Purpose To report 4-year outcomes following the switch to aflibercept in treatment-resistant neovascular age-related macular degeneration (nAMD). Methods In this prospective, open-label, non-controlled, clinical trial, 49 patients with treatment-resistant nAMD received 2 mg intravitreal aflibercept as three loading doses every 4 weeks, followed by injections every 8 weeks for the first 48 weeks, then an individualized regimen for a further 36 months, following previous treatment with ranibizumab and/or bevacizumab. Outcome measures included best-corrected visual acuity (BCVA), central retinal thickness (CRT), pigment epithelial detachment (PED) height and geographic atrophy (GA) surface area. Results Of the 49 patients who were initially recruited, data from 39 eyes of 39 patients were available at 48-month follow-up. Mean age was 76.7 ± 7.2 years. Over the 48 months, these eyes received a mean of 32.1 ± 5.6 injections. The mean BCVA improved significantly following 12 months of treatment (4.9 ± 9.0 ETDRS letters, p Conclusion Aflibercept is an effective alternative therapy for treatment-resistant nAMD. Good anatomical and stable functional responses are achievable with continued therapy. The lack of continued visual improvement may be representative of GA progression, reflecting the progression of late-stage nAMD in these patients.

Long-term outcomes of switching to aflibercept for treatment resistant neovascular age-related macular degeneration

Persistent diabetic macular edema: Definition, incidence, biomarkers and treatment methods.

The blood–brain barrier (BBB) is a physiological barrier maintaining a specialized brain micromilieu that is necessary for proper neuronal function. Endothelial tight junctions and specific transcellular/efflux transport systems provide a protective barrier against toxins, pathogens, and immune cells. The barrier function is critically supported by other cell types of the neurovascular unit, including pericytes, astrocytes, microglia, and interneurons. The dysfunctionality of the BBB is a hallmark of neurological diseases, such as ischemia, brain tumors, neurodegenerative diseases, infections, and autoimmune neuroinflammatory disorders. Moreover, BBB dysfunction is critically involved in epilepsy, a brain disorder characterized by spontaneously occurring seizures because of abnormally synchronized neuronal activity. While resistance to antiseizure drugs that aim to reduce neuronal hyperexcitability remains a clinical challenge, drugs targeting the neurovasculature in epilepsy patients have not been explored. The use of novel imaging techniques permits early detection of BBB leakage in epilepsy; however, the detailed mechanistic understanding of causes and consequences of BBB compromise remains unknown. Here, we discuss the current knowledge of BBB involvement in temporal lobe epilepsy with the emphasis on the neurovasculature as a therapeutic target.

The neurovasculature as a target in temporal lobe epilepsy

As the only blood vessels that can directly be seen in the whole body, pathological changes in retinal vessels are related to the metabolic state of the whole body and many systems, which seriously affect the vision and quality of life of patients. Timely diagnosis and treatment are key to improving vision prognosis. In recent years, with the rapid development of artificial intelligence, the application of artificial intelligence in ophthalmology has become increasingly extensive and in-depth, especially in the field of retinal vascular diseases. Research study results based on artificial intelligence and fundus images are remarkable and provides a great possibility for early diagnosis and treatment. This paper reviews the recent research progress on artificial intelligence in retinal vascular diseases (including diabetic retinopathy, hypertensive retinopathy, retinal vein occlusion, retinopathy of prematurity, and age-related macular degeneration). The limitations and challenges of the research process are also discussed.

Research progress on diagnosing retinal vascular diseases based on artificial intelligence and fundus images

Diabetic retinopathy is a major retinal disorder and a leading cause of blindness. Diabetic macular edema (DME) is an ocular complication in patients with diabetes, and it can impair vision significantly. DME is a disorder of the neurovascular system, and it causes obstructions of the retinal capillaries, damage of the blood vessels, and hyperpermeability due to the expression and action of vascular endothelial growth factor (VEGF). These changes result in hemorrhages and leakages of the serous components of blood that result in failures of the neurovascular units (NVUs). Persistent edema of the retina around the macula causes damage to the neural cells that constitute the NVUs resulting in diabetic neuropathy of the retina and a reduction in vision quality. The macular edema and NVU disorders can be monitored by optical coherence tomography (OCT). Neuronal cell death and axonal degeneration are irreversible, and their development can result in permanent visual loss. Treating the edema before these changes are detected in the OCT images is necessary for neuroprotection and maintenance of good vision. This review describes the effective treatments for the macular edema that are therefore neuroprotective.

https://www.mdpi.com/1422-0067/24/11/9591/pdf?version=1685610938

Current Treatments for Diabetic Macular Edema

Diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) are common retinal vascular diseases responsible for most blindness in the working-age and older population in developed countries. Currently, anti-VEGF agents that block VEGF family ligands, including ranibizumab, bevacizumab (off-label use), brolucizumab, and aflibercept, are the first-line treatment for nAMD and DME. However, due to the complex pathophysiological background of nAMD and DME, non-response, resistance during anti-VEGF therapy, and relapses of the disease are still observed. Moreover, frequent injections are a psychological and economic burden for patients, leading to inadequate adhesion to therapy and a higher risk of complications. Therefore, therapeutic methods are strongly needed to develop and improve, allowing for more satisfactory disease management and lower treatment burden. Currently, the Ang/Tie-2 pathway is a promising therapeutic target for retinal vascular diseases. Faricimab is the first bispecific monoclonal antibody for intravitreal use that can neutralize VEGF and Ang-2. Due to the prolonged activity, faricimab allows extending the interval between successive injections up to three or four months in nAMD and DME patients, which can be a significant benefit for patients and an alternative to implanted drug delivery systems.

/pdf/aflibercept-versus-faricimab-in-the-treatment-of-neovascular-3u5pf5jc.pdf

Aflibercept versus Faricimab in the Treatment of Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema: A Review

Purpose The aim of the study comprised the anatomical and functional assessment of the optic nerves and macular ganglion cells in the population of patients with unilateral wet age-related macular degeneration (wAMD) and comparison of its results to those obtained from the fellow eye with non-advanced dry age-related macular degeneration (dAMD). Furthermore, we aimed to determine if the number of administered injections contributed to the potential differences between the examined eyes. Methods The study was based on 104 eyes of 52 patients in a cross-sectional study. The eyes with chronically treated wAMD were the main subject of the study, while fellow eyes affected with non-advanced dAMD served as the control group. Primary morphological outcomes comprised differences in peripapillary retinal nerve fiber layer (RNFL) and GCC layers between the studied groups (treated and control). In turn, primary functional outcomes included differences in implicit times and amplitudes of the P100 wave of pattern visual evoked potentials (PVEP) and N95 wave of pattern electroretinogram (PERG) between treated and control groups. Results We did not find any differences in total RNFL thickness between wAMD and dAMD groups. The number of injections only affected the RNFL in the nasal quadrant of the optic disc (p = 0.023). We did not find any differences regarding GCL thickness in both groups. In the study group, a longer implicit time of the P100 of PVEP (p = 0.014) and a shorter amplitude of the P50-N95 wave of PERG (p = 0.005) were detected. The total number of injections had no significant effect on these two values. Conclusion We detected worse functional parameters of the optic nerve and retinal ganglion cells in eyes with wAMD, with lack of significant differences in anatomical (RNFL, GCL) parameters compared to the control group. However, the number of injections did not contribute to the differences found.

Morphological and Functional Assessment of the Optic Nerve Head and Retinal Ganglion Cells in Dry vs Chronically Treated Wet Age-Related Macular Degeneration

Introduction: Aflibercept and ranibizumab became the most commonly used drugs in treatment of wet age-related macular degeneration (wAMD). Some patients, however, do not respond to treatment with one of these. Our aim was to determine whether the switch to ranibizumab, and switchback, in a group of patients poorly responding to aflibercept therapy is effective. We assesed best corrected visual acuity (BCVA), central retinal thickness (CRT), and the presence of intra- and subretinal fluid (IRF, SRF, respectively).
Material and methods: We conducted retrospective comparative case series study. 20 eyes of 20 patients, who had no inhibition of disease activity after at least one year of treatment with aflibercept, were included in the study. If after switch to ranibizumb the response to the drug was again inadequate, we returned to aflibercept therapy. We divided the study population into two groups: those who had not been treated with the anti-VEGF injections before starting treatment (treatment-naive), and those who had received injections before entering the Program. 
Results: We observed an improvement in both BCVA and CRT parameters, but only in the group of treatment-naive. We did not observe any statistically credible effects for SRF and IRF in any of the groups studied.
Conclusion: Drug conversion may be beneficial for patients poorly responding to primary therapy. Greater improvement is seen in previously untreated patients.

/pdf/switching-between-aflibercept-and-ranibizumab-in-the-4wl0ip41xu.pdf

Switching Between Aflibercept and Ranibizumab in the Treatment of Refractory Exudative Age-related Macular Degeneration.

The main aim of this study was to characterize the retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness in the macular area eyes affected by wet age-related macular degeneration (wAMD) treated with anti-VEGF and compare the results with the control of fellow untreated eyes affected by early stages of dry age-related macular degeneration (dAMD). Additionally, we aimed to estimate if the number of injections received and other factors, including age, best-corrected visual acuity (BCVA), or sex, may affect the differences in the obtained measurements of retinal nerve fiber layer thickness. We prospectively included 106 eyes of 53 patients with unilateral wet age-related macular degeneration. The fellow eyes with non-advanced dry age-related macular degeneration served as a control group in a cross-sectional study. RNFL and GCL in the macular region were evaluated using optical coherence tomography, with outcomes expressed as differences in the thickness of both examined layers between the study and control groups. We found thinner GCL in wAMD vs. dAMD (p < 0.001). In turn, the RNFL layer did not show any statistically significant differences between the two groups (p = 0.409). Similarly, we found a statistically significant correlation between the number of injections and the layer thickness (p = 0.106). Among all assessed parameters, age over 73 was the only factor significantly affecting the thickness of the retinal nerve fiber layer in both groups (p = 0.042). The morphology of the inner layers of the retina in dry and wet AMD seems to differ, possibly due to differences in the etiopathogenesis of these two forms of the disease. In our study, the retinal ganglion cell layer was thinner in the treated vs. fellow eye (with dry AMD), while the nerve fiber layer was not significantly different between the groups. The number of anti-VEGF injections had no effect on the thickness of the macular nerve fiber layer.

/pdf/examination-of-inner-retinal-layers-in-unilateral-wet-age-1cfm0e6h.pdf

Małgorzata Wichrowska

Papers

Aflibercept versus Faricimab in the Treatment of Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema: A Review

Morphological and Functional Assessment of the Optic Nerve Head and Retinal Ganglion Cells in Dry vs Chronically Treated Wet Age-Related Macular Degeneration

Switching Between Aflibercept and Ranibizumab in the Treatment of Refractory Exudative Age-related Macular Degeneration.

Examination of Inner Retinal Layers in Unilateral Wet Age-Related Macular Degeneration Treated with Anti-VEGF, Compared to Fellow Untreated Eyes