Chapter 139 – Proliferative Vitreoretinopathy
G. WILLIAM AYLWARD
• The proliferation of avascular fibrocellular retinal membranes associated with rhegmatogenous retinal detachment.
• Epiretinal and subretinal fibrous proliferation.
• Contraction of membranes.
• Recurrent or persistent retinal detachment.
• Retinal shortening.
• Reopening of preexisting retinal breaks.
• Formation of new retinal breaks.
• Vitreous opacity.
• Aqueous flare.
• Iris neovascularization.
• Macular pucker.
Proliferative vitreoretinopathy (PVR) is the most common cause of ultimate failure after surgical treatment for rhegmatogenous retinal detachment.   A wound-healing response, PVR is characterized by the formation of surface membranes in the posterior segment. Membranes most commonly form on the inner surface of the neural retina but can also be found in the subretinal space and on the ciliary body. Contraction of these membranes may cause macular pucker, new retinal breaks, recurrent retinal detachment, and ocular hypotony.
EPIDEMIOLOGY AND PATHOGENESIS
PVR occurs following surgical repair of retinal detachment but can develop in untreated cases, particularly those that are long-standing or with large breaks. It may also occur following large choroidal detachments or in eyes with large, treated retinal tears but no previous retinal detachment. It occurs in 5–10% of treated rhegmatogenous retinal detachment cases and represents the major cause of ultimate surgical failure.
Certain types of retinal detachments are more likely to develop PVR than others. For example, those associated with giant retinal tears (greater than 3 clock hours) have a high incidence of postoperative PVR, probably because of the large area of bare retinal pigment epithelium (RPE) that is exposed. Other risk factors have been identified in several studies that used multivariate regression analysis. These include the number and size of retinal breaks, the number of previous operations, the presence
Figure 139-1 Pathogenesis of proliferative vitreoretinopathy. The flow chart illustrates the interaction of various factors in the pathogenesis of proliferative vitreoretinopathy, from the initial retinal detachment to the serious complications of recurrent detachment and hypotony.
of choroidal effusions, the use of cryotherapy, intraocular hemorrhage, aphakia, high vitreous protein levels, and the severity of preoperative PVR.    Young patients who have penetrating trauma, especially double perforating injuries, also have a very high risk of PVR.
The pathogenesis of PVR is multifactorial and is summarized in Figure 139-1 . The primary event is the formation of a retinal break. It is thought that RPE cells then migrate through the break into the preretinal space, where they settle on the retinal surface. Most of the fibrocellular tissue develops inferiorly, which suggests that gravity influences the distribution of the RPE cells. Glial cell proliferation follows, and an extracellular matrix is laid down. These cells take on the characteristics of myofibroblasts in that they have contractile elements and deposit collagen. While the cellular origins of PVR are critical, the extracellular environment plays a decisive role as well. Inflammation
Figure 139-2 Macular pucker following retinal detachment surgery. Contraction of a surface membrane at the macula produces symptoms of distortion and reduced visual acuity. Such epiretinal membranes are identical histologically to those removed from elsewhere on the retina in proliferative vitreoretinopathy.
and breakdown of the blood-retina barrier are associated with further cellular recruitment, modulated by inflammatory mediators and the formation of extensive fibrous membranes.  Collagen is produced and the membranes then contract. It is the contraction of surface membranes that produces the clinical features described below. The cycle of cell dispersion, inflammation, membrane formation, and contraction with eventual redetachment of the retina has a typical time scale of 4–6 weeks after the initial repair.
The clinical spectrum of PVR varies according to the extent and location of membranes and the presence and position of retinal breaks. Macular pucker after successful retinal detachment surgery can be considered a mild form of PVR ( Fig. 139-2 ). In its most severe form, membrane contraction produces a total, funnel-shaped detachment with retina adherent anteriorly to the ciliary body and even to the iris, which results in hypotony and phthisis bulbi.
Surface membranes can be difficult to diagnose when the retina is attached. Many successfully repaired retinal detachments show surface membrane formation if examined histopathologically. Occasionally, surface membranes can result in localized traction retinal detachments, often seen just posterior to a scleral buckle. These localized traction detachments tend to be stable and should be differentiated from recurrent rhegmatogenous detachments associated with open retinal breaks. Traction retinal detachments have a concave surface generated by the RPE pump pulling against traction, in contradistinction to the convex profile of rhegmatogenous detachments. Should a new retinal break develop acutely or a preexisting break reopen, already present but unsuspected membranes may result in dramatic contraction of the newly redetached retina to give the clinical impression of sudden development of severe PVR.
The earliest signs of PVR include marked vitreous flare and clumps of pigment in the vitreous. Increased stiffness of the detached retina often occurs, which can be detected with indirect ophthalmoscopy while the patient’s eye is making saccades. A fresh retinal detachment without PVR appears to undulate under these conditions, an undulation that is reduced if significant
Figure 139-3 Star fold from proliferative vitreoretinopathy. Contraction of a focal retinal surface membrane has resulted in the formation of a star fold. In this case, membranes can also be seen on the posterior surface of the partially detached hyaloid face.
Figure 139-4 Retinal shortening. Surface membrane contraction can result in retinal shortening, which prevents break closure and retinal reattachment.
surface membranes are present. The edges of retinal breaks may be rolled over, as a result of contraction on one surface only, and retinal breaks may appear stretched open. Star folds represent localized areas of puckering in detached retina after focal, localized contraction ( Fig. 139-3 ).
Subretinal fibrosis may accompany surface membranes to give a “Swiss cheese” appearance to the subretinal space. Some of the subretinal sheets of membrane coil together, which results in broad, subretinal strands. A subretinal “napkin ring” of membrane can surround the peripapillary retina to produce a tight posterior funnel configuration and obscure the optic nerve. Significant amounts of surface traction produce retinal shortening, which makes break closure and retinal reattachment impossible ( Fig. 139-4 ). More severe contraction may pull the anterior
retina inward, which leads to an anterior funnel appearance. In severe cases, closure of the anterior end of the funnel may make it impossible to visualize the optic disc even if the posterior retina is relatively unaffected. Contraction of the vitreous base leads to circumferential shortening and anterior loop contraction. Surface membranes on the ciliary body may compromise aqueous production, which results in hypotony.
Associated anterior segment signs include anterior chamber cells and flare and low intraocular pressure. In some eyes, dilated iris vessels or even iris neovascularization develops.
The Retina Society has devised a classification scheme for PVR, which has been useful in clinical trials of treatment. The initial scheme did not distinguish between anterior and posterior PVR, and improvements in the understanding of anterior PVR have led to a modification of the classification.  Anterior PVR is characterized by contraction of membranes associated with the vitreous base; it is seen most commonly after failed vitrectomy and gas
Figure 139-5 Anterior proliferative vitreoretinopathy (1). Fibrous contraction in an anteroposterior direction in the region of the vitreous base pulls up a loop of retina to produce retinal shortening. Coexistent traction on the ciliary body produces hypotony.
Figure 139-6 Anterior proliferative vitreoretinopathy (2). Contraction of the anterior vitreous produces a funnel configuration.
tamponade for retinal detachment or after penetrating trauma. Anteroposterior traction can pull a fold of retina forward to produce a “trough” with posterior shortening ( Fig. 139-5 ), which can be difficult to diagnose preoperatively. Circumferential contraction of the vitreous base produces radial folds in the retina, and perpendicular contraction of the anterior vitreous leads to an anterior funnel-shaped configuration ( Fig. 139-6 ).
In eyes with clear media, the diagnosis of PVR is straightforward. A history of retinal detachment surgery and the clinical features just described do not generally present a diagnostic problem. In eyes with opaque media, B-scan ultrasonography is necessary to reveal the stiffened, detached retina and associated membranes.
The differential diagnosis of PVR is given in Box 139-1 .
Although no direct, significant systemic associations exist, patients who have Stickler’s syndrome have an increased risk of retinal detachment because of large and/or multiple retinal breaks that make subsequent PVR likely.
A large body of pathologic information exists that confirms the role of RPE cells, inflammation, breakdown of the blood-ocular barrier, macrophages, growth factors, cytokines, clotting cascade proteins, adhesion molecules, and extracellular matrices in the development of PVR. In histological specimens, RPE cells are uniformly present, and evidence shows that they can undergo metaplastic change to macrophages or fibroblasts. Glial cells are a major component of PVR membranes and may arise from retinal astrocytes.  Lymphocytes have been identified in excised PVR membranes, although the role of humoral immunity in PVR remains unclear.
The behavior of the RPE cell may be stimulated by several different growth factors. For example, platelet-derived growth factor stimulates chemotaxis,  and fibroblast growth factor and insulin-like growth factor-1 stimulate RPE cell proliferation. In contrast, transforming growth factor-ß has an inhibitory effect on cell proliferation in tissue culture. Interleukins (ILs) also play a role. Elevated levels of IL-1 and IL-6 have been detected in the vitreous of patients with PVR. Many of these growth factors and cytokines are also known to play a significant part in the wound-healing process in general.
The extracellular matrix associated with PVR consists of various types of collagen, particularly types I and III. Other components include fibronectin and the basal lamina proteins, heparan sulfate, laminin, and collagen type IV. Recent work suggests that the matrix metalloproteinases may play a role in the pathogenesis of PVR.
The mechanism of membrane contraction remains poorly understood. Some of the cell types found in membranes are capable of contraction, including fibroblasts and RPE cells. Cytoplasmic
Differential Diagnosis of Proliferative Vitreoretinopathy
Proliferative diabetic retinopathy with traction retinal detachment
Chronic retinal detachment with retinal edema and/or cyst formation
Severe choroidal detachments
Severe vitreomacular traction syndrome with traction retinal detachment
Severe ocular hypotony
myofilaments have been seen in some fibroblastic cells, but simple motility of cells through a collagen matrix may be sufficient to produce shortening.
In the absence of open retinal breaks, PVR does not require treatment unless the macula is involved. Localized traction detachments posterior to a scleral buckle are stable and asymptomatic. Macular pucker after otherwise successful retinal detachment surgery may be responsible for reduced visual acuity and distortion. Such cases often benefit from membrane peeling.
In rhegmatogenous retinal detachment, the choice of treatment is based on the severity and location of the PVR and the
Figure 139-7 Scleral buckling in proliferative vitreoretinopathy. The large inferior buckle seen here was used to support inferior breaks associated with proliferative vitreoretinopathy. Recurrent gray proliferative vitreoretinopathy membranes can be seen on the surface of the buckle, but the retina remains attached posteriorly. Note the dark line on the edge of the buckle, which is an optical effect of the silicone oil fill.
Figure 139-8 Surgery for proliferative vitreoretinopathy. A pick is used to elevate surface membranes prior to removal with forceps.
location of the retinal break or breaks. Scleral buckling alone may be successful if the surface membranes do not prevent break closure. For example, the presence of inferior star folds does not prevent successful closure of a single superior retinal break by means of a scleral buckle. However, it can be difficult to judge the extent of retinal shortening and, therefore, the influence of a star fold on a remote break. If surface membranes occur in close association with retinal breaks, closed intraocular microsurgery with membrane peeling is required to enable break closure, although occasionally a substantial inferior buckle can be used successfully to close breaks associated with a moderate degree of surface contraction ( Fig. 139-7 ).
With an internal approach, a complete pars plana vitrectomy is followed by peeling of surface membranes, using a combination of a retinal pick and microforceps ( Fig. 139-8 ).  The ease with which membranes can be removed varies, but it is important to relieve traction associated with breaks if surgery is to succeed. Perfluorocarbon liquids may assist the process as they highlight the membranes and act as a “third hand” to assist in membrane removal. If long-term intravitreal tamponade with silicone oil is to be used, the membranes may be more visible after oil injection and so are peeled at that stage. If not already present, a circumferential scleral buckle is usually applied to support the vitreous base, which typically is shortened circumferentially. Occasionally, peeling of posterior membranes is insufficient to relieve retinal shortening. In such cases, further dissection of the vitreous base may be successful. Alternatively, a relaxing retinectomy can be performed ( Fig. 139-9 ). 
Rarely, subretinal membranes may be present, usually in a band-like configuration. These can tent up the retina, although in most cases simple closure of the break results in complete reattachment. If necessary, the bands can be divided through a small retinotomy or pulled out hand over hand, as they tend to be only loosely adherent to the overlying retina.
After membrane removal, the retina is reattached by means of internal drainage of subretinal fluid, usually accompanied by a fluid-air exchange. Retinopexy with cryotherapy or laser photocoagulation is applied to all breaks. Laser retinopexy is often preferred because of the theoretically increased risk of further PVR associated with the use of cryotherapy.
A long-acting gas or silicone oil is injected for tamponade; the choice of agent depends on a number of factors. In the Silicone
Figure 139-9 A severe case of anterior proliferative vitreoretinopathy treated with a 270° relaxing retinectomy. The line of laser retinopexy at the edge of the retinectomy can be seen to join with an area of chorioretinal adhesion from cryotherapy.
Figure 139-10 Reproliferation and failed retinectomy for proliferative vitreoretinopathy. Reproliferation of membranes along the edge of a relaxing retinectomy has resulted in elevation of the posterior edge.
Study, the effect of the choice of long-term retinal tamponade on final surgical outcome in PVR cases was examined. The study indicated that both C3 F8 gas and silicone oil were of similar benefit in PVR, and both are superior to SF6 .   In anterior PVR, silicone oil has been shown to yield a better visual outcome than C3 F8 . Silicone oil has certain intraoperative and postoperative advantages over gas, which include improved visualization for retinopexy, less need for positioning, and better vision in the immediate postoperative period.
Despite successful treatment, PVR can recur, which results in the formation of new breaks or the reopening of treated breaks ( Fig. 139-10 ). The tendency of PVR to recur has generated much interest in the use of pharmacological agents for adjuvant therapy to surgery. Figure 139-1 shows that many potential pharmacological targets exist for such therapy. A large-scale randomized controlled trial has shown a weak beneficial effect for perioperative daunomycin. A combination of adjuvant 5-hydroxyuracil and low-molecular-weight heparin has been shown to reduce the incidence of PVR in high-risk cases undergoing vitrectomy.
COURSE AND OUTCOME
Untreated, PVR inevitably leads to severe loss of vision, hypotony, and sometimes phthisis bulbi. Success rates for surgical treatment vary and depend on the severity of PVR and the surgical techniques employed.  Prior to the introduction of closed intraocular microsurgery, success rates were poor. With modern techniques, anatomic success is being achieved in an increasing number of cases. Most recent series report final anatomic success rates of around 70%.   Using perfluorocarbon liquid as an intraoperative tool in conjunction with wide-field viewing systems, success rates for retinal reattachment after one operation can be as high as 78%. With multiple operations, up to 91% of all PVR-affected retinas can be reattached. In one series, 74% of eyes ended up with 20/400 or better vision, with 30% having 20/80 or better. The continued disappointing visual results, despite quite high anatomic reattachment, are the result of a combination of macular dysfunction from previous detachment, macular pucker, and hypotony. The majority of patients who have PVR have a normal fellow eye. Functional vision in these cases may not be useful to the patient; often the operated eye is considered a “spare.”
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