Fabiana D'Esposito

Glaucoma causes progressive damage to the optic nerve, and reducing intraocular pressure is the only clinically proven way to slow the disease. Although current medical, laser, and surgical treatments mainly change aqueous humor dynamics, they do not counteract the cellular and extracellular abnormalities of the conventional outflow pathway. Growing evidence shows that loss and dysfunction of trabecular meshwork cells impair aqueous humor drainage, supporting regenerative approaches that rebuild the outflow system rather than bypass it. In this narrative review, we present novel stem cell-based strategies to regenerate the trabecular meshwork and Schlemm’s canal, particularly trabecular meshwork (TM) stem cells, mesenchymal stem cells, pluripotent stem cell-derived TM-like cells, and neural crest-derived progenitors. We review recent evidence suggesting that transplanted cells may restore outflow not just through engraftment and cellular replacement, but also through paracrine signaling, stimulation of endogenous cell proliferation, extracellular matrix modification, and rejuvenation of the trabecular microenvironment. This review discusses advances in lineage specification, cell targeting and delivery, single-cell and transcriptomic characterization, mechanobiology, and bioengineered models of the human aqueous out-flow pathway. New approaches, such as magnetically guided cell delivery and the identification of cells that promote trabecular tissue regeneration and repopulation, show how rapidly this field has developed. We cover key translational barriers, including cell identity, manufacturing standardization, long-term engraftment, tumorigenicity, immune responses, off-target localization, and limited clinical efficacy data. Reconstructing the aqueous outflow pathway using stem cells remains a preclinical endeavor. However, it may shift the focus from chronic pressure control to biologically restoring outflow function in glaucoma.

Ocular surface malignancies include ocular surface squamous neoplasia (OSSN), con-junctival melanoma, and conjunctival lymphoma. These rare disorders may threaten vi-sion and, in some cases, life. Early identification may be difficult because malignant le-sions can resemble benign ocular surface conditions. Artificial intelligence (AI), including machine learning and deep learning, has emerged as a potential aid to detection, classi-fication, and referral. This structured narrative review, organized with reference to SANRA principles, synthesizes PubMed/MEDLINE literature on AI applications in ocular surface oncology available through 29 August 2026. We examine slit-lamp photography, anterior segment optical coherence tomography, in vivo confocal microscopy, ultrasound biomicroscopy, and smartphone imaging. Deep-learning models have shown promising performance in selected binary OSSN tasks, whereas multiclass studies report lower sen-sitivity for rare malignancies such as conjunctival melanoma and lymphoma. Smartphone-based screening has also been evaluated in a prospective referral pathway, although the reference standard and verification process limit interpretation of popula-tion-level sensitivity. Dataset imbalance, image-acquisition variability, limited external and prospective validation, explainability, and workflow integration remain barriers to implementation. Future work should prioritize multicenter datasets, standardized acquisition, calibrated thresholds, and prospective human–AI evaluations. Current evidence supports further evaluation of AI as an adjunct for detection and referral, not as a re-placement for specialist assessment or histopathology.

The management of glaucoma with drugs is mostly via the topical route, although these treatments have poor ocular bioavailability. Other problems limiting their therapeutic effect include pre-corneal clearance, corneal and ocular surface barriers, and the need for a long-term treatment regimen. Nanoparticle-mediated drug-delivery systems have shown the potential, particularly in preclinical studies, to improve ocular penetration and precorneal retention and to facilitate controlled drug release, with the aim of reducing dosing frequency. In this narrative review, the researchers focus on various nanoparticle-based approaches for sustained intraocular pressure control in glaucoma. The review encompasses carrier-based nanosystems, drug nanocrystals and nanosuspensions, nanoscale permeability or surface modifiers, multiscale nano-enabled formulations, and nanoparticle- or nanocarrier-integrated delivery devices. These approaches are designed to deliver conventional and innovative ocular hypotensive agents. Pharmacokinetics, corneal permeability, drug stability, tolerability, and duration of action of intraocular pressure-lowering drugs are critically reviewed across a predominantly preclinical evidence base; the two small human studies identified (n = 6 and n = 17) support clinical feasibility but do not establish durable clinical effectiveness, long-term safety, adherence benefit, or prevention of glaucoma progression. This review distinguishes improvements in ocular drug disposition from demonstrated IOP-lowering benefit and separates preclinical proof of concept from human evidence by applying an evidence-stratified formulation–performance framework rather than ranking nanocarriers by material class or isolated physicochemical properties. The available evidence is dominated by drugs that lower IOP, which in turn distinguishes prolonged control of IOP from any direct disease-modifying or neuroprotective action, for which glaucoma-specific evidence remains substantially more limited. The review further assesses the obstacles to clinical translation, including long-term safety, manufacturing reproducibility, sterilization, regulatory requirements, and patient and treatment burden. Generally, nanoengineered systems are promising platforms to address pharmacokinetic and treatment-delivery limitations of conventional glaucoma therapy, but comparative clinical effectiveness, long-term safety, adherence benefit, cost-effectiveness, and meaningful effects on glaucoma progression remain insufficiently demonstrated.

Background: Optical coherence tomography (OCT) has been recognised as a non-invasive imaging modality capable of offering high-resolution visualisation of the corneal tissue. Objective: This review evaluates the role of OCT in chronic corneal disease, focusing on how descriptive imaging has progressed to quantitative imaging biomarkers with translational potential. Methods: A comprehensive review of the published literature on OCT imaging in corneal disease was conducted, emphasising structural features, quantitative parameters, and biomarkers. Results: OCT facilitates detailed visualisation of corneal microstructure, including variations in epithelial thickness, stromal reflectivity patterns, corneal thickness distribution, and interface abnormalities. These morphological observations are converted into quantitative measures that function as imaging biomarkers for disease severity, progression, and therapeutic effectiveness. In conditions such as keratoconus, chronic infectious keratitis, and corneal dystrophies, OCT-derived parameters offer valuable information for phenotyping and longitudinal monitoring. Additionally, advances in automated image analysis and artificial intelligence further increase the potential of OCT for biomarker discovery and evidence-based clinical decision-making. Conclusions: The development and validation of robust OCT-based biomarkers have the potential to enable earlier diagnosis, improved disease monitoring, and personalised treatment strategies. Future research that integrates quantitative imaging, computational analysis, and longitudinal clinical data will be essential to fully realise the translational potential of OCT in corneal disease management.

Cocaine-induced ocular toxicity is an increasingly acknowledged but often underestimated clinical condition that includes a wide range of eye-related symptoms. The extensive recreational use of cocaine, together with its powerful sympathomimetic and vasoconstrictive effects, leads to various ocular problems that can impact all anatomical components of the eye. This narrative review aims to deliver a thorough and current synthesis of the existing research on the epidemiology, pathophysiology, clinical symptoms, and therapy of cocaine-related ocular illness. Evidence suggests that cocaine-induced ocular damage involves vascular, local toxic, neuronal, and immunological processes. Reported manifestations in the literature include the ocular surface, optic nerve, posterior segment, orbit, and adnexal tissues. Novel imaging techniques have revealed subclinical retinal microvascular changes in chronic users, suggesting a continuum from initial vascular dysregulation to manifest ischemic injury. Notwithstanding increased awareness, the existing evidence is constrained by heterogeneity, small sample sizes, and a prevalence of case reports. A comprehensive understanding of the pathophysiological mechanisms and long-term ocular effects is crucial for enhancing diagnostic precision, directing management, and informing preventive measures. Enhanced multidisciplinary collaboration between ophthalmologists and addiction experts is essential to tackle this intricate and dynamic clinical dilemma.

Background/Objectives: Intranasal (IN) neuroactivation of trigeminal/nasolacrimal pathways—either pharmacologically (e.g., varenicline nasal spray) or via intranasal electrical neurostimulation—has been shown to increase tear production in dry eye disease (DED) and to improve patient-reported symptoms, with variable effects on ocular surface staining across studies. Intranasal administration can exploit olfactory and trigeminal pathways to access central nervous system (CNS); preclinical studies also report delivery to the optic nerve and ocular compartments (e.g., vitreous) with associated retinal ganglion cell/optic nerve neuroprotection, supporting further investigation of intranasal strategies for ocular neuroprotection. Methods: We conducted a narrative review on the basis of databases of PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library, with ClinicalTrials.gov screened for complete and ongoing studies) through 5 January 2026. The search terms included “intranasal/nasal spray”, “dry eye/tear secretion”, “trigeminal/neurostimulation”, and “neuroprotection/retina/optic nerve”, prioritizing clinical trials, mechanistic studies, and comprehensive reviews. Results: Phase IIb–III randomized, vehicle-controlled trials of varenicline solution nasal spray (OC-01) exhibited statistically significant improvements in tear production (Schirmer test) vs. vehicle and improvements in patient-reported symptoms (with statistical significance found in several symptom endpoints), with tolerability characterized mainly by mild, transient non-ocular adverse events. The product received Food and Drug Administration (FDA) approval for dry eye disease in 2021. Open-label and meta-analytic evidence also supports efficacy of intranasal tear neurostimulation in DED. Preclinical and translational studies demonstrated that IN administration could rapidly deliver proteins and other agents to the eye, optic nerve, and brain, with neuroprotective benefits achieved in optic-nerve and retinal injury models. Reported advantages include bypass of the first-pass metabolism and the blood–brain barrier with non-invasive dosing. Major limitations include mucociliary clearance, dose volume constraints, inter-individual variability, and local nasal adverse events. Conclusions: Evidence supports IN delivery as a clinically relevant modality for DED and a promising platform for ocular neuroprotection. Priorities include standardized ocular/retinal pharmacokinetics after IN dosing, head-to-head comparisons with topical/injectable standards, long-term safety surveillance (including olfactory and nasal mucosa), and optimization of candidate molecules and regimens.

Purpose: To describe the long-term, multimodal follow-up and multidisciplinary evaluation of two pediatric patients with CDH3-related retinopathy, discussing the genotypic and phenotypic spectrum of this rare cadherinopathy. Design: Retrospective observational case series. Methods: Two unrelated children with early-onset macular dystrophy and congenital hypotrichosis underwent a comprehensive ophthalmic examination, including spectral-domain optical coherence tomography (SD-OCT), blue-light fundus autofluorescence (BAF), microperimetry, and full-field electroretinography (ffERG), combined with dermatologic assessment and exome sequencing. Follow-up extended over 4 years in Patient 1 and 15 years in Patient 2. Results: Both patients showed sharply demarcated posterior pole chorioretinal atrophy with preservation of the peripheral retina and stable best-corrected visual acuity throughout follow-up. Microperimetry documented localized sensitivity loss with limited progression. SD-OCT revealed persistent ellipsoid zone disruption, retinal pigment epithelium atrophy, and outer retinal tubulations. Dermatologic evaluation confirmed congenital hypotrichosis without nail abnormalities; one patient exhibited mild fifth finger clinodactyly. Genetic testing identified the following two distinct homozygous CDH3 variants: a splice-site mutation (c.160+1G>A) and a frameshift insertion (c.1837dup, p.(Asp613Glyfs*4)). Conclusions:CDH3 retinopathy presents with a characteristic multimodal imaging pattern of localized macular atrophy and slow functional decline associated with congenital hypotrichosis. A comprehensive multidisciplinary approach was essential for the correct diagnosis and a better and more thorough definition of the clinical presentation. Detailed long-term follow-up supports the hypothesis of retinal pigment epithelium dysfunction or maldevelopment rather than widespread retinal degeneration. Recognition of this phenotype is critical for accurate diagnosis, genetic counseling, and future gene-therapy strategies targeting the preserved peripheral retina.

Optic nerve sheath meningiomas (ONSMs) occupy a unique intersection between neuro-oncology and genetics. Although most cases arise in middle-aged women as solitary, slow-growing tumors, pediatric onset, bilateral disease, or rapid progression frequently signal an underlying germline alteration, most often in neurofibromatosis type II (NF2). This narrative review synthesizes the literature through May 2025, examining clinical behavior, imaging, pathology, hereditary syndromes, and the molecular drivers of ONSMs, with particular emphasis on NF2, SMARCB1, TRAF7, and recent copy-number and methylation studies. Classic sporadic ONSMs seldom exhibit loss of chromosome 22q. However, somatic NF2 alterations and occasional changes in chromatin-remodeling genes still converge on Hippo pathway output (Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ)-driven transcriptional activity), phosphoinositide 3-kinase–protein kinase B (PI3K–AKT), and MAPK signaling. Emerging multi-omics data indicate that optic nerve tumors represent a molecularly distinct subset within the meningioma spectrum. This finding may explain the associated characteristically indolent growth and favorable response to conformal radiotherapy. Genotyping refines risk stratification: early NF2 testing is warranted in children and in bilateral or atypical presentations, enabling timely surveillance and genetic counseling. While fractionated stereotactic radiotherapy remains the mainstay of therapy, pathway-targeted and gene-replacement strategies developed for NF2-associated tumors may soon expand therapeutic options. Given the site-specific diagnostic and functional constraints of peri-optic tumors, larger collaborative cohorts and genotype-guided trials are essential to translate these biological insights into precision care for patients with ONSMs.

Photonic imaging technologies have profoundly transformed neuro-ophthalmic diagnostics by enabling non-invasive visualization of neurodegenerative processes at the retinal level. This review examines how advanced light-based modalities provide unprecedented insights into the structural, physiologic, and biologic relationships between the eye and brain in conditions such as optic neuritis, multiple sclerosis, and glaucoma. Optical coherence tomography has emerged as an essential tool for quantifying thinning of the retinal nerve fiber layer and ganglion cell layer, serving as reliable biomarkers of axonal loss and disease progression across multiple sclerosis subtypes and optic neuropathies. Detection of apoptosing retinal cells imaging enables real-time visualization of retinal ganglion cell apoptosis preceding irreversible structural damage, offering a critical window for early intervention in various neurodegenerative conditions, in particular, glaucoma. Two-photon microscopy with adaptive optics enables subcellular-resolution imaging of retinal neurons, microvascular dynamics, and inflammatory processes in vivo, facilitating the characterization of neurodegenerative mechanisms at unprecedented spatial scales and redefining neuro-ophthalmology by positioning the retina as an accessible extension of the central nervous system. This review critically examines how established and investigational photonic imaging modalities may support earlier disease detection, longitudinal monitoring, and biomarker development in neuro-ophthalmic and neurodegenerative disorders, with potential implications for more timely and targeted management strategies.

Diabetic retinopathy (DR) is increasingly recognized as a complex neurovascular degenerative disorder driven by intertwined immune and metabolic disturbances within the retinal microenvironment. Chronic hyperglycemia induces metabolic stress, mitochondrial dysfunction, and oxidative imbalance, which, in turn, activate innate and adaptive immune pathways. Key mechanisms—including complement dysregulation, microglial activation, leukostasis, cytokine and chemokine signaling, and advanced glycation end-product–mediated inflammation—contribute to endothelial injury, barrier breakdown, and progressive neuronal loss. Parallel alterations in lipid metabolism, amino acid utilization, and mitochondrial bioenergetics further amplify inflammatory cascades and shape the retinal immune landscape. This review synthesizes current evidence on how immune-metabolic crosstalk orchestrates early and late stages of DR, integrating findings from transcriptomic, proteomic, metabolomic, and epigenetic studies. We examine core signaling hubs that couple metabolic dysfunction to inflammatory amplification, including complement components, the advanced glycation end product (AGE)–receptor for AGE (RAGE) pathway, cytokine networks, and immune response regulation. Adopting a systems biology perspective, we highlight how convergent mechanisms can unify vascular, neuronal, and glial pathology under a shared framework of immune-metabolic imbalance. An extensive literature search was conducted (PubMed, accessed December 2025). By positioning DR as a model of inflammatory retinal degeneration, this review outlines a conceptual foundation for network-based diagnostics and therapeutics. Understanding the dynamic interactions among immune signaling, metabolic stress, and neurovascular instability may inform future strategies to restore retinal homeostasis and prevent vision-threatening disease progression.