Posterior vitreous detachment (PVD) involves the separation of the vitreous gel from the retina. It occurs normally with aging as the vitreous liquefies through the processes of synchysis and syneresis. Incomplete PVD can result in vitreomacular adhesion (VMA) which may lead to vitreomacular traction (VMT) or macular hole (MH). Left untreated, VMT and MH can cause severe vision loss or blindness. The current standard treatment is vitrectomy surgery, but pharmacologic therapies offer an alternative to observation in early disease.

15. • PVD is the separation of the posterior vitreous from the retinal ILM1
– This is a normal, physiologic process that occurs with aging
• Processes involved:2
– Synchysis: Pockets of liquefaction form within the vitreous and increase in number/size
– Syneresis: As liquefaction occurs, the collagen fibrillar component collapses
– Weakening of the vitreoretinal adhesion is also required2,3
• The posterior vitreous separates completely from the ILM when these processes have occurred to
a sufficient extent2
• PVD can be asymptomatic, although some patients report floaters (perception of small gray or dark
spots in the visual field) or flashes of light4
ILM, internal limiting membrane; PVD, posterior vitreous detachment
1. Johnson MW. Am J Ophthalmol 2010;149:371; 2. Schneider EW, Johnson MW. Clin Ophthalmol 2011;5:1151;
3. Sebag J. Graefes Arch Clin Exp Ophthalmol 2004;242:690; 4. Hollands H et al. JAMA 2009;302:2243
Early liquefaction Extensive liquefaction Separation

16. • There should be sufficient
weakening at the vitreoretinal
interface when the critical level
of liquefaction has been
achieved1
– If not, incomplete PVD can arise
• VMA:
– Areas of adhesion between the
posterior hyaloid cortex and the
fovea, due to incomplete PVD2
– May cause a range of sequelae,
e.g.1
 VMT
 MH
 Retinal tear
VMA at the optic nerve and
macula resulting in VMT
MH, macular hole; PVD, posterior vitreous detachment; VMA, vitreomacular adhesion; VMT, vitreomacular traction
1. Sebag J. Graefes Arch Clin Exp Ophthalmol 2004;242:690; 2. Dugel P. Retina Today April 2012;50;

17. Vitreomacular Traction
• Tractional forces associated
with VMA1
• Static anterior traction1
– Traction exerted anteriorly,
towards the plane of detachment
– The inner portion of the fovea is
often pulled above the plane of
the surrounding macula
• Dynamic traction1
– Ocular rotations lead to
localization of dynamic tractional
forces at the foveola
Vitreomacular traction
Static anterior
traction
Dynamic
traction
1. Johnson MW. Am J Ophthalmol 2010;149:371

19. Stalmans P et al. Retina 2013;33:2003; Sebag J. Graefes Arch Clin Exp Ophthalmol 2004;242:690;
Sebag J. Br J Ophthalmol 2009;93:989
19
Full-thickness
macular hole
Vitreopapillary
traction
Macula Optic disc Vitreous base
Epiretinal
membrane
Focal
vitreomacular
adhesion
Foveal
retinoschisis
Macular
pucker
Diabetic
macular
edema
AMD Lamellar
hole
Vitreous
hemorrhage
Peripheral
retinal tear
Retinal
detachment
Complete PVD
with fibrosis
Incomplete PVD
with foveal adhesion
Retinal layer
separation
Concomitant
disease
Incomplete PVD with
optic disc adhesion
Increased
peripheral
traction
Vitreomacular
traction
Isolated Concomitant
Vitreoretinal attachment

20. IVTS Definition and Classification of VMT
Duker JS et al. Ophthalmology 2013;doi:10.1016/j.ophtha.2013.07.042
Focal VMT
•The white arrows mark the sites of vitreous attachment
•The area of attachment is ≤1500 μm and is associated with distortion of the foveal
surface
Focal VMT with intrafoveal pseudocyst
Broad VMT
•The white arrowheads mark an ERM and macular pucker
•The area of attachment is >1500 μm and is associated with distortion of the foveal
surface and elevation of the foveal floor

21. Il segmento posteriore del sistema oculare

22. Corpo Vitreo
 Transmette la luce verso il segmento posteriore.
 Sostiene posteriormente il cristallino.
 Contribuisce a mantenere in sede la retina.
 Influisce sulla pressione intraoculare (PIO).

23. Corpo Vitreo
 VOLUME è di 4 ml (70-80% delvolume del globo).
 99% ACQUA - H20
 ACIDO IALURONICO: polisaccaride, fa da
ponte
 FIBRE COLLAGENE : tipo II (IX) di
supporto disposte a banda perodica. Maggior densità
fibre a livello cortex posteriore cortex anteriore e base
vitreale.
 Minor densità a livello vitreo centrale.

24. 1. CORTEX- Corteccia vitreale
 Struttura più densa e fibrillare
 Adiacente a retina cristallino e nervo ottico
 Include la base vitreale
 Condensata in una doppia membrana ialoidea
 Ialoide posteriore aderisce in fibrille alla limitante
interna retinica (c.IV). Spazio clivabile (es.DPV)

26. 1. CORTEX- Corteccia vitreale
1. Adesione lamina basale retinica Muller (limitante)
2. Anello di adesione parafoveale (foro maculare)
3. Adeso ai vasi calibro maggiore (rotture con
emoraggie)
4. Adeso vene periferiche (genesi proliferazione Hb)
5. Saldamente adeso in regioni anomale (degenerazione
palizzata, ciuffi cistici, cicatrici corioretiniche anche da
argon laser), N.O. (Weiss)

27.  Più gelatinoso, meno fibrillare
 Contiene canale Cloquet fossa patellare
 Forma legamento ialoideo-capsulare che
lateralmente si collega all’inserzione fibre zonulari.
 Ialoide anterioree regiona dell’ora con FORTE
ADESIONE a livello PARS CILISRIS base vitreale.

29.  Zona di adesione più importante del vitreo
anteriore.
 1,5 davanti e 3 mm dietro ORA
 5 mm dal limbus
 Tenacemente adesa PARS PLANA
 Arretramento posteriore con l’età: genera trazioni
 Traumi chirurgici da introduzione VPP
3. Base Vitreale

30. Corpo Vitreo

31. Fotocoagulazione ed atrofie

32. The Prognosis of Vitreomacular Traction
and Macular Hole
• The prognosis for patients with VMT is generally poor, and the
development of visual impairment and MH can be rapid1–5
– ~30% of patients have a visual acuity of 20/200 or worse 6 months after
diagnosis of VMT2
– 64% of eyes with VMT experience a loss of ≥2 lines of vision 5 years
after initial presentation2
– In patients with MH:6,7
 Only ~8% have a visual acuity of 20/50 or better
 Up to 54% have a visual acuity of 20/200 or worse
• 74–84% of patients with Stage 2 MH progress to Stage 3 or 4 MH
within 1 year, which if left untreated, can lead to legal blindness8,9
1. Girach A, Pakola S. Expert Rev Ophthalmol 2012;7:311
2. Hikichi T, Yoshida A. Am J Ophthalmol 1995;119:55
3. Gass JD. Arch Ophthalmol 1988;106:629
4. AAO. Preferred Practice Pattern® Guidelines 2008
5. Reese AB et al. Trans Am Ophthalmol Soc 1966;64:134
6. Chew EY et al. Arch Ophthalmol 1999;117:242
7. Casuso LA et al. Ophthalmology 2001;108:1150
8. Kim JW et al. Ophthalmology 1995;102:1818
9. Hikichi T et al. Br J Ophthalmol 1995;79:517

33. Progression of Vitreomacular Traction to Macular Hole
OCT, optical coherence tomography
Normal OCT VMA causing VMT VMA causing macular hole
Normal vision Metamorphopsia Central blindness
MH incidence estimated between 8-30 /100 000
3 times more frequent in females
Bilateral in 11%> 80% have VMT

44. Current Standard of Care for Treatment of Vitreomacular
Adhesion, Vitreomacular Traction, and Macular Hole
• Observation (‘watchful waiting’) until
visual symptoms justify intervention1
– I.e. when patients have, or are at risk
of, severe visual disturbance and/or
central blindness
• Vitrectomy surgery is used to relieve
the adhesion and resulting tractional
forces2
– A surgical procedure that entails
removal of the vitreous gel of the
eye, and may include the peeling of
retinal membranes
1. Girach A, Pakola S. Expert Rev Ophthalmol 2012;7:311;
2. Carpineto P et al. Eur Ophthalmic Rev 2011;5:69
MH, macular hole; VMA, vitreomacular adhesion; VMT, vitreomacular traction

45. Surgical Outcomes in Vitreomacular
Traction
1. American Academy of Ophthalmology Retina Panel. Preferred Practice Pattern®. Idiopathic Macular Hole,
2008. http://www.aao.org/ppp (accessed 12 December 2012); 2. Sonmez K et al. Retina 2008;28:1207; 3.
Engelbert M, Chang S. In: Ophthalmology. 3rd edn. 2009
VMT, vitreomacular traction

52. Pharmacologic Treatments Provide an
Alternative Strategy to ‘Watchful Waiting’
• Eyes with VMA-related disorders can
experience rapid deterioration of
vision and function1
• Early intervention may help to limit
the deterioration2
• Pharmacologic treatment
options have progressed in recent
years2,3
– May be used as an adjunct to surgery
– Offer the possibility for earlier
intervention without surgery
1. Koerner F, Garweg J. Doc Ophthalmol 1997;97:449; 2. Stalmans P. Retinal Physician
2011. http://www.retinalphysician.com/article.aspx?article=105651 (accessed 12
November 2012); 3. Carpineto P et al. Eur Ophthalmic Rev 2011;5:69
MH, macular hole; VMA, vitreomacular adhesion; VMT, vitreomacular traction

57. Ocriplasmin
ILM: inner limiting membrane.
1. 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
Laminin

60. MIVI 6/7
Enzymatic Vitreolysis with Ocriplasmin
for
Vitreomacular Traction and Macular
Holes

62. Inclusion criteria
•≥18 years of age
•Focal VMA on OCT
•BCVA ≤20/25 in the study eye
•BCVA ≥20/800 in the non-study eye
•High myopia (more than -8 diopters)
•Concurrent ocular conditions that could affect visual function
•Prior vitrectomy or laser photocoagulation to the macula
•Treatment with ocular surgery, intravitreal injection, or retinal
laser photocoagulation in the past 3 months
•Proliferative diabetic retinopathy or neovascular AMD
OCT, optical coherence tomography
Stalmans P et al. N Engl J Med 2012;367:606
Defined as vitreous adhesion to the macula within a 6-mm central retinal
field surrounded by elevation of the posterior vitreous cortex

63. Patient Demographics and
Baseline Disease Characteristics
Stalmans P et al. N Engl J Med 2012;367:606 (supplementary material)
The study groups had similar demographic and baseline disease characteristics, with two exceptions:
pseudophakia was more common in the ocriplasmin group compared with the placebo group (37.1% vs
28.2%, respectively; p<0.05), and there were more women in the ocriplasmin group than in the placebo
group (67.7% vs 61.2%, respectively; p<0.05)
Characteristic Placebo (n=188) Ocriplasmin (n=464)
Mean age, years (range) 70.7 (24–97) 72.1 (18–93)
Female, n (%) 115 (61.2) 314 (67.7)
White, n (%) 174 (92.6) 428 (92.2)
Pseudophakic, n (%) 53 (28.2) 172 (37.1)
Mean baseline BCVA,
ETDRS (Snellen)
65.1 (20/50) 63.9 (20/50)
Disease characteristics, n (%)
VMT 126 (67.0) 328 (70.7)
MH 47 (25.0) 106 (22.8)
ERM 68 (36.2) 184 (39.7)

64. 10.1
26.5
0
10
20
30
40
50
60
70
80
90
100
71
VMA, vitreomacular adhesion.
Stalmans P, et al. N Engl J Med. 2012;367(7):606-615.
JETREA. [package insert]. Iselin, NJ: ThromboGenics, Inc.
JETREA® (n=464)Vehicle (n=188)
ProportionofPatientsWith
VMAResolution,%
EU
JETREA® is indicated in adults for the treatment of vitreomacular traction (VMT), including
when associated with macular hole of diameter less than or equal to 400 microns.
P<0.001
n=19 n=123

65. 10.6
40.6
0
10
20
30
40
50
60
70
80
90
100
FTMH Diameter ≤ 400 μm
72
ERM, epiretinal membrane; VMA, vitreomacular adhesion ; FTMH, full-thickness macular hole.
Stalmans P, et al. N Engl J Med. 2012;367(7):606-615.
JETREA UK Summary of Product Characteristics. ThromboGenics. March 2013.
14.6 14.3
34.7 37.4
0
10
20
30
40
50
60
70
80
90
100
VMA Diameter ≤1500 µm No ERM at Baseline
ProportionofPatientsWithVMAResolution,%
18/123 109/314
JETREA® Vehicle
ProportionofPatientsWithFTMHClosure
43/1065/4717/119 101/270

67. • The difference in the proportion of patients experiencing AEs between the
ocriplasmin and placebo groups was driven primarily by those AEs known to
be associated with vitreous detachment1
• The majority of AEs were transient and mild in severity1
1. Stalmans P et al. N Engl J Med 2012;367:606
Placebo
(n=187)
Ocriplasmin
(n=465)
p-value
Any ocular AE, n (%) 100 (53.5) 318 (68.4) <0.001
Any ocular serious AE, n (%) 20 (10.7) 36 (7.7) 0.26
Ocular AEs and serious AEs
MIVI 6/7
AE, adverse event

68. Adverse Events in MIVI 6 and 7
2.7
3.2
1.1
0.5
0.0 0.0 0.0 0.0
0.5
0.0
12.9
10.5
10.1
6.5
4.1
3.2
3.7
0.6
2.6
3.2
0
5
10
15
Proportionofpatients(%)
1. Kaiser P. Retina Society 2012:oral; 2. ThromboGenics. Data on file. 2013; 3. Stalmans P et al. N Engl J Med 2012;367:606
• Majority of events were related to VMA resolution or the injection procedure2
• AEs were mainly transient and mild in severity3
AEs reported Days 0–71
Placebo (n=187)
Ocriplasmin (n=465)

69. Adverse Events in MIVI 6 and 7
4.8
2.7
1.6
2.7
4.3
1.1 1.1
1.6
2.1
0.0
3.9
2.6
1.7 1.9 2.2 2.2
1.7
3.4
1.1
0.4
0
5
10
15
Proportionofpatients(%)
Kaiser P. Retina Society 2012:oral
• Incidences of AEs were similar between treatment groups
AEs reported Day 8 to Month 6
Placebo (n=187)
Ocriplasmin (n=465)

70. Event, n (%)
Placebo
(n=187)
Ocriplasmin (n=465) p-value*
Any ocular AE, n (%) 100 (53.5) 318 (68.4) <0.001
Vitreous floaters 14 (7.5) 78 (16.8) 0.002
Photopsia 5 (2.7) 55 (11.8) <0.001
Conjunctival hemorrhage 24 (12.8) 68 (14.6) 0.53
Injection-related eye pain 11 (5.9) 63 (13.5) 0.005
Blurred vision 6 (3.2) 40 (8.6) 0.01
Visual impairment 3 (1.6) 25 (5.4) 0.02
Increased IOP 10 (5.3) 18 (3.9) 0.50
Retinal tear 5 (2.7) 6 (1.3) 0.25
Cataract 17 (9.1) 26 (5.6) 0.13
Next slidep-values were not adjusted for multiplicity
Stalmans P et al. N Engl J Med 2012;367:606
Ocular Adverse Events
*p-values were calculated with the use of the Cochran–Mantel–Haenszel test, stratified according to study
The injections caused no acute cataracts. Cataract progression was observed in 8.2% of phakic eyes injected
with ocriplasmin and in 11.9% of phakic eyes injected with placebo (p=0.32).
Among the patients who did not undergo vitrectomy, the number of patients with cataract progression was
similar in the ocriplasmin and placebo groups (4.8% and 5.2%, respectively; p=0.97)
Most of these tears occurred during vitrectomy, which was performed for VMT or MH, and were successfully
treated intraoperatively. Two retinal tears with detachment occurred before any surgery in the ocriplasmin
group, and were treated by means of vitrectomy, with successful retinal reattachment. One of these eyes had
a BCVA at baseline of 52 ETDRS letters and had recovery to 44 letters at 6 months; the other eyes with a
baseline BCVA of 70 ETDRS letters had recovery
to 62 letters

71. Rates of Ocular Serious Adverse Events
*p-values were calculated with the use of the Cochran–Mantel–Haenszel test, stratified according to study
A serious ocular adverse event was identified as such by the investigator and was defined as an adverse event
that met one of the following descriptions: an event resulting in persistent or
clinically significant disability, incapacity, or both; an event requiring inpatient hospitalization or prolongation
of an existing hospital stay; or an event that was considered to be medically important
Next slidep-values were not adjusted for multiplicity
Stalmans P et al. N Engl J Med 2012;367:606
Event, n (%) Placebo (n=187) Ocriplasmin (n=465) p-value*
Any serious AE 20 (10.7) 36 (7.7) 0.26
Macular hole 16 (8.6) 24 (5.2) 0.15
Retinal detachment 3 (1.6) 2 (0.4) 0.16
Reduced VA 1 (0.5) 3 (0.6) 0.94

73. OCRIPALSMINA
Discussione

74. Conclusions
• In conclusion, this study shows that enzymatic vitreolysis represents
a means to resolve VMT and to close MH
• Intravitreal injection of ocriplasmin was superior to injection of
placebo in altering the vitreoretinal interface of affected eyes,
although it was accompanied by some, mainly transient, ocular
adverse events
• The proportion of patients who had any ocular adverse event in the study eye was 68.4%
in the ocriplasmin group and 53.5% in the placebo group (p<0.001)
• This difference was driven primarily by adverse events known to be associated with vitreous
detachment
• Most of the adverse events were transient and mild in severity
• The incidence of any serious ocular adverse event in the group treated with ocriplasmin
was 7.7% compared with 10.7% in the placebo group (p=0.26)
• No cases of endophthalmitis were observed
p-values were not adjusted for multiplicity
Stalmans P et al. N Engl J Med 2012;367:606

75. EFFETTI AVVERSI

78. CONSENSO SOI

79. CONSENSO SOI

80. CONSENSO SOI

81. Baseline Characteristics
Age <65 years, n (%)
FTMH present, n (%)
VMA diameter ≤1500 μm, n (%)*
ERM absent, n (%)
Phakic, n (%)
Data on file. ThromboGenics, Inc. 2012
ERM, epiretinal membrane; FTMH, full-thickness macular hole; VMA, vitreous macular adhesion

84. CONSENSO SOI

85. DIFFUSIONE

86. DURATA