Proliferative Vitreoretinopathy

Proliferative Vitreoretinopathy

1. PROLIFERATIVE VITREOR E TINOPATHY Dr. Arindam Rakshit FNB Trainee Vitreo -Retina Sir Ganga Ram Hospital, New Delhi

2. Definition Non angiogenic fibro cellular proliferation Resulting from the cellular reaction due to abnormal vitero retina healing process Clinically have spectrum of manifestation S ubtle retinal wrinkling, to fixed folds and tears with rolled edges and to total rigid retinal detachment, retinal shortening, and Advanced periretinal proliferation

3. Incidence: 5-10% of all RRD Highly aggressive in children Most common cause of failure of RRD surgeries Despite successful surgery the change of having poor visual outcome is high, due to apoptosis induced damage and degeneration of the photo receptor

4. Composition of membranes Retinal glial cells (Muller cells, microglia cells and astrocytes) RPE and Ciliary body epithelial cells Hyalocytes Blood borne inflammatory cells Fibrocytes and myofibrocytes

5. PATHOPHYSIOLOGY

6. The vitreous compartment is normally almost devoid of cellular content with just a few hyalocytes. It is protected from outside invasion by ILM and blood–retinal barrier. With any break the RPE cell migrates on the surface of retina and overlying vitreous.

7. The sequence of overlapping phases (4-8 weeks) Inflammation Cellular proliferation Extracellular matrix remodeling

8. Major cell type involved Epithelial Mesenchymal Transition (EMT): The RPE cells transdifferentiate morphologically into mesenchymal cells and fibroblast-like phenotypes. Role of RPE

9. RRD cause cytokines to leak in subretinal space RPE cells stimulated, lose cell-cell adhesion Undergo EMT Proliferation and migration (in the vitreous cavity and detached retina)

10. Glial Cells (Muller cells, microglia and fibrous astrocytes): Physiology Support neuronal activity Integrity of BRB Ionic and osmotic homeostasis Reactive gliosis: Cellular hypertrophy and upregulation of vimentin filaments Begins within minutes of RD, proceeds as long as retina is detached. Muller cells proliferate, migrate out and be a part of fibroproliferative membrane. Provide focal attachment between membrane and retina.

11. Glial cells replace the dying neuronal and degenerated axons with glial scars Mechanical obstruction for regenerative axon growth Thus, a limiting factor for vision recovery post surgery. Reactive Gliosis limits the outcome

12. Macrophages and circulating fibrocytes are precursors of myofibroblasts Hyalocytes have a role in synthesis of ECM and modulation of inflammation. Hyalocytes also have contractile properties Blood borne cells

13. Influx of inflammatory cells ,growth factor and metalloproteinases into the vitreous and retina. Proliferation of the cells over retina and vitreous. Myofibroblastic transdifferentiation and extracellular matrix remodeling cause membrane contraction resulting in fixed re-detachment of the retina. The vicious cycle of PVR

14. GROWTH FACTORS, CYTOKINES AND INTERLEUKINS Platelet Derived Growth Factor (PDGF) Transforming Growth Factor-B (TGF-B) Insulin-like Growth Factors (IGF) Monocyte Chemotactic Protein-1 (MCP-1) Basic Fibroblast Growth Factor ( bFGF ) Hepatocyte Growth Factor (HGF) Connective Tissue Growth Factor (CTGF) Epidermal Growth Factor (EGF) Vascular Endothelial Growth Factor (VEGF) Interleukins and TNF-alpha

15. BIOMARKERS MMP concentration in vitreous is raised Chemokine CXCL-1 correlates with the grade of PVR Inflammation associated proteins: Alpha 1-Antitrypsin Apolipoprotein A-IV Transferrin Kininogen-1 – Serum biomarker of PVR

16. RISK FACTORS FOR PVR Trauma to the eye Vitreous Hemorrhage with retinal tears Previous eye surgery RD with more than two quadrants RD associated with Choroidal Detachment Inflammation: Viral infections of posterior segment Prolonged chorioretinitis RD associated with: Wagner’s Syndrome Marfan Syndrome FEVR Cryotherapy

17. HOW TO DIAGNOSE PVR ? Early Signs: Very subtle Cellular dispersion in vitreous and on retina Localised fibrocellular membranes – White opacification and small wrinkles or folds

18. Rolled posterior edges of tears Extensive PVR: Fixed folds, mainly inferiorly. Fine membranes bridging the valleys of detached retina Decreased motility

19. Advanced PVR with PVD: Funnel-shaped RD with contracted equatorial membrane. Anterior traction at vitreous base: Draws retina towards Ciliary body or detaches the ora serrata.

20. CLASSIFICATION OF PVR Classifying PVR allows: Cross-comparison of severity of a disease Assessment of effects of various therapies in clinical trials No classification of PVR is without flaws Most commonly used classification system: Retina Society PVR Classification – 1983

21. Retina Society PVR Classification Classifies on basis of: Clinical Signs Geographical Distributions Grade (stag e ) Characteristics A Vitreous haze, vitreous pigment clumps B Wrinkling of the inner retinal surface, rolled edge of retinal break, retinal stiffness, vessel To r tu os i t y C Full-thickness retinal folds in C-1 One quadrant C-2 Two quadrants C-3 Three quadrants D Fixed retinal folds in four quadrants D-1 Wide funnel shape D-2 Narrow funnel shape (anterior end of funnel visible by indirect ophthalmoscopy with 20 diopter lens) D-3 Closed funnel (optic nerve not visible)

22. Grade B

23. Grade C

24. Grade D Grade D2 Grade D3

25. B-scan of an eye with RRD with PVR. A high-intensity echo with a V or funnel shape from the optic disc and lack of mobility of the detached retina are characteristic of advanced PVR.

26. 4 wks post op 7wks post op 12 wks post op

27. Drawbacks: Ignores antero-posterior epiretinal proliferation and hence anterior traction. Ignores degree of cellular proliferative activity at the time of grading. Inactive Grade D may have a better prognosis than a very active Grade C PVR

28. Revised Classification of PVR (1991) Includes location, extent and severity of PVR More useful, mainly for clinical trials Grade Features A Vitreous haze, vitreous pigment clumps, pigment clusters on inferior retina B Wrinkling of the inner retinal surface, Retinal stiffness, vessel tortuosity, rolled and irregular edge of retinal break, decreased mobility of vitreous CP 1-12 Posterior to equator, focal, diffuse or circumferential full-thickness folds, subretinal Strands CA 1-12 Anterior to equator, focal, diffuse, or circumferential full-thickness folds, subretinal strands, anterior displacement, condensed vitreous

29. Type Location (in relation to equator) Features Focal Posterior Star fold posterior to vitreous base Diffuse Posterior Confluent star folds posterior to vitreous base; optic disc may not be visible Subretinal Po s teri o r/ A nteri or Proliferation under the retina; annular strand near disc; linear strands; motheaten-appearing Sheets, Napkin ring around disc Circumferential Anterior Contraction along posterior edge of vitreous base with central displacement of the retina; peripheral retina stretched; posterior retina in radial folds Anterior Anterior Vitreous base pulled anteriorly by proliferative tissue; peripheral retinal trough; displacement ciliary processes may be stretched, may be covered by

30. Purpose : To determine prospectively the accuracy of a predictive risk formula for the development of postoperative PVR when applied in a clinical setting. Study Period: 212 patients with RRD between 1997 and 2000

31. Material and Methods: All Patients were examined meticulously regarding RD extension , position of break and PVR changes. Exclusion Criteria: History of previous surgery for RD Blunt trauma < 6 months History of any penetrating injury Any active infection

32. Risk Factors Chosen: Anterior uveitis Aphakic Preoperative PVR Preoperative Cryo Quadrant of RD Vitreous hemorrhage

33. They proposed a criteria predicting the high-risk factor for post operative PVR changes. 2.92 X (aphakia) 2.88 X (grade C PVR) 1.85 X (grade B PVR) 1.77 X (anterior uveitis) 1.23 X (quadrants of detachment) 1.23 X (previous cryotherapy) 0.83 X (vitreous haemorrhage ) If the cumulative score >= 6.88 there is high risk of developing post op PVR

34. Conclusion: They had proposed the use of 5FU and Heparin for the management of these patients

35. PRIVENT STUDY

36. Study Design: Randomized, double-blind, controlled, multicenter, interventional trial with one interim analysis. High-risk patients for PVR with primary RRD Verum : intraoperative adjuvant application of 5-FU &LMWH via intraocular infusion during routine PPV (b) Placebo : routinely used intraocular infusion with balanced salt solution during routine PPV

37.  PVR risk is assessed by non-invasive aqueous flare measurement by using laser flare photometry. During PPV, the IMP will be administered via intraocular infusion. The verum/placebo containing infusion will be used for a maximum of 60 min. If surgery takes longer, infusion will be changed to normal BSS. Applications of intravitreal steroids or cataract extraction with or without intraocular chamber lens implantation are prohibited during primary PPV.

38. The End Point judged by: PVR CP >= 1 quadrant with in 12 weeks CA within 12 weeks BCVA An occurrence of any adverse effect due to drug The conclusion was presumed to be publish by September 2020 .

39. PREVENT-PVR STUDY

40. The primary objective of the study: To determine if serial intravitreal aflibercept injections (IAI) improve the single surgery anatomic success rate following surgical repair of primary, macula involving RRD deemed at high risk for PVR. Aflibercept group (after conclusion of RRD repair surgery ) Control Group will receive intravitreal aflibercept injection (2mg/0.05mL) SHAM injection during same period of time at post-operative day 30 (plus/minus 7 days) at post-operative day 60 (plus/minus 7 days)

41. All eyes will undergo pars plana vitrectomy with or without scleral buckling and gas tamponade. Post-operative exams (slit lamp biomicroscopy and indirect ophthalmoscopy) will include the following time-points: Day 30, Day 60, Day 90, Day 120. All time points will have a window of plus/minus 7 days, except the Day 120 visit which will be a window of plus/minus 14 days.

42. The primary outcome will be: Single surgery anatomic success (retinal re-attachment) rate. Additional outcomes will include: epiretinal membrane formation; presence of grade C PVR or worse; post-operative complication profile; OCT-measured central macular thickness; change from baseline in visual acuity (Snellen) wearing habitual correction.

43. Conclusion is yet to be published, tentatively by end of 2021.

44. CAN PVR BE PREVENTED? PVR develops almost regardless of the technique of surgery used. Identify the eyes at risk and keep a close watch Intraoperative complications: Choroidal haemorrhage Retained vitreous haemorrhage Intense photocoagulation Heavy cryotherapy Laser may be preferred over cryotherapy.

45. SURGERY FOR PVR Substantial improvement in the success rate of Sx for PVR over the past decades. Timely Sx is of utmost importance in cases with PVR Objective of Sx  To permanently support the retina from any ongoing traction and to close any open retinal breaks. The goals are achieved by an encircling scleral buckle, meticulous relief of all retinal traction with vitrectomy, temporary or long-term tamponade of the retina with longacting gas or SO. Sx must be planned according to the Stage of the diseases

46. It is urgent if the macula is still attached or salvageable. When there is sever inflammation and macula is not salvageable, we can give a course of corticosteroids to reduce the inflammation. Leaving an eye with a retinal detachment and early PVR almost always will lead to further progression and eventual inoperability. Fixed folds tenting the retina can be easily divided or peeled to relieve traction. Extensive retinal fibrosis with shortening may require a relaxing retinotomy. Plan accordingly

47. WHEN NOT TO OPERATE ? Second eye has good vision and no disease, and the affected eye has Chronic RD and no hope of macular redemption Extensive Intraretinal gliosis Inferior retinal shortening with posterior retinal breaks Failure after SO injection If second eye is lost already and affected eye has poor prognosis, surgery may still be attempted for ambulatory vision

48. Decision-making is still flexible and depends a lot on: Patients and relative having thorough understanding of expectations and possible outcomes Judiciousness of the surgeon after considering factors involved for each patient.

49. Scleral Buckling and PVR A 360° encircling scleral buckle remains a fundamental requirement for most eyes with established PVR Vitreous base, particularly inferior , becomes fibrocellular in PVR and continues to contract even after a formal vitrectomy, since it is virtually impossible to remove the whole vitreous base.

50. HOW BUCKLE HELPS? Supports vitreous base against the traction Prevents leakage from new or small missed retinal breaks in periphery Inactive PVR may not need a vitrectomy.

51. Vitrectomy in PVR Comprehensive vitrectomy is essential in the management of PVR. Vitrectomy and SOI without buckling is equally effective like combined procedure. Goal  Remove all vitreous gel, cellular and inflammatory material, blood, and fibroblastic membranes. Relieve all traction by division and peeling or delamination of fixed membranes Divide any membranes causing anterior loop traction and to release the tractional effect on scarred shortened retina. Oyagi T, Emi K. Vitrectomy without scleral buckling for proliferative vitreoretinopathy. Retina 2004;24:215–18.

52. VITRECTOMY WITHOUT SCLERAL BUCKLING FOR PVR TOMOHITO OYAGI, KAZUYUKI EMI, RETINA 24:215–218, 2004 Purpose : To determine whether complete vitrectomy with vitreous shaving and without SB is efficacious for the treatment of PVR. Methods : The vitreous was completely removed by the shaving technique with scleral indentation by an assistant. SF6 gas (20%) was used for gas tamponade for all of the cases. The anatomic success rate and the Vn before and after the Sx were analyzed. Stage No of Patient C3 1 D1 3 D2 3 D3 1

53. Results : The anatomic success rate after the first vitrectomy was 75%, and 100% after the second operation. Preoperatively, the visual acuity was less than counting fingers in 63% and less than 20/200 in 88% of the eyes. Postoperatively, the visual acuity was 20/200 or better in 88%, and 20/100 or better in 63% of the cases. Conclusions : Vitrectomy with vitreous shaving without SB achieved approximately the same rate of anatomic success as vitrectomy with SB in eyes with PVR. Visual acuity was significantly improved postoperatively.

54. Core Vitrectomy and Removal of the Vitreous Base Eyes with established PVR already have a PVD Any remaining central gel is removed completely and peripheral vitreous is removed completely as much as possible. Extra attention should be given to the inferior portion where pigment and inflammatory cells tend to gravitate.

55. Peripheral base shave can be facilitated by assistant indentation with a scleral depressor, squint hook, or cotton-tipped stick.

56. Removal of ERM and Use of PFCL Membranes are peeled from posterior pole to outward directions. If an edge is found, it can be peeled by forceps. Blunt spatula or pick may help to find a plane and elevate the membrane. Any membrane involving the macula must be peeled. Avoid creating iatrogenic retinal breaks.

57. Use of Perfluorocarbon (PFCL) fluid: Displaces SRF anteriorly Flattens posterior retina Highlights membranes Stabilizes the retina Relaxing retinotomy may be resorted to if needed. Persistent retinal elevation after fluid-air exchange indicates presence of traction.

58. Testing Adequacy of Relief of Traction and Relaxing Retinotomy Adequacy of retinal mobilization can be tested by a complete fluid–air exchange. If residual traction is present it fails to flatten the retina completely. Additional dissection is carried out around a retinal tear or relaxing retinotomy or even a circumferential retinotomy may be needed We should aspirate the SRF carefully Avoid spreading the mobilized pigment cells on retinal surface

59. Retinotomy and retinectomy edges may fibrose and retract back to posterior pole

60. Role of Silicone Oil : Less postoperative inflammation Quicker rehabilitation Fewer reoperations Heavy SO gives better inferior tamponade

61. Silicone oil removal: Wound-healing sequence of PVR takes around 3 months, hence SO should be kept in-situ for 3 months Delayed removal of up to 18 months – No improvement in functional outcomes

62. MEDICAL ADJUNCTIVE THERAPY Systemic Prednisolone, subtenon’s injection of Triamcinolone to control inflammation Beneficial dose persists after intraoperative use of Triamcinolone Studies on PDGF and Connective Tissue Growth Factor (CTGF) are in preliminary stages. Antineoplastic drugs: 5-FU and Daunorubicin have been studied, less success and fear of potential toxicity to normal neuronal cells

63. Thank you.