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Aims: To undertake sonographic assessment of nerve blood flow in people with Type 2 diabetes and correlate the findings with neuropathy severity scores and electrophysiological measurements. Methods: Median and tibial nerve ultrasound scans were undertaken in 75 people with diabetes and 30 aged‐matched controls without diabetes, using a high‐resolution linear probe at non‐entrapment sites. Nerve blood flow was quantified using power Doppler techniques to obtain the vessel score and the maximum perfusion intensity. Neuropathy severity was assessed using a total neuropathy score. Results: Diabetic nerves had higher rates of nerve blood flow detection (28%) compared to the control group (P < 0.0001). Significant correlations were found between nerve blood flow measurements and nerve size (P <0.001), reported sensory symptoms (P < 0.05) and neuropathy severity scores (P < 0.001). The cohort with diabetes had significantly larger median (8.5 ± 0.3 mm2 vs 7.2 ± 0.1 mm2; P < 0.05) and tibial nerves (18.0 ± 0.9 mm2 vs 12.8 ± 0.5 mm2; P < 0.05) compared with controls. Conclusion: Peripheral nerve hypervascularity is detectable by ultrasonography in moderate to severe diabetic neuropathy with prominent sensory dysfunction. What's new?: Alterations in nerve blood flow are implicated in the development of diabetic neuropathy, but in vivo techniques for its assessment are either invasive or complicated.Doppler ultrasound techniques have been shown to detect intraneural blood flow in nerve injury reliably, both in real‐time and non‐invasively.Interventions targeting intraneural blood flow may improve neuropathic symptoms in people with diabetes.Intraneural blood flow was reliably detected in 28% of people with diabetic neuropathy and correlated significantly with measures of neuropathy severity.Most of the people with detectable blood flow had moderate to severe neuropathy with prominent sensory symptoms.Intraneural blood flow is a reliable and reproducible biomarker for the assessment of diabetic neuropathy and may be a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Aims: To investigate changes in corneal nerve morphology in Type 2 diabetes and to establish relationships between in vivo corneal confocal microscopy and markers of peripheral nerve structure and function. Participants and methods: We recruited 57 participants with Type 2 diabetes and 26 healthy controls of similar age and sex distribution. We also recruited a disease control group of 54 participants with Type 1 diabetes. All participants were assessed for distal symmetrical polyneuropathy using the Total Neuropathy Score. In vivo corneal confocal microscopy was used to assess corneal nerve fibre length, corneal nerve fibre density, corneal nerve branch density and inferior whorl length. Peripheral nerve structure was assessed using median nerve ultrasonography. Large fibre function was assessed according to median nerve axonal excitability. Small fibre function was assessed using SudoscanTM and the Survey of Autonomic Symptoms. Results: Corneal nerve fibre length, fibre density and branch density and inferior whorl length were significantly lower in individuals with Type 2 diabetes compared to controls (P<0.001 for all). In the Type 2 diabetes cohort, correlations were observed between neuropathy severity and corneal nerve fibre density (P=0.004), corneal nerve branch density (P=0.003), corneal nerve fibre length (P=0.002) and inferior whorl length (P=0.01). Significant correlations were observed between corneal confocal outcomes and axonal excitability measurements. No association was found between corneal confocal microscopy and median nerve cross‐sectional area, Sudoscan measurements or the Survey of Autonomic Symptoms. Conclusions: This study demonstrated significant changes in corneal nerves in individuals with Type 2 diabetes. Reductions in corneal nerve measures correlated with increasing neuropathy severity. Associations were found between corneal confocal microscopy and markers of voltage‐gated potassium channel function. What's new?: In vivo corneal confocal microscopy is a validated diagnostic tool for diabetic peripheral neuropathy in Type 1 diabetes.Multicentre studies have recently demonstrated corneal nerve fibre length (CNFL) to be a valid endpoint for diabetic peripheral neuropathy in Type 2 diabetes.Changes in corneal nerve fibre density (CNFD) were apparent in participants with Type 2 diabetes without neuropathy.CNFL and CNFD were reduced with increasing neuropathy severity.A significant relationship was found between corneal nerves and physiological markers of peripheral nerve function.This study confirms the utility of in vivo corneal confocal microscopy in assessing neuropathy in Type 2 diabetes.Novel insights into the underlying pathophysiology of diabetic peripheral neuropathy in Type 2 diabetes were demonstrated by the significant relationship between corneal nerves and axonal excitability outcomes. [ABSTRACT FROM AUTHOR]

Diabetic peripheral neuropathy (DPN) affects ∼50% of the 500 million people with type 2 diabetes worldwide and is considered disabling and irreversible. The current study was undertaken to assess the effect of metformin on peripheral neuropathy outcomes in type 2 diabetes. Participants with type 2 diabetes (n = 69) receiving metformin were recruited and underwent clinical assessment, peripheral nerve ultrasonography, nerve conduction studies, and axonal excitability studies. Also concurrently screened were 318 participants who were not on metformin, and 69 were selected as disease control subjects and matched to the metformin participants for age, sex, diabetes duration, BMI, HbA1c, and use of other diabetes therapies. Medical record data over the previous 20 years were analyzed for previous metformin use. Mean tibial nerve cross-sectional area was lower in the metformin group (metformin 14.1 ± 0.7 mm2, nonmetformin 16.2 ± 0.9 mm2, P = 0.038), accompanied by reduction in neuropathy symptom severity (P = 0.021). Axonal excitability studies demonstrated superior axonal function in the metformin group, and mathematical modeling demonstrated that these improvements were mediated by changes in nodal Na+and K+conductances. Metformin treatment is associated with superior nerve structure and clinical and neurophysiological measures. Treatment with metformin may be neuroprotective in DPN., (© 2024 by the American Diabetes Association.)

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 K v 1.1 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 K v 1.1 conductances with increasing greater disease severity., Conclusion: The findings are consistent with a progressive upregulation of juxtaparanodal K v 1.1 conductances with increasing clinical severity of diabetic peripheral neuropathy., Significance: From a translational perspective, the study suggests that blockade of K v 1.1 channels using 4-aminopyridine derivatives such as fampridine may be a potential treatment for DPN., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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 &lt; 0.001) and each mTCNS quartile (p &lt; 0.001). Regression analysis demonstrated a correlation between tibial nerve CSA and neuropathy severity (p &lt; 0.001). Using receiver operator curve analysis, tibial nerve CSA of &gt;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., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Clinical Relevance: There is potential benefit in analysing corneal nerve tortuosity as a marker for assessment and progression of systemic diabetic neuropathy., Background: The aim of this work was to determine whether tortuosity significantly differs in participants with type 1 (T1DM) and type 2 (T2DM) diabetes compared to controls and whether tortuosity differed according to neuropathy status., Methods: Corneal nerves of 164 participants were assessed across T1DM, T2DM and control groups. Images of corneal nerves were captured via in vivo corneal confocal microscopy. Diabetic neuropathy status was examined using the Total Neuropathy Score (TNS). Tortuosity was assessed with Cfibre v0.097. Results were compared between groups with a linear mixed model accounting for location of image and controlling for age, producing Tortuosity Factor (TF), an estimate of the marginal means of each group., Results: Tortuosity was significantly reduced in the T1DM group compared to controls (TF = 0.241, 95%CI = 0.225-0.257 vs. TF = 0.272, 95%CI = 0.252-0.292; mean difference = -0.031, p = 0.02) and in the T2DM group compared to controls (TF = 0.261, 95%CI = 0.244-0.278 vs. TF = 0.289, 95%CI = 0.270-0.308; mean difference = -0.029, p = 0.03). Tortuosity did not significantly differ between participants with T1DM and T2DM accounting for age and TNS (TF = 0.240, 95%CI = 0.215-0.265 vs. 0.269, 95%CI = 0.244-0.293, mean difference = -0.029, p = 0.11). Tortuosity was significantly reduced in participants with neuropathy (TNS≥2) compared to participants with no neuropathy (TNS< 2) (TF = 0.248, 95%CI = 0.231-0.265 vs. TF = 0.272, 95%CI = 0.260-0.283; mean difference = -0.024, p = 0.03)., Conclusions: Tortuosity is significantly reduced in participants with T1DM and T2DM compared to age matched controls and in participants with neuropathy compared to those without neuropathy.

Introduction/aims: Sonographic alterations of peripheral nerves in pre-dialytic kidney disease are yet to be determined. We aimed to assess peripheral nerve cross-sectional area (CSA) and intraneural blood flow in patients with pre-dialytic chronic kidney disease (CKD) and diabetic kidney disease (DKD)., Methods: Subjects with CKD (n = 20) or DKD (n = 20) underwent ultrasound to assess CSA of the median and tibial nerves as well as intraneural blood flow of the median nerve. Blood flow was quantified using maximum perfusion intensity. Neuropathy was assessed using the Total Neuropathy Score. A 6-m timed walk test was also performed. Healthy controls (n = 28) were recruited for comparison., Results: The DKD group had more severe neuropathy (p = .024), larger tibial nerve CSA (p = .002) and greater median nerve blood flow than the CKD group (p = .023). Blood flow correlated with serum potassium in disease groups (r = 0.652, p = .022). Disease groups had larger tibial nerve CSA than controls (p < .05). No blood flow was detected in controls. Tibial nerve enlargement was associated with slower maximal walking speeds in disease groups (r = -0.389, p = .021)., Discussion: Subjects with DKD demonstrated enlarged tibial nerve CSA and increased median nerve blood flow compared to those with CKD. Elevations in serum potassium were associated with increased blood flow. Sonographic alterations were detectable in pre-dialytic kidney disease compared to controls, highlighting the utility of ultrasound in the assessment of nerve pathology in these patient groups., (© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

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, HbA 1c , 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 HbA 1c 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

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 A 1c , 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., (© 2021 European Academy of Neurology.)

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., (© 2020 Wiley Periodicals LLC.)

Peripheral neuropathy (PN) is a debilitating complication of diabetes that affects >50% of patients. Recent evidence suggests that obesity and metabolic disease, which often precede diabetes diagnosis, may influence PN onset and severity. We examined this in a translationally relevant model of prediabetes induced by a cafeteria (CAF) diet in Sprague-Dawley rats ( n = 15 CAF versus n = 15 control). Neuropathy phenotyping included nerve conduction, tactile sensitivity, intraepidermal nerve fiber density (IENFD) and nerve excitability testing, an in vivo measure of ion channel function and membrane potential. Metabolic phenotyping included body composition, blood glucose and lipids, plasma hormones and inflammatory cytokines. After 13 weeks diet, CAF-fed rats demonstrated prediabetes with significantly elevated fasting blood glucose, insulin and impaired glucose tolerance as well as obesity and dyslipidemia. Nerve conduction, tactile sensitivity and IENFD did not differ; however, superexcitability was significantly increased in CAF-fed rats. Mathematical modeling demonstrated this was consistent with a reduction in sodium-potassium pump current. Moreover, superexcitability correlated positively with insulin resistance and adiposity, and negatively with fasting high-density lipoprotein cholesterol. In conclusion, prediabetic rats over-consuming processed, palatable foods demonstrated altered nerve function that preceded overt PN. This work provides a relevant model for pathophysiological investigation of diabetic complications.

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.

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/m 2 . 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 (r s  = 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./mm 2 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.

Aim: The present study was undertaken to investigate mechanisms of peripheral nerve dysfunction in latent autoimmune diabetes in adults (LADA)., Materials and Methods: Participants with LADA (n = 15) underwent median nerve ultrasonography and nerve excitability to examine axonal structure and function, in comparison to cohorts of type 1 diabetes (n = 15), type 2 diabetes (n = 23) and healthy controls (n = 26). The LADA group was matched for diabetes duration, glycaemic control, and neuropathy severity with the type 1 and type 2 diabetes groups. A validated mathematical model of the human axon was utilized to investigate the pathophysiological basis of nerve dysfunction., Results: The most severe changes in nerve structure and function were noted in the LADA group. The LADA cohort demonstrated a significant increase in nerve cross-sectional area compared to type 1 participants and controls. Compared to type 1 and 2 diabetes, measures of threshold electrotonus, which assesses nodal and internodal conductances, were significantly worse in LADA in response to both depolarising currents and hyperpolarising currents. In the recovery cycle, participants with LADA had a significant increase in the relative refractory period. Mathematical modelling of excitability recordings indicated the basis of nerve dysfunction in LADA was different to type 1 and 2 diabetes., Conclusions: Participants with LADA exhibited more severe changes in nerve function and different underlying pathophysiological mechanisms compared to participants with type 1 or 2 diabetes. Intensive management of risk factors to delay the progression of neuropathy in LADA may be required., (© 2019 John Wiley & Sons Ltd.)

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., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Chronic kidney disease (CKD) caused by diabetes is known as diabetic kidney disease (DKD). The present study aimed to examine the underlying mechanisms of axonal dysfunction and features of neuropathy in DKD compared to CKD and type 2 diabetes (T2DM) alone., Methods: Patients with DKD (n = 30), CKD (n = 28) or T2DM (n = 40) and healthy controls (n = 41) underwent nerve excitability assessments to examine axonal function. Neuropathy was assessed using the Total Neuropathy Score. A validated mathematical model of human axons was utilised to provide an indication of the underlying causes of nerve pathophysiology., Results: Total neuropathy score was significantly higher in patients with DKD compared to those with either CKD or T2DM (p < 0.05). In DKD, nerve excitability measures (S2 accommodation and superexcitability, p < 0.05) were more severely affected compared to both CKD and T2DM and worsened with increasing serum K + (p < 0.01). Mathematical modelling indicated the basis for nerve dysfunction in DKD was an elevation of extracellular K + and reductions in Na + permeability and the hyperpolarisation-activated cation current, which was similar to CKD., Conclusions: Patients with DKD manifested a more severe neuropathy phenotype and shared features of nerve dysfunction to that of CKD., Significance: The CKD, and not diabetes component, appears to underlie axonal pathophysiology in DKD., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To explore the changes that occur in the concentrations of substance P (SP) and calcitonin gene-related peptide (CGRP) in tears as a result of corneal denervation and its association with diabetic peripheral neuropathy (DPN)., Methods: Sixty-three individuals with type 1 diabetes/type 2 diabetes (T1D/T2D) and 34 age-matched healthy controls underwent a detailed assessment of neuropathy using the Total Neuropathy Score (TNS). The concentration of SP and CGRP in tears was measured by enzyme-linked immunosorbent assay. The corneal sub-basal nerve plexus was imaged using corneal confocal microscopy. Corneal nerve fibre length, fibre density, branch density, total branch density, nerve fractal dimension and inferior whorl length were quantified., Results: In T1D, the median [IQR] concentration of SP in tears was significantly reduced in those with DPN, (130 [61-692]pg/mL) compared to both control subjects (763 [405-1555]pg/mL, P < 0.01) and in those without DPN (914 [339-1832]pg/mL, P = 0.01); the concentration of CGRP was not changed. In T2D, there was no difference in neuropeptides between participants with diabetes and controls, regardless of neuropathic status. In T1D and T2D, corneal nerve parameters were significantly different between those with DPN or without DPN and controls. A significant correlation was noted between the concentration of tear film SP and TNS in T1D (r = -0.49; P < 0.001) and corneal nerve fibre density (r = 0.45; P < 0.001). The concentration of tear film CGRP was correlated significantly with the reduction of corneal nerve fibre density (r = 0.41; P = 0.01) in T1D., Conclusion: Tear film SP may provide a potential non-invasive biomarker for assessing neuropathy in T1D., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Clinical and experimental studies in patients with type 1 and type 2 diabetes have demonstrated changes in ion channel function and nerve structure. In this study, we investigated the relationship between axonal dysfunction and morphological change in diabetic polyneuropathy by using neuromuscular ultrasound and nerve excitability techniques. We also explored possible differences in this relationship between type 1 and type 2 diabetes., Methods: Nerve ultrasound and corresponding motor excitability studies were undertaken in 110 diabetes patients (50 type 1; 60 type 2) and 60 age-matched controls (30 for each group). Neuropathy severity was assessed by using total neuropathy score. Median and tibial nerve cross-sectional areas were measured at nonentrapment sites by using high-resolution linear probe., Results: Median and tibial nerve cross-sectional areas were significantly higher in diabetes patients compared with controls: type 1 (median = 7.6 ± 0.2 mm 2 vs 6.3 ± 0.1 mm 2 ; tibial = 14.5 ± 0.7 mm 2 vs 10.8 ± 0.3 mm 2 , P < .05) and type 2 (median = 9.1 ± 0.3 mm 2 vs 7.2 ± 0.1 mm 2 ; tibial = 18.5 ± 1.0 mm 2 vs 12.8 ± 0.5 mm 2 , P < .05). In the type 1 cohort, significant correlations were found between nerve cross-sectional area and excitability parameters including resting current-threshold slope (median: r = 0.523, P < .0001; tibial: r = -0.571, P = .004) and depolarizing threshold electrotonus at 90 to 100 ms (median: 0.424, P < .01; tibial: r = 0.435, P = .030). In contrast, there was no relationship between excitability values and nerve cross-sectional area in the type 2 cohort., Conclusions: This study has identified correlation between markers of axonal membrane function and structural abnormalities in peripheral nerves of type 1 diabetes patients. The differential relationship in nerve function and structure between type 1 and type 2 diabetes provides clinical evidence that different pathophysiological mechanisms underlie the development of neuropathy in these patient groups., (© 2018 John Wiley & Sons, Ltd.)

Objective: To demonstrate construct validity of the Total Neuropathy Score (TNS) in assessing peripheral neuropathy in subjects with chronic kidney disease (CKD)., Methods: 113 subjects with CKD and 40 matched controls were assessed for peripheral neuropathy using the TNS. An exploratory factor analysis was conducted and internal consistency of the scale was evaluated using Cronbach's alpha. Construct validity of the TNS was tested by comparing scores between case and control groups., Results: Factor analysis revealed valid item correlations and internal consistency of the TNS was good with a Cronbach's alpha of 0.897. Subjects with CKD scored significantly higher on the TNS (CKD: median, 6, interquartile range, 1-13; controls: median, 0, interquartile range, 0-1; p < 0.001). Subgroup analysis revealed construct validity was maintained for subjects with stages 3-5 CKD with and without diabetes., Conclusions: The TNS is a valid measure of peripheral neuropathy in patients with CKD., Significance: The TNS is the first neuropathy scale to be formally validated in patients with CKD., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Patients with chronic kidney disease (CKD) are frequently afflicted with neurological complications. These complications can potentially affect both the central and peripheral nervous systems. Common neurological complications in CKD include stroke, cognitive dysfunction, encephalopathy, peripheral and autonomic neuropathies. These conditions have significant impact not only on patient morbidity but also on mortality risk through a variety of mechanisms. Understanding the pathophysiological mechanisms of these conditions can provide insights into effective management strategies for neurological complications. This review describes clinical management of neurological complications in CKD with reference to the contributing physiological and pathological derangements. Stroke, cognitive dysfunction and dementia share several pathological mechanisms that may contribute to vascular impairment and neurodegeneration. Cognitive dysfunction and dementia may be differentiated from encephalopathy which has similar contributing factors but presents in an acute and rapidly progressive manner and may be accompanied by tremor and asterixis. Recent evidence suggests that dietary potassium restriction may be a useful preventative measure for peripheral neuropathy. Management of painful neuropathic symptoms can be achieved by pharmacological means with careful dosing and side effect considerations for reduced renal function. Patients with autonomic neuropathy may respond to sildenafil for impotence. Neurological complications often become clinically apparent at end-stage disease, however early detection and management of these conditions in mild CKD may reduce their impact at later stages.