**7. Depression and anxiety**

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.

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

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

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*Diabetic Retinopathy and Blindness: An Epidemiological Overview*

inclusion of cases with coexisting proliferations and edema in the cohorts. Detailed assessment in the polymorphisms of the VEGF gene revealed that some of them are related to higher susceptibility to severe retinopathy, but not to the outcome of ranibizumab intravitreal injections [64] in contrast to an earlier report on the response to bevacizumab [65]. In order to confirm the association of several novel genetic loci with severe retinopathy, replication studies and extension in additional cohorts and ethnic groups have been recommended [66]. Research of systemic and retinal inflammation as risk factors for DR and DME [67, 68], upregulated leptin [69, 70] and adiponectin [71], oxidative stress [72], and vitamin D deficiency [73] has provided significant associations. Reliable and accessible markers of these factors can be important predictors of the disease severity and progression and thus provide early guidance in personalizing the monitoring and treatment of the

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,

*DOI: http://dx.doi.org/10.5772/intechopen.88756*

patients at risk of vision loss.

**9. Management of DME**

*Diabetic Retinopathy and Blindness: An Epidemiological Overview DOI: http://dx.doi.org/10.5772/intechopen.88756*

inclusion of cases with coexisting proliferations and edema in the cohorts. Detailed assessment in the polymorphisms of the VEGF gene revealed that some of them are related to higher susceptibility to severe retinopathy, but not to the outcome of ranibizumab intravitreal injections [64] in contrast to an earlier report on the response to bevacizumab [65]. In order to confirm the association of several novel genetic loci with severe retinopathy, replication studies and extension in additional cohorts and ethnic groups have been recommended [66]. Research of systemic and retinal inflammation as risk factors for DR and DME [67, 68], upregulated leptin [69, 70] and adiponectin [71], oxidative stress [72], and vitamin D deficiency [73] has provided significant associations. Reliable and accessible markers of these factors can be important predictors of the disease severity and progression and thus provide early guidance in personalizing the monitoring and treatment of the patients at risk of vision loss.
