Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice.
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ABSTRACT:
SUBMITTER: Stepp MA
PROVIDER: S-EPMC5949876 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionThe quantification of intraepithelial corneal basal nerve parameters by in vivo confocal microscopy represents a promising modality to identify the earliest manifestations of diabetic peripheral neuropathy. However, its diagnostic accuracy is hampered by its dependence on neuron length, with minimal consideration for other parameters, including the origin of these nerves, the corneal stromal-epithelial nerve penetration sites. This study sought to utilize high-resolution images of murine corneal nerves to analyze comprehensively the morphological changes associated with type 2 diabetes progression.Materials and methodsβIII-Tubulin immunostained corneas from prediabetic and type 2 diabetic mice and their respective controls were imaged by scanning confocal microscopy and analyzed automatically for nerve parameters. Additionally, the number and distribution of penetration sites was manually ascertained and the average length of the axons exiting them was computed.ResultsThe earliest detectable changes included a significant increase in nerve density (6.06 ± 0.41% vs 8.98 ± 1.99%, P = 0.03) and branching (2867.8 ± 271.3/mm2 vs 4912.1 ± 1475.3/mm2 , P = 0.03), and in the number of penetration sites (258.80 ± 20.87 vs 422.60 ± 63.76, P = 0.0002) at 8 weeks of age. At 16 weeks, corneal innervation decreased, most notably in the periphery. The number of penetration sites remained significantly elevated relative to controls throughout the monitoring period. Similarly, prediabetic mice exhibited an increased number of penetration sites (242.2 ± 13.55 vs 305.6 ± 30.96, P = 0.003) without significant changes to the nerves.ConclusionsOur data suggest that diabetic peripheral neuropathy may be preceded by a phase of neuron growth rather than regression, and that the peripheral cornea is more sensitive than the center for detecting changes in innervation.
| S-EPMC10034950 | biostudies-literature
Project description:Many studies in multiple sclerosis (MS) have investigated the retina. Little, however, is known about the effect of MS on the cornea, which is innervated by the trigeminal nerve. It is the site of neural-immune interaction with local dendritic cells reacting in response to environmental stimuli.This study aims to investigate the effect of MS on corneal nerve fibres and dendritic cells in the subbasal nerve plexus using in vivo confocal microscopy (IVCM).We measured the corneal nerve fibre and dendritic cell density in 26 MS patients and matched healthy controls using a Heidelberg Retina Tomograph with cornea module. Disease severity was assessed with the Multiple Sclerosis Functional Composite, Expanded Disability Status Scale, visual acuity and retinal optical coherence tomography.We observed significant reduction in total corneal nerve fibre density in MS patients compared to controls. Dendritic cell density was similar in both groups. Reduced total nerve fibre density was associated with worse clinical severity but not with previous clinical trigeminal symptoms, retinal neuro-axonal damage, visual acuity or disease duration.Corneal nerve fibre density is a promising new imaging marker for the assessment of disease severity in MS and should be investigated further.
| S-EPMC5513781 | biostudies-other
Project description:T helper (Th)-17 is a recently identified subtype of Th response that has been implicated in host defense and autoimmunity. We investigated whether there is evidence for a Th-17 response in human and experimental murine dry eye (DE). Gene expression in the human DE conjunctiva showed increased levels of the Th-17 inducers, interleukin (IL)-23, IL-17A, and interferon-gamma (IFN-gamma). In the murine model, we found that desiccating stress increased matrix metalloproteinase-9, Th-17-associated genes (IL-6, IL-23, transforming growth factor-beta1 and -2, IL-23R, IL-17R, IL-17A, retinoid-related orphan receptor-gammat, and CC chemokine attractant ligand-20) and IFN-gamma in cornea and conjunctiva. Furthermore, we found a significantly increased concentration of IL-17 in tears and number of IL-17-producing cells on the ocular surface. Antibody neutralization of IL-17 ameliorated experimental DE-induced corneal epithelial barrier dysfunction and decreased the expression of matrix metalloproteinases 3 and 9. Taken together, these findings suggest that IL-17 has a role in corneal epithelial barrier disruption in DE.
| S-EPMC3594767 | biostudies-literature
Project description:Purpose:Report a case of corneal melt in a patient with conjunctival intraepithelial neoplasia (CIN) treated with topical interferon (IFN) alpha-2B. Observations:An 89-year-old man presented with gelatinous paralimbal lesions of the left eye extending onto the cornea with corneal neovascularization extending 5-6 clock hours. Nasally there was mild absence of the terminal vascular loops of the limbal palisades of Vogt and conjunctivalization. Diffuse punctate epithelial erosions were noted. The corneal graft displayed subepithelial and stromal edema. Anterior segment optical coherence tomography detected hyperreflectivity, sectional thickened epithelium, and abrupt transitions from normal to abnormal tissue. The patient was treated with excision of the corneal and conjunctival lesions with cryotherapy to the conjunctival borders. Excisional biopsy revealed CIN Grade 3 and carcinoma in situ of the cornea. Topical IFN alpha-2B four times daily was initiated postoperatively. Two months later, a central epithelial defect developed. The cornea progressively thinned and corneal melt ensued. The patient had several risk factors for corneal melt including neurotrophic cornea, early limbal stem cell deficiency, history of cryotherapy, keratoconjunctivitis sicca, and chronic use of glaucoma medications and steroid medications. Conclusions:Interferon alpha-2B is an effective first line treatment for CIN with few side effects. It's side effects include punctate epithelial erosions, conjunctival hyperemia, and follicular conjunctivitis. We report a case of pre-existing keratoconjunctivitis sicca, early limbal stem cell deficiency, neurotrophic cornea, and newly diagnosed CIN Grade 3; it was treated with surgical excision, cryotherapy, and topical IFN alpha-2b with development of corneal melt 2 months later. Caution should be taken when using interferon alpha -2b in patients with pre-existing keratoconjunctivitis sicca, neurotrophic cornea, or limbal stem cell deficiency as it could exacerbate these conditions resulting in corneal melt.
| S-EPMC7225610 | biostudies-literature
Project description:PurposeTo evaluate corneal nerve and immune cell alterations in Fuchs' endothelial corneal dystrophy (FECD) and pseudophakic bullous keratopathy (PBK) by laser in vivo confocal microscopy (IVCM) as correlated to corneal sensation and endothelial cell loss.DesignProspective, cross-sectional, controlled study.MethodsThirty-three eyes with FECD were compared to 13 eyes with PBK and 17 normal age-matched control eyes at a tertiary referral center. FECD was classified into early (without edema) and late stage (with edema). Corneal IVCM and esthesiometry were performed. Corneal nerve and immune dendritiform cell (DC) alterations were evaluated and correlated to clinical parameters.ResultsFECD and PBK eyes showed significantly (P = .001) diminished total nerve length (11.5 ± 1.3 and 2.9 ± 0.7 mm/mm2) and number (8.8 ± 1.1 and 2.2 ± 0.4 n/frame), compared to controls (23.3 ± 8.1 mm/mm2 and 25.9 ± 1.3 n/frame). Decreased nerves corresponded to diminished sensation in FECD (4.9 ± 0.2 cm; R = 0.32; P = .045), compared to controls (5.9 ± 0.04 cm). Early- and late-stage FECD showed significantly reduced total nerve length (13.1 ± 1.4 and 9.9 ± 1.2 mm/mm2, respectively) and number (8.2 ± 2.5 and 6.5 ± 2.1 n/frame), compared to controls (P < .001). DC density was significantly increased in FECD (57.8 ± 10.4 cells/mm2; P = .01), but not in PBK (47.7 ± 11.6 cells/mm2; P = .60) compared to controls (22.5 ± 4.5 cells/mm2). A subset of early FECD patients (7/22) demonstrated very high DC density (>100/mm2).ConclusionIVCM demonstrates profound diminishment of subbasal corneal nerves in early- and late-stage FECD and in PBK, correlating to decreased sensation. Increased DC density in early FECD demonstrates potential subclinical inflammation. The data suggest that reduction in subbasal nerves and increased immune activation may play a role in the pathophysiology of FECD.
| S-EPMC6420962 | biostudies-literature
Project description:PurposeObesity is associated with peripheral neuropathy, which bariatric surgery may ameliorate. The aim of this study was to assess whether corneal confocal microscopy can show a change in corneal nerve morphology and keratocyte density in subjects with severe obesity after bariatric surgery.MethodsTwenty obese patients with diabetes (n = 13) and without diabetes (n = 7) underwent assessment of hemoglobin A1c (HbA1c), lipids, IL-6, highly sensitive C-reactive protein (hsCRP), and corneal confocal microscopy before and 12 months after bariatric surgery. Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and keratocyte density (KD) from the anterior, middle, and posterior stroma were quantified. Twenty-two controls underwent assessment at baseline only.ResultsCNFL (P < 0.001), CNBD (P < 0.05), and anterior (P < 0.001), middle (P < 0.001), and posterior (P < 0.001) keratocyte densities were significantly lower in obese patients compared to controls, and anterior keratocyte density (AKD) correlated with CNFL. Twelve months after bariatric surgery, there were significant improvements in body mass index (BMI; P < 0.001), HDL cholesterol (P < 0.05), hsCRP (P < 0.001), and IL-6 (P < 0.01). There were significant increases in CNFD (P < 0.05), CNBD (P < 0.05), CNFL (P < 0.05), and anterior (P < 0.05) and middle (P < 0.001) keratocyte densities. The increase in AKD correlated with a decrease in BMI (r = -0.55, P < 0.05) and triglycerides (r = -0.85, P < 0.001). There were no significant correlations between the change in keratocyte densities and corneal nerve fiber or other neuropathy measures.ConclusionsCorneal confocal microscopy demonstrates early small fiber damage and reduced keratocyte density in obese patients. Bariatric surgery leads to weight reduction and improvement in lipids and inflammation and an improvement in keratocyte density and corneal nerve regeneration.
| S-EPMC7817877 | biostudies-literature
Project description:PurposeTo evaluate whether levels of corneal subbasal nerve fiber length (SNFL) in dry eye disease (DED) could prognosticate the level of improvement in signs and symptoms after treatment.DesignPhase IV, double-masked, randomized clinical trial.ParticipantsSixty patients with meibomian gland dysfunction-associated DED and 27 age-matched controls.MethodsPatients with DED were randomized to receive topical artificial tears, loteprednol etabonate 0.5%, or loteprednol etabonate 0.5%/tobramycin 0.3% twice daily for 4 weeks. At baseline, in vivo confocal microscopy of central cornea was performed in both eyes. Patients with DED were divided into 2 subgroups: those with low baseline SNFL and those with near-normal baseline SNFL for this purpose (the cutoff point: the mean SNFL in controls minus 2 standard deviations). Clinical signs and symptoms at baseline and after 4 weeks of treatment were compared between the subgroups with low and near-normal SNFL for all therapeutic groups.Main outcome measuresSymptom questionnaires, corneal fluorescein staining (CFS), conjunctival staining with lissamine green, tear break-up time, Schirmer's test, and SNFL.ResultsIn patients with DED, baseline SNFL (17.06±5.78 mm/mm(2)) was significantly lower than in controls (23.68±3.42 mm/mm(2), P = 0.001). In the artificial tear and loteprednol groups, although no significant improvement in any sign or symptom was noted in patients with low baseline SNFL (<16.84 mm/mm(2)), subjects with near-normal baseline SNFL (≥16.84 mm/mm(2)) showed significant improvement in both symptoms and CFS score (all P < 0.05). In the loteprednol/tobramycin group, no significant change was evident for any sign or symptom in either subgroup of low or near-normal baseline SNFL.ConclusionsSignificant improvements in CFS and patient symptomatology after DED treatment were evident only in the subgroup with near-normal corneal SNFL. Consideration of SNFL may assist in explaining the variability of patients' response to DED therapy.
| S-EPMC4372494 | biostudies-literature
Project description:Small nerve fiber loss and damage (SNFLD) is a frequent complication of sarcoidosis that is associated with autonomic dysfunction and sensory abnormalities, including pain syndromes that severely degrade the quality of life. SNFLD is hypothesized to arise from the effects of immune dysregulation, an essential feature of sarcoidosis, on the peripheral and central nervous systems. Current therapy of sarcoidosis-associated SNFLD consists primarily of immune suppression and symptomatic treatment; however, this treatment is typically unsatisfactory. ARA 290 is a small peptide engineered to activate the innate repair receptor that antagonizes inflammatory processes and stimulates tissue repair. Here we show in a blinded, placebo-controlled trial that 28 d of daily subcutaneous administration of ARA 290 in a group of patients with documented SNFLD significantly improves neuropathic symptoms. In addition to improved patient-reported symptom-based outcomes, ARA 290 administration was also associated with a significant increase in corneal small nerve fiber density, changes in cutaneous temperature sensitivity, and an increased exercise capacity as assessed by the 6-minute walk test. On the basis of these results and of prior studies, ARA 290 is a potential disease-modifying agent for treatment of sarcoidosis-associated SNFLD.
| S-EPMC3883966 | biostudies-literature
Project description:ObjectivesCorneal confocal microscopy (CCM) is a rapid, non-invasive, reproducible technique that quantifies small nerve fibres. We have compared the diagnostic capability of CCM against a range of established measures of nerve damage in patients with diabetic neuropathy.MethodsIn this cross sectional study, thirty subjects with Type 1 diabetes without neuropathy (T1DM), thirty one T1DM subjects with neuropathy (DSPN) and twenty seven non-diabetic healthy control subjects underwent detailed assessment of neuropathic symptoms and neurologic deficits, quantitative sensory testing (QST), electrophysiology, skin biopsy and corneal confocal microscopy (CCM).ResultsSubjects with DSPN were older (C vs T1DM vs DSPN: 41.0±14.9 vs 38.8±12.5 vs 53.3±11.9, P = 0.0002), had a longer duration of diabetes (P<0.0001), lower eGFR (P = 0.006) and higher albumin-creatinine ratio (P = 0.03) with no significant difference for HbA1c, BMI, lipids and blood pressure. Patients with DSPN were representative of subjects with diabetic neuropathy with clinical signs and symptoms of neuropathy and greater neuropathy deficits quantified by QST, electrophysiology, intra-epidermal nerve fibre density and CCM. Corneal nerve fibre density (CNFD) (Spearman's Rho = 0.60 P<0.0001) and IENFD (Spearman's Rho = 0.56 P<0.0001) were comparable when correlated with peroneal nerve conduction velocity. For the diagnosis of diabetic neuropathy the sensitivity for CNFD was 0.77 and specificity was 0.79 with an area under the ROC curve of 0.81. IENFD had a diagnostic sensitivity of 0.61, specificity of 0.80 and area under the ROC curve of 0.73.ConclusionsCCM is a valid accurate non-invasive method to identify small nerve fibre pathology and is able to diagnose DPN.
| S-EPMC5515394 | biostudies-literature
Project description:BACKGROUND:The initial response to nicotine is an important predictor of subsequent use. Multiple factors may alter this response including genetics and age of first use. Here we investigated the influence of age, genetics, and their interaction on nicotine sensitivity. We then examined whether these factors influence the relationship between initial behavioral responses and voluntary nicotine consumption in adulthood. METHODS:We measured initial nicotine responses, including nicotine-induced locomotor depression and hypothermia following an acute intraperitoneal injection (0, 0.5, or 1?mg/kg), during early-adolescence, middle-adolescence, late-adolescence, or adulthood. Thirty-five days after the initial testing, mice were assessed for voluntary oral nicotine consumption. RESULTS:Early-adolescent mice were more resistant to nicotine-induced hypothermia and locomotor depression than later ages, further hypothermia was influenced by genetics. In the DBA/2J? strain, early-adolescent mice were insensitive to nicotine-induced hypothermia, but this response developed at later ages. In contrast, C57BL/6J? mice were sensitive at all ages, but sensitivity increased across developmental age. There was little evidence of a relationship between initial behavioral response and choice nicotine consumption. CONCLUSION:By understanding how age of exposure and genetics influence initial nicotine behavioral responses, we have a greater understanding of factors that make adolescents differentially sensitive to the effects of this drug.
| S-EPMC6320290 | biostudies-literature