Pain and autonomic dysfunction in patients with sarcoidosis and small fibre neuropathy

Small fibre neuropathy (SFN) has been demonstrated in sarcoidosis. However, a systematic analysis of neuropathic pain and autonomic symptoms, key features of SFN, has not been performed. Clinimetric evaluation of pain and autonomic symptoms using the neuropathic pain scale (NPS) and the modified Composite Autonomic Symptoms Scale (mCOMPASS) was used in sarcoidosis patients for this study. A total of 91 sarcoidosis patients (n = 23 without SFN symptoms, n = 43 with SFN symptoms but normal intraepidermal nerve fibre density (IENFD), n = 25 with SFN symptoms and reduced IENFD) were examined. NPS and mCOMPASS were assessed twice (reliability studies). Severity of pain was compared between the subgroups. Correlation between NPS and a visual analogue pain scale (VAS) was assessed (validity studies). Healthy controls (n = 105) completed the mCOMPASS for comparison with patients’ scores. Patients with sarcoidosis, SFN complaints, and reduced IENFD demonstrated more severe pain scores on the NPS. The mCOMPASS differentiated between subjects with and without SFN symptoms. A significant correlation was obtained between the NPS and VAS, indicating good construct validity. Good reliability values were obtained for all scales. The use of the NPS to evaluate SFN symptoms is suggested, as it shows differences between patients with SFN symptoms with normal or reduced IENFD values. The mCOMPASS might be used to select patients for further testing

Intraepidermal nerve fiber density and its application in sarcoidosis

Background: Intraepidermal nerve fiber density (IENFD) is considered a good diagnostic tool for small fiber neuropathy (SFN). Objectives: To assess stratified normative values for IENFD and determine the reliability and validity of IENFD in sarcoidosis. Methods: IENFD was assessed in 188 healthy volunteers and 72 patients with sarcoidosis (n = 58 with SFN symptoms, n = 14 without SFN symptoms). Healthy controls were stratified (for age and sex), resulting image groups (20-29, 30-39, ... up to >= 70 years) containing at least 15 men and 15 women. A skin biopsy was taken in each participant 10 cm above the lateral malleolus and analyzed in accordance with the international guidelines using bright-field microscopy. Interobserver/intraobserver reliability of IENFD was examined. In the patients, a symptoms inventory questionnaire (SIQ; assessing SFN symptoms) and the Vickrey Peripheral Neuropathy Quality-of-Life Instrument-97 (PNQoL-97) were assessed to examine the discriminative ability of normative IENFD values. Results: There was a significant age-dependent decrease of IENFD values in healthy controls, with lower densities in men compared with women. Good interobserver/intraobserver reliability scores were obtained (kappa values >= 0.90). A total of 21 patients with sarcoidosis had a reduced IENFD score (<5th percentile; 19 [32.8%] in patients with SFN symptoms, 2 [14.3%] in patients without SFN symptoms). The validity of the normative IENFD values was demonstrated by distinguishing between the SIQ scores and various PNQoL-97 values for the different patient groups. Conclusion: This study provides clinically applicable distal intraepidermal nerve fiber density normative values, showing age-and sex-related differences. Neurology (R) 2009; 73: 1142-114

A gain-of-function sodium channel beta 2-subunit mutation in painful diabetic neuropathy

Diabetes mellitus (DM) is a global challenge with many diverse health sequelae, of which diabetic peripheral neuropathy (DPN) is one of the most common. A substantial number of patients with DPN develop chronic pain, but the genetic and epigenetic factors that predispose DPN patients to develop neuropathic pain are poorly understood. Recent targeted genetic studies have identified mutations in \u3b1-subunits of voltage-gated sodium channels (Navs) in patients with painful DPN. Mutations in proteins that regulate trafficking or functional properties of Navs could expand the spectrum of patients with Nav-related peripheral neuropathies. The auxiliary sodium channel \u3b2-subunits (\u3b21-4) have been reported to increase current density, alter inactivation kinetics, and modulate subcellular localization of Nav. Mutations in \u3b2-subunits have been associated with several diseases, including epilepsy, cancer, and diseases of the cardiac conducting system. However, mutations in \u3b2-subunits have never been shown previously to contribute to neuropathic pain. We report here a patient with painful DPN and negative genetic screening for mutations in SCN9A, SCN10A, and SCN11A-genes encoding sodium channel \u3b1-subunit that have been previously linked to the development of neuropathic pain. Genetic analysis revealed an aspartic acid to asparagine mutation, D109N, in the \u3b22 subunit. Functional analysis using current-clamp revealed that the \u3b22-D109N rendered dorsal root ganglion neurons hyperexcitable, especially in response to repetitive stimulation. Underlying the hyperexcitability induced by the \u3b22 subunit mutation, as evidenced by voltage clamp analysis, we found a depolarizing shift in the voltage-dependence of Nav1.7 fast-inactivation and reduced use-dependent inhibition of the Nav1.7 channel

Handgrip performance in relation to self-perceived fatigue, physical functioning and circulating IL-6 in elderly persons without inflammation

BACKGROUND: Low grip strength is recognized as one of the characteristics of frailty, as are systemic inflammation and the sensation of fatigue. Contrary to maximal grip strength, the physical resistance of the muscles to fatigue is not often included in the clinical evaluation of elderly patients. The aim of this study was to investigate if the grip strength and the resistance of the handgrip muscles to fatigue are related to self-perceived fatigue, physical functioning and circulating IL-6 in independently living elderly persons. METHODS: Forty elderly subjects (15 female and 25 male, mean age 75 ± 5 years) were assessed for maximal grip strength, as well as for fatigue resistance and grip work (respectively time and work delivered until grip strength drops to 50% of its maximum during sustained contraction), self perceived fatigue (VAS-Fatigue, Mob-Tiredness scale and the energy & fatigue items of the WHOQOL-100), self rated physical functioning (domain of physical functioning on the MOS short-form) and circulating IL-6. Relationships between handgrip performance and the other outcome measures were assessed. RESULTS: In the male participants, fatigue resistance was negatively related to actual sensation of fatigue (VAS-F, p < .05) and positively to circulating IL-6 (p < .05). When corrected for body weight, the relations of fatigue resistance with self-perceived fatigue became stronger and also apparent in the female. Grip strength and grip work were significantly related with several items of self-perceived fatigue and with physical functioning. These relations became more visible by means of higher correlation coefficients when grip strength and grip work were corrected for body weight. CONCLUSION: Well functioning elderly subjects presenting less handmuscle fatigue resistance and weaker grip strength are more fatigued, experience more tiredness during daily activities and are more bothered by fatigue sensations. Body weight seems to play an important role in the relation of muscle performance to fatigue perception. Elderly patients complaining from fatigue should be physically assessed, both evaluating maximal grip strength and fatigue resistance, allowing the calculation of grip work, which integrates both parameters. Grip work might best reflect the functional capacity resulting from the development of a certain strength level in relation to the time it can be maintained

Correspondence between neurophysiological and clinical measurements of chemotherapy-induced peripheral neuropathy: secondary analysis of data from the CI-PeriNoms study

Chemotherapy-induced peripheral neuropathy (CIPN) lacks standardized clinical measurement. The objective of the current secondary analysis was to examine data from the CIPN Outcomes Standardization (CI-PeriNomS) study for associations between clinical examinations and neurophysiological abnormalities. Logistic regression estimated the strength of associations of vibration, pin, and monofilament examinations with lower limb sensory and motor amplitudes. Examinations were classified as normal (0), moderately abnormal (1), or severely abnormal (2). Among 218 participants, those with class 1 upper extremity (UE) and classes 1 or 2 lower extremity (LE) monofilament abnormality were 2.79 (95% confidence interval [CI]: 1.28-6.07), 3.49 (95%CI: 1.61-7.55), and 4.42 (95%CI: 1.35-14.46) times more likely to have abnormal sural nerve amplitudes, respectively, compared to individuals with normal examinations. Likewise, those with class 2 UE and classes 1 or 2 LE vibration abnormality were 8.65 (95%CI: 1.81-41.42), 2.54 (95%CI: 1.19-5.41), and 7.47 (95%CI: 2.49-22.40) times more likely to have abnormal sural nerve amplitudes, respectively, compared to participants with normal examinations. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes and are useful in identifying CIPN

230th ENMC International Workshop:: Improving future assessment and research in IgM anti-MAG peripheral neuropathy: A consensus collaborative effort, Naarden, The Netherlands, 24–26 February 2017

The 230th European Neuromuscular Center (ENMC) international workshop occurred in Naarden, the Netherlands, from February 24th to 26th, 2017. The aims of the workshop were: 1) to create an IgM associated peripheral neuropathy study group and achieve consensus regarding the registration of patients with IgM associated peripheral neuropathy in a patient-based registry, 2) to improve future assessment of patients with IgM associated peripheral neuropathy from hematological markers to clinical trials, and 3) to discuss promising therapies for future clinical trials. Seventeen clinicians and researchers (sixteen neurologists and one hematologist) from nine countries (Belgium, Curaçao, France, Italy, the Netherlands, Spain, Switzerland, the United Kingdom, and the United States of America) were present. A patient with IgM associated peripheral neuropathy, a representative of the GBS/CIDP Foundation International, and a PhD student, who received support from the ENMC Young Scientist Program, also attended

Network topology of NaV1.7 mutations in sodium channel-related painful disorders

Background: Gain-of-function mutations in SCN9A gene that encodes the voltage-gated sodium channel NaV1.7 have been associated with a wide spectrum of painful syndromes in humans including inherited erythromelalgia, paroxysmal extreme pain disorder and small fibre neuropathy. These mutations change the biophysical properties of NaV1.7 channels leading to hyperexcitability of dorsal root ganglion nociceptors and pain symptoms. There is a need for better understanding of how gain-of-function mutations alter the atomic structure of Nav1.7. Results: We used homology modeling to build an atomic model of NaV1.7 and a network-based theoretical approach, which can predict interatomic interactions and connectivity arrangements, to investigate how pain-related NaV1.7 mutations may alter specific interatomic bonds and cause connectivity rearrangement, compared to benign variants and polymorphisms. For each amino acid substitution, we calculated the topological parameters betweenness centrality (Bct), degree (D), clustering coefficient (CCct), closeness (Cct), and eccentricity (Ect), and calculated their variation (value= mutantvalue-WTvalue). Pathogenic NaV1.7 mutations showed significantly higher variation of |Bct| compared to benign variants and polymorphisms. Using the cut-off value \uc2\ub10.26 calculated by receiver operating curve analysis, we found that Bctcorrectly differentiated pathogenic NaV1.7 mutations from variants not causing biophysical abnormalities (nABN) and homologous SNPs (hSNPs) with 76% sensitivity and 83% specificity. Conclusions: Our in-silico analyses predict that pain-related pathogenic NaV1.7 mutations may affect the network topological properties of the protein and suggest |Bct| value as a potential in-silico marker

Fatigue in neuromuscular disorders: focus on Guillain–Barré syndrome and Pompe disease

Fatigue accounts for an important part of the burden experienced by patients with neuromuscular disorders. Substantial high prevalence rates of fatigue are reported in a wide range of neuromuscular disorders, such as Guillain–Barré syndrome and Pompe disease. Fatigue can be subdivided into experienced fatigue and physiological fatigue. Physiological fatigue in turn can be of central or peripheral origin. Peripheral fatigue is an important contributor to fatigue in neuromuscular disorders, but in reaction to neuromuscular disease fatigue of central origin can be an important protective mechanism to restrict further damage. In most cases, severity of fatigue seems to be related with disease severity, possibly with the exception of fatigue occurring in a monophasic disorder like Guillain–Barré syndrome. Treatment of fatigue in neuromuscular disease starts with symptomatic treatment of the underlying disease. When symptoms of fatigue persist, non-pharmacological interventions, such as exercise and cognitive behavioral therapy, can be initiated