Corneal Innervation Research Articles

Current perspectives and concerns in corneal neurotization.

This study aimed to comprehensively explore the intricacies of corneal neurotization (CN) and the nuanced factors that set it apart from routine clinical practice, exerting a substantial influence on its success. A symbiotic relationship is evident between corneal innervation and ocular surface health. The loss of corneal innervation results in a potentially challenging corneal condition known as neurotrophic keratopathy (NK). The majority of treatments are primarily focused on preventing epithelial breakdown rather than addressing the underlying pathogenesis. Consequently, to address the impaired corneal sensation (underlying etiology), a novel surgical approach has emerged, namely CN, which involves transferring healthy sensory nerve axons to the affected cornea. This review offers valuable insights into the existing body of supporting evidence for CN, meticulously examining clinical studies, case reports, and experimental findings. The aim is to enhance our understanding of the effectiveness and potential outcomes associated with this innovative surgical technique. The exploration of innovative therapeutic avenues holds promise for revolutionizing the management of NK, offering a potentially permanent solution to a condition once deemed incurable and severely debilitating.

Inherited mitochondrial dysfunction triggered by OPA1 mutation impacts the sensory innervation fibre identity, functionality and regenerative potential in the cornea

Mitochondrial dysfunctions are detrimental to organ metabolism. The cornea, transparent outmost layer of the eye, is prone to environmental aggressions, such as UV light, and therefore dependent on adequate mitochondrial function. While several reports have linked corneal defects to mitochondrial dysfunction, the impact of OPA1 mutation, known to induce such dysfunction, has never been studied in this context. We used the mouse line carrying OPA1delTTAG mutation to investigate its impact on corneal biology. To our surprise, neither the tear film composition nor the corneal epithelial transcriptomic signature were altered upon OPA1 mutation. However, when analyzing the corneal innervation, we discovered an undersensitivity of the cornea upon the mutation, but an increased innervation volume at 3 months. Furthermore, the fibre identity changed with a decrease of the SP + axons. Finally, we demonstrated that the innervation regeneration was less efficient and less functional in OPA1+/- corneas. Altogether, our study describes the resilience of the corneal epithelial biology, reflecting the mitohormesis induced by the OPA1 mutation, and the adaptation of the corneal innervation to maintain its functionality despite its morphogenesis defects. These findings will participate to a better understanding of the mitochondrial dysfunction on peripheral innervation.

Tear Fluid Progranulin as a Noninvasive Biomarker for the Monitoring of Corneal Innervation Changes in Patients With Type 2 Diabetes Mellitus.

This study aimed to investigate the expression levels of progranulin (PGRN) in the tears of patients with diabetic retinopathy (DR) versus healthy controls. Additionally, we sought to explore the correlation between PGRN levels and the severity of ocular surface complications in patients with diabetes. In this prospective, single-visit, cross-sectional study, patients with DR (n = 48) and age-matched healthy controls (n = 22) were included and underwent dry eye examinations. Tear fluid was collected, and its components were analyzed using the Luminex assay. The subbasal nerve plexus of all participants was evaluated by in vivo confocal microscopy. Patients with DR exhibited more severe dry eye symptoms, along with a reduction in nerve fiber density, length, and branch density within the subbasal nerve plexus, accompanied by an increase in the number of dendritic cells. Tear PGRN levels were also significantly lower in patients with diabetes than in normal controls, and the levels of some inflammatory factors (TNF-α, IL-6, and MMP-9) were higher in patients with DR. Remarkably, the PGRN level significantly correlated with nerve fiber density (R = 0.48, P < 0.001), nerve fiber length (R = 0.65, P < 0.001), and nerve branch density (R = 0.69, P < 0.001). Tear PGRN levels might reflect morphological changes in the corneal nerve plexus under diabetic conditions, suggesting that PGRN itself is a reliable indicator for predicting the advancement of neurotrophic keratopathy in patients with diabetes. PGRN insufficiency on the ocular surface under diabetic conditions was found to be closely associated with nerve impairment, providing a novel perspective to discover the pathogenesis of diabetic complications, which could help in developing innovative therapeutic strategies.

The Severity of Diabetic Retinopathy Corresponds with Corneal Nerve Alterations and Ocular Discomfort of the Patient.

Diabetic retinopathy (DR) remains the leading cause of blindness in the working-age population. Its progression causes gradual damage to corneal nerves, resulting in decreased corneal sensitivity (CS) and disruption of anterior-eye-surface homeostasis, which is clinically manifested by increased ocular discomfort and dry eye disease (DED). This study included 52 DR patients and 52 sex- and age-matched controls. Ocular Surface Disease Index (OSDI) survey, tear film-related parameters, CS, and in vivo corneal confocal microscopy (IVCM) of the subbasal plexus were performed. Furthermore, all patients underwent tear sampling for neurotrophin and cytokine analysis. OSDI scores were greater in DR patients than in controls (p = 0.00020). No differences in the Schirmer test score, noninvasive tear film-break-up time (NIBUT), tear meniscus or interferometry values, bulbar redness, severity of blepharitis or meibomian gland loss were found. In the DR group, both the CS (p < 0.001), and the scotopic pupil diameter (p = 0.00008) decreased. IVCM revealed reduced corneal nerve parameters in DR patients. The stage of DR was positively correlated with the OSDI (Rs = +0.51, 95% CI: + 0.35-+0.64, p < 0.001) and negatively correlated with IVCM corneal nerve parameters and scotopic pupillometry (Rs = -0.26, 95% CI: -0.44--0.06, p = 0.0097). We found negative correlations between the OSDI and IVCM corneal innervation parameters. The DR group showed lower tear film-brain-derived neurotrophic factor (BDNF) levels (p = 0.0001) and no differences in nerve growth factor (NGF)-β, neurotrophin (NT)-4, vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-4, IL-5, IL-6, or IL-12 concentrations. Tumor necrosis factor (TNF)-α, IL-2, IL-8, IL-10, granulocyte macrophage colony-stimulating factor (GM-CSF), and interferon (IFN)-γ levels were decreased among patients with DR. Corneal innervation defects have a direct impact on patients' subjective feelings. The evolution of DR appears to be associated with corneal nerve alterations, emphasizing the importance of IVCM.

Corneal Nerve Assessment by Aesthesiometry: History, Advancements, and Future Directions.

The measurement of corneal sensation allows clinicians to assess the status of corneal innervation and serves as a crucial indicator of corneal disease and eye health. Many devices are available to assess corneal sensation, including the Cochet-Bonnet aesthesiometer, the Belmonte Aesthesiometer, the Swiss Liquid Jet Aesthesiometer, and the newly introduced Corneal Esthesiometer Brill. Increasing the clinical use of in vivo confocal microscopy and optical coherence tomography will allow for greater insight into the diagnosis, classification, and monitoring of ocular surface diseases such as neurotrophic keratopathy; however, formal esthesiometric measurement remains necessary to assess the functional status of corneal nerves. These aesthesiometers vary widely in their mode of corneal stimulus generation and their relative accessibility, precision, and ease of clinical use. The development of future devices to optimize these characteristics, as well as further comparative studies between device types should enable more accurate and precise diagnosis and treatment of corneal innervation deficits. The purpose of this narrative review is to describe the advancements in the use of aesthesiometers since their introduction to clinical practice, compare currently available devices for assessing corneal innervation and their relative limitations, and discuss how the assessment of corneal innervation is crucial to understanding and treating pathologies of the ocular surface.

The miR-183/96/182 cluster regulates sensory innervation, resident myeloid cells and functions of the cornea through cell type-specific target genes

The conserved miR-183/96/182 cluster (miR-183C) is expressed in both corneal resident myeloid cells (CRMCs) and sensory nerves (CSN) and modulates corneal immune/inflammatory responses. To uncover cell type-specific roles of miR-183C in CRMC and CSN and their contributions to corneal physiology, myeloid-specific miR-183C conditional knockout (MS-CKO), and sensory nerve-specific CKO (SNS-CKO) mice were produced and characterized in comparison to the conventional miR-183C KO. Immunofluorescence and confocal microscopy of flatmount corneas, corneal sensitivity, and tear volume assays were performed in young adult naïve mice; 3′ RNA sequencing (Seq) and proteomics in the trigeminal ganglion (TG), cornea and CRMCs. Our results showed that, similar to conventional KO mice, the numbers of CRMCs were increased in both MS-CKO and SNS-CKO vs age- and sex-matched WT control littermates, suggesting intrinsic and extrinsic regulations of miR-183C on CRMCs. The number of CRMCs was increased in male vs female MS-CKO mice, suggesting sex-dependent regulation of miR-183C on CRMCs. In the miR-183C KO and SNS-CKO, but not the MS-CKO mice, CSN density was decreased in the epithelial layer of the cornea, but not the stromal layer. Functionally, corneal sensitivity and basal tear volume were reduced in the KO and SNS-CKO, but not the MS-CKO mice. Tear volume in males is consistently higher than female WT mice. Bioinformatic analyses of the transcriptomes revealed a series of cell-type specific target genes of miR-183C in TG sensory neurons and CRMCs. Our data elucidate that miR-183C imposes intrinsic and extrinsic regulation on the establishment and function of CSN and CRMCs by cell-specific target genes. miR-183C modulates corneal sensitivity and tear production through its regulation of corneal sensory innervation.

Structural and functional changes of binocular corneal innervation and ocular surface function after unilateral SMILE and tPRK

AimsTo evaluate the bilateral changes in the sub-basal nerve plexus of the cornea and ocular surface function after unilateral small incision lenticule extraction (SMILE) and transepithelial photorefractive keratectomy (tPRK) procedures.Methods34...

Corneal Neurotization: Essentials for The Facial Paralysis Surgeon.

Deficits in corneal innervation lead to neurotrophic keratopathy (NK). NK is frequently associated with facial palsy, and corneal damage can be accelerated by facial palsy deficits. Corneal nerves are important regulators of limbal stem cells, which play a critical role in epithelial maintenance and healing. Nonsurgical treatments of NK have undergone recent innovation, and growth factors implicated in corneal epithelial renewal are a promising therapeutic avenue. However, surgical intervention with corneal neurotization (CN) remains the only definitive treatment of NK. CN involves the transfer of unaffected sensory donor nerve branches to the affected cornea, and a variety of donor nerves and approaches have been described. CN can be performed in a direct or indirect manner; employ the supraorbital, supratrochlear, infraorbital, or great auricular nerves; and utilize autograft, allograft, or nerve transfer alone. Unfortunately, comparative studies of these factors are limited due to the procedure's novelty and varied recovery timelines after CN. Regardless of the chosen approach, CN has been shown to be a safe and effective procedure to restore corneal sensation and improve visual acuity in patients with NK.

Corneal nerves and amyotrophic lateral sclerosis: an in vivo corneal confocal imaging study.

Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disorder. Diagnosis is challenging due to its clinical heterogeneity and the absence of definitive diagnostic tools, leading to delays averaging between 9.1 and 27months. In vivo corneal confocal microscopy, assessing the sub-basal nerve plexus of the cornea, has been proposed as a potential biomarker for ALS. We aimed to determine whether the assessment of corneal nerves using in vivo confocal microscopy can serve as an imaging biomarker for ALS. A single-centre prospective case-control study was conducted in France from September 2021 to March 2023 including patients with ALS according to the revised EI Escorial criteria. The corneal sub-basal nerve plexus was analysed using in vivo confocal microscopy. An automated algorithm (ACCMetrics) was used to evaluate corneal parameters: nerve fibre density, nerve branch density, nerve fibre length, nerve fibre area, nerve total branch density, nerve fibre width, and nerve fractal dimension. Twenty-two patients with ALS and 30 controls were included. No significant differences were found between ALS and control groups for all corneal parameters (p > 0.05). Corneal sensitivity did not differ between groups, and no correlation was identified between corneal nerve parameters and ALS disease duration, severity and rate of progression (p > 0.05). The present study does not support the use of in vivo corneal confocal microscopy as an early diagnostic or prognostic tool for ALS. Further research, especially longitudinal investigations, is needed to understand any potential corneal innervation changes as ALS progresses.

Topical Insulin Treatment for Neurotrophic Corneal Ulcer with Persistent Epithelial Defect

Background: Neurotrophic keratitis (NK) is a degenerative corneal disease caused by impairment of corneal sensory innervation. It is characterized by decreased or absent corneal sensation, leading to epithelial breakdown, impairment of healing, and ultimately to the development of corneal ulceration, melting, and perforation. We described a case of neurotrophic ulcer with persistent epithelial defect and its remarkable healing response to insulin eye drop treatment. Case Presentation: A 62-year-old male patient was referred to our hospital for the management of stage III NK in the left eye. The condition started 6 months ago; the patient developed a sudden onset of left eye diminution of vision, red eye, and tearing. The patient sought an ophthalmic consultation and was diagnosed with herpes simplex keratitis. On examination, visual acuity OS was hand motion (HM), severe conjunctival injection, deep corneal vascularization, corneal opacity with stromal infiltration, epithelial defect about 3.5 x 6 mm, stromal thinning, Descemet membrane folds and loss of corneal sensation by cotton wisp test. The patient was treated with topical insulin eye drops for 6 weeks and showed substantial ulcer healing and reepithelization of the epithelial defect. Conclusion: Insulin drops have been shown to substantially promote persistent epithelial defect healing in the case of neurotrophic ulcers. Therefore, topical insulin use can potentially help in the treatment of refractory neurotrophic keratitis. Further studies with large case numbers and long follow-ups should be the main focus of future research.

Immunocytochemical Analysis of Crocin against Oxidative Stress in Trigeminal Sensory Neurons Innervating the Cornea.

Corneal diseases are a major cause of vision loss, often associated with aging, trauma and disease. Damage to corneal sensory innervation leads to discomfort and pain. Environmental stressors, such as short-wavelength light, can induce oxidative stress that alters mitochondrial function and affects cell and tissue homeostasis, including corneal innervation. Cellular antioxidant mechanisms may attenuate oxidative stress. This study investigates crocin, a derivative of saffron, as a potential antioxidant therapy. In vitro rat trigeminal sensory ganglion neurons were exposed to both sodium azide and blue light overexposure as a model of oxidative damage. Crocin was used as a neuroprotective agent. Mitochondrial and cytoskeletal markers were studied by immunofluorescence analysis to determine oxidative damage and neuroprotection. In vivo corneal innervation degeneration was evaluated in cornea whole mount preparations using Sholl analyses. Blue light exposure induces oxidative stress that affects trigeminal neuron mitochondria and alters sensory axon dynamics in vitro, and it also affects corneal sensory innervation in an in vivo model. Our results show that crocin was effective in preserving mitochondrial function and protecting corneal sensory neurons from oxidative stress. Crocin appears to be a promising candidate for the neuroprotection of corneal innervation.

Analysis of Clinical Characteristics and Neuropeptides in Patients with Dry Eye with and without Chronic Ocular Pain after FS-LASIK.

Chronic ocular pain, particularly prevalent in patients with dry eye disease and post-femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK) surgery, presents with unclear clinical characteristics and an undefined pathogenesis. In this study, we aimed to compare clinical characteristics and tear neuropeptide concentrations in patients with dry eye disease (DED) with and without chronic ocular pain following FS-LASIK, and investigate correlations between ocular pain, clinical characteristics, and tear neuropeptide levels. Thirty-eight post-FS-LASIK patients with DED were assigned to two groups: those with chronic ocular pain and those without chronic ocular pain. Dry eye, ocular pain, and mental health-related parameters were evaluated using specific questionnaires and tests. The morphology of corneal nerves and dendritic cells (DCs) was evaluated by in vivo confocal microscopy. Function of corneal innervation was evaluated by corneal sensitivity. Concentrations of tear cytokines (interleukin [IL]-6, IL-23, IL-17A, and interferon-γ) and neuropeptides (α-melanocyte-stimulating hormone, neurotensin, β-endorphin, oxytocin, and substance P [SP]) were measured using the Luminex assay. Most patients with chronic ocular pain experienced mild to moderate pain; the most common types included stimulated pain (provoked by wind and light), burning pain, and pressure sensation. More severe dry eye (P < 0.001), anxiety symptoms (P = 0.026), lower Schirmer I test values (P = 0.035), lower corneal nerve density (P = 0.043), and more activated DCs (P = 0.041) were observed in patients with ocular pain. Tear concentrations of SP and oxytocin were significantly higher in patients with ocular pain (P = 0.001, P = 0.021, respectively). Furthermore, significant correlations were observed among ocular pain severity, SP, and anxiety levels. Patients with DED after FS-LASIK who have chronic ocular pain show more severe ocular and psychological discomfort and higher tear levels of neuropeptides. Furthermore, ocular pain severity is correlated with tear SP levels. ClinicalTrials.gov identifier: NCT05600985.

Modulation of steroid pathway to preserve corneal transparency

Purpose: Corneal neovascularization (CN) is a major cause of blindness worldwide. We previously showed that endothelial mineralocorticoid receptor (MR) contributed to CN in mice. In this study, we investigated the mechanisms of action of MRA in a rat model of limbal deficiency.Methods: CN was induced in Lewis rats by total corneal de‐epithelialization and limbal scratching. Spironolactone (SPL, 25 mg/kg) or eplerenone was administered daily. Control eyes received vehicle. Rats were euthanized at day 3 and 7, and corneas were dissected for transcriptomic analysis. Proteins extracted from corneas at day 7 were used for western blot. Corneal innervation was evaluated by immunostaining of TUBB3 on corneal flat mounts at day 16. Corneal morphology and CN were assessed in vivo by Micron III optical coherence tomography and fluorescein angiography at day 14.Results: MR antagonists (MRA) favoured epithelial regeneration and nerve growth, reduced corneal angiogenesis, edema and inflammation in a rat model of CN. Transcriptomic analysis showed 75 differentially expressed genes in SPL groups. Gene set enrichment analysis highlighted pathways including wound healing and differentiation, inflammatory and immune responses, hypoxia, angiogenesis and neuroprotection. SPL upregulated Dcn, Col1a1, Timp2 and downregulated Lrg1 at day 3, and induced Pedf at day 7. Increase in DCN protein by SPL was confirmed by western blot.Conclusions: MRA regulates genes/proteins involved in anti‐inflammatory and anti‐angiogenic processes, and improves corneal re‐innervation in CN model. Dcn is one of the downstream regulated targets.

Changes in corneal sensory nerves activity and the protective mechanisms during ocular surface pathologies

The prevalence of dry eye complaints due to tear production disorders is steadily increasing, mainly due to increased life expectancy and changes in lifestyle (contact lens wear, increased time spent in front of computer screens). However, the prevalence of subjective complaints and clinical symptoms of tear production disorders is variable, with only 10%–30% of the population having both subjective complaints and clinical symptoms. A number of in vivo confocal corneal microscopy (IVCM) studies have been performed to qualitatively and quantitatively examine the corneal nerve network in patients with dry eye disease in an attempt to elucidate the changes in corneal innervation and their clinical significance in the disease. Most studies have reported a decrease in nerve density, which may lead to nerve damage, followed by altered sensitivity of the regenerated nerves in patients with dry eye disease, resulting in hyperalgesia or allodynia. This presentation will summarize the role of corneal sensory nerves in the control of tear secretion in healthy eyes and the changes in some pathologies, particularly in dry eye disease. The changes in corneal sensory function in dry eye disease will be described in detail based on animal and human clinical studies. Knowledge of these changes will help to understand the contradictory relationship between objective symptoms and subjective complaints in dry eye patients.

An attempt to evaluate the anterior surface homeostasis in patients with diabetic retinopathy

Aims/Purpose: The aim of our study was to verify the presence of dry eye disease (DED) in diabetic patients. We also tried to determine the relationship between diabetic neuropathy and the presence of ocular surface disease.Methods: 52 type 2 diabetic patients and 52 non‐diabetic, sex and age‐matched controls were included in the study. All participants completed the OSDI questionnaire and undergone the eye surface examination with IDRA analyser including interferometry, tear meniscus height, non‐invasive tear break‐up time (NIBUT), evaluation of blepharitis, blinking pattern, pupillometry and meibography. Corneal sensation in the centre of the cornea and its 4 quadrants was analysed with the Cochet–Bonnet aesthesiometer (CBE). Corneal confocal microscopy images of sub‐basal plexus were evaluated using ACCMetrics. The concentrations of the neurotrophic factors: beta‐NGF, BDNF, NT‐4 as well as inflammatory mediators (TNF‐α, VEGF, IL‐2, ‐1β, ‐4, ‐5, ‐6, ‐8, ‐10, ‐12, GM‐CSF, IFN‐γ) were measured in the tear film using Luminex 200 analytic platform.Results: The OSDI was significantly higher in diabetic patients compared to the controls (mean: 29.08 vs. 11.67 points; p &lt; 0.001). The groups did not differ in the results of the Schirmer test, interferometry, NIBUT and meibography values. Moreover, we did not find the elevation in the concentrations of the ocular surface inflammation indicators in tears of diabetics as compared to controls. There was a significant difference in tear meniscus between groups. Diabetics achieved significantly worse results than the control group in terms of corneal sensation, innervation parameters (average nerve length = 6.70 vs 11.54 mm/mm2; p &lt; 0.001, average density = 9.26 vs. 19.19/mm2; p &lt; 0.001), scotopic pupillometry and blinking interval. Tear film BDNF concentrations were lower in diabetic eyes as compared to controls (mean 1.85 vs. 2.29 pg/mg; p = &lt;0.001).Conclusions: The lack of proinflammatory response in diabetic eyes and no differences between groups in the terms of objective clinical features may suggest that there is no cause‐and‐effect relationship between diabetes and DED. Corneal innervation disorders, clinically noticeable as decreased corneal sensation, result in a number of complications, that have a direct impact on the subjective feelings of the patient.

Corneal nerves and wound healing: No gain without pain

Corneal nerves and wound healing: no gain without pain?Corneal nerves are instrumental to the maintenance of corneal integrity. Their role in promoting epithelial cell migration and proliferation has been extensively described. Recently, the impact of corneal innervation on the limbal stem cell niche is starting to merge. Specifically, nerve‐derived factors orchestrate a complex biological response which involves the generation of pain, immune activation and stem cell interaction. On the other hand, epithelial and leukocyte cells have an impact on corneal nerves through secretion of soluble factors and, possibly, mechanical interaction. While the generation of pain is inevitably associated with wound healing, and its suppression generally impairs this process, excessive inflammation can perpetuate pain and negatively impact on corneal integrity. We will discuss the benefits, and shortcomings, of this nerve‐controlled process and review the potential therapeutic opportunities opened by recent findings in the field.

Clinical applications of confocal microscopy to corneal innervation

In vivo corneal confocal microscopy (IVCM) is a non‐invasive ophthalmic imaging technique that provides images of the cornea at the cellular level. Despite the uses in ocular surface pathologies, in the last decades IVCM has been used to provide more knowledge in refractive surgery wound healing (LASIK and PRK), dry eye disease, and in some corneal infections (amoebas and filamentous fungi). The observation of the corneal cells, both normal and inflammatory, and the possibility of quantification of the corneal nerve density and quality with manual or automated tools, makes IVCM have a significant potential to improve the diagnosis and prognosis in several systemic and corneal conditions. Neuropathic pain has multiple aetiologies, but a major feature is small fibre dysfunction or damage. IVCM has been utilized to show small nerve fibre loss in patients with diabetic and other neuropathies. IVCM has comparable diagnostic utility to intraepidermal nerve fibre density for diabetic neuropathy, fibromyalgia and amyloid neuropathy and predicts the development of diabetic neuropathy. Moreover, in clinical intervention trials of patients with diabetic and sarcoid neuropathy, corneal nerve regeneration occurs early and precedes an improvement in symptoms and neurophysiology. Corneal nerve fibre loss also occurs and is associated with disease progression in multiple sclerosis, Parkinson's disease, and dementia. Patients with small fibre neuropathy have IVCM nerve changes. In conclusion, IVCM has good diagnostic and prognostic capability and fulfils the criteria as an end point for clinical trials in corneal, and peripheral and central neurodegenerative diseases.

Viral ocular surface inflammation

Viral infections of the ocular surface (OS) may cause chronic, and/or recurrent inflammation that disrupt OS homeostasis, impact quality of life, and potentially impair vision through loss of corneal transparency and/or regularity. In this presentation, we'll review basic and clinical findings underlying OS inflammation in the context of the 3 most common viral pathogens affecting the OS, i.e. Adenovirus, Herpes Simplex virus type 1 and Varicella Zoster Virus.During its acute replicative phase, adenoviral keratoconjunctivitis may trigger severe acute conjunctival inflammation, leading to transmucosal exudation and fibrinous pseudo‐membrane formation. If left untreated, the latter induce conjunctival fibrosis with extensive loss of goblet cells. In a second phase of the disease, antigen‐driven immune‐mediated mechanisms may cause chronic corneal subepithelial infiltration.In the context of HSV and VZV keratitis, OS inflammation is caused by a combination of specific immune response to viral replication, causing stromal infiltration, and neovascularisation and ii) non‐specific inflammatory processes caused by corneal innervation alterations that impact tear secretion and osmolarity. While clinical disease is most often unilateral, unaffected side may display subclinical alterations, including decrease in corneal sensitivity and corneal nerve density, and decrease in endothelial cell density.Management of viral ocular surface inflammation involves a combination of strategies aiming at controlling viral replication, decrease associated inflammatory/immune response and restore OS homeostasia.

Minimally Invasive Corneal Neurotization: 10-Year Update in Technique Including Novel Donor Transfer of the Great Auricular Nerve.

Corneal anesthesia, caused by lack of corneal innervation, is a rare but devastating condition that can lead to neurotrophic keratopathy, corneal ulceration, scarring, and blindness. Minimally invasive corneal neurotization enables transfer of regional donor sensory nerves to the cornea to provide sensation and ocular protection. The authors provide an update on technical advances and modifications that have refined the surgery over the past 10 years, as well as step-by-step intraoperative videos of corneal neurotization, noting its critical steps, pitfalls, and caveats. The videos illustrate the novel technique of using the greater auricular nerve with a sural nerve graft extension as the donor nerve for the procedure. The steps and considerations depicted will allow surgeons to carry out corneal neurotization efficiently, safely, and effectively.

Topical Insulin in Neurotrophic Keratopathy: A Review of Current Understanding of the Mechanism of Action and Therapeutic Approach.

Neurotrophic keratopathy is a corneal disease characterized by impaired corneal innervation. It can lead to corneal epithelial defects, ulcerations, and perforations. Topical insulin has been shown to be effective in treating this disorder. Insulin is a growth factor that can promote corneal epithelial cell proliferation and migration. In addition, it can also inhibit corneal epithelial cell apoptosis. Topical insulin has previously been found to enhance corneal wound healing. This article reviews the current understanding of the mechanism of action of topical insulin in the treatment of neurotrophic keratopathy.