Cardiovascular autonomic failure in hereditary transthyretin amyloidosis and TTR carriers is an early and progressive disease marker.

BACKGROUND: The cardiomyopathic and neuropathic phenotype of hereditary transthyretin amyloidosis are well recognized. Cardiovascular autonomic dysfunction is less systematically and objectively assessed. METHODS: Autonomic and clinical features, quantitative cardiovascular autonomic function, and potential autonomic prognostic markers of disease progression were recorded in a cohort of individuals with hereditary transthyretin amyloidosis and in asymptomatic carriers of TTR variants at disease onset (T0) and at the time of the first quantitative autonomic assessment (T1). The severity of peripheral neuropathy and its progression was stratified with the polyneuropathy disability score. RESULTS: A total of 124 individuals were included (111 with a confirmed diagnosis of hereditary transthyretin amyloidosis, and 13 asymptomatic carriers of TTR variants). Symptoms of autonomic dysfunction were reported by 27% individuals at T0. Disease duration was 4.5 ± 4.0 years [mean ± standard deviation (SD)] at autonomic testing (T1). Symptoms of autonomic dysfunction were reported by 78% individuals at T1. Cardiovascular autonomic failure was detected by functional testing in 75% individuals and in 64% of TTR carriers. Progression rate from polyneuropathy disability stages I/II to III/IV seemed to be shorter for individuals with autonomic symptoms at onset [2.33 ± 0.56 versus 4.00 ± 0.69 years (mean ± SD)]. CONCLUSIONS: Cardiovascular autonomic dysfunction occurs early and frequently in individuals with hereditary transthyretin amyloidosis within 4.5 years from disease onset. Cardiovascular autonomic failure can be subclinical in individuals and asymptomatic carriers, and only detected with autonomic function testing, which should be considered a potential biomarker for early diagnosis and disease progression.

Development and Validation of a Prognostic Model to Predict Overall Survival in Multiple System Atrophy.

Background: Multiple system atrophy (MSA) is a devastating disease characterized by a variable combination of motor and autonomic symptoms. Previous studies identified numerous clinical factors to be associated with shorter survival. Objective: To enable personalized patient counseling, we aimed at developing a risk model of survival based on baseline clinical symptoms. Methods: MSA patients referred to the Movement Disorders Unit in Innsbruck, Austria, between 1999 and 2016 were retrospectively analyzed. Kaplan-Meier curves and multivariate Cox regression analysis with least absolute shrinkage and selection operator penalty for variable selection were performed to identify prognostic factors. A nomogram was developed to estimate the 7 years overall survival probability. The performance of the predictive model was validated and calibrated internally using bootstrap resampling and externally using data from the prospective European MSA Study Group Natural History Study. Results: A total of 210 MSA patients were included in this analysis, of which 124 patients died. The median survival was 7 years. The following clinical variables were found to significantly affect overall survival and were included in the nomogram: age at symptom onset, falls within 3 years of onset, early autonomic failure including orthostatic hypotension and urogenital failure, and lacking levodopa response. The time-dependent area under curve for internal and external validation was >0.7 within the first 7 years of the disease course. The model was well calibrated showing good overlap between predicted and actual survival probability at 7 years. Conclusion: The nomogram is a simple tool to predict survival on an individual basis and may help to improve counseling and treatment of MSA patients.

Variant connective tissue (joint hypermobility) and dysautonomia are associated with multimorbidity at the intersection between physical and psychological health.

The symptoms of joint hypermobility extend beyond articular pain. Hypermobile people commonly experience autonomic symptoms (dysautonomia), and anxiety or related psychological issues. We tested whether dysautonomia might mediate the association between hypermobility and anxiety in adults diagnosed with mental health disorders and/or neurodevelopmental conditions (hereon referred to as patients), by quantifying joint hypermobility and symptoms of autonomic dysfunction. Prevalence of generalized joint laxity (hypermobility) in 377 individuals with diagnoses of mental health disorders and/or neurodevelopmental conditions was compared to prevalence recorded in the general population. Autonomic symptom burden was compared between hypermobile and non-hypermobile patients. Mediation analysis explored relationships between hypermobility, autonomic dysfunction, and anxiety. Patient participants had elevated prevalence of generalized joint laxity (38%) compared to the general population rate of 19% (odds ratio: 2.54 [95% confidence interval: 2.05, 3.16]). Hypermobile participants reported significantly more autonomic symptoms. Symptoms of orthostatic intolerance mediated the relationship between hypermobility and diagnosis of an anxiety disorder. Patients with mental health disorders and/or neurodevelopmental conditions have high rates of joint hypermobility. Accompanying autonomic dysfunction mediates the association between joint hypermobility and clinical anxiety status. Increased recognition of this association can enhance mechanistic understanding and improve the management of multimorbidity expressed in physical symptoms and mental health difficulties.

Dysautonomia in the Ehlers-Danlos syndromes and hypermobility spectrum disorders-With a focus on the postural tachycardia syndrome.

Dysautonomia (autonomic dysfunction) occurs in the Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD). Symptoms include palpitations, dizziness, presyncope, and syncope, especially when standing upright. Symptoms of orthostatic intolerance are usually relieved by sitting or lying and may be exacerbated by stimuli in daily life that cause vasodilatation, such as food ingestion, exertion, and heat. Neurocardiovascular dysautonomia may result in postural tachycardia syndrome (PoTS), a major cause of orthostatic intolerance. It is defined by a rise in heart rate of >30 beats per minute (bpm) in adults and >40 bpm in teenagers while upright, without a fall in blood pressure (BP; orthostatic hypotension). In some, it can be compounded by the presence of low BP. For many, there is delay in clinicians recognizing the nature of the symptoms, and recognizing EDS or HSD, leading to delays in treatment. The onset of PoTS may be linked to an event such as infection, trauma, surgery, or stress. Gastrointestinal and urinary bladder involvement may occur, along with thermoregulatory dysfunction. In some, the mast cell activation syndrome may be contributary, especially if it causes vasodilatation. This paper reviews neurocardiovascular dysautonomia with an emphasis on PoTS, its characteristics, associations, pathophysiology, investigation, and treatment.

Multimodal Biomarkers Quantify Recovery in Autoimmune Autonomic Ganglionopathy.

OBJECTIVE: The objective of this study was to evaluate patients with ganglionic acetylcholine receptor antibody (gAChR-Ab) positive autoimmune autonomic ganglionopathy using a multimodal testing protocol to characterize their full clinical phenotype and explore biomarkers to quantify immunotherapy response. METHODS: We conducted a cohort study of 13 individuals (7 women, 21-69 years of age) with autonomic failure and gAChR-Ab >100 pM identified between 2005 and 2019. From 2018, all patients were longitudinally assessed with cardiovascular, pupillary, urinary, sudomotor, lacrimal and salivary testing, and Composite Autonomic Symptom Score (COMPASS-31) autonomic symptom questionnaires. The orthostatic intolerance ratio was calculated by dividing change in systolic blood pressure over time tolerated on head-up tilt. Eleven patients received immunotherapy. RESULTS: At first assessment, all 13 patients had cardiovascular and pupillary impairments, 7 of 8 had postganglionic sudomotor dysfunction, 9 of 11 had urinary retention and xeropthalmia, and 6 of 8 had xerostomia. After immunotherapy, there were significant improvements in orthostatic intolerance ratio (33.3 [17.8-61.3] to 5.2 [1.4-8.2], p = 0.007), heart rate response to deep breathing (1.5 [0.0-3.3] to 4.5 [3.0-6.3], p = 0.02), pupillary constriction to light (12.0 [5.5-18.0] to 19.0 [10.6-23.8]%, p = 0.02), saliva production (0.01 [0.01-0.05] to 0.08 [0.02-0.20] g/min, p = 0.03), and COMPASS-31 scores (52 to 17, p = 0.03). Orthostatic intolerance ratio correlated with autonomic symptoms at baseline (r = 0.841, p = 0.01) and following immunotherapy (r = 0.889, p = 0.02). Immunofluorescence analyses of skin samples from a patient 32 years after disease onset showed loss of nerve fibers supplying the dermal autonomic adnexa and epidermis, with clear improvements following immunotherapy. INTERPRETATION: Patients with autoimmune autonomic ganglionopathy demonstrated objective evidence of widespread sympathetic and parasympathetic autonomic failure, with significant improvements after immunotherapy. Quantitative autonomic biomarkers should be used to define initial deficits, guide therapeutic decisions, and document treatment response. ANN NEUROL 2021;89:753-768.

Autonomic Dysfunction in Autism Spectrum Disorder.

Background: There have been previous reports of enhanced sympathoexcitation in autism spectrum disorder (ASD). However, there has been no formal investigation of autonomic dysfunction in ASD. Also, the joint hypermobile form of Ehlers-Danlos syndrome (hE-DS) that maybe overrepresented in ASD and orthostatic related autonomic dysfunction. This study examined the comorbidity of ASD, autonomic dysfunction and hE-DS in two UK autonomic national referral centers. Proven, documented and globally accepted clinical autonomic investigations were used to assess neuro-cardiovascular autonomic function in a cohort of ASD subjects and in age-matched healthy controls. Methods: Clinical data from 28 referrals with a confirmed diagnosis of ASD over a 10-year period were compared with 19 age-matched healthy controls. Autonomic function was determined using methods established in the centers previously described in detail. Results: 20/28 ASD had a diagnosed autonomic condition; 9 had the postural tachycardia syndrome (PoTS), 4 PoTS and vasovagal syncope (VVS), 3 experienced presyncope, 1 essential hyperhidrosis, 1 orthostatic hypotension, 1 VVS alone and 1 a combination of PoTS, VVS and essential hyperhidrosis. 16/20 ASD with autonomic dysfunction had hE-DS. In ASD, basal heart rate and responses to orthostatic tests of autonomic function were elevated, supporting previous findings of increased sympathoexcitation. However, sympathetic vasoconstriction was impaired in ASD. Conclusion: Intermittent neuro-cardiovascular autonomic dysfunction affecting heart rate and blood pressure was over-represented in ASD. There is a strong association with hE-DS. Autonomic dysfunction may further impair quality of life in ASD, particularly in those unable to adequately express their experience of autonomic symptoms.

Joint Hypermobility Links Neurodivergence to Dysautonomia and Pain.

OBJECTIVES: Autism, attention deficit hyperactivity disorder (ADHD), and tic disorder (Tourette syndrome; TS) are neurodevelopmental conditions that frequently co-occur and impact psychological, social, and emotional processes. Increased likelihood of chronic physical symptoms, including fatigue and pain, are also recognized. The expression of joint hypermobility, reflecting a constitutional variant in connective tissue, predicts susceptibility to psychological symptoms alongside recognized physical symptoms. Here, we tested for increased prevalence of joint hypermobility, autonomic dysfunction, and musculoskeletal symptoms in 109 adults with neurodevelopmental condition diagnoses. METHODS: Rates of generalized joint hypermobility (GJH, henceforth hypermobility) in adults with a formal diagnosis of neurodevelopmental conditions (henceforth neurodivergent group, n = 109) were compared to those in the general population in UK. Levels of orthostatic intolerance and musculoskeletal symptoms were compared to a separate comparison group (n = 57). Age specific cut-offs for GJH were possible to determine in the neurodivergent and comparison group only. RESULTS: The neurodivergent group manifested elevated prevalence of hypermobility (51%) compared to the general population rate of 20% and a comparison population (17.5%). Using a more stringent age specific cut-off, in the neurodivergent group this prevalence was 28.4%, more than double than the comparison group (12.5%). Odds ratio for presence of hypermobility in neurodivergent group, compared to the general population was 4.51 (95% CI 2.17-9.37), with greater odds in females than males. Using age specific cut-off, the odds ratio for GJH in neurodivergent group, compared to the comparison group, was 2.84 (95% CI 1.16-6.94). Neurodivergent participants reported significantly more symptoms of orthostatic intolerance and musculoskeletal skeletal pain than the comparison group. The number of hypermobile joints was found to mediate the relationship between neurodivergence and symptoms of both dysautonomia and pain. CONCLUSIONS: In neurodivergent adults, there is a strong link between the expression of joint hypermobility, dysautonomia, and pain, more so than in the comparison group. Moreover, joint hypermobility mediates the link between neurodivergence and symptoms of dysautonomia and pain. Increased awareness and understanding of this association may enhance the management of core symptoms and allied difficulties in neurodivergent people, including co-occurring physical symptoms, and guide service delivery in the future.

Congenital absence of norepinephrine due to CYB561 mutations.

OBJECTIVE: Cytochrome b561 (CYB561) generates ascorbic acid, a cofactor in the enzymatic conversion of dopamine to norepinephrine by dopamine ß-hydroxylase. We propose that the clinical relevance of this pathway can be revealed by characterizing the autonomic and biochemical characteristics of patients with CYB561 mutations. METHODS: We performed autonomic evaluations in 4 patients with lifelong orthostatic hypotension in whom CYB561 mutations were determined by genomic sequencing. RESULTS: Patients had disabling lifelong orthostatic hypotension (OH) and impaired blood pressure response to the Valsalva maneuver (VM), with exaggerated hypotension during phase 2 and lack of overshoot during phase 4. Heart rate ratios for sinus arrhythmia and the VM were normal. Plasma norepinephrine and metabolites were undetectable, and plasma dopamine and metabolites were normal. Droxidopa restored norepinephrine levels and improved OH. Patients 1 and 2 were sisters and homozygous for a nonsense mutation in exon 2, c.131G>A, p.Trp44 (Circ Res 2018). Their brother (patient 3) died at age 16 and his DNA was not available. Patient 4 was compound heterozygous; one allele had a missense mutation in exon 2, c157C>T, p.His.53Tyr, and the other had an exon 2 deletion. CONCLUSION: CYB561 deficiency is characterized by selective sympathetic noradrenergic failure with lifelong, disabling OH but with normal sympathetic cholinergic (sweating) and parasympathetic (heart rate regulation) functions. We report a novel case of CYB561 deficiency due to an exon 2 deletion in one allele and a missense mutation in the other. These patients highlight the critical role CYB561 plays in sympathetic function and cardiovascular regulation.

Emotional orienting during interoceptive threat in orthostatic intolerance: Dysautonomic contributions to psychological symptomatology in the postural tachycardia syndrome and vasovagal syncope.

Cognitive and emotional processes are influenced by interoception (homeostatic somatic feedback), particularly when physiological arousal is unexpected and discrepancies between predicted and experienced interoceptive signals may engender anxiety. Due to the vulnerability for comorbid psychological symptoms in forms of orthostatic intolerance (OI), this study investigated psychophysiological contributions to emotional symptomatology in 20 healthy control participants (13 females, mean age 36 ±â€¯8 years), 20 postural tachycardia syndrome (PoTS) patients (18 females, mean age 38 ±â€¯13 years) and 20 vasovagal syncope (VVS) patients (15 females, mean age 39 ±â€¯12 years). We investigated indices of emotional orienting responses (OR) to randomly presented neutral, pleasant and unpleasant images in the supine position and during the induced interoceptive threat of symptom provocation of head-up tilt (HUT). PoTS and VVS patients produced greater indices of emotional responsivity to unpleasant images and, to a lesser degree, pleasant images, during interoceptive threat. Our findings are consistent with biased deployment of response-focused emotion regulation (ER) while patients are symptomatic, providing a mechanistic underpinning of how pathological autonomic overexcitation predisposes to anxiogenic traits in PoTS and VVS patients. This hypothesis may improve our understanding of why orthostasis exacerbates cognitive symptoms despite apparently normal cerebral autoregulation, and offer novel therapeutic targets for behavioural interventions aimed at reducing comorbid cognitive-affective symptoms in PoTS and VVS.

Investigating the relationship between cardiac interoception and autonomic cardiac control using a predictive coding framework.

Predictive coding models, such as the 'free-energy principle' (FEP), have recently been discussed in relation to how interoceptive (afferent visceral feedback) signals update predictions about the state of the body, thereby driving autonomic mediation of homeostasis. This study appealed to 'interoceptive inference', under the FEP, to seek new insights into autonomic (dys)function and brain-body integration by examining the relationship between cardiac interoception and autonomic cardiac control in healthy controls and patients with forms of orthostatic intolerance (OI); to (i) seek empirical support for interoceptive inference and (ii) delineate if this relationship was sensitive to increased interoceptive prediction error in OI patients during head-up tilt (HUT)/symptom provocation. Measures of interoception and heart rate variability (HRV) were recorded whilst supine and during HUT in healthy controls (N = 20), postural tachycardia syndrome (PoTS, N = 20) and vasovagal syncope (VVS, N = 20) patients. Compared to controls, interoceptive accuracy was reduced in both OI groups. Healthy controls' interoceptive sensibility positively correlated with HRV whilst supine. Conversely, both OI groups' interoceptive awareness negatively correlated with HRV during HUT. Our pilot study offers initial support for interoceptive inference and suggests OI cohorts share a central pathophysiology underlying interoceptive deficits expressed across distinct cardiovascular autonomic pathophysiology. From a predictive coding perspective, OI patients' data indicates a failure to attenuate/modulate ascending interoceptive prediction errors, reinforced by the concomitant failure to engage autonomic reflexes during HUT. Our findings offer a potential framework for conceptualising how the human nervous system maintains homeostasis and how both central and autonomic processes are ultimately implicated in dysautonomia.

The genesis and presentation of anxiety in disorders of autonomic overexcitation.

INTRODUCTION: We investigated the genesis and presentation of previously-reported anxiety in disorders of autonomic overexcitation in relation to interoception, body vigilance and trauma to test our hypothesis that patients with the postural tachycardia syndrome (PoTS), vasovagal syncope (VVS) and essential hyperhidrosis (EH) represent atypical anxiety phenotypes in whom affective symptoms are more related to apprehension and vigilance of physiological (interoceptive) feedback than neurotic or trauma-related factors. METHODS: The Anxiety Sensitivity Index, Body Vigilance Scale, Self-consciousness Scale, Childhood Traumatic Events Scale and heartbeat tracking tasks were completed by 23 healthy controls, 21 PoTS, 20 EH and 20 VVS patients. Interoceptive accuracy (IA) was assessed during supine rest (9min), isometric exercise (3min), cold pressor (90s) and head up tilt (HUT) (9min). RESULTS: In comparison to controls, PoTS, VVS and EH patients reported increased symptoms of somatic anxiety but not of social anxiety/self-consciousness or trauma. Autonomic patients' IA was diminished and consistently underestimated even during autonomic arousal compared to controls. Controls and EH IA negatively correlated with somatic anxiety/hypervigilance, whereas PoTS and VVS IA and somatic anxiety/vigilance positively correlated. CONCLUSIONS: Affective symptoms in PoTS, VVS and EH appear to be driven by anxiety and vigilance of physical sensations/symptoms, rather than trauma or neurosis. Increased somatic vigilance/anxiety in PoTS and VVS may be due to interoception being anxiogenic in these cohorts. Diminished interoception may be due to a common central dysregulation, as both sudomotor and cardiovascular forms of autonomic dysfunction had comparable IA deficits. These findings provide a possible therapeutic pathway for psychological symptoms in PoTS, VVS and EH.

Orthostatic intolerance and autonomic dysfunction following bariatric surgery: A retrospective study and review of the literature.

The prevalence and costs of the obesity epidemic and obesity-related conditions, including diabetes mellitus, is consistently increasing worldwide. Bariatric medicine is attempting to address this with weight loss and exercise programmes, and with increasing frequency, various forms of bariatric surgery. There has been considerable success reported after bariatric surgery but not without. We describe 14 patients with orthostatic intolerance (OI) post bariatric surgery. We report on OI (postural dizziness, palpitations and fainting), the results of cardiovascular autonomic testing and the associated and/or causative findings as well as reviewing the literature to consider the possible mechanisms. Comprehensive autonomic testing revealed that 35.7% (Buchwald et al., 2004) of these patients fulfilled the criteria for the Postural Tachycardia Syndrome (PoTS), 57.1% (Cremieux et al., 2008) had low levels of basal BP and 42.9% (Cammisotto & Bendayan, 2007) patients were presyncopal and 14.3% (Billakanty et al., 2008) experienced syncope. We propose that the incidence of OI post-bariatric surgery is higher than considered, that certain cohorts may be more susceptible to complications, and that further research is needed to identify the prevalence and, ideally anticipate occurrence. With the increasing prevalence of obesity and required clinical interventions, further understanding of the pathophysiological processes causing autonomic dysfunction after bariatric interventions will aid management, which may differ in those with an underlying disposition to autonomic involvement, such as diabetics, in whom such procedures are increasingly used.

Abnormal cardiovascular sympathetic and parasympathetic responses to physical and emotional stimuli in depersonalization disorder.

BACKGROUND: Depersonalization disorder (DPD) is characterized by a subjective sense of unreality, disembodiment, emotional numbing and reduced psychogenic (sudomotor) sympathoexcitation. AIMS: Three related experiments utilized escalating physical and emotional challenges in 14 DPD participants and 16 controls aimed to elucidate (i) whether the cardiovascular sympathetic (SNS) and parasympathetic (PNS) nervous systems are implicated in DPD pathophysiology and (ii) if possible, to determine whether the blunted sympathoexcitation in DPD is peripherally or centrally mediated. METHOD: Participants completed the Beck Anxiety Inventory (BAI), Dissociative Experience Scale (DES), and Cambridge Depersonalization Scale (CDS). Study I recorded heart rate (HR) and blood pressure (BP) during 5 min supine baseline, 3 min sustained handgrip (HG), 3 min cold pressor (CP) and 5 min 60° head-up tilt (HUT). In study II, HR, BP, and heart rate variability (HRV) were recorded during 5 min simultaneous 60° HUT and continuous presentation of unpleasant images (5 s per image). Study III examined HR and BP orienting responses (ORs) to simultaneous 60° HUT and pseudorandom presentation of unpleasant, neutral and pleasant images (5 s per image 3 min 25 s). OR data was grouped by image valence post hoc. RESULTS: DPD BAI (p = 0.0004), DES (p = 0.0002), and CDS (p ≤ 0.0001) scores were higher than controls. The DPD group produced diminished diastolic BP (DBP) (p = 0.045) increases to HG. Other indices were comparable between groups. DPD participants produced diminished systolic BP (SBP) (p = 0.003) and DBP (p = 0.002) increases, but greater (p = 0.004) HR increases to CP. In study II, DPD high frequency HRV (HF-HRV)-indicating parasympathetic vagal activity-was reduced (p = 0.029). In study III, DPD DBP was higher throughout the 5 s duration of HUT/pseudorandom unpleasant image presentation (1 s, p = 0.002, 2 s p = 0.033, 3 s p = 0.001, 4 s p = 0.009, 5 s p = 0.029). CONCLUSIONS: Study I's BP pressor data supports previous findings of suppressed sympathoexcitation in DPD. The greater HR increases to CP, decreased HF-HRV in study II, and increased DBP during unpleasant ORs in study III implicates the SNS and PNS in DPD pathophysiology. These studies suggest the cardiovascular autonomic dysregulation in DPD is likely to be centrally-mediated.

Structural brain abnormalities in postural tachycardia syndrome: A VBM-DARTEL study.

Postural tachycardia syndrome (PoTS), a form of dysautonomia, is characterized by orthostatic intolerance, and is frequently accompanied by a range of symptoms including palpitations, lightheadedness, clouding of thought, blurred vision, fatigue, anxiety, and depression. Although the estimated prevalence of PoTS is approximately 5-10 times as common as the better-known condition orthostatic hypotension, the neural substrates of the syndrome are poorly characterized. In the present study, we used magnetic resonance imaging (MRI) with voxel-based morphometry (VBM) applying the diffeomorphic anatomical registration through exponentiated lie algebra (DARTEL) procedure to examine variation in regional brain structure associated with PoTS. We recruited 11 patients with established PoTS and 23 age-matched normal controls. Group comparison of gray matter volume revealed diminished gray matter volume within the left anterior insula, right middle frontal gyrus and right cingulate gyrus in the PoTS group. We also observed lower white matter volume beneath the precentral gyrus and paracentral lobule, right pre- and post-central gyrus, paracentral lobule and superior frontal gyrus in PoTS patients. Subsequent ROI analyses revealed significant negative correlations between left insula volume and trait anxiety and depression scores. Together, these findings of structural differences, particularly within insular and cingulate components of the salience network, suggest a link between dysregulated physiological reactions arising from compromised central autonomic control (and interoceptive representation) and increased vulnerability to psychiatric symptoms in PoTS patients.

Neurovisceral phenotypes in the expression of psychiatric symptoms.

This review explores the proposal that vulnerability to psychological symptoms, particularly anxiety, originates in constitutional differences in the control of bodily state, exemplified by a set of conditions that include Joint Hypermobility, Postural Tachycardia Syndrome and Vasovagal Syncope. Research is revealing how brain-body mechanisms underlie individual differences in psychophysiological reactivity that can be important for predicting, stratifying and treating individuals with anxiety disorders and related conditions. One common constitutional difference is Joint Hypermobility, in which there is an increased range of joint movement as a result of a variant of collagen. Joint hypermobility is over-represented in people with anxiety, mood and neurodevelopmental disorders. It is also linked to stress-sensitive medical conditions such as irritable bowel syndrome, chronic fatigue syndrome and fibromyalgia. Structural differences in "emotional" brain regions are reported in hypermobile individuals, and many people with joint hypermobility manifest autonomic abnormalities, typically Postural Tachycardia Syndrome. Enhanced heart rate reactivity during postural change and as recently recognized factors causing vasodilatation (as noted post-prandially, post-exertion and with heat) is characteristic of Postural Tachycardia Syndrome, and there is a phenomenological overlap with anxiety disorders, which may be partially accounted for by exaggerated neural reactivity within ventromedial prefrontal cortex. People who experience Vasovagal Syncope, a heritable tendency to fainting induced by emotional challenges (and needle/blood phobia), are also more vulnerable to anxiety disorders. Neuroimaging implicates brainstem differences in vulnerability to faints, yet the structural integrity of the caudate nucleus appears important for the control of fainting frequency in relation to parasympathetic tone and anxiety. Together there is clinical and neuroanatomical evidence to show that common constitutional differences affecting autonomic responsivity are linked to psychiatric symptoms, notably anxiety.

Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa.

UNLABELLED: We evaluated whether droxidopa, a prodrug converted to norepinephrine, is beneficial in the treatment of symptomatic neurogenic orthostatic hypotension, which results from failure to generate an appropriate norepinephrine response to postural challenge. Patients with symptomatic neurogenic orthostatic hypotension and Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa titration (100-600 mg, 3× daily). Responders then received an additional 7-day open-label treatment at their individualized dose. Patients were subsequently randomized to continue with droxidopa or withdraw to placebo for 14 days. We then assessed patient-reported scores on the Orthostatic Hypotension Questionnaire and blood pressure measurements. Mean worsening of Orthostatic Hypotension Questionnaire dizziness/lightheadedness score from randomization to end of study (the primary outcome; N=101) was 1.9±3.2 with placebo and 1.3±2.8 units with droxidopa (P=0.509). Four of the other 5 Orthostatic Hypotension Questionnaire symptom scores and all 4 symptom-impact scores favored droxidopa, with statistical significance for the patient's self-reported ability to perform activities requiring standing a short time (P=0.033) and standing a long time (P=0.028). Furthermore, a post hoc analysis of a predefined composite score of all symptoms (Orthostatic Hypotension Questionnaire composite) demonstrated a significant benefit for droxidopa (P=0.013). There was no significant difference between groups for standing systolic blood pressure (P=0.680). Droxidopa was well tolerated. In summary, this randomized withdrawal droxidopa study failed to meet its primary efficacy end point. Additional clinical trials are needed to confirm that droxidopa is beneficial in symptomatic neurogenic orthostatic hypotension, as suggested by the positive secondary outcomes of this trial. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00633880.

Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial.

OBJECTIVE: To determine whether droxidopa, an oral norepinephrine precursor, improves symptomatic neurogenic orthostatic hypotension (nOH). METHODS: Patients with symptomatic nOH due to Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa dose optimization (100-600 mg 3 times daily), followed, in responders, by 7-day washout and then a 7-day double-blind trial of droxidopa vs placebo. Outcome measures included patient self-ratings on the Orthostatic Hypotension Questionnaire (OHQ), a validated, nOH-specific tool that assesses symptom severity and symptom impact on daily activities. RESULTS: From randomization to endpoint (n = 162), improvement in mean OHQ composite score favored droxidopa over placebo by 0.90 units (p = 0.003). Improvement in OHQ symptom subscore favored droxidopa by 0.73 units (p = 0.010), with maximum change in "dizziness/lightheadedness." Improvement in symptom-impact subscore favored droxidopa by 1.06 units (p = 0.003), with maximum change for "standing a long time." Mean standing systolic blood pressure (BP) increased by 11.2 vs 3.9 mm Hg (p < 0.001), and mean supine systolic BP by 7.6 vs 0.8 mm Hg (p < 0.001). At endpoint, supine systolic BP >180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients. Adverse events reported in ≥ 3% of double-blind droxidopa recipients were headache (7.4%) and dizziness (3.7%). No patients discontinued double-blind treatment because of adverse events. CONCLUSIONS: In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with symptomatic nOH who respond to open-label droxidopa, droxidopa improves subjective and objective manifestation of nOH at 7 days.

Sudomotor and cardiovascular dysfunction in patients with early untreated Parkinson's disease.

BACKGROUND: According to Braak staging of Parkinson's disease (PD), detection of autonomic dysfunction would help with early diagnosis of PD. OBJECTIVE: To determine whether the autonomic nervous system is involved in the early stage of PD, we evaluated cardiovascular and sudomotor function in early untreated PD patients. METHODS: Orthostatic blood pressure regulation, heart rate variability, skin vasomotor function, and palmar sympathetic sweat responses were examined in 50 early untreated PD patients and 20 healthy control subjects. RESULTS: The mean decrease in systolic blood pressure during head-up tilt in PD patients was mildly but significantly larger than in controls (p = 0.0001). There were no differences between the 2 groups in heart rate variability, with analysis of low frequency (LF; mediated by baroreflex feedback), and high frequency (HF; mainly reflecting parasympathetic vagal) modulation. However, LF/HF, an index of sympatho-parasympathetic balance, was lower in the PD group than in controls (p = 0.02). Amplitudes of palmar sweat responses to deep inspiration (p = 0.004), mental arithmetic (p = 0.01), and exercise (p = 0.01) in PD patients were lower than in controls, with negative correlations with motor severity. Amplitudes of palmar skin vasomotor reflexes in PD patients did not differ from controls. CONCLUSIONS: Our study indicates impairment of sympathetic cardiovascular and sudomotor function with orthostatic dysregulation of blood pressure control, reduced LF/HF and reduction in palm sweat responses even in early untreated PD patients.

Exercise hemodynamics in Parkinson's disease and autonomic dysfunction.

AIM: To clarify the characteristics of hemodynamic responses to exercise and orthostasis in Parkinson's disease patients, especially those with autonomic failure. METHODS: Clinical audit of supine cycling exercise test data (with active standing tests pre- and post-exercise) of Parkinson's patients with autonomic dysfunction. 23 patients (71 ± 7 yr, 7 females) with a confirmed diagnosis of Parkinson's were identified. RESULTS: Group mean systolic blood pressure (SBP) fell during pre-exercise standing (-39 ± 29 mmHg, P < 0.001, 17 patients had orthostatic hypotension (OH)), while heart rate (HR) increased (+13 ± 7 beats min(-1), P < 0.001). SBP (P < 0.001) increased during exercise with a wide variation in responses. SBP increased in 13 patients (INC; +30 ± 14 mmHg) and either did not change or decreased in 10 patients (DEC -12 ± 11 mmHg, P < 0.001 vs INC). The increase in HR was not different between sub-groups (30 ± 12 vs 25 ± 10 beats min(-1), INC vs. DEC, P = 0.29). The size of the pre-exercise stand SBP reduction was greater in DEC vs INC (-64 ± 23 (10 out of 10 had OH) vs -19 ± 16 mmHg (7 out of 13 had OH), respectively, P < 0.001). The HR elevation was not different between sub-groups (13 ± 8 vs 13 ± 4 beats min(-1), DEC vs INC, P = 0.94). Post-exercise SBP/DBP were lower for both sub-groups compared to pre-exercise and the standing SBP reduction post-exercise was not greater relative to pre-exercise in either sub-group. CONCLUSION: Exercise-induced hypotension can occur in Parkinson's disease patients with autonomic failure with the magnitude of the exercise response being related to the severity of autonomic dysfunction. Exercise does not appear to worsen OH in this sample of Parkinson's patients.