Quantitative Sudomotor Axon Reflex Test Research Articles

Bladder dysfunction in adolescents with type 1 diabetes

It is increasingly significant that adults with diabetes experience lower urinary tract symptoms, however, there has been limited research in younger individuals with type 1 diabetes. To investigate bladder function using non-invasive urodynamics as a potential indicator of autonomic neuropathy in adolescents with type 1 diabetes. This involved examining the association between urinary flow disturbances, reported symptoms, and results from other autonomic tests. Cross-sectional study enrolling 49 adolescents with type 1 diabetes and 18 control subjects. All participants underwent uroflowmetry and ultrasound scanning, completed the Composite Autonomic Symptom Score (COMPASS)-31 questionnaire, and were instructed to record their morning urine volume and voiding frequencies and report them back. Cardiovascular reflex tests (CARTs) and the quantitative sudomotor axon reflex test (QSART) were performed. The main results are shown in the Summary figure. In this study, urological abnormalities were not significantly more frequent in adolescents with diabetes, however, urological issues were observed. This is supported by previous findings of Szabo etal. who found that adolescents with type 1 diabetes had reduced flow acceleration and time to maximum flow compared to control subjects. In our study, we observed cases with reduced acceleration and prolonged uroflow curves, possibly indicating detrusor underactivity. People with diabetes had a higher risk of nocturia than healthy controls, which our results supported. Some adolescents reported urination twice per night. Based on these findings, it is considered beneficial to ask about urological symptoms annually to determine if more examinations (frequency-volume charts and uroflowmetry) are necessary and/or if any opportunities for treatment optimization exist. However, uroflowmetry has limitations, as bladder filling and emptying is a complex process involving multiple pathways and neurological centers, making it difficult to standardize and evaluate. Another limitation of this study was that our control group was smaller and consisted of fewer males than females, which could affect the results due to differences in anatomy and physiology in the lower urinary tract system. In conclusion, adolescents with type 1 diabetes, as well as healthy adolescents, frequently experience urological symptoms. Although urological abnormalities were not significantly more frequent in adolescents with diabetes in this study, the focus on nocturia and risk for bladder dysfunction seems relevant, even in adolescents without any other tests indicating autonomic dysfunction.

Abnormal quantitative sudomotor axon reflex test results in patients with tinnitus as a possible indicator of small fiber neuropathy.

A few cases of small fiber neuropathy (SFN) and tinnitus (TN) associated with coronavirus disease 2019 have been reported. However, the relationship between SFN and TN has not been studied. This study investigated a possible relationship between SFN and patients with TN (PwTNs) using autonomic function tests (AFTs) including quantitative sudomotor axon reflex tests (QSART). We performed QSARTs and other AFTs such as the Sympathetic skin response (SSR), Valsalva ratio (VR), and heart rate variability (HRV). The QSART results, obtained at seven hospitals using same protocols, were compared between PwTNs and healthy controls. We confirmed the abnormalities in SSR, VR, and HRV in PwTNs, although those parasympathetic AFTs were not performed in healthy controls. Additionally, we checked Tinnitus handicap inventory (THI) scores for PwTNs and ~50% of PwTNs had low-grade disability, whereas 9.3% had high-grade disability. Data from 57 PwTNs and 122 healthy controls were analyzed. The sweat volumes of QSART in the older age group tended to be higher in the PwTNs than in age-matched healthy controls, and significant differences between the PwTN and control groups were observed in the feet in both sexes (p < 0.001) and in the arms in women (p = 0.013). In the younger age group, the sweat volumes in the feet of men were higher in PwTNs than in healthy controls (p = 0.017). No association was observed between THI and QSART scores. In this study, the sweat volumes in QSARTs were higher in PwTNs than in healthy controls. However, abnormal SSR, HRV, and VR results were not commonly observed in PwTNs. Although the results should be interpreted with caution because of limitations in study, PwTNs might also have SFN apart from dysautonomia. This is the first study to perform QSART with other parasympathetic AFTs in PwTNs. However, larger and more rigorously controlled studies will be needed to reveal the relationship between SFN and TN in the future.

Sudoscan as substitute for quantitative sudomotor axon reflex test in composite autonomic scoring scale and its correlation with composite autonomic symptom scale 31 in type 2 diabetes

ObjectiveThis study aims to evaluate the feasibility of substituting electrochemical skin conductance measurement using SUDOSCAN for sudomotor function testing in the Composite Autonomic Scoring Scale (CASS) and to correlate the results with the Composite Autonomic Symptom Scale 31 (COMPASS 31) among patients with type 2 diabetes mellitus (T2DM). MethodsFifty patients with T2DM underwent cardiovascular autonomic function testing and the SUDOSCAN test and completed the COMPASS 31 questionnaire. We developed a SUDOSCAN-based sudomotor subscore as a substitute for the original sudomotor subscore (based on the quantitative sudomotor axon reflex test [QSART]). The modified CASS score (SUDOSCAN-based sudomotor subscore combined with the adrenergic and cardiovagal subscores) and the original CASS score without suomotor assessment (sum of the adrenergic and cardiovagal subscores) were obtained according to the results of the cardiovascular autonomic function and SUDOSCAN tests. ResultsThe total COMPASS 31 score was significantly correlated with the modified CASS score (p = 0.019 and 0.037 for the raw and weighted scores, respectively) but not with the CASS score without sudomotor assessment. After adding the SUDOSCAN-based sudomotor subscore, the number of patients identified as having diabetic autonomic neuropathy (DAN) increased from 24 (48 %, based on the CASS score without sudomotor assessment) to 35 (70 %, based on the modified CASS score). The modified CASS score enhances the accuracy of assessing autonomic function and improves the diagnosis of diabetic autonomic neuropathy (DAN) among patients with T2DM. In medical settings where QSART is not accessible, SUDOSCAN testing offers a practical and efficient alternative.

Quantitative assessment of painful diabetic peripheral neuropathy after high-frequency spinal cord stimulation: a pilot study.

Randomized trials have demonstrated efficacy of spinal cord stimulation (SCS) for treatment of painful diabetic neuropathy (PDN). Preliminary data suggested that treatment of PDN with high-frequency SCS resulted in improvements on neurological examination. The purpose of the present study was to explore whether patients with PDN treated with high-frequency SCS would have improvements in lower-extremity peripheral nerve function. Prospective cohort study in an outpatient clinical practice at a tertiary care center. Patients with PDN were treated with high-frequency SCS and followed up for 12 months after SCS implantation with clinical outcomes assessments of pain intensity, neuropathic symptoms, and neurological function. Small-fiber sudomotor function was assessed with the quantitative sudomotor axon reflex test (QSART), and large-fiber function was assessed with nerve conduction studies (NCS). Lower-extremity perfusion was assessed with laser Doppler flowmetry. Nine patients completed 12-month follow-up visits and were observed to have improvements in lower-extremity pain, weakness, and positive sensory symptoms. Neuropathy impairment scores were improved, and 2 patients had recovery of sensory responses on NCS. A reduction in sweat volume on QSART was observed in the proximal leg but not at other sites. No significant differences were noted in lower-extremity perfusion or NCS as compared with baseline. The improvement in pain relief was concordant with improvement in neuropathy symptoms. The findings from this study provide encouraging preliminary data in support of the hypothesis of a positive effect of SCS on peripheral neuropathy, but the findings are based on small numbers and require further evaluation. ClinicalTrials.gov ID NCT03769675.

Sweat gland nerve fiber density and association with sudomotor function, symptoms, and risk factors in adolescents with type 1 diabetes

PurposeTo quantify sweat gland nerve fiber density in adolescents with diabetes. Additionally, to investigate associations between sudomotor innervation, sweat responses, and possible risk factors for sudomotor neuropathy.MethodsCross-sectional study where 60 adolescents with type 1 diabetes (duration > 5 years) and 23 control subjects were included. Clinical data, quantitative sudomotor axon reflex test, and skin biopsies were obtained. Skin tissue was immunostained and imaged by confocal microscopy. Quantification of the sweat gland volume and three-dimensional reconstruction of the nerve fibers was performed using a design-unbiased technique.ResultsAdolescents with diabetes had a significant reduction of maximum and mean values of nerve fiber length and nerve fiber density in sweat glands compared to controls (p values < 0.05). No association between nerve fiber density and sweat responses was found (p = 0.21). In cases with reduced sweat gland nerve fiber length, nerve fiber density, and volume, the sweat response was reduced or absent. Height, systolic blood pressure, time in hypoglycemia, and total daily and basal/total insulin dose were positively correlated to sweat response, while low-density lipoprotein, and HbA1c were negatively correlated with sweat response (p values < 0.05). Other microvascular complications and high cholesterol levels increased the relative risk for reduced sweat gland nerve fiber density.ConclusionOur findings of reduced sweat gland innervation in a selected group of adolescents add new knowledge about the structural changes that occur in autonomic nerves due to diabetes. Evaluating both the sweat gland innervation and sweat gland volume was important for understanding the association with sweat responses. Further research is needed to understand its clinical relevance.

Autonomic function in sporadic and familial ALS type 8

ObjectiveTo characterize and compare autonomic function in patients with sporadic (sALS) and familial ALS type 8 (fALS8). MethodsWe selected 11 patients with sALS (7 men), 14 with fALS8 (8 men) and 26 controls (15 men). All groups were gender and age-matched. For each subject, Scale for Outcomes in Parkinson's Disease for Autonomic Symptoms (SCOPA-AUT) was applied and data from heart rate variability, Quantitative Sudomotor Axon Reflex Test (QSART) and skin sympathetic response (SSR) were collected. These data were compared across groups using nonparametric tests. P-values < 0.05 were considered significant. ResultsSCOPA-AUT revealed predominant clinical complaints in thermoregulatory, pupillomotor and sexual domains in fALS8 relative to sALS as well as controls. Neurophysiological tests demonstrated significant differences in Valsalva ratio, Expiratory:Inspiratory index and RR minimum values in both ALS groups relative to controls. Sudomotor dysfunction was also observed in sALS and fALS8 groups, as shown by reduced medial forearm and foot QSART volumes and absence of SSR in lower limbs. ConclusionsDysautonomia – cardiac and sudomotor - is part of the phenotype in sALS and fALS8. The profile of autonomic symptoms, however, is different in each group. SignificancePatients with fALS8 and sALS have autonomic dysfunction involving both sympathetic and parasympathetic divisions.

Prevalence of somatic small fiber neuropathy in elderly: a review

Somatic small fiber neuropathy (SSFN) is a neuromuscular disease that affects peripheral nerves and leads to structural and functional changes involving small myelinated (Aδ) and unmyelinated (C) fibers, and whose pathophysiological mechanisms are not well elucidated, but depend on the underlying etiology. Due to the lack of studies on this pathology, it is likely to be underdiagnosed, which is a problem, since this disease in elderly people can lead to multiple negative effects on daily life due to neuropathic pain, paresthesia, and dysautonomia of various systems. The clinical diagnosis of this pathology is based on data from the clinical history and physical examination, as well as some complementary examinations and tests, such as the quantitative sudomotor axon reflex test (QSART). Moreover, the treatment of the disease is still limited and most approaches focus on the control of symptoms, such as neuropathic pain. The present study consists of a narrative review of the literature conducted in Medline databases from 2010 to 2022 on small-fiber neuropathy, the elderly, and neuralgia, using the terminology indicated by the Health Sciences Descriptor System (DeCS), and aims to highlight the relevance of the association of senile comorbidities and the aging process with somatic small-fiber neuropathy. Thus, future studies investigating the pathophysiological mechanisms of SSFN are of utmost importance, as well as studies aimed at developing more effective diagnostic methods.

Neuropathy in adolescents with type 1 diabetes: Confirmatory diagnostic tests, bedside tests, and risk factors

AimsTo estimate the prevalence of large fiber (LFN), small fiber (SFN), and autonomic neuropathy in adolescents with type 1 diabetes using confirmatory tests known from adults and to identify risk factors and bedside methods for neuropathy. MethodsSixty adolescents with type 1 diabetes (diabetes duration > five years) and 23 control subjects underwent neurological examination and confirmatory diagnostic tests for neuropathy, including nerve conduction studies, skin biopsies determining intraepidermal nerve fiber density, quantitative sudomotor axon reflex test (QSART), cardiovascular reflex tests (CARTs), and tilt table test. Possible risk factors were analyzed. Bedside tests (biothesiometry, DPNCheck®, Sudoscan, and Vagus®device) were compared with the confirmatory tests using ROC analysis. ResultsThe prevalence of neuropathies in the adolescents with diabetes (mean HbA1c 7.6% (60 mmol/mol)) was as follows: 14% confirmed/26% subclinical LFN, 2% confirmed/25% subclinical SFN, 20% abnormal QSART, 8% abnormal CARTs, and 14% orthostatic hypotension. Higher age, higher insulin dose, previous smoking, and higher triglycerides level were found to increase the relative risk for neuropathy. The bedside tests showed poor to acceptable concordance with the confirmatory tests (all, AUC ≤ 0.75). ConclusionsThe diagnostic tests confirmed the presence of neuropathy in adolescents with diabetes and underscore the importance of prevention and screening.

Evaluation of Autonomic Nervous System Dysfunction in Childhood Obesity and Prader-Willi Syndrome.

The autonomic nervous system (ANS) may play a role in the distribution of body fat and the development of obesity and its complications. Features of individuals with Prader-Willi syndrome (PWS) impacted by PWS molecular genetic classes suggest alterations in ANS function; however, these have been rarely studied and presented with conflicting results. The aim of this study was to investigate if the ANS function is altered in PWS. In this case-control study, we assessed ANS function in 20 subjects with PWS (6 males/14 females; median age 10.5 years) and 27 body mass index (BMI) z-score-matched controls (19 males/8 females; median age 12.8 years). Standardized non-invasive measures of cardiac baroreflex function, heart rate, blood pressure, heart rate variability, quantitative sudomotor axon reflex tests, and a symptom questionnaire were completed. The increase in heart rate in response to head-up tilt testing was blunted (p < 0.01) in PWS compared to controls. Besides a lower heart rate ratio with Valsalva in PWS (p < 0.01), no significant differences were observed in other measures of cardiac function or sweat production. Findings suggest possible altered sympathetic function in PWS.

A Pilot Study of Autonomic Function Screening Tests for Differentiating Complex Regional Pain Syndrome Type II and Traumatic Neuropathic Pain.

Background and Objectives: One of the most challenging tasks in a clinical setting is to differentiate between complex regional pain syndrome (CRPS) type II and traumatic neuropathic pain (NeP). CRPS is characterized by several dysautonomic manifestations, such as edema, hyper/hypohidrosis, skin color change, and tachycardia. This study compared the outcomes of autonomic function screening tests in patients with CRPS type II and traumatic NeP for diagnostic differentiation. Materials and Methods: CRPS type II was diagnosed according to the Budapest research criteria, while NeP was diagnosed according to the updated grading system suggested by the International Association for the Study of Pain Special Interest Group on Neuropathic Pain in 2016. Twenty patients with CRPS type II and twenty-five with traumatic NeP were investigated. Results: Twelve patients with CRPS type II presented abnormal results for the quantitative sudomotor axon reflex test (QSART). Abnormal QSART results were more common in the CRPS type II group. Conclusions: Analysis of QSART combined with other ancillary tests can help in the differential diagnosis of CRPS type II and traumatic NeP if factors influencing abnormal QSART are sufficiently controlled.

Transcriptome Profiling of Anhidrotic Eccrine Sweat Glands Reveals that Olfactory Receptors on Eccrine Sweat Glands Regulate Perspiration in a Ligand-Dependent Manner

Sweat maintains systemic homeostasis in humans. Although sweating disorders may cause multifaceted health problems, therapeutic options for sweat disorders have not yet been established. To gain new insight into the mechanism underlying the regulation of perspiration, we compared eccrine sweat gland transcriptomes from hidrotic and anhidrotic lesions from patients with anhidrosis and found out that olfactory receptors were expressed differentially in anhidrotic and hidrotic eccrine sweat glands. We then confirmed OR51A7 and OR51E2 expression in human eccrine sweat glands by in situ hybridization and immunohistochemistry. An alkaline phosphatase-TGFα shedding assay revealed that β-ionone activates G-proteins through OR51A7 or OR51E2. The effect of topically applied β-ionone on sweating was examined with the quantitative sudomotor axon reflex test, which showed that responses to β-ionone differed between sexes. Topical β-ionone attenuated female sweating and augmented male sweating. Taken together, this study suggests that olfactory receptors expressed in eccrine sweat glands may regulate sweating in response to odorous ligands on the basis of sex. These unexpected results indicate that olfactory receptors may modulate sweating and that olfactory receptor modulators may contribute to the management of sweat disorders.

Phenotyping autonomic neuropathy using principal component analysis.

To identify autonomic neuropathy (AN) phenotypes, we used principal component analysis on data from participants (N=209) who underwent standardized autonomic testing including quantitative sudomotor axon reflex testing, and heart rate and blood pressure at rest and during tilt, Valsalva, and standardized deep breathing. The analysis identified seven clusters: 1) normal, 2) hyperadrenergic features without AN, 3) mild AN with hyperadrenergic features, 4) moderate AN, 5) mild AN with hypoadrenergic features, 6) borderline AN with hypoadrenergic features, 7) mild balanced deficits across parasympathetic, sympathetic and sudomotor domains. These findings demonstrate a complex relationship between adrenergic and other aspects of autonomic function.

Early Gastrointestinal Neuropathy Assessed by Wireless Motility Capsules in Adolescents with Type 1 Diabetes

To assess the prevalence of objective signs of gastrointestinal (GI) autonomic neuropathy (AN) in adolescents with type 1 diabetes (T1D). In addition, to investigate associations between objective GI findings and self-reported symptoms or other findings of AN. Fifty adolescents with T1D and 20 healthy adolescents were examined with a wireless motility capsule to assess the total and regional GI transit times and motility index. GI symptoms were evaluated with the GI Symptom Rating Scale questionnaire. AN was evaluated with cardiovascular and quantitative sudomotor axon reflex tests. There was no difference in GI transit times in adolescents with T1D and healthy controls. Adolescents with T1D had a higher colonic motility index and peak pressure than the controls, and GI symptoms were associated with low gastric and colonic motility index (all p < 0.05). Abnormal gastric motility was associated with the duration of T1D, while a low colonic motility index was inversely associated with "time in target range" for blood glucose (all p < 0.01). No associations were found between signs of GI neuropathy and other measures of AN. Objective signs of GI neuropathy are common in adolescents with T1D and it seems to require early interventions in patients at high risk of developing GI neuropathy.

Assessing the Feasibility of Using Electrochemical Skin Conductance as a Substitute for the Quantitative Sudomotor Axon Reflex Test in the Composite Autonomic Scoring Scale and Its Correlation with Composite Autonomic Symptom Scale 31 in Parkinson’s Disease

The Composite Autonomic Scoring Scale (CASS) is a quantitative scoring system that integrates the sudomotor, the cardiovagal, and the adrenergic subscores, and the Composite Autonomic Symptom Scale 31 (COMPASS 31) is based on a well-established comprehensive questionnaire designed to assess the autonomic symptoms across multiple domains. We tested the hypothesis that electrochemical skin conductance (Sudoscan) can be a substitute for the quantitative sudomotor axon reflex test (QSART) in the sudomotor domain and assessed its correlation with COMPASS 31 in patients with Parkinson's disease (PD). Fifty-five patients with PD underwent clinical assessment and cardiovascular autonomic function tests and completed the COMPASS 31 questionnaire. We compared the modified CASS (integrating the Sudoscan-based sudomotor, adrenergic, and cardiovagal subscores) and CASS subscores (the sum of the adrenergic and cardiovagal subscores). The total weighted score of COMPASS 31 was significantly correlated with both the modified CASS and the CASS subscore (p = 0.007 and p = 0.019). The correlation of the total weighted score of COMPASS 31 increased from 0.316 (CASS subscores) to 0.361 (modified CASS). When we added the Sudoscan-based sudomotor subscore, the case numbers for autonomic neuropathy (AN) increased from 22 (40%, CASS subscores) to 40 (72.7%, modified CASS). The modified CASS not only better reflects the exact autonomic function, but also improves the characterization and quantification of AN in patients with PD. In areas in which a QSART facility is not easily available, Sudoscan could be a time-saving substitution.

Functional and structural markers of peripheral microvascular autonomic neuropathy.

Autonomic dysfunction is a common complication of small-fiber neuropathy (SFN). In this study we aimed to assess the applicability of autonomic microvascular indices as a potential marker for SFN assessment. Fifteen patients with confirmed SFN (idiopathic neuropathy [n=10], chemotherapy-induced peripheral neuropathy [n=2], impaired glucose tolerance [n=1], hereditary transthyretin amyloidosis (hATTR) [n=1], pulmonary sarcoidosis [n=1]) and 15 matched control subjects underwent assessment of vascular skin responses assessed through laser Doppler flowmetry and evaluation of microvascular vessel and nerve density in skin biopsies. All participants underwent peripheral autonomic evaluation by quantitative sudomotor axon reflex testing (QSART). We found no significant differences in vascular skin responses, or in any microvascular skin biopsy markers, when comparing SFN with control subjects. We found no correlation between vascular skin responses and skin biopsy indices. We saw no significant difference in any microvascular indices when comparing subjects with and without impaired sudomotor function. Our findings suggest markers of peripheral microvascular innervation and function are not associated with the diagnosis of SFN. Furthermore, we saw no association between microvascular markers and sudomotor function, suggesting that these are independent and unrelated components of the autonomic nervous system.

Coffee intake may promote sudomotor function activation via the contribution of caffeine.

To determine whether drinking coffee with caffeine accelerates the sympathetic response to acetylcholine (ACh). Tests were performed twice at 1-week intervals following the intake of coffee. Subjects were randomly divided into two groups: Group A was administered 16 fluid oz of water (CON), while Group B was given 16 fluid oz of coffee (Coffee). After 1 week, Group A was administered 16 fluid oz of coffee (Coffee), while Group B was given 16 fluid oz of water (CON). The quantitative sudomotor axon reflex test (QSART) was performed after intake of coffee and water and a 40 min break. QSART with iontophoresis and 10% ACh was performed to determine axon reflex (AXR) mediated with and without iontophoresis [AXR (1) and AXR (2), respectively], and directly activated sweating (DIR). The sweat onset time of the AXR was shorter in the Coffee compared with the CON (p < 0.05). The sweat rates in AXR (1) AXR (2) and DIR were significantly higher in the Coffee than in the CON (p < 0.05, p < 0.05, p < 0.01, respectively). In addition, the Coffee showed significantly higher density of activated sweat glands and activated sweat gland output than the CON (p < 0.05, p < 0.01, respectively). The overall results of this study showed that coffee intake could stimulate higher activation in both AXR and DIR sweat responses. Coffee intake can improve sweating sensitivity in both the AXR and DIR by the contribution of caffeine contained in coffee. This suggests that other compounds in coffee may not inhibit the sympathetic response to ACh. Therefore, coffee may be clinically worth considering as a supplement for the activation of the cholinergic and sudomotor function.

Skin Biopsy and Quantitative Sudomotor Axon Reflex Testing in Patients With Postural Orthostatic Tachycardia Syndrome.

No formal diagnostic criteria exist for the neuropathic subtype of postural orthostatic tachycardia syndrome (POTS). Skin biopsy and quantitative sudomotor axon reflex testing (QSORT) are preferred methods of assessment for autonomic small fiber neuropathy (SFN). This study characterizes the utility of these testing methods at a tertiary center and identifies clinical features associated with abnormal testing. Medical records of 2658 patients undergoing tilt table testing at a single institution between June 2018 and December 2020 were reviewed. Patients with postural orthostatic tachycardia syndrome were included for analysis of intraepidermal nerve fiber density (IENFD), sweat output, comorbidities, symptoms, measures of cardiovascular autonomic function, and serum antibody levels. 356 patients (90% female, mean age 31 ± 10) met the diagnostic criteria for postural orthostatic tachycardia syndrome. Of 211 patients who underwent quantitative sudomotor axon reflex testing, 70 (33%) demonstrated reduced sweat output. These patients were more likely to demonstrate sympathetic impairment during the Valsalva maneuver. Of 80 patients who underwent skin biopsies, 19 (24%) demonstrated reduced intraepidermal nerve fiber density. These patients tended to be older and have reduced heart rate variability during deep breathing. Neither test was associated with specific serum antibodies, symptoms, or comorbidities, though there was a trend toward higher rates of comorbid autoimmune disease in patients with abnormal testing. A subset of patients with postural orthostatic tachycardia syndrome have evidence of small fiber neuropathy. These patients tend to have impaired cardiovascular autonomic function but are otherwise similar to patients with no evidence of small fiber neuropathy.

Immune-Mediated Small Fiber Neuropathy With Trisulfated Heparin Disaccharide, Fibroblast Growth Factor Receptor 3, or Plexin D1 Antibodies: Presentation and Treatment With Intravenous Immunoglobulin.

Up to 50% of small fiber neuropathy (SFN) cases are idiopathic, but novel antibodies to Trisulfated Heparin Disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR-3) have been implicated in half of these cases; the role of anti-Plexin D1 is less clear. We aimed to clarify presentation and management of these patients. An 18-month retrospective analysis revealed 54 cases of cryptogenic SFN who had testing for the 3 autoantibodies. Demographics, clinical features, epidermal nerve fiber density, and Quantitative Sudomotor Axon Reflex Test results were analyzed. Intravenous immunoglobulin (IVIG) treatment response was assessed. In total, 44.4% of patients had antibodies (62.5% TS-HDS, 29.2% FGFR-3, and 20.8% Plexin D1). Male patients were more likely to be FGFR-3 positive (P = 0.014). Facial involvement was more common in seropositive patients (P = 0.034), and patients with a higher Utah Early Neuropathy Scale score had a higher TS-HDS titer (P = 0.0469), but other clinical features were not significantly different. Seropositive patients trended toward a higher SFN screening list score (P = 0.16), abnormal Quantitative Sudomotor Axon Reflex Test (P = 0.052), and prior erroneous diagnosis (P = 0.19). In patients who completed IVIG, examinations and questionnaires improved and mean epidermal nerve fiber density increased by 297%. TS-HDS, FGFR-3, and Plexin D1 antibodies are present in a high proportion of cryptogenic SFN cases with more facial involvement, and greater disease severity is associated with higher antibody titers. They are often misdiagnosed but may respond subjectively and objectively to IVIG.

Dysautonomia in RFC1-related disorder: Clinical and neurophysiological evaluation

ObjectiveTo characterize and quantify autonomic involvement in patients with RFC1-related disorder of adult-onset cerebellar ataxia and idiopathic sensory neuropathy. MethodsWe enrolled 16 subjects with biallelic RFC1 (AAGGG)n expansions and 16 age and sex-matched healthy controls that underwent comprehensive clinical and neurophysiological evaluation. Scales for Outcomes in Parkinson’s Disease Autonomic Dysfunction (SCOPA-AUT) score was used to assess autonomic symptoms. Electrophysiological testing included assessment of heart rate variability and quantitative sudomotor axon reflex test (QSART). Between-group comparisons were assessed using non-parametric tests. ResultsIn the patient group, there were 9 men/7 women and the median age was 60.5 years. SCOPA-AUT scores were significantly higher in the RFC1 group compared to controls (22 vs 10, p < 0.001). Half of patients had cardiac autonomic neuropathy. In neurophysiology, there was resting tachycardia combined with abnormal responses during Valsalva maneuver and deep breathing among patients. QSART responses were also significantly reduced in the RFC1 group, especially in the lower limbs. ConclusionsAutonomic dysfunction is frequent, clinically relevant and involves multiple domains in RFC1-related disorder. Patients have both sympathetic and parasympathetic involvement. From a topographical perspective, this condition is characterized by a small fiber autonomic axonopathy. SignificanceDysautonomia is frequent, severe and related to peripheral damage in RFC1-related disorder.

Evaluation of sweating responses in patients with systemic connective tissue disorders using the quantitative sudomotor axon reflex test

AbstractBackgroundIn systemic connective tissue disorders, eccrine sweat glands are frequently attacked by immune cells, as evidenced by pathological observations.AimsSweating affects vascular activity through the autonomic nervous system, while few studies have reported sweating ability in systemic connective tissue disorders or the relationship between sweating ability and Raynaud's phenomenon caused by sympathetic hyperreactivity.Materials &amp; methodsWe performed the quantitative sudomotor axon reflex test on 85 patients diagnosed with systemic sclerosis, mixed connective tissue disease, systemic lupus erythematosus, Sjogren's syndrome, and dermatomyositis. Evaluations were performed once in summer and once in winter. We investigated the relationship between the axon reflex sweat volume or the reaction time and Raynaud's phenomenon assessed by a Raynaud's condition score, skin symptoms such as nailfold capillary changes, skin sclerosis severity, digital ulcers, chilblains, subcutaneous calcifications, and telangiectasia, and patient background.ResultsMost patients did not show a decrease in sweating compared to healthy participants, but patients with systemic sclerosis who were positive for anti‐RNA polymerase III antibodies showed little or no sweating. One in three patients showed less sweating in summer than in winter, which is the opposite of the normal seasonal variation. Although no relationship was observed between the sweat volume and the total Raynaud's condition scores, patients with pain had more sweating than those without pain.ConclusionThis is the first exploratory observational study of sweating ability in patients with systemic connective tissue disorders, revealing several clinical factors associated with acetylcholine‐induced sweating.