The test-retest reliability of large and small fiber nerve excitability testing with threshold tracking.

Objective: Standard nerve excitability testing (NET) predominantly assesses Aα- and Aß-fiber function, but a method examining small afferents would be of great interest in pain studies. Here, we examined the properties of a novel perception threshold tracking (PTT) method that preferentially activates Aδ-fibers using weak currents delivered by a novel multipin electrode and compared its reliability with NET. Methods: Eighteen healthy subjects (mean age:34.06 ±â€¯2.0) were examined three times with motor and sensory NET and PTT in morning and afternoon sessions on the same day (intra-day reliability) and after a week (inter-day reliability). NET was performed on the median nerve, while PTT stimuli were delivered through a multipin electrode located on the forearm. During PTT, subjects indicated stimulus perception via a button press and the intensity of the current was automatically increased or decreased accordingly by Qtrac software. This allowed changes in the perception threshold to be tracked during strength-duration time constant (SDTC) and threshold electrotonus protocols. Results: The coefficient of variation (CoV) and interclass coefficient of variation (ICC) showed good-excellent reliability for most NET parameters. PTT showed poor reliability for both SDTC and threshold electrotonus parameters. There was a significant correlation between large (sensory NET) and small (PTT) fiber SDTC when all sessions were pooled (r = 0.29, p = 0.03). Conclusions: Threshold tracking technique can be applied directly to small fibers via a psychophysical readout, but with the current technique, the reliability is poor. Significance: Further studies are needed to examine whether Aß-fiber SDTC may be a surrogate biomarker for peripheral nociceptive signalling.

Comparison of diabetic and idiopathic sensory polyneuropathies with respect to nerve fibre affection and risk factors.

Background and purpose: Chronic distal sensory or sensorimotor polyneuropathy is the most common pattern of polyneuropathy. The cause of this pattern is most often diabetes or unknown. This cross-sectional study is one of the first studies to compare the demographics, cardiovascular risk factors and clinical characteristics of diabetic polyneuropathy (DPN) with idiopathic polyneuropathy (IPN). Methods: Patients with DPN were included from a sample of 389 patients with type 2 diabetes mellitus (T2DM) enrolled from a national cohort of patients with recently diagnosed T2DM (Danish Centre for Strategic Research in Type 2 Diabetes cohort). Patients with IPN were included from a regional cohort of patients with symptoms of polyneuropathy referred for workup at a combined secondary and tertiary neurological centre (database cohort). Results: A total of 214 patients with DPN were compared with a total of 88 patients with IPN. Patients with DPN were older (67.4 vs 59 years) and had a longer duration of neuropathy symptoms. Patients with DPN had greater body mass index (32 vs 27.4 kg/m2) and waist circumference (110 cm vs 97 cm); higher frequency of hypertension diagnosis (72.9% vs 30.7%); lower total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels; and a higher prevalence of use of statins (81.8% vs 19.3%). DPN was associated with a slightly higher autonomic score and total score on the Neuropathy Symptom Score; lower frequency of hyperalgesia, allodynia and decreased vibration on quantitative sensory testing; lower intraepidermal nerve fibre density count and higher frequency of small-fibre neuropathy. Conclusion: DPN and IPN showed clear differences in neuropathy characteristics, indicating that these two entities are to be regarded as aetiologically and pathogenetically distinct.

The characteristics of pain and dysesthesia in patients with diabetic polyneuropathy.

INTRODUCTION/AIMS: Patients with diabetic polyneuropathy (DPN) may experience paresthesia, dysesthesia, and pain. We aimed to characterize the predictors, symptoms, somatosensory profile, neuropathy severity, and impact of painful DPN and dysesthetic DPN. METHODS: This study was a cross-sectional study of type 2 diabetes patients with confirmed DPN, diagnosed using widely accepted methods including a clinical examination, skin biopsy, and nerve conduction studies. FINDINGS: Of 126 patients with confirmed DPN, 52 had DPN without pain or dysesthesia, 21 had dysesthetic DPN, and 53 painful DPN. Patients with painful DPN were less physically active and suffered from more pain elsewhere than in the feet compared to patients with DPN without pain. Patients with painful DPN had the largest loss of small and large sensory fiber function, and there was a gradient of larger spatial distribution of sensory loss from DPN without dysesthesia/pain to dysesthetic DPN and to painful DPN. This could indicate that patients with dysesthesia had more severe neuropathy than patients without dysesthesia but less than patients with painful DPN. Patients with dysesthetic and painful DPN had higher symptom scores for depression and fatigue than those without dysesthesia/pain with no difference between dysesthetic and painful DPN. CONCLUSIONS: There was a gradient of increasing sensory loss from DPN without dysesthesia/pain to dysesthetic DPN and to painful DPN. Pain and dysesthesia are common in DPN and both interfere with daily life. It is therefore important to consider dysesthesia when diagnosing and treating patients with neuropathy.

Analysis of Macrophages and Peptidergic Fibers in the Skin of Patients With Painful Diabetic Polyneuropathy.

BACKGROUND AND OBJECTIVES: The mechanisms of pain in patients with diabetic polyneuropathy are unknown. Studies have suggested a role of inflammation and increased neuropeptides peripherally in pain generation. This study examined the possible skin markers of painful diabetic polyneuropathy (P-DPN): macrophages, substance P (SP), and calcitonin gene-related peptide (CGRP). METHODS: The participants were included from a large Danish cross-sectional clinical study of type 2 diabetes. We diagnosed definite diabetic polyneuropathy using the Toronto criteria and used the Neuropathic Pain Special Interest Group classification for defining P-DPN. We included 60 skin biopsies from patients with diabetic polyneuropathy-30 with P-DPN and 30 with nonpainful diabetic polyneuropathy (NP-DPN)-and 30 biopsies from healthy controls of similar age and sex. The biopsies were stained using PGP 9.5, IbA1, and SP and CGRP primary markers. RESULTS: There was increased macrophage density in patients with P-DPN (8.0%) compared with that in patients with NP-DPN (5.1%, p < 0.001), and there was increased macrophage density in patients with NP-DPN (5.1%) compared with that in healthy controls (3.1%, p < 0.001). When controlling for neuropathy severity, body mass index, age, and sex, there was still a difference in macrophage density between patients with P-DPN and patients with NP-DPN. Patients with P-DPN had higher median nerve fiber length density (274.5 and 155 mm-2 for SP and CGRP, respectively) compared with patients with NP-DPN (176 and 121 mm-2 for SP and CGRP, respectively, p = 0.009 and 0.04) and healthy controls (185.5 and 121.5 mm-2 for SP and CGRP, respectively), whereas there was no difference between patients with NP-DPN and controls without diabetes (p = 0.64 and 0.49, respectively). The difference between P-DPN and NP-DPN for SP and CGRP was significant only in female patients, although a trend was seen in male patients. DISCUSSION: The findings point to a possible involvement of the innate immune system in the pathogenesis of neuropathic pain in patients with DPN, although markers of activated macrophages were not measured in this study.

Normative reference values for the dorsal sural nerve derived from a large multicenter cohort.

OBJECTIVES: Dorsal sural nerve conduction studies (NCS) may increase the sensitivity for the diagnosis of polyneuropathy, but clinical use is limited by a lack of reliable normative reference values in all age-groups. The aim of our study was to develop reference values for the dorsal sural nerve, based on a large multicenter cohort of healthy subjects. METHODS: Bilateral antidromic NCS were performed using standard surface electrodes in 229 healthy subjects (aged 21-80 years; median: 54 years). We assessed the normality of data distribution for amplitudes and conduction velocity (CV) and for their logarithmic (ln) transformation. The effects of age and height were determined using linear regression analysis. RESULTS: Sensory potentials were present in all subjects. Logarithmically transformed data were normally distributed. Age2 and height were most significantly associated with amplitude, and age and height with CV, respectively. There was no significant side-difference. Mean amplitudes (right and left) were 4.8 and 4.9 µV and mean CV 46.7 and 46.9 m/s. Reference limits were e (3.712515 - 0.0000956 * age2 - 0.0115883 * height ±â€¯1.96 * 0.51137) for amplitude and e (4.354374 - 0.0021081 * age - 0.0023354 * height ±â€¯1.96 * 0.11161) for CV. CONCLUSIONS: Dorsal sural nerve NCS are robust and have well defined normative limits. SIGNIFICANCE: The findings provide a basis for more sensitive NCS in clinical practice and future studies of the diagnostic accuracy of NCS in polyneuropathy.

Small and large fiber sensory polyneuropathy in type 2 diabetes: Influence of diagnostic criteria on neuropathy subtypes.

Diabetic polyneuropathy (DPN) can be classified based on fiber diameter into three subtypes: small fiber neuropathy (SFN), large fiber neuropathy (LFN), and mixed fiber neuropathy (MFN). We examined the effect of different diagnostic models on the frequency of polyneuropathy subtypes in type 2 diabetes patients with DPN. This study was based on patients from the Danish Center for Strategic Research in Type 2 Diabetes cohort. We defined DPN as probable or definite DPN according to the Toronto Consensus Criteria. DPN was then subtyped according to four distinct diagnostic models. A total of 277 diabetes patients (214 with DPN and 63 with no DPN) were included in the study. We found a considerable variation in polyneuropathy subtypes by applying different diagnostic models independent of the degree of certainty of DPN diagnosis. For probable and definite DPN, the frequency of subtypes across diagnostic models varied from: 1.4% to 13.1% for SFN, 9.3% to 21.5% for LFN, 51.4% to 83.2% for MFN, and 0.5% to 14.5% for non-classifiable neuropathy (NCN). For the definite DPN group, the frequency of subtypes varied from: 1.6% to 13.5% for SFN, 5.6% to 20.6% for LFN, 61.9% to 89.7% for MFN, and 0.0% to 6.3% for NCN. The frequency of polyneuropathy subtypes depends on the type and number of criteria applied in a diagnostic model. Future consensus criteria should clearly define sensory functions to be tested, methods of testing, and how findings should be interpreted for both clinical practice and research purpose.

Muscle Velocity Recovery Cycles to Examine Muscle Membrane Properties.

Although conventional nerve conduction studies (NCS) and electromyography (EMG) are suitable for the diagnosis of neuromuscular disorders, they provide limited information about muscle fiber membrane properties and underlying disease mechanisms. Muscle velocity recovery cycles (MVRCs) illustrate how the velocity of a muscle action potential depends on the time after a preceding action potential. MVRCs are closely related to changes in membrane potential that follow an action potential, thereby providing information about muscle fiber membrane properties. MVRCs may be recorded quickly and easily by direct stimulation and recording from multi-fiber bundles in vivo. MVRCs have been helpful in understanding disease mechanisms in several neuromuscular disorders. Studies in patients with channelopathies have demonstrated the different effects of specific ion channel mutations on muscle excitability. MVRCs have been previously tested in patients with neurogenic muscles. In this prior study, muscle relative refraction period (MRRP) was prolonged, and early supernormality (ESN) and late supernormality (LSN) were reduced in patients compared to healthy controls. Thereby, MVRCs can provide in vivo evidence of membrane depolarization in intact human muscle fibers that underlie their reduced excitability. The protocol presented here describes how to record MVRCs and analyze the recordings. MVRCs can serve as a fast, simple, and useful method for revealing disease mechanisms across a broad range of neuromuscular disorders.

Diabetic polyneuropathy and pain, prevalence, and patient characteristics: a cross-sectional questionnaire study of 5,514 patients with recently diagnosed type 2 diabetes.

Most studies of diabetic polyneuropathy (DPN) and painful DPN are conducted in persons with longstanding diabetes. This cross-sectional study aimed to estimate the prevalence of DPN and painful DPN, important risk factors, and the association with mental health in recently diagnosed type 2 diabetes. A total of 5514 (82%) patients (median diabetes duration 4.6 years) enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes cohort responded to a detailed questionnaire on neuropathy and pain. A score ≥4 on the MNSI questionnaire determined possible DPN, whereas pain presence in both feet together with a score ≥3 on the DN4 questionnaire determined possible painful DPN. The prevalence of possible DPN and possible painful DPN was 18% and 10%, respectively. Female sex, age, diabetes duration, body mass index, and smoking were associated with possible DPN, whereas only smoking showed a clear association with possible painful DPN (odds ratio 1.52 [95% confidence interval: 1.20-1.93]). Possible DPN and painful DPN were independently and additively associated with lower quality of life, poorer sleep, and symptoms of depression and anxiety. Possible DPN itself had greater impact on mental health than neuropathic pain. This large study emphasizes the importance of careful screening for DPN and pain early in the course of type 2 diabetes.