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Purpose: To assess whether corneal nerve analysis can identify and differentiate patients with multiple sclerosis (MS) from those with epilepsy., Methods: Participants with MS (n = 83), participants with epilepsy (n = 50), and healthy controls (HCs) (n = 20) underwent corneal confocal microscopy (CCM) and quantification of automated corneal nerve fiber length (ACNFL), automated corneal nerve fractal dimension (ACNFrD), and ACNFrD/ACNFL ratio of the subbasal nerve plexus., Results: ACNFL (MS: P < 0.0001; epilepsy: P = 0.002) and ACNFrD (MS: P < 0.0001; epilepsy: P = 0.025) were significantly lower and the ACNFrD/ACNFL ratio (MS: P < 0.0001; epilepsy: P = 0.018) was significantly higher compared to HCs. ACNFL (P = 0.001), ACNFrD (P = 0.0003), and ACNFrD/ACNFL ratio (P = 0.006) were significantly lower in patients with MS compared to those with epilepsy. ACNFL had the highest diagnostic utility for identifying patients with MS (sensitivity/specificity 0.86/0.85, area under the curve [AUC] 0.90, P < 0.0001), and ACNFrD had the highest diagnostic utility for identifying patients with epilepsy (sensitivity/specificity 0.78/0.75, AUC 0.76, P = 0.0008). ACNFrD had the highest diagnostic utility for differentiating patients with MS from epilepsy (sensitivity/specificity 0.66/0.65, AUC 0.70, <0.0001)., Conclusions: Corneal neurodegeneration occurs in and is characterized by a distinct pattern that differentiates patients with MS and epilepsy., Translational Relevance: CCM identifies and differentiates patients with MS and epilepsy, albeit with moderate performance. Further validation, with a larger sample size, is needed.

Background/aim: Obesity and related metabolic abnormalities in adults are associated with peripheral neuropathy. Acanthosis nigricans (AN) is associated with insulin resistance, fatty liver, hyperlipidemia and glucose intolerance, all of which are risk factors for neuropathy. The aim of this study was to investigate if obese adolescents with AN have evidence of small nerve fiber damage., Material and Methods: Adolescents with obesity with and without AN underwent body composition analysis, assessment of vibration perception threshold (VPT), monofilament sensitivity and corneal confocal microscopy (CCM) to quantify corneal nerve fiber density (CNFD), branch density (CNBD), length (CNFL) and inferior whorl length (IWL)., Results: Forty-six participants with obesity with (n = 31) and without (n = 15) AN aged 15(14-17) years were compared to 20 healthy controls aged 13(12-14) years. There was no difference in VPT, monofilament sensitivity and CCM measures between adolescents with obesity and controls. However, adolescents with AN had a significantly higher weight (P = 0.022), fat% (P = 0.029) and fat-muscle ratio (P = 0.012) with a lower CNFD (P = 0.045) compared to those with obesity without AN., Conclusion: Adolescents with obesity and acanthosis nigricans have a higher fat mass and small nerve fibre loss, indicative of a sub-clinical neuropathy., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Gad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Corneal confocal microscopy (CCM) is an ophthalmic imaging technique that enables the identification of corneal nerve fibre degeneration and regeneration. To undertake a systematic review and meta-analysis of studies utilizing CCM to assess for corneal nerve regeneration after pharmacological and surgical interventions in patients with peripheral neuropathy. Databases (EMBASE [Ovid], PubMed, CENTRAL and Web of Science) were searched to summarize the evidence from randomized and non-randomized studies using CCM to detect corneal nerve regeneration after pharmacological and surgical interventions. Data synthesis was undertaken using RevMan web. Eighteen studies including 958 patients were included. CCM identified an early (1-8 months) and longer term (1-5 years) increase in corneal nerve measures in patients with peripheral neuropathy after pharmacological and surgical interventions. This meta-analysis confirms the utility of CCM to identify nerve regeneration following pharmacological and surgical interventions. It could be utilized to show a benefit in clinical trials of disease modifying therapies for peripheral neuropathy., (© 2024 The Author(s). Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Neurodevelopmental and neurodegenerative pathology occur in Schizophrenia. This study compared the utility of corneal confocal microscopy (CCM), an ophthalmic imaging technique with MRI brain volumetry in quantifying neuronal pathology and its relationship to cognitive dysfunction and symptom severity in schizophrenia. Thirty-six subjects with schizophrenia and 26 controls underwent assessment of cognitive function, symptom severity, CCM and MRI brain volumetry. Subjects with schizophrenia had lower cognitive function (P ≤ 0.01), corneal nerve fiber density (CNFD), length (CNFL), branch density (CNBD), CNBD:CNFD ratio (P < 0.0001) and cingulate gyrus volume (P < 0.05) but comparable volume of whole brain (P = 0.61), cortical gray matter (P = 0.99), ventricle (P = 0.47), hippocampus (P = 0.10) and amygdala (P = 0.68). Corneal nerve measures and cingulate gyrus volume showed no association with symptom severity (P = 0.35-0.86 and P = 0.50) or cognitive function (P = 0.35-0.86 and P = 0.49). Corneal nerve measures were not associated with metabolic syndrome (P = 0.61-0.64) or diabetes (P = 0.057-0.54). The area under the ROC curve distinguishing subjects with schizophrenia from controls was 88% for CNFL, 84% for CNBD and CNBD:CNFD ratio, 79% for CNFD and 73% for the cingulate gyrus volume. This study has identified a reduction in corneal nerve fibers and cingulate gyrus volume in schizophrenia, but no association with symptom severity or cognitive dysfunction. Corneal nerve loss identified using CCM may act as a rapid non-invasive surrogate marker of neurodegeneration in patients with schizophrenia., (© 2022. The Author(s).)

Introduction: Corneal confocal microscopy (CCM) is a rapid non-invasive ophthalmic imaging technique that identifies corneal nerve fiber damage. Small studies suggest that CCM could be used to assess patients with diabetic peripheral neuropathy (DPN)., Aim: To undertake a systematic review and meta-analysis assessing the diagnostic utility of CCM for sub-clinical DPN (DPN - ) and established DPN (DPN + )., Data Sources: Databases (PubMed, Embase, Central, ProQuest) were searched for studies using CCM in patients with diabetes up to April 2020., Study Selection: Studies were included if they reported on at least one CCM parameter in patients with diabetes., Data Extraction: Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and inferior whorl length (IWL) were compared between patients with diabetes with and without DPN and controls. Meta-analysis was undertaken using RevMan V.5.3., Data Synthesis: Thirty-eight studies including ~4,000 participants were included in this meta-analysis. There were significant reductions in CNFD, CNBD, CNFL, and IWL in DPN - vs controls (P < 0.00001), DPN + vs controls (P < 0.00001), and DPN + vs DPN - (P < 0.00001)., Conclusion: This systematic review and meta-analysis shows that CCM detects small nerve fiber loss in subclinical and clinical DPN and concludes that CCM has good diagnostic utility in DPN., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Purpose: The purpose of this study was to evaluate the utility of corneal confocal microscopy (CCM) in identifying small nerve fiber damage and immune cell activation in patients with systemic lupus erythematosus (SLE)., Methods: This cross-sectional comparative study included 39 consecutive patients with SLE and 30 healthy control participants. Central corneal sensitivity was assessed using a Cochet-Bonnet contact corneal esthesiometer and a laser scanning CCM (Heidelberg, Germany) was used to quantify corneal nerve fiber density (CNFD), nerve branch density (CNBD), nerve fiber length (CNFL), and Langerhans cell (LC) density., Results: Age was comparable among patients with SLE (33.7 ± 12.7) and controls (35.0 ± 13.7 years, P = 0.670) and the median duration of disease was 3.0 years (2.0-10.0 years). CNBD (P = 0.003) and CNFL (P = 0.019) were lower and mature LC density (P = 0.002) was higher, but corneal sensitivity (P = 0.178) and CNFD (P = 0.198) were comparable in patients with SLE compared with controls. The SELENA-SLEDAI score correlated with CNFD (ρ = -0.319, P = 0.048) and CNFL (ρ = -0.373, P = 0.019), and the total and immature LC densities correlated with CNBD (ρ = -0.319. P = 0.048, and ρ = -0.328, P = 0.041, respectively). Immature LC density was higher (P = 0.025), but corneal sensitivity and nerve fiber parameters were comparable between patients with (33%) and without neuropsychiatric symptoms and SLE., Conclusions: Corneal confocal microscopy identifies distal corneal nerve fiber loss and increased immune cell density in patients with SLE and corneal nerve loss was associated with disease activity., Translational Relevance: Corneal confocal microscopy may enable the detection of subclinical corneal nerve loss and immune cell activation in SLE.

Axonal loss is the main determinant of disease progression in multiple sclerosis (MS). This study aimed to assess the utility of corneal confocal microscopy (CCM) in detecting corneal axonal loss in different courses of MS. The results were confirmed by two independent segmentation methods. 72 subjects (144 eyes) [(clinically isolated syndrome (n = 9); relapsing-remitting MS (n = 20); secondary-progressive MS (n = 22); and age-matched, healthy controls (n = 21)] underwent CCM and assessment of their disability status. Two independent algorithms (ACCMetrics; and Voxeleron deepNerve) were used to quantify corneal nerve fiber density (CNFD) (ACCMetrics only), corneal nerve fiber length (CNFL) and corneal nerve fractal dimension (CNFrD). Data are expressed as mean ± standard deviation with 95% confidence interval (CI). Compared to controls, patients with MS had significantly lower CNFD (34.76 ± 5.57 vs. 19.85 ± 6.75 fibers/mm 2 , 95% CI - 18.24 to - 11.59, P < .0001), CNFL [for ACCMetrics: 19.75 ± 2.39 vs. 12.40 ± 3.30 mm/mm 2 , 95% CI - 8.94 to - 5.77, P < .0001; for deepNerve: 21.98 ± 2.76 vs. 14.40 ± 4.17 mm/mm 2 , 95% CI - 9.55 to - 5.6, P < .0001] and CNFrD [for ACCMetrics: 1.52 ± 0.02 vs. 1.45 ± 0.04, 95% CI - 0.09 to - 0.05, P < .0001; for deepNerve: 1.29 ± 0.03 vs. 1.19 ± 0.07, 95% - 0.13 to - 0.07, P < .0001]. Corneal nerve parameters were comparably reduced in different courses of MS. There was excellent reproducibility between the algorithms. Significant corneal axonal loss is detected in different courses of MS including patients with clinically isolated syndrome., (© 2021. The Author(s).)

Aims/introduction: This study aimed to investigate whether insulin resistance (IR) in individuals with type 2 diabetes undergoing intensive glycemic control determines the extent of improvement in neuropathy., Materials and Methods: This was an exploratory substudy of an open-label, randomized controlled trial of individuals with poorly controlled type 2 diabetes treated with exenatide and pioglitazone or insulin to achieve a glycated hemoglobin <7.0% (<53 mmol/mol). Baseline IR was defined using homeostasis model assessment of IR, and change in neuropathy was assessed using corneal confocal microscopy., Results: A total of 38 individuals with type 2 diabetes aged 50.2 ± 8.5 years with (n = 25, 66%) and without (n = 13, 34%) IR were studied. There was a significant decrease in glycated hemoglobin (P < 0.0001), diastolic blood pressure (P < 0.0001), total cholesterol (P < 0.01) and low-density lipoprotein (P = 0.05), and an increase in bodyweight (P < 0.0001) with treatment. Individuals with homeostasis model assessment of IR <1.9 showed a significant increase in corneal nerve fiber density (P ≤ 0.01), length (P ≤ 0.01) and branch density (P ≤ 0.01), whereas individuals with homeostasis model assessment of IR ≥1.9 showed no change. IR was negatively associated with change in corneal nerve fiber density after adjusting for change in bodyweight (P < 0.05)., Conclusions: Nerve regeneration might be limited in individuals with type 2 diabetes and IR undergoing treatment with pioglitazone plus exenatide or insulin to improve glycemic control., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

In patients with acute ischemic stroke, pial collaterals play a key role in limiting neurological disability by maintaining blood flow to ischemic penumbra. We hypothesized that patient with poor pial collaterals will have greater corneal nerve and endothelial cell abnormalities. In a cross-sectional study, 35 patients with acute ischemic stroke secondary to middle cerebral artery (MCA) occlusion with poor (n = 12) and moderate-good (n = 23) pial collaterals and 35 healthy controls underwent corneal confocal microscopy and quantification of corneal nerve and endothelial cell morphology. In patients with MCA stroke, corneal nerve fibre length (CNFL) (P < 0.001), corneal nerve fibre density (CNFD) (P = 0.025) and corneal nerve branch density (CNBD) (P = 0.002) were lower compared to controls. Age, BMI, cholesterol, triglycerides, HDL, LDL, systolic blood pressure, NIHSS and endothelial cell parameters did not differ but mRS was higher (p = 0.023) and CNFL (p = 0.026) and CNBD (p = 0.044) were lower in patients with poor compared to moderate-good collaterals. CNFL and CNBD distinguished subjects with poor from moderate-good pial collaterals with an AUC of 72% (95% CI 53-92%) and 71% (95% CI 53-90%), respectively. Corneal nerve loss is greater in patients with poor compared to moderate-good pial collaterals and may act as a surrogate marker for pial collateral status in patients with ischemic stroke., (© 2021. The Author(s).)

Purpose: Increased corneal and epidermal Langerhans cells (LCs) have been reported in patients with diabetic neuropathy. The aim of this study was to quantify the density of LCs in relation to corneal nerve morphology and the presence of diabetic neuropathy and to determine if this differed in patients with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and latent autoimmune diabetes of adults (LADA)., Methods: Patients with T1DM (n = 25), T2DM (n = 36), or LADA (n = 23) and control subjects (n = 23) underwent detailed assessment of peripheral neuropathy and corneal confocal microscopy. Corneal nerve fiber density (CNFD), branch density (CNBD), length (CNFL) and total, immature and mature LC densities were quantified., Results: Lower CNFD (P < 0.001), CNBD (P < 0.0001), and CNFL (P < 0.0001) and higher LC density (P = 0.03) were detected in patients with T1DM, T2DM, and LADA compared to controls. CNBD was inversely correlated with mature (r = -0.5; P = 0.008), immature (r = -0.4; P = 0.02) and total (r = -0.5; P = 0.01) LC density, and CNFL was inversely correlated with immature LC density (r = -0.4; P = 0.03) in patients with T1DM but not in patients with T2DM and LADA., Conclusions: This study shows significant corneal nerve loss and an increase in LC density in patients with T1DM, T2DM, and LADA. Furthermore, increased LC density correlated with corneal nerve loss in patients with T1DM.

Pathological hyperphosphorylated tau is a key feature of Alzheimer's disease (AD) and Frontotemporal dementia (FTD). Using transgenic mice overexpressing human non-mutated tau (htau mice), we assessed the contribution of tau to peripheral and central neurodegeneration. Indices of peripheral small and large fiber neuropathy and learning and memory performances were assessed at 3 and 6 months of age. Overexpression of human tau is associated with peripheral neuropathy at 6 months of age. Our study also provides evidence that non-mutated tau hyperphosphorylation plays a critical role in memory deficits. In addition, htau mice had reduced stromal corneal nerve length with preservation of sub-basal corneal nerves, consistent with a somatofugal degeneration. Corneal nerve degeneration occurred prior to any cognitive deficits and peripheral neuropathy. Stromal corneal nerve loss was observed in patients with FTD but not AD. Corneal confocal microscopy may be used to identify early neurodegeneration and differentiate FTD from AD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Subjects with obesity have metabolic risk factors for nerve fibre damage. Because bariatric surgery improves these risk factors we have assessed whether this can ameliorate nerve fibre damage., Methods: Twenty-six obese subjects without diabetes (age: 46.23 ± 8.6, BMI: 48.7 ± 1.5, HbA1c: 38.0 ± 4.5) and 20 controls (age: 48.3 ± 6.2, BMI: 26.8 ± 4.2, HbA1c: 39.1 ± 2.6) underwent detailed assessment of neuropathy at baseline and 12 months after bariatric surgery., Results: Obese subjects had normal peroneal (45.9 ± 5.5 vs. 48.1 ± 4.5, P = 0.1) and sural (46.9 ± 7.6 vs. 47.9 ± 10.6, P = 0.1) nerve conduction velocity, but a significantly higher neuropathy symptom profile (NSP) (4.3 ± 5.7 vs. 0.3 ± 0.6, P = 0.001), vibration perception threshold (VPT) (V) (10.2 ± 6.8 vs. 4.8 ± 2.7, P < 0.0001), warm threshold (C°) (40.4 ± 3.5 vs. 37.2 ± 1.8, P = 0.003) and lower peroneal (3.8 ± 2.2 vs. 4.9 ± 2.2, P = 0.02) and sural (8.9 ± 5.8 vs. 15.2 ± 8.5, P < 0.0001) nerve amplitude, deep breathing-heart rate variability (DB-HRV) (beats/min) (21.7 ± 4.1 vs. 30.1 ± 14, P = 0.001), corneal nerve fibre density (CNFD) (n/mm 2 ) (25.6 ± 5.3 vs. 32.0 ± 3.1, P < 0.0001), corneal nerve branch density (CNBD) (n/mm 2 ) (56.9 ± 27.5 vs. 111.4 ± 30.7, P < 0.0001) and corneal nerve fibre length (CNFL) (mm/mm 2 ) (17.9 ± 4.1 vs. 29.8 ± 4.9, P < 0.0001) compared to controls at baseline. In control subjects there was no change in neuropathy measures over 12 months. However, 12 months after bariatric surgery there was a significant reduction in BMI (33.7 ± 1.7 vs. 48.7 ± 1.5, P = 0.001), HbA1c (34.3 ± 0.6 vs. 38.0 ± 4.5, P = 0.0002), triglycerides (mmol/l) (1.3 ± 0.6 vs. 1.6 ± 0.8, P = 0.005) and low-density lipoprotein cholesterol (mmol/l) (2.7 ± 0.7 vs. 3.1 ± 0.9, P = 0.02) and an increase in high-density lipoprotein cholesterol (mmol/l) (1.2 ± 0.3 vs. 1.04 ± 0.2, P = 0.002). There was a significant improvement in NSP (1.6 ± 2.7 vs. 4.3 ± 5.7, P = 0.004), neuropathy disability score (0.3 ± 0.9 vs. 1.3 ± 2.0, P = 0.03), CNFD (28.2 ± 4.4 vs. 25.6 ± 5.3, P = 0.03), CNBD (64.7 ± 26.1 vs. 56.9 ± 27.5, P = 0.04) and CNFL (20.4 ± 1.2 vs. 17.9 ± 4.1, P = 0.02), but no change in cold and warm threshold, VPT, DB-HRV or nerve conduction velocity and amplitude. Increase in CNFD correlated with a decrease in triglycerides (r = -0.45, P = 0.04)., Conclusion: Obese subjects have evidence of neuropathy, and bariatric surgery leads to an improvement in weight, HbA1c, lipids, neuropathic symptoms and deficits and small nerve fibre regeneration without a change in quantitative sensory testing, autonomic function or neurophysiology.

Accurately quantifying the progression of diabetic peripheral neuropathy is key to identify individuals who will progress to foot ulceration and to power clinical intervention trials. We have undertaken detailed neuropathy phenotyping to assess the longitudinal utility of different measures of neuropathy in patients with diabetes. Nineteen patients with diabetes (age 52.5 ± 14.7 years, duration of diabetes 26.0 ± 13.8 years) and 19 healthy controls underwent assessment of symptoms and signs of neuropathy, quantitative sensory testing, autonomic nerve function, neurophysiology, intra-epidermal nerve fibre density (IENFD) and corneal confocal microscopy (CCM) to quantify corneal nerve fibre density (CNFD), branch density (CNBD) and fibre length (CNFL). Mean follow-up was 6.5 years. Glycated haemoglobin (p = 0.04), low-density lipoprotein-cholesterol (LDL-C) (p = 0.0009) and urinary albumin creatinine ratio (p < 0.0001) improved. Neuropathy symptom profile (p = 0.03), neuropathy disability score (p = 0.04), vibration perception threshold (p = 0.02), cold perception threshold (p = 0.006), CNFD (p = 0.03), CNBD (p < 0.0001), CNFL (p < 0.0001), IENFD (p = 0.04), sural (p = 0.02) and peroneal motor nerve conduction velocity (p = 0.03) deteriorated significantly. Change (∆) in CNFL correlated with ∆CPT (p = 0.006) and ∆Expiration/Inspiration ratio (p = 0.002) and ∆IENFD correlated with ∆CNFD (p = 0.005), ∆CNBD (p = 0.02) and ∆CNFL (p = 0.01). This study shows worsening of diabetic neuropathy across a range of neuropathy measures, especially CCM, despite an improvement in HbA1c and LDL-C. It further supports the utility of CCM as a rapid, non-invasive surrogate measure of diabetic neuropathy.

Aims/introduction: Corneal confocal microscopy is a rapid, non-invasive ophthalmic technique to identify subclinical neuropathy. The aim of this study was to quantify corneal nerve morphology in children with type 1 diabetes mellitus compared with age-matched healthy controls using corneal confocal microscopy., Materials and Methods: A total of 20 participants with type 1 diabetes mellitus (age 14 ± 2 years, diabetes duration 4.08 ± 2.91 years, glycated hemoglobin 9.3 ± 2.1%) without retinopathy or microalbuminuria and 20 healthy controls were recruited from outpatient clinics. Corneal confocal microscopy was undertaken, and corneal nerve fiber density (n/mm 2 ), corneal nerve branch density (n/mm 2 ), corneal nerve fiber length (mm/mm 2 ), corneal nerve fiber tortuosity and inferior whorl length (mm/mm 2 ) were quantified manually., Results: Corneal nerve fiber density (22.73 ± 8.84 vs 32.92 ± 8.59; P < 0.001), corneal nerve branch density (26.19 ± 14.64 vs 47.34 ± 20.01; P < 0.001), corneal nerve fiber length (13.26 ± 4.06 vs 19.52 ± 4.54; P < 0.001) and inferior whorl length (15.50 ± 5.48 vs 23.42 ± 3.94; P < 0.0001) were significantly lower, whereas corneal nerve fiber tortuosity (14.88 ± 5.28 vs 13.52 ± 3.01; P = 0.323) did not differ between children with type 1 diabetes mellitus and controls. Glycated hemoglobin correlated with corneal nerve fiber tortuosity (P < 0.006) and aspartate aminotransferase correlated with corneal nerve fiber density (P = 0.039), corneal nerve branch density (P = 0.003) and corneal nerve fiber length (P = 0.037)., Conclusion: Corneal confocal microscopy identifies significant subclinical corneal nerve loss, especially in the inferior whorl of children with type 1 diabetes mellitus without retinopathy or microalbuminuria., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Objectives: The aim of this study was to utilise corneal confocal microscopy to quantify corneal nerve morphology and establish the presence of sub-clinical small fibre damage and peripheral neuropathy in children with celiac disease., Methods: This is a cross-sectional cohort study of twenty children with celiac disease and 20 healthy controls who underwent clinical and laboratory assessments and corneal confocal microscopy. Corneal nerve fiber density (no.mm2), corneal nerve branch density (no.mm2), corneal nerve fiber length (mm.mm2), corneal nerve fiber tortuosity and inferior whorl length (mm.mm2) were quantified manually., Results: Corneal nerve fiber density (34.7±8.6 vs. 32.9±8.6; P = 0.5), corneal nerve branch density (47.2±24.5 vs. 47.3±20.0; P = 0.1) and corneal nerve fiber length (20.0±5.1 vs. 19.5±4.5; P = 0.8) did not differ between children with celiac disease and healthy controls. Corneal nerve fiber tortuosity (11.4±1.9 vs 13.5±3.0; P = 0.01) was significantly lower and inferior whorl length (20.0±5.5 vs 23.0±3.8; P = 0.06) showed a non-significant reduction in children with celiac disease compared to healthy controls. Inferior whorl length correlated significantly with corneal nerve fiber density (P = 0.005), corneal nerve branch density (P = 0.04), and corneal nerve fiber length (P = 0.002)., Conclusion: Corneal confocal microscopy demonstrates minimal evidence of neuropathy in children with celiac disease., Competing Interests: The authors have declared that no competing interests exist.

Corneal confocal microscopy is a non-invasive ophthalmic imaging modality, which was initially used for the diagnosis and management of corneal diseases. However, over the last 20 years it has come to the forefront as a rapid, non-invasive, reiterative, cost-effective imaging biomarker for neurodegeneration. The human cornea is endowed with the densest network of sensory unmyelinated axons, anywhere in the body. A robust body of evidence shows that corneal confocal microscopy is a reliable and reproducible method to quantify corneal nerve morphology. Changes in corneal nerve morphology precede or relate to clinical manifestations of peripheral and central neurodegenerative conditions. Moreover, in clinical intervention trials, corneal nerve regeneration occurs early and predicts functional gains in trials of neuroprotection. In view of these findings, it is timely to summarise the knowledge in this area of research and to explain why the case for corneal confocal microscopy is sufficiently compelling to argue for its inclusion as a Food and Drug Administration endpoint in clinical trials of peripheral and central neurodegenerative conditions., (© 2019 Optometry Australia.)

Purpose: The presence of white matter hyperintensities (WMH) on MRI imaging confers an increased risk of stroke, dementia, and death. Corneal confocal microscopy (CCM) can detect nerve injury non-invasively and may be a useful surrogate marker for WMH. The objective is to determine whether corneal nerve pathology identified using CCM is associated with the presence of WMH in patients with acute ischemic stroke., Methods: This is a cross-sectional study where 196 consecutive individuals with acute ischemic stroke were enrolled and underwent neurological examination, MRI brain imaging and CCM. Participants underwent blinded quantification of WMH and corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL)., Results: The prevalence of hypertension [P = .013] was significantly higher and CNFD [P = .031] was significantly lower in patients with WMH compared to those without WMH. CNFD and CNFL were significantly lower in patients with DM without WMH [P = .008, P = .019] and in patients with DM and WMH [P = .042, P = .024] compared to patients without DM or WMH, respectively. In a multivariate model, a 1-unit decrease in the CNFD increased the risk of WMH by 6%, after adjusting for age, DM, gender, dyslipidemia, metabolic syndrome, smoking, and HbA1c. DM was associated with a decrease in all CCM parameters but was not a significant independent factor associated with WMH., Conclusions: CCM demonstrates corneal nerve pathology, which is associated with the presence of WMH in participants with acute ischemic stroke. CCM may be a useful surrogate imaging marker for the presence and severity of WMHs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Visual rating of medial temporal lobe atrophy (MTA) is an accepted structural neuroimaging marker of Alzheimer's disease. Corneal confocal microscopy (CCM) is a non-invasive ophthalmic technique that detects neuronal loss in peripheral and central neurodegenerative disorders., Objective: To determine the diagnostic accuracy of CCM for mild cognitive impairment (MCI) and dementia compared to medial temporal lobe atrophy (MTA) rating on MRI., Methods: Subjects aged 60-85 with no cognitive impairment (NCI), MCI, and dementia based on the ICD-10 criteria were recruited. Subjects underwent cognitive screening, CCM, and MTA rating on MRI., Results: 182 subjects with NCI (n = 36), MCI (n = 80), and dementia (n = 66), including AD (n = 19, 28.8%), VaD (n = 13, 19.7%), and mixed AD (n = 34, 51.5%) were studied. CCM showed a progressive reduction in corneal nerve fiber density (CNFD, fibers/mm2) (32.0±7.5 versus 24.5±9.6 and 20.8±9.3, p < 0.0001), branch density (CNBD, branches/mm2) (90.9±46.5 versus 59.3±35.7 and 53.9±38.7, p < 0.0001), and fiber length (CNFL, mm/mm2) (22.9±6.1 versus 17.2±6.5 and 15.8±7.4, p < 0.0001) in subjects with MCI and dementia compared to NCI. The area under the ROC curve (95% CI) for the diagnostic accuracy of CNFD, CNBD, CNFL compared to MTA-right and MTA-left for MCI was 78% (67-90%), 82% (72-92%), 86% (77-95%) versus 53% (36-69%) and 40% (25-55%), respectively, and for dementia it was 85% (76-94%), 84% (75-93%), 85% (76-94%) versus 86% (76-96%) and 82% (72-92%), respectively., Conclusion: The diagnostic accuracy of CCM, a non-invasive ophthalmic biomarker of neurodegeneration, was high and comparable with MTA rating for dementia but was superior to MTA rating for MCI.

Background: Diabetic peripheral neuropathy (DPN) can lead to foot ulceration and amputation. There are currently no disease-modifying therapies for DPN. The aim of this study was to determine if hypertension contributes to DPN in patients with type 1 diabetes mellitus (T1DM)., Methods: Subjects with T1DM (n = 70) and controls (n = 78) underwent a comprehensive assessment of DPN., Results: Hypertension was present in 40 of 70 T1DM subjects and 20 of 78 controls. Hypertension was associated with abnormal nerve conduction parameters (P = 0.03 to <0.001), increased vibration perception threshold (P = 0.01) and reduced corneal nerve fiber density and length (P = 0.02) in subjects with T1DM. However, after adjusting for confounding factors only tibial compound motor action potential and nerve conduction velocity were associated with hypertension (P = 0.03) and systolic blood pressure (P < 0.01 to <0.0001). Hypertension had no effect on neuropathy in subjects without diabetes., Conclusions: This study shows that hypertension is associated with impaired nerve conduction in T1DM. It supports previous small trials showing that angiotensin-converting enzyme inhibitors improve nerve conduction and advocates the need for larger clinical trials with blood pressure lowering agents in DPN., (© The Author(s) 2019. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)

Objective: To determine if corneal confocal microscopy can identify corneal nerve and endothelial cell abnormalities and may be useful in the prognostication of patients with transient ischemic attack [1] or minor ischemic stroke (IS)., Methods: Thirty-six patients admitted with TIA (n = 14) or minor IS (n = 22) underwent transcranial Doppler evaluation and corneal confocal microscopy and were compared with 18 healthy controls., Results: Corneal nerve fiber density (P = 0.002), branch density (P = 0.004) and fiber length (P = 0.004) were significantly lower in patients with TIA or minor IS compared to controls, with no difference between patients with TIA and minor IS. Endothelial cell density (P = 0.003) was lower and endothelial cell area (P = 0.003) and perimeter (P = 0.006) were significantly higher in patients with TIA or minor IS compared to controls, with no difference between patients with TIA and minor IS. There were no differences in corneal nerve or endothelial cell morphology between patients with and without abnormal cerebrovascular reactivity. HbA1c was independently associated with CNFL, and endothelial cell polymegathism and pleomorphism were associated with both HbA1c and total cholesterol., Conclusion: Corneal confocal microscopy identifies corneal nerve fiber loss and endothelial cell abnormalities in patients with TIA and minor IS and independent associations with HbA1c and cholesterol., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Corneal confocal microscopy (CCM) is a noninvasive ophthalmic technique that identifies corneal nerve degeneration in a range of peripheral neuropathies and in patients with multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. We sought to determine whether there is any association of corneal nerve fiber measures with cognitive function and functional independence in patients with MCI and dementia., Methods: In this study, 76 nondiabetic participants with MCI ( n  = 30), dementia ( n  = 26), and healthy age-matched controls ( n  = 20) underwent assessment of cognitive and physical function and CCM., Results: There was a progressive reduction in corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) ( P  < 0.0001) in patients with MCI and dementia compared to healthy controls. Adjusted for confounders, all three corneal nerve fiber measures were significantly associated with cognitive function ( P  < 0.05) and functional independence ( P  < 0.01) in MCI and dementia. The area under the ROC curve to distinguish MCI with CNFD, CNBD, and CNFL was 69.1%, 73.2%, and 73.0% and for dementia it was 84.8%, 84.2%, and 86.2%, respectively., Interpretation: CCM demonstrates corneal nerve fiber loss, which is associated with a decline in cognitive function and functional independence in patients with MCI and dementia., Competing Interests: We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship and are not listed. We confirm that the order of authors listed in the manuscript has been approved by all authors. None of the authors have received or anticipate receiving income, goods or benefit from a company that will influence the design, conduct, or reporting of the study.

Endothelial dysfunction and damage underlie cerebrovascular disease and ischemic stroke. We undertook corneal confocal microscopy (CCM) to quantify corneal endothelial cell and nerve morphology in 146 patients with an acute ischemic stroke and 18 age-matched healthy control participants. Corneal endothelial cell density was lower (P < 0.001) and endothelial cell area (P < 0.001) and perimeter (P < 0.001) were higher, whilst corneal nerve fibre density (P < 0.001), corneal nerve branch density (P < 0.001) and corneal nerve fibre length (P = 0.001) were lower in patients with acute ischemic stroke compared to controls. Corneal endothelial cell density, cell area and cell perimeter correlated with corneal nerve fiber density (P = 0.033, P = 0.014, P = 0.011) and length (P = 0.017, P = 0.013, P = 0.008), respectively. Multiple linear regression analysis showed a significant independent association between corneal endothelial cell density, area and perimeter with acute ischemic stroke and triglycerides. CCM is a rapid non-invasive ophthalmic imaging technique, which could be used to identify patients at risk of acute ischemic stroke.

Purpose: Patients with diabetes have a propensity to develop dry eye symptoms (DES), with reduced tear secretion and corneal sensitivity. The underlying pathologic basis of DES was explored in patients with Type 1 diabetes., Methods: Forty-two patients with Type 1 diabetes mellitus (T1DM) (age: 49.21 ± 2.53 years, duration of diabetes: 29.98 ± 2.64 years) and 25 control subjects (age: 48.70 ± 2.84 years) underwent assessment of DES using a validated dry eye questionnaire, and tear stability and tear production were assessed using tear breakup time (TBUT) and Schirmer's test, respectively. Corneal confocal microscopy was undertaken to quantify corneal nerve fiber density (CNFD), branch density (CNBD), fiber length (CNFL), keratocyte density (KD), and corneal epithelial basal cell (CEBC) density and area., Results: The prevalence of DES was significantly higher (P = 0.03), and TBUT (P = 0.006), corneal sensation (P < 0.0001), CNFD (P = 0.001), CNBD (P = 0.001), CNFL (P = 0.003), and KD (P = 0.04) were significantly lower in patients with T1DM compared to control subjects. However, these measures did not differ significantly between T1DM patients with and without dry eye. There was no correlation between DES and TBUT or corneal nerve keratocyte and CEBC morphology., Conclusions: DES and TBUT are significantly increased in patients with T1DM, but are not related to corneal nerve, basal epithelial, or keratocyte cell morphology.

Aims/introduction: The aim of the present study was to identify the extent of small fiber neuropathy in diabetic patients with Charcot neuroarthropathy (CN)., Materials and Methods: A total of 20 patients with CN were compared with 20 age- and diabetes duration-matched patients with type 2 diabetes and 20 age-matched control participants. All patients underwent corneal confocal microscopy with quantification of corneal nerve morphology and assessment for vibration perception threshold, and a subset of patients with CN underwent assessment of sudomotor function and neuropathic pain., Results: In patients with CN compared with type 2 diabetes patients and control participants, there was a significant reduction in corneal nerve fiber density (14.94 ± 8.23 vs 23.86 ± 7.71, P = 0.004 vs 34.84 ± 9.13, P < 0.001), corneal nerve branch density (18.61 ± 16.7 vs 41.62 ± 22.67, P = 0.032 vs 76.47 ± 38.44, P < 0.001) and corneal nerve fiber length (8.40 ± 4.83 vs 14.87 ± 4.76, P = 0.001 vs 21.24 ± 6.48, P < 0.001), electrochemical skin conductance on the feet (20.57 ± 13.99 vs 61.50 ± 22.26, P < 0.001 vs 76.23 ± 12.01, P < 0.001) and hands (30.86 ± 18.10 vs 61.13 ± 19.14, P = 0.001 vs 68.31 ± 11.96, P < 0.001), and a significant increase in the vibration perception threshold in the feet (38.46 ± 15.10 vs 14.15 ± 10.25, P < 0.001 vs 7.75 ± 4.01, P < 0.001)., Conclusions: Patients with diabetes and CN have severe large and particularly small fiber neuropathy., (© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Objective: Corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, is a noninvasive and objective imaging biomarker for identifying small nerve fiber damage. We have evaluated the diagnostic performance of previously established CCM parameters to a novel automated measure of corneal nerve complexity called the corneal nerve fiber fractal dimension (ACNFrD)., Methods: A total of 176 subjects (84 controls and 92 patients with type 1 diabetes) with and without diabetic sensorimotor polyneuropathy (DSPN) underwent CCM. Fractal dimension analysis was performed on CCM images using purpose-built corneal nerve analysis software, and compared with previously established manual and automated corneal nerve fiber measurements., Results: Manual and automated subbasal corneal nerve fiber density (CNFD) (P < 0.0001), length (CNFL) (P < 0.0001), branch density (CNBD) (P < 0.05), and ACNFrD (P < 0.0001) were significantly reduced in patients with DSPN compared to patients without DSPN. The areas under the receiver operating characteristic curves for identifying DSPN were comparable: 0.77 for automated CNFD, 0.74 for automated CNFL, 0.69 for automated CNBD, and 0.74 for automated ACNFrD., Conclusions: ACNFrD shows comparable diagnostic efficiency to identify diabetic patients with and without DSPN.

Background and Purpose: Corneal confocal microscopy can identify corneal nerve damage in patients with peripheral and central neurodegeneration. However, the use of corneal confocal microscopy in patients presenting with acute ischemic stroke is unknown., Methods: One hundred thirty patients (57 without diabetes mellitus [normal glucose tolerance], 32 with impaired glucose tolerance, and 41 with type 2 diabetes mellitus) admitted with acute ischemic stroke, and 28 age-matched healthy control participants underwent corneal confocal microscopy to quantify corneal nerve fiber density, corneal nerve branch density, and corneal nerve fiber length., Results: There was a significant reduction in corneal nerve fiber density, corneal nerve branch density, and corneal nerve fiber length in stroke patients with normal glucose tolerance ( P <0.001, P <0.001, P <0.001), impaired glucose tolerance ( P =0.004, P <0.001, P =0.002), and type 2 diabetes mellitus ( P <0.001, P <0.001, P <0.001) compared with controls. HbA1c and triglycerides correlated with corneal nerve fiber density ( r =-0.187, P =0.03; r =-0.229 P =0.01), corneal nerve fiber length ( r =-0.228, P =0.009; r =-0.285; P =0.001), and corneal nerve branch density ( r =-0.187, P =0.033; r =-0.229, P =0.01). Multiple linear regression showed no independent associations between corneal nerve fiber density, corneal nerve branch density, and corneal nerve fiber length and relevant risk factors for stroke., Conclusions: Corneal confocal microscopy is a rapid noninvasive ophthalmic imaging technique that identifies corneal nerve fiber loss in patients with acute ischemic stroke., (© 2017 American Heart Association, Inc.)

Objectives: Corneal 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., Methods: In 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)., Results: Subjects 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., Conclusions: CCM is a valid accurate non-invasive method to identify small nerve fibre pathology and is able to diagnose DPN.

Purpose: To evaluate whether corneal confocal microscopy (CCM) detects axonal degeneration and whether this is associated with retinal nerve fiber degeneration and clinical disability in patients with multiple sclerosis (MS)., Methods: Twenty-five patients with MS and 25 healthy control subjects underwent CCM, optical coherence tomography (OCT), and assessment of neurological disability using the expanded disability status scale (EDSS) and MS severity score (MSSS)., Results: In patients with MS compared with controls, there was a significant reduction in corneal nerve fiber density (CNFD), branch density (CNBD), and length (CNFL). There was no significant difference in CCM parameters between patients with optic neuritis (MS-ON) and without (MS-NON), or between relapsing-remitting (RRMS) and secondary-progressive MS (SPMS). There was significant thinning of the retinal nerve fiber layer (RNFL) in the global, temporal, temporal superior, and temporal inferior quadrants, with no difference between MS-ON and MS-NON. Patients with SPMS compared with RRMS had a significantly lower global, temporal superior, temporal inferior, nasal, and nasal superior RNFL. The EDSS and MSSS correlated significantly with CNBD, nasal, nasal superior, and nasal inferior RNFL and with CNBD and nasal inferior RNFL, respectively., Conclusions: CCM and OCT detect significant corneal and retinal nerve degeneration which relates to the severity of neurological deficits in patients with mild MS.

Unlabelled: Autonomic and somatic denervation is well established in Parkinson's disease (PD)., Objectives: (1) To determine whether corneal confocal microscopy (CCM) can non-invasively demonstrate small nerve fiber damage in PD. (2) To identify relationships between corneal nerve parameters, intraepidermal nerve fiber density (IENFD) and clinical features of PD., Methods: Twenty-six PD patients and 26 controls underwent CCM of both eyes. 24/26 PD patients and 10/26 controls underwent skin biopsies from the dorsa of both feet. PD patients underwent assessment of parasympathetic function [deep breathing heart rate variability (DB-HRV)], autonomic symptoms [scale for outcomes in Parkinson's disease - autonomic symptoms (SCOPA-AUT)], motor symptoms [UPDRS-III "ON"] and cumulative Levodopa dose., Results: PD patients had significantly reduced corneal nerve fiber density (CNFD) with increased corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL) compared to controls. CNBD and CNFL but not CNFD correlated inversely with UPDRS-III and SCOPA-AUT. All CCM parameters correlated strongly with DB-HRV. There was no correlation between CCM parameters and disease duration, cumulative Levodopa dose or pain. IENFD was significantly reduced in PD compared to controls and correlated with CNFD and UPDRS-III. However, unlike CCM measures, IENFD correlated with disease duration and cumulative Levodopa dose but not with autonomic dysfunction., Conclusion: CCM identifies corneal nerve fiber pathology, which correlates with autonomic symptoms, parasympathetic deficits and motor scores in patients with PD. IENFD is also reduced and correlates with CNFD and motor symptoms but not parasympathetic deficits, indicating it detects different aspects of peripheral nerve pathology in PD., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There are multiple neurological complications of cancer and its treatment. This study assessed the utility of the novel non-invasive ophthalmic technique of corneal confocal microscopy in identifying neuropathy in patients with upper gastrointestinal cancer before and after platinum based chemotherapy. In this study, 21 subjects with upper gastrointestinal (oesophageal or gastric) cancer and 21 healthy control subjects underwent assessment of neuropathy using the neuropathy disability score, quantitative sensory testing for vibration perception threshold, warm and cold sensation thresholds, cold and heat induced pain thresholds, nerve conduction studies and corneal confocal microscopy. Patients with gastro-oesophageal cancer had higher heat induced pain (P = 0.04) and warm sensation (P = 0.03) thresholds with a significantly reduced sural sensory (P<0.01) and peroneal motor (P<0.01) nerve conduction velocity, corneal nerve fibre density (CNFD), nerve branch density (CNBD) and nerve fibre length (CNFL) (P<0.0001). Furthermore, CNFD correlated significantly with the time from presentation with symptoms to commencing chemotherapy (r = -0.54, P = 0.02), and CNFL (r = -0.8, P<0.0001) and CNBD (r = 0.63, P = 0.003) were related to the severity of lymph node involvement. After the 3rd cycle of chemotherapy, there was no change in any measure of neuropathy, except for a significant increase in CNFL (P = 0.003). Corneal confocal microscopy detects a small fibre neuropathy in this cohort of patients with upper gastrointestinal cancer, which was related to disease severity. Furthermore, the increase in CNFL after the chemotherapy may indicate nerve regeneration.

Objective: Impaired 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 Methods: Thirty 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., Results: Ten 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., Conclusions: CCM 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., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Purpose: In vivo corneal confocal microscopy (CCM) is increasingly used as a surrogate endpoint in studies of diabetic polyneuropathy (DPN). However, it is not clear whether imaging the central cornea provides optimal diagnostic utility for DPN. Therefore, we compared nerve morphology in the central cornea and the inferior whorl, a more distal and densely innervated area located inferior and nasal to the central cornea., Methods: A total of 53 subjects with type 1/type 2 diabetes and 15 age-matched control subjects underwent detailed assessment of neuropathic symptoms (NPS), deficits (neuropathy disability score [NDS]), quantitative sensory testing (vibration perception threshold [VPT], cold and warm threshold [CT/WT], and cold- and heat-induced pain [CIP/HIP]), and electrophysiology (sural and peroneal nerve conduction velocity [SSNCV/PMNCV], and sural and peroneal nerve amplitude [SSNA/PMNA]) to diagnose patients with (DPN+) and without (DPN-) neuropathy. Corneal nerve fiber density (CNFD) and length (CNFL) in the central cornea, and inferior whorl length (IWL) were quantified., Results: Comparing control subjects to DPN- and DPN+ patients, there was a significant increase in NDS (0 vs. 2.6 ± 2.3 vs. 3.3 ± 2.7, P < 0.01), VPT (V; 5.4 ± 3.0 vs. 10.6 ± 10.3 vs. 17.7 ± 11.8, P < 0.01), WT (°C; 37.7 ± 3.5 vs. 39.1 ± 5.1 vs. 41.7 ± 4.7, P < 0.05), and a significant decrease in SSNCV (m/s; 50.2 ± 5.4 vs. 48.4 ± 5.0 vs. 39.5 ± 10.6, P < 0.05), CNFD (fibers/mm2; 37.8 ± 4.9 vs. 29.7 ± 7.7 vs. 27.1 ± 9.9, P < 0.01), CNFL (mm/mm2; 27.5 ± 3.6 vs. 24.4 ± 7.8 vs. 20.7 ± 7.1, P < 0.01), and IWL (mm/mm2; 35.1 ± 6.5 vs. 26.2 ± 10.5 vs. 23.6 ± 11.4, P < 0.05). For the diagnosis of DPN, CNFD, CNFL, and IWL achieved an area under the curve (AUC) of 0.75, 0.74, and 0.70, respectively, and a combination of IWL-CNFD achieved an AUC of 0.76., Conclusions: The parameters of CNFD, CNFL, and IWL have a comparable ability to diagnose patients with DPN. However, IWL detects an abnormality even in patients without DPN. Combining IWL with CNFD may improve the diagnostic performance of CCM.

Objective: Impaired glucose tolerance (IGT) represents one of the earliest stages of glucose dysregulation and is associated with macrovascular disease, retinopathy, and microalbuminuria, but whether IGT causes neuropathy is unclear., Research Design and Methods: Thirty-seven subjects with IGT and 20 age-matched control subjects underwent a comprehensive evaluation of neuropathy by assessing symptoms, neurological deficits, nerve conduction studies, quantitative sensory testing, heart rate variability deep breathing (HRVdb), skin biopsy, and corneal confocal microscopy (CCM)., Results: Subjects with IGT had a significantly increased neuropathy symptom profile (P < 0.001), McGill pain index (P < 0.001), neuropathy disability score (P = 0.001), vibration perception threshold (P = 0.002), warm threshold (P = 0.006), and cool threshold (P = 0.03), with a reduction in intraepidermal nerve fiber density (P = 0.03), corneal nerve fiber density (P < 0.001), corneal nerve branch density (P = 0.002), and corneal nerve fiber length (P = 0.05). No significant difference was found in sensory and motor nerve amplitude and conduction velocity or HRVdb., Conclusions: Subjects with IGT have evidence of neuropathy, particularly small-fiber damage, which can be detected using skin biopsy and CCM., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Aims: Corneal nerve morphology and corneal sensation threshold have recently been explored as potential surrogate markers for the evaluation of diabetic neuropathy. We present the baseline findings of the 'Longitudinal Assessment of Neuropathy in type 1 Diabetes using novel ophthalmic Markers'(LANDMark) study., Methods: The LANDMark study is a 4-year, two-site, natural history study of three participant groups: type 1 diabetes with neuropathy (T1W), type 1 diabetes without neuropathy (T1WO) and control participants without diabetes or neuropathy. All participants undergo a detailed annual assessment of neuropathy including corneal nerve parameters measured using corneal confocal microscopy and corneal sensitivity measured using non-contact corneal aesthesiometry., Results: 76 T1W, 166 T1WO and 154 control participants were enrolled into the study. Corneal sensation threshold was significantly higher (i.e., sensitivity was lower) in T1W (1.0±1.1mbars) than T1WO (0.7±0.7mbars) and controls (0.6±0.4mbars) (p<0.001), with no difference between T1WO and controls. Corneal nerve fibre length was lower in T1W (14.0±6.4mm/mm(2)) compared to T1WO (19.1±5.8mm/mm(2)) and controls (23.2±6.3mm/mm(2)) (p<0.001). Corneal nerve fibre length was lower in T1WO compared to controls., Conclusions: The LANDMark baseline findings confirm a reduction in corneal sensitivity only in Type 1 patients with neuropathy. However, corneal nerve fibre length is reduced in Type 1 patients without neuropathy with an even greater deficit in Type 1 patients with neuropathy., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To assess the diagnostic validity of a fully automated image analysis algorithm of in vivo confocal microscopy images in quantifying corneal subbasal nerves to diagnose diabetic neuropathy., Methods: One hundred eighty-six patients with type 1 and type 2 diabetes mellitus (T1/T2DM) and 55 age-matched controls underwent assessment of neuropathy and bilateral in vivo corneal confocal microscopy (IVCCM). Corneal nerve fiber density (CNFD), branch density (CNBD), and length (CNFL) were quantified with expert, manual, and fully-automated analysis. The areas under the curve (AUC), odds ratios (OR), and optimal thresholds to rule out neuropathy were estimated for both analysis methods., Results: Neuropathy was detected in 53% of patients with diabetes. A significant reduction in manual and automated CNBD (P < 0.001) and CNFD (P < 0.0001), and CNFL (P < 0.0001) occurred with increasing neuropathic severity. Manual and automated analysis methods were highly correlated for CNFD (r = 0.9, P < 0.0001), CNFL (r = 0.89, P < 0.0001), and CNBD (r = 0.75, P < 0.0001). Manual CNFD and automated CNFL were associated with the highest AUC, sensitivity/specificity and OR to rule out neuropathy., Conclusions: Diabetic peripheral neuropathy is associated with significant corneal nerve loss detected with IVCCM. Fully automated corneal nerve quantification provides an objective and reproducible means to detect human diabetic neuropathy.

Objective: To establish if corneal nerve loss, detected using in vivo corneal confocal microscopy (IVCCM), is symmetrical between right and left eyes and relates to the severity of diabetic neuropathy., Research Design and Methods: Patients (n = 111) with type 1 and type 2 diabetes and 47 age-matched healthy control subjects underwent detailed assessment and stratification into no (n = 50), mild (n = 26), moderate (n = 17), and severe (n = 18) neuropathy. IVCCM was performed in both eyes and corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) and the tortuosity coefficient were quantified., Results: All corneal nerve parameters differed significantly between diabetic patients and control subjects and progressively worsened with increasing severity of neuropathy. The reduction in CNFD, CNBD, and CNFL was symmetrical in all groups except in patients with severe neuropathy., Conclusions: IVCCM noninvasively detects corneal nerve loss, which relates to the severity of neuropathy, and is symmetrical, except in those with severe diabetic neuropathy.

Purpose: To establish intraobserver and interobserver repeatability, agreement, and symmetry of corneal nerve fiber (NF) morphology in healthy subjects using in vivo corneal confocal microscopy., Methods: Nineteen subjects underwent in vivo corneal confocal microscopy (Heidelberg Retinal Tomograph III Rostock Cornea Module) at baseline and 7 days apart. Bland-Altman plots were generated to assess agreement, and the intraclass correlation coefficient and coefficient of repeatability were calculated to estimate intraobserver and interobserver repeatability for corneal NF density (numbers per square millimeter), nerve branch density (NBD; numbers per square millimeter), NF length (millimeters per square millimeter), and NF tortuosity coefficient. Symmetry between the right and left eyes was also assessed., Results: Intraclass correlation coefficient and coefficient of repeatability for intraobserver repeatability were 0.66 to 0.74 and 0.17 to 0.64, for interobserver repeatability 0.54 to 0.93 and 0.15 to 0.85, and for symmetry 0.34 to 0.77 and 0.17 to 0.63, respectively. NBD demonstrated low repeatability., Conclusions: This study demonstrates good repeatability for the manual assessment of all major corneal NF parameters with the exception of NBD, which highlights the difficulty in defining nerve branches and suggests the need for experienced observers or automated image analysis to ensure optimal repeatability.

Diabetic neuropathy is associated with increased morbidity and mortality. To date, limited data in subjects with impaired glucose tolerance and diabetes demonstrate nerve fiber repair after intervention. This may reflect a lack of efficacy of the interventions but may also reflect difficulty of the tests currently deployed to adequately assess nerve fiber repair, particularly in short-term studies. Corneal confocal microscopy (CCM) represents a novel noninvasive means to quantify nerve fiber damage and repair. Fifteen type 1 diabetic patients undergoing simultaneous pancreas-kidney transplantation (SPK) underwent detailed assessment of neurologic deficits, quantitative sensory testing (QST), electrophysiology, skin biopsy, corneal sensitivity, and CCM at baseline and at 6 and 12 months after successful SPK. At baseline, diabetic patients had a significant neuropathy compared with control subjects. After successful SPK there was no significant change in neurologic impairment, neurophysiology, QST, corneal sensitivity, and intraepidermal nerve fiber density (IENFD). However, CCM demonstrated significant improvements in corneal nerve fiber density, branch density, and length at 12 months. Normalization of glycemia after SPK shows no significant improvement in neuropathy assessed by the neurologic deficits, QST, electrophysiology, and IENFD. However, CCM shows a significant improvement in nerve morphology, providing a novel noninvasive means to establish early nerve repair that is missed by currently advocated assessment techniques.