A presentation on Proliferative retinopathy and its management.

1. PROLIFERATIVE
VITREORETINOPATHY
DR. PAVAN SHROFF

2. WHAT IS PVR?
Definition:
The clinical syndrome associated with retinal traction and
detachment in which cells with proliferative potential multiply
and contract on retinal surfaces and in the vitreous
compartment.

3. • Vitreoretinal wound-healing response
• Nonangiogenic and fibrotic
• Seen in:
• Rhegmatogenous Retinal Detachment (RRD)
• Surgical intervention (most common scenario)
• Trauma
• Longstanding inflammation

4. • Incidence: 5-10% of all RRD
• Higher incidence, rapid and aggressive in children
• Most common cause of failure of RRD surgeries

5. PATHOPHYSIOLOGY
The prerequisites:
• Intravitreal dispersion of RPE cells or
• Breakdown of Blood-Retinal barrier (BRB)
Important factors:
• Size of breaks
• Extent of RD
• Preoperative inflammation or PVR

6. The sequence of overlapping phases (4-8 weeks)
1. Inflammation
2. Cellular proliferation
3. Extracellular matrix remodelling

7. Cellular basis of PVR:
Interplay between cytokines/growth factors, matrix proteins and different cell
types  undesirable preretinal membranes
Composition of membranes:
• Retinal glial cells (Muller cells, microglia cells and astrocytes)
• RPE and Ciliary body epithelial cells
• Hyalocytes
• Blood borne immune cells
• Fibrocytes and myofibrocytes

8. THE CELL CYCLE
• G0 phase:
• Resting phase of the cell cycle
• Interphase:
• Gap1, Synthesis and Gap2
phases
• Cell prepares itself for the cell
division
• Mitosis

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

11. Pathogenetic steps:
EMT  Proliferation and
directional migration 
Fibrocellular membranes in
vitreous and both retinal
surfaces

12. 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)

13. 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.

14. Reactive Gliosis
• 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.

15. Proliferation of Muller cells
Downregulation of Potassium channels
• Depolarisation causes reentry into proliferation cycle
• Impairment of regular glial-neuronal interactions

16. Blood borne cells:
• 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

17. 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

18. ECM Remodelling and Myofibroblasts:
• ECM – A dynamic, complex array of collagens, glycoproteins, GAGs
and proteoglycans
• Functions:
• Mechanical and structural support
• Interacts with cytokines and cytoskeleton – transmits biological signals.
• Re-modelling is a healing response detrimental to the retinal
function.

19. HOW REMODELLING HAPPENS
1. Structural proteins
2. Adhesive proteins
3. Antiadhesive proteins
Structural Proteins:
• Collagens of various types.
• Produced by RPE cells, glial cells and fibroblast-like cells

20. Adhesion protein:
• Fibronectin, expression is low in normal retina.
• Promotes adhesion amongst ECM cells.
• Also enhances EMT of RPE cells.
Antiadhesive protein:
• Thrombospondin functions contrary to Fibronectin
• Facilitate the detachment of activated RPE cells and migrate to wounded
areas.

21. The loss of Balance:
• Normally, MMPs and Tissue Inhibitor of MMP (TIMPs) function in
balance.
• In pathology, RPE cells, glial cells and fibroblasts overproduce
MMP-2 and MMP-9.

22. Myofibroblasts:
• Characterized by smooth-muscle actin and generate Tractional
force by contraction
• Transmembrane integrins at the myofibroblast surface link
actin microfilaments
• Cytokines, PDGF, IGF and TNF-B mediate the ECM contraction.

23. BIOMARKERS AND GENETIC PROFILING
• 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
• Laser flare photometry – Risk estimation for PVR development.
• Genetic association – TNF locus and PVR

24. 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

25. …RISK FACTORS
• Inflammation:
• Viral infections of posterior segment
• Prolonged chorioretinitis
• RD associated with:
• Wagner’s Syndrome
• Marfan Syndrome
• FEVR
• Cryotherapy

26. PREDICTION OF PVR
• Asaria et al presented a formula based on risk factors
Preoperative Grade B PVR 1.85+
Preoperative Grade C PVR 2.88+
Aphakia 2.92+
Each quadrant of RD 1.23+
Anterior Uveitis 1.77+
Vitreous Haemorrhage 0.83+
Previous Cryotherapy 1.23+
Score of >6.33+ is a high risk for PDR

27. 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

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

29. • 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.

30. • Preoperative identification of PVR may result in modification of
surgical techniques
• Recognition of PVR post-operatively:
• At 4-12 weeks after surgery
• Allows timely intervention and avoid substantial visual loss

31. 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 AD.

32. Retina Society PVR Classification:
Classifies on basis of:
• Clinical Signs
• Geographical Distributions
Grade
(stage)
Characteristics
A Vitreous haze, vitreous pigment clumps
B Wrinkling of the inner retinal surface,
rolled
edge of retinal break, retinal stiffness,
vessel
Tortuosity
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)

33. GRADE B

34. GRADE C

35. Grade D1 Grade D2

36. GRADE D3

37. 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

38. 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

39. 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 Posterior/Anteri
or
Proliferation under the retina; annular strand near
disc; linear strands; motheaten-appearing Sheets,
Napkin ring around disc
Circumferent
ial
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

40. CAN PVR BE PREVENTED?
• Most eyes with PVR will have undergone some treatment for RD, 1-3 months ago
• 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.

41. PVR in eyes with no intervention yet:
• At early subtle stages – Vitrectomy to prevent the progression
to the full syndrome
• Better to combine scleral buckling with vitrectomy rather than
treating with either of them.
• Longer acting vitreous substitutes should be preferred.

42. SURGERY FOR PVR
• Timely surgery is of utmost importance in cases with PVR
• Urgent if macula is attached and vision salvageable
• Aim of surgery:
• Close any open retinal breaks
• Permanently support the retina and relieve the tractions
• Should be achieved without causing prolonged inflammation or
cellular access to the retinal surface.

43. SCLERAL BUCKLING – FUNDAMENTAL
REQUIREMENT
• Inferior vitreous base
becomes fibrocellular
• Contracts even after a formal
vitrectomy
• Virtually impossible to
remove complete vitreous
base

44. 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.
• For chorioretinal adhesion, laser is better but cannot be used in
a residual SRF.

45. VITRECTOMY
• Meticulous vitrectomy and Silicone oil (SO) tamponade has been reported
comparable to combined procedure
• Vitrectomy is essential for removal of cellular and inflammatory material and
fibroblastic membranes
• Efficiency in surgery due to advances in technology.
• Better view
• Faster core vitrectomy
• Safer cutting and aspiration near retinal surface

47. • 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.

50. Subretinal bands:
• Seen with longstanding PVR
• Cause tenting of retina
• Prevent retinal reattachment
• Removed through a
retinotomy.

51. Fluid-air exchange:
• Done to achieve totally flat
retina
• With or without the aid of PFCL
• Carefully aspirate the egressing
SRF
• Avoid spreading the mobilized
pigment cells on retinal surface
• Persistent retinal elevation
indicates traction

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

53. 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

54. COMPLICATIONS OF SURGERY
• Possibility of substantial vision loss despite anatomical success
• Intraoperative bleeding while dissecting membranes and retinotomy
• Regrowth of membranes (Perisilicone proliferation) and recurrent
detachment (33-50%).
• Commonest: Inferior RD with a new or reopened retinal break
• Reoperate: If fluid extends towards posterior pole and threatens
macula.
• Macular pucker (5-15%): Peeled if significant visual potential

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

56. • Hypotony due to interference with Ciliary body secretory
function
• Rubeosis iridis: Recurrent persisting RD with intraocular
inflammation

57. 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

58. RESULTS OF SURGERY
• Anatomical success: Retinal reattachment for at least 6 months.
• Earlier, Scleral buckling reattached 50% of milder cases
• With all the techniques at disposal, 90% cases are anatomically
reattached
• Many eyes need more than one surgery due to cellular
proliferation and retinal traction
• 360 degree extensive laser and long term SO may improve
success rates

59. • Functional success: Any improvement in vision.
• Macula detached for more than a few days: Unlikely to recover more than 10-20%
Stable visual results:
• Reattachment attained for 6 years after surgery
• Eyes who needed only one surgery
No significant difference was seen in reattachment rates and visual acuity gain with C3F8
and SO, at 6 years follow-up.

60. Dilemma of SO removal:
• Settled eyes were likely to gain >/= 3 lines with improvement
in quality of vision
• 19% eyes developed recurrent RD (twice that of eyes where SO
was not removed)

61. 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

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

63. Thank you.