Postural orthostatic tachycardia syndrome is defined by a sustained heart rate increment upon upright posture without orthostatic hypotension. Despite established criteria, the condition remains frequently underdiagnosed. This narrative review evaluates diagnostic strategies, test accuracy, diagnostic delay, and misdiagnosis patterns. Following prospective registration in PROSPERO (CRD 1248964), 7 databases were searched without date restriction. Eligible studies enrolled individuals aged 12 years or older undergoing evaluation for postural orthostatic tachycardia syndrome and reported diagnostic accuracy, criteria performance, or delay and misdiagnosis data. Dual-reviewer screening and standardized data extraction were performed. Risk of bias was assessed using QUADAS-2 and ROBINS-I. Narrative synthesis followed PRISMA 2020 guidelines. In total, 26 studies met inclusion criteria, enrolling more than 30,000 participants across multiple countries. Diagnostic criteria varied in heart rate thresholds, tilt angle, and test duration. Abbreviated 2-min tilt testing missed 55
The aim of this study was to evaluate sympathetic responses to experimentally induced periodic breathing/Cheyne-Stokes respiration (PB/CSR)-like patterns in optimally treated patients with chronic heart failure (CHF) compared with matched healthy controls. Muscle sympathetic nerve activity (MSNA) was recorded in 22 patients with systolic CHF (63 ± 9 years; left ventricular ejection fraction 31 ± 8
Two mechanisms underlie the development of fecal incontinence (FI), which poses a significant autonomic burden among individuals with neurological disease: neurogenic FI, in which neural lesions innervate the bowel/sphincter, and functional FI, without such lesions but occurring secondarily to cognitive decline and/or immobility. Both neurogenic FI and functional FI hinder a person's toiletings. Neurogenic FI is further divided into two mechanisms: overflow FI due to neurogenic constipation, which is common in older individuals, and sphincter FI caused by neurogenic sphincter weakness due to a lesion in the sacral Onuf's nucleus or its periphery, which is rare among older individuals. This paper reviews (i) autonomic (bowel) and somatic (sphincter) innervation and how to assess them, (ii) geriatric brain diseases and cognitive/gait functions relevant to toileting and how to assess them, and (iii) the management of patients with FI. The current treatments for FI not only maximize patients' quality of life but they also help patients avoid gastrointestinal emergencies, as FI is commonly associated with severe constipation. Collaborations between neurologists and gastroenterologists are recommended to achieve the optimal outcomes for individuals with FI.
To review the cardiovascular effects of pharmacologic dopamine receptor modulation in humans, organized by receptor subtype. Narrative review of human pharmacological, genetic, and clinical evidence linking dopamine receptor agonism and antagonism to blood pressure and heart rate changes in healthy volunteers and in patients with Parkinson disease, autonomic failure, psychiatric disorders, and selected cardiovascular conditions. Dopaminergic receptor agonism generally lowers blood pressure, with the magnitude of hypotension tracking with intrinsic activity: full orthosteric agonists (bromocriptine, ropirinole, apomorphine) carry the highest risk of orthostatic hypotension, and partial agonists (tavapadon) produce attenuated but clinically relevant hypotension. Dopamine D3-preferring agents (PF-592379, mesdopetam, cariprazine) have neutral cardiovascular effects in short-term trials. Levodopa-induced orthostatic hypotension arises from at least five converging mechanisms whose clinical impact is amplified by underlying neurogenic orthostatic hypotension. A notable exception is mevidalen, a centrally acting dopamine D1 positive allosteric modulator that paradoxically raises blood pressure. Despite murine knockout models consistently predicting that dopamine receptor deletion produces hypertension, pharmacological antagonism in humans does not reliably raise blood pressure: dopamine D1, D2, and D3 antagonists show largely neutral cardiovascular profiles, while antipsychotic-associated orthostatic hypotension is driven primarily by α1-adrenergic blockade. The cardiovascular response to dopaminergic agents depends on receptor selectivity, intrinsic activity, and baroreflex integrity. The discrepancy between murine-knockout-predicted hypertension and human pharmacological neutrality with antagonists, and the hypertensive effects of dopamine D1 positive allosteric modulators, represent key unresolved questions.
Vagus nerve stimulation (VNS) is a neuromodulatory intervention with antiinflammatory and autonomic regulatory properties. Although its clinical applications have primarily been explored in neurological disorders, its potential role in pulmonary and respiratory outcomes across preclinical and clinical settings remains incompletely characterized and dispersed across different study domains. This scoping review aimed to map the available evidence on the effects of VNS on the pulmonary and respiratory systems, with particular emphasis on inflammatory and autonomic mechanisms. This scoping review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Three reviewers systematically searched PubMed, Web of Science, and the Cochrane Library for studies published between January 2020 and February 2026. Original preclinical and clinical studies investigating invasive or noninvasive VNS and reporting pulmonary, respiratory physiology, autonomic, or inflammatory outcomes were included. A total of 159 records were identified, of which 12 studies met the inclusion criteria. The evidence base was predominantly preclinical. In animal studies, invasive cervical VNS was frequently associated with reductions in pulmonary inflammation, histopathological lung injury, and proinflammatory cytokine expression. Clinical studies were limited and heterogeneous, but generally indicated variable modulation of autonomic function, including changes in parasympathetic activity, as well as heterogeneous effects on systemic inflammatory markers and limited respiratory outcomes. Current evidence suggests that VNS may modulate pulmonary inflammatory responses in preclinical models. However, clinical evidence remains limited and heterogeneous, particularly regarding autonomic and respiratory outcomes. Well-designed clinical trials using standardized stimulation protocols and predefined respiratory end points are needed to clarify its therapeutic potential in respiratory disorders.
Multiple system atrophy is a progressive neurodegenerative disorder characterized by autonomic failure, parkinsonism, and cerebellar ataxia. Phosphorylated alpha-synuclein in skin nerves has emerged as a promising biomarker, but longitudinal studies remain limited. This study evaluated changes in cutaneous alpha-synuclein deposition over time, its association with autonomic dysfunction, and its concordance with seed amplification assay findings. Seventeen participants with probable multiple system atrophy were followed up for 12 months with clinical assessments, skin biopsies from posterior cervical and distal thigh regions, standardized orthostatic vital signs, and cerebrospinal fluid biomarker collection. Phosphorylated alpha-synuclein deposition was quantified using immunofluorescence microscopy and correlated with autonomic measures and seed amplification assay results. Cutaneous alpha-synuclein deposition increased from baseline to the12-month follow-up visit. Total deposition was associated with orthostatic systolic blood pressure drop (p = 0.80, p = 0.0001) and with higher scores on the Orthostatic Hypotension Questionnaire and Composite Autonomic Symptom Score. Posterior cervical deposition showed stronger autonomic associations than distal thigh deposition. No associations were found with global disease severity or neurofilament light chain levels. Two participants with negative seed amplification assay results showed phosphorylated alpha-synuclein on skin biopsy. In this cohort, cutaneous phosphorylated alpha-synuclein increased over time and correlated with objective orthostatic hypotension and autonomic symptom burden in early synucleinopathy. Skin biopsy may serve as a minimally invasive tool to support diagnosis, monitor progression, and stratify clinical trial participants.
Previous research regarding the association between blood pressure (BP) fall and symptoms yielded inconsistent results in classical orthostatic hypotension (cOH), with some studies proposing specific cut-off values and others reporting only weak or absent correlations. This study examined clinical cOH symptoms in relation to changes in BP and the haemodynamic parameters determining BP. We retrospectively analysed 77 tilt test records showing cOH and selected 40 with and 37 without complaint recognition during the test. We compared absolute values of haemodynamic parameters as well as the differences and ratios compared to supine baseline at three different times during tilt. We also explored relationships between relative haemodynamic changes and symptoms with the log-ratio method. There was a larger blood pressure fall in the group with complaint recognition compared (49.2 vs 37.3, p = 0.043). The log-ratio analysis showed less total peripheral resistance increase and a larger blood pressure decrease in the symptomatic group. Recognised complaints were related to a larger BP fall, while in previous studies complaints were either not related to BP or to minimum BP. These contrasts suggest that the pathophysiology of orthostatic complaints is complex. The chain of events from low BP to awareness of complaints contains multiple links, of which cerebral perfusion is probably a critical one. We suggest that the pathway contains so much variability that we should not expect the relation between low blood pressure and complaints in cOH to be simple.
To elucidate the pathophysiology of the carotid sinus reflex in a large cohort of patients with suspected reflex syncope. We reviewed an electronic database of patients with suspected reflex syncope who underwent carotid sinus massage. The diagnostic protocol included both right and left massage, in supine and upright positions, followed by tilt testing. The cohort included 2249 patients (52
Heart rate variability (HRV) has been linked to cerebral small vessel disease (CSVD) development. This study aimed to investigate the relationship between white matter hyperintensity (WMH) and HRV in older patients with CSVD. Patients with CSVD aged ≥ 60 years, diagnosed via magnetic resonance imaging and treated at Tianjin Huanhu Hospital in October 2022–April 2023, were included. WMH burden was defined as periventricular (PV-WMH) or deep WMH (D-WMH), with Fazekas scores of 3 or 2–3, respectively. Modified WMH burden was categorized based on total Fazekas scores (PV-WMH + D-WMH): grade 0 for 0–2, grade 1 for 3–4, and grade 2 for 5–6. Patient demographics were documented, and HRV was analyzed through 10-min short-range electrocardiography recordings. Time-domain indices included standard deviation of N–N intervals, root-mean-squared differences of successive N–N intervals, and the proportion of N–N intervals exceeding 50 ms. Frequency-domain indices included low-frequency power (LF, 0.04–0.15 Hz), high-frequency power (HF, 0.15–0.4 Hz), and LF/HF. Correlations were examined using univariable and multivariable analyses. Among 108 patients with CSVD (age 60–87 years; median 66.0 years [interquartile range 63.0–71.0]), WMH burden was associated with sex, age, stroke, LF, and LF/HF (p < 0.05), with LF/HF independently linked in multivariable analysis. Modified WMH burden showed similar associations and remained independently correlated with LF/HF (p < 0.05). The presence and severity of WMH in CSVD were related to decreased LF/HF. This is possibly due to decreased cardiac sympathetic activity, indicates that decreased LF/HF may be a potential risk factor for WMH, and can be detected via short HRV recordings.
Carotid sinus massage (CSM) is essential in evaluating recurrent unexplained reflex syncope, as it uniquely identifies cardioinhibitory forms that other tests may miss. CSM is largely underused in clinical practice outside dedicated syncope facilities and, when performed, its execution varies, as does the interpretation of results. Underuse affects the diagnostic yield of CSM in the syncope evaluation, thereby denying patients mechanism-based personalized treatment. There are several barriers to the proper use of CSM in the work-up of patients with unexplained syncope.To address these important limitations, an international panel of experts in the field of syncope provide herein a consensus document with the aim of offering practical guidance for the indications, contraindications, and methodology for performing carotid sinus massage in general and dedicated syncope facilities and in the emergency department.
Carotid sinus massage (CSM) is essential in evaluating recurrent unexplained reflex syncope, as it uniquely identifies cardioinhibitory forms that other tests may miss. CSM is largely underused in clinical practice outside dedicated syncope facilities and, when performed, its execution varies, as does the interpretation of results. Underuse affects the diagnostic yield of CSM in the syncope evaluation, thereby denying patients mechanism-based personalized treatment. There are several barriers to the proper use of CSM in the work-up of patients with unexplained syncope. To address these important limitations, an international panel of experts in the field of syncope provide herein a consensus document with the aim of offering practical guidance for the indications, contraindications, and methodology for performing carotid sinus massage in general and dedicated syncope facilities and in the emergency department.
