Detecting and treating the protean manifestations of diabetic autonomic neuropathy.

The manifestations of diabetic autonomic neuropathy (DAN) are protean and clinically involve multiple systems, including the cardiovascular system, the gastrointestinal system, the genitourinary system as well as the sweat glands (sudomotor dysfunction) and the gallbladder. In addition, cardiac autonomic neuropathy (CAN) is associated with a correctible inability to appreciate and correct hypoglycaemia. While not a clinical problem, pupillary involvement should be the clue and the catalyst to investigate for other manifestations of DAN. This review outlines a practical approach to detecting and investigating the manifestations of DAN. Of particular importance is early detection of cardiovascular involvement where prompt therapy through glycaemic control can decrease the severity of CAN and decelerate the frequency and severity of retinopathy and nephropathy in addition to decreasing cardiovascular events and mortality. CAN also plays a role in accelerating other diabetic complications such as acute ischaemic stroke, heart failure, medial artery calcinosis, foot ulcers, peripheral artery disease and Charcot joints. Many therapies of DAN are available, which should not only decrease morbidity and mortality from DAN, but also improve the patient's quality of life. However, the therapies available are largely symptomatic.

Autonomic dysfunction in hereditary spastic paraplegia type 4.

BACKGROUND AND PURPOSE: SPAST mutations are the most common cause of hereditary spastic paraplegia (SPG4-HSP), which is characterized by progressive lower limb weakness, spasticity and hyperreflexia. There are few studies about non-motor manifestations in this disease and none about autonomic involvement. Therefore, the aim was to determine the frequency and pattern of autonomic complaints in patients with SPG4-HSP, as well as to determine the clinical relevance and the possible factors associated with these manifestations. METHODS: Thirty-four molecularly confirmed SPG4 patients were recruited in a multicenter cross-sectional study, of whom 26 underwent detailed neurophysiological testing (heart rate variability, sympathetic skin response and the Quantitative Sudomotor Axonal Reflex Test). The Scales for Outcomes in Parkinson's Disease - Autonomic Questionnaire (SCOPA-AUT) was applied to quantify the severity of autonomic symptoms. Results were compared with 44 age- and gender-matched healthy controls using non-parametric tests. P values <0.05 were considered significant. RESULTS: In the SPG4-HSP group, there were 18 men with a mean age of 47.7 ± 12.6 years. SCOPA-AUT scores were similar between patients and controls (P = 0.238). Only the urinary domain subscore was significantly higher amongst patients (4 vs. 2.5, P = 0.05). Absent sympathetic skin response in the hands and feet was more frequent amongst patients (20% vs. 0%, P < 0.001, and 64% vs. 0%, P = 0.006, respectively). Quantitative Sudomotor Axonal Reflex Test responses were also smaller throughout all recording regions in the SPG4-HSP group. CONCLUSION: Our results indicate that SPG4-HSP patients have sudomotor dysfunction caused by damaged small post-ganglionic cholinergic fibers. Damage in SPG4-HSP extends to the peripheral nervous system.

Association of sudomotor function with peripheral artery disease in type 2 diabetes.

Peripheral artery disease (PAD) is the major risk factor for cardiovascular disease and lower extremity amputation in patients with diabetes. Autonomic neuropathy is a risk factor for cardiovascular-related morbidity and mortality. Sudomotor dysfunction is well established in type 2 diabetes mellitus (T2DM) and reflects small fibre neuropathy, cardiovascular autonomic neuropathy and peripheral sympathetic autonomic neuropathy. However, the relationship between sudomotor dysfunction and PAD remains unexplored. Therefore, the aim of present study was to explore the association of sudomotor function with ankle-brachial index (ABI) and C-reactive protein (CRP) in T2DM. In this cross-sectional study, we recruited 36 consecutive type 2 diabetes patients and 20 age- and sex-matched healthy controls. Sudomotor function was assessed using Sudoscan (Sudoscan-Impeto Medical Device, EZS 01750010193, Paris, France), which detects sweat gland function through measurement of electrochemical skin conductance of both hands and feet. Measurement of ankle-brachial ABI was carried out with sphygmomanometer and Doppler device (Hadeco Bidop ES-100V3). Glycated haemoglobin (HbA1c), fasting plasma glucose, and inflammatory marker CRP were also measured. Type 2 diabetic patients had significantly impaired sudomotor function (48.14 ± 8.28 vs. 76.48 ± 6.72 µs), lower ABI (0.89 ± 0.25 vs. 1.15 ± 0.11) and elevated CRP (5.32 ± 2.41 vs. 2.45 ± 1.11 mg/l) as compared to healthy controls, respectively (p < 0.01). Sudoscan scores were found to be inversely correlated with CRP and HbA1c, and directly correlated with ABI (p < 0.05) in the patients. Sudomotor dysfunction is associated with significant peripheral artery disease, vascular inflammation and impaired glycaemic status.

Autonomic neuropathic symptoms in patients with diabetes: practical tools for screening in daily routine.

BACKGROUND: Diabetic autonomic neuropathy (DAN) is a frequent complication in people with diabetes whose screening is often neglected. This study aimed to evaluate DAN through practical tools in people with diabetes in a referral center for diabetes treatment. METHODS: DAN symptoms and severity were assessed using the Survey of Autonomic Symptoms (SAS) via digital application (app) in patients attended from June 1, 2021, to November 12, 2021. SAS scoring for DAN was performed using established validated cutoffs. The adhesive with cobalt salt color indicator (Neuropad™) was used as a measure of sudomotor dysfunction. Demographical and clinical data were also collected. RESULTS: Data from 109 participants, 66.9% T2DM, 73.4% female, with a median age of 54.00 (± 20.00) years, were analyzed. Symptomatic DAN was present in 69.7% of participants and was associated with older age (p = 0.002), higher HbA1c (p = 0.043), higher abdominal circumference (p = 0.019), higher BMI (p = 0.013), more likely to have metabolic syndrome (MS) with a 10-fold increased risk, and more frequent association with diabetic peripheral neuropathy (p = 0.005). Sudomotor dysfunction was found in 65 participants with positive Neuropad™ detected in 63.1% of them. CONCLUSION: The use of SAS through an app proved to be a practical and easy-to-use instrument to document symptoms of DAN in busy clinical practice. The high frequency of symptoms draws attention to the importance of screening this underdiagnosed diabetes complication. The risk factors and comorbidities associated with symptomatic DAN highlight the patients' phenotypes linked to MS that should be targeted for DAN evaluations in larger samples in the community.

Unraveling Autonomic Dysfunction in GBA-Related Parkinson's Disease.

Background: Patients with Parkinson's disease (PD) and GBA gene mutations (GBA-PD) develop nonmotor complications more frequently than noncarriers. However, an objective characterization of both cardiovascular and sudomotor autonomic dysfunction using extensive clinical and instrumental measures has never been provided so far. Survival is reduced in GBA-PD regardless of age and dementia, suggesting that other hitherto unrecognized factors are involved. Objectives: To provide instrumental measures of pattern and severity of autonomic dysfunction in GBA-PD and explore their correlation with other non-motor symptoms and implications for clinical practice. Methods: In this cross-sectional study, 21 GBA-PD and 24 matched PD noncarriers underwent extensive assessment of motor and non-motor features, including neuropsychological testing. Cardiovascular autonomic function was explored through a comprehensive battery of indexes, including power spectral analysis of the R-R intervals and blood pressure short-term variability during resting state and active maneuvers. Dynamic Sweat Test was used to assess post-ganglionic sudomotor dysfunction. Results: Despite minimal or absent clinical correlates, cardiovagal and sympathetic indexes, heart rate variability parameters and sudomotor postganglionic function were more severely impaired in GBA-PD than noncarriers (overcoming relatively preserved compensatory peripheral sympathetic function), suggesting more prominent cardiac sympatho-vagal demodulation, efferent baroreflex failure and peripheral sympathetic dysfunction in GBA-PD. Cardiovascular dysautonomia showed marginal correlations with cognitive impairment. Conclusions: Compared to PD noncarriers, GBA-PD display more severe instrumental autonomic abnormalities, which may be underestimated by purely clinical measures, despite their relevance on morbidity and mortality. This supports the necessity of implementing instrumental autonomic assessment in all GBA-PD, regardless of clinically overt symptoms.

Sudomotor dysfunction in diabetic peripheral neuropathy (DPN) and its testing modalities: A literature review.

Long term consequences of diabetes mellitus (DM) may include multi-organ complications such as retinopathy, cardiovascular disease, neuronal, and kidney damage. One of the most prevalent complication is diabetic peripheral neuropathy (DPN), occurring in half of all diabetics, and is the main cause of disability globally with profound impact on a patient's quality of life. Small fiber neuropathy (SFN) can develop in the pre-diabetes stage preceding large fiber damage in DPN. Asymptomatic SFN is difficult to diagnose in early stages, with sudomotor dysfunction considered one of the earliest manifestations of autonomic neuropathy. Early detection is crucial as it can prevent potential cardiovascular events. Although punch skin biopsy is the gold-standard method for SFN diagnosis, implementation as routine screening is hindered due to its invasive, impractical, and time-consuming nature. Other sudomotor testing modalities, most of which evaluate the postganglionic cholinergic sympathetic nervous system, have been developed with varying sensitivity and specificity for SFN diagnosis. Here, we provide an overview on the general mechanism of DPN, the importance of sudomotor assessment for early detection of autonomic dysfunction in DPN, the benefits and disadvantages of current testing modalities, factors that may affect testing, and the importance of future discoveries on sudomotor testing for successful DPN diagnosis.

Electrochemical skin conductances values and clinical factors affecting sudomotor dysfunction in patients with prediabetes, type 1 diabetes, and type 2 diabetes: A single center experience.

BACKGROUND AND AIM: Sudomotor dysfunction is linked to small fibers damage. We investigated sudomotor dysfunction in a large group of participants with diabetes, prediabetes, and nondiabetic healthy subjects. This study aimed to complete knowledge on sudomotor dysfunction in this population, especially regarding the threshold values for the electrochemical skin conductance (ESC) and factors affecting it. MATERIALS AND METHODS: A total of 690 volunteers in four groups were included in the study (type 1 [T1DG]: n = 80, 61.3% women; type 2 diabetes [T2DG]: n = 438, 63.5% women; prediabetes [Pre-DG]: n = 88, 80.7% women; healthy control [HC-G]: n = 84, 67.5% women). All subjects were investigated for clinical diabetic peripheral polyneuropathy and sudomotor dysfunction. The characteristics of participants obtained from outpatient records were evaluated. We used the Sudoscan device to measure ESC which was normalized for BMI, to improve the discriminative capability of the method. RESULTS: Diabetic polyneuropathy was found in 17.5% of T1DG, 27.4% of T1DG, and 10.2% of Pre-DG. The mean ESC/BMI was lower in subgroups with diabetic polyneuropathy than those without. Mean ESC/BMI was lowest in T2DG and highest in HC-G but comparable in T1DG and Pre-DG. We accepted the "mean ESC/BMI-1 SD" in the HC-G as the threshold for sudomotor dysfunction. Accordingly, the prevalence of sudomotor dysfunction was 18.8%, 44.3%, 59.1%, and 15% in T1DG, T2DG, Pre-DG, and HC-G, respectively. In T2DG, sudomotor dysfunction was found in 66.7% of persons with retinopathy, of which 56.3% had clinical diabetic polyneuropathy. The prevalence of sudomotor dysfunction in subjects with peripheral artery disease, chronic kidney disease, cardiovascular disease, and hypertension was 46.7%, 47.4%, 43.4%, and 50%, respectively, and 42.9%, 38.9%, 45.5%, and 37.3% of whom in the same order detected with clinical diabetic polyneuropathy. Considering the entire group, a logistic regression model demonstrated that the variables associated with SMD were: retinopathy (OR: 2.969; 95% CI: 1.723, 5.114), female gender (OR: 1.952; 95% CI: 1.287, 2.962), and e-GFR (OR: 0.989; 95% CI: 0.981, 0.998). Since the rate of complications was very low in T1DG, excluding this group, a new model similarly revealed that retinopathy and female gender were associated with SMD, however, the association with e-GFR was disappeared. CONCLUSION: The prevalence of sudomotor dysfunction is high when established peripheral polyneuropathy was present in diabetes. Even though, sudomotor dysfunction can also occur before clinical polyneuropathy in both types of diabetes (T1DG: 18.8%, T2DG 44.3%), prediabetes (59.1%), and nondiabetic healthy subjects (15%). The variables associated with sudomotor dysfunction were retinopathy and female sex. Normalization of ESC for BMI would be a beneficial approach. However, before this method is included in the routine screening programs for diabetic polyneuropathy, large-scale and prospective studies are required to reach a consensus on the pathological threshold values.

Pharmacological Ischemic Conditioning with Roxadustat Does Not Affect Pain-Like Behaviors but Mitigates Sudomotor Impairment in a Murine Model of Deep Hind Paw Incision.

Purpose: The involvement of hypoxic response mechanisms in local functional impairments in surgical wounds is unclear. In the present study, we characterized tissue hypoxia in surgical wounds and investigated the role of pharmacological ischemic conditioning (PIC) using roxadustat, an oral prolyl hydroxylase domain enzyme inhibitor, in postoperative local functional impairments in a murine model of deep hind paw incision. Methods: Male BALB/cAJcl mice aged 9-13 weeks were used in all experiments. Plantar skins of mice that underwent surgical incision were subjected to immunohistochemistry to localise tissue hypoxia. Pain-like behaviours and sudomotor function were compared between mice treated with 6-week perioperative PIC and control mice. The effects of PIC were examined in vitro by immunocytochemistry using sympathetically differentiated PC12 cells and in vivo by immunohistochemistry using plantar skins collected on postoperative day 21. Results: Prominent tissue hypoxia was detected within axons in the nerve bundles underneath surgical wounds. Six-week perioperative PIC using roxadustat failed to ease spontaneous pain-like behaviors; however, it mitigated local sudomotor impairment postoperatively. Upregulation of sympathetic innervation to the eccrine glands was observed in the PIC-treated skins collected on postoperative day 21, in accordance with the in vitro study wherein roxadustat promoted neurite growth of sympathetically differentiated PC12 cells. Conclusion: This study suggests that tissue hypoxia is involved in the pathogenesis of local sudomotor dysfunction associated with surgical trauma. Targeting the hypoxic response mechanisms with PIC may be of therapeutic potential in postsurgical local sympathetic impairments that can be present in complex regional pain syndrome.

Quantitative gastrointestinal function and corresponding symptom profiles in autonomic neuropathy.

Purpose: Peripheral neuropathies with autonomic nervous system involvement are a recognized cause of gastrointestinal dysmotility for a wide spectrum of diseases. Recent advances in wireless motility capsule testing allow improved sampling of regional and whole gut motility to aid in the diagnosis of gastrointestinal motility disorders and may provide additional insight into segment-specific enteric involvement of peripheral neuropathies affecting autonomic nervous system function. Methods: We utilized standardized autonomic nervous system (ANS) reflex assessment and wireless motility capsule testing to evaluate 20 individuals with idiopathic autonomic neuropathy and unexplained gastrointestinal symptoms. Additionally, we examined the relationship between quantifiable autonomic neuropathy and gastrointestinal dysmotility at specific neuroanatomical levels. Symptom profiles were evaluated using the 31-item Composite Autonomic Symptom Score questionnaire (COMPASS-31) and compared to wireless motility capsule data. Results: We found that transit times were predominately abnormal (delayed) in the foregut (10 of 20; 50%), while contractility abnormalities were far more prominent in the hindgut (17 of 20; 85%), and that motility and symptom patterns, as assessed by the COMPASS-31 GI domain items, generally corresponded. Finally, we also found that there was neuroanatomical overlap in the presence of autonomic reflex abnormalities and WMC-based transit and/or contractility abnormalities. Conclusions: We found that transit times were predominately abnormal in the foregut and midgut, while contractility abnormalities were far more prominent in the hindgut in individuals with idiopathic autonomic neuropathy. There was a high rate of agreement in segmental wireless motility capsule data with neuroanatomically corresponding standardized ANS function measures (e.g., cardiovagal, sudomotor, adrenergic). Expanded sudomotor testing, including additional neuroanatomical segments, could provide additional indirect assessment of visceral involvement in ANS dysfunction.

Management strategies for gastrointestinal, erectile, bladder, and sudomotor dysfunction in patients with diabetes.

There are substantial advances in understanding disordered gastrointestinal autonomic dysfunction in diabetes. It occurs frequently. The underlying pathogenesis is complex involving defects in multiple interacting cell types of the myenteric plexus as well. These defects may be irreversible or reversible. Gastrointestinal symptoms represent a major and generally underestimated source of morbidity for escalating health care costs in diabetes. Acute changes in glycaemia are both determinants and consequences of altered gastrointestinal motility. 35-90% of diabetic men have moderate-to-severe erectile dysfunction (ED). ED shares common risk factors with CVD. Diagnosis is based on medical/sexual history, including validated questionnaires. Physical examination and laboratory testing must be tailored to patient's complaints and risk factors. Treatment is based on PDE5-inhibitors (PDE5-I). Other explorations may be useful in patients who do not respond to PDE5-I. Patients at high cardiovascular risk should be stabilized by their cardiologists before sexual activity is considered or ED treatment is recommended. Estimates on bladder dysfunction prevalence are 43-87% of type 1 and 25% of type 2 diabetic patients, respectively. Common symptoms include dysuria, frequency, urgency, nocturia and incomplete bladder emptying. Diagnosis should use validated questionnaire for lower urinary tract symptoms. The type of bladder dysfunction is readily characterized with complete urodynamic testing. Sudomotor dysfunction is a cause of dry skin and is associated with foot ulcerations. Sudomotor function can be assessed by thermoregulatory sweat testing, quantitative sudomotor axon reflex test, sympathetic skin response, quantitative direct/indirect axon reflex testing and the indicator plaster.

[Thermoregulatory dysfunction in Parkinson's disease]. / Narusheniya termoregulyatsii pri bolezni Parkinsona.

Thermoregulatory dysfunction is considered to be the least investigated among all the autonomic disorders in Parkinson disease. Pathophysiological mechanisms of this phenomena involve as central, as peripheric parts of nervous system. Dopamine deficiency in combination with peripheric autonomic dysfunction leads to temperature balance disturbance, which may be expressed by various clinical symptoms. Dopaminergic innervation of preoptic-anterior hypothalamus area plays a crucial role in thermoregulation function of central nervous system. Current thermoregulatory tests give possibility not only to reveal sudomotor and heat dissipation disorders in patients with Parkinson disease, but also to make differential diagnosis with other neurodegenerative disorders. Early detection and treatment of thermoregulatory dysfunction may improve quality of life in patients with Parkinson disease.

Postganglionic Sudomotor Dysfunction and Brain Glucose Hypometabolism in Patients with Multiple System Atrophy.

BACKGROUND: Sudomotor dysfunction is common in patients with multiple system atrophy (MSA). Postganglionic sudomotor dysfunction in MSA, which can be assessed using quantitative sudomotor axon reflex testing (QSART), results from the degeneration of preganglionic sympathetic neurons and direct loss of postganglionic fibers. OBJECTIVE: We investigate whether abnormal QSART responses in patients with MSA are associated with disease severity. METHODS: In this retrospective study, patients with probable MSA who underwent both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) and autonomic function tests were included. Autonomic function test results were integrated divided into three sub-scores, including sudomotor, cardiovagal, and adrenergic sub-scores. The sudomotor sub-score represented postganglionic sudomotor function. Unified Multiple System Atrophy Rating Scale (UMSARS) Part I, Part II, and sum of Part I and II scores (Part I + II) to reflect disease severity and 18F-FDG-PET/CT results were collected. RESULTS: Of 74 patients with MSA, 62.2%demonstrated abnormal QSART results. The UMSARS Part I + II score was significantly higher in the abnormal QSART group than in the normal QSART group (p = 0.037). In the regression analysis, both UMSARS Part I (ß= 1.185, p = 0.013) and Part II (ß= 1.266, p = 0.021) scores were significantly associated with the sudomotor sub-score. On 18F-FDG-PET/CT, the abnormal QSART group exhibited more severely decreased metabolic activity in the cerebellum and basal ganglia in patients with MSA-P and MSA-C, respectively. The sudomotor sub-score was significantly associated with regional metabolism in these areas. CONCLUSION: Patients with MSA and postganglionic sudomotor dysfunction may have worse disease severity and greater neuropathological burden than those without.

Understanding and managing autonomic dysfunction in persons with multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a chronic demyelinating immune mediated disease of the central nervous system. Autonomic dysfunction (AD) is frequently present in persons with MS (pwMS) and increases with disease duration and progression. AREAS COVERED: Cardiovascular, genitourinary, and sudomotor autonomic dysfunction in pwMS are reviewed and managing of these disorders is addressed. EXPERT OPINION: AD in pwMS can manifest with a myriad of symptoms including cardiovascular, urogenital, and sweating disorders. These symptoms can significantly impact the quality of life of pwMS with poor tolerance of upright position, difficulties in sexual function, and low endurance of physical activity especially in warm environments. Health professionals involved in care of pwMS should possess basic knowledge of the function of the autonomic nervous system and be informed of the way disorders of the autonomic function may manifest in pwMS in order to provide the proper care.

Time in range, especially overnight time in range, is associated with sudomotor dysfunction in patients with type 1 diabetes.

BACKGROUND: Time in range (TIR) is advocated as key metric of glycemic control and is reported to be associated with microvascular complications of diabetes. Sudomotor dysfunction is among the earliest detectable diabetic peripheral neuropathy (DPN). We set about to research the relationship between TIR including overnight TIR and sudomotor function detected by SUDOSCAN with the intention of exploring the correlation of TIR including overnight TIR and early DPN in type 1 diabetes (T1D). METHODS: 95 patients with T1D were enrolled. TIR including nocturnal TIR of 3.9-10.0 mmol/L was evaluated with CGM. SUDOSCAN measured feet electrochemical skin conductance (FESC) and sudomotor dysfunction was defined as average FESC < 60µS. Logistic regressions were applied to examine the independent association of TIR and overnight TIR with sudomotor function. RESULTS: The overall prevalence of sudomotor dysfunction was 28.42%. Patients with sudomotor dysfunction had significantly lower TIR for the whole recorded phase and for nighttime. The sudomotor dysfunction prevalence progressively declined with the ascending tertiles of TIR and nocturnal TIR (P for trend < 0.05). Correlation analysis showed that the relationship between nocturnal TIR and FESC was stronger than that between TIR and FESC with correlation coefficients were respectively 0.362 and 0.356 (P < 0.001). Finally, logistic regression analysis indicated the independently negative relation between TIR and nocturnal TIR and sudomotor dysfunction (P < 0.05), and the correlation between nocturnal TIR and sudomotor dysfunction was more statistically significant. CONCLUSIONS: TIR is negatively correlated with sudomotor dysfunction in T1D independent of HbA1c. Furthermore, decreased nocturnal TIR is more closely related to the impaired function of sudomotor nerves in sweat glands.

Predictors of sudomotor dysfunction in patients with type 1 diabetes without clinical evidence of peripheral neuropathy.

AIM: To investigate the frequency of foot sudomotor dysfunction determined by the electrochemical skin conductance test (ESC) and its independent predictors in individuals with type 1 diabetes mellitus (T1D) and no clinical evidence of diabetic peripheral neuropathy (DPN). METHODS: Adults with T1D for longer than 5 years and without DPN defined by the Michigan Neuropathy Screening Instrument and Neuropathy Disability Score were assessed for foot sudomotor dysfunction by ESC. Multivariate logistic regression analysis was used to examine the association between foot sudomotor dysfunction (ESC < 70 µS) and demographic, clinical, and biochemical variables. RESULTS: A total of 61 individuals with T1D were included. Their mean age was 29.5 ± 8.6 years, and mean diabetes duration was 17.8 ± 7.9 years. Foot sudomotor dysfunction was present in 16 (26.2%) participants, despite no clinical evidence of DPN. Retinopathy, hand sudomotor dysfunction and glycated haemoglobin (HbA1c) levels were identified as independent predictors of foot sudomotor dysfunction by multivariate logistic regression analysis. Retinopathy, hand sudomotor dysfunction, and every 1% increase of HbA1c increased the odds of foot sudomotor dysfunction by 2.48, 2.82, and 1.24-fold, respectively. CONCLUSION: Our findings indicate a high frequency of foot sudomotor dysfunction among individuals with T1D and no overt DPN. Factors associated with DPN, including retinopathy and higher HbA1c levels, independently predicted the occurrence of sudomotor dysfunction, suggesting that ESC assessment is a useful tool in the clinical setting to identify early small-fiber neuropathy.

Continuous glucose monitoring defined time-in-range is associated with sudomotor dysfunction in type 2 diabetes.

BACKGROUND: Time in range (TIR), as a novel metric for glycemic control, has robust relevance with diabetic complications. Diabetic peripheral neuropathy (DPN) is characterized by sudomotor dysfunction. AIM: To explore the relationship between TIR obtained from continuous glucose monitoring (CGM) and sudomotor function detected by SUDOSCAN in subjects with type 2 diabetes. METHODS: The research enrolled 466 inpatients with type 2 diabetes. All subjects underwent 3-d CGM and SUDOSCAN. SUDOSCAN was assessed with electrochemical skin conductance in hands (HESC) and feet (FESC). Average feet ESC < 60 µS was defined as sudomotor dysfunction (+), otherwise it was sudomotor dysfunction (-). TIR refers to the percentage of time when blood glucose is between 3.9-10 mmol/L during 1 d period. RESULTS: Among the enrolled subjects, 135 (28.97%) presented with sudomotor dysfunction. Patients with sudomotor dysfunction (+) showed a decreased level of TIR (P < 0.001). Compared to the lowest tertile of TIR, the middle and the highest tertiles of TIR was associated with an obviously lower prevalence of sudomotor dysfunction (20.51% and 21.94% vs 44.52%) (P < 0.001). In addition, with the increase of TIR, HESC and FESC increased (P < 0.001). Regression analysis demonstrated that TIR was inversely and independently linked with the prevalence of sudomotor dysfunction after adjusting for confounding values (odds ratio = 0.979, 95%CI: 0.971-0.987, P < 0.001). CONCLUSION: The tight glycemic control assessed by TIR is of vitally protective value for sudomotor dysfunction in type 2 diabetes mellitus.

Clinical correlates of sudomotor dysfunction in patients with type 2 diabetes and peripheral neuropathy.

AIMS: To investigate the factors associated with abnormal electrochemical skin conductance (ESC) in patients with type 2 diabetes mellitus (T2D) and early diabetic peripheral neuropathy (DPN). METHODS: We recruited 523 consecutive patients with T2D (median age: 50 [interquartile range: 16] years; median T2D duration: 4 [5] years). Sudomotor dysfunction was defined as an ESC <60 µS, and DPN as a neuropathy disability score (NDS) ≥6. Logistic regression was performed to determine the predictors of sudomotor dysfunction in patients with DPN. RESULTS: The prevalence of sudomotor dysfunction was 29% for all patients and 84.5% for patients with DPN. A significant negative correlation was observed between the NDS and ESC measurements (r = -0.52, p < 0.0001). In the univariate analysis, abnormal ESC measures were associated with age, diabetes duration, glycated hemoglobin, diabetic retinopathy, insulin therapy, and foot abnormalities. In the multivariate analysis, ESC abnormalities were associated with age, diabetes duration, glycated hemoglobin levels, insulin therapy, and foot deformities. There was a robust association between foot deformities and abnormal ESC (p = 0.049; odds ratio = 16.02) in patients with DPN. CONCLUSION: Sudomotor dysfunction is highly prevalent in patients with T2D, especially in those with DPN. Various diabetes-related factors were linked to lower ESC values, indicating an association between chronic hyperglycemia and sudomotor function. We also observed a strong relationship between foot deformities and ESC abnormalities. We conclude that the factors associated with DPN are also relevant to sudomotor dysfunction.

Sweat Gland Denervation in Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS).

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a newly recognized disorder characterized by cerebellar ataxia, nonlength-dependent sensory impairment, and bilateral vestibular loss. Sudomotor dysfunction has been described in CANVAS; however, the underlying pathology is not well characterized. To describe novel histopathological features of this syndrome, 2 siblings are presented who had CANVAS with unique findings of sweat gland denervation. Skin biopsy testing was performed to assess sudomotor structure and revealed markedly reduced sweat gland nerve fiber density below the 2.5th percentile in both patients. These histopathological findings suggest that postganglionic sudomotor dysfunction is an additional feature of CANVAS.

Erythromelalgia as a manifestation of autonomic nervous system involvement in multiple sclerosis.

Erythromelalgia is a rare condition characterized by burning pain, erythema and increased temperature of the hands or the feet. Its etiology is not completely understood but it is believed that the underlying cause is a peripheral vascular dysfunction that leads to simultaneous tissue hypoxia and hyperemia. We present a rare co-occurrence of erythromelalgia and multiple sclerosis in a patient with autonomic nervous system dysfunction and propose a causative interconnection.

Electrochemical skin conductance to detect sudomotor dysfunction, peripheral neuropathy and the risk of foot ulceration among Saudi patients with diabetes mellitus.

BACKGROUND: Sudomotor dysfunction is manifested clinically as abnormal sweating leading to dryness of feet skin and increased risk of foot ulceration. The aim of this study was to test the performance of foot electrochemical skin conductance (ESC) to detect diabetic peripheral neuropathy and the risk of foot ulceration against traditional methods in Saudi patients with diabetes mellitus. METHODS: This cross-sectional study was conducted on 296 Saudi patients with diabetes mellitus. Painful neuropathic symptoms were evaluated using the neuropathy symptom score (NSS). The risk of foot ulceration and diabetic peripheral neuropathy were determined using the neuropathy disability score (NDS). Vibration perception threshold (VPT) was assessed using neurothesiometer. Neurophysiological assessment of the right and left sural, peroneal and tibial nerves was performed in 222 participants. Diabetic peripheral neuropathy was defined according to the definition of the American Academy of Neurology. ESC was measured with Sudoscan. RESULTS: Feet-ESC decreased as the scores of sensory and motor function tests increased. Feet-ESC decreased as the NSS, NDS and severity of diabetic peripheral neuropathy increased. Sensitivity of feet-ESC < 50µS to detect diabetic peripheral neuropathy assessed by VPT ≥ 25 V, NDS ≥ 3, NDS ≥ 6 was 90.1, 61 and 63.8 % respectively and specificity 77, 85 and 81.9 % respectively. Sensitivity of feet-ESC < 70µS to detect diabetic peripheral neuropathy assessed by VPT ≥ 25 V, NDS ≥ 3, NDS ≥ 6 was 100, 80.6 and 80.9 % respectively. Sensitivity and specificity of feet-ESC < 70µS to detect confirmed-diabetic peripheral neuropathy were 67.5 and 58.9 % respectively. CONCLUSION: Sudoscan a simple and objective tool can be used to detect diabetic peripheral neuropathy and the risk of foot ulceration among patients with diabetes mellitus. Prospective studies to confirm our results are warranted.