Pathophysiology ofdiabetic macular oedema Diabetic macular oedemacan be focal or diffuse. Focal oedema typically surrounds clusters ofmicroaneurysms, which have been demonstrated by fluorescein angio-graphy asbeing a major cause of leakage (Ahmadi and Lim, 2009). Diffuse diabetic macularoedema results from general breakdown of the blood–retinal barrier, which canbe induced by chronic hyperglycaemia (Ahmadi and Lim, 2009).
Chronichyperglycaemia leads to accumulation of abnormal metabolites from multipleoveractive biochemical pathways, inducing oxidative stress and causingvascular endothelial growth factor production to be upregulated. Vascularendothelial growth factor is a potent endothelial-specific mitogen that inducesvasodilatation, endothelial cell proliferation, production of pro-inflammatorycytokines and increased vascular permeability (Ferrara et al, 1992), whichultimately results in breakdown of the blood–retinal barrier with extravasationof fluid that accumulates as macular oedema. This process is often furthercompounded by associated conditions such as hypertension, dyslipidaemia andvascular inflammation (Bloomgarden, 2007; Morello, 2007). G.
R. Barile, S.I.Pachydaki, S.R. Tari, et al.The RAGE axis in early diabeticretinopathyInvest OphthalmolVis Sci, 46 (8) (2005), pp.
2916-2924https://www.ncbi.nlm.nih.gov/pubmed/16043866 & http://iovs.arvojournals.org/article.
aspx?articleid=2182667 (accessed on 09/01/2018) Diabetic retinopathy (DR) and diabetic maculopathy or diabetic macularoedema (DMO) are well characterised complications of DM associated with changeswithin the retinal vasculature and retinal thickening respectively, which canultimately result in permanent loss of vision. The development of these complicationscorrelates with the duration of diabetes so earlier onset of diabetes,increasing life expectancy, in addition to the growing number of patients withtype 2 DM, is likely to result in a significantly higher prevalence of DRglobally. DR has been declared a priority eye condition by the World HealthOrganization as timely intervention can prevent or delay loss of vision.
World Health Organization. Priority eye disease – diabetic retinopathy.http://www.
2012.00723.x/full Screening and diagnosis Recognizing the cost ofdiabetic eye disease to individuals and society prompted the launch ofscreening programmes across the world aimed at early detection andintervention. Patients in the UK with diabetes mellitus aged 12 years and overhave been systematically screened on an annual basis using digital fundusphotography for over 10 years (Peto and Tadros, 2012). Some 2.3 millionpatients were offered screening in 2011–12, with a nationwide uptake of 81%(NHS Diabetic Eye Screening Programme, 2013).
Strict grading criteria fordiabetic maculopathy have been defined alongside criteria for referral to thehospital eye service (Table 1). Within the hospital eyeservice there are a number of techniques available to ophthalmologists tovisualize and assess diabetic macular oedema. Clinical ophthalmoscopy with aslit lamp and biomicroscopic lenses is a subjective and qualitative methodroutinely used (Virgili et al, 2011). Fluorescein angiography can be useful inidentifying treatable lesions and areas of leakage. However, opticalcoherence tomography has become the key imaging technique. It producesthree-dimensional and cross-sectional images of the central retina, based onoptical reflectivity (Figure 2). This provides valuable information onretinal structure and thickness (Virgili et al, 2011) and is used as anobjective and quantitative assessment of macular oedema, both for initialevaluation and, importantly, in monitoring response to treatment. Management of diabeticmacular oedema As chronic hyperglycaemia initiates andpropagates the succession of pathogenic events, the ultimate management ofdiabetic macular oedema is strict glycaemic control (Turner et al, 1998).
Microvascular damage is compounded by hypertension, thus tight control of bloodpressure is essential (UK Prospective Diabetes Study Group, 1998). An emergingbody of evidence also supports a role for lipid-lowering agents in the managementof diabetic macular oedema, by reducing the severity of hard exudates andleakage of fluid (Panagiotoglou et al, 2010). However, despite efforts aimed atearly identification and aggressive treatment of diabetes mellitus and theseassociated risk factors, around a quarter of patients will develop diabeticmacular oedema within 10 years (Klein et al, 1995).
Therefore, in addition tothese systemic modifications an array of intraocular treatment modalities havebeen developed. Laser photocoagulation Macular laser photocoagulation has been theunequivocal gold standard of treatment for diabetic macular oedema sincepublication of the Early Treatment Diabetic Retinopathy Study in 1985. Thislarge multi-centre, randomized trial of nearly 4000 patients showed that focalapplication of laser to leaking aneurysms and grid treatment of diffusemacular leakage provided a 50% reduction in moderate visual loss after 3 yearscompared with untreated patients (Early Treatment Diabetic Retinopathy Study,1985) (Figure 3).
This study, which predates optical coherencetomography imaging, recommended laser photocoagulation for all patients withclinically significant macular oedema, as defined by the following criteria:retinal thickening within 500 ?m of the macula centre, hard exudates withassociated retinal thickening within 500 ?m of the macula centre, or a zone ofretinal thickening one disc area in size within one disc diameter of the maculacentre (Early Treatment Diabetic Retinopathy Study, 1985, 1991). Unlike panretinal photocoagulation, whichtreats proliferative diabetic retinopathy by reducing oxygen requirements ofthe retina through tissue destruction, the precise mechanism by which macularphotocoagulation treats diabetic macular oedema remains unknown. It is likelythat focal laser occludes leaking microaneurysms, contributing in part to itsefficacy (Royster et al, 1988).
Grid laser treatment is thought to work throughthe influence of macular tissue damage on autoregulation of retinal blood flow,reducing it and consequently any associated fluid shift (Wilson et al, 1988). Although effective atslowing or preventing further loss of vision, laser photocoagulation is noteffective at restoring vision. Potential complications include visible scarsthat can enlarge and encroach towards the fixation point (Bailey et al, 1999),reduced contrast sensitivity and colour vision (Morgan and Schatz, 1989), aswell as complications such as choroidal neovascularization (Roider et al,2000) and subretinal fibrosis (Stanga et al, 1999).Efforts to reduce therisks associated with thermal laser have led to the development of themicropulsed diode laser that delivers laser energy in short pulses rather thanas a continuous wave. The relative absorption of diode laser is 40% of that ofconventional argon lasers, yet it remains therapeutically effective (Ohkoshiand Yamaguchi, 2010) and with fewer side effects. Nevertheless, it stillproduces its clinical effect by causing iatrogenic retinal damage, and is stillassociated with visual stabilization rather than improvement. Corticosteroids Corticosteroids are anti-inflammatory agentseffective at reducing the permeability of retinal capillaries by enhancingendothelial cell tight junctions and downregulating the vascular endothelialgrowth factor metabolic pathway (Sears and Hoppe, 2005). This reduces leakageof plasma proteins into the interstitial space, helping to restore the osmoticgradient and resolve the oedema (Sivaprasad et al, 2006).
The first intravitrealcorticosteroid to be widely used in the treatment of diabetic macular oedemawas triamcinolone acetonide. Its benefits in treating diabetic macular oedemarefractive to laser photocoagulation and as primary therapy have been welldocumented (Sutter et al, 2004). Intravitreal triamcinolone provided greatershort-term improvements in visual acuity than laser photo-coagulation, but thiswas not sustained beyond 16 months (Beck et al, 2009). In practice, patientsrequire re-injection every 3–6 months as the effect diminishes. As with systemiccorticosteroids, intravitreal triamcinolone causes both cataract (Beck et al,2009) and glaucoma (Beck et al, 2009), and with each subsequent injection therisk increases.
Furthermore, intravitreal injection itself carries risk ofendophthalmitis, retinal detachment and vitreous haemorrhage. Therefore theneed for regular repeat injections is a major drawback of intravitreal triamcinolonetherapy. More recently,sustained-release steroid intraocular implants have been developed thatlengthen the reinjection interval and reduce side effects.
Ozurdex is a sustained-releasedexamethasone injectible device currently licensed for use in macular oedemafollowing retinal vein occlusion and uveitis. Its short-term benefits in themanagement of diabetic macular oedema are well documented, but effects arerarely sustained beyond 3–4 months (Pacella et al, 2013). A multi-centrerandomized controlled trial comparing laser plus Ozurdex with laser plus shamin patients with diffuse diabetic macular oedema found that although asignificant improvement in visual acuity was reported for the first 9 months inthose treated with Ozurdex, this was not maintained and significance was lostat 12 months (Callanan et al, 2013). Rates of raised intraocular pressure andcataract were higher in eyes receiving Ozurdex, but lower than that associatedwith intravitreal triamcinolone. Iluvien is a second-generation injectablefluocinolone acetonide device that has entered phase III trials for diabeticmacular oedema.
In patients with diabetic macular oedema previously treatedwith laser photocoagulation, a maxiumum of one Iluvien insert per year providedgreater improvement in visual acuity after 3 years when compared with sham.Rates of adverse effects were high; almost all phakic eyes developed cataractafter 3 years, and incisional glaucoma surgery was required in 8.1% of the highdose group (Campochiaro et al, 2012). Iluvien is currently approved by theNational Institute for Health and Care Excellence for use in pseudophakicpatients with diabetic macular oedema refractive to other therapies. Together, these trials demonstrate a validrole for steroid therapy in diabetic macular oedema, with well-documentedimprovements in vision. However, despite the development of sustained deliverysystems the duration of effect is limited.
With the risk of side effects beinghigh, a more effective and safer treatment modality is required. Vascular endothelial growth factor inhibitors As previously discussed, vascular endothelial growth factor playsa central role in the pathogenesis of diabetic macular oedema and is thereforea key therapeutic target. Indeed, multiple drugs that target vascularendothelial growth factor have been developed and tested in large phase III randomized trials for safety and efficacy in treatingdiabetic macular oedema.
These drugs are effective atreducing diabetic macular oedema and restoring vision,but require regular intravitreal injection. This exposespatients to higher risk of injection-related adverse eventsand places a strain on both eye clinics and budgets.Ranibizumab (Lucentis) is a humanized monoclonalanti-vascular endothelial growth factor antigen bindingfragment specifically designed for use in the eye. Itpotently inhibits the activity of all known isoforms ofvascular endothelial growth factor. There is a large bodyof robust evidence from multiple large phase III trialsdemonstrating its efficacy in reducing diabetic macularoedema, and three major trials have demonstrated itssuperiority over laser therapy (Nguyen et al, 2012). The3-year results of one trial highlight the importance ofearly treatment with ranibizumab (Brown et al, 2013). Tomaintain these effects, patients required an average ofseven injections with 12 monitoring visits in year one andthree injections with ten monitoring visits in year two,with a total cost of around ?10 000 perpatient (Mitchellet al, 2012).
Bevacizumab (Avastin) is a monoclonal anti-vascularendothelial growth factor antibody that binds and inhibitsall isoforms of vascular endothelial growth factor-A.Ocular use is currently unlicensed, yet numerous randomizedtrials have demonstrated its superiority over lasertherapy, intravitreal steroids and combinations of these,in treating diabetic macular oedema (Rajendram et al,2012). Again, regular repeat injections of bevacizumabwere required for maintenance of effect.Aflibercept (Eylea) is a fusion protein of human immunoglobulinand vascular endothelial growth factor receptorsthat binds multiple isoforms of vascular endothelialgrowth factor with high affinity. A major benefit ofaflibercept is its longer duration of action meaning fewerinjections and monitoring visits are required.
In thephase II clinical trial, laser therapy was compared with anaflibercept dosing regimen consisting of monthly injectionsfor 3 months followed by 2-monthly injections.After 6 months, patients treated with aflibercept demonstrateda significantly greater improvement in mean visualacuity and retinal thickness. One year follow up demonstratedthat 2-monthly injections were sufficient tomaintain these effects, with seven injections required intotal (Do et al, 2012).
Although this initial study ispromising, further data are required before drawing conclusionson aflibercept.Pegaptanib (Macugen) is PEGylated aptamer thatpotently bind vascular endothelial growth factor-165.When compared with sham injection, pegaptanib showedonly weak efficacy in treating diabetic macular oedemaand no further comparative trials were commenced(Sultan et al, 2011).These trials also demonstrated the safety of anti-vascularendothelial growth factor agents for intraocular use.The frequency of reported adverse events was low, withraised intraocular pressure being the only consistentlyreported side effect in a small proportion of patientsacross all anti-vascular endothelial growth factor therapies,excluding bevacizumab in which rates were comparablewith laser. As a result, anti-vascular endothelialgrowth factor agents are now considered first-line managementfor patients with diabetic macular oedema.Enzymatic vitreolysisThe observation that patients with spontaneous or surgicalposterior vitreous detachment had significantlyreduced rates of diabetic macular oedema or improvementof already established diabetic macular oedema(Tachi and Ogino, 1996) led researchers to believe thatvitreoretinal relationships at the macula play a key role.
Plasmin is a protease active against fibronectin and laminin,the proteins responsible for vitreous attachment tothe retinal surface. Researchers using intravitreal plasmin,either in autologous or recombinant forms (Ocriplasmin),to induce posterior vitreous detachment in patients withdiabetic macular oedema found that it effectively reducedmacular thickness and improved vision (Diaz-Llopis et al,2013). When compared to intravitreal triamcinolone,plasmin had a more sustained effect on both macularthickness and visual acuity without the concomitant risein intraocular pressure (Elsawy, 2012). These therapiesrepresent a promising new approach to treating diabeticmacular oedema.DiscussionThe past decade has seen a significant evolution in thetreatment of diabetic macular oedema. Laser was oncethe gold standard therapy, but now its role is debatable.
A robust evidence base supports anti-vascular endothelialgrowth factor drugs as primary therapy for diabeticmacular oedema. Both ranibizumab and bevacizumab aresuperior to laser, and adding laser confers no benefit.However, laser may still be used to treat very focal areasof leakage.There are no direct head-to-head trials of ranibizumaband bevacizumab, therefore choice is at the ophthalmologist’sdiscretion. Bevacizumab is currently unlicensed forintraocular use, but is considerably cheaper than licensedranibizumab.
Anti-vascular endothelial growth factordrugs represent a significant advance, but they are not thesolution; only half of patients gain ?10letters in visualacuity following treatment (Mitchell et al, 2011), andregular injections are required to maintain effect.Studies investigating the efficacy of steroid have mixedresults, but the association with cataract and raisedintraocular pressure is consistent. The effects of dexamethasoneimplants peak at 3 months and then diminish,requiring retreatment. Each retreatment increases the riskof complications. Fluocinolone requires fewer administrations,potentially one every 3 years, but rates of cataractare high. Some patients may opt for infrequent steroidinjections, accepting the considerable risk of cataractand small risk of glaucoma, over frequent anti-vascularendothelial growth factor injections, despite the difference in potentialacuity gain.
There also remains a place for steroids in patients not respondingto anti-vascular endothelial growth factor drugs. Furthermore, cataract is verycommon in diabetes, and many patients are pseudophakic when treatment fordiabetic macular oedema is required. As research continues,the management for diabetic macular oedema will constantly evolve. A range ofpromising new treatment modalities is currently under development that targetvarious elements of the cascade leading to diabetic macular oedema. Some aretopical agents (Callanan and Williams, 2008), which may play a major role inthe future.
The pathogenesis ofdiabetic macular oedema is multifactorial, so a combination of therapiesworking synergistically to target multiple pathways is likely to be needed.The presence of macular ischaemia, as evidenced by an enlarged foveal avascularzone on fluorescein angiography (Figure 4), is thought to contribute topoor visual outcomes following treatment (Chung et al, 2008). In the absenceof an effective therapy for macular ischaemia, complete resolution of visualloss is unlikely to be achievable. Diabetic macular oedema is an ongoingglobal problem, and although recent years have seen a number of significantadvances, the problem is far from solved.
How is diabetic maculopathy / diabetic macularoedema treated?Mildmacular oedema may resolve itself without treatment but most people will needthe first line of diabetic maculopathy treatment which is laserphotocoagulation treatment. Othertreatments include having injections of what are called anti-VEGF drugs(anti-vascular endothelial growth factor), such as Lucentis or Avastin. At the time ofwriting Avastin and Lucentis have not been approved for use in treatingdiabetic macular oedema by NICE but an appeal is underway by health charitiesto reverse the decision. InDecember 2012, Lucentis was approved for use intreating diabetic macular oedema in Scotland.Another treatment, which is rare because of the side effects thatcan exist, is to have injections of intravitreal steroids.
TreatmentTreatmentMedical treatment by the primary carephysician or diabetologistTheprimary care physician or the diabetologist isresponsiblefor the treatment of risk factors for retinalcomplications,including diabetes, arterial hypertension,andrenal disease. It was concluded in a recentreviewthat intense antihyperglycemic therapy in patientswithtype 2 diabetes leads to an approximately3%absolute reduction of the risk of retinopathy. Intensifiedantihyperglycemictherapy (e21) was associatedwith ahigher risk of hypoglycemia. Patients with highHbA1cvalues stand to benefit more from such therapy;forpatients with low HbA1c values, whose risk of diabeticcomplicationsis significantly lower, the benefits and risks of treatment intensificationmust be jointlydiscussedby the patient and the physician. The effect ofintensifiedtreatment of either diabetes or hypertensiononretinal complications is but one of many factors(someof them still inadequately defined) to beconsideredin weighing its benefits against its risks.Moreinformation on this topic can be found in theevidence-basedguidelines on the individualized treatmentofdiabetes and its complications (www.diabetes.
versorgungsleitlinien.de,www.awmf.org/leitlinien/detail/ll/057–013.html).Special ophthalmological treatmentTheophthalmologist is responsible for appropriatediagnosticevaluation and treatment corresponding tothepatient’s stage of disease, and for monitoring thecourseof diabetic retinopathy and/or maculopathy.
Thetreatmentoptions for diabetic retinal complications includelasertherapy and intravitreal operativemedication(IVOM). The most important considerationsfor thechoice of treatment are the distinction betweenproliferativeand nonproliferative retinopathyand thepresence or absence of clinically significantmacular edema, with or without foveal involvementDeutschesÄrzteblatt International | Dtsch Arztebl Int 2016; 113: 816–23 | SupplementarymaterialDiabetic maculopathy is often treated by lasersurgery. For cystoid macular edema due todiabetes or a stroke in the retina, laser treatment is usually recommended asthe first choice. … If the swelling does not go away after thattime or it comes back later, the laser treatment can be repeated.When the macula swells with fluid, acondition called macula edema, vision blurs and can be lostentirely.