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

i.e. RPE cells into the vitreous and subretinal space is induced. Glial cells may spread through the inner limiting membrane onto the retinal surface to give a strong connection allowing in a second phase the formation and contraction of a membranous tissue with the exudation of fibrin, elastin and fibronectin (Figures 5 - 9). Once stabilized, the attached cells start with collagen synthesis clinically delineated as maturation of the more and more compact membrane (Table 3). At this stage, the adherence of a PVR membrane may be strong, but surgical delamination of the membrane from the retina may be facilitated because of a better demarcation and visibility of membrane extension.

In the first phase, local inflammation provides the basis for vascular opening and outgrowth, allowing macrophages to remove

damaged tissue and cells, and serves as a basis for wound repair. Typically, a breakdown of the uveo-vascular barrier becomes evident by an increased Tyndall phenomenon, and in many elder cases, xanthochromatous, protein rich subretinal fluid may be observed during surgery. In this phase, several growth factors are activated, namely TGF beta (transforming growth factor beta), PDGF (platelet-derived growth factor) and EGF (epidermal growth factor) and many others. Polymorphonuclear cells are found from a few hours after detachment and release additional factors, namely FGF (fibroblast growth factor) to further attract monocytes, which are transformed to macrophages.33 The second phase of wound healing, proliferation, may overlap widely with the first one. In this phase, macrophages stimulate the accumulation and proliferation of fibroblastic cells.34 In the third phase, the

number of active cells decreases with maturation of the membranes, which is indicated by reorganisation of the extracellular matrix. At the end of this phase, fibroblasts contract,

which is clinically resembled by the typical pictures of macular pucker and star fold formation (Figures 7A and B).

Interestingly, PVR is not observed in the context of exudative retinal detachment despite its usually inflammatory origin with extensive vascular leakage.35 This led to the conclusion, that it is the retinal break which induces the wound healing process and triggers PVR.18 The switch from the attempted wound healing of a retinal break towards the development of pathologic retinal wound healing, clinically referred to as PVR, is probably driven by the proliferation and functional metamorphosis of local cells such as hyalocytes, glial cells and RPE cells to fibroblasts.36,37 Multiple therapeutic attempts have been undertaken in order to control their proliferation with the use of antiproliferative and mitogenic agents, but these cells may hardly be influenced by any treatment without exposing the retina to a severe risk of toxic damage. Other cells involved in the reparative process, namely platelets, polymorphonuclear cells and macrophages, and inflammatory cells, i.e. lymphocytes which have been implicated in the pathogenesis of PVR, may thus be more feasible as pharmacological targets.38,39,40

Local cell proliferation is unfortunately often overstimulated and the proliferating cells invade the vitreous.41,42 Several growth factors and more recently also matricellular proteins suchasthrombosponin1,tenascin,andsecreted protein acidic and rich in cysteine (SPARC) which modulate the migration of RPE cells in the epiretinal membranes have been identified within the vitreous and periretinal membranes in eyes with PVR. Their biochemical proper-

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ties, either enzymatic, chemotactic, mitogenic or proinflammatory, make them candidates for influencing the evolution of disease alone or in an synergistic way. They may interfere at differentlevelswithcellmigration,proliferation and vitreoretinal contraction. Immune mediated inflammatory reactions have also been described, and vitreoretinal strands may add to mechanical instability.

PVR typically begins at the edges of a retinal break, and first signs of PVR are the movement of pigmented cells through the hole into the vitreous cavity (tobacco dust, PVR grade A) and irregular and enrolled edges of the retinal break (PVR grade B; Figure 8). Once PVR has developed and progressed, its location is not associated with the inducing break. Instead, a break close to a fibrovascular proliferation may develop secondarily to traction.43a

As already mentioned, chronic retinal ischemia may be an important motor for the development of PVR leading to retinal atrophy and fibrotic remodelling as known from vascular retinal disease, such as diabetes, retinal vein occlusion and retinopathy of prematurity. The separation of the retina from the RPE in consequence of retinal detachment leads to outer retinal ischemia in consequence of the loss of nutritional supply from the choroid. Early, photoreceptor outer segments die, and if retinal detachment persists, the complete photoreceptor cell layer becomes atrophic.8 In

the second phase, cystic retinal degeneration with retinal thinning is observed clinically and in histology, and in an attempt of self-repair RPE demarcation lines with fibrotic subretinal tissue may be found at the central edge of the detachment (Figure 3A and B). These may comprise a successful attempt of stabilising the retina, but resemble at the same time the first step in spontaneous subretinal PVR development (Figure 3C).

Since retinal reattachment surgery aims at closing breaks it is dependent on the induction of local and controlled wound healing processes, for which cryoretinopexy, laser photocoagulation and scleral buckling have been used. They induce central RPE atrophy with proliferation of the RPE at the edges; moreover, accumulation of pigmented macrophages and glial cell proliferation are found, which form the chororetinal scar.43b The amount of uveo-vascular barrier damage, resulting from any form of trauma, i.e.

coagulation, may add to that resulting from retinal detachment and be the most relevant iatrogenic risk factor for development of

PVR.44,45

Risk Factors

Thebalancebetweendesiredwoundhealing of retinal tears and excessive wound healing resulting in an uncontrolled growth of fibrotic tissue is based on local environmental factors which may enhance the risk of PVR development.

This risk is influenced by the age of RD, surgical technique, the use of pharmacologic adjuncts and preventive measures. In general, preoperative risk factors have to be differentiated from surgical management and the use of adjuvant therapy.3 Beyond surgical techniques, surgical experience and skills,46 the amount of retinal coagulation47 and the choice of vitreous tamponade may be critical.

AspreoperativeriskfactorsforprimaryPVR, large retinal tears, long duration of retinal detachment, vitreous hemorrhage (Figure 9), aphakia and choroidal detachment have been identified. It may be not the number and size of breaks, but the mechanical trauma leading to these breaks which makes break size a risk; the greater the tissue trauma, the more cytokines are released from damaged tissue into the periretinal space, the greater is the capillary damage with thrombocyte and erythrocyte evasion into the vitreous cavity and the larger is the breakdown of the blood retinal barrier. The levels of proinflammatory

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cytokines, namely interleukin 1, 6 and 8 as well as tumor necrosis factor alpha (TNF-α) and interferon-y (IFN-y) have been found to be increased in PVR.48 But interestingly, they seem not to be correlated to the severity of PVR.49 Vitreous hemorrhage has been identified as a strong risk factor.50,18,51 Aphakia may be a risk factor for PVR development since blooduveal barrier damage from anterior segment may allow diffusion of cytokines posteriorly.52 Failed retinal reattachment surgery and long standing retinal detachment may be additional risk factors.53,50

Postoperative PVR is most strongly associated with the preoperative presence of PVR of any grade, inflammation, vitreous hemorrhage, excessive cryotherapy or photocoagulation, incomplete vitrectomy, repeated surgery, loss of vitreous during external drainage of subretinal fluid, undetected breaks and postoperative choroidal detachment. The use of air and sulfohexafluorides may be of impact, if no or incomplete vitrectomy has been performed.54,53,44

Independent of these, the intravitreal number of RPE cells and persisting damage of the blood-ocular barrier have been identified as relevant risk factors.55

The role of the immune system in the pathogenesis of PVR remains uncertain. Antiretinal auto-antibodies have been described in the context of PVR development,56 so that an autoimmune process in the pathobiology of PVR cannot be excluded. But evidence is lacking that such would be of primary relevance for clinical evolution of the disease. Systemic steroid and immunosuppressive therapy may thus theoretically be supportive in the prevention and treatment of PVR, but have not soundly shown a disease modifying effect in a clinical setting.34,57,32,58,59

Taken together, tissue trauma inducing retinal detachment, tissue trauma secondary to retinal ischemia, and tissue trauma due

to retinal detachment repair will result in a blood ocular barrier break down. This is rather closely correlated to the severity of PVR, and significant vitreous hemorrhage at the end of complete blood retinal barrier break down may be the strongest risk factor for PVR induction. In consequence of bloodretinal barrier breakdown, inflammatory cells and stimulating factors, i.e. cytokines and growth factors are released into the vitreous

cavity.60,35,61,33

Incidence and Timely

Dynamics

PVR is generally expected to occur with an incidence of between 7 and 10% of uncomplicated rhegmatogenous retinal detachments,15 but has been reported in more than 25% in other series.62 Once the underlying reason is not uncomplicated retinal detachment, the risk may climb up to 40% in retinal detachment complicated by vitreous hemorrhage, postoperative inflammation, giant retinal tears and in posttraumatic retinal detachment.63,4 It has been assumed, that with an improvement in surgical techniques, the risk and incidence of PVR development would decrease over time, which has not unequivocally been proven.64,62 Most of the more recent clinical studies report incidences ranging from 5.1 - 11.7%.52,5

Since none of the recognized risk factors correlates with the development or severity of PVR,52 the timely relation between the development of retinal detachment and its repair may be an important issue.65 This has, however, so far not prospectively been evaluated in a clinical setting.66,67,62,68 The process of PVR formation is initiated by the trauma resulting from retinal detachment.22 This makes the identification and application of prophylactic and preventive strategies challenging.

Surgical Treatment

In general, surgery for PVR aims at stable reattachment of the retina, which is not different from the aim of conventional primary retinal reattachment surgery, in that most efforts have to be put into closing breaks and to release vitreoretinal traction.47,69 Nevertheless, these aims are much more difficult to achieve in cases of PVR. It may be challenging, to completely relief vitreoretinal traction. For this, peeling of all periretinal fibrovascular membrane tissue and resection of the vitreous base as far as possible has to be achieved. This is usually complicated by a poor visualisation of the outer retina and vitreous base. Nevertheless, the success rate of surgical intervention for these cases has remarkably improved with the technologic evolution in vitreoretinal surgery, namely the routine use of vitrectomy techniques to relax vitreoretinal forces and the advent of silicone oil and perfluorooctane tamponades in not evidently stable retinal situations.70,71

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In moderate PVR, scleral depression using a local buckle or encircling band may allow the relaxation of vitreoretinal traction, e.g. circumferential traction caused by constriction of the vitreous base.19 The combination of scleral buckling and silicone oil tamponade may fail, namely in vitreoretinal pathologies of the inferior half of the eye, because the retina is - especially at the posterior buckle wall - not strongly depressed due to surface tension of silicone oil. It has therefore to be reinforced, that a mild to moderate buckle prominence is to be attempted to optimally relieve vitreoretinal traction in the lower circumference of the eye in combination with silicone oil.

Intherecentfewyears,vitreoretinalstrategy is tending away from buckling of any vitreoretinal pathology and in favour of vitrectomy techniques including relaxing retinotomies and retinectomies in combination with the use of endolaser and long-term or permanent retinal tamponades, namely in pseudophacic eyes.72,73 The major advantage of primary vitrectomy without scleral buckling may be that this procedure is less traumatising. Anatomical outcomes may be comparable, there is currently no evidence that the functional outcome might be improved.74 It may though seem likely that better outcomes with regard to the binocular function can be achieved due to less extraocular trauma possibly affecting extraocular muscle function. Vitrectomy may be indicated in cases with no evident retinal breaks, where retinal traction and membranes presumably are the major cause for retinal detachment.47,75

In severe PVR, vitrectomy is clearly the surgical technique of choice, including membrane peeling, vitreous replacement techniques and retinotomy or retinectomy, depending on the individual anatomical situation.21 In complex cases, combined lensectomy and vitrectomy might be considered.76 Since PVR is a biologic process, which will proceed even after successful reattachment surgery, usually running 4 - 6 months or more after its initiation before quietening down (Figure 10), these dynamics have to be anticipated for the choice of the optimal tamponade and the timing of tamponade removal besides the local tolerability of the tamponade.70,77 The choice of tamponade and the decision for the timing of its removal are widely based on surgical experience and may be the crucial point determining success or failure in advanced cases of PVR.78,79,71 The use of the more recently introduced heavy silicone oils for PVR located in the inferior half of the retina may be limited by the fact that these have to be removed after two to three months due to their much faster emulsification as compared to pure silicone oils of 5000 centistokes density and their obviously higher complication, but not success rates.80,81,82 In more complex situations with circumferential traction, their sequential use with resolution primarily of inferior and secondarily of superior traction may be an option.83

If stable retinal reattachment cannot be achieved, relaxing retinotomies or retinectomy may become necessary and, at least in experienced hands, allow excellent functional outcomes.84,85,86 This may namely be important if not all periretinal fibrotic tissue can be removed and the residual traction at the end of surgery is expected to lead to retinal redetachment, or if the biological activity of immature periretinal membrane tissue has to be expected to progress and to induce break reopening and retinal redetachment.87 If not all traction is relieved until the placement of the tamponade, this may evade into the subretinal space during surgery or in the postoperative period, its complete removal usually being challenging. Therefore, tamponade placement should only be considered after all retinal traction is alleviated and, optimally, the edges of retinotomies and retinectomies have been sealed by photoor cryocoagulation.

In advanced PVR, reproliferation has to be expected in two thirds of cases. If it involves the macular region, functional outcome is usually poor. Even if not quantifiable on the basis of visual acuity findings, patient satisfaction due to a subjective gain in visual function is surprisingly high in most instances despite several surgeries for the stabilisation of the retina.88,89 This may justify the significantly increased costs associated with the treatment of PVR.90

A typical location of recurrent severe PVR is at the anterior part of the retina towards the pars plana, inducing cyclodialysis, hypotony and pupil distortion, and is usually associated with a poor prognosis.91 This specific entity of anterior PVR is most difficult to treat. Such is usually not possible without removal of the lens together with all capsular material and peeling off of membranes from the ciliary body and pars plana under indentation. Not surprisingly, corneal decompensation may be theconsequence.92 Ifextensiveretinotomieshave to be performed, the risk of new induction of PVR leading to redetachment with macular involvement may be as high as 30%, resulting in poor to very poor visual outcome.93,94,95,48 This has found repercussion in the context of macular translocation surgery using 360° retinotomies.96

Intraand Peroperative

Adjunctive Medical Treatment

Based on the above mentioned pathophysiological considerations, one might imagine several points, where adjuvant therapy for the treatment of PVR might help. We have learned that retinal detachment induces a process within the retinal tissue that goes far beyond wound healing and attempts a remodelling of the neuroretina. All strategies to control and direct wound healing and PVR have thus to be weighted against the potential benefits of retinal remodelling. The functional impact of biologic remodelling has not been profoundly addressed and remains

uncertain, but there is some indication, that retinal remodelling may partially protect the neuroretina and limit photoreceptor degeneration.

Obviously, individual pre-existing risks such as wound healing genetics or the presence of vitreous hemorrhage in the context of retinal detachment cannot be influenced. Beyond the points of influence, most and earliest efforts have been made to control the blood-retinal barrier breakdown and the inflammatory response in the context of PVR development by use of steroids. Interestingly, despite the absence of any clinical evidence and despite potentially severe side effects in the established doses, systemic as well as local, i.e. intravitreal steroids have been used by many vitreoretinal surgeons in the last decades.34,58,97,98,99,59 Antiproliferativeagentshave widely been evaluated, but have a limitation in the high sensitivity of the neuroretina to their dose-dependent toxicity. A number of studies have been undertaken to show the benefit of a variety of pharmacological interventions, including retinoic acid,100,101 dexamethasone,102colchizine,103 taxole,103 daunorubicin104,105 and multiple other antimetabolites,106,107 and also heparinoids,108 have been evaluated alone or in combination in the last decades. Most of these agents have not achieved a level to justify their introduction into clinical evaluation, and none of them have reached entrance into clinical routine use.109 More recently, growth factors and antiinflammatory biologically active agents have been applied in order to control PVR.110,111,112,113