories
of stimuli that matter most to us in our daily lives.
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19
THE EFFICACY OF RETINAL PERCEPTION: FROM A SINGLE PHOTON TO VISUAL PERCEPTION
Alipasha Vaziri
Resarch Institute of Molecular Pathology (IMP)
University of Vienna
Vienna (AUT)
Abstract
How do the dynamics of coupled biological systems confined by their structure lead to function? While we investigate this question in different systems and at different scales, a major goal is to understand how sensory inputs are represented across brain hierarchies, and how
their processing generates innate and learnt motor output. To answer these questions, we focus on the development of optical technologies
for high-speed, single cell-specific and brain-wide modulation and functional imaging of neuronal circuits.
The presentation is focused on the intersection between physics, neuroscience and information theory. We are interested in understanding
how the information processing capabilities of the brain emerge from the dynamic interaction of neuronal networks. Our ultimate aim is
to discover the computational algorithms underlying object recognition, generalization, learning, and decision-making. Addressing these
questions has been hampered by a paucity of appropriate tools and methods that permit parallel and specific spatiotemporal application of
excitation patterns to neuronal populations while capturing the dynamic activity of the entire network at high spatial and temporal resolution.
Imaging vision between retina and brain
Taking a multidisciplinary and reverse engineering approach, we develop and apply new techniques to address the above questions. Over
the last few years we have developed two new high-speed calcium imaging techniques that, for the first time, enable the investigator to
capture the dynamics of the neuronal network at single-cell resolution in-vivo and in whole brains. This provides the opportunity to capture
the flow of information from the primary sensory neurons across different stages of representation, to their processing and interaction with
internal brain states for generating behaviour in real time.
20
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STRUCTURE-FUNCTION CORRELATION BY COMPUTATIONAL RETINAL IMAGING
Sebastian M. Waldstein, Hrvoje Bogunovic, Ana-Maria Philip, Bianca S. Gerendas, Georg Langs, Ursula Schmidt-Erfurth
Department of Ophthalmology and Optometry
Christian Doppler Laboratoy for Ophthalmic Image Analysis (OPTIMA)
Medical University of Vienna
Vienna (AUT)
Background
In intravitreal therapy of exudative macular disease, the baseline condition of the retina and the corresponding levels of functional deficits
are known determinants of the future treatment response. A solid understanding of imaging biomarkers that may predict visual function
and treatment response is therefore required both for patient management as well as to develop more effective endpoints in clinical trials.
Modern three-dimensional spectral-domain optical coherence tomography (OCT) delivers a vast amount of morphologic information that
clearly defies manual analysis by human observers, particularly in a clinical practice setting. Therefore, the development and validation of
computational automated image analysis methods is vital to enable comprehensive structure-function correlations.
Methods
To provide comprehensive data for further microstructural analysis, OCT raw images first undergo standardized processing including denoising, motion correction, longitudinal and inter-patient registration and finally automated feature segmentation.
In detail, geodesic denoising is first applied to remove obfuscating speckle noise while maintaining fine anatomical details. Motion correction is performed to automatically remove motion artefacts occurring during scan acquisition.
To enable a precise comparison of retinal loci over time and across individual patients, the positions of the fovea, retinal vasculature and
optic disc are automatically detected. Using these landmarks, the OCT scans are automatically aligned longitudinally and inter-individually.
A battery of fully automated segmentation methods is applied to detect the individual retinal layers, intra- and subretinal fluid, pigment
epithelial detachment, choroidal layers and vitreomacular interface abnormalities.
Structure-function correlation is finally undertaken using conventional regression analyses as well as advanced machine learning methods
such as convolutional neural networks.
Results
The standardized pre-processing framework enables quantification and investigation of the relevant retinal features in three-dimensional
OCT in high resolution over time and across individuals.
In neovascular age-related macular degeneration, the extension of intraretinal cystoid fluid is strongly correlated to visual acuity loss at
baseline. In contrast, subretinal fluid and pigment-epithelial detachment are not associated with functional loss. The visual deficit induced
by intraretinal cystoid fluid strongly influences further functional gains under therapy, with a permanent reduction in visual acuity observed
in patients with extensive cystoid changes. Mathematical modelling of visual acuity change over time is able to relate a large proportion of
visual acuity change to changes in intraretinal cystoid fluid.
In macular edema secondary to retinal vein occlusions, the volume of intraretinal cystoid fluid is only weakly correlated to poorer visual
acuity. However, subretinal fluid volume is associated with advanced functional losses.
In diabetic macular edema, large cystoid spaces are associated with reduced treatment response profiles, while subretinal fluid presence
is predictive of larger vision gains.
Conclusion
In intravitreal therapy of exudative macular disease, the underlying neurosensory damage and associated functional loss at baseline seem
more important to functional outcomes than use of a particular drug or regimen. The investigated morphologic features demonstrate
differential effects on visual function in the evaluated retinal diseases. Large-scale computational automated image analysis demonstrates
promising initial results, providing an enhanced understanding of the correlation between visual function and high-resolution retinal imaging.
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21
Imaging vision between retina and brain
Advanced machine learning methods demonstrate the feasibility of visual acuity prediction in pilot projects.
STATE-OF-THE-ART RETINAL FUNCTION TESTING IN MACULAR DISEASE
Caterine A. Cukras
Department of Epidemiology and Clinical Applications
National Eye Institute, NIH
Bethesda (USA)
Background
Visual acuity has long been the mainstay of outcome measurements in clinical trials of retinal disease. While the value of visual acuity should
not be minimized, there are many cases in macular disease where acuity alone as an outcome measure is insufficient to track macular disease – especially those with early and late disease.
Methods
The list of functional tests that can be done to test macular function is long – but few have been able to be utilized as accepted outcome
measures. Many of the psychophysical tests we will discuss depend on threshold testing to measure sensitivity of the retina but also influenced
by other aspects of the visual pathway. Direct tests of macular function, such as multifocal ERG, measure physiologic retinal suprathreshold
responses. We will review the pros and cons of several functional tests and emphasize psychophysical and functional tests that have been
useful in identifying defects prior to any obvious used in several macular studies.
Results
Several functional tests have demonstrated ability to identify abnormalities in early macular disease before visual acuity is significantly affected. Many of these tests are demanding in effort, cooperation, and time. However, the ability to measure defects in stages of disease where
patients are for the most part asymptomatic and where visual acuity is unaffected allows study of initial stages of pathogenesis of disease.
Conclusion
Imaging vision between retina and brain
Further evaluation of functional testing in macula disease is necessary to determine which tests have sensitivity and specificity, reproducibility,
and clinical feasibility to be utilized to follow progression of disease and be useful outcome measures for the evaluation of interventional studies.
22
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METhODS AND MEANS TO DETECT FUNCTIONAL DEFICITS
Graham E. Holder
Department of Electrophysiology
Moorfields Eye Hospital and Institute of Ophthalmology
London (UK)
Abstract
There have been great advances in imaging over the last decade or so, and techniques such as fundus autofluorescence imaging and spectral domain optical coherence tomography have rightly become established components of the diagnostic armamentarium. However, it is
important that function is not overlooked in the assessment of the patient.
Imaging vision between retina and brain
The presentation will adopt a case-based approached to illustrate the importance of additional functional assessment using electrophysiological techniques, particularly in inherited retinal disorders where the phenotypic expression of disease may not correspond to that usually
expected.
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THE ROLE OF THE OPTIC NERVE IN VISUAL FUNCTION
Berthold Pemp
Department of Ophthalmology and Optometry
Medical University of Vienna
Vienna (AUT)
Background
The optic nerve is the neuronal highway for visual information, which is collected in retinal ganglion cells and then transmitted to various
structures of the midbrain. Whereas a large part of visual information is relayed to the cortex resulting in conscious visual perception, some
side-ways lead to non-image forming vision including pupillary control, circadian photo entrainment, neuroendocrine regulation and generation of visually guided conscious and unconscious eye movements. Thus, diseases that affect the optic nerve commonly cause vision
loss and regularly also induce other deficiencies that can be clinically detected.
Methods
Knowledge of structure of the neurovisual system enables to differentiate various sites of lesions in the pathway of optic nerve fibers and to
estimate their extent based on results of classical diagnostic tests including visual field testing, examination of pupil reactions and measurement of visual evoked potentials. However, spectral domain OCT is now regularly implemented in the neuro-ophthalmologic workup for
measurement of peripapillary retinal nerve fibers and analysis of inner retinal layers of the macula using automated segmentation algorithms.
Results
Results from clinical studies using OCT in acute and subacute optic nerve lesions show that axonal damage in the optic nerve induces
retrograde degeneration of axons eventually resulting in loss of nerve fibers and ganglion cells in the retina. Hence neurodegeneration of
inner retinal tissue may be detected early, heralding clinically observed irreversible optic neuropathy. Similarly, high resolution OCT enables
close follow up of neurodegenerative processes over time in systemic disorders.
Conclusion
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Imaging vision between retina and brain
Normal visual function depends on intact propagation of electrical signals from the eye to the brain via the ganglion cell axons bundled
together in the optic nerve. Information whether visual loss in optic nerve diseases is permanent or reversible may be reflected by parameters
of retinal structure indicating neurocellular loss.
THE NEUROSCIENCE OF HUMAN VISION FOR PERCEPTION AND ACTION
Jody C. Culham
Department of Psychology, Culham Lab, Brain and Mind Institute
University of Western Ontario
London (CAN)
Background
Functional magnetic resonance imaging (fMRI) in neurologically intact adults has revealed numerous cortical (extrastriate) brain regions
involved in visual perception and visually guided actions. This research can be beneficial in understanding the patterns of deficits and spared
abilities in neuropsychological patients.
Methods
We report the case of an adult woman, Patient M.C. who had bilateral strokes causing bilateral occipitotemporal cortex lesions, which led
to Riddoch phenomenon, the ability to perceive moving but not stationary targets. Despite severely impaired vision, M.C. can use visual
information, particularly dynamic information, to perform actions and navigate through the world. We conducted a series of fMRI studies
to better understand how her brain activation can explain her behavioral profile.
Results
Despite bilateral lesions that encompass most of her early visual areas and temporal-cortex regions implicated in visual recognition, M.C. has
spared processing in a motion-selective brain region (the middle temporal complex, MT+) and in parietal regions implicated in visuomotor
actions.
Conclusion
Imaging vision between retina and brain
Our results enable us to better understand how Riddoch phenomenon and perception-action dissociations can arise through the sparing
of motion- and action-selective pathways, which may receive input from subcortical pathways that bypass primary visual cortex.
26
Advanced retinal Therapy
www.artvienna.eu
IMAGING RETINAL DISEASE IN THE BRAIN
Markus Ritter
Department of Ophthalmology and Optometry
Medical University of Vienna
Vienna (AUT)
Background
Using functional MRI it is possible to acquire a retinotopic map that relates neural populations of voxels in the visual cortex to regions of the
retina. These regions can also be referred to as “population receptive fields” (pRF).
Different retinal diseases involving the central or peripheral retina, eliminate the normal retinal input to different pRFs and therefore alter the
MR signal of the corresponding voxels. As the relation between functional loss at the level of the retina and changes in neuronal activity in
the primary visual cortex is not completely understood, we measured area V1 pRF properties in patients with different retinal diseases and
established a correlation to retinal sensitivity measurements.
Methods
Ten patients with Stargardt disease, five patients with retinitis pigmentosa, and nine healthy subjects were measured on a 3T Siemens Trio
scanner. Structural images were acquired before functional scanning using a magnetization-prepared rapid gradient-echo (MPRAGE) sequence. Functional MR images (TE/TR=30/1500 ms) were acquired using the CMRR multiband sequence with 28 slices. The visual stimulus
consisted of a moving bar, exposing a flickering checkerboard and crossing the screen in eight different directions. In total, the stimulus
covered a central area corresponding to 20 ° visual angle diameter. The mrVista toolbox (Stanford University, Stanford, CA) implemented in
Matlab 7.8 (The MathWorks, Inc., Natick, MA) was used to predict the BOLD response of each voxel using a two-dimensional Gaussian pRF
model, which allowed to correlate each voxel to a specific pRF by estimating the center location and spread. Microperimetry (Nidek MP1)
was used to define the site and stability of fixation and the area of functional loss in all patients. For comparison of the two methods the
retinal sensitivity maps were registered to the corresponding retinotopic MRI maps.
Results
The eccentricity parameter of the pRF model showed the expected course, but failed near the posterior pole of the occipital cortex for Stargardt patients and in the anterior occipital cortex for retinitis pigmentosa patients, implying a lack of stimulus related cortical activity. The
regions where the pRF model managed to explain more than 10 % of the BOLD signal variance corresponded to a large extend to preserved
retinal function as measured by microperimetry. A preferred retinal locus was documented in three patients with Stargardt’s disease, which
seems to result in an anterior shift of the pRF map corresponding to the central fovea.
Conclusion
Advanced retinal Therapy
www.artvienna.eu
27
Imaging vision between retina and brain
High-resolution multiband imaging allowed for robust mapping of the pRF. A model for the relation between retinal sensitivity as measured
by microperimetry and neuronal activity as measured by BOLD fMRI could be established. As no stimulus related activity was detected by
the pRF model in regions corresponding to central or peripheral retinal dysfunction as measured by microperimetry the results imply that
no large-scale cortical reorganization of visual processing occurs in adult humans in response to retinal disease.
1
NEW INDICATION
DME1
Targeted
Inflammation
Control 2
Rapid & Sustained
Vision Improvement 3
For your patients with visual impairment
due to DME who:
1
Known &
Manageable
Safety Profile 3
are considered unsuitable for
non-corticosteroid therapy
are insufficiently responsive to
non-corticosteroid therapy
are pseudophakic
Improves
Capacity & Value 3-5,7
Please see full prescribing information
SEE THE DIFFERENCE
WITH 360° THER APY
References:
References:
1. Austria Codex Fachinformation. OZURDEX®, März 2015
1.2.Austria
Fachinformation.
OZURDEX® , inhibits
August 2014
NehmeCodex
A, Edelman
J. Dexamethasone
high glucose-, TNF-alpha-, and IL-1beta-induced
2. Nehme
A, Edelman
J. Dexamethasone
inhibitsmediators
high glucose-,
and IL-1beta-induced
secretion
secretionof
inflammatory
and angiogenic
fromTNF-alpha-,
retinal microvascular
pericytes.
lnvest
ofOphthalmol
inflammatory
mediators from retinal microvascular pericytes. lnvest Ophthalmol Vis
Vis and
Sci. angiogenic
2008;49(5)2030-38.
2008;49(5)2030-38.
3. Sci.
Boyer
DS et al. Three-Year, Randomized, Sham-Controlled Trial of Dexamethasone Intravitreal Im3. Boyer
et al. Three-Year,
Randomized,
Trial of Dexamethasone
Intravitreal
plant DS
in Patients
with Diabetic
MacularSham-Controlled
Edema. Ophthalmology.
2014 doi:10.1016/j.ophtho
20
Implant
in Patients with Diabetic Macular Edema. Ophthalmology. 2014 doi:10.1016/j.ophtho 20
14.04.024.
4. 14.04.024.
Mitchell P et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser4. Mitchell
P et al.forThe
RESTORE
study:edema.
ranibizumab
monotherapy
or combined with laser versus laser
monotherapy
diabetic
macular
Ophthalmology
2011;118:615-25.
macular
edema.
OphthalmologyTherapy
2011;118:615-25.
5. monotherapy
Brown DM et for
al. diabetic
Long-term
Outcomes
of Ranibizumab
for Diabetic Macular Edema: The365. Brown
et al.from
Long-term
Outcomes
Ranibizumab
Therapy (18)
for Diabetic
Macular Edema: The
Month DM
Results
Two Phase
III Trialsof Opthalmol
2013;120
2013-22.
Two Phase
III TrialsofOpthalmol
2013;120
6. 36-Month
SivaprasadResults
S andfrom
Oyetunde
S. Impact
injection therapy
for (18)
retinal2013-22.
patients with DME or RVO,
6. INCITE
market
research,
on fileon2014.
presented
at 6th
World data
Congress
Controversies in Ophthalmology (COPHy), 26-29 March 2015.
7.7. Appiah A. An emerging option
option toto treat
treat DME.
DME. Retinal
RetinalPhysician,
Physician,Volume:10,
Volume:10,Issue:
Issue:June
June2013:
2013:39-55
39-55
OZURDEX® 700 Mikrogramm intravitreales Implantat in einem Applikator.
AT/0250/2014l
AT/0161/2015
Fits Patient Lifestyle
With Few Injections 3-6
OZURDEX®
700 microgramsZusammensetzung:
intravitreal implantEin
in applicator
Wirkstoff: Dexamethason.
Implantat enthält 700 Mikrogramm Dexamethason. Sonstige Bestandteile: Poly(D,L-Lactid-co-Glycolid) 50:50 mit Ester-Endgruppen, Poly(D,L-Lactid-co-Gly-
Active
Composition:
One implant contains
700 micrograms
of dexamethasone,
Excipients: Ester terminated
50:50
polydiabetischen
D,L-lactide-co-glycolide,
Acid terminated
poly D,L-lactide-co-glycolide;
colid) Substance:
50:50 mit dexamethasone,
Säure-Endgruppen.
Anwendungsgebiete:
Behandlung
von Erwachsenen
mit einer Sehbeeinträchtigung
aufgrund
eines
Makulaödems
(DMÖ), die50:50
pseudophak
sind oder auf eine
Therapeutic
treatment of unzureichend
adult patients with
visual impairment
due to diese
diabetic
oedema
(DME) who
pseudophakic
who are considered
insufficiently als
responsive
to, orretinalen
unsuitableVenenastverschlusses
for non-corticosteroid
Therapie mitindications:
Nicht-Kortikosteroiden
ansprechen
oder bei denen
alsmacular
unpassend
angesehen
wird.areBehandlung
vonorErwachsenen
mit Makulaödem
Folge eines
oder retinalen
Zentralvenenverschlusses.
Behandlung
Erwachsenen
mit einer
des(BRVO)
posterioren
Augensegments,
die sich (CRVO);
als nichttreatment
infektiöseofUveitis
darstellt.
Überempfindlichkeit
therapy;
treatment
of adult patients with macular
oedemavon
following
either Branch
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or Central
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adult patients
withGegenanzeigen:
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posterior segment
gegen
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wieofaktive
epitof
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non-infectious
uveitis. Contraindications:
Hypersensitivity
to the okuläre
active substance
or to any Infektion
of the excipients;
Active ordersuspected
or periocular infection
includingund
most
viral diseases
the cornea
heliale
Herpes-Simplex-Keratitis
(dendritische
Vaccinia-,
Varicellaund mykobakterielle
Fortgeschrittenes
Glaukom,
das which
mit Arzneimitteln
allein nicht
adäquatbybehandelt
and
conjunctiva,
including active epithelial
herpes Keratitis),
simplex keratitis
(dendritic
keratitis),
vaccinia, varicella,Infektionen,
mycobacterialPilzerkrankungen.
infections, and fungal
diseases; Advanced
glaucoma
cannot be adequately
controlled
medicinal
werden
kann.
Aphake
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mit
ruptierter
posteriorer
Linsenkapsel.
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mit
Vorderkammer-Intraokularlinse,
Irisoder
transskleral
fixierter
Intraokularlinse
und
rupturierter
posteriorer
Linsenkapsel.
Nebenwirproducts alone; Aphakic eyes with ruptured posterior lens capsule, Eyes with Anterior Chamber Intraocular Lens (ACIOL), iris or transscleral fixated intraocular lens and ruptured posterior lens capsule. Adverse reactions: Very
kungen: Sehr
häufig:
Erhöhter
intraokulärer
Katarakt,
konjunktivale
Blutung*;
häufig:
Kopfschmerzen,
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Hypertension,
subkapsuläre
Katarakt,
Sehschärfe,
Sehbehincommon:
intraocular
pressure
increased,
cataract,Druck,
conjunctival
haemorrhage,
Common:
headache;
ocular
hypertension, cataract
vitreous
haemorrhage,
visual Glaskörperblutung,
acuity reduced, visualreduzierte
impairment/
disturbance,
vitreous
derung/-störung,
Mouches
volantes,
Blepharitis,
Photopsie,
konjunktivales
konjunktivale
Hyperämie;gelegentlich:
nekrotisierende
detachment,
vitreousGlaskörperabhebung,
floaters, vitreous opacities,
blepharitis,
eye Glaskörpertrübungen,
pain, photopsia, conjunctival
oedema,Augenschmerzen,
conjunctival hyperaemia,
Uncommon:
migraine,Ödem,
Necrotizing
retinitis, endophthalmitis,
glaucoma, Migräne,
retinal detachment,
retinal
Retinitis,
Endophthalmitis,
Glaukom,
Netzhautablösung,
Retinariss,
Hypotonia
bulbi,
Vorderkammerentzündung,
Vorderkammerzellen/-trübung,
Missempfindungen
im
Auge,
Augenlidpruritus,
Hyperämie
der
tear, hypotony of the eye, anterior chamber inflammation, anterior chamber cells/ flares, abnormal sensation in eye, eyelids pruritus, scleral hyperaemia, device dislocation (migration of implant) with or without corneal oedema,
Sklera, Dislokation
Implantats
(Implantatmigration)
mit oder
Hornhautödem,
beim Einsetzen
des Implantats
(Fehlplatzierung
des Implantats)
Hinweis:
OZURDEX®Date
darfofnurpreparation:
von einem
complication
of devicedes
insertion
(implant
misplacement); OZURDEX
mustohne
be administered
by a Komplikation
qualified ophthalmologist
experienced
in intravitreal
injections. OZURDEX
is only available
on prescription.
qualifizierten
Ophthalmologen
mit
Erfahrung
in
der
Durchführung
intravitrealer
Implantationen
verabreicht
werden.
Verschreibungspflichtig.
Stand:
März
2015.
Pharmazeutischer
Unternehmer:
Allergan
PharSeptember 2014; Marketing Authorization Holder: Allergan Pharmaceuticals Ireland, Castlebar Road, Westport, Irland. For full information please refer to Summary of Product Characteristics: Austria Codex Fachinformation.
maceuticals Ireland, Castlebar Road, Westport, Irland. • Weitere Hinweise enthalten die Fach- bzw. die Gebrauchsinformation, deren aufmerksame Durchsicht wir empfehlen.
Complete
11,11,A-1100
Complete Study
StudyReports
Reportscan
canbeberequested
requestedfrom:
from:Pharm-Allergan
Pharm-AllerganGmbH
GmbH,Twin
TwinTower
Tower
A-1100Wien
Wienororviaviae-mail:
e-mail:[email protected]
[email protected]
Advanced retinal Therapy
www.artvienna.eu
© Cover Picture: Rome, National Gallery of Modern and Contemporary Art. By permission of Ministero dei Beni delle Attività Culturali e del Turismo
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