Vitreo-retinal interface pathologies and fibrinolytic treatment approaches

Transcription

1 Vitreo-retinal interface pathologies and fibrinolytic treatment approaches Constantin J. Pournaras Memorial A. de Rothschild Clinical Research Group La Colline Ophthalmology Center

2 Vitreoretinal Interface Constituents: - Posterior vitreous cortex - Internal limiting membrane (ILM) basal membrane of Müller cells Posterior vitreous cortex μm thick. - Densely packed collagen fibrils. - Inserted superficially into the ILM. - Attach to the ILM by glue-like macromolecules, such as: laminin, fibronectin, chondroitin, heparan sulphate proteoglycans

3 Histological Studies: Normal Mouse Eye Blue: Nuclear stainings Green: Collagen IV Red: Fibronectin Vitreous Body Vitreoretinal interface Inner limiting membrane Inner plexiform Inner nuclear layer Outer plexiform Outer nuclear layer Data on file, ThromboGenics, Inc Inner/outer segment and pigmented epithelium Bruch s membrane Sclera

4 Fibronectin + collagen IV Data on file, ThromboGenics, Inc

5 Vitreoretinal Interface Constituents: - Posterior vitreous cortex - Internal limiting membrane (ILM) basal membrane of Müller cells In pathologic conditions: - Müller cells migration/ cells differentiation induces contraction. - Vitreomacular traction syndrome Andreas Bringmann et al., 2006, Christos Haritoglou, et al., 2007, Erica L Fletcher et al., 2007

6 Pathologies inducing contraction or shrinkage of the vitreoretinal interface Vitreoretinal macular adhesion Vitreomacular traction syndrome Macular epiretinal membranes Macular holes Lamelar Macular holes Proliferative microangiopathies (DR, RVO)

7 Vitreoretinal macular adhesion Invest Ophthalmol Vis Sci. 2012;53:

8 SD-OCT Enhances, considerably, imaging of Vitreoretinal Interface (VRI) Facilitates diagnosis, follow-up, prognosis determination, and management of VRI-associated pathologies In disorders aggravated by vitreoretinal adhesion.

9 Macular Epiretinal Membranes Fluoresceine Angiography Red free

10 Macular Pseudohole en-face C scan images

11 Macular holes Foveal Pseudocyst as the First Step in Macular Hole Formation A Prospective Study by Optical Coherence Tomography. Haouchine et al., Foveal Pseudocyst as the First Step in Macular Hole Formation. A Prospective Study by Optical Coherence Tomography. Ophthalmology 2001;108:15 22

12 Lamelar Macular holes

13 Why now? New findings based on OCT Better understanding of pathogenesis Surgical outcomes New therapies ocriplasmin Duker et al. The International Vitreomacular Traction Study Group classification of vitreomacular adhesion, traction, and macular hole. Ophthalmology, 2013 Dec;120(12):

14 International Vitreomacular Traction Study (IVTS) Group Classification Vitreomacular Adhesion (VMA) Vitreomacular Traction (VMT) Full-Thickness Macular Hole (FTMH) Sub-classification Focal ( 1500 µm) or broad (>1500 µm) Isolated or concurrent with other diseases No structural abnormalities in retina Focal ( 1500 µm) or broad (>1500 µm) Isolated or concurrent with other diseases Plus structural abnormalities in macula Small ( 250 µm), medium (>250 µm and 400 µm), or large (>400 µm) With or without VMT Primary or secondary to other conditions Duker et al. The International Vitreomacular Traction Study Group classification of vitreomacular adhesion, traction, and macular hole. Ophthalmology, 2013, Dec;120 (12):

15 VMT: Reclassification OLD NEW Stage 0 macular hole VMA Stage 1 macular hole VMT Stage 2 macular hole FTMH Small or medium Stage 3 macular hole FTMH Medium or large Stage 4 macular hole FTMH No VMA, small, medium, large

16 Ocriplasmin: Truncated Form of Human Plasmin Pre-clinical data shows that ocriplasmin 1,2 Targets fibronectin, laminin and collagen Proteolytic activity against the major components of the vitreoretinal interface Inducing vitreous liquefaction and separation of the vitreous at the vitreoretinal interface Cleanly separates vitreous from the internal limiting membrane 1. Gandorfer et al. Invest Ophthalmol Vis Sci 2004;45: ; 2. In vitro experiments

17 % Patients Proportion of Patients Achieving VMA Resolution 35% 35 30% 30 25% 25 20% 20 15% 15 10% 10 5% 5 Ocriplasmin Study 006 Study 007 Combined Data Placebo Study 006 Study 007 Combined Data 0% Primary Endpoint Days Post-Injection Stalmans P et al. N Engl J Med 2012; 367:

18 % Patients Proportion of Patients with Non-Surgical Macular Hole Closure at Day 28 Placebo Ocriplasmin p=0.002 p=0.03 p<0.001 N= Study 006 Study 007 Combined Data Stalmans P et al. N Engl J Med 2012; 367:

19 % Patients Proportion of Patients Achieving VMA Resolution According to Epiretinal Membrane Status p<0.003 Placebo p<0.001 Ocriplasmin p<0.001 p<0.046 N= 35 Study Study 007 Combined Data Epiretinal Membrane Present Study 006 Study 007 Epiretinal Membrane Absent Combined Data Stalmans P et al. N Engl J Med 2012; 367:

20 Pathologies inducing contraction or shrinkage of the vitreoretinal interface Vitreoretinal macular adhesion Vitreomacular traction syndrome Macular epiretinal membranes Macular holes Lamelar Macular holes Proliferative microangiopathies (DR, RVO) Ocriplasmin: Indications?

21 Ultrastructure of vitreoretinal traction Fibrous astrocytes Fibrocytes Myofibroblasts Macrophages Extracellular matrix -Fibronectin / Laminin -Collagen I to IV Common contracting celullar elements in contracting tissue of PDR, PVR, and ERM, VRTS, MH stage III, DME. a-smooth muscle actin Bochaton-Piallat et al., IOVS 2000, Mendrinos et al., 2012

22 Myofibroblasts induces retractile phenomena SMA-Fusion peptide Inhibits Lung Fibroblast Contraction on Flexible Silicone Substrata Hinz B., et al. The Journal of Cell Biology, 2002, 157:

23 ERM:Double immunofluorescence staining for a-sma and ED-A FN ERM + ILM (10) Image acquisition by use of a Zeiss LSM 510, laser 488 (for FITC) and 563 (for Rhodamine), 63x objective, Zoom=x2, Z sectioning with 21 slices and 0.5 mm interval a-smooth muscle actin EDA fibronectin

24 Quantitative analysis of cellular migration from the macular hole The area of cellular migration gradually enlarged as the macular hole passed through the later stages of development. Stage 2 Stage 3 Stage 4 Hisatomi T et al. Arch Ophthalmol 2006 E Mendrinos, et al.. Immunohistochemical analysis of internal limiting membrane by confocal microscopy in a case of stage 4 idiopathic macular hole. Eye (2010).

25 Angle d examen: 0 Espacement: mm Longueur: 9 mm Vitreoretinal macular traction Premacular fibrocellular tissue, resembling the clinical features of idiopathic Commentaires Signature du médecin epiretinal membranes. SW Ver: Copyright 2012 Carl Zeiss Meditec, Inc All Rights Reserved Page 1 sur 1 Myofibroblast was the predominant cell type. Fibrous astrocytes and fibrocytes were less frequent..

26 Conclusions Improvement of diagnostic tools, surgical techniques and patho-physiologic mechanisms knowledge, expanded the treatment of macular vitreo-retinal pathologies. Active contraction mechanisms and scar tissue formation are expressed in ERMs and underling ILM tissues. Treatments are focused on the release of the abnormal vitreo-retinal adhesion and active tractional mechanisms. Ocriplasmin resulted in a significant resolution of VMA, as observed at the initial stages of the vitreoretinal macular pathogies.