37 Treatment of lattice degeneration and asymptomatic retinal breaks to prevent rhegmatogenous retinal detachment

Background

Lattice degeneration and retinal breaks are visible lesions that are risk factors for later retinal detachment. Lattice degeneration exists in 6–8% of the general population, and asymptomatic retinal breaks are almost as common, although a substantial number of these occur within lattice lesions.1 Retinal detachments occur when fluid in the vitreous cavity passes through tears or holes in the retina and separates the retina from the underlying retinal pigment epithelium. Non-traumatic retinal detachments occur in approximately 1/10 000 persons/year,2,3 and they are significantly more common in eyes with significant myopia4 and following cataract surgery.5,6 Phakic retinal detachments are associated with lattice degeneration in approximately 30% of cases.1 Patients with non-traumatic retinal detachments in their first eye are at significantly greater risk for a similar event in their second eye.

Prevention of retinal detachment has been a major goal for many decades, and this has been of particular interest in patients in whom a detachment has occurred in their first eye and the surgical outcome has been less than desirable. Based upon the traditional mechanisms that lead to retinal detachment, theoretical manoeuvres that might reduce the incidence of detachment would include measures that retard vitreous liquification, reduce vitreoretinal traction, prevent focal lesions that predispose an eye to the development of a retinal break from doing so, and seal existing retinal breaks so that fluid cannot pass through them. Of these options, only the latter two are widely practised at this time.

Thus, creation of an adhesion around lattice degeneration and or retinal breaks, with laser photocoagulation or cryotherapy, has been recommended as an effective contemporary means of preventing retinal detachment. This therapy is of value in the management of retinal tears associated with the symptoms of flashes and floaters and persistent vitreous traction upon the retina, because such

symptomatic retinal tears are associated with a high progression to retinal detachment.7 Lattice degeneration and retinal breaks not associated with acute symptoms are significantly less likely to be the sites of retinal tears that are responsible for later retinal detachment. Nevertheless, treatment of these problems is also frequently recommended, in spite of the fact that the effectiveness of this therapy is unproven.8

Enthusiasm for treating asymptomatic retinal breaks and their precursors such as lattice degeneration was probably most popular before the time that the high frequency of these lesions in the general population and the low risk of retinal detachment, with or without therapy, were appreciated.8 Creation of an adhesion around the retinal break(s) or lattice lesion(s) was originally performed with diathermy, which was replaced by xenon photocoagulation, which in turn was supplanted by trans-scleral cryotherapy or laser photocoagulation. Improved methods of delivering laser energy have resulted in this being most commonly employed modality at the present time. The primary problem in treating focal lesions is not that treatment does not prevent retinal detachment from a break at the treated site, but rather that later breaks will occur elsewhere, in regions of the retina that appeared “normal” prior to detachment. For this reason, some authors have recommended 360 degrees of peripheral laser burns in an effort to treat the regions in which the vast majority of retinal breaks arise. However, such extensive treatment is not without risks, is not always effective, and has not been subjected to prospective randomised trials comparing therapy with observation.8

Question

What is the effectiveness of treating lattice degeneration and asymptomatic retinal breaks to prevent retinal detachment?

The evidence

A systematic search for randomised controlled trials of therapy to prevent retinal detachment is included in a 2001 edition of the Cochrane Library.9 The review attempted to identify any and all trials in which one treatment of lattice degeneration and asymptomatic retinal breaks was compared to control or to another form of therapy.

The review documented a lack of any studies that met the inclusion criteria, because no prospective randomised trials were identified. An additional more recent literature search was unproductive in discovering such trials.

Implications for practice and research

There are no randomised controlled trials to support conclusions regarding the value of treating lattice degeneration or asymptomatic retinal breaks to prevent retinal detachment. Although lattice degeneration and asymptomatic holes are genuine risk factors for rhegmatogenous retinal detachment, the value of treating these lesions is not supported by available evidence in the literature. Prospective randomised trials of treatment of eyes with these lesions and with additional risk factors should

offer the best opportunity to provide outcome data that are statistically meaningful.

References

1.Byer NE. Long-term natural history of lattice degeneration of the retina. Ophthalmology 1989;96:1396–402.

2.Haimann MH, Burton TC, Brown CK. Epidemiology of retinal detachment. Arch Ophthalmol 1982;100:289–92.

3.Wilkes SR, Beard CM, Kurland LT, Robertson DM, O’Fallon WM. The incidence of retinal detachment in Rochester, Minnesota, 1970–1978.

Am J Ophthalmol 1982;94:670–3.

4.The Eye Disease Case–Control Study Group. Risk factors for idiopathic rhegmatogenous retinal detachment. Am J Epidemiol 1993;137:749–57.

5.Tielsch JM, Legro MW, Cassard SD et al. Risk factors for retinal detachment after cataract surgery. A population-based case–control study. Ophthalmology 1996;103:1537–45.

6.Rowe JA, Erie JC, Baratz KH et al. Retinal detachment in Olmsted County, Minnesota, 1976–1995. Ophthalmology 1999;106:154–9.

7.Shea, M, Davis, MD, Kamel, I. Retinal breaks without detachment, treated and untreated. Mod Probl Ophthalmol 1974;12:97–102.

8.Wilkinson, CP. Evidence-based analysis of prophylactic treatment of asymptomatic retinal breaks and lattice degeneration. Ophthalmology 2000;107:12–18.

9.Wilkinson, C. Interventions for asymptomatic retinal breaks and lattice degeneration for preventing retinal detachment retinal detachment (Cochrane Review). In: Cochrane Collaboration: Cochrane Library. Issue 4. Oxford: Update Software, 2001.

Background

Proliferative vitreoretinopathy (PVR) is a condition of cellular proliferation and migration resulting in the formation of contractile periretinal membranes. PVR may complicate rhegmatogenous retinal detachment and variants of the process can occur in other situations, for example, following penetrating ocular trauma. Series of surgical repair of rhegmatogenous retinal detachments report incidences of PVR of between 5% and 12%.1–8 Higher incidences are seen in more complex forms of vitreoretinal disease:16–41% of giant retinal tears9–13 and 10–45% of eyes with penetrating trauma14,15 are complicated by PVR.

Retinal breaks and neural retinal separation result in blood–retinal barrier breakdown, increased concentrations of fibrogenic growth factors and the formation of complex epiand sub-retinal membranes. These consist of mixed retinal pigment epithelial, glial, fibroblastic and inflammatory cells in a collagenous extracellular matrix.16–18 Membranes cause retinal distortion and shortening, which can potentially result in re-opening of retinal breaks and recurrent detachment. Redetachment is normally considered the defining event in PVR development. However, degrees of membrane formation may take place without detaching the retina where the combination of retinopexy and surgical release of vitreoretinal traction are sufficient to counteract the re-detaching force produced by PVR membrane formation. Analysis of the results of PVR clinical trials should take account of the possibility of such subclinical disease. It can also be argued that postdetachment macular pucker reflects a lesser degree of the proliferative process where the retina remains attached.

Once PVR is established and the retina re-detaches, progression to extensive retinal detachment and profound visual loss is inevitable. Anatomic (defined as total retinal reattachment) success rates of 90% and 73% have been reported for initial and repeat PVR surgery in uncontrolled series.19,20 Visual results are often poor with 19% and 11% respectively achieving 20/100.19,20 It has been noted that the vision of the fellow eye in PVR cases is frequently threatened. In a retrospective series, 53% had sightthreatening pathology in the fellow eye and 26% of these had final visual acuity of 20/250 or less.21

Question

What is the optimal intraocular tamponade agent in the surgical management of PVR?

The evidence

The Silicone Study analysed the efficacy and complications of intraocular gas and silicone oil tamponade for severe PVR and reported its results in a series of publications.22–33 The Silicone Study was a prospective, randomised, multi-centre surgical trial which evaluated 1000 centistoke (measure of viscosity) silicone oil against (i) sulphur hexafluoride (SF6) and (ii) perfluoropropane (C3F8) gases in eyes undergoing vitrectomy surgery for severe (grade C31 or worse) PVR. The study protocol was revised after two years: SF6 gas was replaced by C3F8 to preserve the clinical relevance of the trial, which ran for a further three years. Cases were divided into those which had (group 1) and those which had not (group 2) undergone previous vitrectomy surgery. Primary outcome measures were anatomical reattachment of the posterior retina (macula) and visual acuity of 5/200 or better. Secondary outcome measures were lens opacification, intraocular pressure abnormalities and corneal damage. The trial recruited a total of 404 patients.

Silicone oil was demonstrated to be a superior tamponade agent to SF6 both in terms of visual acuity (P <0·05) and macular attachment (P <0·05, Chi square analysis). Hypotony was more common in the SF6 group (P <0·05) as was keratopathy (P <0·05 at 6 and 18 months, P <0·01 at 24 months). Silicone oil and C3F8 gas were similar in visual acuity and anatomical outcomes. There was a borderline advantage of C3F8 gas in achieving complete posterior retinal reattachment in group 1 eyes (P = 0·045). No difference was found in keratopathy rates and persistent hypotony was more common in C3F8 treated eyes (P <0·05). The authors concluded that silicone oil and C3F8 gas produced similar outcomes in PVR surgery and both were superior to SF6 gas.

A further prospective randomised controlled trial has analysed the use of silicone oil and C3F8 gas in the management of giant retinal tears complicated by PVR

(grade C2 or worse).34 There were no significant differences in rates of anatomical success, visual acuity or complications. The total number of patients recruited is relatively small (47 cases) and no details of the method of sample size calculation are given.

Comment

The Silicone Study has provided valuable information on the use of tamponade agents in established PVR. However, the relative efficacy of these agents in other areas of vitreoretinal surgery remains uninvestigated. For example, individual surgeons may have strong preferences for intraocular gas or silicone oil in the management of giant retinal tears or complex primary retinal detachments but as yet there is no evidence base to inform surgical decision making. Likewise in the area of posterior segment trauma there is a lack of good information on the optimal tamponading agent.

Question

Can adjunctive agents prevent the occurrence or recurrence of PVR?

The evidence

One large-scale, multi-centre, randomised controlled trial has investigated the potential of an intraocular infusion of the antiproliferative agent daunorubicin to improve the prognosis in surgery for established PVR.35 A total of 286 patients with established PVR grade C2 or greater were recruited and randomised to a 10 minute intraoperative infusion of daunorubicin (7·5 micrograms/ml) or placebo. Patients underwent vitrectomy surgery with silicone oil tamponade. The primary outcome measure, retinal attachment without additional vitreoretinal surgery at six months, showed a trend towards a benefit in the treatment group, which marginally failed to reach significance: 62·7% success in the treatment group, 54·1% in the placebo group (odds ratio 1·43, 95% CI 0·88–2·30). Of the two secondary outcome measures the number of vitreoretinal re-operations within one year was significantly reduced in the treatment group (50 patients v 65 in the control group, P = 0·005, Cochran-Mantel-Haenszel test) and there was no significant difference in visual acuity change between the groups. The authors concluded that there was some benefit of the adjunctive medication and that PVR was amenable to pharmacological treatment.

A prospective, randomised, controlled trial analysed the effect of postoperative irradiation in preventing reproliferation in eyes with established (grade D1–D3) PVR.36 The

numbers recruited are relatively small (30 in each group) and the sample size calculation is not documented. A total dose of 3000 cGy was given in 8–10 applications postoperatively. No significant difference was seen in retinal reattachment rates at six or 14 months. It was concluded that irradiation does not influence the course of PVR, but the study was probably underpowered.

A prospective, randomised pilot study investigated the potential of combined heparin and dexamethasone in the vitrectomy infusion fluid to reduce reproliferation in established PVR.37 The pilot study randomised 62 patients with PVR grade C3 or worse to heparin 100 units/ml and dexamethasone 4 micrograms/ml in balanced salt solution (BSS) infusion fluid or placebo control. The treatment group had a higher anatomical success rate and a lower rate of reproliferation but these results were not statistically significant. There was significantly more postoperative haemorrhage (hyphaema, vitreous haemorrhage) in the treatment group (P = 0·02, Fisher’s exact test).

The potential of adjunctive medication to improve the outcome in patients with retinal detachment at high risk of developing PVR was investigated in a randomised, controlled study of intraoperative infusion of 5-fluorouracil (5FU) and low molecular weight heparin (LMWH) against placebo.38 Patients were selected as high risk on the basis of a previous prospective analysis of known risk factors for PVR.39 The study medications were infused for one hour during vitrectomy at concentrations of 200 micrograms/ml (5FU) and 5 IU/ml (LMWH) in Hartmann’s solution. A total of 174 patients were recruited. The primary outcome measure, development of postoperative PVR, was significantly improved in the treatment group (12·6% v 26·4%, P = 0·02, Wilcoxon rank sum analysis). Secondary outcome measures did not show significant differences between treatment and control groups and there was no difference in complication rates. It was concluded that this treatment regime should be used routinely in patients at risk of PVR.

Implications for practice

The use of a combination of 5-fluorouracil and low molecular weight heparin in patients at high risk of PVR would now appear to have reasonable justification although the use in other situations remains unproven.

Implications for research

Adjunctive treatments have been proposed to improve the success rates of vitreoretinal procedures for over 20 years, particularly to control intraocular proliferation. It is only recently that prospective randomised studies have been

published on the use of adjuncts in PVR.35,38 Various questions are unanswered – other adjunctive agents may be more effective and the range of vitreoretinal conditions that would benefit is uncertain. Improved control of the biological response following vitreoretinal intervention remains a major target of vitreoretinal research.

References

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2.Speicher MA, Fu AD, Martin JP, von Fricken MA. Primary vitrectomy alone for repair of retinal detachments following cataract surgery. Retina 2000;20(5):459–64.

3.Duquesne N, Bonnet M, Adeleine P. Preoperative vitreous haemorrhage associated with rhegmatogenous retinal detachment: a risk factor for postoperative proliferative vitreoretinopathy? Graefe’s Arch Clin Exp Ophthalmol 1996;234(11):677–82.

4.Greven CM, Sanders RJ, Brown GC et al. Pseudophakic retinal detachments. Anatomic and visual results. Ophthalmology 1992;76(2): 257–62.

5.Girard P, Mimoun G, Karpouzas I, Montefiore G. Clinical risk factors for proliferative vitreoretinopathy after retinal detachment surgery. Retina 1994;14(5):417–24.

6.Gartry DS, Chignell AH, Franks WA, Wong D. Pars plana vitrectomy for the treatment of rhegmatogenous retinal detachment uncomplicated by advanced proliferative vitreoretinopathy. Br J Ophthalmol 1993; 77(4):199–203.

7.Bonnet M, Fleury J, Guenoun S, Yaniali A, Dumas C, Hajjar C. Cryopexy in primary rhegmatogenous retinal detachment: a risk factor for postoperative proliferative vitreoretinopathy? Graefe’s Arch Clin Exp Ophthalmol 1996;234(12):739–43.

8.Heimann H, Bornfeld N, Friedrichs W et al. Primary vitrectomy without scleral buckling for rhegmatogenous retinal detachment.

Graefe’s Arch Clin Exp Ophthalmol 1996;234(9):561–8.

9.Chang S. Giant retinal tears: surgical management with perfluorocarbon liquids. In: Lewis H, Ryan SJ (eds). Medical and Surgical Retina: advances, controversies and management. St Louis: Mosby, 1994, pp. 199–207.

10.Chang S, Lincoff H, Zimmerman NJ, Fuchs W. Giant retinal tears. Surgical techniques and results using perfluorocarbon liquids. Arch Ophthalmol 1989;107(5):761–6.

11.Kertes PJ, Wafapoor H, Peyman GA, Calixto N Jr, Thompson H. The management of giant retinal tears using perfluoroperhydrophenanthrene. A multicenter case series. Vitreon Collaborative Study Group. Ophthalmology 1997;104(7):1159–65.

12.Kreiger AE, Lewis H. Management of giant retinal tears without scleral buckling. Use of radical dissection of the vitreous base and perfluoro-octane and intraocular tamponade. Ophthalmology 1992;99 (4):491–7.

13.Verstraeten T, Williams GA, Chang S et al. Lens-sparing vitrectomy with perfluorocarbon liquid for the primary treatment of giant retinal tears. Ophthalmology 1995;102(1):17–20.

14.Cardillo JA, Stout T, LaBree L et al. Post-traumatic proliferative vitreoretinopathy: the epidemiologic profile, onset, risk factors, and visual outcome. Ophthalmology 1997;104:1166–73.

15.Mittra RA, Mieler WF. Controversies in the management of openglobe injuries involving the posterior segment. Surv Ophthalmol 1999;3:215–25.

16.Charteris DG. Proliferative vitreoretinopathy: pathobiology, surgical management and adjunctive treatment. Br J Ophthalmol 1995;79: 953–60.

17.Pastor JC. Proliferative vitreoretinopathy: an overview. Surv Ophthalmol 1998;43(1):3–18.

18.Campochiaro PA. Pathogenic mechanisms in proliferative vitreoretinopathy. Arch Ophthalmol 1997;115(2):237–41.

19.Lewis H, Aaberg TM, Abrams GW. Causes of failure after initial vitreoretinal surgery for severe proliferative vitreoretinopathy. Am J Ophthalmol 1991;111:8–14.

20.Lewis H, Aaberg TM. Causes of failure after repeat vitreoretinal surgery for recurrent proliferative vitreoretinopathy. Am J Ophthalmol 1991;111:15–19.

21.Schwartz SD, Kreiger AE. Proliferative vitreoretinopathy: a natural history of the fellow eye. Ophthalmology 1998;105:785–8.

22.Azen SP, Boone DC, Barlow W et al. and The Silicone Study Group. Methods, statistical features, and baseline results of a standardized, multicentered ophthalmologic surgical trial: The Silicone Study.

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23.The Silicone Study Group. Vitrectomy with silicone oil or sulfur hexafluoride gas in eyes with severe proliferative vitreoretinopathy: results of a randomized clinical trial. Silicone Study Report 1. Arch Ophthalmol 1992;110:770–9.

24.The Silicone Study Group. Vitrectomy with silicone oil or perfluoropropane gas in eyes with severe proliferative vitreoretinopathy: results of a randomized clinical trial. Silicone Study Report 2. Arch Ophthalmol 1992;110:780–92.

25.McCuen BW, Azen SP, Stern W et al. and The Silicone Study Group. Vitrectomy with silicone oil or perfluoropropane gas in eyes with severe proliferative vitreoretinopathy. Silicone Study Report 3. Retina 1993;13:279–84.

26.Barr CC, Lai MY, Lean JS et al. and The Silicone Study Group. Postoperative intraocular pressure abnormalities in the Silicone Study. Silicone Study Report 4. Ophthalmology 1993;100:1629–35.

27.Blumenkranz MS, Azen SP, Aaberg T et al. and The Silicone Study Group. Relaxing retinotomy with silicone oil or long-acting gas in eyes with severe proliferative vitreoretinopathy. Silicone Study Report 5. Am J Ophthalmol 1993;116:557–64.

28.Hutton WL, Azen SP, Blumenkranz MS et al. for The Silicone Study Group. The effects of silicone oil removal. Silicone Study Report 6.

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29.Abrams GW, Azen SP, Barr CC et al. and The Silicone Study Group. The incidence of corneal abnormalities in the Silicone Study. Silicone Study Report 7. Arch Ophthalmol 1995;113:764–9.

30.Cox MS, Azen SP, Barr CC et al. for The Silicone Study Group. Macular pucker after successful surgery for proliferative vitreoretinopathy. Silicone Study Report 8. Ophthalmology 1995;102:1884–91.

31.Lean J, Azen SP, Lopez PF, Qian D, Lai MY, McCuen B for The Silicone Study Group. The prognostic utility of the Silicone Study classification system. Silicone Study Report 9. Arch Ophthalmol 1996;114:286–92.

32.Diddie KR, Azen SP, Freeman HM et al. for The Silicone Study Group. Anterior proliferative vitreoretinopathy in the Silicone Study. Silicone Study Report 10. Ophthalmology 1996;103:1092–9.

33.Abrams GW, Azen SP, McCuen BW, Flynn HW, Lai MY, Ryan SJ for The Silicone Study Group. Vitrectomy with silicone oil or long-acting gas in eyes with severe proliferative vitreoretinopathy: results of additional and long-term follow-up. Silicone Study Report 11. Arch Ophthalmol 1997;115:335–44.

34.Batman C, Çekiç O. Vitrectomy with silicone oil or long-acting gas in eyes with giant retinal tears: long-term follow-up of a randomized clinical trial. Retina 1999;19:188–92.

35.Wiedemann P, Hilgers RD, Bauer P, Heimann K. Adjunctive daunorubicin in the treatment of proliferative vitreoretinopathy: results of a multicenter clinical trial. Am J Ophthalmol 1998;126:550–9.

36.Binder S, Bonnet M, Velikay M et al. Radiation therapy in proliferative vitreoretinopathy: a prospective randomized study.

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37.Williams RG, Chang S, Comaratta MR, Simoni G. Does the presence of heparin and dexamethasone in the vitrectomy infusate reduce reproliferation in proliferative vitreoretinopathy? Graefe’s Arch Clin Exp Ophthalmol 1996;234:496–503.

38.Asaria RHY, Kon CH, Bunce C et al. Adjuvant 5-fluorouracil and heparin prevents proliferative vitreoretinopathy: results from a randomized, double-blind, controlled clinical trial. Ophthalmology 2001;108:1179–83.

39.Kon CH, Asaria RH, Occleston NL, Khaw PT, Aylward GW. Risk factors for proliferative vitreoretinopathy after primary vitrectomy: a prospective study. Br J Ophthalmol 2000;84:506–11.