**9. Management of DME**

*Visual Impairment and Blindness - What We Know and What We Have to Know*

predictor for retinopathy deterioration [50, 51].

**7. Depression and anxiety**

with proliferative disease—all characteristics of concomitant chronic kidney disease and neuropathy in poorly controlled, long-lasting diabetes. Despite the lack of data on macular edema, the presence of any stage of diabetic foot ulcer is emerging as a

The overall prevalence of depressive symptoms in diabetic patients with retinopathy is estimated in the range of 35% in China to 50% in African Americans and is more prevalent in type 2 [52, 53]. The association between depressive symptoms, diabetes, and diabetic retinopathy is likely to be bidirectional: the impairment and burden of diabetes and its complications can precipitate depression and vice versa, and depression can impair diabetes control through various biological and behavioral pathways [54, 55]. Depression aggregates negative attitudes toward treatment and often leads to poorer glycemic control, less adherence to treatment, higher risk for PDR, greater morbidity and mortality, and higher costs [56]. Low income has been implicated in some research from the USA; however it was not found significant in a large cross-sectional study from Australia. Patients with longer duration of diabetes, worse glycemic control, lower educational level, and severe vision impairment below 20/63 were associated with greater depression symptoms. Symptoms of anxiety were associated with type 1 diabetes, presence of myocardial infarction/ angina, arrhythmia, stroke, asthma, anemia, arthritis or osteoporosis, younger age, and female gender [57]. Severe NPDR and PDR, but not macular edema, were independently associated with depressive symptoms, and the authors suggest that severity of retinopathy could be an indicator to prompt monitoring of depression in at-risk diabetic individuals. Antidepressant medications have been associated with slowing the progression of retinopathy in diabetic patients. However the outcome was limited to subjects with elevated C-reactive protein over 0.3 mg/dL. Selective serotonin reuptake inhibitor users had significantly lower risk of developing severe retinopathy than non-SSRI users [58]. The results of longitudinal studies show that the speed of cognitive decline in type 2 diabetic patients is up to twice as fast as that of normal aging individuals and diabetic patients have an increased risk of mild cognitive impairment (MCI). In addition, type 2 diabetic patients had an almost twofold higher risk of developing Alzheimer's disease than age-matched nondiabetic subjects. This increased risk was maintained even after adjusting for vascular risk factors. The annual conversion rate from MCI to dementia ranges between 10 and 30% in the general population, but this is much higher in the type 2 diabetic population. The impact of cognitive impairment on the compliance with lifelong retinopathy treatment and its outcome needs further evaluation; however clinical

practice indicates the need for personalized multidisciplinary approach.

The variability in the rate of progression to vision-threatening retinopathy and particularly in the response to treatment was noted from the onset of clinical and epidemiological studies in diabetic patients and has been attributed to the effect of genetic predisposition together with systemic and socioeconomic factors. Single-nucleotide polymorphisms [58–60] and genome-wide associations [61–63] have been investigated in patients with proliferative disease and macular edema, and the results so far are inconclusive mainly due to the size of the samples and the

**8. Progression to vision-threatening retinopathy**

**232**

The introduction of intravitreal anti-VEGF drugs and corticosteroid implants revolutionized the management of DME. Prospective randomized clinical trials have addressed the efficacy and safety of different types of agents and administration regimens and have shown wide variations in terms of visual acuity gain. In the DRCR.net trial, after 2 years of treatment, approximately 98% of the patients maintained their visual acuity and attained visual gain in 37% of the patients on ranibizumab, 35% of those on bevacizumab, and 39% of those on aflibercept [74]. Stratified analysis of RESTORE in DME, RETAIN, and Protocol I demonstrated that the most significant gain in number of EDTRS letters after 12–36 months was in patients with baseline BCVA 60 and less letters in the range of 8.6–10.36 letters, versus the gain for patients with baseline BCVA 61–71 letters who achieved 7.96–4.36 letters, and the least gain of 5.42–4.2 letters was in the group with baseline BCVA better that 73 letters [75]. Thus, the patients with most severe vision deterioration and baseline BCVA in the range of 20/320–20/63 who responded favorably to 2 years of intensive therapy improved to BCVA from 20/160 to 20/40. High visual acuity in the range of 20/40–20/32 was achieved only in patients with baseline BCVA over 20/30 despite the small number of gained EDTRS letters. The range and stability of this visual improvement depended on increasing age, level of glycemic control, and previous panretinal photocoagulation [76]. OCT markers of better functional outcome after anti-VEGF treatment were the presence of intact ellipsoid zone and lack of hyperreflective spots or disruption of the inner retinal layers, which are seen in patients with more recent onset of the edema and no previous macular grid laser [77]. Patients with chronic macular edema had considerably better functional and structural results after treatment with steroid implants. Visual gain of more than 15 letters was achieved in 22% after 3 years on intravitreal dexamethasone [78] and in 34% after 3 years on fluocinolone acetonide [79]. Eyes with submacular fluid, no hyperreflective foci, and a continuous IS-OS layer responded better to dexamethasone implants with gain of 10 or more letters after 2 and 4 months [80]. The adverse effects of both implants included the formation of cataract, 13–50% after 1 year on dexamethasone and 82% after 3 years on fluocinolone acetonide, and intraocular pressure rise over 25 mmHg in 42% of the eyes with dexamethasone and 38% with fluocinolone acetonide; however a small percentage required glaucoma surgery—0.5% of the eyes with dexamethasone and 4.8% with fluocinolone acetonide. Patients with poorly controlled diabetes and DME, severe nonproliferative or proliferative disease,

epimacular membranes, myopia, glaucoma, and various degrees of cataract are excluded from the randomized clinical trials; however such cases are predominant in real-world practice and add new dimensions to the challenge of visual rehabilitation. Analysis of large electronic medical record databases from the USA [81] and Korea [82] demonstrated visual outcomes that are meaningfully inferior to those in the clinical trials and were attributed to undertreatment and lack of close monitoring. A sizable group of DME patients were lost to follow-up in the initial stages of anti-VEGF treatment—25% were reported from a single retina practice in the USA and the main risk factors were being Hispanic, Black, or a Pacific islander; low income, AGI less than \$50,000; and decreasing baseline visual acuity [83]. In a study of European DME patients, 46% had at least one break-off in their anti-VEGF treatment for more than 100 days, and the most common reason for poor compliance was comorbidity. In 60% of these cases, the visual acuity deteriorated significantly after the break [84]. Prevention of vision loss from diabetic macular edema is achievable with the current therapeutic modalities; however it requires very early identification at stages with relatively high visual acuity and needs the introduction of best-corrected visual acuity and OCT in the screening protocol. As shown in the Protocol G—Subclinical DME study of the DRCR.net that involved a longitudinal assessment of eyes that had retinal thickening on OCT without thickening on clinical exam, a progression to clinically apparent DME was seen in 23–58% of eyes within 2 years.
