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Objectives: Assessment of sudomotor function by distal electrochemical skin conductance (ESC) can provide an index of peripheral neuropathy. This study explored ESC in fibromyalgia (FM) patients, controlling for tricyclic antidepressant use and body mass index, and its association with the clinical severity of the disease., Methods: ESC, clinical symptoms and an index of central pain sensitisation derived from pressure algometry were explored in thirty-three fibromyalgia patients and 33 healthy women., Results: ESC was significantly lower in fibromyalgia patients than healthy participants. About 51% of patients exhibited moderate-to-severe ESC dysfunction, indicative of possible neuropathy. However, ESC was not related to any indicators of clinical severity, nor to algometry. ESC only correlated with depression levels; the group differences in ESC disappeared after controlling for depression. Finally, ESC was asymmetric in the overall sample, with lower values seen in the right hand relative to the left one., Conclusions: The greater prevalence of sudomotor dysfunction in fibromyalgia patients is consistent with the presence of neuropathy in subgroups of patients, and with the basic heterogeneity of the disorder. However, neuropathy does not appear helpful for determining the clinical features of the disorders, or the level of central sensitisation measured by pressure algometry. Future studies including patients with fibromyalgia suffering and not suffering from depression as well as patients with depression but free from chronic pain, are required to identify the role of depression in the observed low ESC levels.

Sympathetic innervation of the sweat gland (SG) manifests itself electrically as electrodermal activity (EDA), which can be utilized to measure sudomotor function. Since SG exhibits similarities in structure and function with kidneys, quantification of SG activity is attempted through EDA signals. A methodology is developed with electrical stimulation, sampling frequency and signal processing algorithm. One hundred twenty volunteers participated in this study belonging to controls, diabetes, diabetic nephropathy, and diabetic neuropathy. The magnitude and time duration of stimuli is arrived by trial and error in such a way it does not influence controls but triggers SG activity in other Groups. This methodology leads to a distinct EDA signal pattern with changes in frequency and amplitude. The continuous wavelet transform depicts a scalogram to retrieve this information. Further, to distinguish between Groups, time average spectrums are plotted and mean relative energy (MRE) is computed. Results demonstrate high energy value in controls, and it gradually decreases in other Groups indicating a decline in SG activity on diabetes prognosis. The correlation for the acquired results was determined to be 0.99 when compared to the standard lab procedure. Furthermore, Cohen's d value, which is less than 0.25 for all Groups indicating the minimal effect size. Hence the obtained result is validated and statistically analyzed for individual variations. Thus this has the potential to get transformed into a device and could prevent diabetic kidney disease.

Background: More than 50% of patients with palmar hyperhidrosis (PAH) also have plantar hyperhidrosis (PLH). We compared the long-term results of T3 sympathectomy with those of combined T3+T4 sympathectomy among patients with concurrent PAH and PLH., Materials and Methods: We retrospectively analyzed the records of patients with concurrent PAH and PLH who underwent T3 alone or T3+T4 sympathectomy from January 1, 2012, to December 31, 2017. Preoperative and postoperative sweating (hyperhidrosis index) was evaluated through questionnaires, physical examination, and outpatient follow-up. The relief rates and hyperhidrosis index were used as outcome measures to compare the efficacy of the two approaches. Patients' satisfaction and side effects were also evaluated., Results: Of the 220 eligible patients, 60 underwent T3 sympathectomy (T3 group), and 160 underwent T3+T4 sympathectomy (T3+T4 group). Compared with the T3 group, the T3+T4 group showed higher symptom relief rates both for PAH (98.75% versus 93.33%, P = 0.048) and PLH (65.63% versus 46.67%, P = 0.01), and a greater postoperative decrease in both hyperhidrosis indices. The rate of severe compensatory hyperhidrosis also increased (10% versus 5%, P = 0.197), although the rates of overall satisfaction were comparable between the groups. The incidence of postoperative pneumothorax requiring chest tube placement and postoperative neuralgia was also similar. There were no cases of perioperative death, secondary operation, wound infection, or Horner syndrome in either group., Conclusions: Compared with T3 alone, T3+T4 sympathectomy achieved a higher symptom relief rate and a lower hyperhidrosis index. T3+T4 sympathectomy may be a choice for the treatment of concurrent PAH and PLH; however, patients need to be informed that this kind of surgery may increase the risk of compensatory sweating., (Copyright © 2020. Published by Elsevier Inc.)

People with intellectual disability (ID) experience cardiometabolic-related morbidity and mortality. However, it has been suggested that this population presents and lives with underestimated cardiovascular risk factors at a younger age, hence affecting their overall health and quality of life and contributing to early mortality. We assessed autonomic nervous system function in subjects with ID ( n = 39), aged 18-45 yr, through measures of sudomotor function, heart rate and systolic blood pressure variability, and cardiac baroreflex function. Traditional clinical cardiovascular measurements and a biochemical analysis were also undertaken. We found that young adults with ID presented with sudomotor dysfunction, impaired cardiac baroreflex sensitivity, and systolic blood pressure variability, when compared with age-matched control subjects ( n = 38). Reduced hand and feet electrochemical skin conductance and asymmetry were significantly associated with having a moderate-profound ID. Autonomic dysfunction in individuals with ID persisted after controlling for age, sex, and other metabolic parameters. Subjects in the ID group also showed significantly increased blood pressure, body mass index, and waist/hip circumference ratio, as well as increased plasma hemoglobin A1c and high-sensitivity C-reactive protein levels. We conclude that autonomic dysfunction is present in young adults with ID and is more marked in those with more severe disability. These finding have important implications in developing preventative strategies to reduce the risk of cardiovascular disease in people with ID. NEW & NOTEWORTHY Adults with intellectual disability experience higher risk of premature death than the general population. Our investigation highlights increased cardiovascular risk markers and autonomic dysfunction in young adults with intellectual disability compared with control adults. Autonomic dysfunction was more marked in those with a more severe disability but independent of cardiovascular parameters. Assessment of autonomic nervous system (ANS) function may provide insight into the mechanisms of cardiometabolic disease development and progression in young adults with intellectual disability.

Vasoactive Intestinal Peptide (VIP) is the major physiological agonist of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride channel activity. VIP functions as a neuromodulator and neurotransmitter secreted by neurons innervating all exocrine glands. VIP is also a potent vasodilator and bronchodilator that regulates exocrine gland secretions, contributing to local innate defense by stimulating the movement of water and chloride transport across intestinal and tracheobronchial epithelia. Previous human studies have shown that the rich intrinsic neuronal networks for VIP secretion around exocrine glands could be lost in tissues from patients with cystic fibrosis. Our research has since confirmed, in vitro and in vivo, the need for chronic VIP exposure to maintain functional CFTR chloride channels at the cell surface of airways and intestinal epithelium, as well as normal exocrine tissues morphology [1]. The goal of the present study was to examine changes in VIP in the lung, duodenum and sweat glands of 8- and 17-weeks old F508del/F508del mice and to investigate VIPergic innervation in the small intestine of CF mice, before important signs of the disease development. Our data show that a low amount of VIP is found in CF tissues prior to tissue damage. Moreover, we found a specific reduction in VIPergic and cholinergic innervation of the small intestine. The general innervation of the primary and secondary myenteric plexus was lost in CF tissues, with the presence of enlarged ganglionic cells in the tertiary layer. We propose that low amount of VIP in CF tissues is due to a reduction in VIPergic and cholinergic innervation and represents an early defect that constitutes an aggravating factor for CF disease progression., Competing Interests: Conflict of Interest Statement There are no conflicts of interest to declare., (Copyright © 2020. Published by Elsevier B.V.)

Hyperhidrosis is a dermatological condition defined by excessive sweating beyond thermoregulatory needs with significant effects on patients' quality of life. Hyperhidrosis is categorized as primary or secondary: primary hyperhidrosis is mostly focal and idiopathic, whereas secondary hyperhidrosis is commonly generalized and caused by an underlying medical condition or use of medications. Various surgical and nonsurgical therapies exist for primary hyperhidrosis. Although botulinum toxin is one of the deadliest toxins known, when used in small doses, it is one of the most effective therapies for primary hyperhidrosis. Botulinum toxin injections are widely used as a second-line primary hyperhidrosis treatment option once topical treatment strategies have failed. This article provides an overview of the commercially available botulinum toxin formulations and their applications in the treatment of primary hyperhidrosis., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Small fiber neuropathies (SFN) are associated with a reduction in quality of life. In adults, epidermal nerve fiber density (END) analysis is recommended for the diagnosis of SFN. In children, END assessment is not often performed. We analyzed small nerve fiber innervation to elucidate the potential diagnostic role of skin biopsies in young patients with pain., Methods: Epidermal nerve fiber density and sudomotor neurite density (SND) were assessed in skin biopsies from 26 patients aged 7 to 20 years (15 female patients) with unexplained chronic pain. The results were compared with clinical data., Results: Epidermal nerve fiber density was abnormal in 50% and borderline in 35% of patients. An underlying medical condition was found in 42% of patients, including metabolic, autoimmune, and genetic disorders., Discussion: Reduction of epidermal nerve fibers can be associated with treatable conditions. Therefore, the analysis of END in children with pain may help to uncover a possible cause and guide potential treatment options., (© 2019 The Authors. Muscle & Nerve published by Wiley Periodicals, Inc.)

Objective: To quantitatively analyze distribution characteristics of sweat gland nerve fibres (SGNF) in normal Chinese individuals for obtaining a reference for early diagnosis of peripheral neuropathy., Patients and Methods: Skin biopsy samples were collected from 192 normal Chinese individuals and divided into six, four and two groups according to anatomic sites, age and gender, respectively. SGNF morphology was observed and SGNF density (SGNFD) was determined., Results: There was a significant difference in SGNFD among different anatomic sites, age and gender. A degressive tendency was observed from proximal to distal anatomic sites. SGNFD was the lowest in subjects in the 21-40-year-old age group, but was the highest in subjects in the >61-year-old age group. Overall, SGNFD fluctuated with age. SGNFD in males was significantly higher than that in females., Conclusions: Distribution characteristics of SGNF in normal individuals may serve as a reference for early diagnosis of nerve fibre damage., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Forearm QSWEAT recordings are occasionally absent in females, likely due to high skin resistance., Methods: We identified consecutive subjects with no sudomotor abnormalities but absent/markedly reduced QSWEAT forearm volume, and repeated QSWEAT at the same site after gentle abrasion., Results: QSWEAT volumes were absent for 4 subjects and markedly reduced for the other 4 (median 0.01, IQR 0-0.03). After gentle skin abrasion, repeat volumes were significantly higher for all subjects and became normal in 7 of 8 subjects., Discussion: Skin abrasion restores QSWEAT volumes in previously absent/markedly reduced site suggesting that skin preparation using abrasion is more effective., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: The main therapeutic method of treatment for local hyperhidrosis is endoscopic thoracic sympathectomy. Generally, resections of the sympathetic trunk or ganglia are performed between the second rib and sixth rib. However, this procedure can result in compensatory sweating, in which excess sweating occurs on the back, chest, and abdomen. Compensatory sweating has been regarded as a thermoregulatory response and thought to be untreatable. This study suggests that compensatory sweating is not a physiologic reaction and is indeed treatable., Methods: Eight patients with severe compensatory sweating were treated by observing blood perfusion of the skin with laser speckle flowgraphy, which determines the sympathetic nerves related to the area of skin with compensatory sweating. When intraoperative monitoring with laser speckle flowgraphy indicated the position of compensatory sweating by electrical stimulation of the sympathetic ganglion, ganglionectomy was performed., Results: The skin domain that each sympathetic nerve controls was able to be detected by laser speckle flowgraphy. In all patients, compensatory sweating was resolved after interruption of the ganglia or sympathetic nerves related to compensatory sweating., Conclusions: Our results demonstrate that compensatory sweating is caused by denatured sympathetic nerves influenced by endoscopic thoracic sympathectomy and is not the result of a physiological response. With laser speckle flowgraphy, the sympathetic nerve related to the sweating of various parts of the body could be identified. The treatment of compensatory sweating on the back, chest, and stomach was previously considered to be difficult; however, compensatory sweating is demonstrated to be treatable with this technique., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Excessive sweating is a clinical condition that can be improved with type-A botulinum toxin (BTX-A)., Objectives: To evaluate and compare the largest diameter of sweating inhibition halo (SIH) of 5 different commercially available BTX-A, in five different doses, in a 6-month-long clinical evaluation., Methods: Twenty-five adult female volunteers were injected in the dorsal trunk area with both 100 units (100UI) and 500 units (500UI) BTX-A products, reconstituted in a ratio of 1:2.5 IU, respectively. Products were applied in five different concentrations (1:2.5U, 2:5U, 3:7.5U, 4:10U, and 5:12.5U). After 30, 60, 90, 120, 150, and 180 days, a starch-iodine test was performed to obtain the largest diameter of each SIH., Results: The higher the number of units used, the larger the SIH p < 0.05 for all BTX-A. However, Botox®, Botulift®, Dysport®, and Prosigne® have pretty likewise SIH along the study, with some few differences for some doses and months between one and another. However, Xeomin® is the BTX-A with the smallest SIH, in comparison with all others, in any dose and period., Conclusions: Differences were observed among all brands of BTX-As, based on dose and time after injection. Xeomin® provides the smallest SIH in comparison with others BTX-A., (© 2018 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.)

Background:  The present study aimed to evaluate and compare the efficacy of botulinum toxin type A (BTX-A) injection versus thoracic sympathectomy for idiopathic palmar hyperhidrosis., Methods:  Fifty-one patients with idiopathic palmar hyperhidrosis were treated with either BTX-A injection or thoracic sympathectomy between March 2013 and April 2016. The severity of palmar hyperhidrosis was qualitatively measured via the Hyperhidrosis Disease Severity Scale (HDSS). All patients completed a questionnaire that detailed the time taken for the treatment to work, local or systemic adverse effects, and pre- and post-treatment severity of hyperhidrosis. The efficacy and adverse effects of the two treatments were compared and analyzed., Results:  Hyperhidrosis-related quality of life improved quickly and significantly in the BTX-A group (26 patients) and the sympathectomy group (25 patients). Compared with pre-treatment, the HDSS score significantly reduced after treatment in both groups ( p  < 0.05). All patients in the sympathectomy group had cessation of sweating of the hands after treatment, and this curative effect lasted for 12 months. In contrast, the treatment took more time to work in the BTX-A group, and the curative effect lasted for a much shorter period (3 months). The sympathectomy group had a significantly lesser mean HDSS score than the BTX-A group at 1 week, 3 months, 6 months, 9 months, and 12 months after treatment ( p  < 0.05). The sympathectomy group experienced more complications than the BTX-A group., Conclusion:  For palmar hyperhidrosis, thoracic sympathectomy is more effective and has a longer lasting curative effect than BTX-A injection, but thoracic sympathectomy has more complications., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

Background:  Patients with primary hyperhidrosis present with sweating in two or more sites in nearly 85% of cases. In this study, we examined whether the number of hyperhidrosis sites is related to the surgery outcomes., Methods:  One hundred ninety-three hyperhidrosis patients who underwent bilateral videothoracoscopic sympathectomy after failure or dissatisfaction with clinical treatment were distributed into three groups based on the number of hyperhidrosis sites (one site, two sites, and three or more sites of hyperhidrosis). The primary endpoints in the study were as follows: quality of life prior to surgery, improvement of quality of life after surgery, clinical improvement of sweating, presence or absence of compensatory hyperhidrosis, and general satisfaction after 1 month of surgery., Results:  Patients with two or more hyperhidrosis sites had worse quality of life before surgery than patients with a single hyperhidrosis site. There was an improvement in the quality of life in more than 95% of the patients, clinical improvement in more than 95% of patients, severe compensatory hyperhidrosis in less than 10%, and low general satisfaction after 1 month of surgery in only 2.60% of the patients, with no differences among the three groups., Conclusions:  Patients with more than one preoperative hyperhidrosis site present worse quality of life prior to surgery than those with a single hyperhidrosis site, but the number of hyperhidrosis sites before surgery does not affect surgery outcomes., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Background:  Primary hyperhidrosis is a condition that significantly decreases the quality of life (QOL). Thoracic sympathectomy is safe and efficient method of treatment in palmar hyperhidrosis., Objective:  The aim of the study was to evaluate the change in QOL in patients with palmar hyperhidrosis who underwent thoracic sympathectomy., Methods:  The study includes 149 patients (37 men and 112 women) who were treated with bilateral thoracoscopic sympathectomy for primary palmar hyperhidrosis. Subjective and objective evaluation of hyperhidrosis were performed prior to the surgery, 3 and 12 months after the treatment. Control group consists of 305 healthy volunteers (118 men and 187 women). The QOL was measured using Functional Assessment of Chronic Illness Therapy (FACIT) scale., Results:  The average level of palmar hyperhidrosis in the study group prior to surgery was 224.69 ± 179.20 mg/min/m 2 . General QOL (FACIT total) before the surgery was significantly lower in the study group when compared with the control group (66.57 ± 16.33 vs. 91.29 ± 11.13; p  < 0.05). Three months after surgery level of hyperhidrosis decreased significantly and remained at similar level 12 months after the procedure (13.55 ± 15.41 mg/min/m 2 p  < 0.05 and 14.41 ± 18.19 mg/min/m 2 p  < 0.05, respectively). After thoracoscopic sympathectomy, the QOL increased and did not differ when compared with the control group 3 and 12 months after the surgery (90.28 ± 11.13 vs. 91.29 ± 11.13; p  = 0.55 and 89.59 ± 11.34 vs. 91.29 ± 11.13; p  = 0.84, respectively). The highest increase was observed in functional well-being domain (32.25%); however, it was also noticeable in other domains., Conclusion:  Thoracic sympathectomy is an efficient method of treatment in palmar hyperhidrosis which significantly increases patients' QOL especially in a functional domain., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Background:  Video-assisted thoracoscopic surgery (VATS) clipping of the sympathetic branch has become the standard approach for the treatment of essential hyperhidrosis when conservative treatment failed. However, this is associated with relevant potential complications such as postoperative compensatory sweating and recurrent sweating. We report the outcome after selective sympathectomy (ramicotomy) through a miniuniportal VATS approach in patients with therapy-refractory palmar and/or axillary hyperhidrosis., Methods:  A total of 51 consecutive patients (37 females, mean age: 30 years, range: 12-64 years) who suffered from therapy-refractory palmar and/or axillary severe hyperhidrosis were included. Data were prospectively collected and retrospectively analyzed. All patients underwent bilateral miniuniportal VATS ramicotomy. Duration of surgery, hospital stay, recurrent, and compensatory sweating were documented., Results:  All patients had palmar sweating, where 51% had additional axillary sweating and 57% had additional plantar sweating. In all patients, selective division of the rami communicantes of the thoracic sympathetic ganglions Th2 to Th5 was performed. The mean duration of bilateral surgery for both sides was 67 ± 2.5 minutes. The mean postoperative hospital stay was 2 ± 1 days. After surgery and at further follow-up (mean: 12 ± 2.5 months), all patients presented dry and warm hands and axillae, without any evidence of compensatory or recurrent sweating. All patients described a remarkable increase in quality of life., Conclusion:  Miniuniportal VATS ramicotomy represents a feasible surgical technique with a very high success and satisfaction rate. Therefore, this approach should be considered as the method of choice for the treatment of patients with severe therapy-refractory palmar and axillary hyperhidrosis., Competing Interests: None to be declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Background:  Primary palmar hyperhidrosis (PPH) is featured by aberrantly perspiration of the hands, which may bring a lot of inconvenience to patient's daily life and work. The purpose of this study is to summarize the clinical effect of needlescopic video-assisted thoracic bilateral T4 sympathicotomy for the treatment of PPH., Patients and Methods:  Between January 2009 and March 2014, 200 patients received needlescopic video-assisted thoracic bilateral T4 sympathicotomy. We, respectively, took two 5-mm incisions in the third intercostal space on the anterior axillary line and in the fifth intercostal space on the middle axillary line. After collapsing left lung, needlescopic exploration was the first step to determine the targeted sympathetic chain through the third intercostal space. Electric coagulation hook was inserted from another port to cut T4 sympathetic chain and the bypassing nerve fibers for 2 to 3 cm along the surface of the fourth rib. Right thoracic cavity was also administered the same procedure. The palmar temperature was recorded before and after sympathicotomy. The symptom improvement, operative complications, patients' recovery, and satisfaction were evaluated., Finding:  One hundred and ninety-seven patients uneventfully received two 5-mm port bilateral sympathicotomy, and another 3 patients with extensive pleural adhesions completed the surgery through enlarging the third intercostal incision to 2 cm without conversion to open surgery. All operative procedures were completed in 15 to 35 minutes. The hospital stay was 2 to 4 days. The palmar temperature increased by 2.0 ± 0.5°C, and hyperhidrosis immediately disappeared in both hands after surgery. The efficacy rate was 100%. The postoperative complications such as hemorrhage, hemopneumothorax, bradycardia, or Horner's syndrome had no occurrence. During 6 to 60 months follow-up, mild compensatory sweating of buttock, back, and thigh occurred in 30 patients (15%) at 2 to 5 days after surgery and gradually disappeared at postoperative 15 to 30 days or longer time. All patients were greatly satisfied with the effect with better confidence and quality of life. Until now, no recurrent palmar hyperhidrosis happened., Conclusion:  Needlescopic video-assisted thoracic bilateral T4 sympathicotomy could reach an excellent and immediate result of treating PPH. It is a safe, convenient, and minimally invasive method appropriate for wide clinical use., Competing Interests: The authors report no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Skin biopsies have gained increasing popularity as a tool to evaluate disorders affecting small nerve fibers. While reports on sweat gland nerve fiber density (SGNFD) to quantitate sudomotor innervation have been promising, methodologies vary significantly. Although conventional stereology is commonly used, no standard technique has been established. We sought to develop an accurate and reproducible technique to quantify SGNFD. Skin punch biopsies from healthy individuals were cut and stained. Images of sweat glands (SGs) were acquired using confocal and widefield microscopes, and optimized using deconvolution. Nerve fibers were reconstructed and nerve fiber length (NFL) was quantified using three-dimensional (3D) automated software. SGNFD was obtained by dividing NFL by SG volume. SGNFD was also assessed using stereology for comparison. Ninety-two SGs from 10 healthy subjects were analyzed by independent observers. Using confocal microscopy, the software reliably traced nerve fibers. In contrast, rendering of nerve fibers was inferior using widefield microscopy. Interobserver reliability was suboptimal using widefield images compared to confocal (ICC = 0.82 vs ICC = 0.98). Correlation between 3D-reconstruction and stereology was poor (ICC = 0.38). The newly developed technique of SGNFD quantitation using 3D reconstruction of SG innervation with confocal microscopy reliably traces nerve fibers, shows outstanding reproducibility, is almost completely unbiased, and superior to conventional stereology methods., (© 2019 American Association of Neuropathologists, Inc. All rights reserved.)

Objectives: To examine whether post-treatment Lyme disease syndrome (PTLDS) defined by fatigue, cognitive complaints and widespread pain following the treatment of Lyme disease is associated with small fiber neuropathy (SFN) manifesting as autonomic and sensory dysfunction., Methods: This single center, retrospective study evaluated subjects with PTLDS. Skin biopsies for assessment of epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD) and functional autonomic testing (deep breathing, Valsalva maneuver and tilt test) were performed to assess SFN, severity of dysautonomia and cerebral blood flow abnormalities. Heart rate, end tidal CO2, blood pressure, and cerebral blood flow velocity (CBFv) from middle cerebral artery using transcranial Doppler were monitored., Results: 10 participants, 5/5 women/men, age 51.3 ± 14.7 years, BMI 27.6 ± 7.3 were analyzed. All participants were positive for Lyme infection by CDC criteria. At least one skin biopsy was abnormal in all ten participants. Abnormal ENFD was found in 9 participants, abnormal SGNFD in 5 participants, and both abnormal ENFD and SGNFD were detected in 4 participants. Parasympathetic failure was found in 7 participants and mild or moderate sympathetic adrenergic failure in all participants. Abnormal total CBFv score was found in all ten participants. Low orthostatic CBFv was found in 7 participants, three additional participants had abnormally reduced supine CBFv., Conclusions: SFN appears to be associated with PTLDS and may be responsible for certain sensory symptoms. In addition, dysautonomia related to SFN and abnormal CBFv also seem to be linked to PTLDS. Reduced orthostatic CBFv can be associated with cerebral hypoperfusion and may lead to cognitive dysfunction. Autonomic failure detected in PTLDS is mild to moderate. SFN evaluation may be useful in PTLDS., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Novak is advisor - independent Contractor for Dysimmune Diseases Foundation. Dr. Novak received speaker’s honoraria from KabaFusion. All other authors report no disclosures. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Aim: The aim of this study was to assess the relationship between sudomotor function and microvascular perfusion in patients with type 1 diabetes (DM1)., Methods: We evaluated 415 patients (206 women), with DM1, median age of 41 (IQR: 33-53) years, disease duration of 25 (IQR: 20-32) years. We assessed metabolic control of diabetes and the presence of peripheral and cardiac autonomic neuropathy. Sudomotor function was assessed using Sudoscan device by electrochemical skin conductance (ESC). Microvascular function was measured by laser-Doppler flowmetry with basal perfusion, the peak flow after occlusion (PORHpeak) and THmax which is the percentage change between basal perfusion and the peak flow during thermal hyperemia (TH). The accumulation of advanced glycation end products in the skin was assessed by skin autofluorescence (AF) measurement using AGE Reader. We subdivided patients based on the presence of diabetic peripheral neuropathy (DPN), cardiac autonomic neuropathy (CAN) and according to normal value of ESC., Results: Patients with abnormal ESC had higher skin AF [2.5 (2.1-2.9) vs 2.1 (1.9-2.5) AU, p < 0.001], lower eGFR [83 (72-96) vs 98 (86-108) ml/min/1.73 m2, p < 0.001], higher basal perfusion [25 (12-81) vs 14 (7-43) PU, p < 0.001], lower THmax [664 (137-1461) vs 1115 (346-1933) %, p = 0.002], higher PORHpeak [104 (59-167) vs 70 (48-135) PU, p < 0.001] as compared to subjects with normal ESC results. We found negative correlation between THmax and TG level (Rs = -0.14, p < 0.005), AF (Rs = -0.19, p = 0.001), vibration perception threshold - VPT (Rs = -0.24, p < 0.001) and positive correlation with HDL level (Rs = 0.14, p = 0.005), Feet ESC (Rs = 0.21, p < 0.001) and Hands ESC (Rs = 0.14, p = 0.004). We found positive correlation between PORHpeak and TG level (Rs = 0.14, p = 0.003), skin AF (Rs = 0.29, p < 0.001), VPT (0.27, p < 0.001) and negative correlation with eGFR (Rs = -0.2, p < 0.001), HDL (Rs = -0.12, p = 0.01), Feet ESC (Rs = -0.27, p < 0.001) and Hand ESC (Rs = -0.16, p = 0.002)., Conclusion: Impaired microvascular reactivity is associated with sudomotor dysfunction in patients with type 1 diabetes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: There are different techniques for thoracoscopic sympathectomy for management of primary hyperhidrosis. Each technique has the advantage of giving good surgical results, but may cause complications, which depend on the level of sympathectomy used in each technique., Methods: From October 2012 to August 2016, a total number of 120 patients (of primary palmar and axillary hyperhidrosis) were enrolled in this prospective randomized study. Patients were randomized preoperatively and divided into 2 groups: group A (underwent T2, T3, and T4 sympathectomy) and group B (underwent T3 and T4 sympathectomy) with 1 year of follow-up. Improvement of palm sweating, development of complications, patient satisfaction, and quality of life were evaluated., Results: Family history was positive in 33 patients (55%) in group A and in 31 patients (52%) in group B. All patients had improvement of hand sweating. Overdry hands were significant in group A (p = 0.032). Compensatory sweating was significant in group A after the first month (p = 0.016), after 6 months (p = 0.022), and after 12 months (p = 0.025). In group B, very satisfied patients were significant after 6 and 12 months (p = 0.002 and 0.000, respectively)., Conclusions: Limited sympathectomy to the level of T3 and T4 has the same therapeutic effect obtained by T2, T3, and T4 sympathectomy with less complications, greater patient satisfaction, and better quality of life. It should be the technique of choice for treatment of primary palmar and axillary hyperhidrosis., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Previous studies demonstrate that eccrine sweat glands are innervated by both cholinergic and adrenergic nerves. However, it is still unknown whether the secretory coils and ducts of eccrine sweat glands are equally innervated by the sympathetic nerve fibers. To well understand the mechanisms on sweat secretion and reabsorption, the differential innervation of secretory coils and ducts in human eccrine sweat glands was investigated in the study., Methods: From June 2016 to June 2017, six human skins were fixed, paraffin-embedded, and cut into 5 μm-thick sections, followed by costaining for nerve fiber markers protein gene product 9.5 (PGP 9.5), tyrosine hydroxylase (TH) and vasoactive intestinal peptide (VIP), and eccrine sweat gland markers K7, S100P, and K14 by combining standard immunofluorescence with tyramide signal amplification (IF-TSA). Stained sections were observed under the microscope, photographed, and analyzed., Results: The fluorescent signals of PGP 9.5, TH, and VIP were easily visualized, by IF-TSA, as circular patterns surrounding eccrine sweat glands, but only PGP 9.5 could be observed by standard IF. The IF-TSA method is more sensitivity than standard IF in detecting antigens expressed at low levels. PGP 9.5, TH, and VIP appeared primarily surrounding the secretory coils and sparsely surrounding the sweat ducts., Conclusion: Sweat secretion is mainly controlled by autonomic nerves whereas sweat reabsorption is less affected by nerve activity., Competing Interests: There are no conflicts of interest

Introduction: Hypohidrosis and heat intolerance, frequently reported by men and women with Fabry disease (FD), is thought to be related not only to the deposition of globotriaosylceramide (Gb3) in eccrine sweat glands, but also to reduced sweat gland sympathetic innervation., Methods: We performed a case-control study to compare the density of sweat gland innervation between patients with FD and healthy controls by examining lower leg skin punch biopsies. We used a standardized grid of circles superimposed upon the immunofluorescent specimen to create a simple pattern of circles over the sweat gland. Nerve fibers that crossed within the circles were manually counted ("crossed circles"). Nerve fibers that touched the edge of the circle but did not enter were spared ("uncrossed circles"). The percentage of crossed circles from all circles was determined., Results: Biopsy specimens were available of 37 FD patients (median age 44 years, 19-67; n = 18 men) and 16 controls (median age 48 years, 24-83, n = 7 men). Totally there were 153 sweat glands from FD patients and 63 from controls, in which innervation was quantified. While mean sweat gland innervation per biopsy did not differ between the entire FD cohort and controls, data stratification for the reported sweating phenotype revealed a stepwise lower innervation in women with FD and hypohidrosis (n.s.) and anhidrosis (p < .05) compared to women reporting normal sweating., Conclusion: Sweat gland innervation is reduced in women with FD and anhidrosis compared to female patients without sweating impairment. Loss of sweat gland innervation may play a role in FD associated anhidrosis, at least in women., (Copyright © 2018 Elsevier B.V. All rights reserved.)

It has long been known from microneurographic recordings in human subjects that the activity of postganglionic sympathetic axons occurs as spontaneous bursts, with muscle sympathetic nerve activity (MSNA) exhibiting strong cardiac rhythmicity via the baroreflex and skin sympathetic nerve activity showing much weaker cardiac modulation. Here we review the firing properties of single sympathetic neurons, obtained using highly selective microelectrodes. Individual vasoconstrictor neurons supplying muscle or skin, or sudomotor neurons supplying sweat glands, always discharge with a low firing probability (~30%) and at very low frequencies (~0.5 Hz). Moreover, they usually fire only once per cardiac interval but can fire greater than four times within a burst. Modeling has shown that this pattern can best be explained by individual neurons being driven by, on average, two preganglionic inputs. Unitary recordings of muscle vasoconstrictor neurons have been made in several pathophysiological states, including heart failure, hypertension, obstructive sleep apnea, bronchiectasis, chronic obstructive pulmonary disease, depression, and panic disorder. The augmented MSNA in each of these diseases features an increase in firing probability and discharge frequency of individual muscle vasoconstrictor neurons above that seen in healthy subjects, yet firing rates rarely exceed 1 Hz. However, unlike patients with heart failure, all patients with respiratory disease or panic disorder, and patients with hyperhidrosis, exhibited an increase in multiple within-burst firing, which emphasizes the different modes by which the sympathetic nervous system grades its output in pathophysiological states of high sympathetic nerve activity.

Objective: The objective of this study was to assess the reduction in quality of life (QoL) caused by the persistence of primary plantar hyperhidrosis (PPH) symptoms and the level of satisfaction in PPH patients after retroperitoneoscopic lumbar sympathectomy (RLS). The efficacy, safety, and procedure of bilateral RLS in both sexes are also described in this study., Methods: This is a longitudinal study of consecutive patients who sought specific treatment from a private practitioner for severe PPH as classified on the Hyperhidrosis Disease Severity Scale (HDSS) from October 2005 to October 2014. The patients were asked to report the symptoms of PPH experienced in the immediate preoperative period and to complete a standardized QoL questionnaire developed by de Campos at least 12 months after RLS. Disease outcomes, recurrence of symptoms, and any adverse effects of surgery were evaluated after 30 days and at least 12 months after RLS., Results: Lumbar sympathectomy was performed 116 times in 58 patients; 30 days after surgery, PPH was resolved in all patients. Three patients (5.2%) reported transient thigh neuralgia, and 19 (32.7%) reported transient paresthesia in the lower limbs. There were no reports of retrograde ejaculation. At a minimum of 12 months after RLS, 49 of the 58 patients had fully and correctly answered the follow-up questionnaire and noted a mild (HDSS 2) to moderate (HDSS 3) increase in pre-existing compensatory sweating. One patient had a PPH relapse within 6 months. Improvement in QoL due to the resolution of PPH was reported in 98% of the 49 patients. None of the operations necessitated a change in the laparotomy approach, and none of the patients died., Conclusions: RLS is safe and effective for the treatment of severe PPH in both sexes. There were no reports of retrograde ejaculation after resection of L3 and L4 ganglia. There was a mild to moderate increase in compensatory sweating in about half of the patients, but without any regret or dissatisfaction for having undergone the surgery because of a significant improvement in QoL., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Sweat may be an important factor in triggering an exacerbation of atopic dermatitis. It was the aim of this study to evaluate a possible correlation between atopic patients and hyperhidrosis-measured by a questionnaire-and to find out whether there are qualitative differences in sweat response-measured by sudomotor activity (sympathetic skin response test, SSR). Included were 100 study participants, of whom 50 were patients with atopic dermatitis and 50 were serving as control group. The frequency of hyperhidrosis is higher in atopic patients than in the control group (30 vs. 16%), but has no statistical significance. In addition, patients with hyperhidrosis and atopic dermatitis have a significantly higher exacerbation rate of atopic dermatitis in summertime. The group of atopic patients shows a statistically significant prolonged SSR latency period, which indicates an insufficient sympathetic innervation. In our tests, type IV allergic patients showed clear differences in terms of SSR latency and amplitude. Atopic patients have a higher incidence of hyperhidrosis. The study clearly shows that there is a dysfunction of sudomotor activity in the sympathetic nervous system of atopic patients. Our findings suggest that a deficient innervation of sweat glands in atopic patients may lead to an increase in the development of type IV allergies.

Background  Thoracic sympathectomy (TS) is one of the most effective methods of treatment of primary hyperhidrosis. One of the side effects of this procedure is compensatory sweating (CS). Objective  The aim of our study was to evaluate the influence of body mass index (BMI) on CS in patients after TS due to palmar hyperhidrosis. Methods  Data from 157 patients with palmar hyperhidrosis who underwent TS were collected. The patients were subsequently divided in two groups according to their initial BMI: group A, BMI < 25 kg/m 2 , and group B, BMI ≥ 25 kg/m 2 . Objective (gravimetry) and subjective (VAS) measurements of the intensity of hyperhidrosis were taken from the patients' bodies prior to surgery, as well as 3 and 12 months after TS. Results  Average palmar hyperhidrosis levels before the surgery did not differ significantly between the two groups (238.65 vs. 190.15; p  = 0.053). A statistically significant decrease in palmar hyperhidrosis was noted in both groups, both 3 and 12 months after surgery (238.65 vs. 11.86 vs. 13.5; p  < 0.05, and 190.15 vs. 16.67 vs. 11.81; p  < 0.05, respectively). The intensity of sweating over the abdomino-lumbar area differed significantly between the groups before the surgery, both in subjective (1.71 vs. 3.61; p  < 0.05) and objective (13.57 vs. 35.95; p  < 0.05) evaluations. Three months after surgical intervention, an intensification of CS was observed in both the groups; however, no statistically significant differences were observed between the two sets of patients (VAS: 4.58 vs. 5.16; p  = 0.38; gravimetry: 33.87 vs. 53.89; p  = 0.12). Twelve months after TS, CS was higher in the group with an initial BMI ≥ 25 kg/m 2 , both in subjective and objective evaluations (3.23 vs. 4.94; p  = 0.03 and 18.08 vs. 80.21; p  = 0.026, respectively). Conclusion  Patients with a BMI ≥ 25 kg/m 2 experience more severe CS after TS, both in subjective and objective evaluations., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Background  Hyperhidrosis is a dysfunction of the autonomic nervous system that results in regional excessive sweating, mostly in the hands, armpits, and feet. A permanent and effective treatment of hyperhidrosis can be achieved by interruption of the thoracic sympathetic chain with endoscopic thoracic sympathectomy (ETS). However, some side effects, particularly compensatory sweating (CS), are the limitations of this procedure. The mechanism of CS and the associated risk factors are still controversial. The aim of this retrospective study was to determine the relationship with various parameters associated with CS in patients undergoing ETS. Materials and Methods  ETS was performed on a total of 95 patients for palmar hyperhidrosis, axillary hyperhidrosis and facial blushing by the same surgeon. The mean age of the patients was 26.41 (± 7) years, and 54 (56.8%) were males. Palmar hyperhidrosis was present in 54 (56.8%) patients, axillary hyperhidrosis in 33 (34.7%) patients, and facial blushing in 8 (8.5%) patients. Moreover, 38 (40%) patients also had plantar sweating. The severity of CS was rated into three scales as less, moderate, and severe. Results  Regarding the severity of CS, 55 (57.9%) patients had no or less CS, 28 (29.5%) had moderate CS, and 12 (12.6%) patients had severe CS. Higher age group had a significant increased risk of severe CS ( p  = 0.03) ( r  = 0.262). Patients with body mass index (BMI) > 25 kg/m 2 had a statistically significantly increased risk of severe CS ( p  = 0.016). Facial blushing resulted in severe CS in a significantly higher proportion of patients than by palmar and axillary hyperhidrosis ( p  = 0.001). The level of surgery was another important risk factor for CS, with the T2 level showing an increased risk of severe CS compared with T3 level ( p  < 0.001). Furthermore, plantar sweating was inversely and significantly related to the development of CS. Patients with plantar sweating had a significantly decreased incidence of developing CS ( p  = 0.015). Conclusion  CS after thoracic sympathectomy for primary hyperhidrosis is the most displeasing and restrictive side effect. This study demonstrates that older age, operation level, facial blushing, and high BMI are risk factors for CS, as have been shown in several similar studies. An interesting finding of the present study is that there was a decreased incidence of CS among patients with plantar sweating. This situation may help us to distinguish high risk for CS before ETS operation., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Background  Thoracoscopic sympathectomy (TS) was the preferred surgical treatment for palmar hyperhidrosis (PH), but postoperative complications such as compensatory sweating (CS) were common. This study was projected to compare R3 versus R4 TS for treating severe PH. Methods  From April 2009 and March 2015, 106 consecutive patients with severe PH underwent bilateral R3 ( n  = 62) or R4 ( n  = 44) TS at The Second Affiliated Hospital of Nanchang University. The patients were followed up to evaluate symptom resolution, postoperative complications, satisfaction level, and severity of CS. Results  The 106 patients underwent 212 sympathecotomies and were cured with no severe complications or perioperative mortality. The incidence of minor side effects (such as pneumothorax, gustatory sweating, moist hands, and bradycardia) was similar in both groups. More patients had overdry hands in the R3 group than in the R4 group (6/62 vs. 0/44; p  = 0.040). More CS occurred in the R3 group as compared with the R4 group (42/62 vs. 23/44; p  = 0.156). The incidence of moderate-to-severe CS was higher in the R3 group than in the R4 group (14/62 vs. 4/40; p  = 0.045). Most patients were satisfied with the results, except for three (5.84%) in the R3 group and one (2.27%) in the R4 group. Conclusion  PH can be effectively treated by either R3 or R4 TS, with high rates of patient satisfaction. R4 sympathectomy appears to be associated with less severe CS and should be the choice of denervation level., Competing Interests: Conflict of Interest: Wenxiong Zhang, Yiping Wei, Han Jiang, Jianjun Xu, and Dongliang Yu have no conflicts of interest or financial ties to disclose., (Georg Thieme Verlag KG Stuttgart · New York.)

Background  Endoscopic thoracic sympathectomy (ETS) is an effective treatment for primary hyperhidrosis. However, compensatory sweating (CS) may occur in many patients. Sympathetic nerve reconstruction (SNR) can be used to counteract severe CS, but the studies on the effects of SNR are few. Patients and Methods  Nineteen out of 150 SNR patients were contacted by employing a long-term questionnaire. In this questionnaire, different kinds of sweating were evaluated using a four-graded symptom analysis and the visual analog scale before ETS, after ETS, and after SNR. Results  The mean age of the 16 male and 3 female patients at the SNR was 32 years. The mean follow-up was 87 months. According to the long-term questionnaire, the benefit was either excellent (4 patients, 21%), good (3 patients, 15.8%), or reasonable (7 patients, 36.8%) in 14 patients (73.8%), while the benefit was questionable in 1 patient (5.3%). For three patients (15.8%), no benefit was found, and in one patient (5.3%), the situation had deteriorated. Conclusions  Improvement in the side effects of ETS after SNR was found in nearly 75% of the patients. This indicates that SNR can be considered as an alternative treatment for patients with severe CS after ETS that is unresponsive to conservative treatment., Competing Interests: Disclosure: The authors have no conflict of interest or financial ties to disclose., (Georg Thieme Verlag KG Stuttgart · New York.)

Many studies have reported that there are changes in sympathetic activity throughout the menstrual cycle as there are oestrogen receptor in the hypothalamus and all other parts of the sympathetic nervous system. The purpose of this study was to see whether there were variations in sympathetic activity, skin vasomotor and sweat gland sudomotor rhythms during the menstrual cycle. Eight young female subjects with a regular menstrual cycle participated in the study. Subjects were tested once during the follicular phase and once during the luteal phase. Skin blood flow and sweat rate were significantly higher in the luteal phase compared with the follicular phase (p < .05), but the frequency and magnitude of sudomotor and vasomotor rhythms were significantly greater in the follicular phase (p < .05). In contrast, spectral data showed less sympathetic activity in the luteal phase. A significant finding here is that the sudomotor rhythm of sweat glands is altered by the menstrual cycle., (© 2015 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Hypohydration decreases cutaneous vasodilation and sweating during heat stress, but it is unknown if these decrements are from postsynaptic (i.e., sweat gland/blood vessel) alterations. The purpose of this study was to determine if hypohydration affects postsynaptic cutaneous vasodilation and sweating responses. Twelve healthy men participated in euhydrated (EU) and hypohydrated (HY) trials, with hypohydration induced via fluid restriction and passive heat stress. Changes in cutaneous vascular conductance (CVC; % max ) in response to incremental intradermal infusion of the endothelium-independent vasodilator sodium nitroprusside (SNP) and the endothelium-dependent vasodilator methacholine chloride (MCh) were assessed by laser Doppler flowmetry. Local sweat rate (LSR) was simultaneously assessed at the MCh site via ventilated capsule. At the end of the last dose, maximal CVC was elicited by delivering a maximal dose of SNP (5 × 10 -2 M) for 30 min to both sites with simultaneous local heating (~44°C) at the SNP site. The concentration of drug needed to elicit 50% of the maximal response (log EC 50 ) was compared between hydration conditions. The percent body mass loss was greater with HY vs. EU (-2.2 ± 0.7 vs. -0.1 ± 0.7%, P < 0.001). Log EC 50 of endothelium-dependent CVC was lower with EU (-3.62 ± 0.22) vs. HY (-2.93 ± 0.08; P = 0.044). Hypohydration did not significantly alter endothelium-independent CVC or LSR (both P > 0.05). In conclusion, hypohydration attenuated endothelium-dependent CVC but did not affect endothelium-independent CVC or LSR responses. These data suggest that reductions in skin blood flow accompanying hypohydration can be partially attributed to altered postsynaptic function., (Copyright © 2017 the American Physiological Society.)

Sensory and autonomic neuropathy affects the majority of type II diabetic patients. Clinically, autonomic evaluation often focuses on sudomotor function yet this is rarely assessed in animal models. We undertook morphological and functional studies to assess large myelinated and small unmyelinated axons in the db/db type II diabetes mouse model. We observed that autonomic innervation of sweat glands in the footpads was significantly reduced in db/db mice compared to control db/+ mice and this deficit was greater compared to reductions in intraepidermal sensory innervation of adjacent epidermis. Additionally, db/db mice formed significantly fewer sweat droplets compared to controls as early as 6 weeks of age, a time when no statistical differences were observed electrophysiologically between db/db and db/+ mice studies of large myelinated sensory and motor nerves. The rate of sweat droplet formation was significantly slower and the sweat droplet size larger and more variable in db/db mice compared to controls. Whereas pilocarpine and glycopyrrolate increased and decreased sweating, respectively, in 6 month-old controls, db/db mice did not respond to pharmacologic manipulations. Our findings indicate autonomic neuropathy is an early and prominent deficit in the db/db model and have implications for the development of therapies for peripheral diabetic neuropathy., Competing Interests: The authors declare no competing financial interests.

The SUDOSCAN test was recently developed to detect diabetic autonomic neuropathy early and screen for cardiac autonomic neuropathy (CAN) through assessment of sudomotor function. The aim of this study was to investigate the relationship of cardiac autonomic dysfunction estimated by the SUDOSCAN test with arterial stiffness. A total of 4019 subjects without diabetes or established cardiovascular disease were tested with SUDOSCAN, central systolic blood pressure (cSBP) and brachial-ankle pulse wave velocity (baPWV). Hands mean electrochemical skin conductance (ESC) measured by SUDOSCAN was 70±17 μS, feet mean ESC was 71±16 μS and the CAN risk score was 21±10%. The levels of cSBP and baPWV increased across quartiles of CAN risk score (P for trend <0.001 for all). In spearman correlation analyses, the CAN risk score was positively correlated with cSBP (r=0.391, P<0.001) and baPWV (r=0.305, P<0.001). In multivariable analyses, the values of cSBP and baPWV increased 0.17 mm Hg (P=0.002) and 2.01 cm per second (P=0.010), respectively, when CAN risk score increased 1%. The results were unchanged when stratified by glucose tolerance status. In conclusion, cardiac autonomic dysfunction estimated by sudomotor function was correlated with arterial stiffness independent of conventional factors and glucose tolerance status.

Frey syndrome is a common sequela of parotidectomy, and although it is not frequently manifested clinically, it can cause significant morbidity for those affected. Frey syndrome results from synkinetic autonomic reinnervation by transected postganglionic parasympathetic nerve fiber within the parotid gland to the overlying sweat glands of the skin. Many surgical techniques have been proposed to prevent the development of Frey syndrome. For those who develop clinical symptoms of Frey syndrome, objective testing can be performed with a Minor starch-iodine test. Some of the current methods to prevent and treat symptomatic Frey syndrome are reviewed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Sweating disorders are sometimes observed in various systemic diseases that include genetic disorders, organ damage, metabolic impairment, autoimmune diseases, and neuropathic disorders. In these diseases, various symptoms such as autonomic failures, psychopathic disorders, abnormal skin innervation, and sweat gland dysfunction can interact with one another in diverse ways, resulting in impaired sweating. This review focuses on the influence of uremia (with or without hemodialysis) and diabetes mellitus on impaired sweating. Dialysis patients perspire less, but their sweat contains higher levels of uremic toxins than do healthy subjects. Neuropathic disorders in diabetes patients develop in relation to disease severity and can impair sweating. Physicians should consider the development of various problems, such as increased body temperature, dry skin, and increased susceptibility to infection, due to decreased sweating, as they are often found in these systemic abnormalities., (© 2016 S. Karger AG, Basel.)

Background: This study assesses the autonomic function of patients who have regained awareness of hypoglycaemia following islet cell or whole pancreas transplant., Methods: Five patients with type 1 diabetes and either islet cell (four patients) or whole pancreas (one patient) transplant were assessed. These patients were age-matched and gender-matched to five patients with type 1 diabetes without transplant and preserved hypoglycaemia awareness and five healthy control participants without diabetes. All participants underwent (i) a battery of five cardiovascular autonomic function tests, (ii) quantitative sudomotor axonal reflex testing, and (iii) sympathetic skin response testing., Results: Total recorded hypoglycaemia episodes per month fell from 76 pre-transplant to 13 at 0- to 3-month post-transplant (83% reduction). The percentage of hypoglycaemia episodes that patients were unaware of decreased from 97 to 69% at 0-3 months (p < 0.001, Fisher's exact test) and to 20% after 12 months (p < 0.0001, Fisher's exact test). This amelioration was maintained at the time of testing (mean time: 4.1 years later, range: 2-6 years). Presence of significant autonomic neuropathy was seen in all five transplanted patients (at least 2/3 above modalities abnormal) but in only one of the patients with diabetes without transplantation., Conclusions: The long-term maintenance of hypoglycaemia awareness that returns after islet cell/pancreas transplantation in patients with diabetes is not prevented by significant autonomic neuropathy and is better accounted for by other factors such as reversal of hypoglycaemia-associated autonomic failure., (Copyright © 2015 John Wiley & Sons, Ltd.)

Objective: Autonomic neuropathy is a major component of familial amyloid polyneuropathy (FAP) due to mutated transthyretin, with sudomotor failure as a common manifestation. This study aimed to investigate the pathology and clinical significance of sudomotor denervation., Methods: Skin biopsies were performed on the distal leg of FAP patients with a follow-up duration of 3.8 ± 1.6 years. Sudomotor innervation was stained with 2 markers: protein gene product 9.5 (PGP 9.5), a general neuronal marker, and vasoactive intestinal peptide (VIP), a sudomotor nerve functional marker, followed by quantitation according to sweat gland innervation index (SGII) for PGP 9.5 (SGIIPGP 9.5) and VIP (SGIIVIP)., Results: There were 28 patients (25 men) with Ala97Ser transthyretin and late onset (59.9 ± 6.0 years) disabling neuropathy. Autonomic symptoms were present in 22 patients (78.6%) at the time of skin biopsy. The SGIIPGP 9.5 and SGIIVIP of FAP patients were significantly lower than those of age- and gender-matched controls. The reduction of SGIIVIP was more severe than that of SGIIPGP 9.5 (p = 0.002). Patients with orthostatic hypotension or absent sympathetic skin response at palms were associated with lower SGIIPGP 9.5 (p = 0.019 and 0.002, respectively). SGIIPGP 9.5 was negatively correlated with the disability grade at the time of skin biopsy (p = 0.004), and was positively correlated with the interval from the time of skin biopsy to the time of wheelchair usage (p = 0.029)., Interpretation: This study documented the pathological evidence of sudomotor denervation in FAP. SGIIPGP 9.5 was functionally correlated with autonomic symptoms, autonomic tests, ambulation status, and progression of disability., (© 2015 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Numerous studies have detailed involvement of the peripheral autonomic nervous system (PANS) in Parkinson's disease (PD). We assessed autonomic innervation of dermal annexes through quantitative fluorescence measurement from skin obtained via punch biopsies at distal leg region in PD and control subjects. We defined a ratio between the area corresponding to protein gen product (PGP) immunoreactivity and the area corresponding to blood vessel or sweat gland as a quantitative measure of autonomic innervation. Presence of alpha-synuclein (AS) deposits in dermis and hypodermis was also assessed by immunohistochemistry. Skin biopsies form six PD patients and six healthy controls were studied. Autonomic innervation scores were lower in PD than in controls in both blood vessels and sweat glands. No AS or phosphorylated AS (pAS) immunoreactivity was detected in dermis or hypodermis in any of the studied subjects. The results of this investigation suggest that autonomic innervation of dermal annexes in living patients with PD is reduced compared to controls. AS or pAS deposits were not found in dermis or hypodermis suggesting that distal leg skin study is not useful for in vivo detection of AS in PD.

The purpose of this study was to compare smokers and nonsmokers' sudomotor and cutaneous vascular responses to whole body passive heat stress. Nine regularly smoking (SMK: 29 ± 9 yr; 10 ± 6 cigarettes/day) and 13 nonsmoking (N-SMK: 27 ± 8 yr) males were passively heated until core temperature (TC) increased 1.5°C from baseline. Forearm local sweat rate (LSR) via ventilated capsule, sweat gland activation (SGA), sweat gland output (SGO), and cutaneous vasomotor activity via laser-Doppler flowmetry (CVC) were measured as mean body temperature increased (ΔTb) during passive heating using a water-perfused suit. Compared with N-SMK, SMK had a smaller ΔTb at the onset of sweating (0.52 ± 0.19 vs. 0.35 ± 0.14°C, respectively; P = 0.03) and cutaneous vasodilation (0.61 ± 0.21 vs. 0.31 ± 0.12°C, respectively; P < 0.01). Increases in LSR and CVC per °C ΔTb (i.e., sensitivity) were similar in N-SMK and SMK (LSR: 0.63 ± 0.21 vs. 0.60 ± 0.40 Δmg/cm(2)/min/°C ΔTb, respectively, P = 0.81; CVC: 82.5 ± 46.2 vs. 58.9 ± 23.3 Δ%max/°C ΔTb, respectively; P = 0.19). However, the plateau in LSR during whole body heating was higher in N-SMK vs. SMK (1.00 ± 0.13 vs. 0.79 ± 0.26 mg·cm(-2)·min(-1); P = 0.03), which was likely a result of higher SGO (8.94 ± 3.99 vs. 5.94 ± 3.49 μg·gland(-1)·min(-1), respectively; P = 0.08) and not number of SGA (104 ± 7 vs. 121 ± 9 glands/cm(2), respectively; P = 0.58). During whole body passive heat stress, smokers had an earlier onset for forearm sweating and cutaneous vasodilation, but a lower local sweat rate that was likely due to lower sweat output per gland. These data provide insight into local (i.e., forearm) thermoregulatory responses of young smokers during uncompensatory whole body passive heat stress., (Copyright © 2015 the American Physiological Society.)

Background: Using a stereologic approach, the density of nerve fibers innervating sweat gland (SG) fragments in patients with diabetes mellitus (DM) and healthy controls using protein gene product (PGP), tyrosine hydroxylase (TH), and vasoactive intestinal peptide (VIP) was measured to determine which marker best detected differences between the groups. Factors associated with SG nerve fiber (SGNF) innervation were assessed and the change in SG innervation over a 1-year time period was determined., Methods: Ninety-two control subjects and 2 groups of subjects with DM totaling 97 were assessed in this cross-sectional study. Intraepidermal nerve fiber density and SG innervation were determined from leg skin biopsies that were immunohistochemically stained for ubiquitin hydrolase, VIP, and TH. Factors associated with SG innervation were assessed and 15 subjects were longitudinally followed for 1 year., Results: SGNF innervation was reduced in subjects with DM compared with controls. Lower SG innervation values were associated with increasing glycated hemoglobin A1c, body mass index (BMI), men compared with women, and tobacco use, but not diabetes type or age. Sex, A1c, and BMI remained significant in multivariate modeling. SG innervation measured by VIP+ fibers is a more sensitive marker for neuropathy than either PGP or TH. Fifteen subjects with DM followed for 1 year showed a significant decrease in SGNF innervation but not intraepidermal nerve fiber density., Conclusions: Stereologic measurement of SG innervation is feasible to assess postganglionic autonomic nerve fiber densities. SG innervation was reduced in subjects with DM compared with control subjects and was associated with sex, A1c, and BMI in multivariate modeling. VIP+ SGNF is more severely reduced in DM than TH+ or PGP9.5+-based assessments. Progression of diabetic polyneuropathy was detected by SGNF over a 1-year time period., (© 2015 American Academy of Neurology.)

Introduction: Chronic inflammatory demyelinating polyneuropathy (CIDP) is eleven times more common among people with diabetes than the general population and is treatable with appropriate immunotherapy. Treatment response is usually measured clinically (symptomatic and functional improvement). We present a case of a patient with type 2 diabetes (T2D) and CIDP whose treatment response was measurable with the Sudoscan sudomotor function test. This test may represent a new objective evaluation of the treatment of CIDP., Case Description: The patient is a 60year old male initially referred to our center in August 2012, at which time he was diagnosed with CIDP based on AAN electrodiagnostic criteria (NCS). Autonomic functions were significant for low heart rate variability response to expiration/inspiration (E/I), Valsalva maneuver and the ratio of the RR interval for the 30th to the 15th beat upon standing (1.08, 1.12, 1.05 respectively), and frequency analysis of the total spectral power, the standard deviation of the normal RR intervals (sdNN) and their root mean squared (rmsSD). Sudoscan electrochemical skin conductances (ESC), measuring small nerve fiber function on the palms and soles, were very low: 23 μS in the feet and 32 μS in the hands. After one cycle of intravenous immunoglobulin (IVIG: 6 doses total, 75g each) the patient had no change in symptoms of burning, numbness, shooting pains, and gait impairment. However, E/I, Valsalva, and 30:15 ratios (1.19, 1.36, 1.39 respectively) were improved, as were NCS. Sudoscan scores for feet and hands were unchanged (23 μS and 32 μS). In March 2013, the patient's autonomic functions worsened (E/I, Valsalva, and 30:15 ratios 1.1, 1.07, 1.12 respectively), but feet and hand ESC started to show improvement (35 μS and 52 μS respectively). Azathioprine was started. Eight days after a second cycle of IVIG in January 2014, the patient reported for the first time less burning, shooting pains and tingling. E/I, Valsalva, and 30:15 ratios remained low (1.03, 1.07, and not analyzable, respectively), while foot and hand ESC scores continued to improve (43 μS and 55 μS respectively)., Discussion: CIDP diagnosis and treatment response are difficult in the diabetic patient. We found that NCS and autonomic function tests did not correlate well with clinical status while numerical Sudoscan scores matched closely symptomatic changes. ESC have been found to correlate well with peripheral small fiber function and neuropathic symptoms in DPN. The findings in this patient warrant further investigation of the use of Sudoscan to monitor CIDP response to therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Expression of Satb2 (Special AT-rich sequence-binding protein-2) elicits expression of the vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) in cultured rat sympathetic neurons exposed to soluble differentiation factors. Here, we determined whether or not Satb2 plays a similar role in cholinergic differentiation in vivo, by comparing the postnatal profile of Satb2 expression in the rodent stellate ganglion to that of VAChT and ChAT. Throughout postnatal development, VAChT and ChAT were found to be co-expressed in a numerically stable subpopulation of rat stellate ganglion neurons. Nerve fibers innervating rat forepaw sweat glands on P1 were VAChT immunoreactive, while ChAT was detectable at this target only after P5. The postnatal abundance of VAChT transcripts in the stellate ganglion was at maximum already on P1, whereas ChAT mRNA levels increased from low levels on P1 to reach maximum levels between P5 and P21. Satb2 mRNA was detected in cholinergic neurons in the stellate ganglion beginning with P8, thus coincident with the onset of unequivocal detection of ChAT immunoreactivity in forepaw sweat gland endings. Satb2 knockout mice exhibited no change in the P1 cholinergic VAChT/ChAT co-phenotype in stellate ganglion neurons. Thus, cholinergic phenotype maturation involves first, early target (sweat-gland)-independent expression and trafficking of VAChT, and later, potentially target- and Satb2-dependent elevation of ChAT mRNA and protein transport into sweat gland endings. In rat sudomotor neurons that, unlike mouse sudomotor neurons, co-express calcitonin gene-related peptide (CGRP), Satb2 may also be related to the establishment of species-specific neuropeptide co-phenotypes during postnatal development.

Objective: To assess the involvement of small nerve fibers in Charcot-Marie-Tooth type 1A (CMT1A)., Methods: We used indirect immunofluorescence and confocal microscopy on punch biopsies from glabrous (fingertip) and hairy (thigh and leg) skin of 20 unrelated patients with CMT1A to quantify somatic and autonomic nerve fibers. In particular, we quantified epidermal nerve fibers (ENF), Meissner corpuscles (MC), intrapapillary myelinated endings (IME), and sudomotor nerves. We correlated morphologic data with findings from quantitative sensory testing, sudomotor output, sympathetic skin response, and cardiovascular reflexes. A control population of healthy age- and sex-matched controls was included with a matching ratio of 1:2., Results: We found a length-dependent loss of ENFs that worsened with aging. We also observed a loss of MCs, IMEs, and sudomotor nerves. The loss of ENF at distal leg correlated with the increase in heat-pain thresholds (p < 0.05) and with tactile thresholds (p < 0.05). Sudomotor nerve fiber loss correlated with ENF density (p < 0.05) and sweating output (p < 0.001)., Conclusions: We demonstrated through morphologic, physical, and psychophysical testing that small somatic and autonomic fibers are abnormal and cause symptoms in patients with CMT1A. Awareness of such symptoms by the clinician could lead to better treatment., (© 2014 American Academy of Neurology.)

Temporal and thermal differences between the initiation of precursor, eccrine sweat and its surface discharge were investigated during passive heating. Sudomotor activity was evaluated using electrodermal (precursor) and ventilated sweat capsule measurements (dorsal fingers, dorsal hand, forehead, forearm). Passive heating significantly elevated auditory canal (0.5 degrees C) and mean body temperatures (0.9 degrees C). At each site, the precursor sudomotor thresholds occurred at a lower mean body temperature (P < .05), with an average elevation of 0.35 degrees C (SD 0.04). However, discharged thresholds were delayed until this temperature had risen 0.53 degrees C (SD 0.04), producing significant phase delays across sites (mean: 4.1 min [SD 0.5]; P < .05). It is concluded that precise sudomotor threshold determinations require methods that respond to sweat accumulating within the secretory coil, and not discharged secretions, reinforcing the importance of electrodermal techniques., (Copyright © 2014 Society for Psychophysiological Research.)

Aims: Neuropad is a simple visual indicator test, with moderate diagnostic performance for diabetic peripheral neuropathy. As it assesses sweating, which is a measure of cholinergic small nerve fibre function, we compared its diagnostic performance against established measures of both large and, more specifically, small fibre damage in patients with diabetes., Methods: One hundred and twenty-seven participants (89 without diabetic peripheral neuropathy and 38 with) aged 57 ± 9.7 years underwent assessment with Neuropad, large nerve fibre assessments: Neuropathy Disability Score, vibration perception threshold, peroneal motor nerve conduction velocity; small nerve fibre assessments: neuropathy symptoms (Diabetic Neuropathy Symptoms score) corneal nerve fibre length and warm perception threshold., Results: Neuropad has a high sensitivity but moderate specificity against large fibre neuropathy assessments: Neuropathy Disability Score (> 2) 70% and 50%, vibration perception threshold (> 14 V) 83% and 53%, and peroneal motor nerve conduction velocity (< 42 m/s) 81% and 54%, respectively. However, the diagnostic accuracy of Neuropad was significantly improved against corneal nerve fibre length (< 14 mm/mm2) with a sensitivity and specificity of 83% and 80%, respectively. Furthermore, the area under the curve for corneal nerve fibre length (85%) was significantly greater than with the Neuropathy Disability Score (66%, P = 0.01) and peroneal motor nerve conduction velocity (70%, P = 0.03). For neuropathic symptoms, sensitivity was 78% and specificity was 60%., Conclusions: The data show the improved diagnostic performance of Neuropad against corneal nerve fibre length. This study underlines the importance of Neuropad as a practical diagnostic test for small fibre neuropathy in patients with diabetes., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

Introduction: No study has correlated thermoregulatory sweat testing (TST) with histopathologic study of sweat glands (SGs) and SG nerve fibers (SGNFs)., Methods: We studied 10 neuropathy patients in whom anhidrosis was found by TST and 10 matched controls. Skin biopsies were taken from both anhidrotic and sweating skin and immunohistochemical staining was done for nerves and basement membrane. For each biopsy, total tissue volume, total SG volume, and total SGNF length were measured. SGNF length per biopsy volume, SG volume per biopsy volume (SG%), and SGNF length per SG volume were calculated., Results: SGNF length per biopsy volume was reduced in anhidrotic site biopsies of patients compared with controls. SG% was decreased and SGNF length per SG volume increased in patients compared with controls., Conclusions: The results suggest a concomitant loss of SG volume and SGNF length in neuropathy, with greater loss of SGNFs in anhidrotic skin, possibly exceeding collateral reinnervation., (Copyright © 2014 Wiley Periodicals, Inc.)