Clodronate liposome treatment contributes to the nerve regeneration in corneal nerve involvement of diabetic mice.

The dense nerve and thin vascular structure of the corneal tissue provide the refractive function in healthy eyes. Diabetes mellitus causes ocular complications including corneal opacification because of corneal nerve degeneration. Diabetic neurotrophic keratopathy is characterized by reduced corneal sensitivity, delayed corneal wound healing, and nerve degeneration. Neurotization and vascularization inhibit each other in the cornea. Macrophages contribute to the corneal neovascularization. To investigate the role of macrophage in neurotrophic keratopathy, clodronate liposome was subconjunctivally injected into diabetic db/db mice with neurotrophic keratopathy. The clodronate liposome treatment decreased F4/80+ macrophage infiltration into the corneal epithelium, and improved corneal nerve involvement in diabetic db/db mice. Furthermore, we found that interleukin (IL)-1ß and IL-34 mRNA expression was increased in the corneal epithelium of clodronate-treated diabetic db/db mice. These cytokines contribute to the maintenance of nerve tissues via microglia and nerve regeneration; however, their role in corneal nerve involvement remains unknown. Notably, the intraocular injection of recombinant IL-1ß and IL-34 promoted nerve regeneration in the cornea of diabetic db/db mice. These results suggest that clodronate liposome treatment contributes to nerve regeneration during corneal involvement via IL-1ß and IL-34 signaling.

Corneal reinnervation in patients with severe neurotrophic keratopathy secondary to herpes zoster ophthalmicus after treatment with autologous serum tear drops.

Purpose: To study potential corneal reinnervation and recovery of corneal sensation in patients with severe neurotrophic keratopathy (NK) secondary to herpes zoster ophthalmicus (HZO) after treatment with topical autologous serum tears (AST). Method: Four cases of HZO with severe NK were followed clinically and by serial laser in vivo confocal microscopy (IVCM, HRT3/RCM, Heidelberg Engineering) before and during treatment with 20% AST drops eight times a day. Two masked observers reviewed the IVCM images and assessed corneal nerve alterations. Results: At baseline, all patients had complete loss of corneal sensation. In addition, IVCM showed complete lack of the subbasal corneal nerve plexus in all patients. All four patients were refractory to conventional therapies and were treated with AST drops. All patients demonstrated significant nerve regeneration by IVCM within 3-7 months of treatment. The total nerve density increased to a mean ± SEM of 10,085.88±2,542.74 µm/mm2 at the last follow up. Corneal sensation measured by Cochet-Bonnet esthesiometry improved to a mean ± SEM of 3.50±1.30 cm. Interestingly, 3 of 4 patients developed stromal keratitis with ulceration within weeks of corneal reinnervation, which was reversed by adding topical steroids. Conclusion: Autologous serum tears are effective in restoring corneal subbasal nerves and sensation in patients with severe NK secondary to HZO. However, this group of patients may require concurrent topical immunomodulation and antiviral therapy while on AST to prevent stromal keratitis.

The Utilization of Topical Insulin for Ocular Surface Diseases: A Narrative Review.

Various etiologies, including diabetic keratopathy (DK), dry eye disease (DED), and neurotrophic keratopathy (NK), can disrupt corneal homeostasis, exacerbating corneal epithelial defects. Topical insulin has emerged as a promising therapy for promoting corneal wound healing and addressing underlying pathologies. This review systematically evaluates the efficacy of topical insulin across different corneal disorders. A literature review was conducted across the PubMed, Google Scholar, and Scopus research databases. The search resulted in a total of 19 articles, consisting of clinical trials, retrospective studies, and case reports. In DK, topical insulin accelerates corneal wound healing post-vitreoretinal surgery with lower concentrations showing higher outcomes when compared to conventional therapy, possibly due to improved epithelial stem cell migration. In comparison, the dry-eye disease results are inconclusive regarding patient-reported outcomes and corneal staining. For NK, topical insulin accelerates corneal wound healing and restores corneal nerve sensation. Other persistent epithelial defect (PED) etiologies that have been treated with topical insulin are infection, immune-mediated, mechanical and chemical trauma, and chronic ocular surface alterations. Although individual mechanisms for the benefits of topical insulin for each of these etiologies have not been studied, the literature demonstrates that topical insulin is efficacious for PEDs regardless of etiology. Future clinical trials need to be conducted to further evaluate optimal dosing, duration, and use of topical insulin for the restoration of the corneal surface.

Detection of Subclinical Neurotrophic Keratopathy by Noncontact Esthesiometry.

INTRODUCTION: This study aimed to analyze corneal sensitivity with a new noncontact and handheld esthesiometer (Brill Engines, Spain) in patients with dry eye disease (DED) and patients on hypotensive drops, and to compare it with healthy subjects. METHODS: A total of 31 patients (57 eyes) with DED, 23 patients (46 eyes) with glaucoma, and 21 healthy patients (33 eyes) were recruited. In all patients, corneal sensitivity was measured. Subsequently, a keratography test (Keratograph 5M, Oculus) was carried out to measure tear meniscus height (TMH), non-invasive breakup time (NIBUT), bulbar redness (Jenvis scale), and corneal staining (CS, Oxford scale). Both corneal sensitivity and ocular surface parameters were compared between DED, glaucoma, and healthy subjects. Linear mixed models were constructed to utilize data from both eyes of patients. An alpha level of 0.05 was considered statistically significant. RESULTS: The mean age was 56.1 ± 16.1 years in the DED group, 69.5 ± 11.7 years in the glaucoma group, and 37.190 ± 11.677 years in the control group. After adjustment for age and sex, corneal sensitivity was significantly reduced in DED and glaucoma vs control group (P = 0.02 and P = 0.009, respectively). NIBUT was lower in DED and glaucoma groups (P < 0.001 and P = 0.001, respectively). Redness and CS values were higher in the DED group (P = 0.04 and P = 0.001, respectively). TMH was lower in the glaucoma group (P = 0.03). CONCLUSIONS: Corneal sensitivity measured with a novel noncontact esthesiometer was reduced in DED and glaucoma groups compared to controls. In clinical practice, this esthesiometer could be an easy-to-use device to screen for patients with subclinical neurotrophic keratopathy.

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 role of topical insulin in ocular surface restoration: A review.

Corneal epithelial defects are one of the most common ocular disorders. Restoring corneal integrity is crucial to reduce pain and regain function, but in cases of neurotrophic or desensitized corneas, healing can be significantly delayed. Treating neurotrophic corneas is challenging for ophthalmologists, and surgical intervention is often indicated to manage refractory cases that are unresponsive to medical therapy. Over the last decade, as more expensive therapeutics reach the market, topical insulin has returned to the forefront as an affordable option to improve corneal wound healing. There is still a paucity of data on the use and the efficacy of topical insulin, with no consensus regarding its indications, preparation, or posology. Here we review the literature on topical insulin for corneal and ocular surface pathologies, with a focus on the current evidence, its mechanisms of action, and its safety profile. Additionally, we share our experience in the field and provide a potential framework for future research.

Iris neovascularization and neurotrophic keratopathy following ultrasound cycloplasty in refractory glaucoma: case series.

BACKGROUND: Ultrasound cycloplasty is a noninvasive surgery used to reduce intraocular pressure in patients with glaucoma, with fewer severe complications. This report presents several cases of iris neovascularization and neurotrophic keratopathy following ultrasound cycloplasty. CASE PRESENTATION: Six patients diagnosed with refractory glaucoma underwent ultrasound cycloplasty at our clinic. Three cases developed iris neovascularization at postoperative day 3, week 2 and week 4 respectively, with intraocular pressure ranging from 12 to 24 mmHg. The other three cases developed neurotrophic keratopathy at postoperative week 3, week 6 and week 8 which completely healed within 60 days. CONCLUSIONS: Iris neovascularization and neurotrophic keratopathy can be triggered after ultrasound cycloplasty, which are uncommon and self-limited but potentially vision-threatening. Preoperative risk assessment and regular postoperative follow-up are recommended to manage complications effectively.

Predictive performance of corneal and lid margin sensitivity for dry eye disease: An investigator-masked, prospective, prognostic accuracy study.

PURPOSE: To evaluate the prognostic ability of non-contact esthesiometry corneal and lid margin sensitivity measurements in detecting symptoms and signs of dry eye disease, as defined by the global consensus TFOS DEWS II criteria. METHODS: A total of 87 community residents (58 females; mean ± SD age, 53 ± 16 years) were recruited in an investigator-masked, prospective, prognostic accuracy study. Dry eye symptomology, tear film parameters, and ocular surface characteristics were evaluated in a single clinical session, and non-contact esthesiometry corneal and lid margin sensitivity measurements performed by an independent masked assessor. RESULTS: Overall, 49 (56%) participants fulfilled the TFOS DEWS II criteria for dry eye disease, while 57 (66%) exhibited clinical symptoms, and 67 (77%) had positive signs. The prognostic abilities of corneal and lid margin sensitivity measurements were significantly greater than chance for the detection dry eye signs (both p ≤ 0.03), but not for symptoms or overall disease diagnosis (all p > 0.10). The Youden-optimal prognostic cut-offs for corneal and lid margin sensitivity thresholds were both ≥0.8 mbar for the detection of clinical dry eye signs. Lid margin sensitivity demonstrated marginally higher predictive performance than corneal sensitivity (C-statistic, 0.688 versus 0.658), and was significantly correlated with tear film stability, corneal, conjunctival and lid wiper staining (all p < 0.05). CONCLUSIONS: Corneal and lid margin sensitivity demonstrated moderate prognostic utility for detecting clinical dry eye signs. Future research is warranted to investigate the utility of incorporating non-contact esthesiometry in the workup for dry eye disease and neurotrophic keratopathy.

Establishment of mouse model of neurotrophic keratopathy through TRPV1 neuronal ablation.

Neurotrophic keratopathy (NK) is a challenging disease with the reduced innervation to the cornea. To establish a genetic and stable mouse model of NK, we utilized the TRPV1-DTR mice with intraperitoneal injection of diphtheria toxin (DT) to selectively eliminate TRPV1 neurons. After DT administration, the mice exhibited robust ablation of TRPV1 neurons in the trigeminal ganglion, accompanied with reduced corneal sensation and nerve density, as well as the decreased calcitonin-gene-related peptide (CGRP) and substance P levels. According to disease progression of TRPV1 neuronal ablation, tear secretion was reduced from day 3, which followed by corneal epithelial punctate lesions from day 7. From day 11 to day 16, the mice exhibited persistent corneal epithelial defects and stromal edema. By day 21, corneal ulceration and stromal melting were observed with the abundant inflammatory cell infiltration, corneal neovascularization, and enhanced cell apoptosis. Moreover, subconjunctival injection of CGRP delayed the NK progression with the characteristics of reduced severe corneal epithelial lesions and corneal inflammation. In addition, the impairments of conjunctival goblet cells, lacrimal gland, and meibomian gland were identified by the diminished expression of MUC5AC, AQP5, and PPARγ, respectively. Therefore, these results suggest that the TRPV1-DTR mice may serve as a reliable animal model for the research of NK pathogenesis.

Phase IV Multicenter, Prospective, Open-Label Clinical Trial of Cenegermin (rhNGF) for Stage 1 Neurotrophic Keratopathy (DEFENDO).

INTRODUCTION: Cenegermin is approved for treatment of neurotrophic keratopathy (NK) and has been studied in patients with stage 2 or 3 NK. This study evaluated the efficacy and safety of cenegermin in adults with stage 1 NK. METHODS: This was a phase IV, multicenter, prospective, open-label, uncontrolled trial. Adults with stage 1 NK (Mackie criteria) and decreased corneal sensitivity (≤ 4 cm) received 1 drop of cenegermin 20 mcg/ml in the affected eye(s) 6 times/day for 8 weeks with a 24-week follow-up. RESULTS: Of 37 patients, corneal epithelial healing was observed in 84.8% (95% confidence interval [CI] 68.1-94.9%; P < 0.001) at week 8; 95.2% (95% CI 76.2-99.9%; P < 0.001) of those patients remained healed at the end of the 24-week follow-up (week 32). At week 8, 91.2% (95% CI 76.3-98.1%; P < 0.001) of patients experienced improved corneal sensitivity; this improvement was observed in 82.1% (95% CI 63.1-93.9%; P < 0.001) of patients at week 32. Mean best-corrected distance visual acuity change from baseline at week 8 was - 0.10 logMAR (standard deviation [SD], 0.15; 95% CI - 0.16 to - 0.05; P < 0.001) and at week 32 was - 0.05 logMAR (SD, 0.16; 95% CI - 0.11 to 0.01; P = 0.122). At weeks 8 and 32, 15.2% (95% CI 5.1-31.9%; P < 0.001) and 10.7% (95% CI 2.3-28.2%; P < 0.001) of patients, respectively, had a 15-letter gain from baseline. At least one adverse event (AE) was reported by 73.0% and 45.7% of patients during the treatment and follow-up periods, respectively. The most common treatment-related, treatment-emergent AEs were eye pain (37.8%), blurred vision (10.8%), and eyelid pain (8.1%); these were mostly mild or moderate and were only reported during the treatment period. CONCLUSIONS: These results support the potential use of cenegermin for treating patients with stage 1 NK, and future confirmatory studies would be beneficial to elaborate on these findings. TRIAL REGISTRATION: DEFENDO; NCT04485546.

Outcomes and success of amniotic membrane transplantation for the treatment of corneal diseases.

PURPOSE: The amniotic membrane (AM), the inner layer of the placenta, is a semitransparent, avascular, and thin tissue that is useful due to its structure. Amniotic membrane transplantation (AMT) avoids the need for keratoplasty to prevent corneal perforating. The purpose of the study was to evaluate the visual (gain of or no change in visual acuity) and corneal outcomes (closure of the ulcer or corneal healing) of AMT in patients with ocular surface diseases. MATERIALS AND METHODS: This was a retrospective case control study (success or failure of the surgery). It was undertaken at a single academic center. The study cohort consisted of subjects with ocular surface diseases. Patients were treated with AMT for refractory ocular surface diseases. They were divided into five subgroups according to the preoperative diagnosis. The technique of AMT used was the onlay method with two layers of AM. Primary outcome measures included best corrected visual acuity (BCVA), the number of AMTs, and reepithelization of the corneal epithelium at the end of the treatment. Two weeks to six months were given to consider epithelial closure. Treatment success was defined as corneal healing within 6 months. RESULTS: A total of the 66 eyes of 66 patients (39 male/27 female) with a mean age of 44 ± 23 years (range 1-88 years) were included in the study. A single AMT procedure achieved epithelial closure in 74.2% (n = 49) of the eyes (53% in <15 days, 19.6% in 15-30 days, and 1.5% in 1-6 months). The fastest reepithelization occurred in neurotrophic keratopathy, 76.9% of which cases occurred within 15 days after the AMT procedure. Treatment failure was observed in five patients (7.5%), four with keratitis and one with neurotrophic keratopathy. The highest closure rates were found in persistent epithelial defects, graft-versus-host disease (GvHD), and bullous keratopathy, although there was no statistically significant difference in BCVA. Pairwise comparisons were made of neurotropic keratoplasty versus bullous keratopathy (P = 0.025), neurotrophic keratopathy versus keratitis (P = 0.004), GVHD versus keratitis (P = 0.003), and lastly, GvHD versus bullous keratopathy (P = 0.023). CONCLUSIONS: AMT is a safe, valuable, and fast treatment technique to treat corneal epithelial defects stemming from different etiologies that are refractory to conventional treatment.

A New Treatment for Recalcitrant Neurotrophic Keratopathy of Ocular Graft-Versus-Host Disease with Virus Infection.

INTRODUCTION: Neurotrophic keratopathy (NK) is a rare degenerative ocular disease that can be difficult to treat. There were no effective resolutive treatments for severe NK caused by ocular graft-versus-host disease (oGVHD) along with virus infection. To address this question, we designed a prospective cohort study to evaluate the efficacy and safety of topical recombinant human nerve growth factor (rhNGF) in patients with recalcitrant NK of oGVHD and viral infection. METHODS: This prospective cohort study enrolled patients with recalcitrant NK diagnosed with oGVHD and treated with rhNGF. Clinical evaluations included the range of epithelial defects, best corrected visual acuity, intraocular pressure, slit-lamp examination, and corneal fluorescein staining. Examinations of the central corneal thickness, corneal sensitivity, and nerve fiber regeneration were performed at each visit at 4, 8, 12, 20 weeks and 6 months, respectively, after initiating rhNGF treatment. RESULTS: All enrolled patients were diagnosed with NK at stage 2 (7 eyes, 63.6%) or stage 3 (4 eyes, 36.4%) and responded to rhNGF treatment. Five of 11 (45.5%) and 9 of 11 eyes (81.8%) achieved complete corneal epithelial healing after 4 and 8 weeks, respectively. All 11 eyes (100%) achieved complete corneal healing after 12 weeks. There was also a significant reduction in the corneal ulcer area during each visit (P < 0.001), as well as in the corneal fluorescein staining score (P < 0.010). There was a significant improvement in corneal sensation when compared to the baseline (P < 0.050). CONCLUSION: Topical treatment with rhNGF effectively promoted the complete corneal healing of persistent epithelial defects and corneal ulcers in patients with recalcitrant NK in oGVHD and viral infection.

Neurotrophic keratopathy: Clinical presentation and outcomes in 354 eyes in a community-based population.

PURPOSE: To describe the frequency, clinical presentation, and outcomes of neurotrophic keratopathy (NK). METHODS: Retrospective cohort study of Kaiser Permanente Northern California patients diagnosed with NK using ICD-10 code H16.23X from October 1, 2016 through May 31, 2021 was conducted. The electronic medical record was used to obtain demographic information, systemic and ocular comorbidities, corrected distance visual acuity (CDVA), Mackie stage, laterality, etiology, complications, interventions, and medications. The data were analyzed using cross-tabulations. RESULTS: 354 eyes in 322 patients presented with an initial or recurrent episode of NK. 9.9% had bilateral NK, 40% were 75 years and older, and 55% were women. Baseline vision was worse than 20/100 in 47.5%. Mackie staging was stage 1 in 37.3%, stage 2 in 32.5%, and stage 3 in 30.2%. Herpetic causes comprised 34.9%, followed by diabetes (12.4%), ocular surgery (10.4%), and central nervous system etiologies (9.0%). Topical antibiotics (74.5%), steroids (54.0%), autologous serum tears (46.0%), and oral antivirals (43.8%) were the most used treatments. There were 8 eyes with perforation, 4 endophthalmitis, and 3 evisceration/enucleations. An increased difference of approximately 0.1 logMAR in CDVA in the affected eye compared with the unaffected eye over one year was not statistically significant. Clinic utilization for stage 2 (average visits per month, 3.2) and stage 3 (5.0) NK gradually decreased over 6 months. CONCLUSIONS: Summary of the current management, outcomes, and healthcare utilization of NK provides valuable benchmarks in assessing the disease burden in the community and for further development of novel therapies.

Evaluation of the therapeutic effect of autologous serum on neurotrophic keratopathy with persistent corneal epithelial defect / 中华实验眼科杂志

Objective:To evaluate the outcomes of autologous serum eye drops on persistent corneal epithelial defect caused by neurotrophic keratopathy (NK).Methods:An observational case series study was performed.Twenty patients (20 eyes) diagnosed with NK and persistent corneal epithelial defect were enrolled in Beijing Tongren Hospital from January 2020 to January 2021.The affected eyes were graded according to the severity of the lesion and received individualized comprehensive treatment with domestic autologous serum eye drops as the main therapy.The healing time of the corneal epithelial defect after treatment was recorded.The diameter and area of the defect were marked by corneal fluorescein staining.Changes in the diameter and area of the defect before treatment and at 1, 2, 3, 4 and 8 weeks after treatment were observed by slit lamp microscopy at 10×.Logarithm of the minimum angle of resolution (LogMAR) visual acuity was recorded with a standard logarithmic visual chart before treatment and at 1, 2, 4, 12, and 24 weeks after treatment.Changes in corneal nerve fiber distribution and silk length of corneal perception were assessed by confocal laser scanning microscopy and Cochet-Bonnet esthesiometry, respectively, before treatment and at 4, 12, and 24 weeks after treatment.Influences of corneal defect characteristics on the healing time were analyzed by multiple linear regression analysis.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Beijing Tongren Hospital Affiliated to Capital Medical University (No.TRECKY2021-110). Written informed consent was obtained from each subject.Results:The corneal epithelial defect was 5.00 (4.00, 5.75) mm in diameter and 15.50 (12.00, 20.00) mm 2 in area before treatment.There were 45% (9/20) with corneal stroma edema and 35% (7/20) with endothelial fold.One diabetic patient with uveitis had a corneal epithelial defect area greater than 8 mm×6 mm and accepted additional corneal clearance and amniotic membrane transplantation after 2 weeks of autologous serum eye drops application.The other 19 patients received autologous serum eye drops therapy.All eyes showed complete recovery.The pretreatment duration of autologous serum eye drops ranged from 2 weeks to 3 months, with a mean of (39.55±25.34) days.The repair time of corneal epithelium ranged from 12 to 42 days, with a mean of (19.68±9.25) days.There were statistically significant differences in corneal defect diameter and area between before and after treatment ( χ2=43.130, 28.265; both at P<0.001). Corneal defect area and diameter decreased at various time points after treatment compared to before treatment, and the differences were statistically significant (all at P<0.05). There were statistically significant differences in LogMAR visual acuity between before and after treatment ( χ2=84.229, P<0.001). LogMAR visual acuity improved at 1, 2, 4, 12, and 24 weeks after treatment compared to pretreatment, and the differences were statistically significant (all at P<0.05). There were statistically significant differences in silk length of corneal perception between before and after treatment ( χ2=55.295, P<0.001). Silk length of corneal perception improved at 4, 12 and 24 weeks compared to pretreatment, and the differences were statistically significant (all at P<0.05). Baseline corneal defect severity grade was positively correlated with healing time ( β=10.55, P=0.032). Corneal defect diameter and area had no influence on the healing time ( β=-2.02, P=0.501; β=0.49, P=0.199). Conclusions:Autologous serum eye drop therapy is safe and effective for persistent corneal defects caused by NK.Re-application of autologous serum eye drops is still effective in individual patients with recurrent corneal defects after discontinuation of serum treatment.It can be combined with surgery for intractable cases.

Application of corneal neutrotization in the treatment of neurotrophic keratopathy / 中华实验眼科杂志

Neurotrophic keratopathy (NK) is a degenerative disease in which damage to the corneal nerves leads to corneal hypoesthesia and even blindness.Traditional NK treatments aim at supporting corneal healing and preventing progression of corneal damage.In recent years, corneal neurotization has made some progress in NK.Compared with traditional treatment, it can not only solve the problem of corneal nerve defect, and avoid the subsequent keratopathy, but also significantly restore corneal sensitivity, corneal epithelium and vision.Corneal neurotization surgery methods are mainly divided into direct corneal neurotization (DCN) and inderect corneal neurotization (ICN).At present, this surgical method has gradually been used clinically, and has achieved satisfactory effects on unilateral NK caused by herpes virus and neuroma, as well as bilateral NK.However, it is little known about the surgical treatment of NK caused by dry eye, diabetes, and chronic glaucoma.In the future, multi-center prospective randomized studies can be conducted to further improve the treatment of NK with other causes.This article introduces this new surgical technique from three aspects, the specific surgical procedures of corneal neurotization, the selection of surgical methods, and the timing of the operation.

Neurotrophic Keratopathy and Topical Insulin Therapy: A Case Report.

Neurotrophic keratopathy is a rare disorder caused by the loss of corneal sensation. It is characterized by persistent epithelial defects, corneal ulceration, and, ultimately, corneal perforation if not managed in a timely manner. The management includes aggressive lubrication, prophylactic topical antibiotics, therapeutic contact lenses, tarsorrhaphy, and amniotic membrane transplantation. Some novel therapeutic options are also available, one of which is topical insulin therapy. We report the clinical course of a patient with neurotrophic keratopathy that was successfully treated with topical insulin. A 64-year-old male presented to our outpatient department with a three-month history of painless blurring of vision following prior episodes of herpetic keratitis. Ocular examination showed a bilateral reduction in corneal sensations, bilateral corneal opacities, and a corneal ulcer in the left eye. He was diagnosed as a case of neurotrophic keratopathy secondary to prior herpetic keratitis. He was then treated with topical and oral acyclovir along with topical insulin drops. There was a remarkable improvement in his condition after a month with a reduction in the size of the ulcer and, after two months, the ulcer was completely re-epithelialized. This case report illustrates the use of topical insulin in the initial management of neurotrophic keratopathy as opposed to its conventional use in refractory neurotrophic corneal ulcers.

Effect of recombinant human nerve growth factor treatment on corneal nerve regeneration in patients with neurotrophic keratopathy.

Introduction: Neurotrophic Keratopathy (NK) is a neurodegenerative corneal disease that results in diminished corneal sensation. Previous studies have found that Cenegermin 0.002%, a recombinant human nerve growth factor (rhNGF), improves corneal epithelial healing in stage 2 and 3 NK patients. However, rhNGF effect on corneal sensation and nerve regeneration has not been well established. Thus, this study aims to analyze the effect of rhNGF on corneal nerve regeneration using in vivo confocal microscopy (IVCM) and on corneal sensitivity in NK patients. Methods: This is a retrospective, longitudinal, case-control study that included patients with NK, treated with rhNGF for at least 4 weeks, with pre- and post-treatment IVCM images available for analysis. Chart reviews were conducted documenting prior medical and surgical history, clinical signs and symptoms, and corneal sensation using Cochet-Bonnet esthesiometry. Corneal nerve parameters were assessed by IVCM. Sex- and age-matched reference controls were selected from a database of healthy subjects for comparison. Results: The study included 25 patients, with 22 (88%) stage 1, two (8%) stage 2, and 1 (4%) stage 3 NK patients, with a median age of 64 years (range: 30-93 years). Total, main, and branch nerve densities [median (range) in mm/mm2] were lower in the NK group pre-treatment [2.3 (0.0-21.1); 1.7 (0.0-13.0); 0.5 (0.0-10.2); respectively] vs. controls [22.3 (14.9-29.0); 10.1 (3.2-15.4); and 12.1 (6.2-18.4), (p < 0.0001 for all), respectively]. Post-treatment nerve densities increased compared to pre-treatment to 5.3 (0.0-19.4, p = 0.0083) for total, 3.5 (0.0-13.2, p = 0.0059) for main, and 2.0 (0.0-10.4, p = 0.0251) for branch nerves, but remained lower than controls (p < 0.0001 for all). Corneal sensation increased from 2.3 ± 1.1 cm pre-treatment to 4.1 ± 1.4 cm post-treatment (p = 0.001). Median best corrected visual acuity significantly increased following rhNGF treatment from 0.4 (0.0-1.6) to 0.12 (-0.1 to 1.6) (p = 0.007). Conclusion: Patients with NK treated with at least 4 weeks of rhNGF, showed a significant increase in corneal nerve densities after treatment. A significant increase in corneal sensation, as well as best corrected visual acuity, was observed following treatment.

Neurotrophic keratopathy: An updated understanding.

PURPOSE: To propose an updated definition and staging system for neurotrophic keratopathy (NK) and provide consensus on diagnosis and treatment. METHODS: A study group was convened to review the data pertinent to NK using a modified nominal group process. They proposed an updated definition for NK and a new 6-step staging system (Neurotrophic Keratopathy Study Group [NKSG] Classification) that can be used in conjunction with the different treatment options available currently or in the future. RESULTS: NK is defined as the dysfunction of corneal innervation that results in dysregulation of corneal and/or cellular function. It is characterized by loss of corneal sensation and neuronal homeostasis, leading to eventual corneal epithelial breakdown and ultimately keratolysis if untreated. The NKSG classification emphasizes verifying corneal sensation early and distinguishes different epithelial and stromal aspects of NK with the following stages: stage 1 (altered sensation without keratopathy), stage 2 (epitheliopathy/punctate epithelial keratopathy [PEK] without stromal haze), stage 3 (persistent/recurrent epithelial defects without stromal haze), stage 4 (epitheliopathy/PEK or persistent/recurrent epithelial defects with stromal haze), stage 5 (persistent/recurrent epithelial defect with corneal ulceration), and stage 6 (corneal perforation). Treatment consists of a variety of modalities (both indirect and direct). CONCLUSIONS: This updated definition and staging system will provide clinicians with the necessary information to diagnose and treat NK at an early stage before it becomes a sight-threatening disorder. It also provides a framework for evaluating current and future treatment options at distinct stages of the disease.

The Role of Sensory Innervation in Homeostatic and Injury-Induced Corneal Epithelial Renewal.

The cornea is the window through which we see the world. Corneal clarity is required for vision, and blindness occurs when the cornea becomes opaque. The cornea is covered by unique transparent epithelial cells that serve as an outermost cellular barrier bordering between the cornea and the external environment. Corneal sensory nerves protect the cornea from injury by triggering tearing and blink reflexes, and are also thought to regulate corneal epithelial renewal via unknown mechanism(s). When protective corneal sensory innervation is absent due to infection, trauma, intracranial tumors, surgery, or congenital causes, permanent blindness results from repetitive epithelial microtraumas and failure to heal. The condition is termed neurotrophic keratopathy (NK), with an incidence of 5:10,000 people worldwide. In this report, we review the currently available therapeutic solutions for NK and discuss the progress in our understanding of how the sensory nerves induce corneal epithelial renewal.

Ocular-Surface Regeneration Therapies for Eye Disorders: The State of the Art.

The ocular surface is a complex structure that includes cornea, conjunctiva, limbus, and tear film, and is critical for maintaining visual function. When the ocular-surface integrity is altered by a disease, conventional therapies usually rely on topical drops or tissue replacement with more invasive procedures, such as corneal transplants. However, in the last years, regeneration therapies have emerged as a promising approach to repair the damaged ocular surface by stimulating cell proliferation and restoring the eye homeostasis and function. This article reviews the different strategies employed in ocular-surface regeneration, including cell-based therapies, growth-factor-based therapies, and tissue-engineering approaches. Dry eye and neurotrophic keratopathy diseases can be treated with nerve-growth factors to stimulate the limbal stem-cell proliferation and the corneal nerve regeneration, whereas conjunctival autograft or amniotic membrane are used in subjects with corneal limbus dysfunction, such as limbal stem-cell deficiency or pterygium. Further, new therapies are available for patients with corneal endothelium diseases to promote the expansion and migration of cells without the need of corneal keratoplasty. Finally, gene therapy is a promising new frontier of regeneration medicine that can modify the gene expression and, potentially, restore the corneal transparency by reducing fibrosis and neovascularization, as well as by stimulating stem-cell proliferation and tissue regeneration.