Complications from diabetic retinopathy such as diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) constitute leading causes of preventable vision loss in working-age patients. Since vascular endothelial growth factor (VEGF) plays a major role in the pathogenesis of these complications, VEGF inhibitors have been the cornerstone of their treatment. Anti-VEGF monotherapy is an effective but burdensome treatment for DME. However, due to the intensive and burdensome treatment, most patients in routine clinical practice are undertreated, and therefore, their outcomes are compromised. Even in adequately treated patients, persistent DME is reported anywhere from 30% to 60% depending on the drug used. PDR is currently treated by anti-VEGF, panretinal photocoagulation (PRP) or a combination of both. Similarly, a number of eyes, despite these treatments, continue to progress to tractional retinal detachment and vitreous hemorrhage. Clearly there are other molecular pathways other than VEGF involved in the pathogenesis of DME and PDR. One of these pathways is the angiopoietin–Tie signaling pathway. Angiopoietin 1 (Ang1) plays a major role in maintaining vascular quiescence and stability. It acts as a molecular brake against vascular destabilization and inflammation that is usually promoted by angiopoietin 2 (Ang2). Several pathological conditions including chronic hyperglycemia lead to Ang2 upregulation. Recent regulatory approval of the bi-specific antibody, faricimab, may improve long term outcomes in DME. It targets both the Ang/Tie and VEGF pathways. The YOSEMITE and RHINE were multicenter, double-masked, randomized non-inferiority phase 3 clinical trials that compared faricimab to aflibercept in eyes with center-involved DME. At 12 months of follow-up, faricimab demonstrated non-inferior vision gains, improved anatomic outcomes and a potential for extended dosing when compared to aflibercept. The 2-year results of the YOSEMITE and RHINE trials demonstrated that the anatomic and functional results obtained at the 1 year follow-up were maintained. Short term outcomes of previously treated and treatment-naive eyes with DME that were treated with faricimab during routine clinical practice suggest a beneficial effect of faricimab over other agents. Targeting of Ang2 has been reported by several other means including VE-PTP inhibitors, integrin binding peptide and surrobodies.

Full-thickness macular holes (FTMHs) are a rare but recognized complication of macular telangiectasia type 2 (MacTel2). Unlike idiopathic FTMHs, which are primarily driven by vitreofoveal traction, MacTel2-associated holes appear to arise predominantly from progressive neurodegenerative changes. Müller cell dysfunction, intraretinal cavitation, and outer retinal atrophy progressively compromise foveal architecture, ultimately predisposing to tissue dehiscence and full-thickness defects. Although vitreofoveal traction may contribute in individual cases, it is unlikely to be the principal mechanism in most affected eyes. Surgical treatment remains challenging, as current evidence is limited to case reports and small case series. Internal limiting membrane (ILM) flap techniques and, in selected cases, retinal graft or amniotic membrane transplant procedures have yielded encouraging anatomical closure rates, whereas conventional ILM peeling alone appears less predictable. Importantly, restoration of foveal continuity does not necessarily result in meaningful visual improvement, particularly in eyes with established photoreceptor and outer retinal damage. The durability of anatomical repair may be further compromised by continued disease progression. Persistent Müller cell dysfunction, intraretinal cavitation, and progressive outer retinal atrophy can undermine foveal support and lead to recurrent architectural disruption, including reopening of a previously closed hole. Although late recurrence has been documented, its incidence and determinants remain poorly defined because of the limited size and heterogeneity of the available literature. Visual prognosis appears to be determined largely by the amount of structurally and functionally viable retinal tissue remaining at the time of intervention. Smaller defects, less extensive cavitation, and preservation of the external limiting membrane and ellipsoid zone are associated with greater potential for visual recovery. In contrast, extensive cavitation, advanced outer retinal atrophy, and substantial Müller cell or photoreceptor loss are associated with limited functional improvement and may compromise long-term anatomical stability. Overall, a FTMH secondary to MacTel2 should be regarded as a distinct form of macular hole in which surgical repair occurs against a background of ongoing macular neurodegeneration. Preoperative evaluation of hole dimensions, foveal cavitation, and outer retinal integrity may assist in prognostication and in identifying eyes with the greatest likelihood of achieving durable anatomical closure and meaningful visual recovery.