Ординатура / Офтальмология / Английские материалы / Retinal and Vitreoretinal Diseases and Surgery_Boyd, Cortez, Sabates_2010

Background

With the advances in vitreoretinal surgery, the success rate of retinal detachment surgery has grown to more than 90%. The development of proliferative vitreoretinopathy (PVR) is the major cause for failure.1 The Retina Society Terminology Committee 1983). PVR comprises a tissue destructive complication of rhegmatogenous retinal detachment (RD), severe ocular trauma, or intraocular surgery in a frustrating attempt to stabilize the residual function. As such, the response is unspecific and not principally different from that resulting from proliferative intraocular disorders of other origin, namely chronic retinal ischemic diseases such as diabetic retinopathy and retinopathy after central retinal vein occlusion or due to retinopathy of prematurity. Untreated, it will result in progressive and profound intraocular scarring leading to to-

tal retinal and ciliary body detachment and thereby blindness and phthisis. PVR is the most serious complication of failing retinal reattachment surgery and beyond the leading causes of vision loss in developed countries. It is a complex process of events that may comprise a tissue-specific form of a wound healing response with inflammation, migration and proliferation of a variety of cells. The resulting membranes can exert traction and reopen previously closed retinal breaks, create new breaks, and distort or obscure the macula. In the early part of the last century the success rate of retinal reattachment surgery was virtually zero, and it was Jules Gonin who understood RD as a consequence of vitreous detachment and forces resulting in retinal tears and traction. He successfully proved his understanding of the pathophysiology of retinal detachment consequently with a treatment aiming at closing retinal breaks, thereby increasing the surgical success rate

to more than 60%.2 To further increase the final success rate in the treatment of retinal detachment, a better understanding of the risk factors for PVR is needed in patients presenting with acute retinal detachments. Principally three categories of risk factors have to be differentiated, i.e. preoperative eye and patient related risks, best surgical management, and the use of adjuvant therapies.3

The risk of PVR has been reported to vary between 10 and 40% depending on the underlying disease and the situation prior to PVR surgery. Beyond the factors of influence on the development of PVR, surgical technique and skills play the key role, but adjunctive measures such as pharmacological adjuncts and the choice of material for vitreous replacement may significantly add to the outcome.4 At the end of the day, PVR remains a difficult management problem despite all recent advances in vitreoretinal surgery. Surgery for PVR now has a relatively high anatomical success rate but visual results are frequently less striking.5 After 30 years of slow progress, the use of adjunctive treatments to prevent cellular proliferation holds still the strongest promise for prevention and recurrences of PVR after surgery.

This overview provides information about the current understanding of the disease and its stages, an analysis of underlying risk factors, therapeutic options and preventive measures.

Definition and Causes

Retinal detachment results from the separation of the neurosensory retina from the underlying retinal pigment epithelium (RPE). Both layers are of neuroepidermal origin, but they do not have a direct anatomical connection.6 Therefore, attachment of neuroretina and PRE is not strong, allowing the laminar space between the two layers to grow upon tractional forces. Once the retina has separated from the RPE and retinal detachment is evolving, the outer retina becomes ischemic due to the loss of its blood supply from the choroid. Moreover, the biochemical exchange between RPE and retinal photoreceptors is interrupted, resulting in the accumulation of subretinal fluid with loss of photoreceptor outer segments, until at the end the entire photoreceptor cell layer becomes atrophic.7,8 In this context, PVR may be understood as a complex process of tissue induced events including inflammation, migration and proliferation of several types of merely locally derived cells.9,10,11 These grow to cellular membranes which contract within the vitreous, and on retinal surand backfaces.12 As such they are not principally different from membranes driven by other sources and forces such as proliferative diabetic or ischaemic retinopathy or trauma.13 The term proliferative vitreoretinopathy represents a morphological description of the clinically observed process of proliferation involving vitreous cavity and

the retina. PVR was first reported by Gonin (1934) who described his observation as a form of preretinal organisation, as an invasion of the retinal surface by membranes that do not modify the retinal structure. Machemer (1978) proposed a classification of what he termed massive periretinal proliferation,14 which served the basis for the nowadays widely usedclassification of retinaldetachment with proliferative vitreoretinopathy (Table 1).15 This grading system has the great advantage of being simple and widely applicable, but

it does not include important factors such as duration of disease, distinction between preoperative and postoperative PVR, the number and location of retinal breaks, the location of vitreoretinal tractional ring formation, the degree of contraction of vitreous base etc, all of which may be important for surgical strategy and functional outcomes. Therefore, an updated classification of retinal detachment with proliferative vitreoretinopathy was provided by Machemer and coworkers.16 This

modified classification and grading system has remained unchanged for the less severe stages (grade A and B) but attempted to more precisely describe location and severity of advanced PVR (grades C and D; Tables 2A and 2B). Due to its more complex character and eventually due to its less obvious prognostic relevance this classification has not found a

broadacceptancebeyondvitreoretinalsurgeons for routine purposes, but may well be helpful in PVR-treatment studies such as the silicone study.17 None of these classification schemes includes biologic activity of PVR, which may be beyond the clinically relevant factors for progression and treatment outcome.18,19,20

Clinical Presentation

The clinical features of PVR depend on the location of membranes. This in turn is related to the sites of vitreoretinal contact and traction, since the vitreous serves the surface line along which membranes tend to expand. Moreover, the vitreous is not rich regarding

nutritional factors if the uveovascular barrier is maintained. This results consequently in the selection and propagation of cells which do not require specific environmental conditions, i.e. fibroblasts.

Proliferation at the posterior vitreous surface may cause the development of membranes located at the equator or posteriorly.

Proliferation within the vitreous base and anterior cortex may result in anterior traction of the retina towards the pars plana, whereas membrane contraction on the posterior retinal surface may lead to distortional and irregular retinal folds generally referred to as star folds (Figure 1). These are more frequently found in the lower two thirds of the retina. Proliferation may also occur in the subretinal space as fibrous strands and plugs which are not specific of PVR and may well be observed in

other situations, namely after ocular trauma (Figure 2 A-B).21 Once not involving the macula, PVR itself is widely asymptomatic (Figure 3 A-C). Epimacular membranes lead to metamorphopsia and reduced vision (Figure 4 A-B). If PVR membranes contract they can reopen closed retinal breaks and induce new ones, thus leading to retinal redetachment (Figure 5). The mechanical impact on the retina may functionally present with photopsia, but usually remains undetected by the affected

individuals if not complicated by tractional retinal detachment. The progression of membrane formation and maturation may vary widely interindividually, making the predictionofprogressdifficult, but the expected activity of membranes determines the timing of surgical intervention. No systemic condition has been associated with the

development of PVR, and there is no evidence for genetic factors interfering with wound healing.

Histology and Cell Biology of

Wound Healing in PVR

It is clearly the tissue trauma resulting from separation of the neuroretina from the RPE which sets the stage for the development of PVR.22 Control of the biological process, which is involved in cell proliferation and retinal wound healing, might significantly enhance the success of retinal detachment repair and open the floor for nonsurgical therapeutic options. An early identification of cases at risk would allow to apply primary PVR prevention strategies and to control vitreoretinal proliferation prior to adopting surgical techniques. Thus, the knowledge of the pathological process and local environmental changes in response to RD and PVR may gain increasing interest within the next years.

Figure 6: Typical histological image of a PVR membrane (PAS, magnification 200x) with few cells of fibroblastic morphology, no vessels, barely any pigment or inflammatory cells (Image kindly provided by GM Sarra, Department of Ophthalmology, University of Bern).

The histological substrate of PVR are contracting cellularorfibrocellular membranes, which interfere with retinal function by progressive contraction23,24 (Figure 6). In contrast to membranes in diabetic or ischaemic retinopathies, PVR membranes typically contain retinal pigment epithelial cells, but no vasculature. The RPE cells in these membranes typically switch to a fibroblastor macrophagelike cell morphology with fibroblastic cells more present in the contractile elements of those membranes.14, 25,26 There is currently no clue what factors drive the functional switch towards a fibroblastic dedifferentiation of RPE cells, which is also observed at a much slower rate in RPE cell culture. Neural ele-

ments may be detected in PVR membranes, but there is still considerable doubt about the role of the cell types involved. Mueller cells and retinal glial cells are consistently found in epiretinal membranes in PVR. However, their role in PVR has remained uncertain. They might reflect outgrowth from the retina into the developing membrane, resembling the capacity of these cells to respond to the environmental change, the capacity to proliferate, translocate from the retina and alter their phenotype and functional characteristics.27 But their presence in consequence of the tissue damage resulting from membrane excision cannot be excluded.28 It must be kept in mind that the cellular composition of PVR membranes may be altered by surgical intervention, namely in cases of recurrent retinal detachment and by the use of tamponades, namely silicone oil and heavy liquids.29,30 On this basis it has been suggested that the tamponade may attract macrophages which enhance PVR progression by accumulation of cytokines, namely macrophage derived growths factor, in the laminar space between tamponade and retina. Fragments of the retinal inner limiting membrane are frequently found in PVR membranes. They may indicate the strong adherence between membrane and retinal surface, which explains their capability of inducing retinal breaks and detachment as well as the problems evolving in some cases during peeling them off the retinal surfaces.31

In an attempt to reconstitute or preserve visual function, PVR induces an active remodelling process in the retina. This is indicated by an upregulation of local environmental factors, i.e. growth factors and cytokines. Glial cells may be one important source of the growth factors, which potentially protect the neuroretina, but also can exacerbate the proliferative process. Principally, a functional recovery may be possible, but the outcome will result from the balancing between protective and destructive reparative mechanisms regulated by the same factors, and is merely driven by secondary pathology, namely photoreceptor damage due to periretinal gliosis.5

Pathophysiological

Considerations

The pathogenesis of proliferative vitreoretinopathy is poorly understood. Retinal detachment resembles a form of tissue injury which induces a physiological cascade of wound repair mechanisms. This is generally divided in three phases: inflammation, proliferation and tissue remodelling and scar formation.32

In general, the development of PVR may be understood as a three-phasic process of three overlapping phases (Table 3). In the first phase after trauma, migration of local,