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Proliferative Vitreoretinopathy

Article initiated by:

Gary W. Abrams

All authors and contributors:

Leo M. Hall, MD, MS, Anju Goyal, Koushik
Tripathy, MD (AIIMS), FRCS (Glasgow), Gary W.
Abrams, Mary Elizabeth Hartnett,
MD, Christopher Komanski, Jennifer I Lim MD

Assigned editor:
Mary Elizabeth Hartnett, MD

Review:
Assigned status Up to Date

 by Mary Elizabeth Hartnett, MD on September 3,

2022.

Proliferative vitreoretinopathy (PVR), a major complication

of rhegmatogenous retinal detachment (RRD), is an
abnormal process whereby proliferative, contractile
cellular membranes form in the vitreous and on both sides
of the retina, resulting in tractional retinal detachment
with fixed retinal folds. However, it is increasingly being
recognised that PVR may be intraretinal also, which causes
retinal shortening. Research suggests that membranes
form in response to cytokines and inflammatory mediators
that arise following anatomic disruption and tissue damage
caused by rhegmatogenous retinal detachment (RRD) and
resultant inflammation. Treatment is principally surgical
and often requires multiple procedures that, in fact, yield a
high rate of retinal reattachment; nevertheless, many
anatomically successful eyes do not recover good visual
function likely due to the long standing macular
detachment.

Disease Entity
Proliferative vitreoretinopathy (PVR) is classified using the
following International Classification of Disease (ICD)
code: H35.20, other non-diabetic proliferative retinopathy,
unspecified eye.

Disease
Proliferative vitreoretinopathy

Etiology
Proliferative Vitreoretinopathy (PVR)— formerly named
“massive vitreous retraction” and “massive periretinal
proliferation” — describes the aberrant process whereby
epi/subretinal membranes form following rhematogenous
retinal detachment (RRD), ultimately leading to retinal
traction and recurrent retinal detachment.[1] [2] [3]
Intraretinal PVR is caused by glial tissue that is activated to
proliferate within the retina and can cause retinal
shortening. PVR arises in an estimated 5-10% of RRD
cases, and therefore represents a major complication of
retinal detachment.[4]

General Pathology
In general, PVR is comparable to an abnormal wound-
healing process following tissue insult, more specifically,
retinal detachment. Rhematogenous retinal detachment
(RRD) serves as a nidus for membrane formation, in part
through induction of ischemia and subsequent cell death
that arises from separation of the neuroepithelium from its
rich choroidal blood flow. Cell death triggers a break down
in the blood-retinal barrier (BRB),[5] [6] thereby facilitating
the influx of chemotactic and mitogenic factors that permit
cell proliferation, migration, extracellular matrix deposition
and contraction. Similarly, the vitreous is suffused with
growth factors and inflammatory mediators; thus, it serves
as a milieu for cellular proliferation in the case of retinal
detachment.[7] Contractile membranes contain fibroblast-
like cells in extracellular matrix that have characteristics of
RPE and glial cells on the inner surface of the retina and
mostly RPE cells on the outer (subretinal) surface of the
retina.[8]

Pathophysiology
Although the exact pathophysiology remains disputed, the
development of PVR is a complex process involving
humoral and cellular factors. Crucial cells in the
development of PVR are retinal pigment epithelial (RPE)
cells, glial cells, fibroblasts and macrophages.[9] Following
retinal detachment and subsequent ischemia, some RPE
cells lose their polarity and undergo epithelial-
mesenchymal transformation (EMT).[10] EMT is a process
whereby epithelial cells lose their typical epithelial
morphology and phenotype and acquire a mesenchymal-
like morphology and phenotype. Various chemokines and
cytokines, most notably TGFbeta, PDGF,[11] VEGF, IL-1, 6,
8, 10 and IFN-gamma,[12] whose presence is permitted via
breakdown of the BRB, induce cell proliferation, migration,
extracellular matrix deposition and contraction.
Transformed cells in membranes become fibroblast-like
cells that contain actin and myosin and have the ability to
contract. Activation of Muller glia leads to marked gliosis
within the retina that leads to retinal stiffness and
shortening.[13] Macrophages may play a multifactorial role
that involves secretion of enzymes and growth factors (e.g.,
platelet-derived growth factor, PDGF) and
transdifferentiation into fibroblast-like cells.[14] Fibrocytes,
circulating cells derived from bone marrow stem cells that
transform to fibroblasts in tissue, have also been found in
PVR membranes, further evincing the robust cellular
buildup in response to circulating growth factors.[15] It is
even possible that genetic changes in the cytokine TNF
alpha might predispose to PVR in patients with retinal
detachment.[16]

Primary prevention
Risk Factors, Primary Prevention and
Medical Therapy:
The best way to prevent PVR is prompt successful repair of
primary RRD. However, due to patient, ocular and surgical
factors that are not always controllable, PVR continues to
occur. A strategy to prevent PVR is to look for risk factors
for PVR in eyes with RRD and to try to control or influence
those risk factors.

Clinical factors associated with increased risk of PVR

include, but are not limited to:

existing PVR
chronic rhematogenous retinal detachment lasting
longer than several months,
previous history of PVR
aggressive retinitis
choroidal detachment
failed RRD surgery, or multiple retinal surgeries
aphakia
vitreous hemorrhage
choroidal detachment
high vitreous protein levels
positive smoking history
preoperative retinal folds
horseshoe retinal tears exposing three disc diameters
or more of RPE
Giant retinal tear
failure of previous surgery
uveitis.[17] [18] [19] [20] [21] [22] [23]

Operative factors associated with increased risk of PVR

include

intra-/postoperative hemorrhage
vitrectomy
retinectomy
cryopexy
extensive laser
injection of air.[18] [22] [23]

There is no current pharmacologic agent proven to treat or

prevent PVR. A myriad of medical interventions have been
considered for PVR and none have been proven
conclusively to be superior to surgery alone.

Corticosteroids, for example, have been considered

given their mechanism of action and potential to reduce
the massive expansion of growth factors contributing
to membrane formation. Unfortunately, trials have
been variable and have fallen short of expectations. In
one randomized, controlled clinical trial of patients at
high risk of developing PVR, treatment with systemic
corticosteroids led to a decrease in epiretinal
membrane formation, but did not improve visual
acuity.[24] In another trial, when grade C PVR patients
were treated with 4 mg intravitreal triamcinolone
acetonide in silicone oil at the time of surgery, as
compared to control patients without triamcinolone in
silicone oil, treated patients did not exhibit a significant
change in visual acuity or PVR recurrence six months
post-operatively.[25] Additionally, a more recent
prospective trial investigated the use of the slow
release dexamethasone intravitreal implant. Patients
with grade C PVR underwent vitrectomy with silicon oil
tamponade either with or without dexamethasone
implant, and the investigators found no difference in
surgical outcomes.[26]
Anti-neoplastic drugs, irrespective of their side effects,
have also been considered as a means of treating PVR.
5-Fluorouracil (5-FU)has been studied in a variety
of circumstances, but its use is limited by
toxicity.[27] [28] In eyes with retinal detachments at
high risk of developing PVR, intravitreal 5-FU and
high molecular weight heparin infused during
surgery was shown to potentially reduce the
incidence of post-operative PVR.[29] This
combination was not effective in improving
outcome in patients with existing PVR.[30] Moreso,
a large randomized clinical trial investigated 5-FU
with low molecular weight heparin and found no
improvement in outcomes of macula-off retinal
detachments and worse visual outcomes in patients
with macula-on detachments.[31]
Daunorubicin has been used in conjunction with
vitrectomy and silicone oil tamponade, although
there was no apparent improvement in clinical
outcomes.[32]
Methotrexate, an anti-folate anti-metabolite, has
received recent attention as a potential candidate drug
following in vitro studies.[33] A retrospective study
investigated the outcomes of patients with severe
recurrent PVR detachments or severe intraocular
inflammation at high risk of PVR who received
methotrexate infusion at the time of surgery and found
a lower rate of PVR .[34] There is an ongoing
randomized study to further investigate the use of
methotrexate as a series of postoperative intravitreal
injections in eyes with PVR.
Biologics that interact with implicated growth factors
have also shown promise in mitigating PVR. For
example, ranibizumab has been shown to have
prophylactic effects in a rabbit model of PVR, and
decreased bioactivity in the vitreous of patients and
experimental animals.[35] However, a prospective trial
investigated the use of bevacizumab injected at the end
of the case in patients with PVR grade C, who were
undergoing vitrectomy and silicone oil placement, and
found no difference in outcomes.[36]
Retinoic acid and colchine which are inhibitors of RPE
cell growth, have been investigated with mixed
results.[37] [38] A small randomized trial of retinoic acid
showed lower rates of redetachment in PVR cases.[39]
A larger ongoing study investigated this further.

Diagnosis
Diagnosis of PVR is made via an in-depth patient history,
i.e. evidence of longstanding primary RRD or of recent
retinal reattachment surgery, and via physical examination,
most importantly recognition of retinal detachment with
fixed retinal folds.

Classification and Staging

Since publishing its seminal classification system in
1983,[40] the Retinal Society Terminology Committee has
updated its classification—most recently in 1991—to
reflect a greater understanding of the pathogenesis of
proliferative vitreoretinopathy.[41] Additional classification
systems, specifically the classification criteria utilized in the
Silicone Study,[42] have broadened the initial contributions
structured in the seminal Retinal Society report by
stratifying via: 1) membrane location, 2) clinical severity,
and 3) membrane geometry. The updated classification
system, as defined by Machemer and his colleagues in
1991,[41] is presented below in adapted forms:

Table 1- PVR by grade. Reproduced from Glazer, LC, Abrams

GW. Proliferative Vitreoretinopathy. In Freeman, ed. Practical
Atlas of Retinal Disease and Therapy. New York: Raven Press;
1993: 279-297.

Table 2- PVR Grade C by contraction type. Reproduced from

Glazer, LC, Abrams GW. Proliferative Vitreoretinopathy. In
Freeman, ed. Practical Atlas of Retinal Disease and Therapy. New
York: Raven Press; 1993: 279-297.

In practice, the revised system, most notably the use of

clock hours as opposed to quadrants, in addition to the
segregation of membranes into anterior and posterior,
allows for better understanding of the pathology of
individual cases and comparison of severity of PVR among
different clinical studies of PVR.

Example case (Figure 1): Patient presents to the clinic eight

weeks post-operatively following retinal detachment
repair. Patient complains of flashing lights and loss of
vision. On indirect ophthalmic exam, the retina is detached
with inferior starfolds and diffuse posterior contraction.
Using the revised Retinal Society classification system, this
patient’s presentation would be classified as CP12.

Figure 1- Posterior PVR. S, starfold, D, diffuse contraction.

Reproduced from Abrams GW, Aaberg TM: Posterior segment
vitrectomy. In Waltman SR, ed. Surgery of the Eye. New York:
Churchill Livingstone; 1988: 903-1012.

Figure 2- Subretinal “napkin ring” membrane. Reproduced

from Glazer, LC, Abrams GW. Proliferative Vitreoretinopathy.In
Freeman, ed. Practical Atlas of Retinal Disease and Therapy. New
York: Raven Press; 1993: 279-297.

Clinical Presentation
(History/Physical/Signs/Symptoms
Diagnosis)
Patients presenting with PVR may be categorized into two
groups: 1) those presenting with longstanding PVR arising
from primary rhematogenous retinal detachment, and 2)
those who have recently undergone surgical repair of RRD.
In the case of the former, patients will present with
prolonged vision loss often preceded by floaters and/or
flashing lights. Patients presenting post-operatively may
have initially had vision improvement following surgery,
then progressive or rapid onset of vision loss. These
patients often present 4-6 weeks post-operatively. The
clinical presentation of PVR is defined by fixed folds in the
retina on ophthalmic examination, indicative of retinal
traction caused by retinal membranes. In the majority of
cases, membranes localize to the inferior retina due to
gravity.[43] Retinal folds may appear as billows in the retina
and often co-present with haze and pigment in the
vitreous. In the case of posterior PVR, there may be
starfolds with folds radiating from a central area of
contracted retina due to epiretinal membranes, more
diffuse folds from larger membranes, or subretinal
membranes that may look like clotheslines beneath the
retina. These folds may even take an annular configuration
pulling the retina over the optic disc. Anterior PVR most
commonly involves the inferior retina, but in severe cases
may extend 360 degrees. Membranes may be
circumferential at or posterior to the vitreous base. With
contraction at the posterior edge of the vitreous base, the
anterior retina may be stretched centrally while the
posterior retina is thrown into radial folds extending from
the vitreous base posteriorly (Figure 3).

This presentation differs from primary RRD, in that the

latter lacks fixed retinal folds. While eyes with PVR show
little if any movement of the retina during eye movements,
eyes with primary retinal detachment without PVR will
show a “bouncing” movement of the retina with eye
movements. Patients with primary retinal detachments
often initially notice floaters and/or photopsia followed by
loss of visual field in the area of retinal detachment. This
may expand to involve central vision, tracking with the
growing retinal detachment progressing centrally.

Figure 3- PVR Grade CA, circumferential contraction.

Membranes at posterior edge of vitreous base pull retina centrally,
stretching the anterior retina and causing posterior radial folds.
Reproduced from Machemer R, Aaberg TM, Freeman HW, Irvine
AR, Lean JS, Michels RM: An updated classification of retinal
detachment with proliferative vitreoretinopathy. Am J
Ophthalmol 1991; 112: 159-165.

If the circumferential membranes involve the vitreous

base, especially following prior vitrectomy, the retina
posterior to the vitreous base may be pulled by the
contracting membranes anteriorly toward the pars plana,
ciliary body, or even the iris (anterior retinal displacement).

Figure 4- PVR Grade CA, anterior retinal displacement. Retina

at posterior vitreous base drawn to: A) anterior vitreous base, B)
ciliary process, C) posterior iris, D) pupil with iris retraction.
Posterior vitreous base drawn anteriorly to create retinal trough
(right figure). Reproduced from Lewis H, Aaberg TM: Anterior
proliferative vitreoretinopathy. Am J Ophthalmol 1988; 105:277.

Diagnostic procedures
The diagnosis of PVR is by clinical examination in most
patients; however, sometimes other diagnostic techniques
become necessary. If the ocular media are opaque due to
cornea, lens, vitreous or other opacities, the retina cannot
be visualized and other techniques must be used.
Ultrasound examination can demonstrate the presence of
retinal detachment, and there are some characteristics of
the retinal detachment on ultrasound that will indicate the
presence of PVR. Using dynamic ultrasound (moving the
eye while viewing the retinal detachment with ultrasound),
compared to RRD without PVR, there is less retinal
mobility in a RRD with PVR. In RRD without PVR, the
retina attached to the optic nerve usually has a rounded
pattern with good mobility as it approaches the disc on
ultrasound; with PVR, the leaves of the retina may assume
a “V” pattern at the optic disc with the retina straightened
with limited mobility as they approach the optic nerve
(open funnel retinal detachment). With more severe PVR,
the retina may assume a “T” pattern on ultrasound at the
optic disc (closed funnel retinal detachment) with the
leaves of the retina fused together anterior to the disc, only
opening more anterior to the disc with the anterior
immobile retina completing the top bar of the “T”. OCT can
be helpful if there is a question of whether the macula or
other parts of the retina are detached or not.

Differential diagnosis
When assessing a patient for PVR, one should also consider
a variety of other proliferative and contractional retinal
diseases, in addition to other fibrosing conditions,
including:

Proliferative vascular retinopathy (proliferative

diabetic retinopathy, other proliferative ischemic
retinopathies and retinopathy of prematurity)
Retinal detachment following open globe ocular trauma
Retinal detachment following intraocular foreign body

Rarely, a RRD without PVR can have extensive folds that

falsely appear to be fixed. Seen mostly in highly myopic
eyes with very thin retinas, the retina in this instance
remains normally mobile on eye movement, no membranes
are found at surgery and the retina completely flattens
following surgery.

Surgery

Additional Resources

References

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