Preventing and treating neurotrophic keratopathy by a single intrastromal injection of AAV-mediated gene therapy.

PURPOSE: Neurotrophic keratopathy (NK) is a degenerative corneal condition resulting from corneal nerve injury. Current therapies, including the recombinant human nerve growth factor (rhNGF) therapy, requires continuous administration. This study aims to develop a novel and highly effective gene therapy strategy for the prevention and treatment of NK. METHODS: Adeno-associated virus (AAV) was transduced into corneal stromal cells by intrastromal injection. Three dimensional corneal wholemount imaging with co-immunostaining of ZO-1 and tubulin was utilized to assess the transduction of AAV.rh10. The efficacy of prevention and treatment of NK by a single intrastromal injection of AAV-Ngf was tested using capsaicin mouse model, herpes simplex keratitis (HSK) model, type Ⅱ diabetes model and alkali burn model. rhNGF eye drops served as the positive control. RESULTS: Intrastromal injection of AAV.rh10 efficiently transduced the subepithelial nerve plexus and retrogradely transported to the trigeminal ganglion (TG). A single injection of AAV.rh10-Ngf can significantly promote corneal nerve repair, accelerate corneal epithelial repair, reduce corneal stromal edema, and improve corneal sensitivity across the four NK models. The therapeutic effects were consistent with those achieved by continuous administration of rhNGF drops by 6 times daily. CONCLUSIONS: This proof-of-concept study demonstrates that AAV.rh10-Ngf gene therapy is a promising method for preventing and treating of NK. Our results underline the potential for developing clinical trials to further explore the safety and efficacy of such gene therapy.

Topical Application of 0.05% Cyclosporine for the Treatment of Neurotrophic Keratopathy Secondary to Herpes Simplex Keratitis.

PURPOSE: The purpose of this study was to assess the effectiveness and tolerability of 0.05% cyclosporine A (CsA) eye drops for neurotrophic keratopathy (NK) secondary to herpes simplex keratitis (HSK). METHODS: Fifteen patients (15 eyes) with prior HSK and secondary NK, classified as stage 2 or 3 on the basis of the Mackie classification, were enrolled. All patients received a combined treatment regimen of 0.05% CsA eye drops (1 drop 4 times daily), a silicone hydrogel bandage contact lens, and 0.15% ganciclovir ophthalmic gel (1 drop 3 times daily). For patients achieving corneal healing, CsA was continued at a reduced dosage of twice daily for an additional 2 months and other treatments were discontinued. Follow-ups were scheduled at weeks 1, 2, 3, and 4 and at months 2 and 3 after treatment initiation, followed by a 3-month follow-up period. Key outcomes, including best-corrected visual acuity, Schirmer I test, and corneal sensitivity, were assessed at each visit before and after treatment. FINDINGS: Significant reductions were observed in the area of corneal defects, expressed as proportion of total corneal area, throughout follow-up period. Complete corneal healing was achieved by 13.3% of patients by week 2, 60.0% by week 3, 86.7% by week 4, and 100.0% by week 8, with the mean (SD) time to healing being 3.8 (1.8) weeks (range, 2-8 weeks). Additionally, significant improvements were noted in diseased eyes for best-corrected visual acuity, tear secretion (Schirmer I test values), and corneal sensitivity after treatment. IMPLICATIONS: CsA eye drops, with bandage lenses and ganciclovir, effectively resolve NK from HSK, without adverse effects. This combination therapy shows promise for future clinical use and research. CLINICAL TRIAL REGISTRATION: Our study is a retrospective observational study because it involves the analysis of previously collected data, so the study was not registered prior to its commencement. However, if it is necessary for publication, we are willing to proceed with retrospective registration.

Long-Term Evaluation of Patients with Neurotrophic Keratopathy Undergoing Staged Keratoplasty After Corneal Neurotization.

PURPOSE: Corneal neurotization (CN) is a novel, potentially curative surgical procedure for the treatment of neurothophic keratopathy (NK). Patients with severe NK can present with corneal opacification requiring optical keratoplasty, which would likely fail without a proper trophic support of corneal nerves in the recipient cornea. METHODS: This is a pilot study on 4 patients undergoing keratoplasty after CN. Pre- and postoperative data at 12, 24 months and at the last follow-up were collected for the examination of (i) best corrected visual acuity (BCVA), (ii) slit lamp examination and photograph acquisition with and without fluorescein staining, (iii) corneal aesthesiometry, (iv) in vivo confocal microscopy of the central cornea. Neurophysiological study of the corneal reflex before corneal graft and at last follow up was performed. RESULTS: Four female patients (47.25 ± 5.06 y.o.) underwent keratoplasty after CN (3 penetrating keratoplasty, 1 deep anterior lamellar keratoplasty). The mean interval between CN and keratoplasty was 22 (± 12) months. The mean graft survival time was 42 (± 25) months. Graft follow-up ranged from 72 to 132 months. At the final follow-up, BCVA was improved in 2 out of 4 patients. The mean corneal sensitivity was 11.9 ± 8.3 mm at last follow-up. In vivo confocal microscopy confirmed the presence of functioning nerves at the last follow-up in all patients. NK-related complications occurred in 3 eyes (2 persistent epithelial defect, 1 corneal melting). The former complication was successfully treated by autologous serum eye drops while the latter required repeated keratoplasty. CONCLUSIONS: Keratoplasty is a viable strategy to improve visual acuity in patients with corneal opacity who underwent CN for the treatment of NK. Even in the presence of functioning corneal nerves before keratoplasty, surgeons should be aware of the increased rate of NK-related complications that could require the need for repeated procedure.

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.

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.

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.

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.

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.

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.

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.