FEATURE Management of proliferative

BY F ALLEN AND S MANN

iabetic retinopathy is a major stages thus reducing associated vascular endothelial growth factor cause of blindness in the morbidity [1]. It is essential that high- (VEGF), which stimulates endothelial working-age population. risk patients are correctly identified cell proliferation and disrupts D Due to the worsening global and receive appropriate treatment to endothelial tight junctions increasing epidemic of , the incidence avoid progression of disease. vaso-permeability. The subsequent of morbidity caused by the disease is neovascularisation on the surface of set to increase [1]. The prevalence of Pathophysiology the can then lead to vitreous diabetes in the UK in 2013 was 6%. Hyperglycaemia, and haemorrhage and tractional retinal This translates into 3.2 million people hyperlipidemia are all thought to detachment [3]. with a diagnosis of diabetes, compared contribute towards vascular disruption with 1.4 million in 1996 [2]. in the retina leading to DR. Damage Classification of disease There are multiple modifiable to endothelial cells which maintain severity risk factors for developing diabetic the blood retinal barrier leads to There are multiple classification retinopathy (DR); taking an integrated increased vascular permeability in systems of DR. The Early Treatment approach to managing those with the retina. Injury to pericytes and Diabetic Retinopathy Study (ETDRS) diabetes is essential. Modifiable risk thickening of the capillary basement produced a full disease classification factors such as glycaemic control and membrane results in dysregulation system based on characteristics of hypertension must be considered and of the blood flow within the retina DR seen on fundus photographs [4]. minimised to prevent development and development of microaneurysms. International severity scales for both and progression of DR. As capillaries are occluded retinal DR and macular oedema have been Sight-threatening DR can be ischaemia occurs resulting in the developed based on EDTRS findings [5] identified and treated in its early release of angiogenic factors such as (Table 1).

Table 1: Showing international severity scale along with management advice.

Disease severity Appearance on Management advice No diabetic retinopathy No abnormality Optimise modifiable risk factors (glucose, BP, lipids), annual diabetic screening Mild non-proliferative diabetic Microaneurysms only As above retinopathy Moderate non-proliferative diabetic More than just microaneurysms but As above AND refer to ophthalmologist AND retin- opathy not meeting criteria for severe NPDR monitor for maculopathy (All R2s and M1s as per National Screening Programme (NSC) grading criteria should be referred to Hospital Eye Services) Severe non-proliferative diabetic Any one of the following findings with As above AND consider panretinal retinopathy NO evidence of proliferative photocoagulation (PRP) in high risk cases retinopathy: • >20 intraretinal haemorrhages in all 4 retinal quadrants. • Venous beading in ≥2 quadrants • Intraretinal microvascular abnormalities in ≥1 quadrant Proliferative diabetic retinopathy New vessel formation or vitreous / Urgent referral to Hospital Eye Services, preretinal haemorrhage or tractional STRONGLY consider PRP and manage as above [3]

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How to detect high risk proliferative disease The following characteristics of PDR “It is important have been identified by the ETDRS as increasing the risk of severe visual loss to remember that meaning that PRP treatment should not be delayed in the presence of [7]: diabetic retinopathy • new vessels on or within one disc is a posterior diameter of optic disc ≥1/3 disc area (Figure 1) pole disease and • any new vessels on or within one disc diameter of optic disc proliferation occurs at Figure 1: Standard photograph 10A showing new vessels at the disc covering approximately 1/3 of the accompanied by vitreous / pre- the border of perfused disc area. This constitutes high risk PDR requiring retinal haemorrhage PRP [4]. • new vessels elsewhere ≥½ disc and non-perfused diameter which are accompanied by vitreous / pre-retinal tissue rather than the Treatment of proliferative haemorrhage. diabetic retinopathy with far peripheral retina.” panretinal photocoagulation When to start laser The Diabetic Retinopathy Study (DRS) treatment was a randomised clinical trial that DRS and EDTRS findings lead to began in 1971 involving over 1700 the recommendation that severe multispot lasers have been shown patients. It looked at the benefit of preproliferative DR be monitored four to cause increased recurrence of panretinal photocoagulation (PRP) in to six monthly and treated with PRP neovascularisation within six months the treatment of proliferative diabetic as it approaches the high-risk stage. of treatment despite equivalent laser retinopathy (PDR) compared to follow- Holding off laser treatment until the spots being delivered. When using up without treatment. DRS showed that high risk stage balances the risk of standard settings recommended by treatment with PRP reduced the risk of blindness caused by PDR with the risks EDTRS, PASCAL lasers may be less severe visual loss (<5/200) by more than of PRP using argon lasers, particularly effective at preventing progression 50% compared with no treatment [6]. the obliteration of peripheral vision. of disease, meaning that current PRP is still the mainstay of the treatment This, however, relies on the regular treatment parameters most likely for PDR. attendance of patients. Advances in need to be adjusted [10]. EDTRS The EDTRS compared the benefit laser technology have reduced these guidelines recommends that the of early photocoagulation in eyes with risks. Using shorter pulse durations area of treated retina should cover a non-proliferative DR or PDR without during PRP results in reduced pain, minimum area of 236mm2 (range 157- high-risk features compared to deferring scarring, increased stability of the 314mm2) [11]. Using traditional argon until high risk PDR had been reached. laser burn (reducing enlargement over laser burns of 500 µm this equates The five-year risk of severe visual loss time) and less damage to the outer to approximately 1200 burns. When or vitrectomy in those treated before retina resulting in a reduced impact on using multispot lasers, only a spot size the development of high-risk PDR was the peripheral visual field [8]. of 400 µm at the retina is achievable 2-6% compared to 4-10% in those for The development of multispot meaning that approximately 1900 whom treatment was deferred until high lasers such as the pattern scan laser burns are required to treat the same risk characteristics noted. Although this (PASCAL) means that PRP can safely area of retina as recommended by showed a benefit to early treatment, be commenced at an earlier point of EDTRS guidelines. A spot size of 400 both groups retained a good final visual DR with reduced side-effects. These µm at the retina can be achieved using outcome. PRP was associated with side- lasers use shorter pulse duration a Superquad lens with a laser spot size effects such as a reduced visual field due (20-30ms) and allow multiple burns setting of 200 µm. The magnification to retinal ablation. to be administered in one exposure factors of lenses used in PRP can be It was suggested that PRP should and in a shorter time that is more seen in Table 2. be delayed until high risk PDR is comfortable for the patient [9]. Current recommendations from the approached [7]. Interestingly, despite increased usage, Royal College of Ophthalmologists

Table 2: Field of view and magnification factors of commonly used lenses. Taken from the Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012 [8].

Name of lens Field of view (in degrees) Image magnification Laser spot magnification Area Centralis® 70-84 1.06 X0.94 Mainster focal/grid® 90-121 0.96 X1.05 TransEquator® 110-132 0.70 X1.44 Quadraspheric® 120-144 0.51 X1.97 Superquad 160® 160-165 0.50 X2 Mainster PRP 165® 165-180 0.51 X1.96

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provides advice based on EDTRS Destruction of the peripheral field haemorrhage weekly ultrasound guidelines regarding when to should be minimised, therefore, examinations to detect retinal commence PRP in DR. PRP PRP should be stopped when signs detachment should be performed, treatment is not recommended for of regression of the new vessels especially if the patient has had no patients with mild-moderate non- are seen and there is stability of prior photocoagulation [8]. proliferative DR, these patients disease. Blunting of new vessel tips should be monitored annually using will be seen indicating regression of Role of anti-VEGF in retinal photography. This can be neovascularisarion. Areas of stable proliferative diabetic carried out in the community (within neovascularisation should be regularly retinopathy the National Diabetic Screening monitored for signs of new vessel Anti-VEGF treatment is now used Programme in the UK). Those with growth and haemorrhage, although extensively in the treatment of severe non-proliferative DR should haemorrhage can often be a sign of diabetic macular oedema (DMO) have four to six monthly expert traction as opposed to persistant / following work undertaken by the examinations looking for evidence of active new vessels, where referral for diabetic retinopathy clinical research retinal neovascularisation or retinal vitrectomy may be more appropriate. network (DRCRnet) and several other ischaemia. Fundus photographs It is also helpful to look at the studies including the RESTORE study. and fundus remaining retina and if features such These have shown improved visual (FFA) are useful adjuncts to clinical as multiple retinal haemorrhages, outcomes compared to the use of examination. PRP should be venous beading or intraretinal laser alone and this benefit persisted considered as DR approaches the microvascular abnormality (IRMA) (4- at one and two year follow-up [14,15]. proliferative stage [8]. 2-1 rule in severe non proliferative DR) Additional review has also indicated PDR should be treated with PRP. If are present, this points towards active reduced progression of retinopathy high risk PDR is noted, PRP should be retinopathy and the need for further but more research is required on this. commenced that day or at least within laser treatment [8]. The use of anti-VEGF pre vitrectomy two weeks. Obtaining baseline FFA is in PDR has been seen to improve useful but should not delay treatment. When to refer for vitrectomy surgical outcomes. A systematic PRP should be considered earlier in The Diabetic Retinopathy Vitrectomy review of six randomised controlled the severe pre-proliferative stage in Study (DRVS) performed in the 1980s trials and one comparative study the following situations [8]: showed that early vitrectomy (within has shown a statistically significant • pre surgery one month) following severe vitreous reduction in rates of intraoperative • in only eye (first eye lost to PDR) haemorrhage in type 1 diabetics bleeding, recurrent vitreous • when compliance with clinic resulted in improved visual outcome haemorrhage and time taken for attendance is poor. at two years. A statistically significant reabsorption of haemorrhage in improvement was not seen in type those treated preoperatively with How to carry out PRP 2 diabetics [13]. Since these findings intravitreal compared PRP can be performed at a slit-lamp there has been much development to those receiving vitrectomy alone mounted laser under local anaesthetic of the vitrectomy procedure and [16]. Caution must be exercised with use of oxybuprocaine 0.3% or equipment leading to improved when using anti-VEGF treatment tetracaine 1% drops and the use of an outcomes and fewer complications preoperatively as given alone in PDR, appropriate lens such as a SuperQuad (especially the risk of visual loss post without subsequent vitrectomy, it (see table for magnification factors). procedure) meaning early vitrectomy can have adverse effects inducing Once the decision has been made may be more beneficial than tractional retinal detachment as rapid to start PRP, laser sessions should be previously thought. contraction of fibrovascular tissue commenced within two weeks and Patients should be referred for occurs. may be performed over two to three consideration of vitrectomy in the sessions to be completed within four following situations: Conclusion to six weeks [8]. This fractionation • persistant fibrovascular The rising diabetes epidemic is of treatment can reduce the risk of proliferation despite a good PRP one of the major challenges facing maculopathy worsening [12], but if • traction macular detachment modern medicine. Recognition of clinically significant macular oedema confirmed on optical coherence retinal changes caused by the disease is present, it is advised to treat this at tomography (OCT) is crucial to both eye and systemic the same time as starting the PRP. • progressive extra-macular traction health. Retinal changes may be the When treating extensive areas of retinal detachment first sign of end organ damage. A good retina, precautions must be taken • traction / rhegmatogenous retinal understanding of the management to avoid increasing traction on the detachment threatening the of DR as well as earlier detection macula or retina, especially if there macula through screening with continued are persistant vessels at the disc. • pre-macular haemorrhage development of treatment options Often vitrectomy may be more • vitreous haemorrhage persisting are essential if visual deterioration beneficial in these cases. for one month making laser is to be avoided in this large patient photocoagulation difficult population. How to assess if PRP is still In those with vitreous haemorrhage active and when to stop laser who are awaiting vitrectomy treatment or spontaneous clearing of the

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References 14. Diabetic Retinopathy Clinical Research Network. 1. Scanlon P. The English national screening Randomized trial evaluating plus programme for sight-threatening diabetic prompt or deferred laser or triamcinolone retinopathy. J Med Screen 2008;15:1-4. plus prompt laser for diabetic . 2. Diabetes in the UK 2012 (April 2012): Key statistics 2010;117(6):1064-77. on diabetes. Diabetes UK. http://www.diabetes.org. 15. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. uk/About_us/What-we-say/Statistics/Diabetes-in- The RESTORE Study: Ranibizumab monotherapy the-UK-2012/ Last accessed July 2014. or combined with laser versus laser monotherapy 3. Ciulla T, Amador A, Zinman B. Diabetic retinopathy for diabetic macular edema. Ophthalmology and diabetic macular edema. Pathophysiology, 2011;118(4):615-25. screening and novel therapies. Diabetes Care 16. Zhao L, Zhu H, Zhao P, Hu Y. A systematic review 2003;26:2653-64. and meta-analysis of clinical outcomes of 4. Early Treatment Diabetic Retinopathy Study vitrectomy with or without intravitreal bevacizumab Research Group. Grading diabetic retinopathy pretreatment for severe diabetic retinopathy. from stereoscopic color fundus photographs - an Br J Ophthalmol 2011;95:1216-22. extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology TAKE HOME MESSAGE 1991;98(suppl 5):786-806. 5. Wilkinson CP, Ferris FL III, Klein RE, et al. Proposed international clinical diabetic retinopathy and • Always consider modifiable diabetic macular edema disease severity scales. risk factors to reduce the risk of Ophthalmology 2003;110:1677-82. retinopathy progression. 6. The Diabetic Retinopathy Study Research Group. Preliminary report on the effect of photocoagulation • Treat proliferative retinopathy therapy. Am J Ophthalmol 1976;81:383-96. with PRP as it approaches the Dr Felicity Allen, 7. Early Treatment Diabetic Retinopathy Study MBChB, Research Group. Early photocoagulation for high risk stage or earlier in Foundation Year 2 Doctor, diabetic retinopathy. ETDRS Report Number 9. some circumstances. Ophthalmology. 1991;98:766-85. Guy’s and St Thomas’ NHS Foundation Trust. 8. The Royal College of Ophthalmologists. Diabetic • When using multispot lasers Retinopathy Guidelines December 2012. 9. Mugit M, Marcellino G, Gray J, et al. Pain responses for PRP remember to increase of Pascal 20ms multi-spit and 100ms single- the number of burns due to the spot panretinal photocoagulation: Manchester decreased spot size. Pascal Study, MAPASS report 2. Br J Ophthalmol Declaration of 2010;94(11):1493-8.­­­­­­­ Competing Interests • Assess the remaining retina None declared. 10. Chappelow A, Tan K, Waheed N, Kaiser P. Panretinal photocoagulation for proliferative diabetic for evidence of haemorrhages, Mrs Samantha retinopathy: pattern scan laser versus argon laser. venous beading and IRMAs for Am J Ophthalmol 2012;153(1):137-42. S Mann, activity of retinopathy. 11. Diabetic Retinopathy Study Research Group. MD, MRCOphth, Photocoagulation treatment of proliferative FRCOphth BSc, diabetic retinopathy. Clinical application of Diabetic • Consider early referral for Consultant Ophthalmologist, Retinopathy Study (DRS) findings, DRS report vitrectomy with possible anti- St Thomas’ Hospital, number 8. Ophthalmology 1981;88(7):583-600. VEGF preop to improve final London, UK. 12. Dowler J. Laser management of diabetic retinopathy. visual outcome in those with E: samantha.mann J R Soc Med 2003;96(6):277-9. @gstt.nhs.uk 13. Diabetic Retinopathy Vitrectomy Study Research early traction or persistant Declaration of Group. Early vitrectomy for severe vitreous neovascularisation not Competing Interests haemorrhage in diabetic retinopathy. Two year None declared. results of a randomised trial. DRVS report No2. responsive to initial PRP laser. Archives of Ophthalmology 1985;103:1644.

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