Randomized controlled three-arm study of NADA acupuncture for alcohol addiction.

INTRODUCTION: Alcohol addiction compromises cardiovascular health, possibly due to impaired control of the heart and vasculature by the autonomic nervous system. We aimed to assess the effects of National Acupuncture Detoxification Association (NADA) acupuncture on cardiovascular autonomic functions, psychiatric comorbidities and abstinence in patients addicted to alcohol. MATERIAL AND METHODS: A randomized sham controlled three-arm study was undertaken in 72 patients (nine females, aged 43.7 ± 9.2 years, mean ± SD) undergoing in-patient rehabilitation for alcohol addiction. Patients were randomly allocated (1:1:1) to receive twenty 30-minute NADA or sham acupuncture sessions within six weeks or no intervention. They were evaluated for craving, depression, anxiety and autonomic control of the heart (heart rate variability, HRV), vasculature (laser Doppler flowmetry) and sweat glands (sympathetic skin response). Testing was performed at baseline, immediately post intervention (sham intervention or control period, respectively) and another four weeks later. Abstinence was assessed one year after study completion. RESULTS: Patients in the NADA arm displayed increased HRV immediately post-intervention compared to baseline (SDNN: 72.8 ms ± 34.2 ms vs. 57.9 ms ± 31.2 ms, p = 0.001). This increase was sustained four weeks later (66.2 ms ± 32.4 ms, p = 0.015). HRV remained unaltered following sham or no acupuncture (p = n.s.). Autonomic function of vasculature and sweat glands, psychiatric comorbidities and one-year abstinence did not differ between study arms. CONCLUSIONS: NADA acupuncture may improve autonomic cardiac function. However, this improvement appears not to translate into alleviation of psychiatric comorbidities or sustained abstinence.

Autonomic Dysfunction in Preeclampsia: A Systematic Review.

Background: Preeclampsia (PE) is a major obstetric complication that leads to severe maternal and fetal morbidity. Early detection of preeclampsia can reduce the severity of complications and improve clinical outcomes. It is believed that the autonomic nervous system (ANS) is involved in the pathogenesis of PE. We aimed to review the current literature on the prevalence and nature of ANS dysfunction in women with PE and the possible prognostic value of ANS testing in the early detection of PE. Methods: Literature search was performed using Medline (1966-2018), EMBase (1947-2018), Google Scholar (1970-2018), BIOSIS (1926-2018), Web of science (1900-2018); CINAHL (1937-2018); Cochrane Library, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL) and Cochrane Methodology Register (1999-2018). Additionally, the reference lists of articles included were screened. Results: A total of 26 studies were included in the present review presenting data of 1,854 pregnant women. Among these women, 453 were diagnosed with PE, 93.6% (424/453) of which displayed autonomic dysfunction. ANS function was assessed by cardiovascular reflex tests (n = 9), heart rate variability (n = 11), cardiac baroreflex gain (n = 5), muscle sympathetic nerve activity (MSNA) (n = 3), and biomarkers of sympathetic activity (n = 4). Overall, 21 studies (80.8%) reported at least one of the following abnormalities in ANS function in women diagnosed with PE compared to healthy pregnant control women: reduced parasympathetic activity (n = 16/21, 76%), increased sympathetic activity (n = 12/20, 60%), or reduced baroreflex gain (n = 4/5, 80%). Some of these studies indicated that pressor and orthostatic stress test may be useful in early pregnancy to help estimate the risk of developing PE. However, autonomic function tests seem not to be able to differentiate between mild and severe PE. Conclusions: Current evidence suggests that autonomic dysfunction is highly prevalent in pre-eclamptic women. Among autonomic functions, cardiovascular reflexes appear to be predominantly affected, seen as reduced cardiac parasympathetic activity and elevated cardiac sympathetic activity. The diagnostic value of autonomic testing in the prediction and monitoring of autonomic failure in pre-eclamptic women remains to be determined.

Cardiac dysautonomia in depression - heart rate variability biofeedback as a potential add-on therapy.

Depressive disorders are among the most important health problems and are predicted to constitute the leading cause of disease burden by the year 2030. Aside significant impact on quality of life, psychosocial well-being and socioeconomic status of affected patients, depression is associated with impaired cardiovascular health and increased mortality. The link between affective and cardiovascular disease has largely been attributed to dysregulation of the autonomic nervous system resulting in a chronic shift toward increased sympathetic and decreased parasympathetic activity and, consecutively, cardiac dysautonomia. Among proposed surrogate parameters to capture and quantitatively analyze this shift, heart rate variability (HRV) and baroreflex sensitivity have emerged as reliable tools. Attenuation of these parameters is frequently seen in patients suffering from depression and is closely linked to cardiovascular morbidity and mortality. Therefore, diagnostic and therapeutic strategies were designed to assess and counteract cardiac dysautonomia. While psychopharmacological treatment can effectively improve affective symptoms of depression, its effect on cardiac dysautonomia is limited. HRV biofeedback is a non-invasive technique which is based on a metronomic breathing technique to increase parasympathetic tone. While some small studies observed beneficial effects of HRV biofeedback on dysautonomia in patients with depressive disorders, larger confirmatory trials are lacking. We reviewed the current literature on cardiac dysautonomia in patients suffering from depression with a focus on the underlying pathophysiology as well as diagnostic workup and treatment.

Assessment of sudomotor function.

PURPOSE: To review the currently available literature on clinical autonomic tests of sudomotor function. METHODS: We searched PubMED/MEDLINE for articles on technical principles and clinical applications of sudomotor tests with a focus on their drawbacks and perspectives in order to provide a narrative review. RESULTS: The quantitative sudomotor axon reflex sweat test (QSART) is the most widely used test of sudomotor function. The technique captures pathology with low intra- and inter-subject variability but is limited by technical demands. The thermoregulatory sweat test comprises topographic sweat pattern analysis of the ventral skin surface and allows differentiating preganglionic from postganglionic sudomotor damage when combined with a small fiber test such as QSART. The sympathetic skin response also belongs to the more established techniques and is used in lie detection systems due to its high sensitivity for sudomotor responses to emotional stimuli. However, its clinical utility is limited by high variability of measurements, both within and between subjects. Newer and, therefore, less widely established techniques include silicone impressions, quantitative direct and indirect axon reflex testing, sensitive sweat test, and measurement of electrochemical skin conductance. The spoon test does not allow a quantitative assessment of the sweat response but can be used as bedside-screening tool of sudomotor dysfunction. CONCLUSION: While new autonomic sudomotor function testings have been developed and studied over the past decades, the most were well-studied and established techniques QSART and TST remain the gold standard of sudomotor assessment. Combining these techniques allows for sophisticated analysis of neurally mediated sudomotor impairment. However, newer techniques display potential to complement gold standard techniques to further improve their precision and diagnostic value.

Safety and efficacy of recanalization therapy in pediatric stroke: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Safety and efficacy of intravenous (IV) thrombolysis and endovascular therapy in children with acute ischemic stroke (AIS) are unknown to date. We aimed to review and synthesize currently available evidence on these acute recanalization therapies in pediatric stroke patients. METHODS: We performed a systematic review and meta-analysis of all available data on safety and efficacy of acute treatment including thrombolysis and endovascular therapy in pediatric AIS patients aged <18 years. We searched the electronic databases Medline and Cochrane Library for eligible studies published from the earliest date available until August 31, 2016. Safety outcomes included intracerebral hemorrhage (ICH) post-treatment and in-hospital mortality. Efficacy outcomes included functional outcome 3-6 months after index stroke. RESULTS: We identified 222 records, of which 3 studies with a total of 16,987 pediatric stroke patients met our eligibility criteria of whom 181 received IV thrombolysis. No data exists from randomized trials and no data is available on endovascular thrombectomy. Risk of any ICH was increased in children receiving thrombolysis (risk ratio = 3.48, 95%CI: 1.66-7.29; p = 0.001) compared with controls, with no evidence of heterogeneity (I2 = 0%). None of the included studies reported complete data on symptomatic ICH. In-hospital mortality was similar between pediatric stroke patients treated with thrombolysis and controls (risk ratio = 1.44, 95%CI: 0.39-5.40; p = 0.586), with evidence of heterogeneity (I2 = 62%). Efficacy of revascularization therapies could not be analyzed due to lack of outcome data. CONCLUSIONS: Our analyses demonstrate a substantial lack of data on efficacy and safety of acute recanalization therapies in children with AIS. PROSPERO REGISTRATION INFORMATION: URL: http://www.crd.york.ac.uk/PROSPERO. Unique identifier: CRD42016047140.

Should Skin Biopsies Be Performed in Patients Suspected of Having Parkinson's Disease?

In patients with Parkinson's disease (PD), the molecularly misfolded form of α-synuclein was recently identified in cutaneous autonomic nerve fibers which displayed increased accumulation even in early disease stages. However, the underlying mechanisms of synucleinopathic nerve damage and its implication for brain pathology in later life remain to be elucidated. To date, specific diagnostic tools to evaluate small fiber pathology and to discriminate neurodegenerative proteinopathies are rare. Recently, research has indicated that deposition of α-synuclein in cutaneous nerve fibers quantified via immunohistochemistry in superficial skin biopsies might be a valid marker of PD which could facilitate early diagnosis and monitoring of disease progression. However, lack of standardization of techniques to quantify neural α-synuclein deposition limits their utility in clinical practice. Additional challenges include the identification of potential distinct morphological patterns of intraneural α-synuclein deposition among synucleinopathies to facilitate diagnostic discrimination and determining the degree to which structural damage relates to dysfunction of nerve fibers targeted by α-synuclein. Answering these questions might improve our understanding of the pathophysiological role of small fiber neuropathy in Parkinson's disease, help identify new treatment targets, and facilitate assessment of response to neuroprotective treatment.

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.

Cutaneous Autonomic Pilomotor Testing to Unveil the Role of Neuropathy Progression in Early Parkinson's Disease (CAPTURE PD): 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.

Pilomotor function is impaired in patients with Parkinson's disease: A study of the adrenergic axon-reflex response and autonomic functions.

INTRODUCTION: Autonomic nervous system disturbances including sweating abnormalities and cardiovascular symptoms are frequent in Parkinson's disease (PD) and often precede motor involvement. Cholinergic vasomotor and sudomotor skin nerves are impaired in patients with PD even at early disease stages. We hypothesized that adrenergic pilomotor nerve function is similarly impaired in early PD and might constitute a novel diagnostic target. METHODS: We conducted a study in 12 PD patients (Hoehn&Yahr 1-2) and 12 healthy control subjects. Pilomotor function was evaluated after iontophoresis of phenylephrine on the dorsal forearm to elicit axon-reflex mediated pilomotor erection (goose bumps). Silicone impressions were obtained, scanned and quantified for pilomotor muscle impressions by number, area and axon-reflex spread. Vasomotor function was evaluated using laser Doppler flowmetry and sudomotor function via sympathetic skin response. Cardiac autonomic function was assessed via heart rate variability. Severity of autonomic symptoms was evaluated using the Scales for Outcomes in Parkinson's disease-Autonomic questionnaire. RESULTS: Pilomotor response was reduced in PD patients compared to control subjects (impression number: 12.2 ± 8.2 vs. 16.5 ± 5.9, p < 0.05; impression area: 10.8 ± 2.2 mm2 vs. 24.8 ± 3.1 mm2, p < 0.01; axon-reflex spread: 89.0 ± 10.6 mm2 vs. 185.9 ± 10.8 mm2, p < 0.01) and correlated negatively with severity of autonomic symptoms (p < 0.01). Similarly, sudomotor (p < 0.01) and vasomotor (p < 0.05) but not cardiac autonomic (p = n.s.) function were reduced in PD patients versus control subjects. CONCLUSION: Pilomotor function is impaired in early stages of PD. Pilomotor axon-reflex assessment might be useful in the investigation of disease related pathology and supplement other clinical markers of autonomic neuropathy in PD.

Randomized controlled trials - a matter of design.

Randomized controlled trials (RCTs) are the hallmark of evidence-based medicine and form the basis for translating research data into clinical practice. This review summarizes commonly applied designs and quality indicators of RCTs to provide guidance in interpreting and critically evaluating clinical research data. It further reflects on the principle of equipoise and its practical applicability to clinical science with an emphasis on critical care and neurological research. We performed a review of educational material, review articles, methodological studies, and published clinical trials using the databases MEDLINE, PubMed, and ClinicalTrials.gov. The most relevant recommendations regarding design, conduction, and reporting of RCTs may include the following: 1) clinically relevant end points should be defined a priori, and an unbiased analysis and report of the study results should be warranted, 2) both significant and nonsignificant results should be objectively reported and published, 3) structured study design and performance as indicated in the Consolidated Standards of Reporting Trials statement should be employed as well as registration in a public trial database, 4) potential conflicts of interest and funding sources should be disclaimed in study report or publication, and 5) in the comparison of experimental treatment with standard care, preplanned interim analyses during an ongoing RCT can aid in maintaining clinical equipoise by assessing benefit, harm, or futility, thus allowing decision on continuation or termination of the trial.

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.

Selective serotonin reuptake inhibitors to improve outcome in acute ischemic stroke: possible mechanisms and clinical evidence.

BACKGROUND: Several clinical studies have indicated that selective serotonin reuptake inhibitors (SSRIs) administered in patients after acute ischemic stroke can improve clinical recovery independently of depression. Due to small sample sizes and heterogeneous study designs interpretability was limited in these studies. The mechanisms of action whereby SSRI might improve recovery from acute ischemic stroke are not fully elucidated. METHODS: We searched MEDLINE using the PubMed interface to identify evidence of SSRI mediated improvement of recovery from acute ischemic stroke and reviewed the literature on the potential underlying mechanisms of action. RESULTS: Among identified clinical studies, a well-designed randomized, double-blind, and placebo-controlled study (FLAME - fluoxetine for motor recovery after acute ischemic stroke) demonstrated improved recovery of motor function in stroke patients receiving fluoxetine. The positive effects of SSRIs on stroke recovery were further supported by a meta-analysis of 52 trials in a total of 4060 participants published by the Cochrane collaboration. Based on animal models, the mechanisms whereby SSRIs might ameliorate functional and structural ischemic-brain damage were suggested to include stimulation of neurogenesis with migration of newly generated cells toward ischemic-brain regions, anti-inflammatory neuroprotection, improved regulation of cerebral blood flow, and modulation of the adrenergic neurohormonal system. However, to date, it remains speculative if and to what degree these mechanisms convert into humans and randomized controlled trials in large populations of stroke patients comparing different SSRIs are still lacking. CONCLUSION: In addition to the need of comprehensive-clinical evidence, further elucidation of the beneficial mechanisms whereby SSRIs may improve structural and functional recovery from ischemic-brain damage is needed to form a basis for translation into clinical practice.

The Effects of Pretreatment versus De Novo Treatment with Selective Serotonin Reuptake Inhibitors on Short-term Outcome after Acute Ischemic Stroke.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) administered in patients following acute ischemic stroke have shown to improve clinical recovery independently of changes in depression. Animal studies have demonstrated that sustained SSRI treatment is superior to short-term SSRI in evoking neurogenesis but how this benefit translates into humans remains to be answered. We hypothesized that in acute ischemic stroke patients, SSRI treatment started before the event leads to improved short-term outcomes compared to de novo SSRI treatment poststroke. METHODS: We performed an exploratory analysis in consecutive acute ischemic stroke patients and compared patients already receiving fluoxetine, citalopram, or escitalopram with those who started treatment de novo. RESULTS: Of 2653 screened patients, 239 were included (age, 69 ± 14 years; 42% men, baseline median National Institutes of Health Stroke Scale score, 7 [IQR, 10]). Of these patients, 51 started treatment with SSRI before stroke and 188 were prescribed newly SSRIs during hospitalization. In the adjusted multivariate logistic regression models, SSRI pretreatment was associated with favorable functional outcome at discharge defined as a modified Rankin Scale score of 2 or less (odds ratio [OR], 4.00; 95% confidence interval [CI], 1.68-9.57; P < .005), improved early clinical recovery (OR, 2.35; 95% CI, 1.15-4.81; P = .02), and a trend toward prediction of superior motor recovery (OR, 1.82; 95% CI, .90-3.68; P < .01). CONCLUSIONS: Our data suggest that SSRI pretreatment may improve clinical outcomes in the early stages of acute ischemic stroke supporting the hypothesis that prolonged SSRI treatment started prestroke is superior to poststroke SSRI.

Subsequent Bilateral Hippocampal Diffusion Restriction and Atrophy in Repeated Status Epilepticus.

BACKGROUND: Cortical lesions in status epilepticus have been reported but the underlying mechanisms are poorly elucidated. CASE SUMMARY: We report on afemale patient (75 years) with a history of alcohol abuse who presented with complex partial status epilepticus and lateralized epileptiform discharges in the left frontal and temporal regions in EEG. While cranial magnetic resonance imaging (MRI) showed left hippocampal T2-hyperintensity and diffusion restriction, cerebrospinal fluid was normal and revealed no limbic encephalitis-related antibodies. Following treatment with levitiracetam, seizures ceased and the patient was dismissed. Nine months later, she was readmitted with generalized status epilepticus. Cranial MI now showed hippocampal diffusion restriction and T2 hyperintensity, but in the right hemisphere, as well as atrophy and partial gliotic transformation of the initially affected left hippocampus. DISCUSSION: Although hippocampal damage due to antibody-negative limbic encephalitis cannot be ruled out, our observation of subsequent bilateral hippocampal diffusion restriction with gliotic transformation may demonstrate permanent seizure-induced structural brain damage and underlines the importance of further research to elucidate the effects of prolonged epileptic discharges on cerebral structural integrity.

Behavioral and metabolic effects of central injections of orexins/hypocretins in pigeons (Columba livia).

In the present study, the acute behavioral and ingestive effects of ICV injections of mammalian orexin-A (ORXA; vehicle, 0.2, 0.6 or 2 nmol) and of orexin-B (ORXB; vehicle, 0.2, 0.6 or 2 nmol), as well as possible long-term effects (through 24 h of continuous intake monitoring after 0.6 nmol of ORXA or ORXB) of these treatments in food/water intake and in blood levels of metabolic fuels (free fatty acids and glucose, after 0.2 or 0.6 nmol of ORXA) were examined in adult male pigeons. Both ORXA and ORXB treatments failed to produce acute (1-3 h) or long-term effects on feeding and drinking behaviors, and did not change blood free fatty acids and glucose 15 and 30 min after treatments, as compared to vehicle-treated animals. However, ORXA (but not ORXB) treatments evoked a dose-related, intense increase in exploratory behaviors, associated to reduced time spent in alert immobility and sleep-typical postures. These data substantiate the lack of orexigenic effects of ORXs in avian species, and suggest that an important role in vigilance control may represent a conserved functional attribute of orexinergic circuits in vertebrates.