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.

Altered peripheral nerve structure and function in latent autoimmune diabetes in adults.

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.

Relative contributions of diabetes and chronic kidney disease to neuropathy development in diabetic nephropathy patients.

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.

Correlation between markers of peripheral nerve function and structure in type 1 diabetes.

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 mm2 vs 6.3 ± 0.1 mm2 ; tibial = 14.5 ± 0.7 mm2 vs 10.8 ± 0.3 mm2 , P < .05) and type 2 (median = 9.1 ± 0.3 mm2 vs 7.2 ± 0.1 mm2 ; tibial = 18.5 ± 1.0 mm2 vs 12.8 ± 0.5 mm2 , 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.

The provision of written information and its effect on levels of pain and anxiety during electrodiagnostic studies: A randomised controlled trial.

OBJECTIVE: The provision of written information is a low-cost and readily available intervention that has been found to reduce pain and anxiety in a variety of clinical settings. The current study was undertaken to determine if information provision may improve patients' experience during conventional electrodiagnostic studies. METHODS: 128 participants were recruited from a tertiary teaching hospital who were referred for electrodiagnostic studies. They were randomized into 2 groups where the intervention group was provided with written information about the electrodiagnostic testing. Patients were invited to complete a questionnaire that included pain and anxiety using a visual analogue scale (VAS) following the testing. All participants underwent nerve conduction studies (NCS) whilst a subset also underwent subsequent needle electromyography (EMG). RESULTS: Those who received information had a statistically significant lower perception of anxiety during NCS, whilst only females who received information had a statistically significant lower perception of pain to both NCS and EMG. CONCLUSIONS: The provision of written information can reduce the degree of pain and anxiety experienced during electrodiagnostic testing. SIGNIFICANCE: Improving patient comfort and tolerability during electrodiagnostic testing may have practical implications towards more reliable and accurate results obtained from such investigations that may in turn improve patient diagnosis and management.

Effects of hemodialysis on intraneural blood flow in end-stage kidney disease.

INTRODUCTION: We quantified intraneural blood flow (INBF) in 18 patients with end-stage kidney disease (ESKD) and examined its relationship with nerve size, neuropathy severity, and nerve excitability parameters. METHODS: Sonographic measurements of the median nerve were performed at the same site before and after hemodialysis. INBF was quantified by analyzing power Doppler sonograms to obtain the vessel score (VSc) and maximum perfusion intensity (MPI). Corresponding median motor nerve excitability studies were performed. Neuropathy severity was assessed using Total Neuropathy Score. RESULTS: A total of 39% of ESKD patients had detectable INBF compared with none in the control group (P < 0.0001). Patients with detectable INBF had larger nerves and more severe neuropathy (P < 0.01). INBF parameters were significantly reduced after a session of dialysis (VSc: P < 0.01; MPI: P < 0.01). A significant relationship was found between interdialytic change in INBF and changes in nerve excitability. CONCLUSIONS: Increased INBF is a potential marker for neuropathy severity in ESKD patients. Muscle Nerve 57: 287-293, 2018.

Utility of maximum perfusion intensity as an ultrasonographic marker of intraneural blood flow.

We quantified intraneural blood flow (INBF) using perfusion measurement software (PixelFlux), and compared it with the qualitative method of counting blood vessels (vessel score) in a cohort of carpal tunnel syndrome (CTS) patients. METHODS: Forty-seven patients (67 wrists) with a clinical and electrophysiological diagnosis of CTS, and 20 healthy controls (40 wrists) were enrolled. Median nerve ultrasound (US) was performed at the carpal tunnel inlet to measure the cross-sectional area (CSA) and vessel score. Power Doppler sonograms from nerves with detectable INBF were processed with PixelFlux to obtain the maximum perfusion intensity (MPI). RESULTS: Forty-nine percent of CTS patients had detectable INBF compared with none in the control group (P < 0.0001). MPI correlated significantly with vessel score (r = 0.945, P < 0.0001), CSA (r = 0.613, P < 0.0001), and electrophysiological severity (r = 0.440, P < 0.0001). MPI had higher intra- or interobserver reliability compared with vessel score (0.95 vs. 0.47). CONCLUSION: MPI is a better method for quantification of INBF. Muscle Nerve, 2016 Muscle Nerve 55: 77-83, 2017.

Haemodialysis alters peripheral nerve morphology in end-stage kidney disease.

OBJECTIVE: We explored the nerve ultrasound (US) characteristics of 15 patients with end-stage kidney disease (ESKD) and correlated these findings with clinical severity and electrophysiological parameters of neuropathy. METHODS: 15 ESKD patients on thrice-weekly high-flux haemodialysis and 15 healthy controls were enrolled. Sonographic and electrophysiologic studies were conducted before and after a single session of haemodialysis. Serial measurements of median nerve cross-sectional area (CSA) and hypoechoic fraction (HF) were performed at the same non-entrapment site in the mid-forearm. Neuropathy severity was quantified using the total neuropathy score (TNS). RESULTS: 86.7% of the ESKD cohort had neuropathy (TNS>1). ESKD patients had significantly higher baseline CSA (8.9±1.2mm2 vs 7.5±1.0mm2, p<0.05) and HF (56.0±1.0% vs 54.0±1.1%, p<0.05) compared with the control group. The CSA correlated significantly with TNS (r=0.826; p<0.0001) and other electrophysiological parameters. There was a reduction in both the CSA (8.3±1.4mm2; p<0.01) and HF (55.0±1.6%; p<0.05) after a single session of HD. A significant relationship was also found between the change in CSA and change in serum K+ after dialysis (r=0.782, p<0.01). CONCLUSIONS: This study shows that peripheral nerves in ESKD patients are larger and more hypoechoic and that these morphological abnormalities may be reversed by dialysis. SIGNIFICANCE: US may be useful as an early marker of neuropathy in ESKD.

Sonographic differences in carpal tunnel syndrome with normal and abnormal nerve conduction studies.

We evaluated the differences in sonographic parameters in carpal tunnel syndrome (CTS) patients with normal and mildly abnormal nerve conduction studies (NCS). This was a prospective cross-sectional study. We assessed 169 wrists (101 patients) with a clinical diagnosis of carpal tunnel syndrome (CTS), as well as 20 healthy controls (40 wrists). 49 wrists were classified as mild NCS-positive and 38 as NCS-negative based on our laboratory NCS normal values. The cross-sectional area (CSA) of the median nerve at the carpal tunnel inlet and mid-forearm were measured and the wrist-to-forearm ratio (WFR) was calculated. 26% of the NCS-negative group had abnormal CSA. The CSA and WFR also differed significantly between the two groups. There was significant correlation between the sonographic and electrophysiologic variables. Ultrasound was diagnostic for CTS in a third of the NCS-negative wrists. Ultrasound may be useful in clinical CTS patients with normal or borderline NCS.

cVEMP morphology changes with recording electrode position, but single motor unit activity remains constant.

Cervical vestibular evoked myogenic potentials (cVEMPs) recorded over the lower quarter of the sternocleidomastoid (SCM) muscle in normal subjects may have opposite polarity to those recorded over the midpoint. It has thus been suggested that vestibular projections to the lower part of SCM might be excitatory rather than inhibitory. We tested the hypothesis that the SCM muscle receives both inhibitory and excitatory vestibular inputs. We recorded cVEMPs in 10 normal subjects with surface electrodes placed at multiple sites along the anterior (sternal) component of the SCM muscle. We compared several reference sites: sternum, ipsilateral and contralateral earlobes, and contralateral wrist. In five subjects, single motor unit responses were recorded at the upper, middle, and lower parts of the SCM muscle using concentric needle electrodes. The surface cVEMP had the typical positive-negative polarity at the midpoint of the SCM muscle. In all subjects, as the recording electrode was moved toward each insertion point, p13 amplitude became smaller and p13 latency increased, then the polarity inverted to a negative-positive waveform (n1-p1). Changing the reference site did not affect reflex polarity. There was a significant short-latency change in activity in 61/63 single motor units, and in each case this was a decrease or gap in firing, indicating an inhibitory reflex. Single motor unit recordings showed that the reflex was inhibitory along the entire SCM muscle. The cVEMP surface waveform inversion near the mastoid and sternal insertion points likely reflects volume conduction of the potential occurring with increasing distance from the motor point.

Tonsillar Herniation After Lumbar Puncture in Idiopathic Intracranial Hypertension.

A 30-year-old woman with coexisting renal tubular acidosis and idiopathic intracranial hypertension (IIH), treated with acetazolamide, experienced coning (cerebellar tonsillar herniation) after a lumbar puncture (LP). Brain magnetic resonance imaging at initial diagnosis of IIH showed minor tonsillar descent and computed tomographic venography revealed hypoplasia of the left transverse sinus. The patient previously had three uneventful LPs, all of which showed high opening pressures and normal cerebrospinal fluid composition. In retrospect, it was noted that her serum bicarbonate had fallen to 9 mmol/L (normal: 22-28 mm/L) 1 week before the LP. We hypothesize that the combination of cerebral edema (due to worsening metabolic acidosis), poor venous drainage, and preexisting minor tonsillar descent contributed to her post-LP coning.