Vitrectomy for diabetic retinopathy

Background

Diabetic retinopathy is the commonest cause of blind registration in working age in the western world. Blindness in diabetic patients generally occurs by one of two pathological mechanisms.

Proliferative diabetic retinopathy is characterised by the growth of extraretinal new blood vessels. These vessels are prone to rupture (causing vitreous haemorrhage) or act as foci for traction on the retina, leading to retinal detachment. These pathological processes may render photocoagulation ineffective or impossible (advanced diabetic eye disease). Blindness may also occur due to diabetic maculopathy, which is characterised by a microangiopathy affecting the macula with visual loss due the effects of leakage and ischaemia. The exact proportion of patients progressing to sight-threatening retinopathy is dependent on type of diabetes and duration of disease.1,2

Vitrectomy for proliferative diabetic retinopathy was proposed in 1971.3 The rationale of the treatment was to improve vision by clearing the visual axis of blood and removing membranes from the surface of the retina that might distort or detach it. One problem with approaching the evidence in support of vitrectomy is the rapid rate of technical advance. Vitreoretinal instruments and surgical techniques have been constantly refined since Machemer first advocated vitrectomy,3 so that the common surgical practice now is not that of 30 years ago. Particularly important in this respect is the development of fluid–gas exchange techniques to reattach the retina hydraulically, the advent of endolaser probes allowing peroperative laser and the development of special instruments for the excision of fibrovascular scars.

Four questions will be addressed by this review of the evidence:

●Does early vitrectomy reduce the chance of visual loss in eyes with advanced diabetic eye disease with poor vision due to vitreous haemorrhage?

●Does early vitrectomy reduce the chance of visual loss in eyes with advanced diabetic eye disease and useful vision?

●Is vitrectomy beneficial in eyes with diabetic maculopathy?

●Can any adjunctive treatment reduce the risk of surgical complications?

Question

Does early vitrectomy reduce the chance of visual loss in eyes with advanced diabetic eye disease with poor vision due to vitreous haemorrhage?

The evidence

Untreated, advanced diabetic eye disease has a high risk of severe visual loss.4 We found one multi-centre randomised control trial with a total of 600 eyes.5 The Diabetic Retinopathy Vitrectomy Study (DRVS) was a multicentre randomised control trial that studied three groups of patients. Group H consisted of eyes with severe vitreous haemorrhage of less than six months’ duration reducing visual acuity to 5/200 or less. Principal exclusion criteria included photocoagulation in the three months prior to randomisation, severe iris neovascularisation and retinal detachment affecting the macula. Patients with age of onset of diabetes prior to age 20 were classified as type I while those with onset after age 40 were classified as being type II (those with intermediate age of onset being assigned to an intermediate group). Patients were randomly assigned to immediate vitrectomy or deferral for one year. Patients in the deferral group received further photocoagulation at the discretion of the clinician, while patients in the immediate vitrectomy group did not receive photocoagulation during surgery and only received postoperative photocoagulation for rubeosis or for severe and progressive retinal neovascularisation after discussion with the trial coordinators.

The principal outcomes were best corrected visual acuity at two and four years after randomisation. Visual acuity of 10/20 at two years was found in 62 of 253 eyes with early vitrectomy and 37 of 244 eyes in the deferral group (relative risk (RR) of achieving 10/20 1·61, 95% CI 1·1–2·3; number needed to treat (NNT) for benefit 11, 95% CI 7–43). This beneficial effect was more apparent in type I patients (RR of achieving 10/20 3, 95% CI 1·7–5·5); than type II (RR of achieving 10/20 0·87, 95% CI 0·4–1·74). There was no significant difference in the numbers of patients with no

There have been significant technical advances since the DRVS study was carried out. These are likely to have reduced the complication rate of vitrectomy for diabetic retinopathy and increased the benefit from early surgery. The benefits were confined to type I patients who were more likely to have adhesions between the retina and vitreous. A relatively high proportion of eyes in both groups lost perception of light. Rubeotic glaucoma was a significant cause of visual loss after vitrectomy in this study but is seldom seen since the advent of retinal endolaser, so it is possible that the beneficial effect of early vitrectomy would be more marked if the trial were repeated today.

Question

Does early vitrectomy reduce the chance of visual loss in eyes with advanced diabetic eye disease and useful vision?

The evidence

We found no published randomised controlled trials regarding the efficacy of vitrectomy for diabetic macular oedema.7,8

Comment

The current clinical understanding regarding vitrectomy for diabetic macular oedema is that patients fall into four groups. This classification may not, however, stand the test of time. The aim of this review is to identify potentially pertinent subgroups of patients with diabetic macular oedema and to provide a framework against which future publications might be assessed.

Group 1: Patients with clinically identifiable vitreo-retinal traction

The evidence

We found one multi-centre randomised control trial with a total of 370 patients: group P in the DRVS study.6 Patients with advanced preretinal fibrovascular proliferation and best corrected visual acuity of 10/200 or better were eligible – significant exclusion criteria were as for group H of the study (see above). Patients were randomly allocated to early vitrectomy with removal of preretinal membranes or deferral of vitrectomy until retinal detachment or severe vitreous haemorrhage developed. The protocol for photocoagulation was similar to that in the vitreous haemorrhage arm of the study (see above).

The principal outcomes were best corrected visual acuity at four years after randomisation. Visual acuity of 10/20 was found in 64 of 145 eyes with early vitrectomy and 39 of 138 eyes in the deferral group (P = 0·008; RR of achieving 10/20 1·56, 95% CI 1·13–2·1; NNT for benefit 7, 95% CI 4 harm–22 benefit). The investigators state that the type of diabetes did not seem to exert an independent effect on visual outcome. There was no significant difference in the numbers of patients with no perception of light between the two groups at two years (RR 1·2, 95% CI 0·76–1.9, P = 0·51).

Comment

Most of the comments relating to the evidence for early vitrectomy for severe vitreous haemorrhage can equally be applied to eyes with useful vision undergoing vitrectomy.

This group includes patients with epiretinal membranes, fibrovascular tissue resulting from proliferative diabetic retinopathy in the absence of a tractional detachment, vitreous haemorrhage and those with frank tractional detachments. There are only scant uncontrolled data relating to 36 patients on this very diverse group.9,10 A potential treatment effect has been reported. The dearth of data means that it is not possible to draw even preliminary conclusions regarding the role of vitrectomy in this group. The heterogeneous nature of this group of patients also makes it difficult to envisage randomised trials.

Group 2: Patients with a taut thickened posterior hyaloid

Patients in this group demonstrate an exaggerated glistening premacular hyaloid membrane, which is occasionally thick enough to preclude laser.11 The premacular vitreous has a hammered appearance but there are no signs of retinal striae or tractional detachment. Angiography may demonstrate a deep diffuse leak with prominent cystoid oedema.12 Uncontrolled data regarding vitrectomy on 112 eyes fulfilling this definition have been reported.10,11,13–17 Overall, oedema resolved in 61% and acuity improved in 75%. Recent investigations using Optical Coherence Tomography (OCT), suggest that vitreo-retinal microtraction may be important in patients with a taut thickened posterior hyaloid (TTPH).12,18 OCT also provides a reliable objective quantification of macular thickness.19 Accordingly, any randomised controlled trials (RCTs) of this subject should

include OCT quantification of macular thickness as well as qualitative assessment of the vitreo-retinal interface.

Group 3: Patients with no retinal traction and no clinically apparent posterior vitreous detachment

These patients may well constitute the most commonly encountered group in clinical practice. The literature contains uncontrolled reports of surgery on 114 patients.20–23 The studied populations have also been ethnically diverse and a variety of different outcome measures and follow up durations have been employed in a non-systematic fashion. The reported data suggest an acuity benefit from vitrectomy. Rates of oedema resolution were, however, highly variable and recurrence has been observed.21 Randomised trials are clearly required in this area and OCT is likely to form an important part of patient assessment.20,21,24

Group 4: Eyes with a posterior vitreous detachment

There are published uncontrolled data regarding the results of vitrectomy in 20 patients.10,25 These data are insufficient to allow even preliminary conclusions to be drawn.

Summary

Carefully planned and systematically reported randomised trials, which incorporate technical measures of outcome such as acuity and macular thickness as well as qualitative assessments such as OCT vitreo-retinal interface assessment, are required. The costs and inherent risk of vitrectomy might be expected to be greater than those of macular laser. Accordingly, both economic and quality of life assessments will be important.

Question

Can any adjunctive treatment reduce the risk of surgical complications?

The evidence

A number of measures have been proposed to make vitrectomy in diabetic patients easier to perform and to reduce the risk of iatrogenic complications, and some of these have been the subjects of small clinical trials.

Insertion of a gas tamponade at the end of surgery has been the subject of two clinical trials,26,27 the rationale being that the presence of air at the bleeding site may promote haemostasis. Koutsandrea et al.26 investigated the effect of an intravitreal bubble of sulphur hexafluoride (SF6)

gas in an RCT of 33 patients undergoing vitrectomy for diabetic eye disease. The major outcome measure was the incidence of postoperative vitreous haemorrhage. The authors reported no reduction in the incidence of postoperative vitreous haemorrhage (RR of haemorrhage with SF6 1·41, 95% CI 0·31–6·49). Joondeph et al.27 performed a similar study using air, which is resorbed more quickly, with similar findings (RR of haemorrhage with air 1·41, 95% CI 0·87–2·2). Both of these studies noted some evidence of harm in the form of a greater incidence of lens opacity with gas (RR of cataract with SF6 1·64, 95% CI 0·62–4·57; RR of cataract with air 1·95, 95% CI 0·86–4·5).

Two trials have studied the effect of procoagulants to reduce bleeding. Packer et al.28 performed an RCT on 26 patients undergoing vitrectomy for diabetic eye disease.

These eyes were randomly allocated to receiving intravitreal injections of sodium hyaluronate or saline at the end of surgery. There was a significant difference between the two groups (RR of opaque media 0·54, 95% CI 0·28–0·9 with sodium hyaluronate, P = 0·016; NNT 3 for benefit). This benefit had disappeared at two weeks. Thompson et al.29 performed a prospective double-blind study on the effect of the addition of thrombin to the infusate on the bleeding time of severed neovascular stalks. Twenty-eight patients undergoing vitrectomy for diabetic eye disease were studied. The authors reported a significantly reduced bleeding time (12 seconds compared to 111 seconds) in patients receiving thrombin. This study included some nonrandomised patients in its analysis, the report includes few raw data and a significant proportion of the thrombintreated patients developed intraocular inflammation.

There has been much interest in the possibility of chemically removing the vitreous. Tissue plasminogen activator (TPA) converts plasminogen to plasmin which, in addition to its fibrinolytic role, is thought to dissolve the structural proteins at the vitreoretinal interface, thereby facilitating surgical dissection. Le Mer et al.30 randomised 56 patients undergoing vitrectomy for diabetic eye disease to adjunctive TPA or placebo. There was no significant difference between the two groups in either of the two main outcomes studied: retinal breaks (RR 0·93, 95% CI 0·41– 2·1) and retinal detachment (RR 0·93, 95% CI 0·41–2·1). The authors felt that the TPA might not have had enough time to work and considerable interest remains in this area.

Implications for practice

There is a good evidence base for consideration of early vitrectomy in diabetic patients with vitreous haemorrhage and with active fibrovascular proliferation. The procedure still has a significant complication rate, but development of

new surgical approaches and treatment adjuncts are likely in the future. Vitrectomy for diabetic maculopathy is an attractive treatment option because maculopathy is a significant cause of visual loss in diabetic patients and existing treatment has limited therapeutic effect. Clinical trials are underway but to date there is no evidence base supporting this intervention.

Implications for research

There has been a recent explosion in interest in the potential for vitrectomy in diabetic retinopathy and in particular in its use as an alternative to laser in the management of diabetic maculopathy. Carefully planned and systematically reported randomised trials, which incorporate technical measures of outcome such as acuity and macular thickness as well as qualitative assessments such as OCT vitreo-retinal interface assessment, are required. Surgery should also be compared to other emerging treatments such as intravitreal triamcinolone injection or sustained release steroid implants. The financial costs and inherent risk of vitrectomy might be expected to be greater than those of macular laser or drug injection. Accordingly, both economic and quality of life assessments will be important.

References

1.Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin Epidemiologic Study of diabetic retinopathy III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 1984;102:527–32.

2.Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin Epidemiologic Study of diabetic retinopathy II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 1984;102:520–6.

3.Machemer R, Buettner H, Norton EW, Parel JM. Vitrectomy: a pars plana approach. Trans Am Acad Ophthalmol Otolaryngol 1971;75: 813–20.

4.The Diabetic Retinopathy Vitrectromy Study Research Group. Two year course of visual acuity in severe proliferative diabetic retinopathy with conventional management. Ophthalmology 1985;92:492–502.

5.The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Two-year results of a randomized trial. Diabetic Retinopathy Vitrectomy Study Report 2. Arch Ophthalmol 1985;103:1644–52.

6.The Diabetic Retinopathy Vitrectomy Study Research Group. Early Vitrectomy for Severe Proliferative Diabetic Retinopathy in Eyes with Useful Vision. Results of a Randomised Trial – Diabetic Retinopathy Study Report 3. Ophthalmology 1988;5:1307–20.

7.Lewis H. The role of vitrectomy in the treatment of diabetic macular edema. Am J Ophthalmol 2001;131:123–5.

8.Capone A, Jr, Panozzo G. Vitrectomy for refractory diabetic macular edema. Semin Ophthalmol 2000;15:78–80.

9.Hoerle S, Poestgens H, Schmidt J, Kroll P. Effect of pars plana vitrectomy for proliferative diabetic vitreoretinopathy on preexisting diabetic maculopathy. Graefe’s Arch Clin Exp Ophthalmol

2002;240:197–201.

10.Yamamoto T, Akabane N, Takeuchi S. Vitrectomy for diabetic macular edema: the role of posterior vitreous detachment and epimacular membrane. Am J Ophthalmol 2001;132:369–77.

11.Pendergast SD, Hassan TS, Williams GA et al. Vitrectomy for diffuse diabetic macular edema associated with a taut premacular posterior hyaloid. Am J Ophthalmol 2000;130:178–86.

12.Kaiser PK, Riemann CD, Sears JE, Lewis H. Macular traction detachment and diabetic macular edema associated with posterior hyaloidal traction. Am J Ophthalmol 2001;131:44–9.

13.Harbour JW, Smiddy WE, Flynn HW, Jr, Rubsamen PE. Vitrectomy for diabetic macular edema associated with a thickened and taut posterior hyaloid membrane. Am J Ophthalmol 1996;121:405–13.

14.Gandorfer A, Messmer EM, Ulbig MW, Kampik A. Resolution of diabetic macular edema after surgical removal of the posterior hyaloid and the inner limiting membrane. Retina 2000;20:126–33.

15.Abrams GW, Blumenkranz MS, Campo RV. Vitrectomy for diabetic macular traction and edema associated with posterior hyaloidal traction. Ophthalmology 1992;99:753–9.

16.Pendergast SD. Vitrectomy for diabetic macular edema associated with a taut premacular posterior hyaloid. Curr Opin Ophthalmol 1998;9:71–5.

17.van Effenterre G, Guyot-Argenton C, Guiberteau B, Hany I, Lacotte JL. [Macular edema caused by contraction of the posterior hyaloid in diabetic retinopathy. Surgical treatment of a series of 22 cases]. J Fr Ophtalmol 1993;16:602–10.

18.Giovannini A, Amato GP, Mariotti C, Ripa E. Diabetic maculopathy induced by vitreo-macular traction: evaluation by optical coherence tomography (OCT). Doc Ophthalmol 1999;97:361–6.

19.Massin P, Vicaut E, Haouchine B, Erginay A, Paques M, Gaudric A. Reproducibility of retinal mapping using optical coherence tomography. Arch Ophthalmol 2001;119:1135–42.

20.Otani T, Kishi S. Tomographic assessment of vitreous surgery for diabetic macular edema. Am J Ophthalmol 2000;129:487–94.

21.Duguid G, Massin P, Haouchine B, Erginay A, Gaudric A. Vitrectomy for Diabetic Macular Oedema: the effect on visual acuity and optical coherence tomography appearances. Assoc Res Vis Ophthalmol Abstracts 2000:Abstract no. 585.

22.Ikeda T, Sato K, Katano T, Hayashi Y. Vitrectomy for cystoid macular oedema with attached posterior hyaloid membrane in patients with diabetes. Br J Ophthalmol 1999;83:12–14.

23.La Heij EC, Hendrikse F, Kessels AG, Derhaag PJ. Vitrectomy results in diabetic macular oedema without evident vitreomacular traction.

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24.Patel JI, Cree IA, Gregor ZJ, Boulton ME, Hykin PG. Vascular Endothelial Growth Factor and diabetic macular edema. Assoc Res Vis Ophthalmol Abstracts 2001:Abstract no. 3974.

25.Ikeda T, Sato K, Katano T, Hayashi Y. Improved visual acuity following pars plana vitrectomy for diabetic cystoid macular edema and detached posterior hyaloid. Retina 2000;20:220–2.

26.Koutsandrea CN, Apostolopoulos MN, Chatzoulis DZ, Parikakis EA, Theodossiadis GP. Hemostatic effects of SF6 after diabetic vitrectomy for vitreous hemorrhage. Acta Ophthalmol Scand 2001;79:34–8.

27.Joondeph BC, Blankenship GW. Hemostatic effects of air versus fluid in diabetic vitrectomy. Ophthalmology 1989;96:1701–6.

28.Packer AJ, McCuen BW 2nd, Hutton WL, Ramsay RC. Procoagulant effects of intraocular sodium hyaluronate (Healon) after phakic diabetic vitrectomy. A prospective, randomized study. Ophthalmology 1989;96:1491–4.

29.Thompson JT, Glaser BM, Michels RG et al. The use of intravitreal thrombin to control hemorrhage during vitrectomy. Ophthalmology 1986;93:279–82.

30.Le Mer Y, Korobelnik JF, Morel C, Ullern M, Berrod JP. TPA-assisted vitrectomy for proliferative diabetic retinopathy: results of a doublemasked, multicenter trial. Retina 1999;19:378–82.

This section on evidence-based neuro-ophthalmology focuses on acquired optic neuropathies. These diseases are important, firstly from the standpoint of accurate diagnosis of more generalised neurological conditions, and secondly from the point of view of the ophthalmologist’s duty to try to optimise management to prevent avoidable and devastating neural blindness. All the topics which have been selected

have attracted some controversy in recent years. Some are surgical (CSF diversion surgery for visual failure complicating papilloedema and traumatic optic neuropathy). Others are medical (optic neuritis, ischaemic optic neuropathy and toxic optic neuropathies). However, they share the emphasis on the need for well informed and well timed interventions to try to improve visual outcomes in these disorders.