Ferrara final the vitreoretinal interface a new interest for an old story

Borgomanero

The Vitreoretinal Interface: a new interest for an old story

Vincenzo Ferrara, MD SS. Trinità Hospital

Borgomanero - ITALY

Back from the 20’s

studying the vitreous…

to the 90’s with

Jerry Sebag

Molecular Components of the Vitreous

1. Schneider EW, Johnson MW. Clin Ophthalmol 2011;5:1151

2. Bishop PN. Biochem J 1994;299:497

3. Sebag J. Trans Am Ophthalmol Soc 2005;103:473

Vitreous

Water (99%)1 Glycosaminoglycans

Hyaluronan

(>90%)

Chondroitin

sulfate (<10%)

Collagen

(fibrillar component)1,2

Type II (sheath around core) 75%

Type V/XI (fibril core) 10%

Type IX (outermost surface) 15%

The human vitreous3

Anatomical Regions of the Vitreous

• Central – collagen fibrils are

oriented in an anteroposterior

manner1,2

• Basal – collagen fibrils are oriented

perpendicular to the vitreous base,

where they insert into the posterior

ciliary body (pars plana) and the

anterior retina, forming an adhesion

considered unbreakable without

proteolysis1,2

• Cortex – adherent to the ILM of the

retina, but collagen fibrils (type II)

are generally oriented parallel and

do not insert directly into the ILM1,2

Orientation of collagen fibrils

within the vitreous1

1. Le Goff MM, Bishop PN. Eye 2008;22:1214


Central vitreous

Cortical vitreous Vitreous base

Zonules

Lens

Ciliary body

Retina




manner1,2







proteolysis1,2










manner1,2







proteolysis1,2







Here the concentration of both

collagen and HA is higher than

elsewhere in the vitreous body.




manner1,2







proteolysis1,2







Differently from ILM surface

where collagen fibrils are

mostly of type IV

The Vitreoretinal Interface

Courtesy of Greg Hageman, Ph.D.

Vitreous

cortex

ILM

Retina


Vitreous cortex is connected to the

ILM via an ‘extracellular matrix glue’

including:

1. Laminin high affinity with Collagen

2. Fibronectin high affinity with Collagen

3. Chondroitin

Schneider EW, Johnson MW. Clin Ophthalmol 2011;5:1151;

Dugel P. Retina Today April 2012;50

Sebag J. Trans Am Ophthalmol Soc 2005;103:473;

Williams GA. Rev Ophthalmol 2008;


Vitreous cortex is connected to the

ILM via an ‘extracellular matrix glue’

including:



3. Chondroitin

Schneider EW, Johnson MW. Clin Ophthalmol 2011;5:1151;

Dugel P. Retina Today April 2012;50

Sebag J. Trans Am Ophthalmol Soc 2005;103:473;

Williams GA. Rev Ophthalmol 2008;

Vitreous

cortex

ILM

Retina

Posterior Vitreous Detachment (PVD)

There should be sufficient weakening

at the vitreoretinal interface when the

critical level of vitreous liquefaction

has been achieved

If not…

Incomplete Posterior Vitreous Detachment (PVD)

Vitreous Liquefaction with an

incomplete separation of the vitreous

at the Vitreoretinal Interface

In the peripheral fundus, advanced gel

liquefaction in the presence of strong

vitreo-retinal adhesion causes retinal

tears and detachments.

Retinal lattice with overlying

pockets of liquefied vitreous is a

good example of peripheral

anomalous PVD





At the optic disc, can induce various

vitreo-papillopathies, as well as play a role

in promoting neovascularization in

ischemic retinopathies





Vitreoschisis anterior to the level of the

hyalocytes leaves a relatively thick,

cellular membrane attached to the

macula.

Inward (centripetal) contraction of this

membrane induces macular pucker

Vitreoschisis posterior to the hyalocytes,

the remaining premacular membrane is

relatively thin and hypocellular.

Outward (centrifugal) tangential traction

can induce a macular hole


J. Sebag

Anomalous Posterior Vitreous Detachment (PVD)

Scanning electron microscopic observation of the posterior retinal

surface of 59 autopsy eyes with spontaneous vitreous detachment.

In 26 eyes (44%) , there were remnants of the posterior vitreous

membrane in the foveal area


Type 1:

Disc-shaped vitreous cortex

remnant overlying the foveal area

CELLOPHANE MACULOPATHY


Type 2:

Ring-shaped band of vitreous

cortex along the foveal margin

PSEUDOMACULAR HOLE


Type 3:

Disc-shaped vitreous cortex remnant

overlying the foveal area, which is,

attached to the foveal margin but is

detached from its concavity

SENILE MACULAR HOLE


Posterior Vitreous Detachment (PVD)

Impact of Incomplete Posterior Vitreous Detachment

Floaters/photopsia seeking

emergency treatment (n=207)

Patients with incomplete PVD

at baseline: 54/207 (26.1%)

Experienced significantly

more adverse outcomes *

than patients with total PVD

(p=0.01)

*Retinal tears; epimacular membranes;

retinal detachment

Estimated incidence of

adverse outcomes after PVD

Follow-up (years)

Log rank p=0.01

25

20

15

10

5

0

Adver

se o

utc

om

es (

%)

0 1 2 3 4 5 6 7 8

Incomplete PVD at baseline

Complete PVD at baseline

Carrero JL.

Am J Ophthalmol 2012

Clinics

Pucker and Cellophane

No debate on

the indications

for surgery

Macular Hole

No debate on

the indications

for surgery

Diabetic Macular Edema

Surgery ?

“Evidence based” rationale for vitrectomy in DME

• The role of the vitreous in DME: 1. Sebag J et all. Pathogenesis of cystoid DME: an anatomic consideration of vitreoretinal adhesions. Surv

Ophthalmol 1984

2. Nasrallah et all., Ophthalmology 98 ( PVD less frequent in DME)

3. A. Gandorfer et all. Br J Ophthalmol 2002 (glial cell growth on posterior VH and abnormal vitreomacular adhesion)

4. D. Gaucher Am J Ophthalmol 2005 (perifoveal PVD with foveal traction) 49 eyes

5. A. Gandorfer et all. Am J Ophthalmol 2005 (Vitreoschisis and a thickened posterior cortical vitreous: a key role in DME progression).

• Vitrectomy is effective in DME and posterior Hyaloid traction: 1. Lewis H et all. Ophthalmology 1992

2. Otani T et all. Tomographic assessment of vitreous surgery for DME. Am J Ophthal 2000

3. P K Kaiser et all. Am J Ophthalmol 2001 (9 eyes). 4. Pascale Massin et all Am J Ophthalmol 2003;135:169–177. © 2003 OCT for Evaluating DME Before and After Vitrectomy.

5. U Stolba, S. Binder et all. Am J Ophthalmol 2005 (PPV for Persistent DDME) PPV and ILM peeling better than observation alone up to 18 months.; 53% improve of 2 or more line

• Vitrectomy effective even with detached vitreous: 1. Ikeda T et all. Improved visual acuity following PPV for DME and detached posterior hyaloid. Retina 2000

2. La Heij Ecet all. PPV results in DME without evident vitreomacular traction. Graefes A.C.E. Ophthalmol 2001

3. Rosenblatt BJ et all. PPV with ILM peeling for refractory DME without a taut posterior hyaloid Graefes Arch Clin Exp Ophthalmol. 2005.

• The importance of vitreous as “reservoir” of cytokines: 1. Yamamoto T Am J Ophthalmol 2001 ( PPV effective in DME unregardly of PVD)

2. H. Funatsu et all. (AII and VEGF are related to the pathogenesis of DME, irrespective of the presence or absence of PVD). Am J of Ophthalmol 2003

3. Shimada et all. Concentration of VEGF in the vitreous of eyes with DME. IOVS. 2008 (VEGF concentration correlates with OCT mean foveal thickness ).


Surgery ?

ILM peeling ?

Macular

sensitivity !?!

25 eyes of 24 consecutive patients

affected by TDDME divided in 2 groups: mean FU: 9 mos \\ mean age: 65 yrs

G1: Vitreal Hyaloid adherent

14 eyes

G2: Vitreal Hyaloid detached

11 eyes


with ILM peeling up to the arcades

Mean % increment 25% (P<0.001*)

Initial: 0.19 log

Final: 0.03 log

Increment in 88% of cases

Results of surgery for DME

Mean % reduction of 19% (P<0.01*)

Initial mean RT: 516.16 μm

Final mean RT: 391.26 μm

Reduction in 68% of cases

*P value: applying Wilcoxon Test for related samples; differences between groups with Mann Withney Test for independent samples

0,30

0,35

0,40

0,45

0,50

0,55

0,60

0,65

0,70

0,75

0,80

ET

DR

S v

isu

s l

og

detached

adherent

Total

detached 0,65 0,57 0,51 0,51 0,55

adherent 0,62 0,51 0,47 0,40 0,39

Total 0,63 0,54 0,49 0,45 0,45

VISlog_t0 VISlog_t1 VISlog_t2 VISLOG_t3 VISLOG_t4

Visual Acuity

300

350

400

450

500

550

600

Mic

ro

n

detached

adherent

Total

detached 509,73 378,27 427,91 423,45 366,33

adherent 521,21 425,07 409,50 426,33 413,70

Total 516,16 404,48 417,60 424,96 391,26

OCT_t0 OCT_t1 OCT_t2 OCT_t3 OCT_t4

Foveal Thickness

Mean % increment of >100%

(P<0.005*)

Initial FS: 6.64 db

Final FS: 8.65 db.

Increment in 65% of cases.

Mean % increment of 66%

(P<0.001*)

Initial Mean MS: 8.61 db.

Final mean MS:10.28 db.

Increment in 76% of cases

*P value: applying Wilcoxon Test for related samples; differences between groups with Mann Withney Test for independent samples

6

7

8

9

10

11

12

13

14

Decib

el

detached

adherent

Total

detached 8,47 9,13 9,12 9,50 9,70

adherent 8,72 9,34 10,38 10,73 10,81

Total 8,61 9,25 9,80 10,17 10,28

tot_t0 tot_t1 tot_t2 tot_t3 tot_t4

Macular Sensitivity

3

4

5

6

7

8

9

10

11

12

Decib

el

detached

adherent

Total

detached 5,53 6,43 6,37 6,36 7,54

adherent 7,52 8,01 8,42 9,07 9,64

Total 6,64 7,32 7,44 7,83 8,65

fovea_t0 fovea_t1 fovea_t2 fovea_t3 fovea_t4

Foveal Sensitivity

Results of surgery for DME

s Pre-op BCVA: 0,16 1 month Post-op BCVA: 0,2

6 months Post-op BCVA: 0,2

Materiali e Metodi:

MP1 follow-up

ODV:0,16 preop

ODV: 0,6 postop 9 mos

Deroofing the cyst by peeling… ?

VA: 0,2

VA: 0,4

4 months after PPV + ILM peeling + Air

ILM Peeling in Diabetic Macular Edema

ILM Peeling side-effects

The shorter the papillofoveal distance got after surgery,

the smaller the retinal thickness in temporal subfield became


The average retinal sensitivity of

macular area was significantly

lower after peeling: 9.80±2.35 dB

Vs 13.19±2.92 dB in unpeeled.

Paracentral absolute

microscotomas only found in

eyes whose ILM was peeled off


The retinal thickening in the outer sectors returned to the

preoperative level by 6 to 24 months after surgery, whereas the

retina in the inner sectors became progressively thinner for at

least 24 months


Invest Ophthalmol Vis Sci. 2013;54:2417–2428

It required at least 1 month for the DONFL appearance to develop


En face optical coherence tomography of inner retinal

defects after internal limiting membrane peeling for idiopathic

macular hole

Alkabes M, Salinas C, Vitale L, Bur ´es-Jelstrup A, Nucci P, Mateo C. Invest Ophthalmol Vis Sci .2011;52:8349–

8355.


Müller cell endfeet and their adherent inner processes

showed severe swelling or even were extinguished


The leverage effect of cleavage

and peel forces concentrate

stress at smaller areas of the

bond causing failure at lower

force levels than those observed

in tension and shear

ILM Peeling damage mechanism


Extracellular matrix glue’ including



3. Chondroitin

This ‘matrix glue’ is an important target in the pharmacologic

induction of Posterior Vitreous Detachment (PVD)

Vitreous

cortex

ILM

Retina


Ocriplasmin

Gandorfer et al. Invest Ophthalmol Vis Sci. 2004;45:641–647. 2. In vitro experiments. ThromboGenics, Data on File.

Pre-clinical data shows that ocriplasmin1,2

– Targets fibronectin, laminin and collagen

– Induces vitreous liquefaction and separation of the vitreous at the

vitreoretinal interface

– Cleanly separates vitreous from ILM

Collagen

Fibronectin

Collagen

Borgomanero

The Vitreoretinal Interface: a new interest for an old story

Vincenzo Ferrara, MD SS. Trinità Hospital

Borgomanero - ITALY

Grazie!

The IVTS Classification System in a Nutshell

Classification Sub-classification

Vitreomacular

adhesion (VMA)

• Focal (≤1500 μm) or broad (>1500 μm)

• Isolated or concurrent with other diseases

• No structural abnormalities in the retina

Vitreomacular

traction (VMT)

• Focal (≤1500 μm) or broad (>1500 μm)

• Isolated or concurrent with other diseases

• Structural abnormalities in the retina

Full-thickness

macular hole

(FTMH)

• Small (≤250 μm), medium (>250 μm and ≤400 μm),

or large (>400 μm)

• With or without VMT

• Primary or secondary to other conditions

Duker JS et al. Ophthalmology 2013;doi:10.1016/j.ophtha.2013.07.042

Correlation between Common Macular Hole Stages and the

IVTS Classification System for VMA, VMT, and Macular Hole

Gass classification IVTS Classification System

Stage 0 VMA (a specific stage of vitreous separation with no

abnormalities visible on OCT)

Stage 1: impending macular hole VMT (a persisting area of vitreous attachment

associated with an elevation of the foveal surface

from the RPE that is visible on OCT)

Stage 2: small hole Small or medium FTMH with VMT

Stage 3: large hole Medium or large FTMH with VMT

Stage 4: FTMH with PVD Small, medium, or large FTMH without VMT

Duker JS et al. Ophthalmology 2013;doi:10.1016/j.ophtha.2013.07.042

Health & Medicine

Ferrara final the vitreoretinal interface a new interest for an old story