Corneal Nerve Morphology Research Articles

Rapid, automated mosaicking of the human corneal subbasal nerve plexus.

Corneal confocal microscopy (CCM) is an in vivo technique used to study corneal nerve morphology. The largest proportion of nerves innervating the cornea lie within the subbasal nerve plexus, where their morphology is altered by refractive surgery, diabetes and dry eye. The main limitations to clinical use of CCM as a diagnostic tool are the small field of view of CCM images and the lengthy time needed to quantify nerves in collected images. Here, we present a novel, rapid, fully automated technique to mosaic individual CCM images into wide-field maps of corneal nerves. We implemented an OpenCV image stitcher that accounts for corneal deformation and uses feature detection to stitch CCM images into a montage. The method takes 3-5 min to process and stitch 40-100 frames on an Amazon EC2 Micro instance. The speed, automation and ease of use conferred by this technique is the first step toward point of care evaluation of wide-field subbasal plexus (SBP) maps in a clinical setting.

Ophthalmic and clinical factors that predict four-year development and worsening of diabetic retinopathy in type 1 diabetes

AimsTo investigate the role of ophthalmic imaging markers – namely retinal thickness measures and corneal nerve morphology – in predicting four-year development and worsening of diabetic retinopathy (DR) in type 1 diabetes (T1DM). Methods126 eyes of 126 participants with T1DM were examined at baseline and after four years. Diabetic retinopathy (DR) was graded using the Early Treatment Diabetic Retinopathy Study scale. HbA1c, nephropathy, neuropathy, cardiovascular factors, and retinal thickness using optical coherence tomography (OCT) and corneal nerve fiber length (CNFL) using corneal confocal microscopy at baseline were assessed by univariate and step-wise multiple logistic regression, and their diagnostic capabilities for single and combined measures. ResultsFour-year development of DR was 19% (13 of 68 without DR at baseline). Worsening of DR was seen in 43% (25 of 58 with DR at baseline). When adjusted for potential confounders, a lower CNFL (AUC=0.637, p=0.040, 64% sensitivity and 64% specificity at 14.9mm/mm2 cut-off), higher triglycerides (AUC=0.669, p=0.012, 64% sensitivity, 62% specificity at 0.85mmol/L) and an elevated vibration threshold (AUC=0.708, p=0.002, 96% sensitivity, 40% specificity at 3.55Hz) were significant predictors for four-year worsening of DR. ConclusionsReduced CNFL, elevated vibration perception threshold and higher triglycerides can predict future worsening of DR.

The corneal nerves in glaucoma and ocular surface diseases

SummaryIn addition to their important sensory function, corneal nerves provide protective and trophic functions and also regulate corneal epithelial integrity, proliferation and wound healing. The well‐defined in vivo confocal microscopy (IVCM) appearance of the subbasal corneal nerves has facilitated their quantitative in vivo analysis in ocular surface diseases. Although patients with dry eyes and patients treated for glaucoma experience similar ocular surface signs and symptoms, different correlations between corneal sensation and nerve morphology were observed in these two groups of patients. The relationship between corneal nerve function and structure remains complex, and nerve alteration and/or dysfunction could be different among different ocular surface diseases. Improvements in IVCM image acquisition and analysis will be an important step to further evaluate the role of corneal nerves in physiological and pathological ocular surface conditions.

Reduced Corneal Sensitivity and Sub-Basal Nerve Density in Long-Term Orthokeratology Lens Wear.

To investigate changes in corneal sensitivity and nerve morphology in orthokeratology (OK) contact lens wear. In a cross-sectional study, 54 subjects (aged 18-45 years) were grouped into three categories: nonlens (NL), soft lens (SCL), and OK lens wearers. Corneal sensitivity was measured at the corneal apex and 2.5 mm temporal to the apex using the Cochet-Bonnet aesthesiometer. Corneal nerve morphology was assessed by sampling a 1 mm area of the corneal sub-basal nerve plexus using the Heidelberg Retinal Tomograph with Rostock Corneal Module at the corneal apex and 2.5 mm temporal to the apex. Nerve fiber density (NFD) was calculated by measuring the total length of nerve fibers per square millimeter using Image-Pro Analyser. Comparisons between groups were made using mixed analysis of variance and post hoc paired t tests with Bonferroni correction or the Kruskal-Wallis test and post hoc Mann-Whitney U tests as appropriate. There was a significant difference in corneal sensitivity between the three groups (P=0.027). Central threshold was significantly higher in the OK than NL group (0.69±0.42 g/mm vs. 0.45±0.12 g/mm; P=0.048). Mid-peripheral threshold was not different between the three groups (P>0.05). There was a significant difference in NFD between the three groups (P<0.001). Central NFD was significantly less in the OK than NL and SCL groups (OK: 17.89±4.42 mm/mm, NL: 25.87±5.00 mm/mm; SCL: 24.52±4.93 mm/mm; P<0.001). Mid-peripheral NFD was not different between the three groups (P>0.05). Long-term OK lens wear is associated with a decrease in central corneal sensitivity and NFD. The mechanism underlying refractive change during OK treatment seems to impact both corneal sensitivity and nerve morphology.

Corneal Nerve Morphology and Tear Film Substance P in Diabetes.

This work aims to characterize the relationship between tear film neuropeptide substance P and the structural integrity of the sub-basal nerve plexus in diabetes. Seventeen healthy control participants and nine participants with diabetes were recruited in this cross-sectional study. Total protein content and substance P concentrations were determined in the flush tears of participants. Corneal nerve morphology was assessed by capturing the corneal sub-basal nerve plexus using the Heidelberg Retinal Tomograph II with the Rostock Corneal Module (Heidelberg Engineering GmbH, Heidelberg, Germany) in the central cornea. Corneal nerve fiber density (CNFD) was measured using ACCMetrics (M.A. Dabbah, Imaging Science and Biomedical Engineering, Manchester, UK) on eight captured images. Comparisons between groups were made using independent samples t-tests. Correlations between parameters were analyzed using Pearson's correlations. Substance P concentrations were significantly higher in the tears of the control group compared to participants with diabetes (4150 ± 4752 and 1473 ± 1671 pg/mL, respectively, P = .047). There was no significant difference in total protein content between the groups (3.4 ± 1.8 and 2.6 ± 1.7 mg/mL in the control and diabetes groups, respectively, P = .262). CNFD was significantly lower in the participants with diabetes compared to the control group (16.1 ± 5.7 and 21.5 ± 7.0 mm/mm, respectively, P = .041). There was a moderate correlation between substance P and CNFD (r = 0.48, P = .01). Substance P is expressed at a significantly lower level in the tears of people with diabetes compared with healthy controls. The positive correlation between substance P and corneal nerve density indicates that substance P may be a potential biomarker for corneal nerve health.

Efficacy of 2-Month Treatment With Cord Blood Serum Eye Drops in Ocular Surface Disease: An In Vivo Confocal Microscopy Study.

To investigate the morphological changes of corneal epithelium and subbasal nerves by in vivo confocal microscopy in patients with ocular surface disease (OSD) treated with cord blood serum (CBS) eye drops. Twenty patients with OSD (mean age 61.1 ± 12.6 years) were included in this prospective 1-arm study and treated with CBS eye drops for 2 months. Corneal sensitivity, Schirmer test score, breakup time, subjective symptoms [Ocular Surface Disease Index (OSDI) and Visual Analogue Scale (VAS)], and corneal staining were evaluated before (T0) and after (T1) treatment. In vivo confocal microscopy analyzed giant epithelial cells, subbasal nerve number and tortuosity, neuromas, beading, and dendritic cells (DCs) in the central cornea. OSDI, Visual Analogue Scale, and Oxford grading values significantly decreased at T1 versus T0 (respectively, 44.1 ± 18.9 vs. 74.2 ± 13.9; 3.7 ± 1.5 vs. 8.9 ± 0.9; and 2.4 ± 1.1 vs. 3.3 ± 1.3; P < 0.0001), whereas corneal sensitivity, Schirmer test score, and breakup time significantly increased (respectively, 49.5 ± 2.6 vs. 47.9 ± 2.9; 3.2 ± 2.0 vs. 2.4 ± 2.2; 4.6 ± 3.1 vs. 3.8 ± 2.1; P < 0.0001). Corneal nerve morphology improved at T1 versus T0 with a higher total nerve number (3.4 ± 1.6 vs. 2.5 ± 1.6 per frame) and lower tortuosity (3.0 ± 0.7 vs. 3.5 ± 0.6) (P < 0.01). The number of patients presenting with giant epithelial cells, beading, and neuromas decreased at T1. DC density did not change after treatment. The detection of neuromas and higher DC density at T0 were associated with greater OSDI reduction at T1 (P < 0.001). CBS eye drops significantly improved corneal nerve morphology and subjective symptoms in patients with severe OSD. The presence of neuromas and higher dendritic cell density at baseline were associated with greater reduction of discomfort symptoms after treatment.

Corneal confocal microscopy best identifies the development and progression of neuropathy in patients with type 1 diabetes

A sub-set of 38 individuals with type 1 diabetes that fulfilled a strict criterion of "normal" classification for all 7 measures of neuropathy at baseline, were identified and followed. Corneal nerve morphology, as captured with corneal confocal microscopy demonstrated the greatest, and most sustained degeneration over a 4 year period.

Corneal Nerve Morphology, Sensitivity, and Tear Neuropeptides in Contact Lens Wear.

To determine tear neuropeptide levels in contact lens wearers and non-wearers, and to examine relationships with indices of corneal innervation, tear function, and ocular discomfort. A cross-sectional, single-visit, investigator-masked pilot study. Assessments included Ocular Comfort Index (OCI), central and mid-peripheral corneal nerve density and morphology (HRT-Rostock), corneal sensitivity (Cochet-Bonnet aesthesiometer), tear Substance P and calcitonin gene-related peptide (CGRP) concentration (ELISA), in situ tear osmolarity (TearLab), tear secretion (Phenol Red Thread), and noninvasive tear break-up time (NITBUT; Keeler Tearscope). Groups were compared using independent t-test or Mann-Whitney U test, and regional differences assessed using paired t-tests. Associations were analyzed using Pearson or Spearman correlation. Significance was determined at P < .05. Twenty contact lens wearers (7M:13F, 32 ± 5 years) and 20 non-wearers (7M:13F, 31 ± 5 years) completed the study. OCI score was numerically higher in lens wearers (32.27 ± 5.33) than non-wearers (27.66 ± 9.94). Tear osmolarity was higher [298.0 (IQR 291.0-309.8) vs. 288.5 (282.3-298.3) mOsmol/L; P = .01] whereas NITBUT was lower (9.8 ± 3.4 vs. 13.8 ± 5.6 s; P = .01) in lens wearers compared with non-wearers. Tear neuropeptide concentrations were not different between groups [Substance P 4.29 ng/ml (IQR 1.57-6.05), CGRP 14.89 ng/ml (5.08-59.26)], and there were no differences in nerve morphology or ocular surface sensitivity. Higher nerve density, interconnections, and tortuosity were observed in the central cornea than mid-peripherally (P < .05). OCI score was moderately associated with nerve tortuosity (r = 0.42, P = .01). CGRP was associated with central nerve density (ρ = 0.38, P = .02), as was tear secretion (r = -0.37, P = .02). Nerve interconnections were strongly associated with corneal sensitivity (ρ = 0.64, P < .001). Relationships were demonstrated between nerve density, tear CGRP, and corneal sensitivity. Markers of corneal neurobiology and sensory function do not appear to be altered in contact lens wear despite worse tear function (osmolarity and stability) in lens wearers. This suggests that mechanisms other than overt changes in corneal innervation regulate tear function during lens wear. The relationship between nerve tortuosity and ocular discomfort requires elucidation.

Alterations in corneal nerves following crack cocaine use mimic diabetes-induced nerve damage.

SummaryThe use of in vivo confocal microscopy (IVCM) is rapidly emerging as an important clinical tool to evaluate changes in corneal sensory nerves as a surrogate measure for diabetic peripheral neuropathy. Commonly used metrics to document and grade the severity of diabetes and risk for diabetic peripheral neuropathy include nerve fiber length, density, branching and tortuosity. In addition to corneal nerves, thinning of the retinal fiber layer has been shown to correlate with the severity of diabetic disease. Here, we present a case report on a pre-diabetic 60-year-old native American woman with abnormal corneal nerve morphology and retinal nerve fiber layer thinning. Her past medical history was positive for illicit substance abuse. IVCM showed a decrease in nerve fiber density and length, in addition to abnormally high levels of tortuosity. OCT revealed focal areas of reduced retinal nerve fiber layer thickness that were asymmetric between eyes. This is the first report of abnormally high levels of tortuosity in the corneal sub-basal nerve plexus in a patient with a past history of cocaine abuse. It also demonstrates, for the first time, that illicit substance abuse can have long-term adverse effects on ocular nerves for years following discontinued use of the drug. Studies using IVCM to evaluate changes in corneal nerve morphology in patients with diabetes need to consider a past history of illicit drug use as an exclusionary measure.Learning points:Multiple ocular and systemic factors can impede accurate assessment of the corneal sub-basal nerve plexus by IVCM in diabetes.Although current history was negative for illicit substance abuse, past history can have longstanding effects on corneal nerves and the retinal nerve fiber layer.Illicit drug use must be considered an exclusionary measure when evaluating diabetes-induced changes in corneal nerve morphology and the retinal nerve fiber layer.

Select noxious stimuli induce changes on corneal nerve morphology.

The surface of the cornea contains the highest density of nociceptive nerves of any tissue in the body. These nerves are responsive to a variety of modalities of noxious stimuli and can signal pain even when activated by low threshold stimulation. Injury of corneal nerves can lead to altered nerve morphology, including neuropathic changes which can be associated with chronic pain. Emerging technologies that allow imaging of corneal nerves in vivo are spawning questions regarding the relationship between corneal nerve density, morphology, and function. We tested whether noxious stimulation of the corneal surface can alter nerve morphology and neurochemistry. We used concentrations of menthol, capsaicin, and hypertonic saline that evoked comparable levels of nocifensive eye wipe behaviors when applied to the ocular surface of an awake rat. Animals were sacrificed and corneal nerves were examined using immunocytochemistry and three-dimensional volumetric analyses. We found that menthol and capsaicin both caused a significant reduction in corneal nerve density as detected with β-tubulin immunoreactivity 2 hr after stimulation. Hypertonic saline did not reduce nerve density, but did cause qualitative changes in nerves including enlarged varicosities that were also seen following capsaicin and menthol stimulation. All three types of noxious stimuli caused a depletion of CGRP from corneal nerves, indicating that all modalities of noxious stimuli evoked peptide release. Our findings suggest that studies aimed at understanding the relationship between corneal nerve morphology and chronic disease may also need to consider the effects of acute stimulation on corneal nerve morphology.

Changes in corneal subbasal nerve morphology and sensitivity during orthokeratology: Recovery of change

PurposeTo investigate the recovery of orthokeratology (OK)-induced changes in corneal nerve morphology and sensitivity following lens wear discontinuation, over a 3-month period. MethodsSixteen myopic subjects who wore OK lenses during sleep for 3 months discontinued lens wear for 3 months. Corneal nerve morphology and sensitivity were assessed on the right eye only 3 h after waking at the pre-lens wear baseline and after lens wear discontinuation. Corneal nerve fiber density (NFD) and global nerve fiber orientation (GNFO) were assessed by sampling a 1 mm2 area of the subbasal nerve plexus at the corneal apex and temporal mid-periphery using in vivo confocal microscopy. Corneal sensitivity was measured using the Cochet-Bonnet aesthesiometer at similar corneal locations. ResultsSignificant changes in corneal sensitivity, NFD, and GNFO were observed at various corneal locations during the lens wear discontinuation period. In the central cornea, NFD and corneal sensitivity increased during the 3-month non-lens wear period (p < 0.01); no significant changes in NFD or corneal sensitivity were noted in the mid-peripheral cornea. Central corneal sensitivity recovered to pre-lens wear levels after 1 month of non-lens wear. Central NFD appeared to remain slightly decreased after 3 months of non-lens wear compared to pre-lens wear levels, but this difference did not reach statistical significance (p = 0.09). GNFO did not change significantly at the central cornea during the 3-month non-lens wear period, but altered in a counter-clockwise rotational direction (reversal of OK-induced change) at the mid-peripheral cornea (p < 0.05), although it did not appear to fully recover to pre-lens wear orientation (p = 0.05). ConclusionsOK lens-induced reduction in corneal sensitivity recovers with cessation of lens wear, returning to pre-lens wear levels shortly after lens wear discontinuation. Changes to nerve morphology induced by OK lens wear, however, appear to recover more slowly towards pre-lens wear levels. This requires confirmation in a longer non-lens wear period.

Effect of Inhibition or Deletion of Neutral Endopeptidase on Neuropathic Endpoints in High Fat Fed/Low Dose Streptozotocin-Treated Mice.

Previously we demonstrated that a vasopeptidase inhibitor of angiotensin converting enzyme and neutral endopeptidase (NEP), a protease that degrades vaso- and neuro-active peptides, improves neural function in diabetic rodent models. The purpose of this study was to determine whether inhibition or deletion of NEP provides protection from neuropathy caused by diabetes with an emphasis on morphology of corneal nerves as a primary endpoint. Diabetes, modeling type 2, was induced in C57Bl/6J and NEP deficient mice through a combination of a high fat diet and streptozotocin. To inhibit NEP activity, diabetic C57Bl/6J mice were treated with candoxatril using a prevention or intervention protocol. Twelve weeks after the induction of diabetes in C57Bl/6J mice, the existence of diabetic neuropathy was determined through multiple endpoints including decrease in corneal nerves in the epithelium and sub-epithelium layer. Treatment of diabetic C57Bl/6J mice with candoxatril improved diabetic peripheral neuropathy and protected corneal nerve morphology with the prevention protocol being more efficacious than intervention. Unlike C57Bl/6J, mice deficient in NEP were protected from the development of neuropathologic alterations and loss of corneal nerves upon induction of diabetes. These studies suggest that NEP contributes to the development of diabetic neuropathy and may be a treatable target.

Changes in Corneal Subbasal Nerve Morphology and Sensitivity During Orthokeratology: Onset of Change

PurposeTo investigate changes in corneal subbasal nerve fiber density and orientation during a 3-month orthokeratology (OK) lens wear period and their relationship with concurrent changes in corneal sensitivity. MethodsSixteen subjects wore overnight OK lenses for 90 days and were assessed at baseline, Day 30, and Day 90. Nerve images at the corneal apex and temporal mid-periphery were captured from the right eye only using in vivo confocal microscopy and analyzed to calculate nerve fiber density (NFD) and global nerve fiber orientation (GNFO). Corneal sensitivity was measured using the Cochet-Bonnet aesthesiometer at similar corneal locations. Control groups of non-lens (NL) wearing and conventional rigid gas-permeable (GP) lens-wearing subjects were also examined. ResultsSignificant changes in NFD, GNFO and corneal sensitivity were observed during OK lens wear over the study period. In the central cornea, both NFD and corneal sensitivity decreased by Day 30, with further reductions at Day 90. Reduced NFD was associated with reduced corneal sensitivity. In the mid-peripheral cornea only, GNFO was rotated in a clockwise direction at Day 30, with further rotation at Day 90. Corneal sensitivity reduction plateaued by Day 30. In the GP lens-wearing subjects, only corneal sensitivity decreased by Day 30 at both corneal locations. No changes were observed in the NL control subjects. ConclusionsAlterations in corneal nerve morphology occur rapidly with commencement of OK lens wear and appear to underpin functional sensitivity loss. Nerve fiber orientation can provide a useful index for changes in corneal nerve morphology.

Long-term Effects of LASIK on Corneal Innervation and Tear Neuropeptides and the Associations With Dry Eye.

To investigate the associations between dry eye, corneal nerves, and tear neuroptides in dry eye after LASIK. A single visit cross-sectional study was performed. Twenty participants who had LASIK more than 12 months prior and 20 healthy participants were recruited. Ocular comfort, tear functions, ocular surface sensitivity, basal tear collection, and corneal nerve morphology assessments were conducted. Tear substance P and calcitonin gene-related peptide (CGRP) concentrations were determined using ELISAs. Differences in variables between groups were examined using an independent t test or Mann-Whitney U test, as appropriate. Associations between variables in the post-LASIK group were examined using a Spearman's correlation test. A P value of less than .05 was considered significant. Central corneal nerve morphology parameters were all altered in the post-LASIK group (P < .05). Higher ocular discomfort (P = .01), tear CGRP concentration (P = .001), and conjunctival sensitivity (P < .009) were found in the post-LASIK group. There was a positive association between dry eye symptoms and superior corneal sensitivity (P = .51, P = .02) and tear substance P concentration (P = .52, P < .03). This study provides evidence of the association between tear neuropeptides, conjunctival sensitivity, and symptoms in symptomatic patients after LASIK. The differences in nerve morphology, neuropeptide, and ocular surface sensitivity between symptomatic and asymptomatic patients after LASIK are required to better understand the mechanism of dry eye after LASIK. [J Refract Surg. 2016;32(8):518-524.].

A rapid decline in corneal small fibers and occurrence of foot ulceration and Charcot foot

We present clinical, neuropathy and corneal nerve morphology data in a participant with type 2 diabetes who developed diabetic foot ulceration, partial amputation and Charcot during a longitudinal observational study. While conventional measures of neuropathy did not deteriorate significantly, corneal nerve parameters showed a rapid reduction prior to the development of foot complications.

An In Vivo Confocal Microscopic Study of Corneal Nerve Morphology in Unilateral Keratoconus.

Purpose. To study the corneal nerve morphology and its importance in unilateral keratoconus. Materials and Methods. In this prospective cross-sectional study, 33 eyes of 33 patients with keratoconus in one eye (Group 3) were compared with the other normal eye of the same patients (Group 2) and 30 eyes of healthy patients (Group 1). All patients underwent detailed ophthalmic examination followed by topography with Pentacam HR and in vivo confocal microscopy (IVCM). Five images obtained with IVCM were analyzed using an automated CCmetrics software version 1.0 for changes in subbasal plexus of nerves. Results. Intergroup comparison showed statistically significant reduction in corneal nerve fiber density (CNFD) and length (CNFL) in Group 3 as compared to Group 1 (p < 0.001 and p = 0.001, resp.) and Group 2 (p = 0.01 and p = 0.02, resp.). Though corneal nerve fiber length, diameter, area, width, corneal nerve branch density, and corneal total branch density were found to be higher in decentered cones, only the corneal nerve branch density (CNBD) was found to be statistically significant (p < 0.01) as compared to centered cones. Conclusion. Quantitative changes in the corneal nerve morphology can be used as an imaging marker for the early diagnosis of keratoconus before the onset of refractive or topography changes.

Hyperosmolar Tears Induce Functional and Structural Alterations of Corneal Nerves: Electrophysiological and Anatomical Evidence Toward Neurotoxicity.

In an effort to elucidate possible neural mechanisms underlying diminished tearing in dry eye disease, this study sought to determine if hyperosmolar tears, a ubiquitous sign of dry eye disease, produce functional changes in corneal nerve responses to drying of the cornea and if these changes correlate with alterations in corneal nerve morphology. In vivo extracellular electrophysiological recordings were performed in rat trigeminal ganglion neurons that innervated the cornea before, and up to 3 hours after, the ocular application of continuous hyperosmolar tears or artificial tears. In corollary experiments, immunohistochemical staining was performed to compare corneal nerve morphology in control and in eyes treated with hyperosmolar solutions. Our previous studies identified a population of corneal afferents, dry-sensitive neurons that are strongly excited by corneal dessication ("dry response"), a response thought to trigger the lacrimation reflex. In the present study, we found that the dry responses of corneal dry-sensitive neurons were depressed or even completely abolished by hyperosmolar tears in a time- (30 minutes to 3 hours) and dose (450- to 1000-mOsm solutions)-dependent manner. Furthermore, eyes treated with hyperosmolar tears for 3 hours contained large numbers of morphologically abnormal (granular, fragmented, or prominently beaded) subbasal nerves that appeared to be undergoing degeneration. These results demonstrate that tear hyperosmolarity, considered to be a "core" mechanism of dry eye disease, significantly decreases physiological sensitivity and morphologic integrity of the corneal nerves important in tear production. These alterations might contribute to the diminished tearing seen clinically in dry eye patients.

Structural and functional changes in corneal innervation after laser in situ keratomileusis and their relationship with dry eye.

The most likely etiology of post-LASIK dry eye is corneal nerve damage; however, no direct relationship between post-LASIK dry eye symptoms and nerve damage has been established, and limited information is available about the relationship between dry eye signs and corneal reinnervation after LASIK. Tear neuropeptides (SP and CGRP) are important in the maintenance of corneal nerve health, but the impact of LASIK has not yet been studied. This study evaluated changes in nerve morphology, tear neuropeptide, and dry eye, so as to establish the relationship between reinnervation and dry eye and to assess the role of tear neuropeptides in reinnervation post-LASIK. Twenty non-dry eye volunteers who had undergone bilateral myopic-LASIK completed this study. Corneal nerve morphology (density, width, interconnections, and tortuosity), SP and CGRP concentration, and dry eye were monitored over time prior to, 1 day, 1 week, 1, 3, and 6 months post-LASIK. Dry eye symptoms and tear function, except for osmolarity (P = 0.003), remained unchanged post-LASIK. Corneal nerve morphology decreased immediately, and did not return to preoperative levels by 6 months post-LASIK (P < 0.001). Increased tear SP concentration was observed 3 months post-LASIK (P < 0.001). Associations between reinnervation as measured by increased density and lower tear SP (P = 0.03), and between increased density and decreased dry eye symptoms (P = 0.01) were found post-LASIK. An inverse relationship between reinnervation post-LASIK and dry eye symptoms was found, confirming that post-LASIK dry eye is a neuropathic disease. This study is the first to demonstrate an association between tear SP and post-LASIK reinnervation, suggesting that strategies for manipulating neuropeptide concentration to improve reinnervation may improve ocular comfort post-LASIK.

Corneal Confocal Microscopy Identifies Small-Fiber Neuropathy in Subjects With Impaired Glucose Tolerance Who Develop Type 2 Diabetes.

OBJECTIVEImpaired glucose tolerance (IGT) through to type 2 diabetes is thought to confer a continuum of risk for neuropathy. Identification of subjects at high risk of developing type 2 diabetes and, hence, worsening neuropathy would allow identification and risk stratification for more aggressive management.RESEARCH DESIGN AND METHODSThirty subjects with IGT and 17 age-matched control subjects underwent an oral glucose tolerance test, assessment of neuropathic symptoms and deficits, quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy (CCM) to quantify corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) at baseline and annually for 3 years.RESULTSTen subjects who developed type 2 diabetes had a significantly lower CNFD (P = 0.003), CNBD (P = 0.04), and CNFL (P = 0.04) compared with control subjects at baseline and a further reduction in CNFL (P = 0.006), intraepidermal nerve fiber density (IENFD) (P = 0.02), and mean dendritic length (MDL) (P = 0.02) over 3 years. Fifteen subjects who remained IGT and 5 subjects who returned to normal glucose tolerance had no significant baseline abnormality on CCM or IENFD but had a lower MDL (P < 0.0001) compared with control subjects. The IGT subjects showed a significant decrease in IENFD (P = 0.02) but no change in MDL or CCM over 3 years. Those who returned to NGT showed an increase in CNFD (P = 0.05), CNBD (P = 0.04), and CNFL (P = 0.05), but a decrease in IENFD (P = 0.02), over 3 years.CONCLUSIONSCCM and skin biopsy detect a small-fiber neuropathy in subjects with IGT who develop type 2 diabetes and also show a dynamic worsening or improvement in corneal and intraepidermal nerve morphology in relation to change in glucose tolerance status.

Corneal nerve structure and function after long-term wear of fluid-filled scleral lens.

The aim of this study was to determine whether long-term wear of a fluid-filled scleral lens alters basal tear production, corneal sensation, corneal nerve density, and corneal nerve morphology in 2 disease categories. Patients recruited from the Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) treatment program at the Weill Cornell Medical College were categorized into 2 groups: distorted corneas (DC) or ocular surface disease (OSD). We measured tear production, central corneal sensation, subbasal nerve density and tortuosity, and stromal nerve thickness before and after long-term wear of the prosthetic device used in PROSE treatment, defined as at least 60 days of wear for a minimum of 8 hours a day. Twenty patients were included in the study. After long-term wear of the prosthetic device, tear production decreased in patients with DC (21.2 ± 8.5 to 10.4 ± 4.6 mm; P < 0.0001) but did not change in patients with OSD (7.5 ± 5.2 to 8.7 ± 7.2 mm; P = 0.71). Corneal sensation increased in the DC group (45.6 ± 9.2 to 55.0 ± 5.6 mm; P < 0.05). There was no significant change in sensation in patients with OSD (45.0 ± 8.7 to 49.1 ± 14.8 mm; P = 0.37). Subbasal nerve density, subbasal nerve tortuosity, and stromal nerve thickness remained unchanged in both DC and OSD groups after long-term wear (P > 0.05). Patients with DC had significantly reduced basal tear production and increased corneal sensation after long-term wear of the scleral lens, but patients with OSD did not show any changes in tear production or corneal sensation.