Proliferative vitreoretinopathy (PVR) is defined as the “growth of membranes on both surfaces of the detached retina and on the posterior surface of the detached vitreous gel.” The name was introduced in 1983 by the Retina Society Terminology Committee as part of a classification scheme for a group of intraocular complications previously known by more descriptive terms, including “massive vitreous retraction,” “massive preretinal retraction,” and “massive periretinal proliferation.” PVR is not a distinct disease per se, but is instead a complication common to a variety of clinical disorders. It is most prevalent as a clinical complication of surgical procedures to correct rhegmatogenous retinal detachments, which are detachments that follow formation of a retinal tear or hole. Tractional forces generated within the scar tissue-like PVR membranes can be transmitted to the retina and cause complete retinal detachment, retinal degeneration, and permanent blindness.
Studies of PVR chronology report average development times between the initial symptoms and retinal detachment ranging between 1 and 2 months and which vary with the type of initiating event and disease severity. Tissue changes associated with PVR can vary widely in both severity and location at initial diagnosis. The classification scheme used to describe these two features was suggested by the Retina Society Terminology Committee in 1983. Stage A PVR refers to minimal or earliest signs of potential disease, including vitreous haze, protein flare, or the presence of pigmented cell clumps thought to be derived from the retinal pigmented epithelium (RPE: Figure 78.1A ). PVR stage B describes moderate, but nonetheless overt, signs of PVR, including traction or wrinkling of the retinal surface, rolled edges of a retinal break, or blood vessel distortion ( Figure 78.1B ). PVR stage C was originally proposed to describe marked and then massive, full-thickness retinal folds that involved one to three quadrants of the eye ( Figure 78.1C ) and stage D indicates complete retinal detachment into a funnel shape. However, this portion of the classification scheme was later modified to include a single stage C that was subdivided into six categories providing specific information about the severity and location of advanced PVR ( Table 78.1 ).
|Grade||Type of contraction||Location||Summary|
|A||Retinal pigment epithelium clumps in vitreous and on retina, protein flare|
|B||Surface wrinkling, rolled edges of tears, vascular tortuosity|
|C||Full-thickness retinal folds|
|2||Posterior||Confluent irregular folds in posterior retina, remainder of retina drawn posteriorly, optic disc may not be visible|
|3||Anterior||Subretinal napkin ring or irregular elevation of the retina|
|4||Posterior||Irregular folds in anterior retina, series of radial folds more posteriorly, irregular circumferential retinal fold in coronal plane|
|5||Anterior||Smooth circumferential retinal fold in coronal plane|
|6||Anterior||Circumferential fold of retina at insertion of posterior hyaloid pulled forward; trough of peripheral retinal, ciliary processes under traction with possible hypotony; iris may be retracted|
PVR development is most often associated with the formation of retinal holes or tears and its prevalence under these circumstances correlates with the size and/or number of retinal defects. The ultimate success rate of surgical procedures to close retinal defects and correct the rhegmatogenous retinal detachments is now extremely high, exceeding 90%. However, PVR develops in 5–10% of these cases and remains the leading cause of surgical failure. Depending on the severity or location, penetrating ocular injuries and other ocular trauma also have a high risk of developing PVR. This is also true for conditions that lead to retinal or vitreous hemorrhage. PVR is also associated with seemingly unrelated conditions such as aphakia, which is the absence of the natural crystalline lens, and pseudophakia, which indicates the presence of a synthetic lens. Genetic predisposition per se does not appear to be a major factor in the development of PVR. However, PVR may be more common in genetic diseases in which risk factors such as the formation of retinal holes, tears, and detachments are more prevalent, such as severe myopia and connective tissue disorders such as Stickler and Marfan syndromes.
Treatments for PVR vary according to disease severity and the perceived risk of developing more aggressive disease. Early PVR that does not involve new retinal holes or tears or otherwise alter visual acuity might be monitored in the hope that it will remain asymptomatic. Light to moderate PVR might be treated with an encircling scleral band designed to close the retinal break through external deformation of the globe. More severe disease may require vitrectomy which involves surgical removal of the vitreous gel and replacement with a buffered saline solution. It may also be necessary to dissect and peel the epiretinal scar tissues off to lessen traction on the retina. Severe cases involving large expanses of retinal detachment under traction may require even more aggressive procedures such as temporary replacement of vit reous fluid with gas or silicone oil to encourage retinal reattachment and tamponade the retinal defects. In the most advanced cases it may be necessary to remove retinal tissue in relaxing retinectomies. The extraordinary skill with which these techniques are applied has resulted in a surprisingly high rate of surgical success. Anatomic correction, defined by successful retinal reattachment, is accomplished in 60–80% of PVR cases. This is somewhat lower in cases of extremely severe or advanced disease. Unfortunately, high surgical success rates are not necessarily indicative of visual success. The risk of developing recurrent PVR is extremely high (approximately 40%) and often requires revision surgeries. Also, the more aggressive treatment options like gas or silicone oil tamponade, while essential to a successful surgical outcome, can lead to other unrelated complications such as cataractous changes or glaucomatous increases in intraocular pressure. Finally, and perhaps most importantly, even relatively brief periods of retinal detachment can lead to significant loss of retinal function. Successful, uncomplicated surgical correction of retinal detachments within 7 days allows more than 80% of patients to recover ambulatory vision of 20/200 or better. However, when recurrent disease and other complications are considered, these percentages fall to between 40 and 80%.
While the initiating events and disease course can be highly variable, PVR is ultimately a cellular disorder in that it is dependent upon the combined actions of individual cells. Minimally, the intravitreal form of PVR requires that the pathogenic cells gain access to the vitreal space through avenues which vary according to cell type. The pathogenic cells must then proliferate to achieve the required critical mass and generate the tractional forces that ultimately cause traction retinal detachment. The ability to arrest any of these critical activities would result in control of PVR and prevent its recurrence. As a result, much of the research into PVR pathogenic mechanisms has focused on identifying the cells involved ( Box 78.1 ) and on the critical pathogenic activities ( Box 78.2 ).
Retinal pigmented epithelial cells
Immune cells (macrophages, lymphocytes, hyalocytes)
Fibroblasts of unknown origin
Cell migration or dispersion into vitreous
Tractional force generation
Cells derived from the RPE have long been considered key players in the pathogenesis of PVR. The RPE is a monolayer of darkly pigmented cells that underlies and provides physiologic support to the attached neural retina ( Figure 78.2 ). Studies of PVR epiretinal tissues originally identified RPE based on pigment content and ultrastructural morphology. With the advent of immunochemical labeling techniques for microscopy, RPE have since been positively identified in these tissues using antibodies raised against cytokeratins present in normal RPE and other proteins with limited ocular distribution such as cellular retinaldehyde-binding protein. RPE can be detected in nearly all PVR epiretinal membranes. However, in studies in which cell populations were actually quantified, RPE usually represents less than 25% of the total population. Under normal conditions RPE cells are not in direct physical contact with the vitreous and so their involvement in PVR is thought to require the creation of a retinal defect such as a hole or tear. In addition to migration through retinal defects, there is evidence that RPE can be physically dispersed into the vitreous if attached to a large, horseshoe-shaped retinal tear or even during retinal detachment surgeries that involve physical manipulation of the external globe wall.
Evidence of glial involvement in the pathogenesis of PVR is similar to RPE except that the glia are potentially derived from two retinal cell types. Retinal astrocytes are derived from the nerve fiber layer near the vitreoretinal interface ( Figure 78.3 ). Müller cells are radially oriented, transretinal glia whose broad endfeet join and comprise the vitreoretinal interface ( Figure 78.4 ). Early light microscopic studies of PVR scar tissues tentatively identified glia in these tissues by size and morphology. The immunochemical studies that followed confirmed these findings by detecting cells positive for glial fibrillary acid protein (GFAP) in most of the PVR epiretinal membranes examined. However, when quantified, glia detected using this antigen consistently represented a minority of the overall cell population. At least two studies distinguished between astrocytes and Müller glia using proteins specific to the latter cell type, including cellular retinaldehyde-binding protein, carbonic anhydrase, and glutamine synthetase. Cells positive for these antigens were detected, indicating that some of the glia present in PVR epiretinal membranes are derived from Müller cells. Recent studies have now provided direct evidence of retinal glial cell migration on to the retinal surface in human and animal studies. In this case, vitreal Müller cell migration was induced by retinal detachment and then reattachment.