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Disorders of the Vitreous

Sebag J, Trans Am Ophthalmol Soc 2005 (9 month old)

The material covered aims to:
a. describe normal vitreous humor development &
anatomy (brief review from VISN2111)
b. describe the main components of the vitreous &
vitreous function.
c. discuss main age-related changes in vitreous
d. comment on how to clinically view the vitreous & grade
vitreous haze
e. explain things in the vitreous (opacities - endogenous
and exogenous), causes & what these mean
f. comment (briefly) on vitrectomy & vitreous substitutes
 First, a few vitreous terms
Synchisis: vitreous liquefication (formation of collagen-free
liquid-filled spaces)
Syneresis: exudation of liquid from vitreous gel as collagens &
other molecules clump / aggregate, vitreous collapse
PVD: posterior vitreous detachment
Weisss ring: peripapillary glial tissue that remains attached to
the posterior vitreous cortex following PVD
Vitreoschisis: a split in the posterior vitreous cortex
Abnormalities of regression of the hyaloid system:
PFV: persistent foetal vasculature
PHTVL: persistent hyperplastic tunica vasculosa lentis
PHVP: persistent hyperplastic primary vitreous
PPM: persistent (pre)pupillary membrane
 a. Vitreous humor development and anatomy
(vitreous: from Latin, vitrum, meaning glass)
- optically clear media (normally)
- mainly water (~98%),
- occupies ~2/3 of volume (~4 to 5ml) of human eye,
giving eye form and shape
- viscous properties allow the eye to return to its normal
shape if compressed
- in children, vitreous consistency is similar to egg
white
- with age vitreous becomes more liquid (from as
early as age 4 years!)
- review vitreous development from VISN2111
Vitreous Development

Phase I: primary vitreous

(PV) = hyaloid and
posterior tunica vasculosa
lentis

* primary vitreous provides

developing lens (ciliary
body?) with nourishment
etc.

* PV including blood
vessels begin to regress
from ~12WG
Development of the Human Eye, Ida Mann @ 1956
Phase II and beyond:

- avascular secondary vitreous forms and

expands to compress central primary vitreous
anteriorly

- tertiary vitreous: vitreous fibrils condense to

form lens-associated zonules, primary vitreous
continues to regress
Primary vitreous Secondary vitreous Zonules - vitreous

From Vitreous in Health & Disease, J. Sebag (Editor), 2014

 ON

A
Madigan 2012

18WG human eye: anterior segment (lens, iris and cornea) removed. Hyaloid
vessels (arrow) at the optic nerve head (ON) extending within the eyecup.
 Hyaloid regression not always complete and hyaloid
(Cloquets canal) remnants are seen in adult eyes

http://www.missionforvisionusa.org/anato
my/2007/07/mittendorfs-dot.html

Mittendorf's dot: a small remnant of anterior hyaloid artery,

usually axial in location on posterior lens surface
Mittendorf's dot: remnants of anterior end of hyaloid
artery, usually axial in location on posterior lens surface
(white spot by slit lamp, black spot by ophthalmoscopy)
Bergmeister papilla (glial remnants of hyaloid)
http://imagebank.asrs.org/file
http://www.mrcophth.com /15667/bergmeister-papilla

http://imagebank.asrs.org/file/13458/remnant-of-hyaloidal-artery
Adult vitreous: Review normal structures
 Adult Vitreous: orientation of collagen fibrils in vitreous.
Central vs cortical vitreous vs vitreous base. Properties differ related to
differences in fibrillar collagen concentration and orientation.

Le Goff and Bishop, Eye 2008

 Posterior vitreous cortex

Vitreous

Posterior cortical vitreous

ILM

Retina

Condensation of peripheral collagen fibrils creates a boundary or

membrane (cortical vitreous). Note lamellar structure.
Ultrastructure of human ILM. Transmission electron microscopy of the retina
from an adult human - separation of retina from the vitreous cortex.

A: Posterior pole, ILM has a smooth anterior surface, whereas posterior aspect is
irregular, following the contour of the underlying nerve fibers and Mller cell foot
processes.

B: In the periphery, both anterior and posterior aspect are smooth & continuous,
(Both4500.) (Sebag J)
Retina / Vitreous interactions
Condensation of peripheral
collagen fibrils creates a
boundary

Attached to adjacent
structures

1. posterior lens capsule

2. vitreous base (ora
serrata)
3. surrounding optic disc
4. macula region
5. larger retinal vessels
Vitreous Attachments
1. vitreous base (strongest, most extensive adhesion)
- extends 1.5 to 2 mm anterior to ora serrata 1 to 3
mm posterior + several mm into the vitreous
- vitreal fibres embedded firmly in the BM of non-
pigmented ciliary epithelium and ILM of the peripheral
retina

2. annular attachment 1 to 2 mm wide x 8 to 9 mm

diameter between posterior lens surface and
anterior vitreous (also called hyaloideocapsular
ligament (of Weiger), or retrolental ligament)
- within the ring is a potential space, the retrolental
space (of Berger)
 Vitreous base location

http://www.jove.com/Details.stp?ID=2455
Transition of epithelium (pigmented & non-
pigmented....ora serrata
 Anterior vitreous and space of Berger

Madigan 2016
Vitreous Attachments (cont.)

3. peripapillary adhesion around edge of optic disc

4. macular annular ring of attachment ~3 to 4 mm

5. larger retinal blood vessels: attachment of

vitreous via fine strands that extend through the ILM to
branch and surround the larger retinal vessels.
- the ILM varies in thickness across the posterior
eye; ILM represents the basement membrane of
retinal Mller cells
 b. Whats in the vitreous?
* cells - resident hyalocytes, macrophage/myeloid-
lineage cells (infiltrating cells associated with
inflammation, infection)
* 98- 99% water a transparent colloidal gel*
* structural collagens (II, V/VI, IX, XI)
* hyaluronan (hyaluronic acid (HA) and other
glycosaminoglycans (GAGs) & proteoglycans
* non-collagenous proteins (opticin, fibrillin)
* metabolites including ascorbate (anti-oxidant)
(human vitreous ~300g/ml collagen)

Gels = mostly liquid but 3D network of collagens + GAGs gel structure

Hyalocytes - cells in posterior vitreous cortex, along inner
surface of the retina.

chp%3A10.1007%2F978-1-4939-1086-1_10.pdf
 Collagen structural arrangement
Type II collagen ~ 60-70% (widely
spaced, small fine fibrils 8 to 16
nm); type IX ~ 25% collagen

(a) Collagen fibrils (thick grey lines) form

extended network; organised into
small bundles interconnected by
collagen fibrils running one bundle to
another. Type IX collagen-CS chains
connect and space collagen fibrils in
each bundle (thin black lines).

(b) aging, loss of type IX collagen-CS

chains from collagen fibril surfaces +
increased surface exposure of type II
collagen aggregation of collagen
Le Goff and Bishop, Eye 2008 fibrils
 Whats in the vitreous?
Hyaluronan (hyaluronic acid) (HA) =
glycosaminoglycan
- responsible for high water content of vitreous gel
- stabilise the collagen network, chains form networks
(with other GAGs)
- HA is not uniformly distributed within vitreous, highest
concentration in posterior vitreous cortex
- adult human vitreous: HA concentration between
~65 and 400 ug/ml
Other non-collagenous proteins

Opticin: glycoprotein secreted by non-pigmented ciliary

epithelium into vitreous during life
- can bind HS and CS (co-localizes with vitreous collagen fibrils)
- also localized to the ILM and lens capsule
opticin is anti-angiogenic and inhibits growth of new
vessels in vitreous
(Goff et al., IOVS, 2012; also Bishop PN since about 2004.....)

Fibrillins: microfibrils with characteristic beaded structure, minor

compared to collagen fibrils.
NOTE: fibrillin-1 = major structural component of zonules that
hold the lens in place
Metabolites & other compounds in vitreous

Ascorbate: anti-oxidant, scavenges free-radicals, protects

retina and lens. Note high levels in vitreous cf. plasma
What are normal functions of the vitreous?

a. transmit and refract light; minimal light scattering

due to extremely low concentration of particles +
interfibrillar spacing ensured by HA-collagen
complex
b. provides a buffer to protect the retina against
transmitted forces e.g. during trauma
c. provides for transfer of metabolites between
anterior and posterior portions of globe
d. regulate eye growth and shape during
development
Review: What are normal vitreous functions?

e. serve as a barrier to cellular invasion/migration

and diffusion of large macromolecules; this
contributes to maintaining transparency of the
vitreous cavity (e.g. opticin is an inhibitor of new
vessel growth)
f. vitreous gel, compared to liquefied vitreous, lowers
oxygen tension around lens and in retina
(Holekamp et al., 2010, 2011)
- if the vitreous gel changes (for example with age,
surgery) what happens to the lens?
 Is the lens vulnerable to changes in oxygen levels
secondary to vitreous changes?

- sensitivity of the human lens to oxygen is reported with long

term hyperbaric therapy nuclear cataracts developed
(Palmquist et al.,1984; Fledelius et al., 2002)

- vitreous gel lowers the oxygen tension around the lens and in
retina (Holekamp et al., 2010, 2011; Beebe et al., 2011)
Does vitreous gel normally protect
the lens from oxidative changes
and slow the development of
nuclear cataract?

(a) normally oxygen diffuses from

retinal vessels in to gel, and is
used in other regions of the
retina; in central vitreous,
ascorbate (~2mM) + oxygen
(antioxidant)

(b) after degeneration or removal of

vitreous body, vitreous cavity fills with
liquid that re-distributes oxygen in the
vitreous cavity

Beebe D C et al. Phil. Trans. R. Soc. B

2011;366:1293-1300
 Does vitreous gel normally protect
the lens from oxidative changes and
slow the development of nuclear
cataract?

Vitreous cavity is filled with liquid

(rather than gel) that mixes and moves
oxygen from the retinal surface
throughout the vitreous

More oxygen delivered to the posterior
lens surface than occurs normally in (a)
and oxygen diffuses into the lens,
including nucleus

Antioxidants in lens cortex (e.g.
glutathione) provide relative protection
from oxidative damage (lens nucleus
glutathione with age)

Beebe D C et al. Phil. Trans. R. Soc. B

2011;366:1293-1300
 c. Normal age-related changes in vitreous
(liquefaction & posterior vitreous detachment
(PVD))

- with aging, pockets of collagen-free liquid appear

within central vitreous & gradually coalesce
- weakening of vitreoretinal adhesion occurs (non-
uniformly)
- progression to PVD liquid vitreous dissects
residual cortical gel away from retinal ILM (inner retinal
surface)
- occurs posterior to the vitreous base
Normal age-related changes in vitreous liquefaction
 Posterior Vitreous Detachment (PVD)

Age-related vitreous
liquefaction & PVD
liquid - pockets of liquid appear
within central vitreous and
gradually coalesce.
-weakening of vitreoretinal
adhesion.
- progression to PVD
- liquid vitreous dissects
residual cortical gel away
liquid
from ILM (inner retinal
liquid surface)
- extends forward to the
posterior border of vitreous
base.

From Le Goff and Bishop, Eye 2008

Total PVD: cortical vitreous separated from retina except at vitreous base
(Courtesy of W. Richard Green, MD.) [Yanoff & Duker, 2004]

Vitreous
Lens

Retina

Vitreous
base
Patient complaining of a floater in the vision. Fundus photograph shows a Weiss ring
pulled away from the optic nerve head.

http://imagebank.asrs.org/file/7400/weiss-ring-floater
Weiss ring
Main issue for PVD: may be incomplete, with attachments
remaining to the retina
Clinical problem = vitreomacular traction / vitreomacular
attachment potential for macula hole formation, retinal
detachment/tear, vision problems etc.
 Floaters (physiological vs pathological)

Little cobwebs or things that float in the visual field

* move when eyes move, seen in bright background light,

MORE COMMON with age (think about vitreous-collagen
changes), PVD, and for example in people with myopia,
diabetes, post-cataract surgery..

Sudden increase in floaters & flashes (+ vision loss)

= suggest possible retinal detachment
= URGENT!!

Note: flashes / photopsias can be associated with retinal

traction + non-ocular causes such as migraines,
neurological (e.g. brain tumours), vascular triggers .
 Vitreous floaters due to clumping of collagen, PVD etc

A) B-scan ultrasound showing vitreous floaters in a -6.75D myope.

B) B-scan ultrasound showing PVD in a -8.50D myope, VA 6/9; contrast sensitivity
was reduced. Limited vitrectomy was performed with a good outcome improved
contrast sensitivity although VA still 6/9.
Combined SD-OCT and scanning laser ophthalmoscopy of visual flaoters.
The floaters produces an umbra (U) (shadow) and penumbra (P) (partial shadow) on
the retinal surface.
More examples of floaters with different imaging techniques

Milston et al., 2015

http://stopthefloaters.com/eye-floaters-anxiety/
 What about floaters?
Physiological vs patholgical

[From Scott Geller, MD Fort Myers, Florida]

What to do about floaters?
- for some patients, floaters may lead to visual symptoms
(visual axis location); some patients are sensitive to floaters;
reduced quality of vision, floater anxiety.
Management
- currently surgical vitrectomy vs YAG laser (no large trials to date
for laser; no good evidence for laser)
What are the risks with each approach?
 Posterior vitreous
detachment (PVD)

- major risk factor for retinal

tears and retinal detachment.

Risk factors: myopia, age,

one eye often follows the
other ......

More in S2 OPTM3231
Summary
Flashes and floaters are usually signs of benign changes
BUT a small percentage have sight-threatening disease
all patients require a dilated fundus examination.
Acute onset of flashes and floaters = urgent same day
referral
Acute-onset flashes and floaters + visual field defect
suggests retinal detachment - REFERRAL
 d. Clinical examination of vitreous & grading vitreous haze

Examination methods: combined approach is best

- slit lamp (anterior third); retroillumination

- fundoscopy (+60, +78, +90D lens) (to exam posterior
vitreous)
- scanning laser ophthalmoscopy
- direct and indirect ophthalmoscopy
- B-scan ultrasound
- SD-OCT (vitreo-retinal interface)

[see for example, Sebag J (2002) Imaging vitreous. Eye 16: 429-439]
Retroillumination and B-scan ultrasound
 Observation of Posterior Pre-cortical Vitreous Pocket Using Swept-Source Optical Coherence Tomography
Invest. Ophthalmol. Vis. Sci.. 2013;54(5):3102-3107. doi:10.1167/iovs.13-11769

Cross-sectional views of Cloquet's canal (C) in vertical SD-OCT scan. Cloquet's

canal extended forward and tilted superiorly.
https://www.youtube.com/watch?v=MSO1BkOpenM
 Grading vitreous haze: cell infiltration + protein leakage
(fundoscopy, BIO) BUT are there other measures?

Recent clinical studies also assess contrast sensitivity,

straylight measurements, quality of life questionnaires
 Acquired exogenous opacities
e.g. vitreous infection, inflammation, tumour cells

* infectious: bacteria, fungi, viral, parasitic

* non-infectious, autoimmune, idiopathic, tumour-related
* grading cells and protein in vitreous (similar to aqueous)
 e. Other vitreous opacities - endogenous & exogenous

Class Examples
Congenital Remnants of hyaloid vasculature

(i) Asteroid bodies

Endogenous
(ii) synchisis scintillans

(i) Exudative cells

(ii) Blood
(iii) Tissue cells: epithelial, histiocytic, glial
Exogenous
(iv) Tumour cells
(v) Pigmented cells: melanotic & blood cells
(haematogenous)

[Adapted from Coupland SE Eye 2008]

 Endogenous vitreous opacifications

Asteroid hyalosis: usually unilateral degeneration,

characterised by calcium deposits in collagen = not
very mobile. Snow flurries

Synchysis scintillans (cholesterolosis):

appears golden, often unilateral, frequently follows
intravitreal haemorrhage, free-floating cholesterol
crystals that settle inferiorly without movement

Vitreous amyloidosis: very rare, autosomal

dominant condition; amyloid deposits around collagen
fibres
 Asteroid hyalosis
form of vitreous degeneration, aggregates of calcium
and phosphorous and lipids (soaps)
male to female 2:1, typically >70 years, PVD
association?
aetiology not clearly understood.
Symptoms: rarely affects patient's VA even if severe
Asteroid hyalosis

http://www.optos.com/RecognizingPathology/pages/Vitre
ous/AsteroidHyalosis-10.html
 Asteroid hyalosis

Signs:
white to yellow-white small round to oval opacities
suspended throughout vitreous body
75 - 90% unilateral
move as vitreous body moves and tend to return to
original positions
differential diagnoses: amyloidosis, cholesterolosis

Management: No treatment required, BUT vitrectomy

may be indicated when vision affected (rare) or fundus
hard to see.
 Vitreous amyloidosis
isolated or part of systemic amyloidosis.
can be hereditary such as in Familial Amyloidotic
Polyneuropathy or non-hereditary.
Clinical features
Symptoms: slowly progressive bilateral or unilateral
decrease in VA
Signs:
Unilateral or bilateral typical glass-wool or cobweb
appearance of vitreous opacities
Hazy view of the fundus

Management: therapeutic vitrectomy in visually significant

cases.
Cholesterolosis (synchysis scintillans)

Amyloidosis
 Acquired exogenous opacities
e.g. vitreous infection, inflammation, tumour cells

* infectious: bacteria, fungi, viral, parasitic

* non-infectious, autoimmune, idiopathic, tumour-related
* grading cells and protein in vitreous (similar to aqueous)
 Inflammation of the vitreous (S2 OPTM3231)
Vitreous inflammation (vitritis) (anterior vs posterior)
Cells from choroid, retina, ciliary body; grading of cells can be
difficult
Location of cells: immediately behind lens, anterior or posterior
vitreous, adjacent to retinal lesion, snowballs
Vitreous haze = cell infiltration + protein leakage
 Acquired vitreous
opacities: haemorrhages
Bleeding into the vitreous
- from normal retinal vessels
following trauma, acute vitreous
detachment or retinal tear
- from abnormal retinal vessels
(e.g. retinal new vessels in
http://imagebank.asrs.org/file/27132/subhyaloid-hemorrhage
diabetic retinopathy)
Common causes of vitreous haemorrhage
PVD with/without retinal tears
proliferative diabetic retinopathy, branch retinal vein occlusion, wet age-
related macular degeneration, blood dyscrasias, sickle-cell, leukaemias.
Tersons syndrome (associated with intracranial, subarachnoid, or subdural
haemorrhage)
Treatment: unresolved haemorrhage = removed via vitrectomy

Pre-retinal (subhyaloid) haemorrhage: between the posterior vitreous and

retina ILM. Distinct appearance (blood spreading within 2 layers)

www.thelancet.com
Acquired vitreous opacities: revised
* improved diagnostic techniques better understanding of
underlying causes of acquired vitreous opacities;
* improved classification including genetic, inflammatory non-
infectious & infectious, iatrogenic, degenerative, traumatic,
neoplastic, idiopathic conditions
 Sampling vitreous for pathology - application of
cytology
Cellular vs acellular samples

Cellular: hameorrhage, inflammation (infectious &

non-infectious), tumours (including retinoblastoma,
lymphoma)

Acellular: amyloid, calcium, cholesterol, bits of

conjunctival cells displaced during vitrectomy, pigment
granules following retinal tear, lens bits post-cataract
surgery (fibres)
 e. Things in the vitreous
(vitreous opacities - endogenous & exogenous)

Class Examples

Congenital Remnants of hyaloid vasculature

(i) Asteroid bodies

Endogenous
(ii) synchisis scintillans

(i) Exudative cells

(ii) Blood
(iii) Tissue cells: epithelial, histiocytic, glial
Exogenous
(iv) Tumour cells
(v) Pigmented cells: melanotic & blood cells
(haematogenous)

[Adapted from Coupland SE Eye 2008]

DISEASE TYPE
GENETIC
e.g. amyloidosis
INFLAMMATORY
NON-INFECTIOUS
e.g. sarcoidosis
e.g. Fuchs iridocyclitis
e.g. Behets syndrome
INFLAMMATORY
INFECTIOUS
e.g. parasitic - toxoplasmosis
e.g. fungal - endophthalmitis
e.g. spirochaetal - syphilis
e.g. bacterial - TB
IATROGENIC
(inflammation) e.g. following
photocoagulation, cryotherapy
DEGENERATIVE
e.g. Vitreous detachment
e.g. pigment granules
MORPHOLOGY CAUSE (if known)
Dense amorphous excrescences Transthyretin gene mutation
Macrophages, giant cells, some lymhocytes
Non-specific chronic infiltrates with small
lymphocytes
Neutrophils, lymphocytes. B-cells, HLA B5 in >50% patients
Chronic inflammatory cells eosinophils, T. gondii
lymphocytes
Macrophages, neutrophils, ?granulomatous, Candida, aspergillus,
necrotic debris, fibrin aggregates cryptococcus
Non-specific chronic inflammatory cells treponema
Macrophages, giant cells, granulomatous, few Mycobacterium tuberculosis
lymohocytes
Non-specific chronic inflammatory cells, RPE,
retinal bits, protein
Non-specific inflammatory cells
Pigment granules - vitreous strands, dispersed Melanocytic, haemorrhage
TRAUMA
e.g. vitreous detachment, non-specific inflammatory cells, clumps of
haemorrhage, erythrocytes, macrophages
e.g. sympathetic chronic granulomatous inflammation, melanin-
ophthalmia containing cells, lymphocytes, B-cells
NEOPLASIA
Primary
e.g. Retinoblastoma, atypical tumour cells, lymphocytes
lymphoma, melanoma
Secondary
e.g. Metastatic carcinoma, atypical clumping of cells, atypical lymphocytes,
leukaemia, lymphoma, atypical melanocytes
cutaneous melanoma
IDIOPATHIC
Asteroid hyalosis Round yellow-white bodies, calcium Miminal inflammation

Synchisis scintillans Crystals - cholesterol Minimal inflammation

[Adapted from Coupland SE Eye doi:10.1038/eye2008.31]

f. Vitrectomy and vitreous substitutes
Vitrectomy: removal of vitreous for various reasons e.g.
haemorrhage, diagnostic purposes, epiretinal membrane
- usually through pars plana

https://www.youtube.com/watch?v
=JJ-BK9cKJ4w

https://www.youtube.com/watch?
v=lF82FOGtLRs
 Vitreous substitutes
What properties are ideal?
Inert (not toxic), optically clear, viscoelastic not rigid

Examples: gases, silicon oils, N-perflurohydrocarbons,

(see for example Foster WJ, Exp Rev Ophthalmol 2008)

Other options? Inflatable hydrogel vitreal inserts

Pharmacological vitreolysis: induce a PVD to minimise
clinical problems such as vitreomacular adhesion or traction
- cleave vitreoretinal junction + liquefy vitreous gel

Jetrea (ocriplasmin) = 27kDA

serine protease that leads to lysis
of laminin and fibronectin at the
vitreoretinal interface and releases
vitreomacular attachments
 Overview - Jetrea Phase III
Trials
- appropriate patient selection is
critical: focal vitreomacular
adhesions, small early-stage
macular holes, NO epiretinal
membrane.
- most patients experience
worsening symptoms, i.e., flashes,
floaters and/or reduced vision,
before they improve.
- if no effect within a month after
injection, it likely will not work.
- vitrectomy not precluded for
patients who do not achieve
posterior vitreous detachment with
ocriplasmin.
http://www.scottpautlermd.com/jetrea-injection-
ocriplasmin/
Summary

1. Vitreous changes with age physiological

floaters & vitreal detachment
2. Floaters physiological vs pathological
3. Increased risk of posterior vitreal detachment (PVD)
associated with age, myopic refractive error
4. PVD associated with risk for retinal tears and
detachment (anomalous PVD)
5. Pigment in vitreous, anterior chamber: RPE-related
check for retinal tear; also bleeding
6. Various types of opacities in the vitreous
- congenital/development related remnants of the
hyaloid e.g. Mittendorfs dot, Bergmeisters papilla
- degenerative changes 2ndy to ageing
- endogeneous (cholesterol, amyloid)
- exogeneous (other sources such as tumours,
infection)

7. Loss of vitreous clarity grade haziness

dilated fundus exam

Vitreous inflammation (retinal / choroid/ ciliary

body) = vitritis
Thank you any questions?