Chapter 107 Proliferative Vitreoretinopathy
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Introduction
Proliferative vitreoretinopathy (PVR) is the clinical syndrome associated with retinal traction and detachment in which cells with proliferative potential multiply and contract on retinal surfaces and in the vitreous compartment.1–4 PVR presents with a spectrum of severity ranging from subtle retinal wrinkling, to fixed folds and tears with rolled edges and to total rigid retinal detachment, retinal shortening and advanced periretinal proliferation (Figs 107.1, 107.2). PVR is the most common cause of failure in retinal detachment surgery. It can occur in untreated eyes with retinal detachment, especially with vitreous hemorrhage, or after cryotherapy or even laser retinopexy, pneumatic retinopexy, scleral buckling or vitrectomy and after a variety of surgical complications. It is common after penetrating injuries and a variety of conditions associated with prolonged inflammation. Although surgical reattachment of retinas associated with PVR can now be achieved in most cases, visual results remain disappointing. Therefore, prevention through early recognition of risk factors and subtle signs of PVR and appropriate modification of standard surgical techniques for retinal detachment remain all-important. Some degree of PVR is found in up to 10% of retinal detachments.5–7 If PVR is progressive and macula reattachment delayed, then despite complex surgery, low vision is the result in the majority of eyes.
Pathophysiology
The pathophysiology of PVR is discussed in detail in Chapter 97, Pathogenesis of proliferative vitreoretinopathy.
PVR is characterized by proliferation of cells derived from retinal pigment epithelium, glia, or inflammatory recruitment on the retinal surfaces and within the vitreous gel.8,9 These metaplastic cells transdifferentiate and assume contractile properties through internal cellular contractile proteins and by laying down extracellular collagen.10 They multiply and grow along available scaffolding, either the retinal surfaces or elements of residual vitreous gel. Mass contraction leads to retinal wrinkles, folds, tears, and traction retinal detachment. The vitreous compartment is normally almost devoid of cellular content with just a few hyalocytes. It is protected from outside invasion by the internal limiting membrane of the retina and from cytokines and other chemoattractants by the blood–retinal barrier. The process of PVR can start when there is an interruption to the surface lining such as can occur with a posterior vitreous detachment and local preretinal membrane formation or retinal tears in the periphery. Retinal tears with surrounding detachment may encourage inflow of freed-up pigment epithelial cells through the break into the vitreous and onto the retinal surface or onto residual contracted vitreous strands and the vitreous base. Simultaneous breakdown of the blood–retinal barrier with retinal detachment or any cause of intraocular inflammation, including cryotherapy, laser and the trauma associated with scleral buckling, can all lead to the influx of circulating inflammatory cells and a whole range of proteins associated with inflammation.11 The process is more likely to be triggered in patients with posterior segment trauma, uveitis, choroidal detachment or severe diabetic retinopathy in the presence of retinal tears. The PVR process is self-propagating and can be considered an inappropriate excess wound-healing response. Cellular proliferation and contraction increases the breakdown of the blood–ocular barrier, in turn causing more traction and more influx of inflammatory cytokines and inflammatory cells. Macular pucker after retinal detachment repair can be considered a mild form of PVR. PVR most frequently develops in the inferior retinal quadrants, probably because the retinal pigment epithelial and inflammatory cells liberated into the vitreous cavity through retinal tears or those associated with vitreous hemorrhage, settle inferiorly with gravity.12 The PVR process usually takes 4–12 weeks to develop a critical mass of cells and significant retinal traction after retinal detachment surgery or other ocular interference such as trauma. As in normal wound healing, the proliferating cells go through a life cycle and as they progressively lay down collagen, the membranes become hypocellular leaving contracted collagen sheets, membranes, and cords in the vitreous cavity, or on the retinal surfaces and sometimes under the retina. Contraction of equatorial membranes may lead to a funnel-shaped retinal detachment while shortening of the inferior retina may lead to large, inoperable posterior retinal breaks. Severe PVR may also be superimposed on diabetic tractional retinal detachment when associated with retinal tears. PVR also may occur in other vascular retinopathies such as Eales disease in the presence of retinal breaks and especially in penetrating ocular trauma. The proliferative/inflammatory process underlying PVR complicating retinal detachment is typically associated with loss of central vision even after successful surgery and this may be due to inflammation-induced apoptosis of the receptor cells at the macula13 or degeneration of the receptors associated with prolonged retinal detachment.14 The cellular and biochemical processes underlying PVR are complex and are explored in detail in Chapter 97, Pathogenesis of proliferative vitreoretinopathy.
Risk factors for development of PVR
The most common clinical setting is the development of clinically significant PVR a few weeks after previous retinal detachment repair, whether by scleral buckling, primary vitrectomy, or both (Fig. 107.3). A few eyes develop PVR spontaneously with retinal detachment prior to surgery.6 Previous trauma, prolonged inflammation of the posterior segment, viral infections of the posterior segment and prolonged chorioretinitis are also associated with spontaneous PVR. The risks in the presence of retinal detachment are increased with large retinal breaks or giant tears, vitreous hemorrhage associated with retinal tears, multiple previous eye surgery, previous trauma to the posterior segment and pre-existing signs of localized PVR such as fixed folds.15–17 The risk is increased in retinal detachments with more than two quadrants involved and those with coexisting choroidal detachment. The risk is also increased in retinal detachments associated with a variety of systemic conditions such as Wagner disease, Stickler syndrome, Marfan syndrome, and familial exudative vitreoretinopathy. A high rate of PVR is reported following a range of novel complex surgical procedures, including macular translocation, retinal prosthesis implantation and endoresection of ocular tumors. Surgical problems that increase the risk of PVR include vitreous and subretinal bleeding, choroidal detachment,18 failure to close retinal breaks resulting in prolonged retinal detachment, incarceration of retina in an external subretinal fluid drainage site, and heavy or excessive cryotherapy.19–21 Seeding of pigment epithelial cells onto the retinal surface at the time of drainage of subretinal fluid through an internal retinotomy or retinal break may increase the risk. Prolonged inflammation after retinal detachment surgery increases the risk of PVR, especially if associated with postoperative uveitis, residual intraocular blood or failure to remove all traction off the retina and failure to support it with a scleral buckle. The greatest risk period is 4–12 weeks after detachment surgery. A patient with any of the above predisposing risk factors, either preoperatively, or as a result of surgery should be followed more frequently in the postoperative period to ensure early detection of PVR and recurrence of retinal detachment.
Clinical signs and diagnosis of PVR
The early signs of PVR are subtle and include cellular dispersion in the vitreous and on the retinal surface and localized fibrocellular membranes, which appear as a white opacification of the retinal surface and small wrinkles or fixed folds (Figs 107.4, 107.5). Cellular proliferation at the edge of a retinal tear can lead to local contraction and a rolled posterior edge (Fig. 107.6). More extensive PVR has fixed folds with retinal detachment especially inferiorly and fine membranes bridging the valleys between folds, as well as decreased mobility of the detached retina. Advanced PVR with posterior vitreous detachment results in the eventual formation of a funnel-shaped detachment with a contracted equatorial membrane (Figs 107.1, 107.2). In some cases, anterior traction at the vitreous base draws retina forward towards the ciliary body or detaches the ora serrata (Fig. 107.7). Diagnosis of established PVR in the presence of rhegmatogenous retinal detachment is made by indirect ophthalmoscopy and slit-lamp biomicroscopy with a +78 or +90 diopter lens or corneal contact lens. In eyes with opaque media, B-scan ultrasonography outlines immobile retinal folds of detachment and prominent vitreous membranes (Fig. 107.8). Early and subtle signs of PVR should always be looked for and noted in the preoperative assessment of retinal detachment as it may result in modification of the choice of surgical techniques outlined below during primary repair. Early recognition of signs of impending PVR following reattachment of a retina in the 1–3-month period following surgery, allows more timely intervention. In many cases of early PVR, timely intervention can avoid the substantial visual loss that almost invariably occurs with macula detachment in patients with delayed diagnosis and reoperation.
Classification of PVR
There is benefit in classifying and recording the extent of PVR in all eyes with retinal detachment. This active process prompts a thorough search for the signs in all patients before surgery and in the postoperative period. It allows cross-comparison of severity of disease in any clinical series that may be audited or published and is the basis for assessing the effect of various therapies through clinical trials. The most commonly used classification system remains that published by the Retina Society Terminology Committee in 1983.3 It classifies the appearance of PVR on the basis of clinical signs and geographic distribution into four grades (Table 107.1). A major drawback is that it ignores antero-posterior epiretinal proliferation and hence the importance of anterior traction in PVR. It is also a static classification that says nothing about the degree of cellular proliferative activity at the time of the grading. An inactive Grade D PVR affecting all quadrants may have a better prognosis with surgery than a very cellular, active, proliferating PVR affecting only two or three quadrants as in Grade C. The revised classification of PVR of 1991,4 took into account more detailed information about the location, extent and severity of PVR in an individual eye and hence is more useful especially for clinical trials (Tables 107.2, 107.3). Further modifications of the classification of PVR were proposed as part of the multicenter controlled trial of silicone oil (SO) as an adjunct treatment for PVR,22 but the added complexity was found to be less reproducible between different examiners than the more simplified classifications. Nevertheless, the description of PVR and accompanying preoperative retinal drawing should always be sufficiently detailed to allow any eye to be graded for clinical research and auditing of results of surgery.
Table 107.1 Retina Society PVR Classification (1983)
| Grade (stage) | Characteristics |
|---|---|
| A | Vitreous haze, vitreous pigment clumps |
| B | Wrinkling of the inner retinal surface, rolled edge of retinal break, retinal stiffness, vessel tortuosity |
| C | Full-thickness retinal folds in |
| C-1 | One quadrant |
| C-2 | Two quadrants |
| C-3 | Three quadrants |
| D | Fixed retinal folds in four quadrants |
| D-1 | Wide funnel shape |
| D-2 | Narrow funnel shape (anterior end of funnel visible by indirect ophthalmoscopy with 20 diopter lens) |
| D-3 | Closed funnel (optic nerve not visible) |
(Reprinted from: Retina Society Terminology Committee. The classification of retinal detachment with proliferative vitreoretinopathy. Ophthalmology 1983;90:121–5. ©1983, with permission from the American Academy of Ophthalmology.)
Table 107.2 Updated Proliferative Vitreoretinopathy Grade Classification (1991)
| Grade | Features |
|---|---|
| A | Vitreous haze, vitreous pigment clumps, pigment clusters on inferior retina |
| B | Wrinkling of the inner retinal surface, retinal stiffness, vessel tortuosity, rolled and irregular edge of retinal break, decreased mobility of vitreous |
| CP 1–12 | Posterior to equator, focal, diffuse or circumferential full-thickness folds, *subretinal strands |
| CA 1–12 | Anterior to equator, focal, diffuse, or circumferential full-thickness folds, *subretinal strands, *anterior displacement, *condensed vitreous strands |
* Expressed in the total number of clock-hours involved. (Reproduced with permission from Machemer R, Aaberg TM, Freeman HM, et al. Am J Ophthalmol 1991;112:159–65.)
Table 107.3 Updated Proliferative Vitreoretinopathy Contraction Type Classification (1991)
| Type | Location (in relation to equator) | Features |
|---|---|---|
| Focal | Posterior | Star fold posterior to vitreous base |
| Diffuse | Posterior | Confluent star folds posterior to vitreous base; optic disc may not be visible |
| Subretinal | Posterior/anterior | Proliferation under the retina; annular strand near disc; linear strands; motheaten-appearing sheets |
| Circumferential | Anterior | Contraction along posterior edge of vitreous base with central displacement of the retina; peripheral retina stretched; posterior retina in radial folds |
| Anterior | Anterior | Vitreous base pulled anteriorly by proliferative tissue; peripheral retinal trough; displacement ciliary processes may be stretched, may be covered by membrane; iris may be retracted |
(Reproduced with permission from Machemer R, Aaberg TM, Freeman HM, et al. Am J Ophthalmol 1991;112:159–65.)
Surgery for PVR
There has been substantial improvement in the success rate of surgery for PVR progressively over the past four decades.23,24 The clinical severity of PVR is very variable and therefore the extent of surgery is planned accordingly. PVR varies from a single inactive fixed star fold on the retinal surface to a rigid total retinal detachment with a funnel shape and dense equatorial fixed membranes. There may be fixed folds involving only the posterior retina or fibrotic organization of the vitreous base with both circumferential and anterior loop traction dragging the retina forward or detaching the pars plana ciliaris. Fixed folds may tent the retina and be relatively easily divided or peeled to relieve traction, or there may be extensive surface retinal fibrosis and consequent shortening of the retina in the anterior/posterior plane requiring a relaxing retinotomy. The severity of PVR may also differ markedly in terms of current inflammation and cellular proliferative activity or take the form of fixed, quiescent acellular membranes which are unlikely to recur if divided or peeled. These factors may affect the timing of repeat vitreoretinal surgery. It is urgent if the macula is still attached or salvageable. It may sometimes be better to wait a few days and quiet the eye down with corticosteroids if the macular vision is not salvageable until the inflammatory activity is less intense. On the other hand, leaving an eye with a retinal detachment and early PVR almost always will lead to further progression and eventual inoperability, so that most eyes deemed to be operable should be operated on as soon as possible. The objects of vitreoretinal surgery for PVR are to permanently support the retina from any ongoing traction and to close any open retinal breaks. These goals are achieved by an encircling scleral buckle, meticulous relief of all retinal traction with vitrectomy and temporary or long-term tamponade of the retina with long-acting gas or SO. These steps must be achieved without causing prolonged ocular inflammation or further cellular access to the retinal surface, or else recurrence is frequent.
Vitrectomy and PVR
A comprehensive vitrectomy is essential in the management of PVR. Some surgeons rely on a meticulous vitrectomy and SO tamponade without scleral buckling and report comparable results with a combined proceedure.25 In any event, almost all eyes with retinal detachment and PVR also require a vitrectomy to remove all vitreous gel, cellular and inflammatory material, blood, and fibroblastic membranes. It is necessary to relieve all traction by division and peeling or delamination of fixed membranes and to remove as much as possible of the vitreous base. It is also important to divide any membranes causing anterior loop traction and to release the tractional effect on scarred shortened retina. This surgery is greatly facilitated by the extraordinary advances in the technology now available. Wide-angle viewing systems are either indirect and attached to the operating microscope, or consist of an operating corneal contact lens and a microscope image inverter. Contact lenses provide a crisper image and easier visual access to the far inferior periphery but need frequent repositioning and replenishing with viscoelastic. Indirect viewing systems provide a less panoramic view and the view is dependent on precise eye positioning, making angulation more difficult. Wide-field illumination is achieved with a range of fiberoptic light sources or a chandelier arrangement inserted into the eye through a separate pars plana entry site. Vitreous cutting and suction probes (vitrectors) have vastly improved and the surgeon has a choice of 25G, 23G, and the traditional 20G instruments. Air-driven vitrectors can cycle at up to 5000 cycles per minute and have a variable duty cycle controlled by electronic sensors. This allows faster removal of core vitreous and opacities, but also safer cutting and aspiration close to the retinal surface. Another major advance has been the intraoperative use of heavier-than-water perfluorocarbon fluid which displaces subretinal fluid anteriorly and flattens the bullous posterior retina. This highlights tractional membranes and facilitates peeling and dissection by stabilizing the posterior retina. Sometimes relaxing retinotomy is required to fully relieve traction caused by densely adherent fixed folds or shortened fibrosed retina. Rarely subretinal membranes need to be removed or divided through a small deliberate retinotomy. Internal drainage of subretinal fluid and fluid–air exchange of the vitreous compartment allows the testing of release of all retinal traction. Any persistent retinal elevation after fluid–air exchange means that complete release of traction or retinal shortening has not been achieved. Reattached retina and open retinal breaks are sealed with endolaser photocoagulation or cryotherapy and a decision made as to whether temporary tamponade with perfluoropropane (C3F8) gas will be sufficient or SO–air exchange is necessary. Although a controlled trial showed the eventual outcomes to be similar, many surgeons prefer SO to gas because it results in less postoperative inflammation, quicker rehabilitation and fewer reoperations. The use of heavier-than-water SO can also improve inferior retinal tamponade in severe cases of PVR, and is being increasingly used.
VIDEO 7Management of the lens in PVR
In most cases, wide-angle viewing systems provide an adequate view of the periphery and the lens is preserved. It always becomes cataractous with SO and is conveniently replaced after phacoemulsification at the time of SO removal or when it becomes visually significant. If lens opacities are sufficient to impede the view of the posterior segment, then the cataract must be removed. Most surgeons now favor a formal phacoemulsification procedure, as this allows insertion of an intraocular lens during the operation. Some surgeons still favor fragmentation of the lens via the pars plana sclerotomy and removal of the whole capsule or retention of the anterior capsule. In this case, the eye is rendered aphakic. If the capsule is totally removed, then there is risk from SO contact to the corneal endothelium in the longer term. An inferior iridotomy reduces this risk.26 If the anterior capsule is left intact, then it always becomes opaque in the presence of SO and subsequent YAG laser capsulotomy or formal capsulotomy with a sharp instrument is carried out at the time of insertion of an intraocular lens in the sulcus 2–3 months later. In younger patients with a softer lens, it is possible to remove the contents and still preserve both anterior and posterior capsules. In this case, an intraocular lens is inserted after vitrectomy but before fluid–gas exchange into the bag.
Core vitrectomy and removal of the vitreous base
During vitrectomy, the cornea is kept clear by a viscoelastic coating of methyl cellulose and the wide-angle view contact lens if used. The microscope is refocused for internal viewing and after insertion of a fiberoptic light probe and the vitrector. The three available probe sizes are all acceptable. The 25G has the smallest opening and is the safest. It is also the slowest. Because it is more flexible it can be difficult to rotate the eye superiorly enough to comfortably remove vitreous off a superior retinal break with a mobile detached retina. The 20G probe has the largest opening and most efficient fluidics but needs suturing. The 23G probe is the most popular compromise. Most eyes with established PVR already have a posterior vitreous detachment. Any remaining central gel is removed completely and then peripheral vitreous is removed meticulously and as completely as possible, particularly inferiorly where pigment and inflammatory cells tend to gravitate. This process is facilitated by the modern, high-speed, vitrectomy cutters with the port close to the tip. With these cutters, it is possible to shave the attached vitreous off the surface, without engaging the retina. A bimanual technique with an illuminated probe or pic held in the second hand can also be helpful in protecting the retina. Removal of the inferior vitreous base is also facilitated by having an assistant indent with a scleral depressor, squint hook, or cotton-tipped stick (Fig. 107.9). Formed vitreous attached to the peripheral retina is also very difficult to remove if the retina is detached and mobile, in which case it can be stabilized at this stage by partly filling the vitreous compartment with heavy fluorocarbon liquid (Fig. 107.10) (Video 7, available online). This has the dual effect of flattening the retina by displacing subretinal fluid anteriorly and breaking down invisible microscopic retinal bridges of scar tissue. In cases where vitreous remains attached to the retinal surface posteriorly as well as at the vitreous base, the process of removal may be facilitated by an intravitreal injection of triamcinolone. The white suspension sticks to vitreous membranes and residual vitreous gel, making them both more visible (Video 7, available online).27–29
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