**10. Management of proliferative disease**

Vision loss in approximately 25% of patient with diabetic retinopathy is associated with complications of proliferative disease. An estimated 17 million diabetic people worldwide have PDR [17], and without treatment more than half of the patients with high-risk PDR will be blind within 5 years. Panretinal photocoagulation was established as an effective treatment to reduce by 50% the incidence of severe vision loss, if performed prior to the development of vitreous hemorrhages and tractional retinal detachment [85]. Still, the EDTRS has shown that 5% of patients with PDR will require vitreous surgery despite having received adequate PRP [86]. The Diabetic Retinopathy Vitrectomy Study validated the superiority of vitrectomy over observation; however despite the fact that the trial did not include patients with macula, involving traction, the visual outcome was low. Subsequent studies on vitrectomy for PDR reported that between 10 and 20% of the patients did not improve their visual acuity above hand motion or less [87]. Favorable factors for visual rehabilitation after vitrectomy for macula-involving tractional retinal detachment included short duration of detachment, previous panretinal photocoagulation, and lack of severe neovascularization and vitreous hemorrhage. Predictors of poor visual results were iris neovascularization and neovascular glaucoma, papillo-vitreal traction, baseline visual acuity below 20/200, initial macular detachment, intraoperative iatrogenic break, or use of heavy silicone oil [88–90]. Functional outcome was significantly affected in patients with postoperative macular ischemia, recurrent vitreous hemorrhage, optic atrophy, epiretinal membranes, and recurrent retinal detachment [91, 92]. The introduction of small-gauge vitrectomy instruments and trans-scleral cannulas enabled the fast and effective removal of most fibrovascular membranes with the vitrectomy probe applying the lift and shave technique [93]. Visual outcomes were poorer in older age group, tractional retinal detachments involving macula and eyes with extensive membranes and with silicone oil as tamponade; however both 23-gauge and 25-gauge groups were comparable in relation to visual improvement, anatomical success, and intraoperative

**235**

*Diabetic Retinopathy and Blindness: An Epidemiological Overview*

and postoperative complications [94]. The integration of swept-source optical coherence tomography and digital displays can provide important guidance during surgery for PDR complications and facilitate decision-making [95]; however further research will show whether these technological advances will translate into

Medical treatment for PDR has had minimal advancement over the past 40 years since the wide acceptance of panretinal photocoagulation in the early management of the disease. Regression of proliferative activity was noted in eyes treated with anti-VEGF for concomitant macular edema [96] and that lead to a series of trials on aflibercept and ranibizumab versus panretinal photocoagulation in the management of PDR. Both drugs were superior to PRP in 1 [97] and 2 years [98] in terms of visual acuity and visual field sensitivity. Assessment of the peripapillary retinal nerve fiver layer thickness in patients treated with ranibizumab revealed reduction that was due to decreased edema rather than loss of axons [99]. Patients with mild and moderate vitreous hemorrhages treated with ranibizumab had significantly less need for vitrectomy, less recurrences of hemorrhage, and better visual acuity on all follow-up visits than the patient under observation or operated for non-resolving or aggravated hemorrhages [100]. However, despite the improvement in retinopathy severity on color photographs, the retinal perfusion did not improve on wide-field fluorescein angiography that revealed no reperfusion of small vessels in areas of previous capillary non-perfusion [101]. Diabetic patients are prone to significant loss to follow up due to illness, financial hardship, and lack of compliance. The rate of complications and loss of vision after unintentional interruptions for more than 6 months in PDR patients treated only on anti-VEGF was considerably higher than the eyes that received PRP, with a significantly higher number of eyes with tractional retinal detachment and neovascularization of the iris [102]. In a retrospective review of 13 eyes treated exclusively with anti-VEGF for PDR with or without macular edema or severe NPDR with macular edema, with hiatus of 12 months, 9 presented with vitreous hemorrhage, 5 with neovascular glaucoma, and 4 with tractional retinal detachment. Despite the aggressive treatment of the complications, 10 eyes lost more than 3 lines of vision, and 2 had final vision hand motions [103]. So, while anti-VEGF proved to be effective for PDR in the clinical trials, in real-world the unclear long-term advantages of pharmacological monotherapy over PRP, the increased cost, and treatment burden are not optimal for many diabetic patients. Neovascular glaucoma is a late complication of proliferative disease with chronic ischemia in the posterior segment and development of a fibrovascular membrane on the anterior surface of the iris and iridocorneal angle of anterior chamber, and usually its onset correlates with poor glycemic control. In the early stages, iris neovascularization can be found without elevated IOP. Panretinal photocoagulation remains the mainstay in controlling the neovascular drive and should be considered in all cases of neovascularization of the anterior segment when retinal ischemia is present. After panretinal photocoagulation, complete regression of retinal neovascularization can be reached in 67–77% of cases, visual loss can be prevented in 59–73%, and IOP reduction can be achieved in 42% [104]. Anti-VEGF injections can lead to regression of both iris and angle neovascularization and improve intraocular pressure control when the angle remains open. However, the effects of anti-VEGF agents seemed to induce only a temporary regression of new vessels in the anterior chamber angle and IOP reduction, generally lasting between 4 and 6 weeks [105]. Glaucoma drainage devices are usually considered the first treatment option for refractory glaucoma. Neovascular glaucoma patients are at greater risk for surgical failure after glaucoma valve surgery compared with non-neovascular glaucoma controls. A recent retrospective, comparative, case series of 163 eyes of 151 patients with neovascular glaucoma included 99 treated without and 64 treated

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

better postoperative visual outcome.

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

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

23–58% of eyes within 2 years.

**10. Management of 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

Vision loss in approximately 25% of patient with diabetic retinopathy is associated with complications of proliferative disease. An estimated 17 million diabetic people worldwide have PDR [17], and without treatment more than half of the patients with high-risk PDR will be blind within 5 years. Panretinal photocoagulation was established as an effective treatment to reduce by 50% the incidence of severe vision loss, if performed prior to the development of vitreous hemorrhages and tractional retinal detachment [85]. Still, the EDTRS has shown that 5% of patients with PDR will require vitreous surgery despite having received adequate PRP [86]. The Diabetic Retinopathy Vitrectomy Study validated the superiority of vitrectomy over observation; however despite the fact that the trial did not include patients with macula, involving traction, the visual outcome was low. Subsequent studies on vitrectomy for PDR reported that between 10 and 20% of the patients did not improve their visual acuity above hand motion or less [87]. Favorable factors for visual rehabilitation after vitrectomy for macula-involving tractional retinal detachment included short duration of detachment, previous panretinal photocoagulation, and lack of severe neovascularization and vitreous hemorrhage. Predictors of poor visual results were iris neovascularization and neovascular glaucoma, papillo-vitreal traction, baseline visual acuity below 20/200, initial macular detachment, intraoperative iatrogenic break, or use of heavy silicone oil [88–90]. Functional outcome was significantly affected in patients with postoperative macular ischemia, recurrent vitreous hemorrhage, optic atrophy, epiretinal membranes, and recurrent retinal detachment [91, 92]. The introduction of small-gauge vitrectomy instruments and trans-scleral cannulas enabled the fast and effective removal of most fibrovascular membranes with the vitrectomy probe applying the lift and shave technique [93]. Visual outcomes were poorer in older age group, tractional retinal detachments involving macula and eyes with extensive membranes and with silicone oil as tamponade; however both 23-gauge and 25-gauge groups were comparable in relation to visual improvement, anatomical success, and intraoperative

**234**

and postoperative complications [94]. The integration of swept-source optical coherence tomography and digital displays can provide important guidance during surgery for PDR complications and facilitate decision-making [95]; however further research will show whether these technological advances will translate into better postoperative visual outcome.

Medical treatment for PDR has had minimal advancement over the past 40 years since the wide acceptance of panretinal photocoagulation in the early management of the disease. Regression of proliferative activity was noted in eyes treated with anti-VEGF for concomitant macular edema [96] and that lead to a series of trials on aflibercept and ranibizumab versus panretinal photocoagulation in the management of PDR. Both drugs were superior to PRP in 1 [97] and 2 years [98] in terms of visual acuity and visual field sensitivity. Assessment of the peripapillary retinal nerve fiver layer thickness in patients treated with ranibizumab revealed reduction that was due to decreased edema rather than loss of axons [99]. Patients with mild and moderate vitreous hemorrhages treated with ranibizumab had significantly less need for vitrectomy, less recurrences of hemorrhage, and better visual acuity on all follow-up visits than the patient under observation or operated for non-resolving or aggravated hemorrhages [100]. However, despite the improvement in retinopathy severity on color photographs, the retinal perfusion did not improve on wide-field fluorescein angiography that revealed no reperfusion of small vessels in areas of previous capillary non-perfusion [101]. Diabetic patients are prone to significant loss to follow up due to illness, financial hardship, and lack of compliance. The rate of complications and loss of vision after unintentional interruptions for more than 6 months in PDR patients treated only on anti-VEGF was considerably higher than the eyes that received PRP, with a significantly higher number of eyes with tractional retinal detachment and neovascularization of the iris [102]. In a retrospective review of 13 eyes treated exclusively with anti-VEGF for PDR with or without macular edema or severe NPDR with macular edema, with hiatus of 12 months, 9 presented with vitreous hemorrhage, 5 with neovascular glaucoma, and 4 with tractional retinal detachment. Despite the aggressive treatment of the complications, 10 eyes lost more than 3 lines of vision, and 2 had final vision hand motions [103]. So, while anti-VEGF proved to be effective for PDR in the clinical trials, in real-world the unclear long-term advantages of pharmacological monotherapy over PRP, the increased cost, and treatment burden are not optimal for many diabetic patients.

Neovascular glaucoma is a late complication of proliferative disease with chronic ischemia in the posterior segment and development of a fibrovascular membrane on the anterior surface of the iris and iridocorneal angle of anterior chamber, and usually its onset correlates with poor glycemic control. In the early stages, iris neovascularization can be found without elevated IOP. Panretinal photocoagulation remains the mainstay in controlling the neovascular drive and should be considered in all cases of neovascularization of the anterior segment when retinal ischemia is present. After panretinal photocoagulation, complete regression of retinal neovascularization can be reached in 67–77% of cases, visual loss can be prevented in 59–73%, and IOP reduction can be achieved in 42% [104]. Anti-VEGF injections can lead to regression of both iris and angle neovascularization and improve intraocular pressure control when the angle remains open. However, the effects of anti-VEGF agents seemed to induce only a temporary regression of new vessels in the anterior chamber angle and IOP reduction, generally lasting between 4 and 6 weeks [105]. Glaucoma drainage devices are usually considered the first treatment option for refractory glaucoma. Neovascular glaucoma patients are at greater risk for surgical failure after glaucoma valve surgery compared with non-neovascular glaucoma controls. A recent retrospective, comparative, case series of 163 eyes of 151 patients with neovascular glaucoma included 99 treated without and 64 treated

with intravitreal bevacizumab. IOP decreased to 18.3 ± 13.8 mmHg in the nonbevacizumab group and 15.3 ± 8.0mmHg in the bevacizumab group. Panretinal photocoagulation substantially reduced the need for glaucoma surgery (*P* < 0.001) in bevacizumab-treated eyes. Therefore, although bevacizumab delayed the need for glaucoma surgery, panretinal photocoagulation was the most important factor that reduced the need for surgery. Vision and IOP in eyes with neovascular glaucoma treated with bevacizumab showed no long-term differences when compared with eyes that were not treated with bevacizumab. Thus, intravitreal anti-VEGF drugs serve as an effective temporizing treatment but are not a replacement for close monitoring and definitive treatment of neovascular glaucoma [106, 107].

Impairment of vision in diabetic patients is not limited to retinopathy—the leading causes of deteriorated vision and progression of vision loss in a cohort from South India were cataracts and uncorrected refractive errors [108]. The introduction of phacoemulsification significantly reduced the surgical trauma and leads to a growing tendency toward earlier cataract surgery in diabetic patients [109]. This approach facilitates panretinal photocoagulation and allows for the identification and adequate treatment of diabetic macular edema before and after cataract surgery. Preexisting macular edema can increase the risk of edema progression by 20–50%, and intravitreal anti-VEGF agents are recommended perioperatively [110]. Steroids, on the other hand, have been shown to be effective for persistent or refractory diabetic macular edema prior to and after cataract procedures. Dexamethasone implants and fluocinolone implants resulted in significant improvement in clinically significant macular edema and visual outcomes [111]. Despite the advancement in phacoemulsification technology, poor visual acuity following cataract extraction is still common in patients with diabetes. Posterior capsule opacification, postoperative cystoid macular edema, diabetic macular edema [112], and worsening of the DR are the main complications seen in diabetic patients. According to the Early Treatment of Diabetic Retinopathy Study, the presence of clinically significant diabetic macular edema at the time of cataract surgery was significantly associated with poor visual acuity and was a predictor of final visual acuity worse than 20/200 following uncomplicated phacoemulsification [113]. The severity of DR at the time of cataract surgery is also a significant determinant of postoperative VA; more severe retinopathy seems to be associated with an increased prevalence of macular ischemia or edema and a reduced tendency for spontaneous resolution of postoperative macular edema with associated poor postoperative VA. Treatment-naïve PDR before cataract surgery may progress to vitreous hemorrhage and tractional retinal detachment following phacoemulsification, thus threatening good visual outcome [114].

In conclusion, vision loss due to diabetic complications in the eye is growing worldwide despite availability of screening programs, advanced diagnostic tools, pharmacotherapy, and rapidly evolving surgical technology. Prevention requires:


**237**

**Author details**

Maya Georgieva Pandova

mayapandova@gmail.com

KOC Ahmadi Hospital, Ahmadi, Kuwait

provided the original work is properly cited.

\*Address all correspondence to: mpandova@kockw.com;

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Diabetic Retinopathy and Blindness: An Epidemiological Overview*

• Close, continuous collaboration with the treating diabetology team

and mental disability, and improvement of quality of life

• Involvement of the family, community, diabetic patients' organizations, and social media in patient care, adherence to treatment, prevention of physical

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

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

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

with intravitreal bevacizumab. IOP decreased to 18.3 ± 13.8 mmHg in the nonbevacizumab group and 15.3 ± 8.0mmHg in the bevacizumab group. Panretinal photocoagulation substantially reduced the need for glaucoma surgery (*P* < 0.001) in bevacizumab-treated eyes. Therefore, although bevacizumab delayed the need for glaucoma surgery, panretinal photocoagulation was the most important factor that reduced the need for surgery. Vision and IOP in eyes with neovascular glaucoma treated with bevacizumab showed no long-term differences when compared with eyes that were not treated with bevacizumab. Thus, intravitreal anti-VEGF drugs serve as an effective temporizing treatment but are not a replacement for close monitoring and definitive treatment of neovascular glaucoma [106, 107]. Impairment of vision in diabetic patients is not limited to retinopathy—the leading causes of deteriorated vision and progression of vision loss in a cohort from South India were cataracts and uncorrected refractive errors [108]. The introduction of phacoemulsification significantly reduced the surgical trauma and leads to a growing tendency toward earlier cataract surgery in diabetic patients [109]. This approach facilitates panretinal photocoagulation and allows for the identification and adequate treatment of diabetic macular edema before and after cataract surgery. Preexisting macular edema can increase the risk of edema progression by 20–50%, and intravitreal anti-VEGF agents are recommended perioperatively [110]. Steroids, on the other hand, have been shown to be effective for persistent or refractory diabetic macular edema prior to and after cataract procedures. Dexamethasone implants and fluocinolone implants resulted in significant improvement in clinically significant macular edema and visual outcomes [111]. Despite the advancement in phacoemulsification technology, poor visual acuity following cataract extraction is still common in patients with diabetes. Posterior capsule opacification, postoperative cystoid macular edema, diabetic macular edema [112], and worsening of the DR are the main complications seen in diabetic patients. According to the Early Treatment of Diabetic Retinopathy Study, the presence of clinically significant diabetic macular edema at the time of cataract surgery was significantly associated with poor visual acuity and was a predictor of final visual acuity worse than 20/200 following uncomplicated phacoemulsification [113]. The severity of DR at the time of cataract surgery is also a significant determinant of postoperative VA; more severe retinopathy seems to be associated with an increased prevalence of macular ischemia or edema and a reduced tendency for spontaneous resolution of postoperative macular edema with associated poor postoperative VA. Treatment-naïve PDR before cataract surgery may progress to vitreous hemorrhage and tractional retinal detachment following phacoemulsification, thus threatening good visual

In conclusion, vision loss due to diabetic complications in the eye is growing worldwide despite availability of screening programs, advanced diagnostic tools, pharmacotherapy, and rapidly evolving surgical technology. Prevention requires:

• Identification of the social groups and individuals at high risk of vision-

• Coverage with diabetic retinopathy screening with introduction of AI tools, wide-field retinal assessment, telemedicine, and OCT of the posterior segment

• Early, intensive management before significant vision loss

• Outreach of qualified management closer to the diabetic patients' communities

• Lifetime, highly qualified monitoring and early management of complications

threatening diabetic complications

**236**

outcome [114].

