The Investigation of the Cardiovascular and Sudomotor Autonomic Nervous System—A Review

The autonomic nervous system as operating system of the human organism permeats all organ systems with its pathways permeating that it is involved with virtually all diseases. Anatomically a central part, an afferent part and sympathetic and parasympathetic efferent system can be distinguished. Among the different functional subsystems of the autonomic nervous system, the cardiovascular autonomic nervous system is most frequently examined with easily recordable cardiovascular biosignals as heart rate and blood pressure. Although less widely established, sudomotor tests pose a useful supplement to cardiovascular autonomic assessment as impaired neurogenic sweating belongs to the earliest clinical signs of various autonomic neuropathies as well as neurodegenerative disorders and significantly reduces quality of life. Clinically at first, the autonomic nervous system is assessed with a detailed history of clinical autonomic function and a general clinical examination. As a lof of confounding factors can influence autonomic testing, subjects should be adequately prepared in a standardized way. Autonomic testing is usually performed in that way that the response of the autonomic nervous system to a well-defined challenge is recorded. As no single cardiovascular autonomic test is sufficiently reliable, it is recommended to use a combination of different approaches, an autonomic test battery including test to measure parasympathetic and sympathetic cardiovascular function (deep breathing test, Valsalva maneuver, tilt, or pressor test). More specialized tests include carotid sinus massage, assessment of baroreceptor reflex function, pharmacological tests or cardiac, and regional hemodynamic measurements. Techniques to measure functional integrity of sudomotor nerves include the quantitative sudomotor axon reflex sweat test, analysis of the sympathetic skin response as well as the thermoregulatory sweat test. In addition to these rather established techniques more recent developments have been introduced to reduce technical demands and interindividual variability such as the quantitative direct and indirect axon reflex testing or sudoscan. However, diagnostic accuracy of these tests remains to be determined. We reviewed the current literature on currently available autonomic cardiovascular and sudomotor tests with a focus on their physiological and technical mechanisms as well as their diagnostic value in the scientific and clinical setting

Exploring the risk-factor association between depression and incident stroke: a systematic review and meta-analysis

There is growing evidence that depression increases the risk of incident stroke. However, few studies have considered possible residual confounding effects by preexistent cerebrovascular and cardiac diseases. Therefore, we synthesized data from cohort studies to explore whether depressed individuals free of cerebrovascular and cardiac diseases are at higher risk of incident stroke. We searched the electronic databases PubMed and Medline for eligible cohort studies that examined the prospective association between depression and first-ever stroke. A random-effects model was used for quantitative data synthesis. Sensitivity analyses comprised cohort studies that considered a lag period with exclusion of incident strokes in the first years of follow-up to minimize residual confounding by preexistent silent strokes and excluded cardiac disease at baseline. Overall, we identified 28 cohort studies with 681,139 participants and 13,436 (1.97%) incident stroke cases. The pooled risk estimate revealed an increased risk of incident stroke for depression (relative risk 1.40, 95% confidence interval [CI] 1.27–1.53; P<0.0001). When we excluded incident strokes that occurred in the first years of follow-up, the prospective association between depression and incident stroke remained significant (relative risk 1.64, 95% CI 1.27–2.11; P<0.0001). This positive association also remained after we considered only studies with individuals with cardiac disease at baseline excluded (relative risk 1.43, 95% CI 1.19–1.72; P<0.0001). The prospective association of depression and increased risk of first-ever stroke demonstrated in this meta-analysis appears to be driven neither by preexistence of clinically apparent cerebrovascular and cardiovascular diseases nor by silent stroke

Heart rate variability biofeedback in patients with alcohol dependence: a randomized controlled study

Background and objective In patients with alcohol dependence, ethyl-toxic damage of vasomotor and cardiac autonomic nerve fibers leads to autonomic imbalance with neurovascular and cardiac dysfunction, the latter resulting in reduced heart rate variability (HRV). Autonomic imbalance is linked to increased craving and cardiovascular mortality. In this study, we sought to assess the effects of HRV biofeedback training on HRV, vasomotor function, craving, and anxiety. Methods: We conducted a randomized controlled study in 48 patients (14 females, ages 25–59 years) undergoing inpatient rehabilitation treatment. In the treatment group, patients (n=24) attended six sessions of HRV biofeedback over 2 weeks in addition to standard rehabilitative care, whereas, in the control group, subjects received standard care only. Psychometric testing for craving (Obsessive Compulsive Drinking Scale), anxiety (Symptom Checklist-90-Revised), HRV assessment using coefficient of variation of R-R intervals (CVNN) analysis, and vasomotor function assessment using laser Doppler flowmetry were performed at baseline, immediately after completion of treatment or control period, and 3 and 6 weeks afterward (follow-ups 1 and 2). Results: Psychometric testing showed decreased craving in the biofeedback group immediately postintervention (OCDS scores: 8.6±7.9 post-biofeedback versus 13.7±11.0 baseline [mean ± standard deviation], P<0.05), whereas craving was unchanged at this time point in the control group. Anxiety was reduced at follow-ups 1 and 2 post-biofeedback, but was unchanged in the control group (P<0.05). Following biofeedback, CVNN tended to be increased (10.3%±2.8% post-biofeedback, 10.1%±3.5% follow-up 1, 10.1%±2.9% follow-up 2 versus 9.7%±3.6% baseline; P=not significant). There was no such trend in the control group. Vasomotor function assessed using the mean duration to 50% vasoconstriction of cutaneous vessels after deep inspiration was improved following biofeedback immediately postintervention and was unchanged in the control group (P<0.05). Conclusion: Our data indicate that HRV biofeedback might be useful to decrease anxiety, increase HRV, and improve vasomotor function in patients with alcohol dependence when complementing standard rehabilitative inpatient care

Effect of short-term heart rate variability biofeedback on long-term abstinence in alcohol dependent patients – a one-year follow-up

Background: A randomized controlled study (RCT) recently showed that short-term heart rate variability (HRV) biofeedback in addition to standard rehabilitation care for alcohol dependence can reduce craving, anxiety and improve cardiovascular autonomic function. In this one-year follow-up study we aimed to explore whether completion of 2-week HRV-Biofeedback training is associated with long-term abstinence. Furthermore, we sought to identify potential predictors of post-treatment abstinence. Methods: We conducted a survey on abstinence in patients with alcohol dependence 1 year after completion of an RCT comparing HRV-biofeedback in addition to inpatient rehabilitation treatment alone (controls). Abstinence rates were compared and analysed for association with demographic data as well as psychometric and autonomic cardiac assessment before and after completion of the biofeedback training using bivariate and multivariate regression analyses. Results: Out of 48 patients who participated in the RCT, 27 patients (9 females, ages 42.9 ± 8.6, mean ± SD) completed our one-year follow-up. When including in the analysis only patients who completed follow-up, the rate of abstinence tended to be higher in patients who underwent HRV-biofeedback 1 year earlier compared to those who received rehabilitative treatment alone (66.7% vs 50%, p = ns). This non-significant trend was also observed in the intention-to-treat analysis where patients who did not participate in the follow-up were assumed to have relapsed (46,7% biofeedback vs. 33.3% controls, p = ns). Neither cardiac autonomic function nor psychometric variables were associated with abstinence 1 year after HRV-biofeedback. Conclusion: Our follow-up study provide a first indication of possible increase in long-term abstinence after HRV-biofeedback for alcohol dependence in addition to rehabilitation. Trial registration The original randomized controlled trial was registered in the German Clinical Trials Register (DRKS00004618). This one-year follow-up survey has not been registered

Protocol for a Multicenter Study

Background: In Parkinson’s disease (PD), alpha-synuclein accumulation in cutaneous autonomic pilomotor and sudomotor nerve fibers has been linked to autonomic nervous system disturbances even in the early stages of the disease. This study aims to assess the association between alpha-synuclein-mediated structural autonomic nerve fiber damage and function in PD, elucidate the role of neuropathy progression during the early disease stages, and test reproducibility and external validity of pilomotor function assessment using quantitative pilomotor axon-reflex test and sudomotor function via quantitative direct and indirect test of sudomotor function. Methods/design: A prospective controlled study will be conducted at four study sites in Europe and the USA. Fifty-two male and female patients with idiopathic PD (Hoehn and Yahr 1–2) and 52 age- and sex-matched healthy controls will be recruited. Axon-reflex-mediated pilomotor erection will be induced by iontophoresis of phenylephrine on the dorsal forearm. Silicone impressions of the response will be obtained, scanned, and quantified for pilomotor muscle impressions by number, impression size, and area of axon-reflex spread. Axon-reflex-mediated sweating following acetylcholine iontophoresis will be quantified for number and size of droplets and axon-reflex spread. Sympathetic skin responses, autonomic and motor symptoms will be evaluated. Tests will be performed at baseline, after 2 weeks, 1, 2, and 3 years. Skin biopsies will be obtained at baseline and after 3 years and will be analyzed for nerve fiber density and alpha-synuclein accumulation. Discussion: We anticipate that progression of autonomic nerve dysfunction assessed via pilomotor and sudomotor axon-reflex tests is related to progression of autonomic symptom severity and alpha- synuclein deposition. Potential applications of the techniques include interventional studies evaluating disease-modifying approaches and clinical assessment of autonomic dysfunction in patients with PD. Clinical trail registration: TRN NCT03043768

Intravenous thrombolysis and endovascular therapy for acute ischemic stroke in COVID-19: a systematic review and meta-analysis

BackgroundThe impact of COVID-19 on clinical outcomes in acute ischemic stroke patients receiving reperfusion therapy remains unclear. We therefore aimed to synthesize the available evidence to investigate the safety and short-term efficacy of reperfusion therapy in this patient population.MethodsWe searched the electronic databases MEDLINE, Embase and Cochrane Library Reviews for randomized controlled trials and observational studies that investigated the use of intravenous thrombolysis, endovascular therapy, or a combination of both in acute ischemic stroke patients with laboratory-confirmed COVID-19, compared to controls. Our primary safety outcomes included any intracerebral hemorrhage (ICH), symptomatic ICH and all-cause in-hospital mortality. Short-term favorable functional outcomes were assessed at discharge and at 3 months. We calculated pooled risk ratios (RR) and 95% confidence intervals (CI) using DerSimonian and Laird random-effects model. Heterogeneity was evaluated using Cochran’s Q test and I2 statistics.ResultsWe included 11 studies with a total of 477 COVID-19 positive and 8,092 COVID-19 negative ischemic stroke patients who underwent reperfusion therapy. COVID-19 positive patients exhibited a significantly higher risk of experiencing any ICH (RR 1.54, 95% CI 1.16–2.05, p &lt; 0.001), while the nominally increased risk of symptomatic ICH in these patients did not reach statistical significance (RR 2.04, 95% CI 0.97–4.31; p = 0.06). COVID-19 positive stroke patients also had a significantly higher in-hospital mortality compared to COVID-19 negative stroke patients (RR 2.78, 95% CI 2.15–3.59, p &lt; 0.001). Moreover, COVID-19 positive stroke patients were less likely to achieve a favorable functional outcome at discharge (RR 0.66, 95% CI 0.51–0.86, p &lt; 0.001) compared to COVID-19 negative patients, but this difference was not observed at 3-month follow-up (RR 0.64, 95% CI 0.14–2.91, p = 0.56).ConclusionCOVID-19 appears to have an adverse impact on acute ischemic stroke patients who undergo reperfusion therapy, leading to an elevated risk of any ICH, higher mortality and lower likelihood of favorable functional outcome.Systematic review registrationPROSPERO, identifier CRD42022309785

Autonomic Dysfunction in α-Synucleinopathies

The α-synucleinopathies are a group of neurodegenerative diseases characterized by abnormal accumulation of insoluble α-synuclein in neurons and glial cells, comprising Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Although varying in prevalence, symptom patterns, and severity among disorders, all α-synucleinopathies have in common autonomic nervous system dysfunctions, which reduce quality of life. Frequent symptoms among α-synucleinopathies include constipation, urinary and sexual dysfunction, and cardiovascular autonomic symptoms such as orthostatic hypotension, supine hypertension, and reduced heart rate variability. Symptoms due to autonomic dysfunction can appear before motor symptom onset, particularly in MSA and PD, hence, detection and quantitative analysis of these symptoms can enable early diagnosis and initiation of treatment, as well as identification of at-risk populations. While patients with PD, DLB, and MSA show both central and peripheral nervous system involvement of α-synuclein pathology, pure autonomic failure (PAF) is a condition characterized by generalized dysregulation of the autonomic nervous system with neuronal cytoplasmic α-synuclein inclusions in the peripheral autonomic small nerve fibers. Patients with PAF often present with orthostatic hypotension, reduced heart rate variability, anhydrosis, erectile dysfunction, and constipation, without motor or cognitive impairment. These patients also have an increased risk of developing an α-synucleinopathy with central involvement, such as PD, DLB, or MSA in later life, possibly indicating a pathophysiological disease continuum. Pathophysiological aspects, as well as developments in diagnosing and treating dysautonomic symptoms in patients with α-synucleinopathies are discussed in this review

Report of first recurrent glioma patients examined with PET-MRI prior to re-irradiation

Background and purpose The advantage of combined PET-MRI over sequential PET and MRI is the high spatial conformity and the absence of time delay between the examinations. The benefit of this technique for planning of re-irradiation (re-RT) treatment is unkown yet. Imaging data from a phase 1 trial of re-RT for recurrent glioma was analysed to assess whether planning target volumes and treatment margins in glioma re-RT can be adjusted by PET-MRI with rater independent PET based biological tumour volumes (BTVs). Patients and methods Combined PET-MRI with the tracer O-(2-F-18-fluoroethyl)-1-tyrosine (F-18-FET) prior to re-RT was performed in recurrent glioma patients in a phase I trial. GTVs including all regions suspicious of tumour on contrast enhanced MRI were delineated by three experienced radiation oncologists and included into MRI based consensus GTVs (mRGTVs). BTVs were semiautomatically delineated with a fixed threshold of 1.6 x background activity. Corresponding BTVs and mRGTVs were fused into union volume RET-NARGIVs. The Sorensen Dice coefficient and the conformity index were used to assess the geometric overlap of the BTVs with the mRGTVs. A recurrence pattern analysis was performed based on the original planning target volumes (PTVs = GTV + 10 mm margin or 5 mm in one case) and the RET-NARGTVs with margins of 10, 8, 5 and 3 mm. Results Seven recurrent glioma patients, who received PET-MRI prior to re-RT, were included into the present planning study. At the time of re-RT, patients were in median 54 years old and had a median Karnofsky Performance Status (KPS) score of 80. Median post-recurrence survival after the beginning of re-RT was 13 months. Concomitant bevacizumab therapy was applied in six patients and one patient received chemoradiation with temozolomide. Median GTV volumes of the three radiation oncologists were 35.0, 37.5 and 40.5 cubic centimeters (cc) and median (MR)GTV volume 41.8 cc. Median BTV volume was 36.6 cc and median (PET-MR)GTV volume 59.3 cc. The median Sorensen-Dice coefficient for the comparison between (MR)GTV and BTV was 0.61 and the median conformity index 0.44. Recurrence pattern analysis revealed two central, two in-field and one distant recurrence within both, the original PTV, as well as the (PER-MR)GTV with a reduced margin of 3 mm. Conclusion PET-MRI provides radiation treatment planning imaging with high spatial and timely conformity for high-grade glioma patients treated with re-RT with potential advancements for target volume delineation. Prospective randomised trials are warranted to further investigate the treatment benefits of PET-MRI based re-RT planning

Autonomic dysregulation in multiple sclerosis

Multiple sclerosis (MS) is a chronic, progressive central neurological disease characterized by inflammation and demyelination. In patients with MS, dysregulation of the autonomic nervous system may present with various clinical symptoms including sweating abnormalities, urinary dysfunction, orthostatic dysregulation, gastrointestinal symptoms, and sexual dysfunction. These autonomic disturbances reduce the quality of life of affected patients and constitute a clinical challenge to the physician due to variability of clinical presentation and inconsistent data on diagnosis and treatment. Early diagnosis and initiation of individualized interdisciplinary and multimodal strategies is beneficial in the management of autonomic dysfunction in MS. This review summarizes the current literatureon the most prevalent aspects of autonomic dysfunction in MS and provides reference to underlying pathophysiological mechanisms as well as means of diagnosis and treatment. © 2015 by the authors; licensee MDPI, Basel, Switzerland