Proliferative Vitreoretinopathy (PVR) Update: Current Surgical Techniques and Emerging Medical Management

Introduction

Proliferative vitreoretinopathy (PVR) is a complex vision-threatening disease process that develops as a complication of surgical repair for rhegmatogenous retinal detachment (RD). Approximately 5% to 10% of RD surgeries are complicated by PVR, and among all causes of RD surgical failures, approximately 75% are due to PVR. ¹ Therefore, although an uncommon event, it is the most significant obstacle to successful RD surgeries. Additionally, PVR develops following penetrating ocular trauma, with a mean incidence of approximately 25%. ² The purpose of this review is to provide an update on current surgical techniques and emerging medical management in PVR.

Methods of Literature Search

The literature search was conducted through MEDLINE and Google Scholar, including all years covered in the database and using the following words: PVR, proliferative vitreoretinopathy, ocular trauma, pathogenesis, pathobiology, current trends, techniques, prophylaxis medical treatment, surgical treatment, models, pars plana vitrectomy, retinectomy, retinotomy, membrane peeling, scleral buckle, tamponade agents, chorioretinectomy, chromovitrectomy, vital dyes, and visualization. Particular attention was placed on studies from 2006 to 2016 while historical, landmark studies were included. All English language journal articles or reviews were considered.

Pathophysiology

In RDs complicated by PVR, there is a separation of the neurosensory retina and the retinal pigment epithelium (RPE), which induces a complex process of both a healing response and excessive inflammation. ³ Retinal pigment epithelium cells migrate through the retinal breaks (RBs), proliferate on retinal surfaces as well as any remaining vitreous collagen, and cause fibrous tissue formation. ⁴ The periretinal membranes produced by RPE cells have contractile properties, which further complicate by means of tractional RD. ⁵ Due in large part to the effects of gravity, PVR is most commonly seen in the inferior retina. ⁵ Similarly, it has been suggested that glial cells and macrophages play an important role in the active remodeling of the retina, which not only protects the neuroretina but also causes further cellular proliferation, retinal ischemia, and inflammation. ⁶ Numerous trophic factors such as platelet-derived growth factor (PDGF), ⁷ vascular endothelial growth factor, ⁸ tumor growth factor-β (TGF-β), epidermal growth factor, tumor necrosis factor-α, and fibroblast growth factor ⁹ as well as cytokines such as interleukin (IL)-1, IL-6, IL-8, and IL-10, and interferon-γ ¹⁰ have been suggested to play a role in this response. However, these factors are nonspecific to the anomalous healing response in PVR, and thus, pharmacological inhibition also affects the aspects of protective healing, making pharmacological management of PVR not yet proven or beneficial. ¹¹

Classification

Proliferative vitreoretinopathy is an independent clinical entity that replaces previously named conditions “massive vitreous traction” or “massive periretinal proliferation.” In 1983, The Retina Society Terminology Committee divided PVR into 4 grades of increasing severity: A, B, C, and D. ¹² Due to numerous limitations, including the inability to determine the location and magnitude of the vitreoretinal traction, a new classification system was introduced by the Silicone Study Group in 1989 and later updated in 1991 by the Retina Society Classification. ^13,14 This system is graded as A, B, and C. Grade C is further divided to provide additional details about the location (anterior or posterior) and the types of contraction (Table 1). The use of these grading systems by clinicians and researchers over the past 15 years has been demonstrated to be inconsistent and of limited use, especially when considering the advancements made in the field of PVR since its inception. ¹⁵ It is noteworthy that despite these advancements, there has been little to no decline in the prevalence of PVR after RD surgery.

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Table 1.

The Revised Retina Society Classification (1991) Based on the New Classification System Introduced by the Silicone Study Group (1989).^a

Grade	Type	Clinical Signs
A		Vitreous haze, pigment clumps, and pigment clusters on inferior retina
B		Wrinkling of inner retinal surface, retinal stiffness, vessel tortuosity, rolled and irregular edge of retinal break, and decreased mobility of vitreous
CP (posterior)		Full-thickness retinal folds or subretinal strands posterior to equator (1-12 clock hours involvement)
	Focal	Starfolds posterior to vitreous base
	Diffuse	Confluent starfolds posterior to vitreous base and optic disc that may not be visible
	Subretinal	Proliferation under the retina, annular strand near disc, linear strands, and moth-eaten-appearing sheets
CA (anterior)		Full-thickness retinal folds or subretinal strands anterior to equator (1-12 clock hours involvement), anterior displacement, and condensed vitreous strands
	Circumferential	Retina contraction inward at the posterior edge of the vitreous base, with central displacement of the retina, peripheral retina stretched, and posterior retina in radial folds
	Anterior	Anterior contraction on the retina at the vitreous base, ciliary body detachment and epiciliary membrane, and iris retraction

^aAdapted from Lean et al. ¹³

Risk Factors

All RD repairs undergo a healing process, but only a minority subsequently develops PVR. This development is dictated by risk factors, which can be categorized as preoperative risk factors and perioperative risk factors.

Preoperative risk factors include preoperative eye and patient-related risks. Previously studied preoperative risk factors include uveitis; large, giant, or multiple tears; long-standing (chronic) RD; large detachment involving greater than 2 quadrants of the eye; choroidal detachment; multiple previous surgeries; ocular trauma; vitreous hemorrhage; high levels of vitreous proteins; and aphakia (Table 2). ^{1,3,16 –18} In a preliminary study, Xu, Chin, Bennett, et al (unpublished data, 2017) identified 2 additional preoperative risk factors to PVR formation in those with uncomplicated primary RD repair—smoking and macula-involving RDs. This study did not find any significance to other risk factors including duration of RD symptoms, high myopia, location of RBs, number of RBs, lattice degeneration, large tears, preoperative best corrected visual acuity (BCVA), and preoperative intraocular pressure (IOP). In a population of 138 patients who had undergone surgical repair following RD secondary to open-globe injuries, smoking was again cited as a risk factor for PVR development and retinal redatchment. ¹⁹ A compilation of studies analyzing risk factors for the development of PVR has been cited elsewhere. ²⁰

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Table 2.

List of Preoperative and Perioperative Risk Factors in PVR.

Preoperative	Perioperative
Uveitis	Surgical technique, experience, and skill
Large, giant, or multiple tears	Degree of retinal coagulation
Longstanding retinal detachment	Choice of vitreal tamponade
Large detachment involving greater than 2 eye quadrants	Pharmacological adjuvant use
Choroidal detachment
Vitreous hemorrhage
High levels of vitreous proteins
Aphakia
Multiple previous surgeries
Smoking
RD with macular involvement

Abbreviations: PVR, proliferative vitreoretinopathy; RD, retinal detachment.

Perioperative risk factors include surgical technique, experience, and skill ²¹ ; degree of retinal coagulation ²² ; choice of vitreal tamponade agent ²³ ; and pharmacological adjuvant use (Table 2). ¹⁸ The current trends and success of these various techniques will be discussed in the next section. Using these preoperative and perioperative risk factors, various predictive models have been designed to assess the risk of PVR development after RD surgery. In an external validation study, none of the formulas were found to be accurate enough for routine clinical use. ²⁴

With respect to the incidence of PVR following ocular trauma, it has been shown that not only is it a common occurrence but also the frequency, onset, and outcome are highly dependent on the severity of the ocular trauma. In a retrospective study, the frequency of PVR following contusion, intraocular foreign body (IOFB), penetration, rupture, and perforation was 1%, 11%, 15%, 21%, and 43%, respectively. ²⁵ Similarly, the time for PVR onset was shorter for more severe traumas (perforation at a median of 1.3 months) and longer for less severe traumas (contusion at a median of 5.7 months). ²⁵ This study also identified vitreous hemorrhage as the strongest independent risk factor for the development of PVR in this subgroup of patients.

Current Trends and Emerging Techniques

Medical

In order to mitigate the anomalous healing process following surgical trauma for RD paired with the growing body of the literature on PVR pathogenesis, researchers have investigated the role of various pharmacological agents in this disease process. Adjunct medical management of PVR treatment can be categorized based on 4 areas—anti-inflammatory, antineoplastic/proliferative, antigrowth factor, and antioxidant. Some studies are clinical trials, whereas newer ones are being investigated in animal models. Here, we summarize the therapies that show future potential as adjunct medical management in PVR.

Discussion

To date, PVR remains a common complication following RD surgery and has a tremendous impact on the patient’s visual recovery. Over the past few decades, we have learned a lot about PVR as a debilitating disease process but are still unable to reliably predict or prevent its occurrence. Despite this, the classification system, which is supposed to help clinicians compare results of treatment, has not been revised over 2 decades. It may be prudent and beneficial to introduce a more clinically useful classification system, which incorporates advancements in PVR pathophysiology, in order to promote consistent use among basic researchers and clinicians. Some suggest that the use of the word “proliferative” has steered the direction of medical research toward investigating antiproliferative agents while excluding other drug classes.

Over the past few decades, the advent of vital dyes for the visualization of membranes has facilitated surgical removal of membranes and therefore predicts better surgical success. Newer vital dyes continue to be investigated, but a larger randomized control trial is warranted to better elucidate outcomes. Strategies to most effectively treat PVR will probably require a multimodal approach with particular attention to adjunct medical management. Despite the successes of the various surgical modalities in treating PVR, each patient’s surgical and medical management must be uniquely considered based on the cause of PVR development as well as preoperative and perioperative risk factors. New findings concerning smoking as a risk factor in uncomplicated RD repair and open-globe injury repair highlight the need for a broad consideration during patient counseling.

It is evident that the number of randomized control trials in this field of research is limited. Most are retrospective in design, and as such, cannot prove causality and are susceptible to selection bias. High-quality randomized control trials are warranted, possibly with combination drug formulations. Moreover, surgical techniques to reduce ocular trauma in order to avoid the inflammatory response, should continue to be investigated.