**11. Diabetic macular edema after vitrectomy**

The development and use of smaller gauge instrumentation has been associated with a trend towards earlier surgical intervention for diabetic retinopathy. PPV indications include non-clearing vitreous hemorrhages, traction retinal detachment in PDR, and vitreoretinal interface abnormalities impeding macular edema resolution. The role of pars plana vitrectomy (PPV) for eyes with DME without traction elements is less clear. Debate still exists as to the necessity of ILM removal during vitrectomy for DME [39]. Several studies over the past 3 decades have established the structural improvements following vitrectomy in recalcitrant DME cases. Visual improvements however have not been as consistent and as significant as the reduction in retinal thickness following the procedure. Surgical intervention continues to be reserved for those cases that have had chronic and severe forms of DME when retinal damage is usually irreversible thereby compromising the results [40]. Vitrectomy itself is associated with morphological changes in the posterior pole. Detailed evaluation of the macular microstructure after vitrectomy has demonstrated deteriorated photoreceptor outer segment (PROS) length, ellipsoid zone (EZ) and external limiting membrane (ELM). The postoperative recovery was uneven – while PROS increased significantly after 12 months, ELM recovered but did not improve by 24 months when compared to baseline, and the EZ continued improving up to 24 months [41, 42]. Another factor contributing to lower postoperative visual results is post-vitrectomy cystoid macular edema that ranges between 5–47% and has been associated with combined cataract surgery, silicone oil tamponade and its removal, and removal of retained lens fragments in the diabetic eye. This inflammatory condition needs to be differentiated from a recurrence of pre-existing DME after PPV. The presence of dense hard exudates, disorganized retinal layers in the edematous macula, paramacular laser spots, capillary dropout on OCTA and persistent ischemic changes anywhere in the retina indicate the increased risk of poor postoperative vision, however, early intensive management on intravitreal steroids and anti-VEGF combined with careful laser treatment will significantly improve the prognosis (**Figure 6**). A recent meta-analysis estimated the overall pooled incidence of neovascular glaucoma (NVG) after PPV in PDR patients at 6%. The study showed a positive correlation for NVG after PPV in PDR patients with higher baseline IOP, preoperative iris neovascularization, lack of panretinal photocoagulation, preoperative or intraoperative combined cataract surgery, postoperative vitreous hemorrhage and a negative correlation with age [43]. Persistent macular edema in these eyes is a therapeutic challenge. Early glaucoma valve surgery with perioperative anti-VEGF, followed by appropriate intravitreal treatment can stabilize these eyes despite the grave prognosis, moreover that successful combined management of DME correlated closely with long-term recovery of photoreceptor integrity and visual outcome in patients with resolved DME in the presence of retained vascular density in the deep capillary plexus [44].

#### **12. Age**

The participants in Protocol T were enrolled at an average age of 61 years [45–58]. Secondary analysis of the baseline factors associated with visual outcome after 2 years of intensive anti-VEGF treatment revealed that even in such a relatively young cohort with every decade of age the scope of mean visual improvement decreased by 2.1 EDTRS letters. When the change in visual acuity over 2 years was estimated longitudinally as area under the curve (AUC), the improvement was reduced by 1.9 letters for each decade of life [9]. This

association supports previous findings from DRCR.net Protocol I on treatment with a single anti-VEGF [59] and the RISE and RIDE trials where the odds of achieving at least a 15-letter gain at 2 years fell for every 5-year increase in the age of the patients.
