Search Results (218)

Glaucoma is the leading cause of irreversible blindness worldwide and is characterized by progressive retinal ganglion cell (RGC) loss and optic nerve degeneration. While elevated intraocular pressure (IOP) remains the primary modifiable risk factor, a certain proportion of patients continue to deteriorate despite adequate IOP control, pointing to IOP-independent mechanisms of neurodegeneration. Oxidative stress—defined as an imbalance between the production of reactive oxygen species and the capacity of endogenous antioxidant defenses—has emerged as a central, multi-tiered contributor to glaucoma pathogenesis. In the anterior segment, chronic oxidative damage to the trabecular meshwork impairs aqueous humor outflow and drives IOP elevation. In addition, oxidative stress may impair ocular biomechanical integrity, including corneal hysteresis and lamina cribrosa, resulting in heightened susceptibility to IOP fluctuations. In the posterior segment, oxidative stress directly contributes to mitochondrial damage and vascular endothelial injury, leading to RGC apoptosis. The nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway coordinates the principal endogenous antioxidant response, while nicotinamide adenine dinucleotide (NAD⁺) depletion links redox imbalance to metabolic vulnerability of RGCs. This narrative review synthesizes evidence published up to March 2026 on the molecular mechanisms of oxidative stress in glaucoma, the role of biomarkers in aqueous humor and systemic circulation, and the translational landscape of antioxidant-based neuroprotection—including nicotinamide, coenzyme Q10, alpha-lipoic acid, and Nrf2-activating compounds. We highlight gaps between preclinical promise and clinical evidence, and outline priorities for future randomized controlled trials. Full article

Periodontitis and type 2 diabetes mellitus (T2DM) are linked through systemic inflammation and endothelial dysfunction, yet it remains uncertain whether periodontal inflammatory burden independently reflects early, multi-organ microvascular vulnerability beyond glycemic exposure. This study aimed to assess the independent association between periodontal inflammatory burden, measured by PISA, and retinal microvascular impairment on OCT-A, and to examine relationships with renal trajectories, small-fiber neuropathy, and inflammatory/endothelial biomarkers. This cross-sectional observational study included 285 never-smoking adults with T2DM. The primary outcome was a pre-specified OCT-A microvascular impairment composite. Secondary outcomes included eGFR slope and log(UACR) slope, corneal nerve fiber length (CNFL), and a multi-organ microvascular burden score. Biomarkers comprised hsCRP, IL-6, sICAM-1, sVCAM-1, sE-selectin, PAI-1, angiopoietin-2 (Ang-2), and vWF:Ag. Multivariable linear regression estimated associations per 1 SD higher PISA, adjusting for age, sex, diabetes duration, HbA1c, CGM time in range, CGM coefficient of variation, systolic blood pressure, LDL cholesterol, BMI, and medication classes (SGLT2 inhibitors, GLP-1 receptor agonists, ACEi/ARB, statins). False discovery rate (FDR) control (q = 0.10) was applied for secondary endpoints. Higher PISA was independently associated with worse OCT-A microvascular impairment (adjusted β = 0.138, 95% CI 0.061–0.216; p = 0.0005). Although statistically significant, the effect sizes were modest in magnitude, and their translation into clinically meaningful differences in microvascular outcomes warrants investigation in prospective settings. Higher PISA was also associated with greater multi-organ microvascular burden (β = 0.101, 95% CI 0.040–0.163; p = 0.0014; FDR q = 0.005) and lower CNFL (β = −0.224, 95% CI −0.397 to −0.052; p = 0.0113; FDR q = 0.023). PISA was associated with higher levels of inflammatory and endothelial activation/injury biomarkers (all FDR q < 0.10). In this cross-sectional study, periodontal inflammatory burden was independently associated with quantitative retinal microvascular impairment, lower corneal nerve fiber length, and a consistent pattern of endothelial activation biomarker elevations in never-smoking adults with T2DM. The clinical significance of the observed effect sizes requires further evaluation, and longitudinal studies are needed to establish temporality. Full article

Background/Aims: Glutamate is the primary excitatory neurotransmitter in the central nervous system, and elevated levels have been implicated in neurotoxicity. Corneal nerves are integral to ocular surface health and abnormalities can contribute to dry eye disease (DED). This study evaluates the relationship between serum glutamate levels, DED signs and symptoms, and corneal nerve parameters. Methods: A total of 124 veterans evaluated at the Miami Veterans Affairs Eye Clinic were included. Participants completed standardized questionnaires assessing ocular surface symptoms and pain, underwent comprehensive ocular surface examination and in vivo confocal microscopy, and provided blood samples for serum glutamate analysis. Results: Mean age was 55.67 ± 4.59 years; 90.3% were male, 55.6% White, and 35.5% Hispanic. Serum glutamate ranged from 0.26 to 3.16 µM/µL (mean 1.22 ± 0.57 µM/µL). Glutamate levels were not associated with DED symptoms as assessed by standardized questionnaires. Higher glutamate levels were linked with DED signs including reduced tear production (right eye: r = −0.05, p = 0.55; left eye: r = −0.25, p = 0.01) and increased corneal staining (right eye: r = 0.10, p = 0.29; left eye: r = 0.20, p = 0.03). Most notable were associations between elevated glutamate and corneal nerve health, including reduced corneal sensation (right eye: r = −0.20, p = 0.03; left eye: r = −0.18, p = 0.047) and decreased corneal nerve fiber width (r = −0.23, p = 0.01). Conclusions: Our findings support an association between systemic neurochemical status, specifically circulating glutamate, and ocular surface and corneal nerve health. Full article

Craniofacial and corneal neuropathic pain are disabling conditions characterized by persistent pain that is frequently refractory to conventional pharmacologic and interventional therapies. These disorders arise from complex interactions between peripheral nerve injury, neuroinflammation, and maladaptive central sensitization within trigeminal pathways, features that span neuropathic and nociplastic pain mechanisms as defined by the International Association for the Study of Pain, thus emphasizing the need for mechanism-based, patient-stratified treatment strategies. Regenerative medicine offers a paradigm shift from symptom suppression toward structural nerve repair and functional restoration. This narrative review examines the pathophysiological mechanisms underlying craniofacial and corneal neuropathic pain and critically evaluates emerging regenerative therapies, including autologous biologics (autologous serum tears and platelet-rich plasma), mesenchymal stem cells and their derivatives, exosomes and extracellular vesicles, and neurotrophic peptides. Particular emphasis is placed on corneal neuropathic pain as a translational model, given the cornea’s dense sensory innervation and the ability to non-invasively quantify nerve regeneration using in vivo confocal microscopy as an objective biomarker of treatment response. Clinical evidence across regenerative modalities varies by indication: cenegermin has demonstrated robust efficacy and regulatory approval for neurotrophic keratitis, while platelet-rich plasma shows growing evidence in temporomandibular disorders, myofascial pain, and occipital neuralgia. Cell-based and cell-free therapies demonstrate strong preclinical promise but remain limited by heterogeneous protocols and a paucity of large-scale randomized trials. Key barriers to translation include regulatory uncertainty, lack of standardized outcome measures, and workforce and implementation challenges. Advancing regenerative therapies for craniofacial and corneal neuropathic pain will require rigorous clinical trials, biomarker-driven patient selection, and multidisciplinary collaboration. Sex as a biological variable remains underexplored across all regenerative modalities and represents a priority for future research. Full article

Objective: This study aimed to compare time-dependent changes in visual acuity (VA), central corneal thickness (CCT), intraocular pressure (IOP), and the structure and elasticity of ocular tissues, as measured by shear wave elastography (SWE), in the preoperative, postoperative 1st week, and 1st month periods. Methods: This prospective observational study with repeated measurements included 22 individuals aged 44–86 years who underwent trabeculectomy for medically resistant glaucoma. VA, CCT, and IOP were measured preoperatively and at 1 week and 1 month postoperatively for the study. The elastic properties of ocular tissues were evaluated using the SWE method by obtaining quantitative measurements of lens SWE (LSWE), vitreous SWE (VSWE), optic nerve head SWE (OSWE), and retrobulbar fat SWE (RSWE). The changes in the obtained structural and elasticity parameters were compared preoperatively, 1 week postoperatively, and 1 month postoperatively. Results: When anterior segment parameters were evaluated in individuals who underwent trabeculectomy, there were significant differences in VA (p = 0.001, ${\mathrm{ƞ}}_p^2$ = 0.401), CCT (p = 0.001, ${\mathrm{ƞ}}_p^2$ = 0.806), and IOP (p = 0.001, ${\mathrm{ƞ}}_p^2$ = 0.853) values (p < 0.05). There was no statistically significant difference between preoperative and postoperative measurements at 1 week and 1 month for the elasticity parameters of LSWE, VSWE, OSWE, and RSWE (p > 0.05). Conclusions: This study suggests that the biomechanical adaptation of ocular tissues may be incomplete in the early postoperative period. Non-invasive methods such as SWE can be considered a potential tool for postoperative follow-up and predicting surgical success. Full article

Background/Objectives: The co-occurrence of diabetic peripheral neuropathy and depression increases the symptom burden and risk of long-term complications. Methods: This cross-sectional study enrolled 131 patients with type 1 (age: 58.47 years; duration of diabetes: 35.61 years) and type 2 diabetes (age: 63.60 years; duration of diabetes: 11.49 years). All patients underwent assessment of socioeconomic status and evaluation using the Hospital Anxiety and Depression Scale, the Mental Component Score of the Short Form Healthy Survey Questionnaire, neuropathy disability score, nerve conduction studies, corneal confocal microscopy and intraepidermal nerve fibre density (IENFD) assessment. Results: The prevalence of foot pain (45% vs. 23.9%, p = 0.019), tingling (56.7% vs. 32.9%, p = 0.013), weakness (35% vs. 9.9%, p < 0.001), ataxia (40% vs. 16.9%, p = 0.001), and upper limb symptoms (45% vs. 19.7%, p = 0.001) were statistically significantly higher, while cold perception threshold (22.50 ± 8.47 vs. 26.34 ± 3.08, p = 0.007), corneal nerve fibre density (20.49 ± 7.55 vs. 24.16 ± 5.68, p = 0.002) and length (20.06 ± 6.98 vs. 22.95 ± 6.22, p = 0.014) were statistically significantly lower, but no differences in nerve conduction studies or IENFD were observed in patients with depression compared to patients without depression. Furthermore, patients with depression were from a lower socioeconomic class (51.7% vs. 21.1%, p < 0.001), had lower educational attainment (37.9% vs. 12.9%, p < 0.001), had lower income < £37,000 (29.3% vs. 11.4%, p = 0.010) and lived in areas of high deprivation (62.1% vs. 31.4%, p < 0.001). Conclusions: Comorbid depression in people with diabetes was linked to increased socioeconomic deprivation and a greater prevalence of neuropathic symptoms and small fibre pathology. Full article

Small fiber neuropathy (SFN) is an early and common manifestation of diabetic polyneuropathy in type 2 diabetes mellitus (T2DM), often presenting with pain, dysesthesia, and autonomic dysfunction. Conventional diagnostic methods primarily assess large nerve fibers and may miss early small fiber damage, while skin biopsy, though considered the reference standard, is invasive. Corneal confocal microscopy (CCM) offers a rapid, noninvasive alternative for visualizing and quantifying small nerve fiber pathology in vivo. This was a monocentric observational study including 80 adults with T2DM (18–75 years), conducted at Alexandrovska Hospital, Sofia. Peripheral neuropathy was evaluated using a modified Neuropathy Disability Score and CCM-derived corneal nerve fiber density (CNFD), length (CNFL), and branching density (CNBD). Autonomic and sudomotor function were assessed by cardiovascular reflex tests and Sudoscan. Additional measures included vibration perception threshold, carotid intima–media thickness, body composition analysis, and laboratory parameters. Autonomic neuropathy was present in 66.7% and peripheral neuropathy in 57.5% of participants. Affected patients were older and had higher BMI and longer diabetes duration; peripheral neuropathy was additionally associated with higher HbA1c. Corneal nerve parameters negatively correlated with diabetes duration, HbA1c, intima–media thickness, and vibration threshold. Patients with diabetic retinopathy showed significantly reduced CNFD and CNFL. ROC analysis demonstrated significant discriminative ability of the HRV index for identifying peripheral neuropathy and of CNFD for detecting sudomotor dysfunction. These findings support CCM as a valuable, noninvasive marker of small fiber damage, closely linked to metabolic control, vascular impairment, and both sensory and autonomic dysfunction in T2DM. Full article

Background/Objectives: To characterize sectoral corneal thickness (CT) profiles in eyes with primary open-angle glaucoma (POAG) compared with healthy eyes and to evaluate potential associations between CT, retinal nerve fiber layer (RNFL) thickness, and optic disc rim area (RA). Methods: In this cross-sectional study, 192 participants (91 with POAG and 101 controls) contributed 297 eyes (145 glaucoma eyes and 152 control eyes). All participants underwent comprehensive ophthalmological examination and spectral-domain optical coherence tomography (OCT; Optovue Solix, Fremont, CA, USA) to obtain peripapillary RNFL measurements, optic disc rim area, and corneal pachymetry maps across five sectors (central, superior, inferior, temporal, and nasal). Repeated-measures correlation analyses were used to assess within-subject associations between CT and RA, and generalized estimating equation (GEE) models were applied to evaluate independent associations between CT, glaucoma status, disease severity, and RNFL thickness while adjusting for relevant covariates. Results: Eyes with POAG exhibited significantly thinner corneas across all sectors compared with controls (all p < 0.05), with the greatest differences observed in the superior (median 607.0 μm vs. 640.0 μm, p < 0.001) and temporal (562.0 μm vs. 579.5 μm, p < 0.001) regions. Average RNFL thickness and rim area were also significantly reduced in glaucoma eyes (all p < 0.001). However, no independent associations between sectoral CT and RNFL thickness or RA were observed after adjustment for multiple comparisons. Although nominal associations between thinner inferotemporal CT and reduced RNFL thickness were observed in unadjusted analyses, these did not remain statistically significant after false discovery rate correction. In multivariable GEE models, glaucoma diagnosis and greater disease severity were consistently associated with reduced RNFL thickness (β range: −11.0 to −42.2 μm; all p < 0.001), whereas CT was not independently associated with RNFL thickness (all adjusted p > 0.07). Conclusions: Sectoral corneal thickness is significantly reduced in eyes with POAG but does not independently correlate with RNFL thickness or optic disc rim area after adjustment for confounding factors. These findings support the concept that corneal thinning reflects structural and biomechanical susceptibility to glaucoma rather than serving as a marker of established neuroretinal damage severity. Further longitudinal studies incorporating comprehensive biomechanical assessments are warranted to clarify the role of corneal structure in glaucoma pathophysiology. Full article

The ocular surface is a neuro–epithelial–immune unit in which corneal innervation is essential for maintaining tissue integrity and visual function. Sensory nerves regulate reflex tearing and blinking, provide trophic support, and modulate local immune responses. Nerve injury resulting from trauma, surgery, infection, systemic disease, or chronic inflammation disrupts epithelial homeostasis and may lead to neurotrophic keratopathy, neuropathic pain, and pathological remodeling. Beyond classical neurotrophic disease, nerve dysfunction contributes to severe dry eye and immune-mediated cicatricial disorders. Depending on the neuro-inflammatory context, remodeling may evolve toward stromal thinning, as in keratoconus, or progressive fibrosis, as in ocular cicatricial pemphigoid. Blood-derived eye drops, including serum- and platelet-based formulations, represent biologically active therapies that support epithelial repair and nerve regeneration, although greater standardization is needed. Full article

Corneal scarring (fibrosis) is a blinding condition affecting millions of sufferers worldwide. It is not only in common ocular injuries but also in genetically inherited rare diseases such as epidermolysis bullosa (EB), keratitis-ichthyosis-deafness (KID) syndrome and aniridia. In rare diseases like EB or KID syndrome, corneal fibrosis arises from chronic inflammation, structural instability and neuro-immune dysfunction driven by genetic mutations. Current therapies are not effective in addressing the needs of affected individuals due to limited efficacy nor the considerable side effects of treatment. Extracellular vesicles (EVs) from various cell types such as mesenchymal stem cells not only possess high biocompatibility but have shown promising results in limiting corneal fibrosis. Rather than targeting a single molecular signaling pathway, EVs which contain regulatory RNAs and proteins are hypothesized to target multiple pathways synergistically. Macrophage-derived EVs (Mac-EVs) with an immunomodulatory nature may offer a promising therapeutic effect for rare diseases. Various EV delivery platforms have been proposed in preclinical studies. However, not all of these delivery techniques are appropriate for the cornea in rare diseases. In this review, we delineate recent advances in understanding corneal fibrosis from a rare disease point of view, including the impact on corneal immune cells and nerves. We then provide critical considerations of therapeutic development for corneal fibrosis in rare diseases. Furthermore, we used this knowledge to comprehensively consider the various EVs, especially Mac-EVs, synthesis methods and delivery techniques. Ultimately, this review aims to enable biomolecule researchers to develop EV-based therapies that not only exert anti-fibrotic effects but also address clinical compatibility for corneal fibrosis in rare diseases. Full article

Corneal nerves (CNs) are essential to maintain corneal epithelial integrity and ocular surface homeostasis. In vivo confocal microscopy (IVCM) enables the acquisition of high-resolution visualization of CNs, allowing visualization on a microscopic level. Traditionally, CN images must be analyzed by manual examination, which is time consuming and labor intensive. Artificial intelligence (AI) has facilitated reliable analysis of CN parameters, allowing for automatic and semiautomatic analysis of CNs. These include the identification, segmentation, and quantitative analysis of various CN parameters. This review summarizes the applications of AI-driven, automatic, and semiautomatic models in the CN analysis of IVCM images while also focusing on their diagnostic relevance in dry eye disease (DED) and neuropathic corneal pain (NCP). Recent advancements in AI have transformed IVCM image analysis by improving reproducibility and reducing operator dependency and time. The AI-based algorithm has been demonstrated to have good performance and sensitivity to identify and quantify the CN metrics. AI has also been utilized to improve the diagnostic accuracy of DED with IVCM scans, involving multiple portions of the CNs, such as the inferior whorl region. When employed with IVCM images of patients with NCP, AI-assisted identification of microneuromas and changes in CN metrics has provided an improvement in diagnostic accuracy. Despite promising advances and outcomes, the widespread implementation of these AI models in CN image analysis requires large-scale validation. Future integration of multimodal AI algorithms remains a promising endeavor to enhance diagnostic accuracy and disease stratification. Full article

Emerging evidence highlights the critical role of corneal nerves in the pathophysiology of dry eye disease (DED) and other related ocular surface disorders (OSDs). These conditions increasingly demonstrate neuropathic and neurotrophic components, wherein alterations in corneal nerve morphology and function contribute to symptomatology and disease progression. Recent advances in imaging and diagnostic modalities have enabled detailed, in vivo evaluation of corneal nerve architecture and sensory function, offering novel insights into underlying mechanisms and therapeutic responses. This review comprehensively examines current and emerging technologies for corneal nerve assessment, both structural and functional. The structural methods include in vivo confocal microscopy (IVCM), optical coherence tomography (OCT)-based nerve imaging (e.g., micro-OCT), and emerging technologies like multiphoton microscopy. The functional methods of corneal nerve assessment include advanced esthesiometers, quantitative sensory testing (QST), and functional magnetic resonance imaging (fMRI). The emerging technologies also include AI-driven analytical platforms that can be applied to both structural and functional methods. These various nerve assessment modalities can aid in delineating DED subtypes, selecting targeted treatments, monitoring nerve regeneration, and predicting treatment outcomes. By integrating structural and functional assessments, these technologies are reshaping the diagnosis, phenotyping, and management of DED and other related OSDs, paving the way for personalized therapeutic approaches. Full article

Corneal nerves are essential for maintaining the functional integrity of the ocular surface. Damage to corneal nerves can lead to corneal issues and impaired vision. Current treatments for corneal nerve damage are inadequate, thus highlighting the need for innovative therapeutic approaches. In this study, we present a hydrogel microneedle system designed to facilitate the sustained release of recombinant human nerve growth factor (rhNGF). The microneedle features a tip composed of glycidyl methacrylate modified silk fibroin (SFMA) loaded with rhNGF, photopolymerized for structural integrity, while its base is formed using silk fibroin (SF). This design allows the microneedles to penetrate the corneal epithelium and deliver rhNGF to the sub-epithelial layer. The crosslinking process not only provides the mechanical strength required for microneedle penetration but also enables sustained drug release. The proposed rhNGF-loaded SF hydrogel microneedle provides a platform for drug delivery, serving as a novel therapeutic option for corneal tissue engineering. Full article

Dry eye disease (DED) is a common condition that can be associated with cataract surgery, requiring pre- and postoperative considerations. Pre-existent DED and disruption of the tear film homeostasis due to incisional corneal nerve damage, intra-operative ocular surface drying, microscope phototoxicity, or the toxic effects of preservatives and active ingredients of postoperative drops or a combination thereof, represents a potential mechanism for worsening or developing DED after cataract surgery. Recent diagnostic advancements have enabled us better to understand the pathophysiology of DED after cataract surgery. For patients with pre-existing DED before cataract surgery, early intervention can improve surgical outcomes. In contrast, failure to recognize DED risk factors or subtle signs can result in inaccurate refractive measurements, poor surgical outcomes, including serious complications, worsening of dry eye symptoms, patient dissatisfaction, and decreased quality of life. This review presents an overview of the perioperative management of DED in patients undergoing cataract surgery with an emphasis on pre-operative diagnosis and treatment, and its impact on improving surgical refractive outcomes and decreasing complications. Full article

Background/Objectives: Diabetic neuropathy (DN) is one of the most common complications of type 2 diabetes mellitus (T2DM), involving complex metabolic, vascular, and epigenetic mechanisms. MicroRNA-210-3p (miR-210-3p), a hypoxia-responsive molecule, has been implicated in various diabetic complications, but its role in DN is not well defined. This study aimed to investigate the relationship between miR-210-3p expression, measured as delta Ct (ΔCt), and the presence and type of diabetic neuropathy, as well as correlations with corneal nerve parameters assessed by corneal confocal microscopy (CCM). Methods: Eighty patients with T2DM were stratified into four groups: no neuropathy, autonomic neuropathy, peripheral neuropathy, and combined neuropathy. Expression of miR-210-3p was quantified using RT-qPCR, and CCM was used to measure corneal nerve fiber density (CNFD), length (CNFL), and branch density (CNBD). Results: ΔCt values were significantly lower in patients with combined neuropathy compared to those without neuropathy, indicating higher miR-210-3p expression. Intermediate values were observed in autonomic and peripheral neuropathy groups. CCM parameters were significantly reduced in patients with DN. ΔCt was inversely correlated with neuropathy severity but positively associated with diabetes duration. Conclusions: These findings suggest that miR-210-3p may serve as a biomarker of nerve damage and cellular stress in diabetes, and that combining gene expression profiling with CCM could improve DN diagnosis and monitoring. Full article