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
2. Schneider EW, Johnson MW. Clin Ophthalmol 2011;5:1151
Central vitreous
Cortical vitreous Vitreous base
Zonules
Lens
Ciliary body
Retina
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
1. Le Goff MM, Bishop PN. Eye 2008;22:1214
2. Schneider EW, Johnson MW. Clin Ophthalmol 2011;5:1151
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
1. Le Goff MM, Bishop PN. Eye 2008;22:1214
2. Schneider EW, Johnson MW. Clin Ophthalmol 2011;5:1151
Here the concentration of both
collagen and HA is higher than
elsewhere in the vitreous body.
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
1. Le Goff MM, Bishop PN. Eye 2008;22:1214
2. Schneider EW, Johnson MW. Clin Ophthalmol 2011;5:1151
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
The Vitreoretinal Interface
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;
The Vitreoretinal Interface
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
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
Vitreous Liquefaction with an
incomplete separation of the vitreous
at the Vitreoretinal Interface
Incomplete Posterior Vitreous Detachment (PVD)
At the optic disc, can induce various
vitreo-papillopathies, as well as play a role
in promoting neovascularization in
ischemic retinopathies
Vitreous Liquefaction with an
incomplete separation of the vitreous
at the Vitreoretinal Interface
Incomplete Posterior Vitreous Detachment (PVD)
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
Incomplete Posterior Vitreous Detachment (PVD)
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
Anomalous Posterior Vitreous Detachment (PVD)
Type 1:
Disc-shaped vitreous cortex
remnant overlying the foveal area
CELLOPHANE MACULOPATHY
Anomalous Posterior Vitreous Detachment (PVD)
Type 2:
Ring-shaped band of vitreous
cortex along the foveal margin
PSEUDOMACULAR HOLE
Anomalous Posterior Vitreous Detachment (PVD)
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
Anomalous Posterior Vitreous Detachment (PVD)
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 ).
Diabetic Macular Edema
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
Diabetic Macular Edema
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
ILM Peeling side-effects
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
ILM Peeling side-effects
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
ILM Peeling side-effects
Invest Ophthalmol Vis Sci. 2013;54:2417–2428
It required at least 1 month for the DONFL appearance to develop
ILM Peeling side-effects
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.
ILM Peeling side-effects
Müller cell endfeet and their adherent inner processes
showed severe swelling or even were extinguished
ILM Peeling side-effects
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
The Vitreoretinal Interface
Extracellular matrix glue’ including
1. Laminin high affinity with Collagen
2. Fibronectin high affinity with Collagen
3. Chondroitin
This ‘matrix glue’ is an important target in the pharmacologic
induction of Posterior Vitreous Detachment (PVD)
Vitreous
cortex
ILM
Retina
The Vitreoretinal Interface
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
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