Diabetic macular oedema Image: Retina gallery.com
Associate Professor Jolly Gilhotra
MBBS MMed FRANZCO
Adelaide Eye and Retina Centre
Dr Megan Wood
Royal Adelaide Hospital
Diabetes is a growing health epidemic and the leading cause of acquired blindness in the working population in developed countries.1 The most common cause of vision loss in these patients is diabetic macular oedema (DME).2
Traditionally, macular focal and grid laser photocoagulation were the only treatments available for DME, with the aim of preventing further vision loss. With better understanding of the pathology and role of vascular endothelial growth factor (VEGF), intravitreal anti-VEGF injections have emerged as superior to laser and in many cases result in visual gain. In this case report our patient’s management for DME echoes the developments over the past 10 years.
A 55-year-old salesman presented for diabetic review with a visual acuity (VA) of R 6/7.5 L 6/7.5 in May 2007. He had been a non-insulin dependent type 2 diabetic patient for more than 12 years with an HbA1c of eight per cent. He had a diagnosis of proliferative diabetic retinopathy (PDR) and DME in both eyes.
He initially underwent a course of macular laser for DME in both eyes, receiving three sessions on the left and two on the right over the next year. Alongside macular laser, he also underwent pan retinal photocoagulation (PRP) for PDR. The PRP was given at lower doses over an extended period to reduce the well-recognised detrimental effect of PRP on DME. Despite the macular laser treatment, after one year his vision had worsened, VA R 6/24 L 6/15, with OCT consistent with gross DME.
Over the next two years (May 2008 to April 2010) the patient received two intravitreal triamcinolone in each eye combined with two additional sessions of laser in each eye. As a result of intravitreal steroid, the patient developed elevated intraocular pressure (IOP) and posterior subcapsular white cataracts. The pressure was initially controlled with a combination of brimonidine, timolol and latanoprost. After the triamcinolone was ceased, the IOP normalised and the patient was successfully weaned off these drops.
Due to subcapsular cataracts in January 2010, the patient experienced a deterioration in vision to R 0.5/60 L 6/48. Cataract surgery was complicated by the ‘Argentinian flag sign’, a common complication with intumescent cataracts. It essentially describes a spontaneous tear across the equator of the capsule which is stained with trypan blue, revealing a white stripe of cataract.
Fortunately, the tear was not too extensive and we were able to insert the new lens into the capsule. At this point the patient was finding work in sales extremely difficult with binocular reading vision of N20 and was referred to the low vision clinic for assessment and assistance. Over this period of two years, he had experienced a slight deterioration in vision; R 6/30 L 6/19 and OCT still showed significant DME (Figure 1).
Figure 1. OCT right eye April 2010 before anti-VEGF treatment
Figure 2. OCT right eye December 2010 after eight months of intravitreal bevacizumab
In April 2010 he was started on a course of intravitreal anti-VEGF, initially bevacizumab (Figure 2) then ranibizumab and finally aflibercept in August 2015. To date he has received 77 anti-VEGF injections in both eyes. Over this time, he experienced an improvement in vision and OCT revealed gradual resolution of DME (Figures 3 and 4). His vision is currently R 6/24 L 6/15.
Figure 3. OCT right eye December 2015 before intravitreal aflibercept
Figure 4. OCT right eye March 2016 after course of intravitreal aflibercept
Since the 1980s, grid/focal macular laser has been the mainstay of treatment for DME. This was established by the Early Treatment Diabetic Retinopathy Study, which showed laser reduced the risk of moderate vision loss by 50 per cent at three years.3 The focus was on prevention of vision loss, and laser was associated with complications such as reduced colour vision and scotoma.
In the early 2000s, intravitreal triamcinolone emerged as an alternative treatment for refractory or persistent DME. In our case report, laser failed to prevent vision loss over the first year of treatment, therefore the patient was commenced on intravitreal triamcinolone. This combination of treatment also did not prevent his vision loss and he developed complications of cataract and raised IOP from the triamcinolone.
In 2008, as part of protocol B, DRCR.net found that after two years focal/grid laser resulted in better visual acuity and fewer side-effects than intravitreal triamcinolone for DME. Since then, its popularity has diminished.4
At this point our understanding of the pathophysiology of DME and role of VEGF led to an explosion of research into intravitreal anti-VEGF. In diabetes, chronic hyperglycaemia results in breakdown of the retinal blood barrier leading to hypoxia, release of inflammatory mediators and expression of VEGF. VEGF leads to increased vascular permeability and neovascularisation. The level of VEGF in the vitreous has been shown to correlate directly with the severity of DME.5
Pegatanib was the first anti-VEGF to be investigated, leading to an improvement in visual acuity compared to sham injection; however, soon more potent anti-VEGFs took over.6
In 2010, the READ-2 study showed that two-monthly intravitreal ranibizumab injections resulted in better visual acuity than three-monthly laser or a combination of laser and ranibizumab.7 After three years, monthly follow-up for ranibizumab was recommended to avoid undertreatment.8
RISE and RIDE, parallel ramdomised controlled trials, found intravitreal ranibizumab resulted in better visual acuity than sham injections maintained at three years.9,10 Interestingly, patients who subsequently crossed over from the sham injections to the treatment arm of the study achieved a limited vision gain compared to patients originally receiving ranibizumab. RESOLVE again supported the superiority of ranibizumab over sham injections.
The role for laser alongside ranibizumab has also been investigated. READ-2 initially showed that using laser to complement ranibizumab reduced the number of intravitreal injections required with similar visual outcome. However, RESTORE found ranibizumab monotherapy rather than combination with laser led to better visual acuity outcomes.11 DRCR.net protocol-I found prompt laser treatment at the initiation of intravitreal ranibizumab no better than deferring laser treatment for more than 24 weeks. However, if laser is deferred, eyes may require more intravitreal injections to receive the same results.12
Aflibercept, another anti-VEGF, has been shown to give superior results compared to laser with sham injections in the Da Vinci study.13
VISTA/VIVID also revealed better visual gains compared to laser up to 100 weeks, with less than 10 per cent of patients receiving aflibercept alone requiring rescue laser treatment.14 Bevacizumab has also proved itself superior to laser in the BOLT trial.15
DRCR.net attempted to compare the three anti-VEGF treatments currently available for DME treatment with protocol T. It found no significant difference between the agents unless visual acuity was less than 6/15, then aflibercept gave a better visual outcome.16
Anti-VEGF has controlled our patients previously refractory DME with great success, providing visual gain and stability over the past six years where laser and intravitreal triamcinolone had failed. However, it must be remembered that intravitreal injections involve significant risks including endophthalmitis, raised IOP and damage to surrounding structures such as retinal detachment.
Management of DME with anti-VEGF creates a significant treatment burden with patients requiring potentially lifelong monthly follow-up. Questions remain about the frequency of follow-up and injections. The RETAIN study recently showed the viability of a treat-and-extend management rather than a monthly follow-up regime.17
This case follows a patient through the rapid development in the management of DME over the past 10 years. For our patient anti-VEGF treatment gave him visual improvement and stability, where laser and intravitreal triamcinolone previously failed, and allowed him to continue in his employment.
1. Prokofyeva E, Zrenner E. Epidemiology of major eye diseases leading to blindness in Europe: a literature review. Ophthalmic Res 2012; [cited 2016 Apr 24]; 47: 4: 171–188. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22123077.
2. Klein R, Klein BE, Moss SE et al. The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema. Ophthalmology 1984; [cited 2016 Apr 24]; 91: 12: 1464–1474. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6521986.
3. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol (Chicago, Ill 1960) 1985; [cited 2016 Apr 24]; 103: 12: 1796–1806. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2866759.
4. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2008; [cited 2016 Apr 24]; 115: 9: 1447–1449.e1–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18662829.
5. Funatsu H, Yamashita H, Nakamura S et al. Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology 2006; [cited 2016 Apr 24]; 113: 2: 294–301. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16406543.
6. Sultan MB, Zhou D, Loftus J et al. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology 2011; [cited 2016 Apr 24]; 118: 6: 1107–1118. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21529957.
7. Nguyen QD, Shah SM, Khwaja AA et al. Two-year outcomes of the ranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology 2010; [cited 2016 Apr 24]; 117: 11: 2146–2151. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20855114.
8. Do DV, Nguyen QD, Khwaja AA et al. Ranibizumab for edema of the macula in diabetes study: 3-year outcomes and the need for prolonged frequent treatment. JAMA Ophthalmol 2013; [cited 2016 Apr 24]; 131: 2: 139–45. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23544200.
9. Nguyen QD, Brown DM, Marcus DM et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012; [cited 2016 Apr 24]; 119: 4: 789–801. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22330964.
10. Brown DM, Nguyen QD, Marcus DM et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology 2013; [cited 2016 Apr 24]; 120: 10: 2013–2022. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23706949.
11. Schmidt-Erfurth U, Lang GE, Holz FG et al. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. Ophthalmology 2014; [cited 2016 Apr 24]; 121: 5: 1045–1053. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24491642.
12. Diabetic Retinopathy Clinical Research Network, Elman MJ, Qin H et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology 2012; [cited 2016 Apr 24]; 119: 11: 2312–2318. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22999634.
13. Do DV, Nguyen QD, Boyer D et al. One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology 2012; [cited 2016 Apr 24]; 119: 8: 1658–1665. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22537617.
14. Brown DM, Schmidt-Erfurth U, Do DV et al. Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies. Ophthalmology 2015; [cited 2016 Apr 24]; 122: 10: 2044–2052. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26198808
15. Michaelides M, Kaines A, Hamilton RD et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology 2010; [cited 2016 Apr 24]; 117: 6: 1078–1086.e2. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20416952.
16. Diabetic Retinopathy Clinical Research Network TDRCR, Wells JA, Glassman AR et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 2015; [cited 2016 Apr 24]; 372: 13: 1193–1203. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25692915.
17. Prünte C, Fajnkuchen F, Mahmood S et al. Ranibizumab 0.5 mg treat-and-extend regimen for diabetic macular oedema: the RETAIN study. Br J Ophthalmol 2015; [cited 2016 Apr 24]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/26453639.