DIABETES/METABOLISM RESEARCH AND REVIEWS Diabetes Metab Res Rev 1999; 15: 373377.

CLINICAL CHALLENGES IN DIABETES

Treatment of Severe Proliferative Retinopathy and Diabetic Maculopathy

Cheong G. Ooi Kevin J. Hardy*
Department of Diabetes and Endocrinology, Whiston Hospital, Prescot, Merseyside L35 5DR, UK *Correspondence to: Department of Diabetes and Endocrinology, Whiston Hospital, Prescot, Merseyside L35 5DR, UK E-mail: Kevin.Hardy@gwise. sthkh-tr.nwest.nhs.uk

Summary
Strict blood glucose control, early detection and surveillance of diabetic retinopathy by means of validated screening programmes, and judicious use of laser photocoagulation can greatly reduce the risk of visual loss in diabetes. Some patients however, have aggressive neovascular disease resistant to laser treatment, or present at a late stage with advanced broproliferative disease, and may progress rapidly to blindness. In the elderly with Type 2 disease, diabetic maculopathy is more common and requires a different therapeutic approach. The present article describes two diabetic patients and discusses the management of patients with severe proliferative retinopathy or diabetic maculopathy. Copyright # 1999 John Wiley & Sons, Ltd. Keywords diabetes mellitus; laser photocoagulation; maculopathy; proliferative retinopathy; vitrectomy

Background
Sight-threatening diabetic retinopathy is common in clinical practice. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), prevalence of proliferative retinopathy after 15 years of diabetes was 23% in those with onset of diabetes before 30 years of age [1], and varied between 3 and 14% in older-onset patients, depending on whether they were treated with oral hypoglycaemic agents or insulin, respectively [2]. Clinically signicant macular oedema (CSME) was more prevalent in older-onset insulin-treated patients, rising from 5%, 2 years after diagnosis to 15%, after 15 years of diabetes [3]. In the Diabetic Retinopathy Study (DRS), 26% of untreated eyes with new vessels and vitreous haemorrhage developed severe visual loss (visual acuity (VA) 1/60 or worse) within 2 years [4]. In the Early Treatment Diabetic Retinopathy Study (ETDRS), untreated macular oedema with preproliferative retinopathy or early proliferative retinopathy was associated with a 30% 5-year risk of moderate visual loss (decreased visual acuity by two or more lines), and 5% 5-year risk of severe visual loss [5]. Laser photocoagulation reduces the risk of severe visual loss by at least 50% in both broproliferative disease [4] and maculopathy [5,6]. In a minority of patients, however, aggressive disease resistant to laser therapy, early involvement of the centre of the fovea, or late presentation with established vitreous haemorrhage or traction retinal detachment are associated with poor visual outcome. It is salutary to note that despite treatment, 26% of eyes with severe proliferative retinopathy progress inexorably to severe visual loss within 4 years [7], and 13% of eyes with CSME involving the centre of the macula suffer signicant visual loss at 3 years [6]. In this article, illustrated by two case reports, we discuss the main therapeutic options that are available for the treatment of these challenging patients with aggressive or advanced broproliferative retinopathy or diabetic maculopathy.
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Case histories
Patient 1
A 39-year old woman with Type 1 diabetes of 25 years duration was found to have preproliferative retinopathy in both eyes (microaneurysms, blot haemorrhages, cotton wool spots and intraretinal microvascular abnormalities (IRMAs)) at annual eye examination. She was asymptomatic and visual acuity (VA) was 6/4 in both eyes. She had been treated with twice daily insulin, and average HbA1c over the preceding ve years was 8.6% (normal range 4.66.2%). Six months later, she had developed new vessels in her left eye and underwent panretinal photocoagulation (PRP). Despite this treatment, her disease progressed and she developed extensive new vessels in both eyes. She was treated with intensive fractionated PRP to both eyes, but two months later noticed a `oater' in her left eye and was found to have a large left preretinal haemorrhage with traction retinal detachment. The new vessels in the right eye had regressed. Further PRP was administered to the left eye, but despite this, she developed a large vitreous haemorrhage and her vision deteriorated (VA 6/18). In view of the aggressive nature of her eye disease and the poor response to laser therapy, she was referred to a retinal surgeon and underwent left pars plana vitrectomy with endolaser therapy. Her vision improved after two months (VA 6/6), and her retinopathy has remained quiescent for 2 years without further treatment.

not been investigated. She had background diabetic retinopathy on initial assessment and HbA1c was 8.4%. She did not receive annual eye checks and 4 years later, she complained of poor vision in her left eye. Early cataract and preproliferative retinopathy were present in the right eye, and circinate maculopathy was observed with exudates surrounding and within one disc diameter of the fovea on the left (VA right 6/6, VA left 6/18). Slit lamp biomicroscopy conrmed the presence of clinically signicant macular oedema on the left and uorescein angiography revealed diffuse capillary leakage. She underwent PRP to the right eye and macular grid laser to the left. Her hypertension was treated aggressively (reduced from 172/92 mm Hg to 140/64 mm Hg) and she was prescribed a statin for hypercholesterolaemia, resulting in an improvement in total cholesterol from 7.2 mmol/l to 5.8 mmol/l. Glycaemic control was achieved with standard doses of glicazide and at her latest assessment, HbA1c was 6.8%. Three years later, her right eye remains quiescent with normal visual acuity, and after early deterioration following the laser therapy, vision in her left eye has stabilised at 6/24, with almost complete resolution of the exudates.

Discussion
Only a minority of patients with broproliferative disease do not respond to PRP [7,8]. Patient 1 illustrates the potential value of timely vitrectomy in such patients. Pars plana vitrectomy is a closed procedure in which microsurgical instruments inserted into the vitreous cavity via the pars plana, an area just lateral to the corneoscleral junction, are used to remove vitreous haemorrhage, divide and remove epiretinal membranes, attach retinal detachments and perform intraoperative laser photocoagulation (endolaser) (Figure 1). Vitrectomy is thought

Patient 2
A 58-year old woman was diagnosed as having Type 2 diabetes during investigation for recurrent candidal infection. Six years earlier, glycosuria had been noted at the time of a day-case surgical procedure, but had

Figure 1. Pars plana vitrectomy. A three port approach is used; allowing the infusion of saline to maintain intraocular pressure, illumination by a light source and microsurgical instrumentation. Reprinted from Textbook of Diabetes, 2nd Edn, Pickup JC and Williams G (eds), 1997, by permission of the publisher Blackwell Science Ltd
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Figure 2. Age related shrinkage of the vitreous humour, resulting in separation of vitreous and retina leaving a uid lled space

to work in several ways. Haemorrhage obscuring light from the retina can obviously be removed, but in addition, removal of the vitreous humour eliminates the framework used as scaffolding by new vessels which grow forward up out of the retina into the vitreous humour. In the absence of this supporting framework, new vessels cannot ourish and neovascularisation is often aborted. Moreover, as a normal feature of ageing (Figure 2), or as a result of contraction of broproliferative tissue extending between retina and vitreous, the vitreous humour may separate from the retina behind. Ordinarily, this has little if any adverse effect on vision, but when the vitreous humour is attached to the retina by new vessels or brous tissue, separation of vitreous and retina may not occur and instead the retina may become detached

from its underlying neural tissue (Figures 3 and 4). Such tractional retinal detachment often leads to severe visual loss. Surgical removal of the vitreous humour prevents this process of tractional retinal detachment and existing tears may be repaired at operation. Finally, removal of the vitreous humour is thought to remove a means by which growth factors diffuse from one area of retina to another, reducing the concentration of growth factors at any one point in the retina and thus diminishing the stimulus to further neovascularisation. It is believed that the increased incidence of corneal neovascularisation, rubeosis iridis, following vitrectomy is also a consequence of the altered diffusion of growth factors, with greater exposure of the anterior compartment to growth factors following removal of the vitreous barrier. The Diabetic Retinopathy Vitrectomy Study (DRVS) compared early vitrectomy to laser photocoagulation (with vitrectomy only if retinal detachment involved the macula); in patients with severe proliferative retinopathy who had VA 3/60 or better [9]. After 4 years, early vitrectomy resulted in 44% of patients with good vision (VA 6/12 or better) compared with 28% in the conventionally managed group. The greatest benet was to patients with the most severe and extensive proliferative changes. In the ETDRS, in patients who required vitrectomy for vitreous haemorrhage and/or retinal detachment, vitrectomy was similarly effective at preserving good vision [8]. The DRVS investigators also examined benets of early vitrectomy in severe vitreous haemorrhage where visual acuity was less than 1/60 [10,11]. In the rst 12 months, recovery of useful vision (6/60 or better) was more rapid in those undergoing early vitrectomy, but no signicant difference was found after 24 months. Benet was greatest (recovery to VA 6/12 or better) in patients with Type 1 diabetes undergoing early vitrectomy (36%

Figure 3. As a result of broproliferative disease, retina and vitreous humour are attached by brovascular ingrowths. Age related shrinking of the vitreous and/or contraction of broproliferative tissue extending between retina and vitreous, leads to vitreous haemorrhage, preretinal haemorrhage and traction retinal detachment
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Figure 4. Advanced diabetic eye disease with preretinal haemorrhage and retinal detachment (top left), vitreous haemorrhage (left), new vessels arising from the optic disc and extensive brosis (bottom)

Figure 5. Extensive circinate maculopathy

vs. 12%) and the procedure was not helpful to older patients with Type 2 diabetes. The difference in outcome between patient groups may have been associated with better pre-treatment macular function in the patients with Type 1 diabetes, or possibly disease of greater severity in the Type 2 groups. The investigators concluded that in elderly diabetic patients with severe vitreous haemorrhage, deferral of vitrectomy was preferable unless there was poor spontaneous clearing of vitreous haemorrhage. In summary, vitrectomy can be highly effective in preventing visual loss in patients with aggressive proliferative retinopathy which is resistant to PRP, though up to 30% may progress to severe visual loss or blindness, and so timely intervention is essential [9,11]. As in patient 2, 20% of Type 2 patients will have some degree of retinopathy at diagnosis [2,12] and diabetic maculopathy is more common in this group [3]. Studies based on retinopathy status suggest that median duration of diabetes before diagnosis may be as long as 8 years [13]. This case also illustrates the potential dangers of inadequate follow-up of Type 2 patients with so-called `mild' diabetes. Diabetic maculopathy causes gradual and largely irreversible loss of central vision. It is caused by oedema leaking from capillaries and/or ischaemia due to capillary loss. Visual loss is largely due to disruption of the fovea and perifoveal neuro-retina and may be ameliorated by appropriate macular photocoagulation [5,6,14]. Optimal management depends upon detection and treatment of oedema before the fovea is involved. Focal maculopathy, areas of focal leakage usually at the centre of exudative rings (Figure 5), may respond to direct focal treatment using a 50100 mm beam. The most frequently used wavelengths are 514 nm (green) or 810 nm (from an infrared diode laser). Blue/green argon laser is avoided close to the fovea because the blue component is absorbed by the xantophyll pigment over
Copyright # 1999 John Wiley & Sons, Ltd.

the parafoveal area and can cause nerve bre layer damage leading to parafoveal scotomata [15]. Blue laser has been abandoned because of potential damage to users [16]. More diffuse leakage responds better to a grid laser, in which 100200 mm burns are delivered in a grid pattern over the central macula avoiding the fovea itself (Figures 6 and 7). Sometimes post-laser oedema may result in a deterioration in vision which may be temporary or occasionally irreversible. Maculopathy unresponsive to grid laser photocoagulation may benet from vitrectomy with removal of the

Publisher's Note: Permission to reproduce this image online was not granted by the copyright holder. Readers are kindly requested to refer to the printed version of this article.

Figure 6. Retinal burns following pan-retinal photocoagulation sparing the area within the vascular arcades. Reprinted from A colour Atlas of the Eye and Systemic Disease, Kritzinger E and Wright B, 1989, by permission of the publisher Mosby
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References
1. Klein R, Klein BEK, Moss SE, et al. 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; 520526. 2. Klein R, Klein BEK, Moss SE, et al. 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; 527532. 3. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: IV. Diabetic macular edema. Ophthalmology 1984; 91; 14641474. 4. Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of diabetic retinopathy study (DRS) ndings, DRS report number 8. Ophthalmology 1981; 88: 583600. 5. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy. ETDRS Report no. 9. Ophthalmology 1991; 98: 766785. 6. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: ETRDS Report no. 4. Int Ophthalmol Clin 1987; 27: 265272. 7. Diabetic Retinopathy Study Research Group. Indications for photocoagulation treatment of diabetic retinopathy: DRS Report no. 14. Int Ophthalmol Clin 1987; 27: 239253. 8. Early Treatment Diabetic Retinopathy Study Research Group. Pars plana vitrectomy in the Early Treatment Diabetic Retinopathy Study. ETDRS Report no. 17. Ophthalmology 1992; 99: 13511357. 9. Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. Results of a randomized trial DRVS Report 3. Ophthalmology 1988; 95: 13071320. 10. Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous haemorrhage in diabetic retinopathy. Two-year results of a randomized trial. DRVS Report 2. Arch Ophthalmol 1985; 103: 16441652. 11. Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous haemorrhage in diabetic retinopathy. Four-year results of a randomized trial. DRS Report 5. Arch Ophthalmol 1990; 108: 958964. 12. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with Type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837853. 13. Thompson TJ, Engelgau MM, Hegazy M, et al. The onset of NIDDM and its relationship to clinical diagnosis in Egyptian adults. Diabet Med 1996; 13: 337340. 14. British Multicenter Study Group. Photocoagulation for diabetic maculopathy. Diabetes 1983; 32: 10101016. 15. Olk RJ. Modied grid argon (blue-green) laser photocoagulation for diffuse diabetic macular edema. Ophthalmology 1986; 93: 938950. 16. Hardy KJ, Lipton J, Foster DH, Scarpello JH. Laser safety and ophthalmologists. Lancet 1991; 338: 1338. 17. Takagi H, Otani A, Kiryu J, Ogura Y. New surgical approach for removing massive foveal hard exudates in diabetic macular edema. Ophthalmology 1999; 106: 249256. 18. The Diabetes Control and Complication Trial. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977986. 19. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in Type 2 diabetes. UKPDS 38. BMJ 1998; 317: 703713.

Figure 7. Macular grid photocoagulation is directed around the macula, avoiding the foveola, in contrast to PRP (see Figure 6). Reprinted from Management of Diabetic Retinopathy, Hamilton AMP, Ulbig M, Polkinghorne P, 1996, with permission of the publisher BMJ Books

attached posterior hyaloid face, as may patients with maculopathy and massive foveal exudates, where vitrectomy with removal of exudates may result in improvements in visual acuity of two lines or more [17].

Summary
In bro-proliferative retinopathy, early vitrectomy can be an effective intervention in patients with aggressive and advanced diabetic eye disease. In maculopathy, earlier detection and treatment with focal laser or macular grid laser photocoagulation together with vitrectomy for specic indications may prevent signicant visual loss. Nevertheless, prevention of complications by good control of blood glucose [10,18] and appropriate treatment of hypertension [19] should remain the primary therapeutic goal.

Acknowledgements
We are grateful to Blackwell Scientic, Mosby and BMJ Publishing Group for permission to reproduce gures 1, 6 and 7, respectively.

Copyright # 1999 John Wiley & Sons, Ltd.

Diabetes Metab Res Rev 1999; 15: 373377.