UNASSIGNED: 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).
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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 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)-1β 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-1β 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-1β and IL-34 signaling.

BACKGROUND: 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.

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.

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.

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.
METHODS: 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.

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.

OBJECTIVE: 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.

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.

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.