**22. Vitrectomy as first choice**

The introduction of small gauge platforms and refined instrumentation have greatly improved the safety and reliability of PPV as primary treatment for eyes with DME and vitreomacular traction. The role of primary PPV for eyes with DME without traction elements is less clear. An earlier publication of Michalewska Z et al. [52] on 20-G vitrectomy and ILM removal, the multicenter trial of Iglicki M et al. [53] using 25-G PPV and ILM peeling and the report of Lin HC et al. [54] on 23-G vitrectomy with ILM peeling as a first line treatment for DME demonstrate substantial increase and stabilization of visual acuity, macular fluid resolution and rapid regression of hard exudates, without additional therapy up to 24 months post surgery. Prognostic factors associated with a greater visual gain include no history of prior macula laser treatment, lower hemoglobin A1c, recent onset of the edema and younger age, however delay of the procedure and damage of the IS/OS and ellipsoid zone at baseline had negative effect on the vision gain 12 and 24 months postoperatively. The complications after PPV can not be ignored – lamellar and full-thickness macular holes, non-resolving preretinal hemorrhages and rhegmatogenous retinal detachments have all been reported, and up to 50% of the phakic eyes develop significant cataract during the next 12 to 24 months that requires surgery compared to 7.14% of the eyes in the pharmacotherapy group [53]. These results suggest that earlier intervention with pars plana vitrectomy may be beneficial for treatmentnaïve eyes, but they need to be replicated in larger prospective controlled trials.

## **23. Management of diabetes and its complications**

Partnership and regular consultations with the diabetologist or treating physician are essential part of the management in high-risk DME patients. The adjustments or frank replacement of diabetic medications, provision of glycemic monitoring devices, lifelong screening for cardiovascular and renal complications, prompt referral to the necessary subspecialist create the foundation for better glycemic control, improved stability and less severe retinal complications. Regular measurements of HbA1c at the retinal clinic and RBS prior to intravitreal injections easily screen patients with unsatisfactory glycemic control and have become routine in our practice. Sudden worsening of the retinopathy and macular edema are often preceding serious systemic complications and a swift arrangement for medical assessment may prevent a major disability or even save the life of the patient (**Figure 1**). Discussing the medical background with a patient presenting with relapsing DME reveals sometimes bureaucratic and financial barriers to qualified medical care. Direct contacts with a dedicated medical team and suitable procedures for referral are particularly helpful in challenging situations that need consistent management. Holistic approach, continuous interest and candid conversations with the patients improve substantially the compliance and, in the long run, the outcome of DME treatment.

#### **24. First outcome – review and adjustments of the treatment**

Careful observation of high-risk eyes one week after the first anti-VEGF intravitreal injection reveals a degree of fluid resolution (**Figure 2c**) and its recurrence one month later. Rather than lack of response, this indicates ongoing retinal ischaemia and the need for tight metabolic control and management of systemic comorbidities. An early positive response on OCT may not be associated with immediate improvement of the visual acuity, however the monthly injections with the chosen drug need to be

#### *High-Risk Diabetic Maculopathy: Features and Management DOI: http://dx.doi.org/10.5772/intechopen.99748*

continued until the loading dose is completed. Meanwhile, if patient and physician have decided to perform further laser treatment for eyes with PDR and severe ischemia, it is split in suitable intervals. Intensive metabolic control - and the much needed changes in the diet – are usually followed by short episodes of hypoglycemia and deterioration of the retinopathy severity and recurrences of the edema. The patients need to be prepared for this difficult initial period in order to comply with the visits and procedures without anxiety and confusion. Monthly monitoring of eyes with advanced maculopathy is highly advisable – edema that is persistent after one or two anti-VEGF injections and is associated with large cysts, hyperreflective spots and particularly progressive disorganization in the outer retinal layers indicate severe disruption of the blood-retinal barrier and active inflammation. Extending the loading dose to 24 weeks will not provide better functional or anatomic outcomes and prompt transition to a dexamethasone implant at this point will be more beneficial (**Figure 4g**). At month 12, the probability of achieving a BCVA improvement of ≥10 letters was reported as 3.71 times greater after intravitreal dexamethasone vs. anti-VEGF treatment [55]. High-risk eyes with good response to anti-VEGF in terms of vision gain and fluid resolution by the end of the 3rd to 4th month, need sufficient number of injections and comprehensive medical care in the next years in order to maintain the outcome. Patients with high vision and completed intravitreal course in the first 2 years may present with recurrences - they are still at high risk – however they continue responding well to treatment and retain the acuity with minor variations.

An eye with a high-risk DME, good response to dexamethasone implant as initial treatment and well controlled IOP is already facing recurrence of the edema and deterioration of vision after 3 to 4 months (**Figure 4h**). Insertion of the implant at this point reduces the fluctuations in the edema and resulting detrimental changes in the outer retina. Improved metabolic control, successful cardio-vascular management and particularly, induction into hemodialysis are associated with more stable maculopathy – this allows increase the intervals between implants or even transition to anti-VEGF on "as needed" regimen.

### **25. Further management**

The eyes with high-risk DME remain unstable even after they have responded well to intravitreal treatment. The patients often present with recurrences during and after severe systemic infections, major surgeries, trauma and stress. There are also fluctuations in the edema associated with variations in the metabolic control, ongoing ischemic events in patient with cardiac and renal complication and ocular surgeries. The visual acuity of a well treated diabetic eye is not severely affected by the new fluid in the first few months, however if left untreated, it causes gradual functional deterioration that may not be reversible. The management of these eyes is oriented towards early detection of the recurrences and timely treatment, in parallel with dynamic collaboration with the diabetologist in order to control the systemic complications.

Frequent assessment, sufficient number of intravitreal injections and adequate treatment of the retinopathy in the first 2 years are critical, and they need to continue for lifetime in order to maintain the visual outcome. The initial therapy needs modifications and combinations in response to the challenges of the disease.

A shift to a longer acting medication needs to be considered for eyes that can not remain stable for more than 45–60 days. There are some early results from the KITE and KASTREL studies on brolucizumab where 55.1% of the eyes in KESTREL and 50.3% of the eyes in KITE remained on a three-month dosing interval through year one, based on a treatment approach determined by disease activity assessment. If disease activity was detected, the patients were switched to two-month intervals through the end of the first

year [56]. Faricimab, the first bispecific antibody to target both anti-Angiopoietin-2 and anti-vascular endothelial growth factor (VEGF) was investigated in YOSEMITE and RHINE trials as monotherapy for DME. More than 70% of patients achieved every-12 week or better dosing status at week 52--73.8% in the YOSEMITE study and 71.1% in the RHINE study with every 12-week and every-16-week dosing [57].

Temporary use of dexamethasone implants is convenient for systemically unstable patients or in preparation for major surgeries or ocular procedures - this will reduce the probability of severe inflammation and macular edema, provided the patient is able to use the antiglaucoma drops.

A patient with favorable response to dexamethasone is a good candidate for an intravitreal fluocinolone sustained-release Implant (**Figure 4g** and **m**). Two parallel, prospective, randomized, sham injection-controlled, double-masked, multicenter clinical trials (FAME trials) demonstrated significant reduction of the central macular thickness, mean BCVA improvement and a higher proportion of patients achieving a BCVA improvement of ≥15 letters in eyes with the implant vs. sham. The need of glaucoma surgery was 3.7% and 0.5% in the implant and sham groups, respectively [58]. A comparison of the effectiveness and safety of the fluocinolone acetonide intravitreal implant between the observational Iluvien Clinical Evidence study in the United Kingdom (ICE-UK) and the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) randomized controlled trials (RCTs) in people with diabetic macular edema demonstrated statistically significant improvements in visual acuity 12 months after implantation in both the real-world study and in the RCTs. The improvement in vision and central retinal thickness in the RCTs was marginally greater than in the real-world study; however, recruits in the real-world study had more severe visual morbidity at baseline [68].

Flexible arrangements for walk-in visits or open appointments prevent delays in the evaluation of patients missing their regular review or presenting with a deterioration. Leaving a few empty slots for such unplanned patients in the daily schedule decreases the disorder in the medical retina clinic. A registry of the DME patients is useful in tracking any lapse in treatment of 3 months or longer that increases the probability of poorer outcome.

#### **Author details**

Maya G. Pandova New Ahmadi KOC Hospital, Ahmadi, Kuwait

\*Address all correspondence to: mayapandova@gmail.com

© 2021 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, provided the original work is properly cited.

*High-Risk Diabetic Maculopathy: Features and Management DOI: http://dx.doi.org/10.5772/intechopen.99748*
