Diabetic eyecare part 4: New medical treatments for diabetic macular oedema

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1 Country CET/CPD information Audience Competencies MCQs Available via UK This article offers a choice of 1 non-interactive CET point (C-52930) or 1 interactive CET point (C-52929) (For instructions on how to complete the interaction see the end of this article.) 6 ilearn: specsaverspeople.com ROI All articles are CPD accredited in the Republic of Ireland 6 ilearn: specsaverspeople.com Diabetic eyecare part 4: New medical treatments for diabetic macular oedema by Chris Steele, BSc(Hons) FCOptom DCLP DipOC DipTp(IP) FBCLA Outline: Diabetic macular oedema (DMO) is a complication of diabetic retinopathy and is a leading cause of visual loss worldwide. Development of DMO is linked to duration of disease, poor blood glucose control and in type 2 diabetes, the need for insulin. With the increasing number of people with diabetes increasing worldwide the prevalence of DMO is likely to increase with significant implications for patients in terms of health and social care provision. This article explains clinical features of DMO and treatment options - from laser to anti- VEGF and intravitreal steroids, discussing NICE guidance on treatment and explaining the findings of clinical trials. This article promotes an understanding of the condition and evidence-base for treatment, so that practitioners achieve a better understanding, and therefore will be able to advise and refer patients according to current best practice. About the author: Chris Steele graduated from City University in 1988 and qualified in July 1989 after his pre-registration year at The Royal East Sussex Hospital, Hastings. He is Consultant Optometrist, Head of Optometry at Sunderland Eye Infirmary (SEI) in Sunderland. Over the past 22 years he has developed a wide range of extended roles within his optometry team involving medical retina, cataract, glaucoma, anterior segment and paediatric case loads. He has maintained his special interest in medical therapeutic contact lenses and still runs a specialist scleral lens tertiary referral service at SEI. He has also continued to undertake regular locum work in community optometric practice. He has authored over seventy publications re: glaucoma, ocular therapeutics, medical retina, specialist medical contact lenses, refractive surgery, and clinical risk management and has undertaken many presentations both nationally and internationally on these topics. He has also authored a book in the Eye Essentials series: Diabetes and the eye first published in A fully updated second edition is due out soon. Chris is a member of the AOP Hospital Optometrists Committee and was Chairman from He has been a College Examiner for Pre-registration Final Exit Examinations and Post Graduate Higher Qualifications (Diabetes and Glaucoma) since He is now a questions writer/ editor for The College of Optometrists Therapeutics Central Final Assessments in Independent Prescribing as well as a co-editor for Specsavers Profile journal. Chris was a member of the NICE Glaucoma Guideline Development Group from 2007 that produced the NICE glaucoma guidelines (CG85) published in 2009, and is still involved in the on-going NICE periodic reviews of this Glaucoma Guideline. In the past 2-3 years he was also a member of the College of Optometrists Medical Retina Development Group that produced the new Medical Retina Higher Qualifications for optometrists. Introduction Diabetic retinopathy (DR) remains a leading cause of preventable vision loss, despite advances in diabetes care. Diabetic macular oedema (DMO) is a complication of diabetic retinopathy and is a leading cause of visual loss worldwide. There is now evidence however, that because of screening for diabetic retinopathy in England and Wales, diabetic retinopathy is no longer the number one cause of sight loss in these countries 5. Development of DMO is linked to duration of disease 6, poor blood glucose control 7 and, in type 2 diabetes, the need for insulin 8. With the increasing number of people with diabetes burdgeoning worldwide, the prevalence of DMO is likely to increase with significant implications for patients in terms of health and social care provision 9. What causes DMO? As discussed in earlier parts of this series, DMO is caused mainly by disruption of the blood-retinal barrier, resulting in leakage (exudation) of serous fluid and lipids 10. This leakage may be focal or diffuse (figure 1). Focal oedema (retinal thickening) is often associated with a circinate or semi-circinate ring of exudate. In diffuse oedema, multiple adjoining circinate rings of exudates may be evident as in figure 1. Where chronic hyperglycaemia (raised blood glucose) exists, this causes a complex series of physiological processes to cascade involving increased vascular permeability, cytokine activation (these are a collection of different small blood proteins released by cells that influence the behaviour of other cells), altered haemodynamics (blood flow), hypoxia, inflammation and neuronal dysfunction leading to vision loss 11. Leukocytes and monocytes (white cells) also play a role in capillary wall damage and occlusion. Leukocytes are thought to migrate and adhere to the retinal vasculature (on the endothelial layer) via cellular adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and beta-integrins on the leukocytes. Other molecules also thought to be involved in this process include the vascular cell adhesion molecules, fibronectin and osteopontin. Leukocyte migration into the neural retina is associated with breakdown of the blood-retinal barrier, premature endothelial cell death and capillary ischaemia. All these changes occur before any lesions are observed clinically in the fundus. Hypoxia caused by microvascular disease stimulates the release of a signal protein VEGF-A, which is a vasodilator and increases microvascular Specsavers Optical Group

2 Figure 1: Diffuse macular oedema with multiple circinate exudates permeability to help with perfusion. There are at least six isoforms of VEGF-A (121, 145, 165, 183, 189 and 206). VEGF-A is thought to produce inflammation by inducing ICAM-1 expression and leukocyte adhesion. When ICAM-1 activity is blocked, VEGF induced blood retinal barrier breakdown is suppressed. Similarly when VEGF is blocked, ICAM-1 up-regulation, leukocyte adhesion and blood-retinal barrier breakdown are all reduced 12. With perifoveal focal (exudative) macular oedema there is focal leakage from discrete microaneurysms on fluorescein angiography. These normally respond well to focal laser therapy. According to the Early Treatment for Diabetic Retinopathy Study (ETDRS) the prognosis post laser photocoagulation is good but with approximately 10% of patients suffering moderate visual loss at 1 year post laser treatment (see below). Sub-foveal DMO cannot be successfully treated with laser 13. Diffuse macular oedema is where there is more diffuse leakage evident on fluorescein angiography. Macular oedema is clinically a very subtle finding to detect and requires a stereoscopic view as obtained with slit lamp binocular indirect ophthalmoscopy and volk condensing lens. The best way to view macular oedema or retinal thickening is with a gonio-fundus contact lens. Unless the oedema is severe it cannot usually be detected with direct ophthalmoscopy. Diffuse oedema generally responds less favourably to focal laser, although grid laser photocoagulation may be quite successful in many cases. The prognosis for this group is 20% of patients suffer moderate visual loss at 1 year post focal/ grid laser treatment. Ischaemic diabetic maculopathy laser treatment is much less effective, with at least 30% of patients suffering moderate visual loss at 1 year. Some patients may have a combination of exudative and ischaemic DMO 9. Laser photocoagulation Focal and grid photocoagulation (figure 2) have been the mainstay of treatment for DMO as described in the landmark ETDRS trials 14 (this is discussed more fully in part 3 of this series). Currently, these remain the gold standard treatment for diabetic maculopathy and continue to be an effective therapy for preventing vision loss in diabetic patients with clinically significant macular oedema. This may be laser treatment alone or, increasingly, in combination with pharmacological agents (see below). Clinically significant macular oedema (CSMO) was defined by the ETDRS as: Retinal thickening within 500 microns of the foveal centre Hard exudates within 500 microns of the foveal centre with adjacent retinal thickening, or retinal thickening greater than 1 disc diameter in size within one disc diameter of the foveal centre (ETDRS) 9,10. Figure 2: Focal and grid laser patterns for diabetic maculopathy treatment The ETDRS was the first randomised trial to examine treatment for diabetic macular oedema using laser therapy. The original ETDRS photocoagulation technique was adopted throughout the world and gradually modified over the years Although there was definite benefit of applying focal laser therapy, it is far from perfect as many ETDRS patients failed to respond to laser treatment, thus losing vision, and the majority did not actually achieve any visual improvement (ETDRS 1985) 15. Laser photocoagulation is not very successful at restoring vision once lost. Also patients with perifoveal ischaemia are not amenable to these laser treatments. Laser treatment is not without its side effects which include foveal burns (laser cannot be used in cases of sub-foveal DMO), visual field defects, retinal fibrosis and laser scars 16. Despite aggressive laser treatment, a significant proportion of patients still suffer severe visual loss. Using the original conventional long duration (100 millliseconds) laser burns, the subsequent laser burn scarring can expand by 16.5% per year for up to four years. This can then lead to areas of confluent retinal pigment epithelial (RPE) atrophy causing paracentral scotomata and vision loss, particularly where the fovea becomes involved 17. These findings resulted in the modified ETDRS technique that utilised smaller (50 micron) light grey threshold ( millisecond duration) focal and grid laser pattern burns that are still used today. New laser treatment methods including these shorter pulse durations and pattern scanning (PASCAL) or the VALON system have improved the effectiveness and risk profile of laser for diabetic patients (this is discussed more fully in part 3 of this series) 18,19,20. It is likely that multi-modality therapy may play an increasingly important role in the future 21. New treatments for DMO - as stand alone or in combination with laser In the last few years, clinical trials have demonstrated that both steroids and anti-vegf agents are superior to conventional laser photocoagulation in reducing DMO 22,23. The National Institute for Health and Clinical Excellence (NICE) has now approved the use of certain anti-vegf agents for the treatment of DMO. In England, unlike the rest of the world, treatment may only be offered to patients where the central macular thickness is greater than 400 microns as measured by OCT 24. Another alternative option is intravitreal steroids in certain selected cases. These new treatments will now be discussed. 2 Specsavers Optical Group 2016

3 Anti-vascular endothelial growth factor (VEGF) therapy Vascular endothelial growth factors (VEGFs) are a group of molecules (signal proteins) that promote growth of new blood vessels by stimulating vasculogenesis and angiogenesis (the formation of new blood vessels) 25. They are cytokines that are expressed at increased concentrations in macular oedema and are a potent promoter of vascular permeability. VEGF-A is the factor that has been most studied in ophthalmology. There is growing evidence from multiple robust randomised case control trials (RCTs) (see below) that anti-vegf agents are effective compared with laser treatment and placebo for DMO and more effective than steroids at improving best corrected visual acuity (BCVA). They have been shown to be safe in the short term but do require frequent injections to maintain their desired theraputic effects. There are reports that some patients have had over 100 injections and (per eye) is not uncommon in the treatment of wet age related macular degeneration. Because of its central role in the pathogenesis of both proliferative diabetic retinopathy and DMO, particularly the isoform VEGF-165, molecules designed to inactivate extracellular VEGF A have been explored as potential treatments for DMO and even rubeosis 18. Examples of these medications available that target VEGF A include: Pegaptanib sodium (Macugen), Bevacizumab (Avastin) and Ranibizumab (Lucentis). Anti-VEGF treatments have been used in the treatment of wet AMD for several years now. Two year results from the CATT (Comparison of AMD Treatment Trials) and IVAN (inhibit VEGF in age related choroidal neovascularisation) trials have shown anti-vegf therapies to be safe, with all agents having similar clinical efficacy 26. Pegaptanib (Macugen) Macugen was the first anti-vegf inhibitor approved for human use. It produced improvement in median visual acuity with 0.3 mg of drug compared with sham control 27. The beneficial results from initial studies involving Pegaptinib paved the way for more studies investigating Bevacizumab and Ranibizumab for DMO treatment. Pegaptanib specifically binds (as an antagonist) to the 165 isoform of VEGF, a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels). Bevacizumab and Ranibizumab, however, bind to all isoforms of VEGF thus rendering them more effective. Bevacizumab (Avastin) Bevacizumab is a recombinant humanised antibody directed at all isoforms of VEGF A and is approved for intravenous therapy of certain cancers e.g. bowel and lung. Its intravitreal use has been demonstrated to be useful in the treatment of a wide variety of ophthalmic diseases, including DMO 28. The BOLT (Intravitreous Bevavcizumab (IVB) or Laser Therapy) study was the first randomised controlled trial published comparing IVB with focal laser for treatment of diabetic macular oedema 29. In the BOLT IVB study cohort, superior visual acuity at 12 months and reduced macular thickness on OCT were found compared with laser therapy alone. Bevacizumab is not licensed for eye use, however, and is currently only available off-licence. In some parts of the world off-licence use is made of Bevacizumab at the ophthalmologist s own risk and that of the patient. There are a number of possible side effects that can occur with the use of this drug. These include anterior chamber reaction, raised IOP and infection (endophthalmitis). If a patient developed serious complications with the use of a non-licensed drug (just because it was cheaper to use), when a licensed drug for intravitreal use is already available, it would be very difficult to defend medico-legally. Also clinical commissioning groups (CCGs) will only fund the use of licensed products that have been approved by NICE. So, if ophthalmic units did offer Bevacizumab off-licence they would not get paid for these treatments and soon go out of business as a result! Ranibizumab (Lucentis) Ranibizumab is a fully licensed and approved humanised antibody fragment directed at all isoforms of VEGF-A, is fabricated specifically for intra-vitreal applications and is commonly used for treatment of wet age-related macular degeneration as well as macular oedema following retinal vein occlusions 30. A total of nine RCTs have evaluated Ranibizumab as a treatment for patients with DMO. Of note is that seven of these RCTs were funded by industry with only two being undertaken by independent investigators, thus raising the possibility of bias. The phase II, READ-2 was the first RCT, followed by extended results at two years 31. These demonstrated the efficacy of Ranibizumab in the treatment of DMO. In the initial study a total of 126 patients with DMO were randomised 1 : 1 : 1 to receive either: 0.5 mg Ranibizumab at baseline and at months 1, 3, and 5 focal grid photocoagulation at baseline and month 3, if needed a combination of both, at months 1 and 3. At six months, the BCVA had improved significantly in the Ranibizumab alone group compared with laser alone or Ranibizumab plus laser. Giving laser treatment in addition to Ranibizumab did not improve BCVA. The REVEAL study (n=396) compared Ranibizumab (0.5mg) with Ranibizumab plus laser and laser alone. At 12 months, those patients receiving Ranibizimab had significantly improved BCVA. The addition of laser did not produce any significant benefits to BCVA. Several other important RCTs evaluating Ranibizumab as a treatment for patients with DMO include RESTORE, RISE, RIDE and DRCRN. RESTORE was an industry-sponsored, multicentre (73 centres in 13 countries) study with a similar design to READ-2 (which had a shorter follow-up period) 25. Ranibizumab improved mean BCVA; the addition of laser did not produce any extra benefit. The improvements continued even at two years. RESOLVE demonstrated the efficacy of Ranibizumab treatment in 0.3mg and 0.5mg dosages compared with the controls (sham injections). A total of 68.8% of patients receiving Ranibizumab gained at least 10 letters, compared with just 18.4% in the control group 32. RISE and RIDE were identical in design with study arms similar to the RESOLVE study (0.3mg, 0.5mg v sham). At 24 months in the RISE study the greatest proportion of patients gaining at least 15 letters were in the group receiving 0.3mg whereas in the RIDE this was in the patients receiving 0.5mg 25. The Diabetic Retinopathy Clinical Research Network (DRCRN) (n=854) reported 12-month results from the first phase III randomised trial with 4 study arms comparing laser to Triamcinolone and Ranibizumab treatments. This clearly demonstrated a role for anti- VEGF therapy for DMO 33. For the 2 groups receiving Ranibizumab, these had the greatest proportion of patients gaining at least 10 letters logmar visual acuity. Specsavers Optical Group

4 Figure 3: Baseline OCT images and post-lucentis treatment for DMO Aflibercept (Eylea) Aflibercept (Eylea) is another more recently introduced vascular endothelial growth factor (VEGF) receptor fusion protein. NICE approval was granted in 2015 following the outcomes of the Da Vinci study, VISTA and VIVID trials. As with Ranibizimab, Aflibercept is administered by intravitreous injection and has a longer lasting effect than Ranibizumab, requiring injections only bi-monthly rather than monthly. Aflibercept holds a UK marketing authorisation for treating DMO. It is currently being studied in clinical trials compared with laser photocoagulation, Bevacizumab and Ranibizumab in adults with DMO. Aflibercept originally held a UK marketing authorisation for adults for the treatment of neovascular (wet) age-related macular degeneration (AMD) and macular oedema secondary to central retinal vein occlusion (CRVO). Current treatment protocols re: Ranibizumab (Lucentis) for DMO With cost-effectiveness being such an important consideration, to be eligible for Lucentis DMO treatment in England according to NICE, the central macular thickness (CMT) should be at least 400 microns with BCVA greater than 25 letters LogMAR (Snellen 6/96) and a history of a reduction in VA of less than 6 months duration according to NICE. This CMT cut-off is currently not used anywhere else in the world. Prior to treatment all patients should have undergone an intravenous fluorescein angiogram (IVFA). Patients usually receive 5 injections, then bi-monthly up to 9 injections in the first year (figure 3). Currently visual improvement is defined as an increase in 5 logmar letters and/ or 15% reduction in CMT. Focal/ grid macular laser may be considered where extra-foveal untreated microaneurysms (MAs) remain within an area of thickening after 5 months. Where no further improvement is achievable i.e. the patient can achieve a BCVA of 85 logmar letters (Snellen 6/6) and/or their OCT scan shows an absence of macular fluid with less than 5 letters of logmar change in BCVA over the previous 3 visits further injections should be withheld, but they should attend monthly clinic follow-up for a further 4-6 months. If DMO returns, then injections may be resumed. No achieved improvement is defined as less than 5 logmar letters better than baseline and less than 15% reduction in OCT CMT. Patients who fail to respond to Lucentis intravitreal injections may now be considered for intravitreal slow release steroid implants. A recently published study investigated whether eyes with DMO and CMT > 400 microns had better visual and anatomical outcomes compared with eyes with a CMT < 400 microns when treated with intravitreal Bevacizumab (Avastin). These results do not support a 400 micron Figure 4: Lucentis and Eylea packs baseline CMT cut-off for treating DMO with Bevacizumab, in contrast to published data on Ranibizumab (Lucentis). The results also indicated that patients with a thicker CMT required more Bevacizumab injections, making treatment less cost-effective for these patients. In future these results could be used by clinicians to support the use of Bevacizumab in DMO without applying a CMT cut-off. However the chances of this drug being given NICE approval in the UK are very unlikely at the present time as Bevacizumab will not be granted a licence for eye use as is the case with Ranibizumab (figure 4). One of the main concerns is the practice of splitting a vial of Bevacizumab to treat several patients. Recent studies have compared the storage of compounded Bevacizumab in polycarbonate and polypropylene syringes as opposed to multi use vials that were employed previously. As a result Bevacizumab is now available in pre-filled single dose syringes, thus avoiding cross-contamination risks that previously existed with multidose vials. Intravitreal steroids Intravitreal steroids have potent anti-inflammatory and other effects in the eye. They can reduce vascular permeability in the retina by decreasing the release of arachidonic derivatives in the retina such as prostaglandins 35. Corticosteroids have also been found to inhibit vascular epithelial growth factor (VEGF) production 36,37. Clinically, intravitreal steroids have also been shown to inhibit pre-retinal neovascularisation in pig and rat models as well as decreasing vascular permeability and reducing macular oedema. Intravitreal Triamcinolone (IVTA) has been used for years in patients with uveitis and its role in the treatment of diffuse and cystic DMO has also been an area of interest. Over the past 10 years Triamcinolone (Kenalog), although not licensed for eye treatments, was used to treat DMO with disappointing results. This was administered by intravitreal injection through the pars plana using a gauge needle. Typically 4mg of Triamcinolone in 0.1ml would be injected. It is white in appearance and after injection patients often noticed visual floaters for several days to weeks. Improvements in visual acuity of up to 3 lines were reported and a reduction in CMT, measured by OCT, by as much as 60% 25. There are significant potential long-term complications of using intravitreal steroids including cataracts and glaucoma that limits their use in certain patients (particularly phakic patients). Unfortunately the effects of IVTA only last for up to ~6 months in most patients, when re-injection is required. Consequently this treatment is no longer used as a treatment of choice. The DRCRN group results from a large phase III study showed no difference in visual acuity between IVTA injections plus laser and laser alone after 1 year. Macular thickness (measured using OCT) was better in the IVTA group after 1 year, but not at 2 years. The lack of difference in 4 Specsavers Optical Group 2016

5 Figure 5: Iluvien pack visual acuity between these two groups could have been partially explained by the formation of cataract in the combination treatment group (IVTA + laser) as another sub-group of pseudophakic eyes produced better visual acuity results 34. This has consequently led to more recent developments involving the selective use of intravitreal steroids in pseudophakic patients. Patients who have DMO and cataract already may be treated with steroid injections first, in order to dry out the macula. As intravitreal steroids induce cataract, this is not such an issue if cataract surgery is planned anyway, with more favourable results post-operatively if DMO is minimised prior to cataract surgery. Now slow release intravitreal steroid implants have been introduced and are licensed for eye use. These include Fluocinolone acetonide (Iluvien, Almera Sciences) and Dexamthethasone (Ozurdex, Allergan) (figures 5&6). Iluvien has now been approved by the NICE for use in pseudophakic patients with chronic DMO that have failed to respond to laser or anti-vegf therapy e.g. Bevacizumab (Avastin, Genenetch/ Roche), Ranibizumab (Lucentis Genenetch/Roche) and most recently, Aflibercept (Eylea, Regeneron/ Bayer Healthcare) (see later). This is usually after a course of 6 Lucentis intravitreal injections with no clinically significant visual improvement (see below). This is in addition to their role in the treatment of central retinal and branch retinal vein occlusion (further discussion of these treatment modalities is beyond the scope of this article). Fluocinolone acetonide (Iluvien) Iluvien (Alimera Sciences Alpharetta GA) is a sustained release drug delivery device that has now received NICE approval for the treatment of chronic DMO. According to NICE ~90% of eligible patients with DMO respond well to anti-vegf therapy as discussed above. The remaining ~10% consist predominantly of pseudophakic patients with chronic DMO. In Phase II and III trials Iluvien showed favorable results where the steroid implant improved vision in almost twice as many patients as those treated with placebo. In addition, 75% of patients required only one application of the device 39. Iluvien releases fluocinolone acetonide over a month period, after injection (currently costing 5,000 per injection) into the eye. There is a significant risk of raised IOP and many of these patients need anti-glaucoma treatment. Approximately 40%- 50% of patients may experience a rise in IOP. A few may even need glaucoma filtration surgery as a result. For a variety of reasons, some diabetic patients are poor clinic attenders, so careful selection and monitoring of patients is required to ensure any IOP rises are detected in a timely way and treated appropriately. After this month period, some DMO may return. Iluvien treatment is not dependent on a minimum central macular thickness (CMT) of 400 microns as with anti-vegf treatments, which enables it to be used in any patient with chronic DMO who has failed to respond to laser or anti-vegf treatments. In summary, studies assessing the use of steroids (triamcinolone, dexamethasone and fluocinolone) have produced rather mixed results. In carefully selected cases however, where close monitoring is possible, Figure 6: Ozurdex pack they can be effective where other treatment modalities have not been successful. The main advantage of their use is the need for fewer injections, now that slow release steroid implants are available. Conclusions All current evidence suggests that the use of anti-vefg treatment is an effective treatment in DMO, especially with Ranibizumab and Bevacizumab. Patients with DMO (with CMT > 400 microns) are now being offered anti-vegf treatment in line with latest NICE guidance for the treatment of DMO using Ranibizumab in England. Ranibizumab, which has the most robust evidence in support of its use, is superior to laser treatment and adding laser treatment does not significantly improve visual outcomes for DMO. Aflibercept (Eylea) is now being routinely used as a new alternative to Ranibizumab in the treatment of wet AMD with the advantage of fewer injections being required compared to Ranibizumab. Aflibercept (which is licensed for eye treatment) is now increasingly used in DMO as an alternative to Ranibizumab with the advantage of needing fewer injections. Intravitreal steroid treatment has demonstrated mixed and disappointing outcomes because of the risks of causing cataract and inducing raised intraocular pressure and glaucoma. However the newer, slow release intravitreal steroid implants will increasingly be used for treatment of selected (pseudophakic) cases of chronic DMO where other treatment modalities have failed. In future it is likely that varying combinations of these treatment modalities may increasingly play an important role in managing DMO. References 1. Chen E, Looman M, Laouri M, et al., Burden of illness of diabetic macular oedema: literature review. Curr Med Res Opinion 2010; 26: Knudsen L, Lervang H, Lundbye-Christensen S, et al. The North Jutland county diabetic retinopathy study (NCDRS) 2. Non-ophthalmic parameters and clinically significant macular oedema. Brit J Ophthalmol 2007; 91: Thomas R, Dunstan F, Luzio S, et al,. Incidence of diabetic retinopathy in people with type 2 diabetes mellitus attending the diabetic retinopathy screening service for Wales: retrospective analysis. BMJ 2012; 344-e Minassian DC, Owens DR, Reidy A. Prevalence of diabetic macular oedema and related health and social card resource use in England. Brit J Ophthalmol 2012; 96: Liew G, Michaelides M, Bunce C. A comparison of the causes of blindness certificates in England and Wales in working age adults (16-64 years), with Chen E, Looman M, Laouri M, et al., Burden of illness of diabetic macular oedema: literature review. Curr Med Res Opinion 2010; 26: Knudsen L, Lervang H, Lundbye-Christensen S, et al. The North Jutland county diabetic retinopathy study (NCDRS) 2. Non-ophthalmic parameters and clinically significant macular oedema. Brit J Ophthalmol 2007; 91: Thomas R, Dunstan F, Luzio S, et al,. Incidence of diabetic retinopathy in people with type 2 diabetes mellitus attending the diabetic retinopathy screening service for Wales: retrospective analysis. BMJ 2012; 344-e Minassian DC, Owens DR, Reidy A. Prevalence of diabetic macular oedema and related health and social card resource use in England. Brit J Ophthalmol 2012; 96: Steele CF, Steel DHW, Wain C (2007) Eye Essentials: diabetes and the eye ISBN 13: BUTTERWORTH HEINEMANN 11. Barile GR, Pachydaki SI, Tari SR, et al,. The RAGE axis in early diabetic retinopathy. Invest Ophthalmol Vis Sci 2005; 46: Yancopoulos GD, Davis S, Gale NW. (2000) Vascular-specific growth factors and blood vessel formation. Nature 407, Specsavers Optical Group

6 13. Early Treatment of Diabetic Retinopathy Study Group (1985). Photocoagulation for for DME: early treatment diabetic retinopathy study report number 1. Arch Ophthalmol 103, Early Treatment of Diabetic Retinopathy Study Group (1987). Photocoagulation for diabetic macular oedema. ETDRS report no 4. Int Ophthalmol Clin 27, Early Treatment of Diabetic Retinopathy Study Group (1985). Photocoagulation for for DME: early treatment diabetic retinopathy study report number 1. Arch Ophthalmol 103, Lovestam-Adrian M, Agardh E. Photocoagulation of diabetic macular oedema complications and visual outcome. Acta Ophthalmol Scand 2000; 78: Jain A, Blumenkraz MS Paulus Y, Wilberger MW, Anderson DE. Huie P, et al (2008) Effect of pulse duration on size and character of the lesion in retinal photocoagulation. Arch Ophthalmol 126(1), Jain A, Collen J, Kaines A, et al. (2010) Short duration focal pattern grid macular photocoagulation for diabetic macular oedema. Retina 30, Blumenkraz MS, Yellachich D, Anderson DE, Wiltberger MW, MordauntD, Marcellino GO, et al. (2006) Semi-automated pattern scanning laser for retinal photocoagulation. Retina 26(3), Sivaprasad S, Elagouz M, McHugh D, et al. (2010) MIcropulsed diode laser therapy: evolution and clinical applications. Surv Ophthalmol 55, Witkin AJ and Brown GC (2011). Update on nonsurgical therapy for diabetic macular oedema. Curr Opin Ophthalmol 22, Aiello LP, Avery RL, Arrigg PG, et al. (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Eng J Med 331, Blumenkranz MS (2010) Optimal current and future treatments for diabetic macular oedema. Eye 24, Ranibizumab for treating diabetic macular oedema (rapid review of technology appraisal guidance 237) (accessed1/5/14) 25. Yancopoulos GD, Davis S, Gale NW (2000). Vascular-specific growth factors and blood vessel formation. Nature 407, Chakravarthy U, Harding S, Rogers C, et al,. (2013) Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. The Lancet 382 (9900): lancet/article/piis %2813% /abstract (accessed 1/5/14) 27. Cunningham ET, Adamis AP, Altaweel M, et al. (2005) A phase II randomized clinical trial of pegaptanib, an antivasculr endothelial growth factor aptamer, for diabetic macular oedema. Ophthalmology 112, Goyal S, Lavalley M, Subramian ML (2011) Meta-analysis and review on the effect of bevacizumab in diabetic macular edema. 29. Michaelides M, Fraser-Bell S, Hamilton R et al. (2010) Macular perfusion determined by fundus fluorescein angiography at 4 month time point in a prospective randomized trial of intravitreal bevacizumab or laser in the management of diabetic macular oedema. (BOLT study): report 1. Retina 30, Witkin AJ and Brown GC (2011). Update on nonsurgical therapy for diabetic macular oedema. Curr Opin Ophthalmol 22, Nguyen QD, Shah SM Heier JS, et al. (2009) Primary end point (six months) results of ranibizumab for oedema of the macula in diabetes (READ-2) study. Ophthalmology 117, Massin P, Bandello F, Garweg JG, et al (2010). Safety and efficacy of ranibizumab in diabetic macular oedema (RESOLVE study): a 12 month randomised, controlled, double masked, multi-centre phase II study. Diabetes Care 33, Diabetic Retinopathy Clinical Research Network. (2010) Randomised trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic oedema. Ophthalmology 117, Mushtaq B, Crosby NJ, Dimopoulos AT, et al,. Effect of initial retinal thickness on outcome of intravitreal bevacizumab therapy for diabetic macular oedema. Clinical Ophthalmology, 2014: Nussenblatt RB, Byrnes G, Sen N, et al (2010). A randomised pilot study of systemic immunosuppression in the treatment of age related macular degeneration. with choroidal neovascularisation. Retina 30, Nauck M, Karakiuliakis G, Perruchoud AP, et al. (1998) Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muslecle cells. Eur J Pharmacol 341, Joussen AM, Smyth N, Niessen C (2007). Pathophysiology of diabetic macular oedema. Dev Ophthlmol 39, Diabetic Retinopathy Clinical Research Network (2008). A Randomised trial comparing intravitreal triamcinolone actinide and focal /grid photocoagulation for diabetic oedema: a pilot study. Ophthalmology 115, Campochiaro PA, Hafiz G, Sha SM, et al. (2010). Sustained ocular delivery of fluocinolone acetonide bt an intravitreal insert. Ophthalmology 117, GOC s Enhanced CET Scheme CET and CPD regulators require practitioners to reflect on their learning. Additional activities are required to gain CET for distance learning. When you have completed your reading, close this window and return to ilearn/spectrum to choose your practitioner group and either interactive or non-interactive CET quiz. If you choose non-interactive you have to pass (>60%) a 6-question multiple choice quiz. If you choose interactive you must pass a MCQ quiz and complete a further 30-minute discussion with a colleague, and upload a short summary of your discussion and reflections within 30 days. Note you must complete both tasks before your CET can be awarded. If you want the CET counted within a calendar year make sure you submit the online record of discussion and remind your colleague to verify it online at least 2 weeks before the end of the year. Further instructions for interactive learning are as follows: The following steps must be completed within 30 days of completing the MCQ quiz: 1. Discuss the interactive questions below with a registered colleague. Note if you are an optometrist, the colleague must also be an optometrist. If you are a dispensing optician, the colleague may be a dispensing optician, a contact lens optician or an optometrist. The discussion should be in a quiet environment where you are not interrupted for at least 30 minutes. Discuss the set questions and record a summary of the output of your discussion. Please ensure to create a paper copy of your record, sign and date the document and keep it safely stored in case your CET is audited in future by the GOC. 2. In the event of an audit we need to be able to show the GOC that the interaction has taken place in accordance with the instructions. Therefore, before you can be given points for this activity you must, within 30 days, record your answers to the set questions in the online Discussion Record and Reflection form (link provided on ilearn/spectrum). 3. You will be asked for the GOC number, name and address of the colleague who has completed the interaction with you, so please have those ready. Your colleague will be contacted by (so please make sure you enter their correct address) and will be sent a link to verify the interaction took place. 4. You can only be awarded interactive CET points if these steps are completed within 30 days. The learning objectives for the interactive article are: Optometrists will have an understanding of the causes and clinical features of diabetic macular oedema enabling them to make appropriate clinical decisions and referrals. Optometrists and dispensing opticians will have an evidencebased understanding of treatments for diabetic macular oedema enabling them to give advice /answer patients questions. The discussion tasks for the interactive learning option are as follows. 1. What are the features of diabetic macular oedema (DMO) that are visible with standard optometric examination techniques, and what are the mechanisms which underlie the clinical features? 2. Discuss with your colleague anti-vascular endothelial growth factor (anti-vegf) therapy for macular oedema. What are the principal agents, their indications and are there any side-effects? 3. Reflecting on the reading and discussion a. what are the main things you learned from the reading? b. how will you apply this learning in your future practice? c. has this module identified for you any areas in which you wish to pursue further learning? 6 Specsavers Optical Group 2016