Cochet-Bonnet Esthesiometry Research Articles

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...

Local anaesthetic delivery through indwelling retrobulbar catheters for ocular pain control in horses

AbstractBackgroundEquine corneal disease is common and painful. Current pain mitigation strategies are often suboptimal, especially early in the disease.ObjectivesTo evaluate the effects of local anaesthetic delivery via indwelling retrobulbar catheter on corneal sensitivity, pupil size, pupillary light responses (PLRs), and ocular motility in normal horses.Study designRandomised, controlled crossover experiment.MethodsOne eye was randomly selected from seven horses. A 20‐gauge catheter was placed in the retrobulbar space and injected with 10 mL of 0.5% bupivacaine or 0.9% saline. Cochet–Bonnet esthesiometry (CBE), pupil photogrammetry, PLRs, and oculocephalic reflexes were evaluated before injection (t = 0) and t = 0.25, 1, 3, 6, 9 and 12 h after injection. Following a 7–14 day washout period, this procedure was repeated using the alternative injection solution. Corneal touch thresholds (CTTs) derived from CBE and pupillary areas (PA; as measured from photographs) were compared across time for each group. PLRs and oculocephalic reflexes were compared between groups at each evaluation time point.ResultsSaline did not affect CBE, PA, PLRs or oculocephalic reflexes at any time point. Bupivacaine reduced CTT compared with saline for 6 h, with maximum reduction at t = 1 h (bupivacaine: 0.08 ± 0.20 cm; saline: 4.21 ± 0.39 cm; p < 0.001). Bupivacaine increased PA compared with saline for 3 h, with maximum increase at t = 3 h (bupivacaine: 349.75 ± 84.80 mm2; saline: 194.65 ± 27.03 mm2; p = 0.04). Bupivacaine injection reduced PLRs for 9 h and oculocephalic reflexes for 3 h; saline had no effect. Mild adverse effects included chemosis, blepharoedema, and transiently reduced palpebral reflex.Main limitationsReduction in CTT may not directly translate to pain control in clinical horses with corneal disease. Adverse effects of repeated injections were not evaluated.ConclusionsInjection of bupivacaine via an indwelling retrobulbar catheter in horses reduces corneal sensitivity and may be useful in reducing pain in horses with corneal disease.

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

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). 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. 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. 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.

A novel animal model of neuropathic corneal pain-the ciliary nerve constriction model.

Neuropathic pain arises as a result of peripheral nerve injury or altered pain processing within the central nervous system. When this phenomenon affects the cornea, it is referred to as neuropathic corneal pain (NCP), resulting in pain, hyperalgesia, burning, and photoallodynia, severely affecting patients' quality of life. To date there is no suitable animal model for the study of NCP. Herein, we developed an NCP model by constriction of the long ciliary nerves innervating the eye. Mice underwent ciliary nerve constriction (CNC) or sham procedures. Safety was determined by corneal fluorescein staining to assess ocular surface damage, whereas Cochet-Bonnet esthesiometry and confocal microscopy assessed the function and structure of corneal nerves, respectively. Efficacy was assessed by paw wipe responses within 30 seconds of applying hyperosmolar (5M) saline at Days 3, 7, 10, and 14 post-constriction. Additionally, behavior was assessed in an open field test (OFT) at Days 7, 14, and 21. CNC resulted in significantly increased response to hyperosmolar saline between groups (p < 0.0001), demonstrating hyperalgesia and induction of neuropathic pain. Further, animals that underwent CNC had increased anxiety-like behavior in an open field test compared to controls at the 14- and 21-Day time-points (p < 0.05). In contrast, CNC did not result in increased corneal fluorescein staining or decreased sensation as compared to sham controls (p > 0.05). Additionally, confocal microscopy of corneal whole-mounts revealed that constriction resulted in only a slight reduction in corneal nerve density (p < 0.05), compared to naïve and sham groups. The CNC model induces a pure NCP phenotype and may be a useful model for the study of NCP, recapitulating features of NCP, including hyperalgesia in the absence of ocular surface damage, and anxiety-like behavior.

Topical fosaprepitant for the treatment of ocular pain and inflammation

PurposeTo assess whether topical administration of fosaprepitant improves intractable chronic ocular pain and inflammation. MethodsWe report three clinical cases of female patients with drug-resistant ocular pain associated with inflammatory diseases of the ocular surface. The patients were treated for 3 (case 1) and 4 (cases 2–3) weeks with fosaprepitant eyedrops (0.1 mg/mL for case 1; 10 mg/mL for case 2–3). Patients were then followed up for at least 3 weeks. We measured ocular pain with the Visual Analogue Scale (VAS), the Ocular Surface Disease Index (OSDI), and corneal sensitivity with the Cochet-Bonnet esthesiometry. Slit-lamp photography and corneal confocal imaging were used to assess ocular surface integrity/conjunctival hyperemia and corneal nerve morphology, respectively. ResultsAll three patients had severe ocular pain (score higher than 6/10 VAS scale). All patients reported a significant improvement in ocular pain after 1 week of treatment. We also observed reduced corneal epitheliopathy (case 1) and conjunctival hyperemia (cases 1–2). In two patients (cases 2–3) the treatment was repeated after 1 year and 9 weeks, respectively, and pain reduction was similar in magnitude to what we observed after the first administration. ConclusionsTopical administration of fosaprepitant ameliorates ocular pain and clinical symptoms in three patients with intractable ocular pain associated with inflammatory diseases of the ocular surface, without adverse effects. ImportanceFosaprepitant instillation holds promise as a treatment of chronic ocular pain, an area of unmet medical need.

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

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. 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. 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). 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.

Concomitant Bandage Contact Lens, Oral Nicergoline, and Topical Autologous Serum for Severe Neurotrophic Keratitis.

To report the outcomes of using the combination of oral nicergoline, autologous serum, and contact lens to enhance corneal epithelization in neurotrophic keratitis and to discuss the clinical potential of this management. This was a prospective consecutive case series study of eight patients treated for neurotrophic keratitis at the "Conde de Valenciana" Institute of Ophthalmology. Oral nicergoline, autologous serum, and bandage contact lens were initiated at the same time, immediately after stage 3 diagnosis keratitis was confirmed clinically, and until corneal epithelialization was achieved or eminent corneal perforation was seen. In patients where diabetes was a cause, glycosylate hemoglobin was measured to asses metabolic control. Corneal esthesiometry and corrected distance visual acuity were assessed before and after treatment. This study included eight eyes of eight patients (5 men [62.5%], average age 57±17.9 years). All patients completed at least 1 month of follow-up after nicergoline and contact lens suspension. Of the eight eyes, no one had positive culture growth and complete epithelial healing was achieved in all cases. Half of patients had diabetes and had a poor metabolic control. Corneal sensitivity improved in all eyes almost 2 centimeters in Cochet-Bonnet esthesiometry ( P= 0.01). In addition, final visual acuity gains were obtained ( P= 0.100). The combination of oral nicergoline, autologous serum, and bandage contact lens simultaneously could be an alternative in the management of stage 3 neurotrophic keratitis when conventional medical treatment has no improvement of corneal epithelization.

Small-fibre neuropathy in leprosy the role of in vivo confocal microscopy: A cross-sectional study.

Background Leprosy (or Hansen's disease) continues to present considerable challenges regarding containment and early diagnosis. Leprosy is considered to be primarily a neural disease that first affects the sensory function of small fibres. Although the condition is well described in terms of clinical manifestations and histology, few studies have been undertaken to detect damage done to small-fibre sensory nerves. In vivo confocal microscopy is a useful tool for conducting a detailed evaluation of these structures, although its use in individuals affected by leprosy has still not been explored. Objective To evaluate in vivo confocal microscopy findings in Hansen's disease patients and their association with clinical variables relating to this disease. Method A cross-sectional case-series type study was carried out between October 2019 and May 2021, in Recife, Pernambuco, Brazil. Socio-demographic and clinical data were gathered from 21 patients with leprosy. The douleur neuropathique 4 neuropathic pain questionnaire was used to evaluate pain. In vivo confocal microscopy of the cornea was employed to evaluate the small-calibre fibres. Findings were compared with those for a control group of 23 healthy individuals. Results In relation to clinical parameters, 90.5% of the patients were classified as "multibacillary" according to the World Health Organization criteria, and 70% as dimorphic or borderline, in accordance with the Madrid classification. Around 52.4% had received a diagnosis after one year or less of living with the disease, while 95.2% presented alterations in small-fibre sensory function and 35% presented such alterations in the large fibre. Neuropathic pain was present in 81% of the patients. In vivo confocal microscopy found no statistically significant difference in mean age and distribution according to sex between the Hansen disease patients and the control group of healthy individuals. The median-of-means for dendritic cells and volume of sub-basal nerve fibres in the control group were used to test for normality. Both eyes of all leprosy patients examined contained higher number of dendritic cells than the median value and a volume of sub-basal nerve fibres lower than the mean. These differences were statistically significant (P < 0.001 and P < 0.001, respectively). Multibacillary individuals had a median number of dendritic cells two times that of paucibacillary individuals (P = 0.035). Limitations No association was found between the variables examined using in vivo confocal microscopy and clinical variables relating to small-fibre damage, the neuropathic pain questionnaire or alterations detected by the neurological examination. We believe, however, that Cochet-Bonnet esthesiometry of the cornea may have revealed such an association. Conclusion In vivo confocal microscopy is a useful diagnostic tool for detecting small fibre loss in individuals affected by leprosy and may constitute a useful addition to the range of tools available to help curb the effects of neuropathy in these patients.

Evaluation of Ocular Surface after Cataract Surgery-A Prospective Study.

This study evaluated tear film and ocular surface parameters in patients after cataract surgery. Methods: a prospective clinical study included 48 eyes of 48 patients who underwent uncomplicated phacoemulsification performed by one surgeon. Tear break-up time (TBUT), Schirmer’s I test, Cochet–Bonnet esthesiometry and in vivo laser scanning confocal microscopy was carried out and the OSDI questionnaire was filled out. All tests were assessed before and 1 month after the surgery. Results: there were 32 (66.7%) women; 16 (33.3%) men, mean age was 74.08 ± 5.37. Mean TBUT at baseline was 8.6 ± 1.9 s, after the surgery, it was 7.7 ± 2.7 s, p = 0.004. Schirmer’s I test was 8.7 ± 3.9 mm versus 8.1 ± 3.7 mm, p = 0.002. Mean corneal nerve density at baseline was 15.70 ± 2.34 and at the first postoperative month 14.94 ± 1.48 mm/mm2, p = 0.02. The OSDI questionnaire score increased from 12.15 ± 10.34 before the surgery to 13.79 ± 10.88 in the first postoperative month, p = 0.001. Conclusions: the ocular surface was affected 1 month after the cataract surgery: TBUT was shorter, Schirmer’s I test and corneal nerve density were decreased while the OSDI score increased.

Corneal Sensitivity and Patient-Reported Dry Eye Symptoms in a Prospective Randomized Contralateral-Eye Trial Comparing Laser In Situ Keratomileusis and Small Incision Lenticule Extraction

To prospectively compare corneal sensation and patient-reported symptoms of dry eye in individuals undergoing laser in situ keratomileusis (LASIK) and small incision lenticule extraction (SMILE). Prospective randomized contralateral-eye clinical trial. 80 eyes of 40 patients with myopia at Byers Eye Institute at Stanford University were randomized to receive wavefront-guided femtosecond LASIK in one eye and SMILE in the fellow eye. Cochet-Bonnet esthesiometry was performed to assess corneal sensitivity preoperatively and at the 1-, 3-, 6-, and 12-month postoperative visits. Participants also completed questionnaires at each visit to determine the Ocular Surface Disease Index (OSDI). Eyes that underwent LASIK compared to SMILE demonstrated more corneal denervation at the postoperative 1-month (mean 2.1 vs 3.6 cm, P < .001), 3-month (3.5 vs 5.4 cm, P < .001), and 6-month (4.7 vs 5.7 cm, P < .001) visits. At the 12-month visit, both groups had returned to baseline corneal sensitivity (5.9 vs 5.9 cm, P=.908). There was no difference in OSDI between the 2 groups at any visit. Mean OSDI improved from the preoperative to the postoperative 12-month visit in both LASIK (15.3 to 8.6, P=.020) and SMILE (15.1 to 9.5, P=.029) groups. LASIK resulted in greater corneal denervation compared to SMILE in the early postoperative period, though this difference was no longer apparent after 12 months. Despite this, there was no difference in self-reported dry eye symptoms between the 2 groups. Patient-reported dry eye symptoms improved after both LASIK and SMILE procedures.

Eight months follow-up of corneal nerves and sensitivity after treatment with cenegermin for neurotrophic keratopathy

BackgroudCenegermin (Oxervate, Dompè Farmaceutici, Milan, IT), a recombinant human NGF, is a potentially healing new drug for neurotrophic keratopathy (NK), a rare but challenging disease affecting the cornea. To date, studies that evaluate its mid-term effect on corneal nerves and sensitivity are lacking.ObjectiveTo evaluate the recovery and morphology of subbasal corneal nerves in patients treated with Cenegermin for NK and assess their correlation with corneal sensitivity.MethodsThis prospective, observational case series study was carried out between May 2018 and August 2020 at the Ophthalmic Clinic of the University of Verona. Clinical evaluation, sensitivity, and in vivo confocal microscopy (IVCM) were performed in the central and all four corneal sectors at baseline, the end of therapy (8 weeks), and 2, 4, and 8 months after therapy. Consecutive patients with NK (stage 2–3), treated with Cenegermin (1 drop 6 times daily for 8 weeks), were enrolled. During each visit, Corneal nerve fiber length (CNFL), corneal nerve fiber total branch density (CTBD), corneal nerve fiber fractal dimension (CNFraD) and Cochet-Bonnet esthesiometry (CBE) were measured.ResultsWe enrolled 18 patients. Complete NK healing was noted in 14/18(78%) patients after 8 weeks of treatment; then in 14(78%), 15(83%), and 13(72%) patients at 2-, 4-, and 8-months, respectively. Starting at 8 weeks through 4-month follow-up there was progressive improvement in CBE in all corneal sectors (p ≤ 0.01), which continued thereafter. There was significant corneal nerve regrowth especially in the peripheral cornea: centripetal progression starting at 8 weeks (CNFL and CNFrad) and significant branching starting at 2 months (CTBD), which continued through to the end of follow up. Sector-coupled IVCM and CBE findings correlated at all evaluations (all r ≥ 0.62 starting at 2 months, with highest values in the peripheral sectors).ConclusionsAfter Cenegermin we observed a subbasal corneal nerve regeneration, a recovery of sensitivity and a lasting epithelial healing, suggesting that the effect of its action persists several months after discontinuation in patients with NK.

The structural and functional corneal reinnervation mechanism at different regions after LASIK-an in vivo confocal microscopy study.

To determine the recovery of structural and functional corneal sensory nerves within the LASIK flap in order to provide insight to more proximal corneal reinnervation and symptoms post-LASIK. Twenty participants underwent femtosecond LASIK with a superior flap hinge. Ocular Comfort Index in Chinese (OCI-C), Cochet-Bonnet esthesiometry, and in vivo confocal microscopy were conducted before surgery and 1week, 1-, 3-, and 6-months post-LASIK to measure symptoms, corneal sensitivity, nerve fiberdensity, width, and the numberofinterconnections within the flap (central and mid-temporal regions), and next to the superior flap hinge. Linear mixed models were used to compare differences between corneal regions at each time point post-LASIK and changes over time post-LASIK. Spearman's correlation tests were used to examine the associations between variables post-LASIK. The least reduction in sensitivity (P < 0.03) and in nerve fiber density (P < 0.02) was found near the flap hinge compared to other regions, but no regional differences were found in nerve fiber width and interconnections. Nerve fiberdensity and the number of interconnections at all regions within the flap recovered over time (P < 0.02). The recovery of corneal sensitivity and nerve fiber width was only seen at the central and temporal regions (P < 0.04). No association was found between sensitivity and nerve parameters, but a higher OCI-C score was associated with a lower nerve fiber density near the hinge (r = - 0.43, P = 0.003) over time post-LASIK. Corneal sensitivity and density are preserved in the hinge, but this preservation of the corneal nerve damage does not affect the nerve morphology.

Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits.

The purpose of this study was to evaluate the ocular pharmacokinetics, bio-distribution and local tolerability of γ-cyclodextrin (γCD) based irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple topical administration in rabbit eyes. In this randomized, controlled study, a total number of 59 New Zealand White albino rabbits were consecutively assigned to two study groups. Group 1 (n = 31) received irbesartan 1.5% and group 2 (n = 28) candesartan 0.15% eye drops. In both groups, single dose and multiple administration pharmacokinetic studies were performed. Rabbits were euthanized at five predefined time points after single-dose administration, whereas multiple-dose animals were dosed for 5 days twice-daily and then euthanized 1 h after the last dose administration. Drug concentration was measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the retinal tissue, vitreous humor, aqueous humor, corneal tissue and in venous blood samples. Pharmacokinetic parameters including maximal drug concentration (Cmax), time of maximal drug concentration (Tmax), half-life and AUC were calculated. To assess local tolerability, six additional rabbits received 1.5% irbesartan eye drops twice daily in one eye for 28 days. Tolerability was assessed using a modified Draize test and corneal sensibility by Cochet Bonnet esthesiometry. Both γCD based eye drops were rapidly absorbed and distributed in the anterior and posterior ocular tissues. Within 0.5 h after single administration, the Cmax of irbesartan and candesartan in retinal tissue was 251 ± 142 ng/g and 63 ± 39 ng/g, respectively. In the vitreous humor, a Cmax of 14 ± 16 ng/g for irbesartan was reached 0.5 h after instillation while Cmax was below 2 ng/g for candesartan. For multiple dosing, the observed Cmean in retinal tissue was 338 ± 124 ng/g for irbesartan and 36 ± 10 ng/g for candesartan, whereas mean vitreous humor concentrations were 13 ± 5 ng/g and <2 ng/g, respectively. The highest plasma concentrations of both irbesartan (Cmax 5.64 ± 4.08 ng/mL) and candesartan (Cmax 4.32 ± 1.04 ng/mL) were reached 0.5 h (Tmax) after single administration. Local tolerability was favorable with no remarkable differences between the treated and the control eyes. These results indicate that irbesartan and candesartan in γCD based nanoparticle eye drops can be delivered to the retinal tissue of the rabbit’s eye in pharmacologically relevant concentrations. Moreover, safety and tolerability profiles appear to be favorable in the rabbit animal model.

Functional and Structural Changes Following Corneal Neurotisation in the Management of Neurotrophic Keratopathy: UK Single Centre Series.

ObjectiveTo report the functional and anatomical outcomes including structural changes in corneal nerve density and morphology using in vivo confocal microscopy (IVCM) after corneal neurotisation in patients with neurotrophic keratopathy (NK), using a sural nerve graft.Patients and MethodsProspective study of patients undergoing corneal neurotisation for NK. Functional outcomes were measured through visual acuity, slit-lamp examination of corneal and conjunctival staining, tear production (Schirmer’s 1 test), tear film break-up time, tear film meniscus height, quality and osmolarity, central corneal thickness and corneal sensation using Cochet–Bonnet esthesiometry. Structural outcomes were assessed from changes in corneal nerve density and morphology with IVCM. Subjective outcomes were assessed using VFQ-25 and latest telephonic consultation.ResultsBetween February 2016 and April 2018, 11 corneal neurotisations were performed on 11 patients (3 males, 8 females). Median age was 43 (range 25–62) years. Mean follow-up was 14.5 (range, 4–36) months. Snellen visual acuity improved in 6 patients, corneal and conjunctival staining decreased in 10, tear film breakup time increased in 9, tear meniscus height increased in 7, Schirmers test readings increased in 4, tear film osmolarity reduced in 8 and central corneal thickness increased in 10 patients. Corneal sensation improved in nine patients. Complete IVCM data were available in five cases and demonstrated an improvement of corneal nerve density and length at 12 months.ConclusionThis series confirms the fact that the outcomes of this technique are reproducible and that corneal neurotisation surgery helps restore trophic nerve function more consistently than touch-related sensation.

Clinical Outcomes and Patient Satisfaction After Corneal Neurotization.

The aim of this study was to assess clinical outcomes of corneal neurotization (CN) and determine patient perception of postoperative results. This was a retrospective study involving 29 eyes in 28 patients who underwent CN. Chart review data included demographic and clinical history; ophthalmic examination including visual acuity, ocular surface quality, and corneal sensation; surgical technique; and postoperative course. Subjective self-reported patient outcomes of surgical success were also assessed. Only eyes with at least 6 months of follow-up were included in the statistical analysis. A total of 24 eyes and 23 patients were included in statistical analyses. The median postoperative follow-up time was 12.2 months (interquartile range 10.9-18.5 mo). Twenty-three eyes (92%) achieved improvement in ocular surface quality. Eleven of 13 (85%) demonstrated healing of persistent epithelial defects at their last follow-up. Patients gained a median of 2.3 cm in Cochet-Bonnet esthesiometry measurements of sensation. No significant difference was found between preoperative and postoperative visual acuity. All 17 patients who provided self-assessment of their surgical outcome indicated they would undergo CN again if given the choice. Most of the patients reported that the postoperative pain was tolerable, with a median pain score of 3.0 on a 10-point scale (interquartile range 0.0-4.0). Sixteen patients (94%) reported full or partial return of skin sensation along the donor nerve distribution. CN provides improvement in corneal health and sensibility, with high patient satisfaction and minimal postoperative pain and morbidity.

Comparison of amniotic membrane transplantation with and without cultured limbal epithelium for persistent corneal ulcers

This study compared the clinical outcomes of amniotic membrane transplantation with and without cultured limbal epithelium for persistent corneal ulcers. The study included 30 patients that were assigned to either human amniotic membrane transplantation (AMT) only or a two-step cultured limbal epithelial transplant (CLET) with amniotic membrane carrier. The patients underwent a comprehensive ocular examination, Cochet-Bonnet esthesiometry, impression cytology and anterior segment optical coherence tomography (AS-OCT). Slit-lamp images before and after treatment were analyzed using ImageJ to compare the fibrovascular tissue area. The state of epithelialization was assessed by fluorescein staining on day 30. Mean age of patients was 64 ± 20.39 in the AMT group and 55.17 ± 14.51 in the CLET group (p = 0.16). Visual acuity improved significantly in both groups after treatment, but the improvement was significantly greater in the CLET group (p = 0.022). Impression cytology demonstrated PAS + cells in the corneal epithelium in 9 patients from the CLET group and 10 patients in the AMT group (p = 0.704). Cochet-Bonnet esthesiometry increased significantly after treatment with a similar rate between groups (p = 0.435). Improvement with reduction of the fibrovascular tissue area was achieved in both groups (p < 0.01 and p = 0.001 in the CLET and AMT group, respectively). Independent samples T-test demonstrated a greater reduction in the CLET group (p = 0.028). Kaplan-Meier analysis of epithelialization demonstrated higher success rate in the CLET group (p = 0.006). Persistent corneal ulcers could be associated with partial limbal stem cell deficiency (LSCD). In refractory cases, CLET should be the preferred treatment option with more sustainable results regarding corneal epithelialization and stromal scarring.

Changes in Corneal Subbasal Nerves after Punctal Occlusion in Dry Eye Disease

ABSTRACT Purpose To evaluate corneal subbasal nerve plexus by in vivo confocal microscopy (IVCM) following punctal occlusion in patients with moderate to severe dry eye disease (DED). Materials and Methods Patients with grade 3 or 4 severity of DED based on Delphi Panel dry eye severity grading scheme were enrolled in the study. Permanent inferior punctal occlusion was performed. A comprehensive ophthalmic evaluation, including Ocular Surface Disease Index (OSDI) questionnaire, tear break-up time (TBUT), corneal fluorescein staining, conjunctival Rose bengal staining, Schirmer’s test, and corneal sensation by Cochet-Bonnet esthesiometry, were performed at baseline, and 1 and 3 months after punctal occlusion. Furthermore, density and number of corneal subbasal nerves were evaluated by IVCM. Results Forty-one eyes of 23 patients with a mean age of 46.3 ± 9.0 years were enrolled. Corneal fluorescein staining, Rose bengal staining, and TBUT significantly improved at 3 months following punctal occlusion (p < .015). Corneal esthesiometry significantly increased at both postoperative visits (p < .03), and OSDI scores improved only at 3-month follow-up (p < .005). Nerve density and total number significantly increased 3 months after punctal occlusion (p < .045). Baseline nerve density had significant correlations with TBUT, fluorescein staining, Rose bengal staining (p < .012), but not with esthesiometry, Schirmer scores, or OSDI scores (p > .329). Conclusions Corneal subbasal nerve density and total number increased following punctal occlusion in patients with moderate to severe DED. These findings were associated with improvements in corneal sensation, and signs and symptoms of DED. This emphasizes the effect of punctal occlusion in regeneration of corneal subbasal nerve plexus.

Topical citicoline and vitamin B12 versus placebo in the treatment of diabetes-related corneal nerve damage: a randomized double-blind controlled trial

BackgroundTo evaluate the effects of topical citicoline and vitamin B12 (Cit-B12: OMK2, Omikron Italia srl, Italy) on corneal innervation of patients with diabetic neuropathy.MethodsThis prospective, randomized, double blind, placebo-controlled study included 30 patients randomised with a 2:1 ratio to Cit-B12 or placebo 3 times daily for 18 months. At baseline and at months 4, 8, 12, 18 patients underwent the Ocular Surface Disease Index questionnaire (OSDI), tear break-up time, evaluation of corneal and conjunctival staining, Schirmer I test, Cochet-Bonnet esthesiometry, and confocal biomicroscopy of corneal sub-basal plexus (SBP). Fiber lenght density (FLD) was calculated using NeuronJ and expressed in mm/mm2. Raw data and differences from baseline were analysed in the two groups.Results29/30 patients concluded the study. The two groups had similar FLD at baseline; it progressively improved up to month 18 in both groups (Cit-B12, p < 0.0001; controls, < 0.0001–0.03); improvement at month 18 vs baseline was higher in Cit-B12 than placebo (33% vs 15%, p = 0.04). A progressive amelioration of corneal sensitivity (baseline, 28 ± 18 mm; month 18, 52 ± 10 mm, p < 0.0001), conjunctival staining (P = 0.04) and OSDI questionnaire (P = 0.05) were shown on Cit-B12 group alone. Both treatments were well tolerated and adherence during the study was high.ConclusionsCit-B12 ameliorated both morphology and function of corneal nerves in patients with diabetes, thus suggesting a neuroregenerative effect.Trial registrationTrial registration NCT03906513, retrospectively registered on 08 April 2019.

Glaucoma-associated pain results in mechanical sensitivity changes in dogs: A pilot study.

To explore the effects of chronic, uncontrolled glaucoma on pressure sensitivity in dogs before and after enucleation of the painful globe. Client-owned dogs undergoing enucleation for chronic glaucoma with no other sources of pain were enrolled. Normal dogs of similar breeds and skull morphology were enrolled as controls. Craniofacial ratio (CFR) and relative palpebral fissure width (RPFW) were assessed in all patients. Serial mechanical quantitative sensory testing (QST) was performed the day before surgery, and 14, 30, 60, and 120days after surgery. QST consisted of electronic Von Frey (eVF), and blunt algometry (BA) performed above and below the nonglaucomatous eye, the metacarpus, and metatarsus. Cochet-Bonnet esthesiometry (CB) was also performed on the remaining eye. Twelve dogs (6 per group) were included. Compared to baseline values, sensitivity tended to decrease over time (increased thresholds) in treatment dogs while it stayed constant or increased slightly in control dogs. The difference in change from baseline sensitivity between control and treatment groups was significant at day 120 using BA at supraorbital (P=.0153), infraorbital (P=.0209), and metacarpal sites (P=.007) and overall (P=.0470). This divergence was also significant using CB (P=.0470) on the opposite cornea. As patient CFR and RPFWV increased, both eVF (P=.005-.023) and BA (P=.004-.041) increased. Sensitivity to mechanical stimuli decreased both locally and at remote sites in dogs following enucleation for painful chronic glaucoma. Cranial conformation is associated with differences in sensitivity.

Corneal Neurotization for Postherpetic Neurotrophic Keratopathy: Initial Experience and Clinical Outcomes.

To assess early outcomes of corneal neurotization for postherpetic neurotrophic keratopathy (NK). Retrospective analysis of patients who underwent corneal neurotization for postherpetic NK by a single experienced oculoplastic surgeon was performed. Collected data included stage and etiology of NK as well as comorbidities, prior treatment history, neurotization technique, donor nerve site, preoperative and postoperative examination findings (i.e., ocular surface quality, corneal clarity, corneal sensation by Cochet-Bonnet esthesiometry, and visual acuity [VA]), and follow-up duration. Differences between preoperative and postoperative values were analyzed by Wilcoxon signed-rank test. Of 23 adult patients who underwent corneal neurotization, 3 (13%) had history of herpes simplex keratitis and/or endotheliitis, and 4 (17%) had history of herpes zoster ophthalmicus. One patient with herpes zoster ophthalmicus was excluded due to inadequate follow-up duration. Of the 6 patients included in the study, 3 (50%) had Mackie stage 1 disease, 1 (17%) had stage 2, and 2 (33%) had stage 3 with impending perforation, but all had markedly diminished corneal sensation, with a median denervation time of 11.8 months (interquartile range [IQR] 9.4-29.2 months). Following neurotization, median corneal sensation improved significantly from 1.6 cm (interquartile range 0.0-1.9 cm) to 3.6 cm (IQR 3.0-5.6 cm, p = 0.028), with 1 patient achieving full sensation by postoperative month 5. All patients with a persistent epithelial defect preoperatively showed complete corneal healing by their last follow-up visit. VA also improved postoperatively in all patients (p = 0.028). Median follow-up duration was 11.3 months (interquartile range 9.6-17.9 months). Corneal neurotization can successfully reinnervate corneas previously devitalized by herpetic disease and halt the progressive nature of postherpetic NK. If utilized appropriately and early in the disease process, neurotization may reduce morbidity and maximize visual potential in postherpetic NK.