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Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes (SCG) expressed in a nociceptive pathway in painful and painless DPN and painful and painless SFN patients, and to provide a perspective for clinicians who assess patients with painful peripheral neuropathy. Between June 2014 and September 2016, 1125 patients with painful-DPN (n = 237), painless-DPN (n = 309), painful-SFN (n = 547) and painless-SFN (n = 32), recruited in four different centers, were analyzed for SCN3A, SCN7A-SCN11A and SCN1B-SCN4B variants by single molecule Molecular inversion probes-Next Generation Sequence. Patients were grouped based on phenotype and the presence of SCG variants. Screening of SCN3A, SCN7A-SCN11A, and SCN1B-SCN4B revealed 125 different (potential) pathogenic variants in 194 patients (17.2%, n = 194/1125). A potential pathogenic variant was present in 18.1% (n = 142/784) of painful neuropathy patients vs. 15.2% (n = 52/341) of painless neuropathy patients (17.3% (n = 41/237) for painful-DPN patients, 14.9% (n = 46/309) for painless-DPN patients, 18.5% (n = 101/547) for painful-SFN patients, and 18.8% (n = 6/32) for painless-SFN patients). Of the variants detected, 70% were in SCN7A, SCN9A, SCN10A and SCN11A. The frequency of SCN9A and SCN11A variants was the highest in painful-SFN patients, SCN7A variants in painful-DPN patients, and SCN10A variants in painless-DPN patients. Our findings suggest that rare SCG genetic variants may contribute to the development of painful neuropathy. Genetic profiling and SCG variant identification should aid in a better understanding of the genetic variability in patients with painful and painless neuropathy, and may lead to better risk stratification and the development of more targeted and personalized pain treatments. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to determine electrocardiographic (ECG) criteria predicting abnormal infrahissian conduction in patients with myotonic dystrophy type 1 (DM1), as these criteria could be used to identify the need for an electrophysiological study (EPS).Methods and Results: A retrospective multicentre study was conducted including DM1-affected individuals who underwent EPS between 2007 and 2018. For each individual, EPS indication, His-ventricle (HV) interval, resting ECG parameters prior to EPS, left ventricular ejection fraction (LVEF), neurological status, and DM1 DNA analysis results were collected. Electrocardiographic parameters of patients with a normal HV interval were compared with ECG parameters of patients with a prolonged HV interval. Logistic regression was performed to determine predictors for a prolonged HV interval of ≥70 ms on EPS and diagnostic accuracy of ECG parameters was ascertained. Among 100 DM1-affected individuals undergoing EPS, 47 had a prolonged HV interval. The sole presence of a PR interval >200 ms [odds ratio (OR) 8.45, confidence interval (CI) 2.64-27.04] or a QRS complex >120 ms (OR 9.91, CI 3.53-27.80) on ECG were independent predictors of a prolonged HV interval. The combination of both parameters had a positive predictive value of 78% for delayed infrahissian conduction on EPS. His-ventricle interval was independent of DM1 genetic mutation size, neuromuscular status, and LVEF.Conclusion: The combination of a prolonged PR interval and widened QRS complex on ECG accurately predicts abnormal infrahissian conduction on EPS in patients with DM1. These ECG parameters could be used as a screening tool to determine the need for referral to a specialized multidisciplinary neuromuscular team with EPS capacity. [ABSTRACT FROM AUTHOR]

Background: Neuropathic pain is common in peripheral neuropathy. Recent genetic studies have linked pathogenic voltage-gated sodium channel (VGSC) variants to human pain disorders. Our aims are to determine the frequency of SCN9A, SCN10A and SCN11A variants in patients with pure small fibre neuropathy (SFN), analyse their clinical features and provide a rationale for genetic screening.Methods: Between September 2009 and January 2017, 1139 patients diagnosed with pure SFN at our reference centre were screened for SCN9A, SCN10A and SCN11A variants. Pathogenicity of variants was classified according to established guidelines of the Association for Clinical Genetic Science and frequencies were determined. Patients with SFN were grouped according to the VGSC variants detected, and clinical features were compared.Results: Among 1139 patients with SFN, 132 (11.6%) patients harboured 73 different (potentially) pathogenic VGSC variants, of which 50 were novel and 22 were found in ≥ 1 patient. The frequency of (potentially) pathogenic variants was 5.1% (n=58/1139) for SCN9A, 3.7% (n=42/1139) for SCN10A and 2.9% (n=33/1139) for SCN11A. Only erythromelalgia-like symptoms and warmth-induced pain were significantly more common in patients harbouring VGSC variants.Conclusion: (Potentially) pathogenic VGSC variants are present in 11.6% of patients with pure SFN. Therefore, genetic screening of SCN9A, SCN10A and SCN11A should be considered in patients with pure SFN, independently of clinical features or underlying conditions. [ABSTRACT FROM AUTHOR]

Symptomatic treatment of neuropathic pain in small fibre neuropathy is often disappointing. The finding of voltage-gated sodium channel mutations in small fibre neuropathy (with mutations in SCN9A, encoding for Nav1.7) being most frequently reported suggest a specific target for therapy. The anticonvulsant lacosamide acts on Nav1.3, Nav1.7, and Nav1.8. The aim of this study was to evaluate the efficacy, safety, and tolerability of lacosamide as a potential treatment for pain in Nav1.7-related small fibre neuropathy. The Lacosamide-Efficacy-'N'-Safety in SFN (LENSS) was a randomized, placebo-controlled, double-blind, crossover-design study. Subjects were recruited in the Netherlands between November 2014 and July 2016. Patients with Nav1.7-related small fibre neuropathy were randomized to start with lacosamide followed by placebo or vice versa. In both 8-week treatment phases, patients received 200 mg two times a day (BID), preceded by a titration period, and ended by a tapering period. The primary outcome was efficacy, defined as the proportion of patients with 1-point average pain score reduction compared to baseline using the Pain Intensity Numerical Rating Scale. The trial is registered with ClinicalTrials.gov, number NCT01911975. Twenty-four subjects received lacosamide, and 23 received placebo. In 58.3% of patients receiving lacosamide, mean average pain decreased by at least 1 point, compared to 21.7% in the placebo group [sensitivity analyses, odds ratio 5.65 (95% confidence interval: 1.83-17.41); P = 0.0045]. In the lacosamide group, 33.3% reported that their general condition improved versus 4.3% in the placebo group (P-value = 0.0156). Additionally, a significant decrease in daily sleep interference, and in surface pain intensity was demonstrated. No significant changes in quality of life or autonomic symptoms were found. Lacosamide was well tolerated and safe in use. This study shows that lacosamide has a significant effect on pain, general wellbeing, and sleep quality. Lacosamide was well tolerated and safe, suggesting that it can be used for pain treatment in Nav1.7-related small fibre neuropathy. [ABSTRACT FROM AUTHOR]

Background: Whereas the treatment of motor symptoms in Huntington's disease (HD) receives much attention, less is known about the treatment of neuropsychiatric symptoms., Objective: We aim to give an overview of psychotropic drug use in the treatment of neuropsychiatric symptoms across disease stages in HD., Methods: We conducted a descriptive cross-sectional study of psychotropic drug prescriptions in a large longitudinal database of HD patients, Enroll HD. Across disease stages, the number of prescriptions per medication class, as well as the registered indications for these prescriptions were listed, and compared with that in gene negative participants., Results: Of the 8967 included HD patients, 80% were using at least one psychotropic drug, compared to 27% of gene negative participants. In HD patients, 51% of all drug prescriptions was for psychotropic drugs. The average number of psychotropic drugs used per patient increased from 1.3 in the premanifest stage to 2.5 in stage 5. With progressing disease stages, the proportion of antidepressant drug prescriptions gradually decreased from 74.1% of all prescriptions to 27.3%, and antipsychotic drug prescriptions increased from 7.0% to 38.7%. In line with this, depression and anxiety as listed indications for prescription decreased with advancing disease stages (from 63.0% to 31.5% and from 30.0% to 15.4% respectively), whereas irritability and psychosis increased (from 3.1% to 28.6% and from 0.9% to 16.0% respectively)., Conclusions: Psychotropic medication is widely prescribed in HD, for various indications. Antidepressant use decreases proportionally and antipsychotic use increases with advancing disease stages, suggesting a relative decrease in prevalence of anxiety and depression over disease stages on one hand, and a relative increase in prevalence of irritability and delusions on the other., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Stimulated skin wrinkling test (SSW) has been launched as a non-invasive diagnostic procedure. However, no normative age dependent values have been reported that can be applied in clinical practice. The objectives of the study were to (1) collect age-dependent normative values according to the 5-point scale assessment for the SSW, to (2) determine reliability scores for the obtained norm values, and to (3) introduce a new digital method for SSW assessment, the Digit Wrinkle Scan© (DWS©) for detection of wrinkles in a more quantitative manner., Methods: Firstly, 82 healthy participants were included, divided in 5 age groups. The participants underwent SSW using lidocaine and prilocaine topical cream. Secondly, 35 healthy participants were included to test whether the DWS© could be a novel manner to assess the grade of wrinkling quantitatively. We determined the inter-observer reliability of both methods. Also, the intra-observer reliability was calculated for the DWS©., Results: We found a decrease in normative values over age. The inter-observer reliability of assessment by the 5-point scale method was moderate after SSW (Cohen's k: 0.53). Results of the DWS© indicate that total wrinkle length per mm 2 showed moderate to good agreement for the 4th and 5th digits after SSW, and a low agreement for the other digits., Conclusions: Age-dependent normative values were obtained according to the 5-point scale, but its clinical application is doubtful since we found a moderate inter-observer reliability. We introduced the DWS© as a possible new method in order to quantify the grade of wrinkling., Significance: We found unsatisfactory reliability scores, which hampers its usefulness for clinical practice., Competing Interests: None of the authors have potential conflicts of interest to be disclosed., (© 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)

Aims: The role of inflammation in conventional cutaneous melanoma has been extensively studied, whereas only little is known about the inflammatory microenvironment and immunogenic properties of spitzoid melanocytic neoplasms. The composition of infiltrating immune cells and the architectural distribution of the inflammation, in particular, are still obscure. This is the first study, to our knowledge, to systematically characterise the inflammatory patterns and the leucocyte subsets in spitzoid melanocytic lesions., Methods and Results: We examined 79 spitzoid neoplasms including banal Spitz naevi (SN, n = 50), atypical Spitz tumours (AST, n = 17) and malignant Spitz tumours (MST, n = 12) using histopathological analysis and immunohistochemistry. Spitzoid melanocytic lesions showed a high frequency (67.1%, n = 53 of 79) of inflammation. Four inflammatory patterns were identified according to architectural composition, distribution and intensity of inflammation. The majority of the inflammatory infiltrate corresponded to CD3 + /CD8 + T lymphocytes (56.1%), followed by CD3 + /CD4 + T cells (35.7%) and CD68 + histiocytes (20.3%). CD3 + /TIA-1 + cytotoxic T lymphocytes constituted 3.7% of inflammatory cells. Rarely, CD3 + / granzyme B + cytotoxic T lymphocytes (2.7%) and CD138 + plasma cells (0.5%) were detected in the infiltrating immune cells. There was no significant difference in the inflammatory cellular composition among the spitzoid melanocytic subgroups (SN versus AST versus MST)., Conclusion: Our findings demonstrate that Spitz tumours are highly immunogenic lesions. Inflammation with the presence of lymphocytic aggregates predominated in SN, but was not distinctive for this melanocytic category. A strong and intense inflammation was suggestive of an underlying malignancy. The infiltrating cytotoxic T lymphocyte subsets in Spitz tumours deserve further investigation in larger study cohorts to elucidate prognostic and immuno-oncological therapeutic relevance., (© 2020 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Aims: The aim of this study was to determine electrocardiographic (ECG) criteria predicting abnormal infrahissian conduction in patients with myotonic dystrophy type 1 (DM1), as these criteria could be used to identify the need for an electrophysiological study (EPS)., Methods and Results: A retrospective multicentre study was conducted including DM1-affected individuals who underwent EPS between 2007 and 2018. For each individual, EPS indication, His-ventricle (HV) interval, resting ECG parameters prior to EPS, left ventricular ejection fraction (LVEF), neurological status, and DM1 DNA analysis results were collected. Electrocardiographic parameters of patients with a normal HV interval were compared with ECG parameters of patients with a prolonged HV interval. Logistic regression was performed to determine predictors for a prolonged HV interval of ≥70 ms on EPS and diagnostic accuracy of ECG parameters was ascertained. Among 100 DM1-affected individuals undergoing EPS, 47 had a prolonged HV interval. The sole presence of a PR interval >200 ms [odds ratio (OR) 8.45, confidence interval (CI) 2.64-27.04] or a QRS complex >120 ms (OR 9.91, CI 3.53-27.80) on ECG were independent predictors of a prolonged HV interval. The combination of both parameters had a positive predictive value of 78% for delayed infrahissian conduction on EPS. His-ventricle interval was independent of DM1 genetic mutation size, neuromuscular status, and LVEF., Conclusion: The combination of a prolonged PR interval and widened QRS complex on ECG accurately predicts abnormal infrahissian conduction on EPS in patients with DM1. These ECG parameters could be used as a screening tool to determine the need for referral to a specialized multidisciplinary neuromuscular team with EPS capacity., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Determination of disease onset in Huntington's disease is made by clinical experience. The diagnostic confidence level is an assessment regarding the certainty about the clinical diagnosis based on motor signs. A level of 4 means the rater has ≥99% confidence motor abnormalities are unequivocal signs of disease. However, it does not state which motor abnormalities are signs of disease and how many must be present., Objective: Our aim is to explore how accurate the diagnostic confidence level is in estimating disease onset using the Enroll-HD data set. For clinical disease onset we use a cut-off total motor score >5 of the Unified Huntington's Disease Rating Scale. This score is used in the TRACK-HD study, with ≤5 indicating no substantial motor signs in premanifests., Methods: At baseline premanifest participants who converted to manifest (converters) and non-converters were compared for clinical symptoms and diagnostic confidence level. Clinical symptoms and diagnostic confidence levels were longitudinally displayed in converters., Results: Of 3731 eligible participants, 455 were converters and 3276 non-converters. Baseline diagnostic confidence levels were significantly higher in converters compared to non-converters ( P < 0.001). 232 (51%) converters displayed a baseline motor score >5 (mean = 6.7). Converters had significantly more baseline clinical symptoms, and higher disease burden compared to non-converters ( P < 0.001). Diagnostic confidence level before disease onset ranged between 1 and 3 in converters., Conclusions: According to this data the diagnostic confidence level is not an accurate instrument to determine phenoconversion. With trials evaluating disease modifying therapies it is important to develop more reliable diagnostic criteria., Competing Interests: No specific funding was received for this research. The authors declare that there is no conflict of interest., (© 2021 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.)

Introduction: Endometriosis is a benign gynecological disease with a high disease burden and significant, multifaceted impact on health-related quality of life (HRQoL) and sexual quality of life (SQoL)., Aim: To explore which patient- and disease-specific characteristics were independently associated with SQoL., Methods: A literature search was carried out to identify characteristics with an evidence-based or hypothesized effect on SQoL. Subsequently, data on HRQoL in women with endometriosis (n = 224), collected between 2013 and 2018 in a prospective longitudinal Dutch cohort study performed in 7 referral centers, were used to perform a cross-sectional cohort study. Data were collected using an online self-administered survey including the validated Endometriosis Health Profile-30. Inclusion criteria were recently diagnosed endometriosis patients or newly referred patients with a clinical diagnosis of endometriosis. Patients were excluded in case of incomplete answers on the SQoL questions. Univariate analyses and multiple linear regression analyses were performed., Outcomes: SQoL, measured by the 5-item "sexual intercourse" dimension score of the modular Endometriosis Health Profile-30 questionnaire, was the primary outcome with scores ranging from 0 to 100 (0 indicating the best and 100 indicating the worst health status)., Results: Based on a literature search, 29 characteristics potentially associated with SQoL were selected from the survey and included in the analyses. In total, 192 women (mean age 36 years) met the inclusion criteria. The majority of women (86.5%) had had intercourse in the period before completing the survey and the study population showed a mean SQoL score of 47.5 ± 29.6, indicating moderate SQoL. Worse SQoL was independently associated with dyspareunia (P < .001), worse HRQoL (P = .001), severity of dysmenorrhea (P = .017), and unemployed work status (P = .022)., Conclusion: In a cohort of women with endometriosis, worse SQoL was significantly and independently associated with the presence of dyspareunia, more severe dysmenorrhea, worse HRQoL, and unemployed work status. van Poll M, van Barneveld E, Aerts L, et al. Endometriosis and Sexual Quality of Life. Sex Med 2020;8:532-544., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Microelectrode recordings (MER) are used to optimize lead placement during subthalamic nucleus deep brain stimulation (STN-DBS). To obtain reliable MER, surgery is usually performed while patients are awake. Procedural sedation and analgesia (PSA) is often desirable to improve patient comfort, anxiolysis and pain relief. The effect of these agents on MER are largely unknown. The objective of this study was to determine the effects of commonly used PSA agents, dexmedetomidine, clonidine and remifentanil and patient characteristics on MER during DBS surgery., Methods: Data from 78 patients with Parkinson's disease (PD) who underwent STN-DBS surgery were retrospectively reviewed. The procedures were performed under local anesthesia or under PSA with dexmedetomidine, clonidine or remifentanil. In total, 4082 sites with multi-unit activity (MUA) and 588 with single units were acquired. Single unit firing rates and coefficient of variation (CV), and MUA total power were compared between patient groups., Results: We observed a significant reduction in MUA, an increase of the CV and a trend for reduced firing rate by dexmedetomidine. The effect of dexmedetomidine was dose-dependent for all measures. Remifentanil had no effect on the firing rate but was associated with a significant increase in CV and a decrease in MUA. Clonidine showed no significant effect on firing rate, CV or MUA. In addition to anesthetic effects, MUA and CV were also influenced by patient-dependent variables., Conclusion: Our results showed that PSA influenced neuronal properties in the STN and the dexmedetomidine (DEX) effect was dose-dependent. In addition, patient-dependent characteristics also influenced MER.

Background: Though obesity is a well-known risk factor for vascular disease, the impact of obesity on stroke outcome has been disputed. Several studies have shown that obesity is associated with better functional outcome after stroke. Whether obesity influences the benefit of endovascular treatment (EVT) in stroke patients is unknown. We evaluated the association between body mass index (BMI) and outcome in acute ischemic stroke patients with large vessel -occlusion (LVO), and assessed whether BMI affects the -benefit of EVT., Methods: This is a post hoc analysis of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands trial (-ISRCTN10888758). BMI was used as a continuous and categorical variable, distinguishing underweight and normal weight (BMI <25), overweight (BMI 25-30), and obesity (BMI ≥30). We used multivariable ordinal logistic regression analysis to estimate the association of BMI with functional outcome (shift analysis), assessed with modified Rankin Scale (mRs) at 90 days. The impact of BMI on EVT effect was tested by the use of a multiplicative interaction term., Results: Of 366 patients, 160 (44%) were underweight or normal weight, 145 (40%) overweight, and 61 (17%) were obese. In multivariable analysis with BMI as a continuous variable, we found a shift toward better functional outcome with higher BMI (mRS adjusted common OR 1.04; 95% CI 1.0-1.09), and mortality was inversely related to BMI (aOR 0.92; 95% CI 0.85-0.99). Safety analysis showed that higher BMI was associated with lower risk of stroke progression (aOR 0.92, 95% CI 0.87-0.99). Additional analysis showed no interaction between BMI and EVT effect on functional outcome, mortality, and other safety outcomes., Conclusion: Our study confirms the effect of obesity on outcome in acute ischemic stroke patients with LVO, meaning better functional outcome, lower mortality, and lower risk of stroke progression for patients with higher BMI. As we found no interaction between BMI and EVT effect, all BMI classes may expect the same benefit from EVT., (The Author(s). Published by S. Karger AG, Basel.)