Permutation Entropy and Signal Energy Increase the Accuracy of Neuropathic Change Detection in Needle EMG

Background and Objective. Needle electromyography can be used to detect the number of changes and morphological changes in motor unit potentials of patients with axonal neuropathy. General mathematical methods of pattern recognition and signal analysis were applied to recognize neuropathic changes. This study validates the possibility of extending and refining turns-amplitude analysis using permutation entropy and signal energy. Methods. In this study, we examined needle electromyography in 40 neuropathic individuals and 40 controls. The number of turns, amplitude between turns, signal energy, and “permutation entropy” were used as features for support vector machine classification. Results. The obtained results proved the superior classification performance of the combinations of all of the above-mentioned features compared to the combinations of fewer features. The lowest accuracy from the tested combinations of features had peak-ratio analysis. Conclusion. Using the combination of permutation entropy with signal energy, number of turns and mean amplitude in SVM classification can be used to refine the diagnosis of polyneuropathies examined by needle electromyography

The Role of Cutaneous Innervation in the Sensory Abnormalities Associated with Diabetic Neuropathy

Diabetes-induced nerve damage results in cutaneous denervation, nerve conduction slowing, suppressed regenerative responses, and debilitating painful or insensate sensory symptoms. The increasing prevalence of diabetic neuropathy and its persistent treatment difficulties justify continued study into the mechanisms underlying the disease and the exploration of animal models useful for assessing its complications. The purpose of this study was to elucidate the relationship between cutaneous nerve fiber density and the presence of neuropathy and its accompanying symptoms. Experiments were conducted in various animal models of diabetes and in diabetic human patients. To explore mechanisms underlying insensate neuropathy, we evaluated behavioral responses to noxious stimuli in three animal models. Diabetic mice consistently displayed decreased sensitivity and hypoalgesia, indicative of insensate neuropathy. We also assessed peripheral innervation both indirectly, via spinal Fos expression, and directly, by quantifying footpad innervation. The diabetes-induced behavioral responses were paralleled by progressive reductions in dorsal horn activation by peripheral afferents. In contrast, direct quantification of peripheral fibers did not reveal deficits in total nerve fiber density. However, a subpopulation-specific reduction was found; peptidergic c-fibers were preferentially lost early in the diabetes progression, and their loss correlated with loss of nociceptive sensitivity. These results suggest that diabetes-induced behavioral deficits are more closely associated with the peptidergic, rather than the nonpeptidergic, subpopulation, underscoring the importance of peptidergic fibers in pain sensation. In addition, human diabetic and nondiabetic subjects were recruited and tested for measures of sensory nerve fiber function and evaluated for cutaneous nerve fiber density. While both epidermal and dermal nerve densities were highly specific and sensitive measures for diagnosing diabetic neuropathy, correlations with sensory measures were varied, and nerve fiber density could only account for at most 60% of the variability in any given neuropathic symptom. Collectively, results from the animal and human investigations demonstrate there are subtle disconnects in the degree to which nerve fiber density indicates pain sensitivity. Future studies should be directed toward understanding other mechanisms important in nociception during neuropathic disease. In addition, before nerve fiber density is relied upon as an outcome measure of treatment efficacy, the ability of cutaneous innervation to predict pain or lack of pain in human subjects should be addressed

Neuropathic pain in an elderly population of an urban area of iran with a special focus on carpal tunnel syndrome : epidemiological aspects, clinical characteristics, and non-surgical therapy

Background: People are getting older, and aging problems and disorders are increasing fast. Knowing the rates, causes, symptomatology, treatment, relief, and prognosis of associated disorders can help and facilitate the elderly, their families, primary health care providers, and health policymakers. Chronic pain in the elderly is a common complaint and its prevalence differs in society and depends on many factors, including type, severity, and localization but also comorbidities, socio-economic factors, and genetics. Pain is in two main categories, nociceptive and neuropathic. Nociceptive pain usually occurs after end-organ damage or derangement such as musculoskeletal problems, osteoarthritis, or trauma. Neuropathic pain arises from central or peripheral nervous system injuries. One of the most common types of peripheral neuropathic pain is hand pain caused by the carpal tunnel syndrome (CTS). Hand pain and CTS are common among the elderly, especially in women. The etiology usually remains uncertain until the late stages of the disorder, when intrinsic hand muscles become weak or atrophy, when it is too late to manage the CTS adequately. Thus, it is important to be aware of its clinical symptoms, signs, and provocation maneuvers, but also to have a noninvasive diagnostic tool when CTS is suspected. Also, it is important to have a solution for mild and moderate types of CTS to prevent surgery in older adults, especially in those with frailer constitutions. Objectives: We evaluated the prevalence of pain, with special focus on neuropathic pain and CTS, in a large population-based study in Tehran, the capital of Iran. We chose CTS as being the most common symptom of focal neuropathy and evaluated the median nerve by noninvasive, high-resolution ultrasonography. We investigated and diagnosed CTS and determined its severity. Following the results of our diagnostic study, we performed interventional treatment studies on patients diagnosed with CTS. To find the optimum steroid dose site, we examined three different doses of steroid in a mixture injected in the tunnel near the affected nerve medianus with an adhesion removal technique called hydro dissection. Finally, we compared different methods of injection in our last study to examine a hypothesis about nonsurgical flexor retinaculum release. Methods and material: More than 5,000 patients were investigated randomly by a multistage cluster sample. Participants were then interviewed using a sociodemographic checklist, a standard pain questionnaire, and general health through GHQ-28. In the 2nd study, demographics were noted along with the clinical presentation of CTS, and the median nerve anatomy was assessed by ultrasound and electrodiagnostic tests. The median nerve cross-sectional area (CSA) at the tunnel inlet and four different areas over the median nerve were measured and analyzed. In the 3rd paper with an intervention, we designed a prospective three group, randomized, double-blind trial to evaluate 40, 80, and 0 mg triamcinolone in a mixture of 3 mL containing 1 cc of lidocaine 2%. Outcome measures included the Boston Carpal Tunnel Questionnaire, VAS (visual analog scale), median nerve conduction criteria, and the ultrasound median CSA. All data were recorded at the baseline, 14 days, 1 month, and 6 months after the injection. In the 4th study, the design was similar to the 3rd one, though we had only two groups and the injecting mixture was 40 mg of triamcinolone and 1 cc of lidocaine 2%. The location of the injection was different with one group injected in the flexor retinaculum and the other near the nerve. All data were recorded as in the 3rd study but only at baseline, and 6 weeks after injection. Results: We found a 13.7% prevalence of chronic neuropathic pain and 30% of chronic nociceptive pain, overall chronic of 31.7% and overall acute of 39.1% which, in combination, add up to 70.8%. The major comorbidities were osteoporosis, diabetes, disability, and stroke. In the 2nd study with 203 CTS and 103 control subjects, CSA at the tunnel inlet with a threshold of 8.5 mm2 had a sensitivity and specificity of 96.9% and 93.6% respectively. In the 3rd study with 161 patients, we did not find any statistically significant differences between groups, i.e., all groups with a steroid dose had similar results. In the last study with 50 eligible subjects randomized into two groups, there was a significant improvement in Boston scores (p-value 0.023), VAS (p-value 0.026), and ultrasonographic measure (p-value 0.004), in favor of intra-flexor retinaculum steroid injection compared to near the nerve. Conclusions: Neuropathic pain prevalence is relatively high; 13.7% among Iranian elderly people, and the overall pain is very high around 70 %. It should be addressed by health policymakers, primary care physicians, and caregivers. High-resolution ultrasonography is a noninvasive diagnostic tool with about 95% sensitivity and specificity in detecting CTS in the elderly and should be introduced as a screening tool by primary physicians engaged in elderly care. The use of plain lidocaine was beneficial in managing CTS in elderly patients, and we did not find any superiority for the steroids. Finally, in case of no contraindication for steroids, we prefer the intra-flexor retinaculum injection. Larger studies should be performed in future studies in this field to confirm our results

Sphingomyelin as a myelin biomarker in CSF of acquired demyelinating neuropathies

Fast, accurate and reliable methods to quantify the amount of myelin still lack, both in humans and experimental models. The overall objective of the present study was to demonstrate that sphingomyelin (SM) in the cerebrospinal fluid (CSF) of patients affected by demyelinating neuropathies is a myelin biomarker. We found that SM levels mirror both peripheral myelination during development and small myelin rearrangements in experimental models. As in acquired demyelinating peripheral neuropathies myelin breakdown occurs, SM amount in the CSF of these patients might detect the myelin loss. Indeed, quantification of SM in 262 neurological patients showed a significant increase in patients with peripheral demyelination (p\u2009=\u20093.81\u2009*\u200910\u2009-\u20098) compared to subjects affected by non-demyelinating disorders. Interestingly, SM alone was able to distinguish demyelinating from axonal neuropathies and differs from the principal CSF indexes, confirming the novelty of this potential CSF index. In conclusion, SM is a specific and sensitive biomarker to monitor myelin pathology in the CSF of peripheral neuropathies. Most importantly, SM assay is simple, fast, inexpensive, and promising to be used in clinical practice and drug development

Serum neurofilament light chain: a promising early diagnostic biomarker for hereditary transthyretin amyloidosis?

Background and purpose: Hereditary transthyretin amyloidosis (ATTRv) is a life-threatening disease caused by mutations in the gene encoding transthyretin (TTR). The recent therapeutic advances have underlined the importance of easily accessible, objective biomarkers of both disease onset and progression. Preliminary evidence suggests a potential role in this respect for neurofilament light chain (NfL). In this study, the aim was to determine serum NfL (sNfL) levels in a late-onset ATTRv population and evaluate whether it might represent a reliable biomarker of disease onset (i.e., 'conversion' from the asymptomatic status to symptomatic disease in TTR mutation carriers). Methods: In all, 111 individuals harbouring a pathogenic TTR variant (61 symptomatic ATTRv patients and 50 presymptomatic carriers) were consecutively enrolled. Fifty healthy volunteers were included as the control group. Ella™ apparatus was used to assess sNfL levels. Results: Serum NfL levels were increased in ATTRv patients compared to both presymptomatic carriers and healthy controls, whilst not differing between carriers and healthy controls. An sNfL cut-off of 37.10 pg/mL could discriminate between asymptomatic and symptomatic individuals with high diagnostic accuracy (area under the curve 0.958; p < 0.001), sensitivity (81.4%) and specificity (100%). Conclusions: Serum NfL seems to be a promising biomarker of peripheral nerve involvement in ATTRv amyloidosis and might become a reliable, objective measure to detect the transition from the presymptomatic stage to the onset of symptomatic disease. Further longitudinal studies are needed to confirm such a role and determine whether it could equally represent a biomarker of disease progression and response to therapy

Plantar thermography is useful in the early diagnosis of diabetic neuropathy

OBJECTIVES: This study evaluated plantar thermography sensitivity and specificity in diagnosing diabetic polyneuropathy using cardiac tests (heart rate variability) as a reference standard because autonomic small fibers are affected first by this disease. METHODS: Seventy-nine individuals between the ages of 19 and 79 years old (28 males) were evaluated and divided into three groups: control (n = 37), pre-diabetics (n = 13) and type 2 diabetics (n = 29). The plantar images were recorded at baseline and then minutes after a provocative maneuver (Cold Stress Test) using an infrared camera that is appropriate for clinical use. Two thermographic variables were studied: the thermal recovery index and the interdigital anisothermal technique. Heart rate variability was measured in a seven-test battery that included three spectral indexes (in the frequency domain) and four Ewing tests (the Valsalva maneuver, the orthostatic test, a deep breathing test, and the orthostatic hypotension test). Other classically recommended tests were applied, including electromyography (EMG), Michigan inventory, and a clinical interview that included a neurological physical examination. RESULTS: Among the diabetic patients, the interdigital anisothermal technique alone performed better than the thermal recovery index alone, with a better sensitivity (81.3%) and specificity (46.2%). For the pre-diabetic patients, the three tests performed equally well. None of the control subjects displayed abnormal interdigital anisothermal readouts or thermal recovery indices, which precluded the sensitivity estimation in this sample of subjects. However, the specificity (70.6%) was higher in this group. CONCLUSION: In this study, plantar thermography, which predominately considers the small and autonomic fibers that are commonly associated with a sub-clinical condition, proved useful in diagnosing diabetic neuropathy early. The interdigital anisothermal test, when used alone, performed best

Transmembrane protease serine 5: a novel Schwann cell plasma marker for CMT1A

OBJECTIVE: Development of biomarkers for Charcot-Marie-Tooth (CMT) disease is critical for implementing effective clinical trials. The most common form of CMT, type 1A, is caused by a genomic duplication surrounding the PMP22 gene. A recent report (Neurology 2018;90:e518-3524) showed elevation of neurofilament light (NfL) in plasma of CMT1A disease patients, which correlated with disease severity. However, no plasma/serum biomarker has been identified that is specific to Schwann cells, the most directly affected cells in CMT1A. METHODS: We used the Olink immuno PCR platform to profile CMT1A patient (n = 47, 2 cohorts) and normal control plasma (n = 41, two cohorts) on five different Olink panels to screen 398 unique proteins. RESULTS: The TMPRSS5 protein (Transmembrane protease serine 5) was elevated 2.07-fold (P = <0.0001) in two independent cohorts of CMT1A samples relative to controls. TMPRSS5 is most highly expressed in Schwann cells of peripheral nerve. Consistent with early myelination deficits in CMT1A, TMPRSS5 was not significantly correlated with disease score (CMTES-R, CMTNS-R), nerve conduction velocities (Ulnar CMAP, Ulnar MNCV), or with age. TMPRSS5 was not significantly elevated in smaller sample sets from patients with CMT2A, CMT2E, CMT1B, or CMT1X. The Olink immuno PCR assays confirmed elevated levels of NfL (average 1.58-fold, P < 0.0001), which correlated with CMT1A patient disease score. INTERPRETATION: These data identify the first Schwann cell-specific protein that is elevated in plasma of CMT1A patients, and may provide a disease marker and a potentially treatment-responsive biomarker with good disease specificity for clinical trials

Reference values of the distal sensory median and ulnar nerves among newly hired workers

2021 Fall.Includes bibliographical references.Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy in the upper extremity and more common among workers in industrial occupations than in the general population (Atroshi et al., 1999; Mattioli et al., 2009; Palmer, Harris, & Coggon, 2007). Because of the high prevalence of CTS in certain industries, some employers have implemented post-offer pre-placement screening programs using nerve conduction studies (NCS) to identify those at higher risk of developing CTS. NCS are commonly used to identify the median neuropathy characteristic of CTS by assessing the nerve conduction speed of the median nerve. There have been a number of retrospective and prospective cohort studies that have examined the relationship between NCS indicating median neuropathy among workers and the subsequent development of CTS (Werner et al., 2001; Franzblau et al., 2004; Gell et al., 2005; Silverstein et al., 2010; Dale et al., 2014). These studies have indicated that workers with NCS indicating median neuropathy across the carpal tunnel who were initially asymptomatic for CTS, eventually developed CTS at a statistically significant greater rate than workers with normal nerve studies. Some employers have used NCS to identify workers at higher risk of developing CTS and placing them into low hand-intensive work tasks to reduce the high prevalence of work-related CTS. To identify workers at higher risk, their NCS results are often compared to population-based reference values. However, many of these published reference values are limited by their small samples sizes and unsuitable statistical methodologies (Dillingham et al., 2016). Further, some researchers have questioned whether population-based reference values are representative of working populations, especially those in industries with a high prevalence of abnormal NCS (Dale, Gardner, Buckner-petty, Strickland, & Evanoff, 2016; Salerno et al., 1998). The purpose of this dissertation research was to (1) establish reference values for NCS outcomes of the distal upper extremity from a large sample (N=17,630) of newly hired manufacturing workers using novel statistical methods more appropriate for nerve conduction data, (2) investigate comorbid conditions associated with nerve conduction outcomes, and (3) determine the sensitivity and specificity of CTS symptoms for identifying workers with median mononeuropathy