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Purpose of Review: This article reviews disorders of sweating, including hyperhidrosis and anhidrosis due to central or peripheral autonomic nervous system causes., Recent Findings: Disorders of thermoregulation and sweating may manifest with hyperhidrosis or hypohidrosis/anhidrosis. Primary disorders of hyperhidrosis may significantly impact quality of life yet tend to be benign. Many sweating disorders present with compensatory hyperhidrosis due to areas of anhidrosis. Anhidrosis may occur due to either central or peripheral damage to the autonomic nervous system. The thermoregulatory control of sweating involves central pathways from the hypothalamus to the brainstem and then spinal cord as well as projections to peripheral structures, including the sympathetic chain ganglia, peripheral nerves, and eccrine sweat glands. Disruption at any point of this pathway may lead to impaired sweating. Characterization of sweating dysfunction helps localize different autonomic disorders to guide diagnosis and may allow for evaluation of treatment effect., Summary: Sweating dysfunction manifests in myriad ways, including essential hyperhidrosis, complete anhidrosis with heat intolerance, and compensatory hyperhidrosis due to anhidrosis, and often indicates involvement of underlying central or peripheral autonomic dysfunction.

Background: Variation of spontaneous respiratory rates and influences of spontaneous and paced breathing rates on heart rate variability (HRV) were assessed in patients with epilepsy or migraine, and HRV parameters were compared between the groups., Materials and Methods: Thirty neurologic outpatients, 16 diagnosed with epilepsies and 14 with migraine, were included. Autonomic testing consisted of short-term HRV, the deep breathing test (DBT), and measurement of HRV at systematically changed breathing rates (paced breathing, 5-18 breaths per minute, bpm)., Results: Spontaneous respiratory rate during short-term HRV varied from 9 to 23 bpm in the epileptic group and from 5 to 21 bpm in migraine patients and was significantly and negatively correlated with SD of all normal RR intervals (SDNN) and total power (TP) in epileptic patients but not in migraine patients. Paced breathing rate had a significant effect on all HRV parameters assessed in both groups. HRV (SD1, SDNN, TP) and DBT (E-I, SD1, SDNN) parameters were significantly lower in the epileptic group. Group differences were significantly greater during slow compared to fast breathing., Conclusions: An important and new finding is the wide variation of spontaneous respiratory rate in both groups, along with the significant negative correlation with the assessed HRV parameters. The reduction of HRV during slow breathing in epileptic patients may indicate a diminished cardiorespiratory coupling caused by a probable loss of sensitivity within the cardiovagal brainstem circuitry., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Harlequin syndrome is a rare combination of symptoms, characterized by unilateral facial anhidrosis and paleness on the affected side, becoming obvious by contralateral flushing mainly during sports activity. The syndrome is mostly idiopathic, however it is also described as a complication of thoracic surgery, i.e. superior lobectomy. Here, we report on two cases of Harlequin syndrome following scoliosis surgery at the cervicothoracic junction.

Introduction: Antiretrovirals have immensely increased the average life expectancy of HIV-positive patients. However, the incidence of QT interval prolongation and other arrhythmias has also increased., Methods: Pubmed and Google Scholar were searched for relevant literature published between 1990 and 2019., Results and Discussion: HIV-positive patients with high viral load, low CD4 count, chronic inflammation, and autonomic neuropathy can develop QT interval prolongation. Another factor prolonging QT interval includes exposure to the HIV transactivator protein, which inhibits hERG K (+) channels controlling IKr K (+) currents in cardiomyocytes. Protease inhibitors inhibiting the CYP3A4 enzyme can also lead to QT interval prolongation. QT interval prolongation can potentially be exacerbated by opioids, antipsychotics, antibiotics, and antifungals, the adjunct medications often used in HIV-positive patients. Hepatic insufficiency in seropositive patients on antiretrovirals may also increase the risk of QT interval prolongation., Conclusion: Baseline and follow-up EKG in the susceptible population is suggested., Competing Interests: Conflicts of interest The authors have no conflict of interest., (Copyright © 2019 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the effects of physical exercise on autonomic dysfunction in patients with fibromyalgia syndrome (FM)., Literature Survey and Methodology: A systematic review of experimental studies published until December 2017 that analyzed the effect of physical exercise on autonomic dysfunction in patients with FM was performed using the PubMed, Pedro, Scopus, ScienceDirect, and Web of Science databases., Synthesis: A total of 1105 articles were identified, 12 of which were included in the final analysis. The most analyzed exercise modalities were aerobic and resistance exercises. Overall, the studies demonstrated that aerobic exercise performed twice a week with moderate to high intensity was effective in reducing autonomic dysfunction by increasing heart rate variability. Resistance training was associated with reduced symptoms of anxiety and depression as well as increased muscle strength; however, it did not reduce autonomic dysfunction in these patients in the short or long term., Conclusions: Preliminary evidence suggests that aerobic exercise reduces autonomic dysfunction in patients with FM, whereas resistance training reduces psychological symptoms such as anxiety and depression., Level of Evidence: I., (© 2019 American Academy of Physical Medicine and Rehabilitation.)

Background: The identification of autoantibodies directed against neuronal antigens has led to the recognition of a wide spectrum of neurological autoimmune disorders (NAD). With timely recognition and treatment, many patients with NAD see rapid improvement. Symptoms associated with NAD can be diverse and are determined by the regions of the nervous system affected. In addition to neurological symptoms, a number of these disorders present with prominent gastrointestinal (GI) manifestations such as nausea, diarrhea, weight loss, and gastroparesis prompting an initial evaluation by gastroenterologists., Purpose: This review provides a general overview of autoantibodies within the nervous system, focusing on three scenarios in which nervous system autoimmunity may initially present with gut symptoms. A general approach to evaluation and treatment, including antibody testing, will be reviewed., (© 2019 John Wiley & Sons Ltd.)

Background: Among the most common autonomic signs visible in preterm neonates, apnea can represent the first sign of several neurologic and non-neurologic disorders, and seizure is a relatively infrequent cause. Herein authors present a case of neonatal autonomic apnea, discussing the polygraphic video-EEG features of this pathological entity and the differential diagnosis with central apnea and autonomic apnea., Case Report: A female preterm Caucasian infant (29 + 4 weeks' gestational age (GA)), first twin of a twin pregnancy, at birth was intubated and surfactant administration was performed. She was ventilated via invasive ventilation for three days, with subsequent weaning with non-invasive ventilation for other two days, when she stopped requiring any ventilator support. After one week the ventilation weaning, the child presented episodes of cyanosis associated with sudden oxygen desaturation, skin pallor, apnea, and bradycardia. Therefore, the child underwent a continuous video-eeg recording with polygraphic study. The exam showed the presence of apneic episodes with an abrupt and clear start, associated with oxygen desaturation at 70%, with minimal thoracic effort at onset, and then evolving into central apnea. Central apnea lasted about 16 s and presented clear start- and end-points. These episodes were also associated with suppression of the EEG trace in frequency and amplitude, and after about 10 s of central apnea an abrupt decrease of the child's heart rate (more than 50% variation, from 160 bpm to 65 bpm) was recorded. In the suspect of epileptic apneas of autonomic origin, a therapy with oral Levetiracetam, at a starting dose of 10 mg/Kg/day, then increased up to 40 mg/Kg/day, was initiated, and after about 48 h the first administration of the anticonvulsant therapy, no new episodes of cyanosis or electrical apneas were recorded., Hypothesis: Herein the authors suggest to consider the diagnosis of autonomic seizures in those neonates with apneic events associated with EEG suppression. Considering that apnea events are not only present in preterm infants but also in term neonates, it is mandatory to diagnose in this context neonatal seizures for a correct diagnosis and a proper therapeutic choice., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Cardiovascular autonomic neuropathy (CAN) is a risk factor for arrhythmias and adverse cardiovascular events, but the relationship between CAN severity and nocturnal arrhythmias needs to be clarified. This study evaluated the association between nocturnal arrhythmias and CAN severity in patients with type 2 diabetes (T2D)., Methods: In all, 219 T2D patients were recruited from January 2017 to May 2018. Subjects were classified into no CAN (NCAN), early CAN (ECAN), definite CAN (DCAN), or advanced CAN (ACAN) based on cardiovascular autonomic reflex tests (CARTs). A 24-hour electrocardiogram was recorded and daytime (0700-2300 hours) and night-time (2300-0700 hours) heartbeats were analyzed separately., Results: After adjusting for age, the incidence of ventricular arrhythmias increased with CAN severity at night-time (18.6%, 29.9%, 36.2%, and 60.0% in the NCAN, ECAN, DCAN, and ACAN groups, respectively; P trend  = 0.034). Patients with nocturnal ventricular arrhythmias (NVAs) had higher CART scores (2.0 ± 1.0 vs 1.5 ± 0.9; P < 0.001) and lower heart rate variability (HRV) during deep breathing (9.5 ± 5.7 vs 11.6 ± 6.6 b. p. m; P = 0.021), HRV during the Valsalva maneuver (1.2 ± 0.1 vs 1.2 ± 0.2; P = 0.006), and postural blood pressure change (-8.8 ± 15.5 vs -4.1 ± 11.2 mmHg; P = 0.023). Multivariate regression analysis revealed that CAN stage (odds ratio 1.765; 95% confidence interval 1.184-2.632; P = 0.005) was independently associated with NVAs., Conclusions: In T2D, CAN stage was independently associated with the presence of NVAs. Early detection, diagnosis, and treatment of CAN may help predict and prevent adverse cardiovascular events and cardiovascular mortality in diabetes., (© 2019 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Autonomic dysfunction is common in REM-sleep behavior disorder (RBD). Several studies have demonstrated abnormalities in heart rate variability, cardiac scintigraphy, and cardiovascular autonomic reflex testing. In addition, the type and severity of these abnormalities may correlate with rate of phenoconversion from idiopathic RBD (iRBD) to manifest neurodegenerative disease. This article summarizes the current literature on autonomic impairment in iRBD, with specific focus on the role of autonomic impairment as a potential biomarker of disease progression. REM sleep physiology and relevant anatomy is also discussed in relation to the central autonomic network and autonomic neurodegeneration., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Orthostatic hypotension (OH) is a common cause of hospitalization, particularly in the elderly. Hospitalized patients with OH are often severely ill, with complex medical comorbidities and high rates of disability. Droxidopa is a norepinephrine precursor approved for the treatment of neurogenic OH (nOH) associated with autonomic failure that is commonly used in the outpatient setting, but there are currently no data regarding the safety and efficacy of droxidopa initiation in medically complex patients. We performed a retrospective review of patients started on droxidopa for refractory nOH while hospitalized at Vanderbilt University Medical Center between October 2014 and May 2017. Primary outcome measures were safety, change in physician global impression of illness severity from admission to discharge, and persistence on medication after 180-day follow-up. A total of 20 patients were identified through chart review. Patients were medically complex with high rates of cardiovascular comorbidities and a diverse array of underlying autonomic diagnoses. Rapid titration of droxidopa was safe and well tolerated in this cohort, with no cardiovascular events or new onset arrhythmias. Supine hypertension requiring treatment occurred in four patients. One death occurred during hospital admission due to organ failure associated with end-stage amyloidosis. Treating physicians noted improvements in presyncopal symptoms in 80% of patients. After 6 months, 13 patients (65%) continued on droxidopa therapy. In a retrospective cohort of hospitalized, severely ill patients with refractory nOH, supervised rapid titration of droxidopa was safe and effective. Treatment persistence was high, suggesting that symptomatic benefit extended beyond acute intervention., (©2019 Wiley Periodicals, Inc.)

Pure autonomic failure (PAF) is a progressive syndrome of neurogenic orthostatic hypotension, widespread anhidrosis, urinary retention, and constipation without other neurologic manifestations. It is generally considered a peripheral ganglionic synucleinopathy. Natural history studies have described risk factors for the conversion of PAF to Parkinson's disease, multiple system atrophy, or dementia with Lewy bodies, yet the early stages of PAF are not well characterized. We present a patient with unilateral anhidrosis, contralateral facial flushing and hyperhidrosis consistent with Harlequin syndrome that, over 6 years, progressed to PAF, suggesting that PAF may present with focal autonomic impairment prior to generalized autonomic failure., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Multiple mechanisms may modulate an association between restless legs syndrome/Willis-Ekbom disease (RLS/WED) and cardiovascular disease (CVD), including chronic sleep deprivation, intermittent, periodic limb movements in sleep (PLMS)-related autonomic fluctuations and possible autonomic dysfunction intrinsically associated with RLS per se. The purpose of this paper is to review the existing RLS/WED literature focusing on the pathophysiologic evidence for possible associations between RLS/WED and PLMS with CVD and events (CVE). Specific intrinsic dysautonomic aspects of the disease, which may contribute to generating CVD, are separately discussed. The association between RLS/WED and both CV risk factors and CVD still remains elusive. Although several shared pathophysiological causes could explain these possible relationships, the emerging body of literature focusing on these disorders remains controversial. Not only longitudinal population-based studies and meta-analyses, but also more animal models and therapeutic interventions are needed in order to build a sufficiently robust body of evidence on this topic., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cardiac autonomic neuropathy (CAN) is a common complication in type 1 and 2 diabetes and is defined as the impairment of autonomic control of the cardiovascular system. CAN is strongly associated with increased mortality, and in some studies with morbidity of vascular complications, such as stroke, coronary artery disease and myocardial infarction. At the early stages, CAN can be subclinical and it becomes clinically evident as the disease progresses. Subclinically, the disease is defined by cardiovascular reflex testing, which may have prognostic implications. Clinically, the impairment in autonomic function is associated with resting tachycardia, exercise intolerance, orthostatic hypotension, syncope, intraoperative cardiovascular instability, silent myocardial infarction and ischemia, and increased mortality. Although very common and serious, CAN is a frequently overlooked complication of diabetes. Because the progression of cardiovascular denervation is partly reversible or can be slowed down in the early stages of the disease, recent guidelines strongly recommend screening for CAN in patients with diabetes. In this review we summarize the diagnostic tools suggested in the screening for diabetic CAN. Orv Hetil. 2019; 160(35): 1366-1375.

Objective: To investigate the early diagnosis and treatment for burn complicated with severe paroxysmal sympathetic hyperactivity (PSH). Methods: Medical records of patients with burn complicated with severe PSH, admitted to our department from April 2016 to March 2019 and meeting the inclusion criteria were analyzed retrospectively. There were 4 males and 1 female, aged 17 months to 39 years, with an average of (21±16) years. During occurrence of PSH, the vital signs of patients were routinely monitored and oxygen were given. Other treatment included central venous catheterization and infusion of electrolyte solution, infusion of plasma according to patients' condition, use of opioid analgesics and benzodiazepine sedatives, physical cooling and drug cooling, and establishment or maintenance of artificial airway and use of ventilator. Heart rate was controlled below 120 beats per minute in adults and 140 beats per minute in children with comprehensive treatment dominated by analgesia and sedation. Besides, single or multiple vasoactive agents, even in large doses were used to maintain normal blood pressure of patients. The occurrence characteristics, time, and treatment outcome of PSH were analyzed. Results: PSH happened rapidly, with a sharp increase in several minutes to dozens of minutes. Five patients were with symptoms such as high body temperature, shortness of breath, very fast heart rate, normal or elevated systolic blood pressure, hyperhidrosis, and dystonia at the onset. The symptoms occurred simultaneously or successively. According to the Clinical Feature Scale, the above-mentioned 6 indexes achieved the highest score of 3 points except of systolic blood pressure. Four patients showed dilated pupils and impaired consciousness. Among the patients, PSH occurred in the acute exudation stage in 3 patients, in the fluid reabsorption stage in 1 patient, and in the late repair stage in 1 patient. PSH of patients lasted for 3 hours to 12 days. The symptoms of 4 patients were effectively controlled, and 1 patient died of deterioration. No PSH occurred in the cured patients during follow-up of 3 to 14 months. Conclusions: Burn complicated with PSH can occur at any time before wound repair and in patients with different injury conditions. The causes of PSH include sudden burn, persistent pain, fright and fear, strange environment, low blood volume, and other adverse stimuli, and PSH is more likely to occur in children with underdeveloped brain function. Intravenous infusion of analgesics sedatives, physical therapy and medication to lower body temperature, stabilizing blood pressure and respiration are effective measures to treat PSH. PSH should be distinguished from the common complications of burns, such as sepsis, cerebral edema, hyperpyretic convulsion, transfusion response, stress disorder, etc.

: Supine hypertension is defined as a blood pressure at least 140 mmHg systolic or at least 90 mmHg diastolic in the supine position; supine hypertension is present in over 50% of patients with autonomic failure and orthostatic hypotension, but it is often overlooked. It may be related to antihypotensive drugs, but its presence in untreated patients suggests a neurogenic origin. Supine hypertension is often asymptomatic although it is associated with multiple organ damage. There are no official guidelines on its treatment and long-term benefits have never been proved. The present review is focused on the management of supine hypertension, including nonpharmacological and pharmacological approach. All the tested drugs have been individually revised, focusing on their hypotensive effect and their ability to act on ancillary targets, such as morning orthostatic tolerance or sodium urine excretion. Moreover, the main pathogenic mechanisms and the correct approach to the diagnosis of supine hypertension have been resumed.

Fatal Familial Insomnia (FFI) is a hereditary prion disease caused by a mutation at codon 178 of the prion-protein gene leading to a D178N substitution in the protein determining severe and selective atrophy of mediodorsal and anteroventral thalamic nuclei. FFI is characterized by physiological sleep loss, which polygraphically appears to be a slow wave sleep loss, autonomic and motor hyperactivation with peculiar episodes of oneiric stupor. Alteration of autonomic functions is a great burden for FFI patients consisting in sympathetic overactivation, dysregulation of its physiological responses and disruption of circadian rhythms. The cardiovascular system is the most frequently and severely affected confirming the increased sympathetic drive with preserved parasympathetic responses. Sleep loss, autonomic and motor hyperactivation define Agrypnia Excitata (AE), which is not exclusive to FFI, but it has been canonically described also in Morvan Syndrome and Delirium Tremens. These three conditions present different pathophysiological mechanisms but share the same thalamo-limbic impairment of which AE is one of the possible clinical presentations. FFI, and consequently also AE, is a model for the investigation of the essential role of the thalamus in the organization of body homeostasis, integrating both sleep and autonomic function control., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Management of hypertension in subarachnoid hemorrhage patients within the preaneurysmal treatment period remains ambiguous, in part due to the lack of high-level, evidence-based guidelines. Despite this, current recommendations offer guidance regarding certain parameters (e.g., mean arterial pressure, systolic blood pressure). However, managing hypertension within this critical period is difficult because a fine balance must be achieved between lowering blood pressure enough to minimize the risk of rebleeding and preventing reduced cerebral perfusion and subsequent ischemic damage. Furthermore, the different causes of hypertension within the preaneurysmal treatment period are polyfactorial and include pathophysiologic responses, sympathetic nervous system activation, and iatrogenic from hyperdynamic therapy and vasopressors, which requires consideration for these patients to receive optimal management. Other factors including loss of autoregulation and concomitant conditions must also be considered when deciding whether to start antihypertensive therapy., Methods: We review the literature and provide a comprehensive update on management of hypertension within the preaneurysmal treatment period, which we hope stresses the need for better evidence-based guidelines that will in turn help manage this cohort., Results: Thorough review revealed no high-grade, evidence-based guidelines to manage these patients, which results in variation in clinical practice among different clinicians and institutions. Despite this, current recommendations seem reasonable until such guidelines are established., Conclusions: It is clear that further, larger studies are warranted in order to clarify the effect of antihypertensive therapy on patient outcome and what the BP thresholds are, along with establishing the best treatment, for commencing antihypertensive therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Autonomic nervous system dysfunction is associated with impaired glucose metabolism, but the temporality of this association remains unclear in individuals without diabetes. We investigated the association of autonomic function with 5-year changes in glucose metabolism in individuals without diabetes., Research Design and Methods: Analyses were based on 9,000 person-examinations for 3,631 participants without diabetes in the Whitehall II cohort. Measures of autonomic function included 5-min resting heart rate and six heart rate variability (HRV) indices. Associations between baseline autonomic function measures and 5-year changes in fasting and 2-h plasma glucose, serum insulin concentrations, insulin sensitivity (insulin sensitivity index [ISI 0-120 ] and HOMA of insulin sensitivity), and β-cell function (HOMA of β-cell function) were estimated in models adjusting for age, sex, ethnicity, metabolic factors, and medication., Results: A 10-bpm higher resting heart rate was associated with 5-year changes in fasting and 2-h insulin and ISI 0-120 of 3.3% change (95% CI 1.8; 4.8), P < 0.001; 3.3% change (1.3; 5.3), P = 0.001; and -1.4% change (-2.4; -0.3), P = 0.009, respectively. In models adjusted for age, sex, and ethnicity, higher baseline values of several HRV indices were associated with a 5-year decrease in fasting and 2-h insulin and ISI 0-120 . However, significance was lost by full adjustment. A majority of HRV indices exhibited a trend toward higher values being associated with lower insulin levels and higher insulin sensitivity., Conclusions: Higher resting heart rate in individuals without diabetes is associated with future unfavorable changes in insulin levels and insulin sensitivity. Associations may be mediated via autonomic function; however, results are inconclusive. Resting heart rate may be a risk marker for future pathophysiological changes in glucose metabolism., (© 2019 by the American Diabetes Association.)

Competing Interests: The authors declare that they have no conflict of interest.

Introduction: Migraine is a common neurovascular disease characterised with recurrent attacks by pain-free periods. It has been suggested that both sympathetic and parasympathetic dysfunctions play a role in its pathophysiology., Aim: The aim of our study was to investigate the ECG changes during attack-free period in children with migraine, in terms of QTc interval, QTc, and P-wave dispersion to evaluate the autonomic nervous system disturbance., Methods: Sixty children who were diagnosed with migraine were included as patient group and 50 healthy, age- and body mass index-matched children who were examined for innocent murmur were included as control group. The patients' routine ECG records were screened from the outpatient clinic files. The durations of P-wave, QT, and QTc intervals and dispersion values and heart rates (beats/minute) were compared between the patient and control groups., Results: P maximum and P dispersion were significantly higher, and P minimum was significantly lower in the migraine group compared with the control group. QT-QTc maximum and QT-QTc dispersion were significantly higher and QT-QTc minimum was significantly lower in the migraine group compared with the control group., Conclusion: According to our findings, although migraine patients were asymptomatic and no arrhythmia was detected in the surface ECG, sympathovagal balance in the sympathetic system, which may be disrupted in favour of the sympathetic system, should continue even in the attack-free period, and we should be careful in terms of serious arrhythmias that may develop in these patients.

Background: Peripheral neuropathy contributes to morbidity and mortality among diabetic patients., Objectives: We aimed to determine the prevalence of distal symmetrical polyneuropathy (DSP) and cardiovascular autonomic neuropathy (CAN) and their predictors among diabetic patients in Ilorin, North-central Nigeria., Materials and Methods: : This was a cross-sectional study in which 175 consenting diabetic patients were recruited consecutively. We assessed DSP using the Michigan Neuropathy Screening Instrument (MNSI), and it was defined by MNSI symptom score ≥7 or physical examination score ≥2. CAN was assessed using five tests of cardiovascular autonomic function, and abnormalities in ≥2 tests defined CAN. Logistic regression analysis was used to identify the predictors of DSP and CAN., Results: The prevalence of DSP and CAN was 41.7% and 26.9%, respectively, while 19.4% had both. Hypertension (odds ratio [OR]: 2.401; 95% confidence interval [CI]: 1.169-4.930, P = 0.017) and poor glycaemic control (OR: 2.957; 95% CI: 1.488-5.878, P = 0.002) independently predicted DSP. Hypertension (OR: 2.215; 95% CI: 1.023-4.414, P = 0.043) and serum creatinine (OR: 1.035; 95% CI: 1.014-1.056, P ≤ 0.001) were independent predictors of CAN., Conclusion: DSP and CAN are common among diabetic patients, and thus efforts should be made to prevent their occurrence by intensifying blood pressure and glucose control while regularly monitoring renal function., Competing Interests: None

Autonomic nervous system control of the heart is a dynamic process in both health and disease. A multilevel neural network is responsible for control of chronotropy, lusitropy, dromotropy, and inotropy. Intrinsic autonomic dysfunction arises from diseases that directly affect the autonomic nerves, such as diabetes mellitus and the syndromes of primary autonomic failure. Extrinsic autonomic dysfunction reflects the changes in autonomic function that are secondarily induced by cardiac or other disease. An array of tests interrogate various aspects of cardiac autonomic control in either resting conditions or with physiological perturbations from resting conditions. The prognostic significance of these assessments have been well established. Clinical usefulness has not been established, and the precise mechanistic link to mortality is less well established. Further efforts are required to develop optimal approaches to delineate cardiac autonomic dysfunction and its adverse effects to develop tools that can be used to guide clinical decision-making., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Autonomic dysfunction is a feature of glaucoma patients, which are reported to be related to glaucoma progression. We investigated pupil responses to a light flash using dynamic pupillometry in glaucoma patients to assess autonomic nervous system status. In total, 97 glaucoma patients, including 21 eyes of 21 glaucoma patients with cardiac autonomic dysfunction, were enrolled. Pupil reactions were assessed using 1 flash of white light after 2 minutes of dark adaptation and recorded using dynamic pupillometry. Changes in the radius of the pupil were evaluated as a function of several time-dependent and pupil/iris (P/I) diameter ratio parameters. Autonomic function was assessed using a cardiac heart-rate-variability test which performs 5 autonomic function tests and classifies patients with cardiac autonomic neuropathy (CAN). Comparison of pupil parameters between eyes with and without disc hemorrhage indicated larger P/I ratios in darkness, greater changes in the P/I ratio during examination, shorter latency to plateau, and shorter duration of constriction in eyes with disc hemorrhages. A comparison of pupil parameters between eyes with and without CAN showed larger P/I ratios in darkness, larger P/I ratios at maximum constriction, and prolonged latency to maximum constriction. The presence of CAN was significantly related to the P/I ratio in darkness and the latency of maximum constriction. Using dynamic pupillometry, we found that glaucoma patients with CAN dysfunction have larger baseline pupils in darkness and different constriction responses to light. Assessing the pupils might be a good method of identifying patients with autonomic dysfunction.

Eosinophilic myenteric ganglionitis (EMG) is characterised by eosinophilic infiltration of the myenteric plexus. EMG has been rarely reported as a cause of chronic intestinal pseudo-obstruction (CIPO), and its histopathological features are not fully elucidated. We analysed seven patients with CIPO. Three of them were diagnosed with EMG and four patients were categorised as non-EMG. Clinicopathological features were similar in both groups. These features included subtle to mild lymphocytic infiltration at the myenteric ganglia/muscularis propria, loss of myenteric ganglions and interstitial cells of Cajal (ICC), and no significant findings in the mucosa. The exceptions were moderate to severe degree of eosinophilic infiltration at the myenteric ganglia/muscularis propria in EMG. Functional gastrointestinal obstruction may be associated with inflammatory cell infiltration at the myenteric ganglia/muscularis propria, leading to subsequent hypoganglionosis and deficiency of ICC in EMG. Pathologists and clinicians should be aware of this distinction during differential diagnosis of patients with CIPO.

Orthostatic hypertension (OHT), that is, sustained increase in blood pressure after standing, is an increasingly recognized cardiovascular disorder having been examined in much fewer studies compared with orthostatic hypotension (OH). However, in both OHT and OH, dysfunction of the autonomous nervous system is considered to be the primary pathophysiological disturbance, while significant associations with essential hypertension have been observed. Although in many studies OHT has been related to subclinical or clinical target organ damage, there is also evidence denying such an association. Because OHT is defined variably across different studies, the comparison of relevant outcomes is at least problematic. Since evidence about OHT treatment is exclusively based on limited non-randomized studies, no specific recommendations have been developed. Therefore, both the prognostic role and the clinical significance of OHT remain largely undefined. The aim of the present review is to summarize the available evidence regarding the definition, diagnosis, pathophysiology, prognostic role and treatment of OHT and highlight potential clinical implications of this underestimated condition., (©2019 Wiley Periodicals, Inc.)

The burden of diabetic cardiovascular autonomic neuropathy (CAN) is expected to increase due to the diabetes epidemic and its early and widespread appearance. CAN has a definite prognostic role for mortality and cardiovascular morbidity. Putative mechanisms for this are tachycardia, QT interval prolongation, orthostatic hypotension, reverse dipping, and impaired heart rate variability, while emerging mechanisms like inflammation support the pervasiveness of autonomic dysfunction. Efforts to overcome CAN under-diagnosis are on the table: by promoting screening for symptoms and signs; by simplifying cardiovascular reflex tests; and by selecting the candidates for screening. CAN assessment allows for treatment of its manifestations, cardiovascular risk stratification, and tailoring therapeutic targets. Risk factors for CAN are mainly glycaemic control in type 1 diabetes mellitus (T1DM) and, in addition, hypertension, dyslipidaemia, and obesity in type 2 diabetes mellitus (T2DM), while preliminary data regard glycaemic variability, vitamin B12 and D changes, oxidative stress, inflammation, and genetic biomarkers. Glycaemic control prevents CAN in T1DM, whereas multifactorial intervention might be effective in T2DM. Lifestyle intervention improves autonomic function mostly in pre-diabetes. While there is no conclusive evidence for a disease-modifying therapy, treatment of CAN manifestations is available. The modulation of autonomic function by SGLT2i represents a promising research field with possible clinical relevance., Competing Interests: Vincenza Spallone has received research grants from Biocure srl Italy and Boehringer Ingelheim Italy. She has received remunerations for lectures or consultations for AWP srl Italy, Boehringer Ingelheim Italy, Daiichi Sankyo Europe, Ely-Lilly Italy, IRIS Servier France, Laborest Italy, Pfizer Italy, Sanofi Aventis Italy, Schwarz Pharma Europe, Wörwag Pharma Germany. She has served on advisory boards for Angelini S.p.A Italy, TRIGOcare International Germany, and Wörwag Pharma GmbH & Co Germany., (Copyright © 2019 Korean Diabetes Association.)

Aims: Type 1 diabetes is associated with increased cardiovascular (CV) morbidity and mortality, and cardiovascular autonomic neuropathy (CAN) is an important CV risk factor. The study aimed to explore associations between CAN and altered cardiac chamber sizes in persons with type 1 diabetes., Methods: This was a cross-sectional study of 71 asymptomatic, normoalbuminuric participants with long-term type 1 diabetes (39 with CAN, determined by >1 abnormal autonomic function test) examined with cardiac multi detector computed tomography scans, which allowed measurements of left ventricular mass and all four cardiac chamber volumes. Cardiac chambers were indexed according to body surface area (ml/m 2 or g/m 2 )., Results: Persons with and without CAN had mean ± SD age of 57 ± 7 and 50 ± 8 years (p < 0.001) and diabetes duration of 36 ± 11 and 32 ± 9 years (p < 0.05), respectively. Increasing autonomic dysfunction, evaluated by decrease in heart rate variability during deep breathing (in beats per minute), was associated with larger right (-0.5, 95% CI -1.0 to -0.0, p < 0.05) and trend towards larger left (-0.4, 95% CI -0.8-0.0, p < 0.1) ventricular volumes in multivariable linear regression., Conclusions: Our results suggest that impaired autonomic function may be associated with modest enlargement of ventricular volumes; this might be an early sign of progression towards heart failure., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: To study the impact of diabetic neuropathy, both peripheral sensorimotor (DPN) and cardiac autonomic neuropathy (CAN), on transcutaneous oxygen tension (TcPO 2 ) in patients with type 2 diabetes mellitus (T2DM)., Methods: A total of 163 participants were recruited; 100 with T2DM and 63 healthy individuals. Peripheral arterial disease (PAD) was defined as ankle-brachial index (ABI) values ≤0.90. Diagnosis of DPN was based on neuropathy symptom score and neuropathy disability score (NDS), while diagnosis of CAN on the battery of the cardiovascular autonomic function tests. TcPO 2 was measured using a TCM30 system., Results: Patients with T2DM had lower TcPO 2 levels when compared with healthy individuals. Among the diabetic cohort, those who had either PAD, DPN or CAN had significantly lower TcPO 2 values than participants without these complications. Multivariate linear regression analysis, after controlling for diabetes duration, diastolic blood pressure, HbA1c, albumin to creatinine ratio and CAN score, demonstrated that TcPO 2 levels were significantly and independently associated with current smoking (p = 0.013), ABI (p = 0.003), and NDS (p = 0.013)., Conclusion: Presence of DPN is independently associated with impaired cutaneous perfusion. Low TcPO 2 in subjects with DPN may contribute to delay in healing of diabetic foot ulcers, irrespectively of PAD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

While the involvement of the central and peripheral autonomic networks is thought to play an integral role in the development of autonomic symptoms in Parkinson's disease (PD), there is little evidence for an association between autonomic symptoms and striatal dopaminergic depletion. We compared dopamine transporter activity in striatal subregions with various autonomic symptoms covered by the SCOPA-AUT domains including gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor, and sexual symptoms in 418 untreated patients with PD. We found evidence for a dopaminergic association with only urinary symptoms. Moreover, dopaminergic denervation in the putamen but not in the caudate may underlie these symptoms., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Intrathecal baclofen (ITB) is an effective treatment for managing primary and secondary dystonia. Intraventricular baclofen (IVB) was first developed to allow treating patients in which the use of ITB was difficult due to anatomic anomalies. After that, several studies indicate that intraventricular administration of baclofen, is more effective than ITB in refractory dystonia., Clinical Material: We report three cases of children with acute dystonic and dysautonomic storm, treated with IVB. The clinical outcome was satisfactory. The response to the treatment continued after the pump disconnection, suggesting that in this kind of cerebral dysregulations, short-term IVB is an effective treatment., Conclusion: Early treatment with IVB may be an effective option in patients with post-anoxic dysautonomic and dystonic storm.

Autoimmune autonomic ganglionopathy (AAG) is a rare acquired immune-mediated disorder that leads to autonomic failure. It is sometimes complicated by mental and behavioral symptoms. We report a case of 72-year-old male with AAG who was admitted to the psychiatric department for prolonged severe delirium. Repeated loss of consciousness attributed to severe orthostatic hypotension disturbed recovery from delirium. In addition, intracerebral hemorrhage occurred during hospitalization, and this cerebrovascular event may have been substantially affected by unstable blood pressure due to AAG. This case suggests importance of differential diagnosis of AAG in patients with mental and behavioral symptoms accompanying severe autonomic failure., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: : Autonomic dysfunction (AD) is infrequently evaluated preoperatively despite having profound perioperative implications. The ANSiscope™ is a monitoring device that quantifies AD. This study aims to determine the potential of the device to predict hypotension following anesthetic induction, occurrence of arrhythmias, and inotrope requirement for patients undergoing off-pump coronary artery bypass surgery (OPCAB)., Study Design: : Prospective observational double-blinded study., Materials and Methodology: Seventy-five patients undergoing OPCAB had their autonomic function assessed by ANSiscope™. They were classified into four groups based on their AD and compared to perioperative adverse events., Results: Patients with diabetes had a higher ANSindex (P = 0.0263). They had a greater decrease in systolic blood pressure (P = 0.001) and mean arterial pressure (P = 0.004) postinduction, had an increased incidence of arrhythmias (P = 0.009), required higher inotropic support immediately (P = 0.010) and at 24 h after surgery (P = 0.018), and longer duration of postoperative ventilation (P < 0.001). They also had a higher incidence of emergency conversion of OPCAB to on-pump surgery (P = 0.009)., Conclusions: An increased association between AD as quantified by the ANSiscope™ and perioperative adverse outcomes was observed. An increased rate of emergency conversion of OPCAB to on-pump surgery with higher dysfunction was noted. The authors opine that the threshold for conversion must be lower in patients deemed to be at a higher risk. Proper evaluation of the autonomic nervous system empowers the anesthesiologist to anticipate and adequately prepare for complications., Competing Interests: None

Background: Despite its negative impact on quality of life, fatigue in Parkinson's disease (PD) remains an under-recognized issue and the underlying pathology is undetermined., Objective: To contribute at understanding the pathogenesis of fatigue in a naturalistic cohort of cognitively intact PD patients., Methods: In a Caucasian population of PD patients (n = 27), we evaluated to what extent fatigue (quantified as PFS-16 score) is associated with PD duration and with autonomic dysfunction, studied by both MIBG scintigraphy and autonomic nervous system testing. The latter included the head-up tilt test, Valsalva maneuver, deep breathing, and handgrip tests., Results: PFS-16 score correlated with disease duration (R = 0.57, p = 0.002). Fatigue showed a clear correlation with deep breathing test (R = - 0.53, p = 0.004) but not with the MIBG H/M ratios., Conclusions: Our data are consistent with a multifactorial pathogenesis of fatigue and with effects of dopamine depletion in PD-related fatigue; on the other hand, our findings do not support a role for sympathetic denervation in PD-related fatigue.

A failure of cardiorespiratory control mechanisms, together with an impaired arousal response from sleep, are believed to play an important role in the final event of sudden infant death syndrome (SIDS). The 'triple risk model' describes SIDS as an event that results from the intersection of three overlapping factors: (1) a vulnerable infant, (2) a critical developmental period in homeostatic control and (3) an exogenous stressor. In an attempt to understand how the triple risk hypothesis is related to infant cardiorespiratory physiology, many researchers have examined how the known risk and protective factors for SIDS alter infant cardiovascular control during sleep. This review discusses the association between the three components of the triple risk hypothesis and major risk factors for SIDS, such as prone sleeping, maternal smoking, together with three "protective" factors, and cardiovascular control during sleep in infants, and discusses their potential involvement in SIDS.

Introduction: From newfound parasomnia to a marker of future synucleinopathy, since its first description in 1986, REM sleep behavior disorder (RBD) has been systematically tackled from virtually many viewpoints in basic, translational, and clinical studies. The time delay between RBD and synucleinopathy onset offers an exceptional window for observation and design of neuroprotective trials. In the last few years, research has focused on characterizing possible differences within RBD patients in order to draw potential profiles more or less susceptible to further neurodegeneration. Attention has been drawn towards autonomic dysfunction in RBD as one of such variables., Overview: In this review, REM sleep physiology and relevant brain anatomy is briefly mentioned and integrated with neuroanatomical and physiological concepts regarding the central autonomic network. A detailed summary of works showing the presence of autonomic dysfunction in RBD is provided, and clinical and electrophysiological features of RBD in synucleinopathies are discussed. A short overview of RBD in other neurodegenerative diseases is also provided.

Aim: To investigate the association between cardiovascular autonomic neuropathy and bone metabolism in people with Type 1 diabetes., Methods: We assessed cardiovascular autonomic neuropathy in 329 people with Type 1 diabetes according to heart rate response to deep breathing, to standing and to the Valsalva manoeuvre, and 2-min resting heart rate. More than one pathological non-resting test was defined as cardiovascular autonomic neuropathy. Bone mineral density of the femoral neck (BMDfn) was assessed by dual energy X-ray absorptiometry. Serum parathyroid hormone levels and other bone markers were measured., Results: The mean (sd) age of the participants was 55.6 (9.4) years, 52% were men, and the mean (sd) diabetes duration was 40 (8.9) years, HbA 1c 62 (9) mmol/mol and estimated GFR 78 (26) ml/min/1.73m 2 . In all, 36% had cardiovascular autonomic neuropathy. Participants with cardiovascular autonomic neuropathy had 4.2% (95% CI -8.0 to -0.2; P=0.038) lower BMDfn and 33.6% (95% CI 14.3 to 53.8; P=0.0002) higher parathyroid hormone levels compared with participants without cardiovascular autonomic neuropathy in adjusted models. Higher resting heart rate remained associated with higher parathyroid hormone level and lower BMDfn after additional adjustment for eGFR (P<0.0001 and P = 0.042, respectively)., Conclusions: The presence of cardiovascular autonomic neuropathy was associated with reduced BMDfn and increased levels of parathyroid hormone. Kidney function may either confound or mediate these findings. Cardiovascular autonomic neuropathy could be associated with increased risk of osteoporosis in Type 1 diabetes. Whether cardiovascular autonomic neuropathy directly affects bone metabolism detrimentally or if this association is mediated via decreased kidney function should be investigated further., (© 2018 Diabetes UK.)

Introduction: Given the limited data on autonomic dysfunction in patients with primary restless legs syndrome (pRLS), we compared autonomic dysfunction and presence of irritable bowel syndrome (IBS) between patients with pRLS and control patients., Methods: Consecutive adult drug-naïve patients with pRLS, and age- and gender-matched healthy control patients were enrolled in this study. Diagnoses, based on validated self-reported questionnaires, were made using the following guidelines: Rome III classification system for functional gastrointestinal disorders for IBS; Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) for the presence of anxiety and depression, respectively; Pittsburgh Sleep Quality Index (PSQI) for severity of sleep disturbances; and Scales for Outcomes in Parkinson's disease-Autonomic (SCOPA-AUT) for autonomic dysfunction., Results: There were 88 patients with pRLS (18 male, 70 female) and 128 control patients (40 men, 88 women). The mean age of the pRLS patients and control patients was 50.3 ± 9.3 years and 49.7 ± 8.2 years, respectively. Overall, 41 (46.6%) of the patients with pRLS and 16 (12.5%) of the control patients had IBS. Among patients with pRLS, IBS was significantly more common and the total autonomic SCOPA-AUT scores were higher than those found among control patients. Among pRLS patients with IBS, total autonomic SCOPA-AUT, PSQI, BAI and BDI scores were significantly higher than among pRLS patients without IBS. The presence of IBS did not affect the severity of restless legs syndrome., Conclusion: The presence of autonomic nervous system impairment in patients with pRLS and the strong link between IBS and pRLS merit further, more extensive investigation., (Copyright: © Singapore Medical Association.)

Purpose: Patients suffering from cardiovascular autonomic failure often develop neurogenic supine hypertension (nSH), i.e., high blood pressure (BP) in the supine position, which falls in the upright position owing to impaired autonomic regulation. A committee was formed to reach consensus among experts on the definition and diagnosis of nSH in the context of cardiovascular autonomic failure., Methods: As a first and preparatory step, a systematic search of PubMed-indexed literature on nSH up to January 2017 was performed. Available evidence derived from this search was discussed in a consensus expert round table meeting in Innsbruck on February 16, 2017. Statements originating from this meeting were further discussed by representatives of the American Autonomic Society and the European Federation of Autonomic Societies and are summarized in the document presented here. The final version received the endorsement of the European Academy of Neurology and the European Society of Hypertension., Results: In patients with neurogenic orthostatic hypotension, nSH is defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, measured after at least 5 min of rest in the supine position. Three severity degrees are recommended: mild, moderate and severe. nSH may also be present during nocturnal sleep, with reduced-dipping, non-dipping or rising nocturnal BP profiles with respect to mean daytime BP values. Home BP monitoring and 24-h-ambulatory BP monitoring provide relevant information for a customized clinical management., Conclusions: The establishment of expert-based criteria to define nSH should standardize diagnosis and allow a better understanding of its epidemiology, prognosis and, ultimately, treatment.

Background: Cardiovascular autonomic neuropathy (CAN) is a common complication of diabetes and is associated with cardiovascular morbidity and mortality. Despite its prevalence, it is usually underdiagnosed. Objective to assess frequency of CAN in type 2 diabetes, treated at the Diabetology Service at Cordoba Hospital, Argentina., Method: Cross-sectional study was conducted from May 2015 to May 2016. Cardiovascular Autonomic Tests (Ewing´s battery) were performed: response to Valsalva maneuver, expiration-to-inspiration ratio (E/I ratio), standing to lying flat and postural hypotension., Results: 100 type 2 diabetes patients, 53% females. The mean age and diabetes duration 52 years old and 8.4 years, respectively. Hemoglobin A1c level of 8.7% and 47% were insulin-requiring type 2 diabetes patients. 29% had early CAN, 54% confirmed CAN (10% severe CAN) and 17% normal cardiovascular tests. Confirmed CAN was higher in those with longer duration of diabetes; longer duration of insulin therapy, older patients and severe hypoglycemia events was higher in those with confirmed CAN versus without CAN or early CAN (p 0.003). The risk factors associated were hypertension OR 2.55 (p 0.02), peripheral neuropathy OR 11.7 (p <0.0001), diabetic retinopathy OR 9.03 (p 0.001), diabetic nephropathy OR 3.12 (p 0.03) and hemoglobin A1c > 7% OR 2.57 (p 0, 03)., Conclusions: frequency of CAN was high, was associated with hypertension, microvascular complications, older age, poor metabolic control, longer duration of disease and insulin therapy. Patients with a higher risk of developing CAN should be identified, in order to reduce the impact of this complication.

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients frequently show autonomic symptoms which may be associated with a hypothalamic dysfunction. This study aimed to explore circadian rhythm patterns in rest and activity and distal skin temperature (DST) and their association with self-reported outcome measures, in CFS/ME patients and healthy controls at two different times of year. Ten women who met both the 1994 CDC/Fukuda definition and 2003 Canadian criteria for CFS/ME were included in the study, along with ten healthy controls matched for age, sex and body mass index. Self-reported measures were used to assess fatigue, sleep quality, anxiety and depression, autonomic function and health-related quality of life. The ActTrust actigraph was used to record activity, DST and light intensity, with data intervals of one minute over seven consecutive days. Sleep variables were obtained through actigraphic analysis and from subjective sleep diary. The circadian variables and the spectral analysis of the rhythms were calculated. Linear regression analysis was used to evaluate the relationship between the rhythmic variables and clinical features. Recordings were taken in the same subjects in winter and summer. Results showed no differences in rhythm stability, sleep latency or number of awakenings between groups as measured with the actigraph. However, daily activity, the relative amplitude and the stability of the activity rhythm were lower in CFS/ME patients than in controls. DST was sensitive to environmental temperature and showed lower nocturnal values in CFS/ME patients than controls only in winter. A spectral analysis showed no differences in phase or amplitude of the 24h rhythm, but the power of the second harmonic (12h), revealed differences between groups (controls showed a post-lunch dip in activity and peak in DST, while CFS/ME patients did not) and correlated with clinical features. These findings suggest that circadian regulation and skin vasodilator responses may play a role in CFS/ME., Competing Interests: The authors have declared that no competing interests exist.