Progression of axonal excitability abnormalities with increasing clinical severity of diabetic peripheral neuropathy.

OBJECTIVE: Diabetic peripheral neuropathy (DPN) is a frequent complication for persons with type 2 diabetes. Previous studies have failed to demonstrate any significant impact of treatment for DPN. The present study assessed the role of axonal ion channel dysfunction in DPN and explored the hypothesis that there may be a progressive change in ion channel abnormalities that varied with disease stage. METHODS: Neurophysiological studies were conducted using axonal excitability techniques, a clinical method of assessing ion channel dysfunction. Studies were conducted in 178 persons with type 2 diabetes, with participants allocated into four groups according to clinical severity of neuropathy, assessed using the Total Neuropathy Grade. RESULTS: Analysis of excitability data demonstrated a progressive and stepwise reduction in two parameters that are related to the activity of Kv1.1 channels, namely superexcitability and depolarizing threshold electrotonus at 10-20 ms (p < 0.001), and mathematical modelling of axonal excitability findings supported progressive upregulation of Kv1.1 conductances with increasing greater disease severity. CONCLUSION: The findings are consistent with a progressive upregulation of juxtaparanodal Kv1.1 conductances with increasing clinical severity of diabetic peripheral neuropathy. SIGNIFICANCE: From a translational perspective, the study suggests that blockade of Kv1.1 channels using 4-aminopyridine derivatives such as fampridine may be a potential treatment for DPN.

Glucagon-like peptide-1 receptor agonists reverse nerve morphological abnormalities in diabetic peripheral neuropathy.

AIMS/HYPOTHESIS: Diabetic peripheral neuropathy (DPN) is a highly prevalent cause of physical disability. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are used to treat type 2 diabetes and animal studies have shown that glucagon-like peptide-1 (GLP-1) receptors are present in the central and peripheral nervous systems. This study investigated whether GLP-1 RAs can improve nerve structure. METHODS: Nerve structure was assessed using peripheral nerve ultrasonography and measurement of tibial nerve cross-sectional area, in conjunction with validated neuropathy symptom scores and nerve conduction studies. A total of 22 consecutively recruited participants with type 2 diabetes were assessed before and 1 month after commencing GLP-1 RA therapy (semaglutide or dulaglutide). RESULTS: There was a pathological increase in nerve size before treatment in 81.8% of the cohort (n=22). At 1 month of follow-up, there was an improvement in nerve size in 86% of participants (p<0.05), with 32% returning to normal nerve morphology. A 3 month follow-up study (n=14) demonstrated further improvement in nerve size in 93% of participants, accompanied by reduced severity of neuropathy (p<0.05) and improved sural sensory nerve conduction amplitude (p<0.05). CONCLUSIONS/INTERPRETATION: This study demonstrates the efficacy of GLP-1 RAs in improving neuropathy outcomes, evidenced by improvements in mainly structural and morphological measures and supported by electrophysiological and clinical endpoints. Future studies, incorporating quantitative sensory testing and measurement of intraepidermal nerve fibre density, are needed to investigate the benefits for small fibre function and structure.

Impact of SGLT2 Inhibitors on Corneal Nerve Morphology and Dendritic Cell Density in Type 2 Diabetes.

PURPOSE: This study aims to determine the effects of SGLT2 inhibitors on corneal dendritic cell density and corneal nerve measures in type 2 diabetes. METHODS: Corneal dendritic cell densities and nerve parameters were measured in people with type 2 diabetes treated with SGLT2 inhibitors (T2DM-SGLT2i) [n = 23] and those not treated with SGLT2 inhibitors (T2DM-no SGLT2i) [n = 23], along with 24 age and sex-matched healthy controls. RESULTS: There was a reduction in all corneal nerve parameters in type 2 diabetes groups compared to healthy controls (All parameters: p < 0.05). No significant differences in corneal nerve parameters were observed between T2DM-SGLT2i and T2DM-no SGLT2i groups (All parameters: p > 0.05). Central corneal dendritic cells were significantly reduced [mature (p = 0.03), immature (p = 0.06) and total (p = 0.002)] in the T2DM-SGLT2i group compared to the T2DM-no SGLT2i group. Significantly, higher mature (p = 0.04), immature (p = 0.004), total (p = 0.002) dendritic cell densities in the T2DM-no SGLT2i group were observed compared to the healthy controls. In the inferior whorl, no significant difference in immature (p = 0.27) and total dendritic cell densities (p = 0.16) between T2DM-SGLT2i and T2DM-no SGLT2i were observed except mature dendritic cell density (p = 0.018). No differences in total dendritic cell density were observed in the central (p > 0.09) and inferior whorl (p = 0.88) between T2DM-SGLT2i and healthy controls. CONCLUSION: The present study showed a reduced dendritic cell density in people with type 2 diabetes taking SGLT2 inhibitors compared to those not taking these medications.

Chronic Kidney Disease Has No Impact on Tear Film Substance P Concentration in Type 2 Diabetes.

PURPOSE: The study aimed to ascertain the potential effects of chronic kidney disease (CKD) on substance P concentration in the tear film of people with type 2 diabetes. METHODS: Participants were classified into two groups: type 2 diabetes with concurrent chronic kidney disease (T2DM-CKD (n = 25)) and type 2 diabetes without chronic kidney disease (T2DM-no CKD (n = 25)). Ocular surface discomfort assessment, flush tear collection, in-vivo corneal confocal microscopy, and peripheral neuropathy assessment were conducted. Enzyme-linked immunosorbent assays were utilized to ascertain the levels of tear film substance P in collected flush tears. Correlation analysis, hierarchical multiple linear regression analysis, and t-tests or Mann-Whitney U tests were used in the analysis of data for two-group comparisons. RESULTS: There was no substantial difference between the T2DM-CKD and T2DM-no CKD groups for tear film substance P concentration (4.4 (0.2-50.4) and 5.9 (0.2-47.2) ng/mL, respectively; p = 0.54). No difference was observed in tear film substance P concentration between the low-severity peripheral neuropathy and high-severity peripheral neuropathy groups (4.4 (0.2-50.4) and 3.3 (0.3-40.7) ng/mL, respectively; p = 0.80). Corneal nerve fiber length (9.8 ± 4.6 and 12.4 ± 3.8 mm/mm2, respectively; p = 0.04) and corneal nerve fiber density (14.7 ± 8.5 and 21.1 ± 7.0 no/mm2, respectively; p < 0.01) were reduced significantly in the T2DM-CKD group compared to the T2DM-no CKD group. There were significant differences in corneal nerve fiber density (21.0 ± 8.1 and 15.8 ± 7.7 no/mm2, respectively; p = 0.04) and corneal nerve fiber length (12.9 ± 4.2 and 9.7 ± 3.8 mm/mm2, respectively; p = 0.03) between the low- and high-severity peripheral neuropathy groups. CONCLUSION: In conclusion, no significant difference in tear film substance P concentration was observed between type 2 diabetes with and without CKD. Corneal nerve loss, however, was more significant in type 2 diabetes with chronic kidney disease compared to type 2 diabetes alone, indicating that corneal nerve morphological measures could serve greater utility as a tool to detect neuropathy and nephropathy-related corneal nerve changes.

Conjunctival microcirculation in ocular and systemic microvascular disease.

The conjunctival microcirculation is an accessible complex network of micro vessels whose quantitative assessment can reveal microvascular haemodynamic properties. Currently, algorithms for the measurement of conjunctival haemodynamics use either manual or semi-automated systems, which may provide insight into overall conjunctival health, as well as in ocular and systemic disease. These algorithms include functional slit-lamp biomicroscopy, laser doppler flowmetry, optical coherence tomography angiography, orthogonal polarized spectral imaging, computer-assisted intravitral microscopy, diffuse reflectance spectroscopy and corneal confocal microscopy. Furthermore, several studies have demonstrated a relationship between conjunctival microcirculatory haemodynamics and many diseases such as dry eye disease, Alzheimer's disease, diabetes, hypertension, sepsis, coronary microvascular disease, and sickle cell anaemia. This review aims to describe conjunctival microcirculation, its characteristics, and techniques for its measurement, as well as the association between conjunctival microcirculation and microvascular abnormalities in disease states.

The effectiveness of activity pacing interventions for people with chronic fatigue syndrome: a systematic review and meta-analysis.

PURPOSE: To investigate whether activity pacing interventions (alone or in conjunction with other evidence-based interventions) improve fatigue, physical function, psychological distress, depression, and anxiety in people with chronic fatigue syndrome (CFS). MATERIALS AND METHODS: Seven databases were searched until 13 August 2022 for randomised controlled trials that included activity pacing interventions for CFS and a validated measure of fatigue. Secondary outcomes were physical function, psychological distress, depression, and anxiety. Two reviewers independently screened studies by title, abstract and full text. Methodological quality was evaluated using the PEDro scale. Random-effects meta-analyses were performed in R. RESULTS: 6390 articles were screened, with 14 included. Good overall study quality was supported by PEDro scale ratings. Activity pacing interventions were effective (Hedges' g (95% CI)) at reducing fatigue (-0.52 (-0.73 to -0.32)), psychological distress (-0.37 (-0.51 to -0.24)) and depression (-0.29 (-0.49 to -0.09)) and improving physical function (mean difference 7.18 (3.17-11.18)) when compared to no treatment/usual care. The extent of improvement was greater for interventions that encouraged graded escalation of physical activities and cognitive activities. CONCLUSION: Activity pacing interventions are effective in reducing fatigue and psychological distress and improving physical function in CFS, particularly when people are encouraged to gradually increase activities. REGISTRATION: PROSPERO CRD42016036087. IMPLICATIONS FOR REHABILITATIONA key feature of chronic fatigue syndrome (CFS) is a prolonged post-exertional exacerbation of symptoms following physical activities or cognitive activities.Activity pacing is a common strategy often embedded in multi-component management programs for CFS.Activity pacing interventions are effective in reducing fatigue and psychological distress and improving physical function in CFS, particularly when patients are encouraged to gradually increase their activities.Healthcare professionals embedding activity pacing as part of treatment should work collaboratively with patients to ensure successful, individualised self-management strategies.

Impact of Peripheral and Corneal Neuropathy on Markers of Ocular Surface Discomfort in Diabetic Chronic Kidney Disease.

SIGNIFICANCE: There is a reduction in corneal nerve fiber density and length in type 2 diabetes mellitus with chronic kidney disease compared with type 2 diabetes mellitus alone; however, this difference does not result in worse ocular surface discomfort or dry eye disease. PURPOSE: This study aimed to determine the clinical impact of corneal nerve loss on ocular surface discomfort and markers of ocular surface homeostasis in people with type 2 diabetes mellitus without chronic kidney disease (T2DM-no CKD) and those with type 2 diabetes mellitus with concurrent chronic kidney disease (T2DM-CKD). METHODS: Participants were classified based on estimated glomerular filtration rates into two groups: T2DM-CKD (n = 27) and T2DM-no CKD (n = 28). RESULTS: There was a significant difference between the T2DM-CKD and T2DM-no CKD groups in corneal nerve fiber density (14.9 ± 8.6 and 21.1 ± 7.1 no./mm 2 , respectively; P = .005) and corneal nerve fiber length (10.0 ± 4.6 and 12.3 ± 3.7 mm/mm 2 , respectively; P = .04). Fluorescein tear breakup time was significantly reduced in T2DM-CKD compared with T2DM-no CKD (8.1 ± 4.4 and 10.7 ± 3.8 seconds, respectively; P = .01), whereas ocular surface staining was not significantly different (3.5 ± 1.7 and 2.7 ± 2.3 scores, respectively; P = .12). In terms of ocular surface discomfort, there were no significant differences in the ocular discomfort score scores (12.5 ± 11.1 and 13.6 ± 12.1, respectively; P = .81) and Ocular Pain Assessment Survey scores (3.3 ± 5.4 and 4.3 ± 6.1, respectively; P = .37) between the T2DM-CKD and T2DM-no CKD. CONCLUSIONS: The current study demonstrated that corneal nerve loss is greater in T2DM-CKD than in T2DM-no CKD. However, these changes do not impact ocular surface discomfort or markers of ocular surface homeostasis.

Diagnostic accuracy of nerve ultrasonography for the detection of peripheral neuropathy in type 2 diabetes.

BACKGROUND AND PURPOSE: Nerve conduction studies (NCS) are the current objective measure for diagnosis of peripheral neuropathy in type 2 diabetes but do not assess nerve structure. This study investigated the utility of peripheral nerve ultrasound as a marker of the presence and severity of peripheral neuropathy in type 2 diabetes. METHODS: A total of 156 patients were recruited, and nerve ultrasound was undertaken on distal tibial and distal median nerves. Neuropathy severity was graded using the modified Toronto Clinical Neuropathy Scale (mTCNS) and Total Neuropathy Score (TNS). Studies were undertaken by a single ultrasonographer blinded to nerve conduction results. RESULTS: A stepwise increase in tibial nerve cross-sectional area (CSA) was noted with increasing TNS grade (p < 0.001) and each mTCNS quartile (p < 0.001). Regression analysis demonstrated a correlation between tibial nerve CSA and neuropathy severity (p < 0.001). Using receiver operator curve analysis, tibial nerve CSA of >12.88 mm yielded a sensitivity of 70.5% and specificity of 85.7% for neuropathy detection. Binary logistic regression revealed that tibial nerve CSA was a predictor of abnormal sural sensory nerve action potential amplitude (odds ratio = 1.239, 95% confidence interval [CI] = 1.142-1.345) and abnormal neuropathy score (odds ratio = 1.537, 95% confidence interval [CI] = 1.286-1.838). CONCLUSIONS: Tibial nerve ultrasound has good specificity and sensitivity for neuropathy diagnosis in type 2 diabetes. The study demonstrates that tibial nerve CSA correlates with neuropathy severity. Future serial studies using both ultrasound and NCS may be useful in determining whether changes in ultrasound occur prior to development of nerve conduction abnormalities and neuropathic symptoms.

Tear film and ocular surface neuropeptides: Characteristics, synthesis, signaling and implications for ocular surface and systemic diseases.

Ocular surface neuropeptides are vital molecules primarily involved in maintaining ocular surface integrity and homeostasis. They also serve as communication channels between the nervous system and the immune system, maintaining the homeostasis of the ocular surface. Tear film and ocular surface neuropeptides have a role in disease often due to abnormalities in their synthesis (either high or low production), signaling through defective receptors, or both. This creates imbalances in otherwise normal physiological processes. They have been observed to be altered in many ocular surface and systemic diseases including dry eye disease, ocular allergy, keratoconus, LASIK-induced dry eye, pterygium, neurotrophic keratitis, corneal graft rejection, microbial keratitis, headaches and diabetes. This review examines the characteristics of neuropeptides, their synthesis and their signaling through G-protein coupled receptors. The review also explores the types of neuropeptides within the tears and ocular surface, and how they change in ocular and systemic diseases.

Peripheral neuropathy: an important contributor to physical limitation and morbidity in stages 3 and 4 chronic kidney disease.

BACKGROUND: Impaired physical function drives adverse outcomes in chronic kidney disease (CKD). Peripheral neuropathy is highly prevalent in CKD, though its contribution to physical function in CKD patients is unknown. This study examined the relationships between peripheral neuropathy, walking speed and quality of life (QoL) in stages 3 and 4 CKD. METHODS: This was a prospective observational study investigating neuropathy in CKD patients with an estimated glomerular filtration rate (eGFR) 15-60 mL/min/1.73 m2. A total of 109 patients were consecutively recruited. The presence and severity of peripheral neuropathy was determined using the total neuropathy score. Walking speed was assessed at both usual and maximal speed, and QoL was assessed using the Short- Form 36 (SF-36) questionnaire. RESULTS: Peripheral neuropathy was highly prevalent: 40% demonstrated mild neuropathy and 37% had moderate-severe neuropathy. Increasing neuropathy severity was the primary predictor of reduced walking speed (R2 = -0.41, P < 0.001) and remained so after multivariable analysis adjustment for diabetes. This association was evident for both usual and maximal walking speeds. Neuropathy correlated significantly with low scores on multiple domains of SF-36 including physical function (r = -0.570, P < 0.001). Subanalysis according to diabetic status revealed a high prevalence of neuropathy both with and without diabetes; relationships to walking speed remained evident in subgroup analysis. However, those with diabetes demonstrated greater severity of neuropathy, slower walking speed and lower scores in QoL. CONCLUSIONS: Moderate to severe peripheral neuropathy was common in stages 3 and 4 CKD, associated with reduced walking speed independent of diabetes status and was correlated with patient-reported QoL. This suggests that neuropathy is an important contributor to declining physical function in CKD irrespective of diabetes status. Targeted diagnosis and management of peripheral neuropathy during CKD progression may improve functional outcomes and QoL.

Effect of a Fundamental Motor Skills Intervention on Fundamental Motor Skill and Physical Activity in a Preschool Setting: A Cluster Randomized Controlled Trial.

PURPOSE: To determine the effect of a 12-week fundamental motor skill (FMS) program on FMS and physical activity (PA) on preschool-aged children. METHOD: A cluster randomized controlled trial. The intervention (PhysicaL ActivitY and Fundamental Motor Skills in Pre-schoolers [PLAYFun] Program) was a 12-week games-based program, delivered directly to the children in childcare centers by exercise physiologists. Children in the control arm received the usual preschool curriculum. Outcomes included FMS competence (Test of Gross Motor Development-2) and PA (accelerometer) assessed at baseline, 12 weeks, and 24 weeks (12-wk postintervention). RESULTS: Fifty children (mean age = 4.0 [0.6] y; 54% male) were recruited from 4 childcare centers. Two centers were randomized to PLAYFun and 2 centers were randomized to the waitlist control group. Children attended on average 2.0 (1.0) 40-minute sessions per week. The PLAYFun participants demonstrated significant increases in object control (P < .001) and total FMS (P = .010) competence at week 12, compared with controls in a group × time interaction. Girls, but not boys, in PLAYFun significantly increased moderate to vigorous PA after the intervention (P = .004). These increases were not maintained 12-week postcompletion of PLAYFun. CONCLUSIONS: The PLAYFun Program is effective at improving FMS competence in boys and girls and increasing PA in girls. However, improvements are not maintained when opportunities to practice are not sustained.

Impact of Chronic Kidney Disease on Corneal Neuroimmune Features in Type 2 Diabetes.

Aim: To determine the impact of chronic kidney disease on corneal nerve measures and dendritic cell counts in type 2 diabetes. Methods: In vivo corneal confocal microscopy images were used to estimate corneal nerve parameters and compared in people with type 2 diabetes with chronic kidney disease (T2DM-CKD) (n = 29) and those with type 2 diabetes without chronic kidney disease (T2DM-no CKD) (n = 29), along with 30 healthy controls. Corneal dendritic cell densities were compared between people with T2DM-CKD and those with T2DM-no CKD. The groups were matched for neuropathy status. Results: There was a significant difference in corneal nerve fiber density (p < 0.01) and corneal nerve fiber length (p = 0.04) between T2DM-CKD and T2DM-no CKD groups. The two diabetes groups had reduced corneal nerve parameters compared to healthy controls (all parameters: p < 0.01). Immature central dendritic cell density was significantly higher in the T2DM-CKD group compared to the T2DM-no CKD group ((7.0 (3.8−12.8) and 3.5 (1.4−13.4) cells/mm2, respectively, p < 0.05). Likewise, central mature dendritic cell density was significantly higher in the T2DM-CKD group compared to the T2DM-no CKD group (0.8 (0.4−2.2) and 0.4 (0.6−1.1) cells/mm2, respectively, p = 0.02). Additionally, total central dendritic cell density was increased in the T2DM-CKD group compared to T2DM-no CKD group (10.4 (4.3−16.1) and 3.9 (2.1−21.0) cells/mm2, respectively, p = 0.03). Conclusion: The study showed that central corneal dendritic cell density is increased in T2DM-CKD compared to T2DM-no CKD, with groups matched for peripheral neuropathy severity. This is accompanied by a loss of central corneal nerve fibers. The findings raise the possibility of additional local factors exacerbating central corneal nerve injury in people with diabetic chronic kidney disease.

Effect of exenatide on peripheral nerve excitability in type 2 diabetes.

OBJECTIVE: To assess the effect of exenatide (a GLP-1 receptor agonist), dipeptidyl peptidase-IV (DPP-IV) inhibitors, and sodium-glucose co-transporter 2 (SGLT-2) inhibitors on measures of peripheral nerve excitability in patients with type 2 diabetes. METHODS: Patients receiving either exenatide (n = 32), a DPP-IV inhibitor (n = 31), or a SGLT-2 inhibitor (n = 27) underwent motor nerve excitability assessments. Groups were similar in age, sex, HbA1c, diabetes duration, lipids, and neuropathy severity. An additional 10 subjects were assessed prospectively over 3 months while oral anti-hyperglycaemic therapy was kept constant. A cohort of healthy controls (n = 32) were recruited for comparison. RESULTS: Patients receiving a DPP-IV or SGLT-2 inhibitor demonstrated abnormalities in peak threshold reduction, S2 accommodation, superexcitability, and subexcitability. In contrast, patients treated with exenatide were observed to have normal nerve excitability. In the prospective arm, exenatide therapy was associated with an improvement in nerve function as patients demonstrated corrections in S2 accommodation, superexcitability, and subexcitability at follow-up. These changes were independent of the reductions in HbA1c following exenatide treatment. CONCLUSIONS: Exenatide was associated with an improvement in measures of nerve excitability in patients with type 2 diabetes. SIGNIFICANCE: Exenatide may improve peripheral nerve function in type 2 diabetes.

Impact of the metabolic syndrome on peripheral nerve structure and function in type 2 diabetes.

BACKGROUND AND PURPOSE: There is a strong association between the metabolic syndrome in diabetes and the development of peripheral neuropathy; however, the pathophysiological mechanisms remain unknown. METHODS: Participants with type 2 diabetes and metabolic syndrome (T2DM/MetS, n = 89) and type 2 diabetes alone (T2DM; n = 59) underwent median nerve ultrasound and excitability studies to assess peripheral nerve structure and function. A subset of T2DM/MetS (n = 24) and T2DM (n = 22) participants underwent confocal microscopy to assess central and inferior whorl corneal nerve structure. Neuropathy severity was assessed using the modified Toronto Clinical Neuropathy Score (mTCNS). Diabetes groups were similar for age, sex distribution, diabetes duration, hemoglobin A1c , insulin treatment, and renal function. Sixty healthy controls similar for age and sex distribution were recruited for comparison. RESULTS: Participants with T2DM/MetS manifested with a greater mTCNS compared to T2DM (p < 0.05). Median nerve cross-sectional area was larger in the T2DM/MetS group compared to the T2DM cohort (p < 0.05). Participants with T2DM/MetS had reductions in central (all p < 0.01) and inferior whorl (all p < 0.05) nerve measures. Compared to T2DM, the T2DM/MetS group demonstrated more severe changes in nerve excitability measures, which was due to reduced sodium channel permeability and sodium-potassium pump function. In comparison, only sodium channel permeability was reduced in the T2DM group. CONCLUSIONS: Compared to participants with type 2 diabetes alone, those with diabetes and metabolic syndrome manifested greater alterations in peripheral nerve structure and function, which may be due to reduced function of the sodium-potassium pump.

Motor unit number estimation of facial muscles using the M Scan-Fit method.

INTRODUCTION: M Scan-Fit, an automated method for motor unit number estimation (MUNE), was assessed in muscles innervated by the facial nerve. METHODS: Healthy volunteers were recruited. M Scans were recorded twice from nasalis and depressor anguli oris (DAO) muscles, and then fitted to a probabilistic model. RESULTS: Twenty-one subjects were evaluated; 38% were females and 62% were males, with a mean age of 34.71 years. The average number of MUs was 38.57 on both testing occasions (t ≤ 0.0001; P = 1.0) for the nasalis. For the DAO, results were 20.62 MUs for the first and 23.48 for the second (t = -2.12; P = .04). Pearson's interrater correlation coefficients were 0.96 (P < .0001) for nasalis and 0.87 (P ≤ .01) for DAO. Intraclass correlation coefficients were 0.88 (P ≤ .01) for nasalis and 0.39 (P = .37) for DAO. DISCUSSION: M Scan-Fit MUNE is an automated, accurate, reliable method of estimating MU number and size from facial muscles.

The Effect of Age, Gender and Body Mass Index on Tear Film Neuromediators and Corneal Nerves.

Purpose: To evaluate the effect of age, gender and body mass index (BMI) on the levels of tear film neuromediators and corneal nerve parameters in healthy individuals.Methods: Twenty-six healthy subjects were screened for any neurological deficits. The concentration of substance P and calcitonin gene-related peptide (CGRP) in tears was measured by enzyme-linked immunosorbent assay. Corneal nerve fibers were imaged using confocal microscopy and assessed by automated image analysis software. Associations between the clinical variables were analyzed using Pearson or Spearman correlation. Univariate general linear regression was performed to examine the independent relationship between age, BMI and gender of the subjects with concentrations of substance P, CGRP and corneal nerve fiber parameters.Results: Fifteen (58%) of the study participants were male. The mean age of the study cohort was 36 ± 12 years (range, 21-59) with an average BMI of 25 ± 4 kg/m2. The median [IQR] concentrations of substance P and CGRP was 715 [372-1463] pg/mL and 38 [15-74] ng/mL respectively. Moderate but significant positive correlations were found between the concentration of substance P and corneal nerve fiber density (r = 0.467, P = .016), nerve fiber length (r = 0.528, P = .006) and nerve fractal dimension (rs = 0.614, P = .002). There was a significant age-dependent reduction in the concentration of substance P (-6% pg/mL per year, P = .001) and CGRP (-8% ng/ml per year, P < .001). Corneal nerve fiber density (-0.171 no./mm2 per year, P = .029) and nerve fractal dimension (-0.001 per year, P = .021) showed reductions with advancing age. Gender and BMI did not influence any of the measurements.Conclusions: The concentrations of substance P and CGRP in tears, as well as corneal nerve fiber density and nerve fractal dimension, are significantly reduced with advancing age. Age should be considered when evaluating patients for diagnosis and follow-up of corneal neuropathy or ocular surface disorders.

A Comparative Study on the Diagnostic Utility of Corneal Confocal Microscopy and Tear Neuromediator Levels in Diabetic Peripheral Neuropathy.

AIMS: To determine the utility of corneal confocal microscopy and tear neuromediator analysis in the diagnosis of diabetic peripheral neuropathy (DPN) as a result of type 1 and type 2 diabetes. METHODS: Seventy individuals with either type 1 diabetes or type 2 diabetes (T1D/T2D) underwent corneal confocal microscopy to assess the corneal nerve morphology. The concentration of substance P and calcitonin gene-related peptide (CGRP) in tears was measured by enzyme-linked immunosorbent assay. Motor excitability studies were conducted on the median nerve to assess axonal ion channel function. Based on total neuropathy score (TNS), participants were stratified into DPN (DPN+ve; TNS ≥ 2; T1D, n = 19; T2D, n = 16) and without DPN (DPN-ve; TNS ≤ 1; T1D, n = 19; T2D, n = 16). Areas under the receiver operating characteristic curves (AUCs) were calculated to obtain specificity and sensitivity of the measures to diagnose DPN. RESULTS: In T1D, the concentration of substance P and confocal microscopy measures were significantly reduced (P < .010) in DPN+ve. Also, for the nerve excitability measures, mean peak response, percentage of threshold electrotonus at peak and after 90-100 ms, superexcitability and subexcitability were significantly reduced (P < .050) in DPN+ve. In T2D, except for inferior whorl length (P = .190), all other corneal confocal microscopy measures were significantly reduced (P < .010) in DPN+ve, but there was no difference in substance P concentration. For the diagnosis of DPN in T1D, the AUC for inferior whorl length (0.910), mean peak response (0.800) and concentration of substance P (0.770) were high and in T2D, the AUC for corneal nerve fiber length (0.809) and nerve fractal dimension (0.777) were high. CONCLUSION: Corneal confocal microscopy parameters provide a better diagnostic ability to detect DPN in T1D and T2D than nerve excitability measures or concentrations of tear neuromediators. The concentration of substance P could also be useful in diagnosing DPN but for T1D only.

Association of corneal nerve loss with markers of axonal ion channel dysfunction in type 1 diabetes.

OBJECTIVE: Corneal confocal microscopy (CCM) has been identified as a non-invasive technique to assess corneal nerve fiber morphology. It is not known how corneal nerve changes relate to measures of peripheral nerve function in diabetic peripheral neuropathy (DPN). The present study investigates the relationship between nerve structure and function in DPN. METHODS: Fifty participants with type 1 diabetes (T1DM) and 29 healthy controls underwent CCM to assess corneal nerve fiber density (CNFD), branch density (CNBD), fiber length (CNFL), total branch density (CTBD), nerve fractal dimension (CNFrD) and inferior whorl length (IWL). The severity of DPN was assessed as Total Neuropathy Score (TNS). Motor nerve axonal excitability tests were conducted to assess axonal function. RESULTS: Significant correlations were noted between CNFD (rho = -0.783; P < 0.01) or superexcitability (rho = 0.435; P < 0.01) and TNS. CNFrD was significantly correlated with peak response to stimulus (r = 0.414; P < 0.01) and superexcitability (r = -0.467; P < 0.01) measurements. CONCLUSION: Corneal nerve loss demonstrates a significant association with axonal ion channel dysfunction in T1DM. SIGNIFICANCE: Detection of altered corneal nerve morphology may lead to the earlier diagnosis of DPN.

Corneal nerve fiber loss in diabetes with chronic kidney disease.

AIMS: Patients with chronic kidney disease (CKD) in type 2 diabetes typically manifest with severe peripheral neuropathy. Corneal confocal microscopy is a novel technique that may serve as a marker of nerve injury in peripheral neuropathy. This study examines the changes that occur in corneal nerve morphology as a result of peripheral neuropathy due to renal dysfunction in people with type 2 diabetes. METHODS: Sixty-two participants (mean age, 62 ± 12 years) with type 2 diabetes and 25 age-matched healthy controls underwent a comprehensive assessment of neuropathy using the total neuropathy score (TNS). The corneal sub-basal nerve plexus was imaged using corneal confocal microscopy. Corneal nerve fiber length, fiber density, branch density, total branch density, nerve fractal dimension, inferior whorl length and inferior whorl nerve fractal dimension were quantified. Based on the eGFR, participants were classified into those with diabetic CKD (eGFR < 60; n = 22) and those without CKD (eGFR ≥ 60; n = 40). RESULTS: Participants with diabetic CKD had significantly lower corneal nerve fiber density (P = 0.037), length (P = 0.036) and nerve fractal dimension (P = 0.036) compared to those without CKD. Multiple linear regression analysis revealed that reduced corneal nerve fiber density (ß coefficient = 0.098, P = 0.017), length (ß coefficient = 0.006, P = 0.008) and nerve fractal dimension (ß coefficient = 0.001, P = 0.007) was associated with low eGFR levels when adjusted for age, duration of diabetes and severity of neuropathy. CONCLUSION: Corneal confocal microscopy detects corneal nerve loss in patients with diabetic CKD and reduction in corneal nerve parameters is associated with the decline of kidney function.