A Flow Cytometric Assay to Detect Functional Ganglionic Acetylcholine Receptor Antibodies by Immunomodulation in Autoimmune Autonomic Ganglionopathy.

Autoimmune Autonomic Ganglionopathy (AAG) is an uncommon immune-mediated neurological disease that results in failure of autonomic function and is associated with autoantibodies directed against the ganglionic acetylcholine receptor (gnACHR). The antibodies are routinely detected by immunoprecipitation assays, such as radioimmunoassays (RIA), although these assays do not detect all patients with AAG and may yield false positive results. Autoantibodies against the gnACHR exert pathology by receptor modulation. Flow cytometric analysis is able to determine if this has occurred, in contrast to the assays in current use that rely on immunoprecipitation. Here, we describe the first high-throughput, non-radioactive flow cytometric assay to determine autoantibody mediated gnACHR immunomodulation. Previously identified gnACHR antibody seronegative and seropositive sera samples (RIA confirmed) were blinded and obtained from the Oxford Neuroimmunology group along with samples collected locally from patients with or without AAG. All samples were assessed for the ability to cause gnACHR immunomodulation utilizing the prototypical gnACHR expressing cell line, IMR-32. Decision limits were calculated from healthy controls, and Receiver Operating Characteristic (ROC) curves were constructed after unblinding all samples. One hundred and ninety serum samples were analyzed; all 182 expected negative samples (from healthy controls, autonomic disorders not thought to be AAG, other neurological disorders without autonomic dysfunction and patients with Systemic Lupus Erythematosus) were negative for immunomodulation (<18%), as were the RIA negative AAG and unconfirmed AAG samples. All RIA positive samples displayed significant immunomodulation. There were no false positive or negative samples. There was perfect qualitative concordance as compared to RIA, with an Area Under ROC of 1. Detection of Immunomodulation by flow cytometry for the identification of gnACHR autoantibodies offers excellent concordance with the gnACHR antibody RIA, and overcomes many of the shortcomings of immunoprecipitation assays by directly measuring the pathological effects of these autoantibodies at the cellular level. Further work is needed to determine the correlation between the degree of immunomodulation and disease severity.

Association of lipoprotein levels with sleep apnea: role of autonomic dysfunction.

Objectives. Although multiple mechanisms, including autonomic dysfunction, seem to link sleep-disordered breathing (SDB) with dyslipidemia in animal studies, the data in clinical studies are limited. The aim of this study was to explore the association of lipoprotein levels with SDB measures in healthy habitual snorers. We supposed that autonomic dysfunction is the linking mechanism.Methods. We enrolled 110 previously healthy subjects with complaints of habitual snoring. To assess SDB, polysomnography was performed. Blood samples for the analysis of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) were obtained in a fasting condition after the polysomnography. Baroreflex sensitivity (BRS) was used to assess the autonomic dysfunction.Results. In stepwise multiple linear regression analysis, minimal nocturnal blood oxygen saturation (beta=-0.240, p=0.020) and neck circumference (beta=0.224, p=0.03) were the only significant contributors in model predicting TG. SDB measures were not identified as significant contributors in models predicting TC, LDL, and HDL. We failed to find any significant difference in BRS in SDB subjects when compared according to the presence or absence of hypercholesterolemia/ hypertriglyceridemia. In SDB subjects, the area under the curve in a receiver operating curve to predict hypercholesterolemia and hypertriglyceridemia by BRS was 0.468 (95% CI: 0.328-0.608) and 0.425 (95% CI: 0.304-0.546), respectively.Conclusions. Our results suggest that minimal nocturnal blood oxygen saturation is significant contributor in model predicting TG. No significant decrease in BRS was found in SDB subjects with hypercholesterolemia and hypertriglyceridemia. In SDB subjects, the role of autonomic dys-function in the development of dyslipidemia remains controversial.

Association of serum CTRP9 levels with cardiac autonomic neuropathy in patients with type 2 diabetes mellitus.

AIMS: Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes and is associated with adipokines. The C1q tumor necrosis factor-related protein 9 (CTRP9) is a newly discovered adipokine. This study aimed to evaluate the association of serum CTRP9 levels with the prevalence and severity of CAN in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: We enrolled 262 patients (aged ≥18 years) with type 2 diabetes mellitus into this study. Standard cardiovascular autonomic reflex tests (CARTs) were used to assess CAN and patients were divided into three groups accordingly: a non-CAN group, an early CAN group, and a definite CAN group. Serum CTRP9 levels were measured by enzyme-linked immunosorbent assay, and the tertiles were calculated. RESULTS: Serum CTRP9 levels decreased significantly in the early CAN and definite CAN groups (P < 0.05). The percentage of definite CAN was the highest at the minimum tertile of serum CTRP9 level (T1; P < 0.05). Additionally, serum CTRP9 levels were negatively correlated with age, DM duration, hemoglobin A1c (HbA1c), and fasting plasma glucose (FPG) while positively correlated with high-density lipoprotein cholesterol (HDL; P < 0.05). The level of CTRP9 was also significantly associated with the four indexes of CARTs (P < 0.05). Furthermore, CTRP9 was a protective factor for definite CAN (P < 0.05). Compared with the maximum tertile (T3) of the serum CTRP9 levels, a decreased level of serum CTRP9 in T1 significantly increased the prevalence ratio of definite CAN in patients with type 2 diabetes mellitus (P < 0.05). CONCLUSION: Serum CTRP9 levels were independently associated with definite CAN. CTRP9 represents a reliable biomarker for exploring CAN in patients with type 2 diabetes mellitus.

Autonomic dysfunction syndrome in pregnant women.

Available studies and information on the regulatory effect of the autonomic nervous system (ANS) in pregnancy are insufficient and contradictory due to a variety of research methods of ANS, the lack of a single standardized approach to the assessment of the functional tone of the ANS departments, and interpretation of the results. The aim of the study is investigation and predictive assessment of clinical and laboratory data in pregnant women with suprasegmental autonomic dysfunction with or without hypertension to determine the main directions of effective prevention of the nervous system damage. The material of the study included 206 pregnant women diagnosed with the syndrome of autonomic dysfunction in different variants. Age ranged from 17 to 47 years. All pregnant women had the following laboratory tests: general clinical tests, biochemical blood tests, including prothrombin index, fibrinogen, von Willebrand factor activity. The clinical and laboratory data were analyzed in pregnant women with autonomic dysfunction with or without hypertension. According to the results, it was found that in all groups of pregnant women a sympathetic effect prevails. This study showed that in the group of normotensive pregnant women, the main symptom is venous dysfunction, which poses a risk of an adverse course of cerebrovascular disease.

Association of cardiac autonomic dysfunction with higher levels of plasma lipid metabolites in recent-onset type 2 diabetes.

AIMS/HYPOTHESIS: Emerging evidence suggests that in addition to hyperglycaemia, dyslipidaemia could represent a contributing pathogenetic factor to diabetic neuropathy, while obesity and insulin resistance play a role in the development of diabetic cardiac autonomic neuropathy (CAN) characterised by reduced heart rate variability (HRV), particularly in type 2 diabetes. We hypothesised that distinct lipid metabolites are associated with diminished HRV in recent-onset type 2 diabetes rather than type 1 diabetes. METHODS: We analysed 127 plasma lipid metabolites (11 acylcarnitines, 39 NEFA, 12 sphingomyelins (SMs), 56 phosphatidylcholines and nine lysophosphatidylcholines) using MS in participants from the German Diabetes Study baseline cohort recently diagnosed with type 1 (n = 100) and type 2 diabetes (n = 206). Four time-domain HRV indices (number of normal-to-normal (NN) intervals >50 ms divided by the number of all NN intervals [pNN50]; root mean square of successive differences [RMSSD]; SD of NN intervals [SDNN]; and SD of differences between adjacent NN intervals) and three frequency-domain HRV indices (very-low-frequency [VLF], low-frequency [LF] and high-frequency [HF] power spectrum) were computed from NN intervals recorded during a 3 h hyperinsulinaemic-euglycaemic clamp at baseline and in subsets of participants with type 1 (n = 60) and type 2 diabetes (n = 95) after 5 years. RESULTS: In participants with type 2 diabetes, after Bonferroni correction and rigorous adjustment, SDNN was inversely associated with higher levels of diacyl-phosphatidylcholine (PCaa) C32:0, PCaa C34:1, acyl-alkyl-phosphatidylcholine (PCae) C36:0, SM C16:0 and SM C16:1. SD of differences between NN intervals was inversely associated with PCaa C32:0, PCaa C34:1, PCaa C34:2, PCae C36:0 and SM C16:1, and RMSSD with PCae C36:0. For VLF power, inverse associations were found with PCaa C30:0, PCaa C32:0, PCaa C32:1, PCaa C34:2 and SM C16:1, and for LF power inverse associations were found with PCaa C32:0 and SM C16:1 (r = -0.242 to r = -0.349; p ≤ 0.0005 for all correlations). In contrast, no associations of lipid metabolites with measures of cardiac autonomic function were noted in participants recently diagnosed with type 1 diabetes. After 5 years, HRV declined due to ageing rather than diabetes, whereby prediction analyses for lipid metabolites were hampered. CONCLUSIONS/INTERPRETATION: Higher plasma levels of specific lipid metabolites are closely linked to cardiac autonomic dysfunction in recent-onset type 2 diabetes but not type 1 diabetes, suggesting a role for perturbed lipid metabolism in the early development of CAN in type 2 diabetes. Graphical abstract.

Plasma Epinephrine Contributes to the Development of Experimental Hypoglycemia-Associated Autonomic Failure.

BACKGROUND: Recurrent hypoglycemia blunts counter-regulatory responses to subsequent hypoglycemic episodes, a syndrome known as hypoglycemia-associated autonomic failure (HAAF). Since adrenergic receptor blockade has been reported to prevent HAAF, we investigated whether the hypoglycemia-associated rise in plasma epinephrine contributes to pathophysiology and reported interindividual differences in susceptibility to HAAF. METHODS: To assess the role of hypoglycemia-associated epinephrine responses in the susceptibility to HAAF, 24 adult nondiabetic subjects underwent two 2-hour hyperinsulinemic hypoglycemic clamp studies (nadir 54 mg/dL; 0-2 hours and 4-6 hours) on Day 1, followed by a third identical clamp on Day 2. We challenged an additional 7 subjects with two 2-hour infusions of epinephrine (0.03 µg/kg/min; 0-2 hours and 4-6 hours) vs saline on Day 1 followed by a 200-minute stepped hypoglycemic clamp (90, 80, 70, and 60 mg/dL) on Day 2. RESULTS: Thirteen out of 24 subjects developed HAAF, defined by ≥20% reduction in average epinephrine levels during the final 30 minutes of the third compared with the first hypoglycemic episode (P < 0.001). Average epinephrine levels during the final 30 minutes of the first hypoglycemic episode were 2.3 times higher in subjects who developed HAAF compared with those who did not (P = 0.006).Compared to saline, epinephrine infusion on Day 1 reduced the epinephrine responses by 27% at the 70 and 60 mg/dL glucose steps combined (P = 0.04), with a parallel reduction in hypoglycemic symptoms (P = 0.03) on Day 2. CONCLUSIONS: Increases in plasma epinephrine reproduce key features of HAAF in nondiabetic subjects. Marked interindividual variability in epinephrine responses to hypoglycemia may explain an individual's susceptibility to developing HAAF.

In Amateur Athletes With Type 1 Diabetes, a 9-Day Period of Cycling at Moderate-to-Vigorous Intensity Unexpectedly Increased the Time Spent in Hyperglycemia, Which Was Associated With Impairment in Heart Rate Variability.

OBJECTIVE: In type 1 diabetes, autonomic dysfunction may occur early as a decrease in heart rate variability (HRV). In populations without diabetes, the positive effects of exercise training on HRV are well-documented. However, exercise in individuals with type 1 diabetes, particularly if strenuous and prolonged, can lead to sharp glycemic variations, which can negatively impact HRV. This study explores the impact of a 9-day cycling tour on HRV in this population, with a focus on exercise-induced glycemic excursions. RESEARCH DESIGN AND METHODS: Twenty amateur athletes with uncomplicated type 1 diabetes cycled 1,500 km. HRV and glycemic variability were measured by heart rate and continuous glucose monitoring. Linear mixed models were used to test the effects of exercise on HRV, with concomitant glycemic excursions and subject characteristics considered as covariates. RESULTS: Nighttime HRV tended to decrease with the daily distance traveled. The more time the subjects spent in hyperglycemia, the lower the parasympathetic tone was. This result is striking given that hyperglycemic excursions progressively increased throughout the 9 days of the tour, and to a greater degree on the days a longer distance was traveled, while time spent in hypoglycemia surprisingly decreased. This phenomenon occurred despite no changes in insulin administration and a decrease in carbohydrate intake from snacks. CONCLUSIONS: In sports enthusiasts with type 1 diabetes, multiday prolonged exercise at moderate-to-vigorous intensity worsened hyperglycemia, with hyperglycemia negatively associated with parasympathetic cardiac tone. Considering the putative deleterious consequences on cardiac risks, future work should focus on understanding and managing exercise-induced hyperglycemia.

Effect of renal function on association between uric acid and prognosis in acute ischemic stroke patients with elevated systolic blood pressure.

BACKGROUND AND AIMS: The prognostic value of uric acid in ischemic stroke remains controversial, and it is unclear whether renal function status modifies the prognostic value of uric acid in ischemic stroke patients. METHODS: A total of 3284 acute ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) with creatinine and uric acid measurements were included in this analysis. The primary outcome was a composite of death and major disability (modified Rankin Scale score ≥3) at 1 year after stroke. RESULTS: The prognostic value of uric acid in ischemic stroke was appreciably modified by patients' renal function status (p for interaction <0.05). After multivariate adjustment, higher uric acid level was significantly associated with a better prognosis in patients with normal renal function (odds ratio, 0.61; 95% confidence interval, 0.45-0.83), but not in those with abnormal renal function (odds ratio, 0.87; 95% confidence interval, 0.48-1.55), when two extreme quartiles were compared. Linear association between uric acid and primary outcome was observed among patients with normal renal function (p for linearity = 0.023). CONCLUSION: The present study suggests that high serum uric acid concentration is associated with better prognosis in ischemic stroke patients with normal renal function, but not in those with abnormal renal function. The establishment of causality between increased uric acid levels and better stroke prognosis needs more suitably designed randomized clinical trials.

Factors associated with sclerostin levels - A calcification inhibitor - In individuals with type 2 diabetes mellitus; Is autonomic neuropathy the missing link?

BACKGROUND: Sclerostin inhibits bone formation and its expression is upregulated in the vasculature during the arterial calcification process as a counterregulatory mechanism preventing further calcification. Lower extremity arterial calcification (LEAC) is common in neuropathic patients with type 2 diabetes (T2DM). Herein, we investigated for associations between plasma sclerostin levels and diabetic neuropathy as well as LEAC in subjects with T2DM. METHODS: A total of 74 individuals with and 76 without T2DMwere recruited. Plasma sclerostin levels were measured by ELISA. Diagnosis of cardiac autonomic neuropathy (CAN) was based on the battery of the four autonomic tests, while of somatosensory peripheral neuropathy (DPN) on neuropathy symptom score and neuropathy disability score. LEAC was assessed with conventional ankle and foot x-rays. RESULTS: Plasma sclerostin levels were higher in participants with LEAC vs. those without LEAC in both diabetes and non-diabetes cohorts (p = 0.035 and p = 0.003, respectively). In the diabetes cohort, patients with CAN, but not with DPN, had higher sclerostin levels when compared with those without CAN (p < 0.001). Multivariate analysis in the diabetes cohort demonstrated that sclerostin levels were associated positively with CAN and LEAC, while in the non-diabetes cohort there was a trend for a positive association with male gender and presence of LEAC. CONCLUSION: Plasma sclerostin levels are increased in individuals with LEAC irrespectively of diabetes status. In addition, plasma sclerostin concentrations are associated independently with LEAC and CAN in people with T2DM.

Treatment induced neuropathy of diabetes.

BACKGROUND: Treatment induced neuropathy of diabetes (TIND) is an iatrogenic painful sensory and autonomic neuropathy. Although the prevalence is not known, it is seen in up to 10% of tertiary cases referred for evaluation of diabetic neuropathy. EVIDENCE: TIND is associated with a decrease in the glycosylated hemoglobin A1C in individuals with longstanding hyperglycemia. TIND is more common in individuals with type 1 diabetes, but can occur in anyone with diabetes through the use of insulin, oral hypoglycemic medications or diet control. There is an acute or subacute onset of neuropathy that is linked to the change in glucose control. Although the primary clinical manifestation is neuropathic pain there is a concurrent development of autonomic dysfunction, retinopathy and nephropathy. CONCLUSION: TIND is more common than previously suspected. The number of cases reported over the past 10 years is much greater than historical literature predicted. Increased attention to target glucose control as a physician metric could suggest a possible explanation for the increased in TIND cases reported in recent years. At present, supportive care is the only recommended treatment. Future research is necessary to define the underlying mechanism, prevent development and to guide treatment recommendations.

High glucose level as a modifier factor in CMT1A patients.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common type of hereditary neuropathy worldwide and diabetes mellitus (DM) is the most frequent cause of peripheral neuropathy in the Western world. CMT1A typically manifest as a predominant motor neuropathy, while, DM-related neuropathy often manifests as a predominant sensory disorder. There are some evidences that CMT1A patients that also had DM had a more severe neuropathy. Although the real frequency and the underlying mechanisms related to this association has not yet been addressed in the literature. We sought to characterize the phenotypic variability of CMT1A patients with persistent high glucose levels (DM or impaired glucose tolerance [IGT]). Nineteen patients with CMT1A and DM (CMTdiab), seven with CMT1A and IGT (CMTintol) and 27 with CMT1A without comorbidities were analyzed. They were evaluated through clinical assessment, application of the following scales: visual analogue scale, McGill, CMTNS, SF-36 and COMPASS 31 and electrophysiological studies. Patients CMTdiab had a more severe motor and sensory neuropathy, more intense autonomic symptoms and worse quality of life. Surprisingly, proximal weakness and temporal dispersion on nerve conduction studies are frequently observed in this group. Patients CMTintol also had a more severe neuropathy. Curiously, we observed that the association of CMT1A and glucose metabolism disorders (CMTglic) clustered in some families. Patients CMTglic develop a more severe neuropathy. As there is yet no cure to CMT1A, a strict blood sugar control may be a useful measure.

A comprehensive analysis of the clinical characteristics and laboratory features in 179 patients with autoimmune autonomic ganglionopathy.

The clinical importance of autoantibodies against the ganglionic acetylcholine receptor (gAChR) remains to be fully elucidated. We aimed to identify the clinical characteristics of autoimmune autonomic ganglionopathy (AAG) in patients with gAChR autoantibodies. For this cohort investigation, serum samples were obtained from patients with AAG between 2012 and 2018 in Japan. We measured the levels of autoantibodies against gAChRα3 and gAChRß4 and evaluated clinical features, as well as assessing the laboratory investigation results among the included patients. A total of 179 patients tested positive for antibodies, including 116 gAChRα3-positive, 13 gAChRß4-positive, and 50 double antibody-positive patients. Seropositive AAG patients exhibited widespread autonomic dysfunction. Extra-autonomic manifestations including sensory disturbance, central nervous system involvement, endocrine disorders, autoimmune diseases, and tumours were present in 118 patients (83%). We observed significant differences in the frequencies of several autonomic and extra-autonomic symptoms among the three groups. Our 123I-metaiodobenzylguanidine myocardial scintigraphy analysis of the entire cohort revealed that the heart-to-mediastinum ratio had decreased by 80%. The present study is the first to demonstrate that patients with AAG who are seropositive for anti-gAChRß4 autoantibodies exhibit unique autonomic and extra-autonomic signs. Decreased cardiac uptake occurred in most cases, indicating that 123I- metaiodobenzylguanidine myocardial scintigraphy may be useful for monitoring AAG. Therefore, our findings indicate that gAChRα3 and gAChRß4 autoantibodies cause functional changes in postganglionic fibres in the autonomic nervous system and extra-autonomic manifestations in seropositive patients with AAG.

Association Between Serum C-Peptide Level and Cardiovascular Autonomic Neuropathy According to Estimated Glomerular Filtration Rate in Individuals with Type 2 Diabetes.

OBJECTIVE: To investigate the association between serum C-peptide level and cardiovascular autonomic neuropathy (CAN) in individuals with type 2 diabetes mellitus (DM) according to estimated glomerular filtration rate (eGFR) METHODS: In a cross-sectional study, we examined 939 individuals with type 2 DM. We measured fasting C-peptide, 2-hour postprandial C-peptide, and ΔC-peptide (postprandial C-peptide minus fasting C-peptide) levels. The individuals were classified into 2 groups based on eGFR: individuals without impaired renal function (eGFR ≥60 ml∙min-1 1.73m-2) and those with impaired renal function (eGFR <60 ml∙min-1 1.73m-2). RESULTS: Individuals with CAN had lower fasting C-peptide, postprandial C-peptide, and ΔC-peptide levels in patients both with and without impaired renal function. Multivariate logistic regression analyses adjusted for gender, age, and other confounders, including eGFR, showed that serum C-peptide level was significantly associated with CAN (odds ratio [OR] per standard deviation increase in the log-transformed value, 0.67; 95% confidence interval [CI], 0.52-0.87 for fasting C-peptide, P < 0.01; OR, 0.62; 95% CI, 0.47-0.83 for postprandial C-peptide, P < 0.01; OR, 0.71; 95% CI, 0.54-0.93 for ΔC-peptide, P < 0.05). CONCLUSIONS: Serum C-peptide level was negatively associated with CAN in individuals with type 2 DM independent of eGFR.

Association Between Systemic Inflammation, Carotid Arteriosclerosis, and Autonomic Dysfunction.

Systemic inflammation is associated with arteriosclerotic disease progression and worse stroke outcome in patients with carotid arteriosclerotic disease. We hypothesize that systemic inflammation is mediated by impaired carotid baroreceptor and chemoreceptor function induced by carotid arteriosclerosis rather than by the generalized inflammatory arteriosclerotic process.Heart rate variability (HRV), serum levels of inflammatory markers, demographic and life style factors, and concomitant diseases with potential impact on systemic inflammation were determined in 105 patients with asymptomatic carotid stenosis of varying degree. Multivariate linear regression analyses were performed to ascertain independent determinants of carotid stenosis severity, autonomic function, and inflammation.Systemic inflammation (C-reactive protein, beta = .255; P = .014), age (beta = .232; P < .008), and arterial hypertension (beta = .206; P = .032) were associated with carotid stenosis severity. Only carotid stenosis severity and not generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia, hypothyroidism), life style factors (smoking, obesity), or age was associated with a reduction in vagal tone (HRV HF band power beta = - .193; P < 0.049). Systemic inflammation was related to a reduction in vagal tone (HRV HF band power, beta = - .214; P = .031), and not to generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia), life style factors (smoking, obesity), and age.In conclusion, systemic inflammation is associated with carotid rather than with generalized arteriosclerotic disease. The association between systemic inflammation and carotid arteriosclerosis is mediated by a reduction in vagal tone which indicates a major role of carotid arteriosclerosis-mediated autonomic dysfunction in the pathogenesis of systemic inflammation in arteriosclerotic disease.

Nocturnal blood pressure changes in Parkinson's disease: correlation with autonomic dysfunction and vitamin D levels.

Nocturnal blood pressure (BP) changes are an indicator of autonomic dysfunction. We aim to investigate the correlation between nocturnal blood pressure (BP) variability, vitamin D levels and Parkinson's disease severity (PD) in this study. Thirty-five patients with PD participated in the study. Disease severity was evaluated by United Parkinson's Disease Rating Scale (UPDRS) and Hoehn and Yahr Scale (HYS). Equivalent levodopa dose was calculated and 25-hydroxyvitamin D levels were measured. The Non-Motor Symptom Questionnaire (NMSQ) was applied to all patients. Ambulatory BP monitoring for 24 h was established. Patients were divided into three groups according to nocturnal BP results: dippers (normal finding-a decline in mean nighttime BP of more than 10%); non-dippers (pathological-a decline in mean nighttime BP of less than 10%); reverse dippers (pathological-an increase in mean nighttime BP) .The mean score of the NMSQ was higher in the group with HYS > 2 (p = 0.050). Four patients were dipper, 17 patients were non-dipper and 16 patients were reverse dipper. There was no significant difference between the three groups in terms of age, gender, disease duration, age of the disease onset, disease stage, disease duration, dopamine agonist usage, levodopa equivalent dose, vitamin D level and NMSQ scores. NMSQ scores are high in advanced PD. Ambulatory BP monitoring is useful in detecting autonomic dysfunction. The number of patients with non-dipping and reverse dipping is high in PD, independent from PD severity, drug dose, vitamin D and the other NMS symptoms.

Adrenergic hyperactivity: a missing link between multiple sclerosis and cardiovascular comorbidities?

The aim of the study is to investigate differences in non-standard adrenergic baroreflex sensitivity (BRS) indices in patients with different phenotypes of multiple sclerosis (pwMS) and healthy controls (HC). Retrospective analysis of types of systolic blood pressure (BP) curves during Valsalva maneuver (VM) [balanced (BAR), augmented (AAR) and suppressed (SAR) autonomic responses] and adrenergic baroreflex sensitivity (BRSa) measured with BRSa1, α-BRSa and ß-BRSa in patients with clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), progressive multiple sclerosis (PMS) and HC. We also investigated correlations between BRSa1, α-BRSa, ß-BRSa and resting catecholamine levels. pwMS had higher α-BRSa compared to HC (p = 0.02). There was no difference in BRSa1, s and ß-BRSa between patients with CIS, RRMS and PMS. There was no association between pwMS and HC, and the type of sBP curve [χ2 = 4.332, p = 0.114]. pwMS and BAR or AAR had higher supine systolic and diastolic BP compared to pwMS and SAR. There was a significant correlation between α-BRSa and upright systolic BP (rp =0.194, p = 0.017), α-BRSa and norepinephrine (rs =0.228, p = 0.021), and BRSa1 and epinephrine (rs = 0.226, p = 0.040). pwMS and HC exhibit different alpha-adrenergic response to Valsalva maneuver. These results may explain the connection between MS and increased cardiovascular risk.

Vitamin D, vitamin D binding protein, vitamin D receptor levels and cardiac dysautonomia in patients with multiple sclerosis: a cross-sectional study / Vitamina D, proteína de ligação à vitamina D, níveis de receptores de vitamina D e disautonomia cardíaca em pacientes com esclerose múltipla: um estudo transversal

ABSTRACT Vitamin D is a pleiotropic steroid hormone that modulates the autonomic balance. Its deficiency has been described as an environmental risk factor for multiple sclerosis (MS). The aim of this study was to investigate the serum levels of vitamin D, vitamin D binding protein (VDBP) and vitamin D receptors (VDR) and to evaluate cardiac dysautonomia in MS patients due to bidirectional interaction between vitamin D and the autonomic nervous system. Methods: The current cross-sectional study was conducted on 26 patients with relapsing-remitting MS and on 24 healthy controls. Twenty-four-hour ambulatory blood pressure variability (BPV) was calculated and the participants were evaluated for orthostatic hypotension and supine hypertension. Serum levels of vitamin D, VDBP and VDR were measured. Results: The mean serum vitamin D level was significantly lower in MS patients than in controls (p = 0.044); however there was no significant difference in terms of VDR and VDBP levels between the groups. Supine hypertension and orthostatic hypotension were significant and the 24-hour systolic BPV was significantly decreased in patients with MS (p < 0.05) compared to controls. No correlation was found between vitamin D, VDBP and VDR with supine hypertension, orthostatic hypotension and systolic BPV values (p > 0.05). Also, there was a negative correlation between VDBP and the EDSS (p = 0.039, r = −0.406). Conclusion: There was no correlation between orthostatic hypotension, supine hypertension and systolic BPV values and serum vitamin D, VDBP and VDR in MS patients. Future prospective studies with large number of patients may help us to better understand the relationship between vitamin D and the autonomic nervous system.

RESUMO A vitamina D é um hormônio esteroide pleiotrópico que modula o equilíbrio autonômico. Sua deficiência tem sido descrita como fator de risco ambiental para esclerose múltipla (EM). O objetivo deste estudo foi investigar os níveis séricos de vitamina D, proteína de ligação à vitamina D (VDBP) e receptor de vitamina D (VDR) e avaliar a disautonomia cardíaca em pacientes com EM devida à interação bidirecional entre vitamina D e sistema nervoso autônomo. Métodos: O presente estudo transversal foi realizado em 26 pacientes com EM remitente-recorrente e em 24 controles saudáveis. A variabilidade da pressão arterial ambulatorial (BPV) por 24 horas foi calculada e os participantes foram avaliados quanto à hipotensão ortostática e hipertensão supina. Os níveis séricos de vitamina D, VDBP e VDR foram medidos. Resultados: O nível sérico médio de vitamina D foi significativamente menor nos pacientes com EM do que nos controles (p = 0,044); no entanto, não houve diferença significativa em termos de níveis de VDR e VDBP entre os grupos. Hipertensão supina e hipotensão ortostática foram significativas e a BPV sistólica de 24 horas diminuiu significativamente em pacientes com EM (p < 0,05) em comparação aos controles. Não foi encontrada correlação entre vitamina D, VDBP e VDR com hipertensão supina, hipotensão ortostática e BPV sistólica (p > 0,05). Também houve correlação negativa entre VDBP e EDSS (p = 0,039, r = −0,406). Conclusão: Não houve correlação entre hipotensão ortostática, hipertensão supina e valores de BPV sistólica e vitamina D sérica, VDBP e VDR em pacientes com EM. Futuros estudos prospectivos com grande número de pacientes podem nos ajudar a entender melhor a relação entre vitamina D e sistema nervoso autônomo.

Pheochromocytoma as a Clinical Model of Peripheral Sympathetic Overdrive: Old and New Findings.

PURPOSE OF REVIEW: The present paper will review the results of experimental and clinical studies aimed at defining the functional behavior of the central and peripheral nervous system in adrenal pheochromocytoma. RECENT FINDINGS: The contribution of sympathetic neural influences to the development of high blood pressure values in pheochromocytoma is complex. Studies performed in experimental animal models have shown that hypertension and the concomitant high circulating levels of catecholamines can lead to inhibition of central sympathetic neural outflow by reflex mechanisms and direct stimulation of central adrenergic receptors, respectively. However, these studies have also shown that high circulating levels of catecholamines favor a downregulation of alpha- and beta-adrenergic receptors, lessening their response to endogenous and exogenous adrenergic stimulation. The present paper reviews results of human studies performed by our group and others on the behavior of the central and peripheral nervous system in human pheochromocytoma. We discuss data collected in patients with different levels of peripheral sympathetic drive, i.e., before and after surgical removal of the adrenal pheochromocytoma. In the presence of elevated plasma catecholamine level, such as that characterizing adrenal pheochromocytoma, microneurography shows that central sympathetic neural activity is normal or even inhibited. At the peripheral vascular level, pheochromocytoma is characterized by a reduced vascular reactivity to exogenous sympathetic stimulation but a normal response by the vessels to endogenous adrenergic stimulation.

Anti-Hypothalamus and Anti-Pituitary Auto-antibodies in ROHHAD Syndrome: Additional Evidence Supporting an Autoimmune Etiopathogenesis.

BACKGROUND: Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD) is a very rare and complex pediatric syndrome characterized by altered hypothalamic thermal regulation, pain threshold, and respiratory control, hyperphagia with rapid weight gain and, often, hypothalamic-pituitary dysfunction. Its etiopathogenesis remains undetermined. We investigated the presence of alterations to target genes and hypothalamic-pituitary autoimmunity in a patient with -ROHHAD syndrome. METHODS: A 3-year-old girl presenting with obesity after rapid weight gain was diagnosed with ROHHAD syndrome based on clinical features and abnormal biochemical and functional testing results. Because of worsening of rapid symptoms and demonstration of oligoclonal bands on cerebrospinal fluid (CSF) analysis, she was treated with plasmapheresis, methylprednisolone, anti-CD20 monoclonal antibodies, and azathioprine. Despite initial partial clinical improvement, the patient soon died of cardiorespiratory arrest. Post-mortem, whole exome sequencing, high-resolution comparative genomic hybridization array, and optimized indirect immunofluorescence (IIF) analysis were performed on blood and CSF. RESULTS: No putative causative genomic variants compatible with dominant or recessive inheritance nor clinically significant structural rearrangement were detected. IIF on serum and CSF demonstrated the presence of anti-pituitary and anti-hypothalamus autoantibodies. CONCLUSIONS: These findings support the involvement of autoimmunity in ROHHAD syndrome. However, response to immunosuppressive treatment was only transient and the patient died. Further cases are required to define the complex disease pathogenesis.

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia.

The impaired ability of the autonomic nervous system to respond to hypoglycemia is termed "hypoglycemia-associated autonomic failure" (HAAF). This life-threatening phenomenon results from at least two recent episodes of hypoglycemia, but the pathology underpinning HAAF remains largely unknown. Although naloxone appears to improve hypoglycemia counterregulation under controlled conditions, hypoglycemia prevention remains the current mainstay therapy for HAAF. Epinephrine-synthesizing neurons in the rostroventrolateral (C1) and dorsomedial (C3) medulla project to the subset of sympathetic preganglionic neurons that regulate peripheral epinephrine release. Here we determined whether or not C1 and C3 neuronal activation is impaired in HAAF and whether or not 1 wk of hypoglycemia prevention or treatment with naloxone could restore C1 and C3 neuronal activation and improve HAAF. Twenty male Sprague-Dawley rats (250-300 g) were used. Plasma epinephrine levels were significantly increased after a single episode of hypoglycemia (n = 4; 5,438 ± 783 pg/ml vs. control 193 ± 27 pg/ml, P < 0.05). Repeated hypoglycemia significantly reduced the plasma epinephrine response to subsequent hypoglycemia (n = 4; 2,179 ± 220 pg/ml vs. 5,438 ± 783 pg/ml, P < 0.05). Activation of medullary C1 (n = 4; 50 ± 5% vs. control 3 ± 1%, P < 0.05) and C3 (n = 4; 45 ± 5% vs. control 4 ± 1%, P < 0.05) neurons was significantly increased after a single episode of hypoglycemia. Activation of C1 (n = 4; 12 ± 3%, P < 0.05) and C3 (n = 4; 19 ± 5%, P < 0.05) neurons was significantly reduced in the HAAF groups. Hypoglycemia prevention or treatment with naloxone did not restore the plasma epinephrine response or C1 and C3 neuronal activation. Thus repeated hypoglycemia reduced the activation of C1 and C3 neurons mediating adrenal medullary responses to subsequent bouts of hypoglycemia.