Comprehensive discussion on Vitreo-Macular interface disorder, with ILM peeling and Ocriplasmin in details

1. Vitreo-Macular Interface Disorder
-Dr. Deepayan Sarkar

2. Contents
• Functional Anatomy of Vitreous
• Vitreo-Retinal Interface
• Posterior Vitreous Detachment (PVD)
• Epiretinal Membrane, Cellophane Maculopathy.
• Vitreomacular Adhesion (VMA)
• Vitreomacular Traction (VMT)
• Macular Hole
• Pharmacological Vitreolysis
• Surgical Management , ILM Peeling

3. Biblography
1. Kanski’s Clinical Ophthalmology 9th Edition
2. Anatomy and Physiology of Eye. 3rd Edition.
3. Ophthalmology- Myron Yanoff Vol.2
4. Retinal and Vitreoretinal Disease and Surgery- Boyd & Nelson.
5. Clinical Ophthalmology Retina- Will’s Eye Hospital. 3rd Edition.
6. Albert and Jackobiec’s Principal and Practice of Ophthalmology 3rd Edition. Idiopathic
Macular Hole Page no. 2029-2037
7. “A Review of Current Management of Vitreomacular Traction and Macular Hole” Alfredo
García-Layana Journal of Ophthalmology. Volume 2015 |Article ID 809640 | 14 pages |
https://doi.org/10.1155/2015/809640

4. Functional Anatomy of Vitreous
• Vitreous is a jelly like substance of 4cc, weighing 4g present in the
posterior segment of the eye behind the lens, embryologically derived
from the mesenchymal cells.
• Vitreous consists of –
-Water (99%)
- Collagen fibrils (Type 2 Collagen)
- Glycosaminoglycans [Hyaluronic acid > Chondroitin sulphate]
• Parts of the vitreous:
1)Hyaloid membrane – Anterior and Posterior Hyaloid
membrane
2) Cortical vitreous- It is present along the periphery and
contains Hyalocytes, that secrete Hyaluronic acid and is at highest
concentration at near the vitreous base and the posterior pole.
3) Medullary vitreous- It forms the majority of the vitreous body
it is similar to cortical vitreous but contains less fibrillar structure and is
essentially cell-free.

5. Vitreous Attachments
1)Vitreous Base (Strongest attachment- Collagen fibres of
the cortical vitreous are inserted at right angle at the ora
serrata) 3-4mm annular attachment across ora.
2)Weigert’s ligament- 8-9mm along posterior surface of
posterior lens surface, anterior part of the Cloquet’s canal.
3)Peripheral margin of the Optic Nerve Head
Posterior pole. (along the posterior end of the
Cloquet’s canal)
4) Margin of the fovea
5) Along the retinal veins (most variable and most weakest)
Pathologic attchments:
Areas of vitreous degenerations- Lattice degenerations, retinal
cystic tufts.

6. Vitreo-Retinal interface
• The Vitreo-retinal interface is an adhesive sheet that facilitates the
connection of the posterior vitreous cortex of the vitreous body to the
internal limiting membrane of the retina.
• The vitreoretinal interface consists of matrix proteins -laminin,
fibronectin and collagen IV (concentrated on the surface of the ILM) and
acts as an extracellular matrix glue.

7. Posterior Vitreous Detachment
• Separation between posterior vitreous cortex and neurosensory retina, with vitreous
collapsing anteriorly toward the vitreous base.
• Starting in the fourth decade of life, the vitreous body witnesses a significant
decrease in gel volume with a concomitant increase in the liquid volume
• The vitreous gel forms pockets of fluid within the vitreous (synchysis) which
leads to a contraction or condensation (syneresis) of the vitreous
• As the age advances vitreous detaches from retina Posterior vitreous Detachment
(PVD) sets in.

8. Causes of PVD:
1) Senile.
2) Myopic.
3) Post-inflammatory.
4) Post- vitreous haemmorhage.
5) Diabetes.
Pathogenesis of PVD:
• Liquefaction of the vitreous from the normal gel state causing fluid
pockets in the vitreous –Synchysis.
• Collapse of the central vitreous ocuurs-Syneresis.
• This collapse causes a rupture in the posterior cortical vitreous
leading to accumulation of fluid in the retrohyaloid space causing
detachment of the cortical vitreous from the ILM; causing PVD.
• It typically starts in the peri-foveal region and is usually
asymptomatic till it detaches the peripapillary vitreous.

9. Symptoms:
1) Photopsia.
2) Floaters - the floaters of PVD are much more prominent
the vitreous syneresis and is described by the patient as
in the visual field and the patient can look around the shadow.
3) Weiss ring- it is also a circular floater seen in cases of
complete PVD, it is the shadow of the peripapillary attachment
of the vitreous which presents as a ring in front of the eye.
Weiss Ring

10. Stages of PVD:

11. Epiretinal membrane
• It is a sheet like fibro-cellular structure that develops on or above the
surface of the retina.
Proliferation of the cellular component and contraction of the membrane
leads to visual symptoms, primarily due to retinal wrinkling, obstruction
and localized elevation with or without pseudocyst formation and CMO.
• Etiology-
1) Idiopathic- No apparent cause. Residual vitreous tissue remains on the
retinal surface following cortical separation in around 50% of the eyes
with subsequent proliferation. The predominant cellular constituent is
the glial cells, probably derived from the indigenous posterior hyaloid
membrane cell population. ERM development can occur at any stage of
PVD. Symptoms are milder than secondary causes.
2) Secondary- Occurs following retinal detachment surgery (most
frequent cause of secondary ERM, retinal break, panretinal
photocoagulation, retinal cryopexy, retinal vascular disease,
inflammation and trauma). Cell type is more varied pigment cells
derieved from RPE are prominent.

12. • Symptoms-
Blurring of vision and metamorphosia.
• Signs-
1) VA is highly variable
2) An irregular translucent sheen (cellophane maculopathy) is present
early ERM, often best detected using green light.
3) As the membrane thickens and contracts it becomes more
obvious(macular pucker) and typically causes mild distortion of
vessels.
4) Advanced ERM gives severe distortion of blood vessels, marked
wrinkling and striae.
5) Associated findings- macular pseudohole, CMO, retinal
and small haemorrhage.
• Amsler grid- Testing typically shows distortion.
• OCT- Highly reflective surface layer associated with retinal
thickening. Disruption of the IS-OS junction may be associated with
worse visual outcome following surgery. OCT also helps to diagnose
tractional component of ERM.

13. Treatment:
A) Observation- Membrane is mild and non progressive.
Spontaneous resolution of visual symptoms sometimes occur,
typically due to separation of the ERM from the retina as a
previously incomplete PVD completes.
B) Surgical removal- Surgical removal of the membrane via
vitrectomy to facilitate peeling usually improves or eliminates
distortion with an improvement of visual acuity of atleast 2 lines
in around 75% or more. Removal of ILM can also be done.
Macular Pseudo-hole: The lesion mimics the clinical appearance of a FTMH, but is caused by
distortion of the perifoveal retina due to the heaped edges by the ERM without any loss of retinal
tissue.

14. Cellophane Maculopathy
• It is a mild variation of epimacular proliferation but still
interpreted as a distinct entity since no membrane is visible on
the surface.
• Careful examination reveals fine wave formation of the retinal
surface, often best seen intraoperatively.
• With the membrane causing retinal traction to the superior
retina, this causes mild metamorphosia. Visual acuity is usually
maintained.
• If metamorphosia is severe and bothering the patient, complete
vitrectomy is advised.Epimacular proliferation/Macular Pucker
• It is characterized by proliferative cells forming a visible membrane
on the ILM, causing full-thickness macular effects, inner folding,
vascular distortion, leakage, macular oedema and cystic changes.
• Causes tractional symptoms of metamorphosia and photopsia (rare).
• Pharmacological vitreolysis/ Pars plana vitrectomy should be done.

15. Vitreo-macular adhesion
• It refers to residual attachment of the vitreous within 3mm
radius of the central macula in the presence of perifoveal
vitreous separation.
• It constitutes a stage in a dynamic process of PVD .
• There is no tractional component and no distortion of the
foveal contour.

16. OCT Based classification:
• Focal VMA- Involves an area of attachment of <1500um diameter.
• Broad VMA- Involves an area of attachment of >1500um diameter.
• Isolated VMA- Not associated with other macular pathology.
• Concurrent VMA- Associated with underlying macular pathology (ARMD,
Retinal vein occlusion, Diabetic macular oedema)
• Grade 1: incomplete cortical vitreous separation with
attachment at the fovea
• Grade 2: Grade 1 findings plus intraretinal cysts or clefts
• Grade 3: Grade 2 findings plus subretinal fluid

17. OCT Diagnosis of VMA-
• Partial vitreous detachment in the perifoveal region.
• Partial vitreous attachment to the macula within 3mm
radius from center of fovea.
• Acute angle between posterior hyaloid and inner retinal
surface.
• Absence of changes in foveal contour and retinal
morphology.
VMA is generally asymptomatic and no intervention is
required.

18. Vitreo-Macular Traction
• It refers to presence of retinal changes on OCT with evident
perifoveal vitreous attachment within 3mm of central macula.
• It is associated with tractional component of the PVD and
associated foveal and retinal changes.
• Focal <1500um area of attachment.
• Broad >1500um area of attachment.

19. Pathophysiology of VMT-
• With loss of vitreous volume, there is a tractional pull exerted at sites of
vitreoretinal and vitreo-papillary attachments by means of the
condensing densevitreous cortex.
• At the same time, there is weakening of these attachments
between the vitreous and the internal limiting membrane (ILM).
• When anterior vitreous pull and weakening of attachments occur
synchronously, a normal posterior vitreous detachment (PVD)
occurs.
• However, when these occur asynchronously (tractional component
preceding or proceeding faster than the vitreoretinal detachment), an
anomalous PVD develops which can result in VMT and other
vitreoretinal diseases.
• Anomalous PVD is defined as partial vitreous detachment with
persistent attachment in the macular region featuring an
anomalous strength of adhesion to one or more structures in the
posterior pole, resulting in tractional deformation of retinal tissue

20. Types of VMT as per OCT:
V shaped- the vitreous cortex is detached from the retina, both temporal
and nasal to the fovea and attached only at the fovea.
J shaped- the vitreous cortex is detached temporal to the fovea and
remains attached to the retina nasal to the fovea and to the fovea itself.

21. Symptoms of VMT-
1) Blurred vision or reduced vision.
2) Metamorphopsia.
3) Photopsia.
4) Micropsia.
Onset and progression of symptoms are usually gradual, but there
may be sudden onset of vision loss/scotoma due to severe traction
causing foveal detachment.
Signs of VMT-
1) Retinal surface thickening.
2) Retinal surface distortion.
3) Foveal pseudocyst.
4) Cystoid macular oedema.
5) Macular schisis and detachment.
6) Loss of foveal reflex.

22. OCT Diagnosis of VMT-
1. A partial PVD as indicated by elevation of cortical
above the retinal surface in the perifoveal region.
2. Persistent vitreous attachment to the macula with 3mm
radius from the centre of the fovea.
3. Acute angle between posterior hyaloid and inner retinal
surface.
4. Presence of changes of foveal contour or retinal
morphology (distortion of foveal surface, intraretinal
structural changes such as pseudocyst formation,
of fovea from RPE or combination of any of these 3
features).
5. Absence of full thickness interruption of all the layers of
retina.

23. Treatment of VMT:
A) Observation- Spontaneous separation occurs in a propotion of patients
with VMT and is likely in milder cases. Observation is done in cases that are
incidental on finding and has no symptoms.
B) Pharmacological vitreolysis- Intravitreal injection of Ocriplasmin ( a
recombinant form of human plasmin releases VMT by proteolytic action in
over 25% of the eyes).
C) Surgical- Pars plana vitrectomy to release the antero-posterior traction with
ILM peeling gives good results. The retinal architecture reconstitutes with
time after removal of the tractional forces.
D) Pneumatic Vitreolysis- Not preffered due to risk of inducing tears and
glaucoma.

24. Complications of VMT-
1) Full Thickness macular hole.
2) Tractional macular schisis.
3) Tractional foveal/macular detachment.

25. Macular Hole
• A full-thickness depletion of the neural retinal tissue in the
center of the macula.
• Incidence of macular hole- 0.3%
• 12% bilateral
• Common in women 3:1 aged >70 years
• Etiology:
1) Idiopathic 90%
2) Trauma- contusion injury (6%), accidental laser injury,
lightening
3) High myopia
4) ERM
5) Cystoid macular oedema
6) Proliferative diabetic retinopathy
7) Hypertensive retinopathy
8) Choroidal neovascularization
9) Solar retinopathy

26. Classification:
A) Primary Macular Hole- Is commonly an idiopathic macular hole.
Caused by vitreous traction on the fovea from an abnormal vitreous
separation.
B) Secondary Macular Hole- Caused by other pathologies not
associated with VMT.
Blunt trauma, High myopia, Macular telangiectasia Type 2.

27. Pathogenesis theories:
A) Lister (1924)- Vitreous is pathogenic.
A) Gass (1988)-
Focal shrinkage of foveal vitreous cortex  Intraretinal foveolar cyst
formation Unroofing of the cyst.
C) Tornambe et al (2003) Hydration theory-
Post hyaloid traction of fovea Tear in inner fovea Seepage of fluid vitreous
into spongy layers of macula Cavity in inner retina  Enlargement of hole  Spread to outer
retina  Swollen retina remains elevated and retracted.
D) Retinal/Choroidal ischaemia theory-
RPE dysfunction and possible intraretinal fluid accumulation in the fovea. (obsolete).

28. Traumatic Theory-
• Associated with direct or indirect trauma.
• Trauma causes macular hole formation by the mechanical energy
created by vitreous fluid waves and contrecoup macular necrosis
or laceration.
• Common in young boys.
Cystoid degeneration theory-
• Cystic degeneration of the central macula
• Due to hypertension, retinal vessel occlusion, trauma.
• Cyst coalescence  FTMH

29. Role of ILM in pathogenesis of Macular hole:
Scaffold for proliferation of cellular
components like myofibroblasts, fibrocytes,
RPE and fibrous astrocytes.
Causing tangential traction along the fovea.
FTMH formation

30. Revised GASS Classification of Macular Hole :
International Vitreomacular Traction Study
(IVTS) group is an OCT based classification

31. Stage 0 macular hole:
• IVTS classification-VMA
• It is an OCT finding of oblique foveal
vitreo-retinal traction before the
appearance of clinical changes.
• No symptoms

32. Stage 1a :
• IVTS classification-VMT
• Impending macular hole.
• OCT- Appears as flattening of the foveal
depression.
• Fundus examination- Appears as a yellow
spot.
• Pathologically- The Muller cell layers
detach from the underlying photoreceptor
layer , often with formation of cyst like
schisis cavity

33. Stage 1 b:
• IVTS classification-VMT
• Occult macular hole.
• Fundus picture- Seen as a yellow ring
(donut shaped)
• Pathologically- Further foveal traction cause
centrifugal displacement of the
photoreceptor layer with loss of structural
support. The cystic space extends
posteriorly and there is a break in the
photoreceptor layer.

34. Stage 2:
• IVTS classification- small or medium FTMH
with VMT. (Small -<250um, Medium 250-
400um, Large >400um)
• Small full thickness hole.
• Consists of a full thickness hole less than
400um in diameter at its narrowest point.
• Pathology- Dehiscence central, slightly
eccentric or crescent shaped of the roof of
the schitic cavity with formation of pseudo-
operculum. Posterior hyaloid is attached to
the operculum.

35. Stage 3:
• IVTS classification- medium or large
FTMH with VMT
• Full size macular hole.
• A full thickness hole greater than 400um
in diameter .
• It has a red base with yellow white dots
seen, with a surrounding grey cuff of sub-
retinal fluid and the overlying operculum
may be seen.
• Visual acuity is commonly reduced to
6/60.

36. Stage 4:
• IVTS classification- small, medium
or large FTMH without VMT.
• Full size macular hole with
complete PVD.
• The clinical appearance is
indistinguishable from Stage 3.
• Posterior vitreous is completely
detached often suggested by the
presence of Weiss ring.

37. Symptoms of Macular hole:
1) Reduced Visual acuity/ Blurring of vision- depends on the stage
of macular hole and increases with the progression. But if the
hole is eccentric, visual acuity is not much affected.
2) Metamorphosia, Photopsia, Micropsia – It is due to foveal
contour distortion.
3) Loss of central vision/Scotoma- Due to full-thickness macular
hole.

38. Investigations:
A) Amsler grid- Show non-specific central distortion.
B) Watzke-Allen Test- Performed by projecting a narrow slit
beam over the center of the hole vertically and horizontally,
using a findus contact lens. A patient with macular hole will
report the beam is thinned or broken. Patients with other
pathologies see a distorted beam of uniform thickness.

39. C) OCT- (Gold standard)
OCT helps to ascertain the diagnosis of macular hole and also
helps in staging the disease.
D) Fluorescence Angiography-
A full thickness hole shows an early well-defined window
defect due to xanthophyll displacement and RPE atrophy.
E) Laser aiming beam test- A 50 um photocoagulator aiming
beam is aimed at the macular hole, patient with macular hole
will not be able to detect it, but patient with ERM or
pseudohole will be able to appreciate the beam

40. F) Dynamic B Scan USG-
VMT syndrome may demonstrate the peripherally detached hyaloid
with attached hyaloid over the posterior pole, differentiating this
syndrome from idiopathic macular pucker in which a complete PVD
and Weiss ring is usually present. Ultrasonic B-scan has higher
sensitivity and specificity for evaluating the vitreoretinal relationship
as compared to stereoscopic slit lamp biomicroscopy , and can be
useful in eyes with opaque media, where OCT is not possible, or
when OCT devices are not available

41. Lamellar Macular Hole:
• Sharply circumscribed
• Partial-thickness defects of the macula
• Represents either as an aborted full-thickness
lesions or a complication of chronic cystoid
macular edema
• Characterized by a flat, round, reddish hue,
well circumscribed lesion.
• Careful evaluation will reveal retinal tissue in the
base of the lesion
• No evidence of subretinal fluid

42. Witkin et al Diagnostic Criteria for Lamellar Macular hole:
1) Break in the inner fovea with irregular foveal contour.
2) Absence of full-thickness foveal defect with intact foveal
photoreceptors
OCT is the gold standard for diagnosis of Lamellar Macular Hole.

43. Management of Macular Hole

44. Observation
• Spontaneous separation occurs in a propotion of
patients with VMT and is probably more likely in
milder cases.
• Patient should be advised to perform periodic self
examinations with the Amsler grid or monocular
reading tests
• Observe for 3 months and re-examine the patients using
OCT. In case intensity of symptoms or disability
increases they can be reassessed earlier.

45. Pharmacological Vitreolysis
• Intravitreal injection of Ocriplasmin (recombinant form
of human plasmin).
• Mechanism of action- Weakens or cleaves vitreous-
retinal surface before or concurrently with liquefaction of
core vitreous and relieves the tractional components.
• These agents break down the peptide bonds in laminin
and fibronectin molecules which keeps the adhesion
between ILM and vitreous.
• Ocriplasmin, is a recombinant truncated form of
human plasmin with molecular weight 27.8kDa. It is a
DNA molecule which is more stable than plasmin and
has emerged as new vitreolytic agent. It is recombinant
protease with activity against fibronectin and laminin.

46. MIVI Studies
• Multicentric, randomized, placebo controlled, double-masked studied
652 eyes to understand safety, efficacy of Ocriplasmin.

47. • Phase 1 & 2 - 60 patients studied. Ocriplasmin was found to be
safe and well tolerated.
• Phase 2- 60 patients studied. Best dose is 125ug, capable of PVD
inducing.
• Phase 3- 652 patients studied. Dose of 125ug. Superior than
placebo.

48. Final outcome:

49. Ocular side effects of Ocriplasmin injection-
• Vitreous floaters
• Photopsia
• Blurred vision
• Conjunctival hemorrhage
• Lens subluxation
• Retinal breaks .

50. Surgical management
Indications:
 decreased visual acuity generally below 6/12
 good visual acuity with severe metamorphopsia and
 moderately symptomatic VMT that fail to improve with observation, or
demonstrate progression of the traction effects are indications for PPV.
 Stage 2or higher staging macular holes.
Pars plana vitrectomy may be combined with one or more additional
interventions including stripping of the posterior hyaloid, ERM peeling, ILM
peeling, air-fluid exchange, and gas or air endo tamponade.

51. A) PPV / Delamination of corticalvitreous
– Standard 3-port PPV
– Anterior and middle vitreous is removed
– Traction relieved either by removing perimacular vitreous
combining it with complete PVD. Staining with Triamcolone acetonide helps to identify cortical
vitreous and helps in completely removing the vitreous.
– Soft tipped silicon cannula vitrectomy cutter is used to remove the vitreous completely
– Fish strike sign / bending of silicon cannula denotes complete PVD.
– Surgical adjuvants like TGF-beta, autologous serum, platelet concentrates have not shown
effective clinical results.
B) Delamination of ILM
C) Peeling of Epiretinal membrane

52. taining of Vitreous & ILM (Chromovitrectomy):
 Trypan Blue(0.15%): stains ERM, but not
ILM.
 Triamcinolone Acetonide(40mg/ml):
stains residual vitreous.
 Brilliant Blue(0.025% &0.05%): excellent
stain for ILM, relatively non toxic.
 Indocyanine Green: High affinity for
Laminin, stains ILM.

53. ILM removal instruments:
1) Forceps: ILM is 2-4um thick and forceps allow more precise tearing.
• A forceps with a large platform (end-gripping) reduces the risk of shredding
the ILM.
• Morris/Witherspoon forceps has a small platform has a hollowed shaft and
allows better visual control.
2) Tano membrane scraper : This instrument is used to create the initial break in
the ILM and complete the peeling with it.
The silicon tip of the scraper is attached to a diamond crystal which can cause
retinal damage.
3) Cannula: A specially designed microcannula is inserted under the ILM and
viscoelastic is injected to simulate ILM separation.

54. Surgical Techniques of ILM peeling :
A) Key-Hole Technique : The initial opening of the ILM is done using the pinch technique
with forceps. The forceps is inserted in an oblique, vertical orientation to the retina. The
retina is contacted at a avascular region inside the arcuate vessels at 6ó clock or
12oclock. The forceps jaws are closed and then elevated, the stained ILM is seen to rise
and as the forceps is opened the ILM breaks. The edge formed is used for parafoveal
rehxis.
B) The “Apple-peel” technique : The stained ILM is grasped 500-700um above and below
the fovea and a thin strip is peeled radially, almost to the fovea and then released. The
exposed edge is then grasped at its midpoint and a parafoveal strip of ILM is started with
a circumferential movement peeling of the ILM from the parafoveal region.
C) The FILMS technique: Viscoelastic fluid is injected underneath the ILM using a special 36
G microcannula. The cannula should be placed in correct position and the flow is maintained
by foot control of the surgeon. A microbubble is formed beneath the ILM and it is peeled of
using forceps.

55. Tamponade of hole
– Nonexpansile concentration of a long-acting gas is
exchanged for air
– Perfluoropropane (C3F8) or sulfur hexafluoride (SF6)
– Silicone oil has also been used as an internal
tamponade for patients with difficulty positioning or
altitude restrictions
– Patient kept in face down position post-operatively for
1 week duration.

56. Macular hole surgery

57. Complications of Surgery:
• Cataract (75%)
• Late macular hole reopening (2-10%)
• Retinal Detachment (3%)
• Retinal breaks (5.5%)
• Raised IOP (1stwk)
• Endophthalmitis(<1%)
• Visual Field defects

58. Types of Macular hole closure:
A) Type 1 closure : Indicates that macular hole is closed
without foveal defect of the neurosensory retina.
B)Type 2 closure: Indicates a foveal defect of
neurosensory retina persists postoperatively
though the whole rim of macular hole is attached
to the underlying RPE with flattening of the cuff.

59. Thank You