Two-Year observational study of autonomic skin function in patients with Parkinson's disease compared to healthy individuals.

BACKGROUND AND PURPOSE: We characterized autonomic pilomotor and sudomotor skin function in early Parkinson's disease (PD) longitudinally. METHODS: We enrolled PD patients (Hoehn and Yahr 1-2) and healthy controls from movement disorder centers in Germany, Hungary, and the United States. We evaluated axon-reflex responses in adrenergic sympathetic pilomotor nerves and in cholinergic sudomotor nerves and assessed sympathetic skin response (SSR), predominantly parasympathetic neurocardiac function via heart rate variability, and disease-related symptoms at baseline, after 2 weeks, and after 1 and 2 years. CLINICALTRIALS: gov: NCT03043768. RESULTS: We included 38 participants: 26 PD (60% females, aged 62.4 ± 7.4 years, mean ± SD) and 12 controls (75% females, aged 59.5 ± 5.8 years). Pilomotor function was reduced in PD compared to controls at baseline when quantified via spatial axon-reflex spread (78 [43-143], median [interquartile range] mm2 vs. 175 [68-200] mm2 , p = 0.01) or erect hair follicle count in the axon-reflex region (8 [6-10] vs. 11 [6-16], p = 0.008) and showed reliability absent any changes from baseline to Week 2 (p = not significant [ns]). Between-group differences increased over the course of 2 years (p < 0.05), although no decline was observed within groups (p = ns). Pilomotor impairment in PD correlated with motor symptoms (rho = -0.59, p = 0.017) and was not lateralized (p = ns). Sudomotor axon-reflex and neurocardiac function did not differ between groups (p = ns), but SSR was reduced in PD (p = 0.0001). CONCLUSIONS: Impairment of adrenergic sympathetic pilomotor function and SSR in evolving PD is not paralleled by changes to cholinergic sudomotor function and parasympathetic neurocardiac function, suggesting a sympathetic pathophysiology. A pilomotor axon-reflex test might be useful to monitor PD-related pathology.

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.

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.

Intraoperative biomarkers in renal transplantation.

The emerging need for biomarkers in the management of renal transplantation is highlighted by the severity of related complications such as acute renal failure and ischaemia/reperfusion injury (IRI) and by the increasing efforts to identify novel markers of these events to predict and monitor delayed graft function (DGF) and long-term outcome. In clinical studies candidate markers such as kidney injury molecule-1, neutrophil gelatinase-associated lipocalin and interleukin-18 have been demonstrated to be valid biomarkers with high predictive value for DFG in a post-transplant setting. However, studies investigating biomarkers for early diagnosis of IRI and assumable DGF as well as identification of potential graft recipients at increased risk at the time point of transplantation lack further confirmation and translation into clinical practice. This review summarizes the current literature on the value of IRI biomarkers in outcome prediction following renal transplantation as well their capacity as surrogate end points from an intraoperative perspective.

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.

Polymyositis with cytochrome C oxidase negative fibers--a pathological and clinical challenge.

Polymyositis (PM) with cytochrome C oxidase negative fibers also referred to as PM with mitochondrial pathology (PM-Mito) is characterized by the symptoms of inclusion body myositis (IBM) and by the myopathological findings of PM except for an increase of muscle fibers with insufficient mitochondrial cytochrome C oxidase activity. Few PM-Mito cases are published; mitochondrial ultrastructure has not been studied in these patients. We report 2 PM-Mito patients with later onset than usually seen in IBM and poor responsiveness to glucocorticoids. Electron microscopy of muscle fibers showed irregular mitochondrial ultrastructure. Sjögren syndrome related antinuclear antibodies (Anti-Ro and Anti-La) were found in one of the two patients but the typical clinical symptoms of Sjögren syndrome such as xerostomia and keratoconjunctivitis were absent in this patient. Taken together, our observations, viewed in conjunction with the current literature, suggest that PM-Mito is an underdiagnosed disease with a multifactorial pathogenesis that should be elucidated in further studies. We want to encourage clinicians and pathologists to consider the possibility of PM-Mito in patients with atypical PM or sIBM.

Etiology, pathological characteristics, and clinical management of black pleural effusion: A systematic review.

BACKGROUND: Pleural effusion is characterized by excessive fluid collection in the pleural cavity. Black pleural effusion (BPE) is a rare entity with only limited scientific data. We aimed to review the current literature on black pleural effusion to characterize demographics, etiology, clinical presentation, pathological findings, available treatment strategies, and prognosis of this rare condition. METHODS: We performed a systematic review of case reports and series and synthesized data on demographics, manifestations, management, and outcomes of patients with BPE. We searched Cochrane Library, PubMed, SCOPUS, and Google Scholar for any date until January 10, 2021. All studies (n = 31) that reported black pleural effusion in patients were added to the review. Prospective Register of Systematic Reviews registration number: CRD42020213839. Summary and descriptive analysis was performed on Jamovi version 1.2. RESULTS: The mean age of 32 patients with BPE was 53 years, with male predominance (69%). The commonest risk factor was smoking (n = 9) followed by alcohol intake (n = 8). Dyspnea was the commonest symptom (n = 24, 75%). Pleural fluid was mostly exudative (n = 21). The commonest associated diagnosis was malignancy (n = 14), with 50% secondary to metastatic melanoma. The commonest intervention was therapeutic thoracocentesis (n = 25, 78%), and the effusion recurred in half of the cases where recurrence was reported (n = 13). In our review, we found the mortality rate to be at 20.8% (n = 20.8%). 58.3% of the patients were successfully treated and discharged home (n = 14). CONCLUSION: Although rare, BPE appears to be a relevant symptom as it seems to be frequently associated with modifiable risk factors and underlying malignancy. Our systematic review substantiates a vital research gap as observational research is imperative to characterize BPE further and form a basis for designing tailored diagnostic, preventive, and therapeutic strategies for BPE.

Mapping of predictors of the disengagement of the descending inhibitory pain modulation system in fibromyalgia: an exploratory study.

BACKGROUND: The main symptoms of fibromyalgia comprise diffuse pain, disability, depressive symptoms, catastrophizing, sleep disruption and fatigue, associated with dysfunction of the descending pain-modulating system (DPMS). OBJECTIVES: We aimed to identify patterns of main symptoms of fibromyalgia and neuroplasticity biomarkers (i.e. brain-derived neurotrophic factor (BDNF) and S100B protein) in non-responders to the conditioned pain modulation task (CPM-task) induced by immersion of hand in cold water (0-1°C). Furthermore, we evaluated if these patterns predict responsiveness to CPM-task. METHODS: This cross-sectional study included 117 women with fibromyalgia ((n = 60) non-responders and (n = 57) responders), with age ranging from 30 to 65 years old. We analysed changes in numerical pain scale (NPS-10) during the CPM-task using a standardized protocol. RESULTS: A hierarchical multivariate logistic regression analysis was used to construct a propensity score-adjusted index to identify non-responders compared to responders to CPM-task. The following variables were retained in the models: analgesic use four or more times per week, heat pain threshold (HPT), poor sleep quality, pain catastrophizing, serum levels of BDNF, number of psychiatric diagnoses and the impact of symptoms of fibromyalgia on quality of life. Receiver operator characteristics (ROC) analysis showed non-responders can be discriminated from responders by a composite index of more frequent symptoms of fibromyalgia and neuroplasticity markers (area under the curve (AUC) = 0.83, sensitivity = 100% and specificity = 98%). CONCLUSION: Patterns of fibromyalgia symptoms and neuroplasticity markers may be helpful to predict responsiveness to the CPM-task which might help personalize treatment and thereby contribute to the care of patients with fibromyalgia.

Cerebrovascular Risk Profiles in a Saudi Arabian Cohort of Young Stroke Patients.

Background: The constantly increasing incidence of stroke in younger individuals substantiates an urgent need for research to elucidate underlying risk factors and etiologies. Heretofore, the vast majority of studies on stroke in the young have been carried out in European and North American regions. We aimed to characterize cerebrovascular risk profiles in a Saudi Arabic cohort of consecutive young stroke patients. Methods: We retrospectively analyzed data from consecutive ischemic stroke patients aged 15 to 49 years who underwent detailed cardiocerebrovascular evaluation at a tertiary stroke care center in Makkah, Saudi Arabia. Distributions of risk factors and stroke etiologies were assessed in the entire cohort and in two strata of very young (15-40 years) and young to middle-aged patients (41-49) to account for variability in suggested age cutoffs. Results: In the entire cohort [n = 63, ages 44 (34-47) median, interquartile range], dyslipidemia (71.4%) and small vessel occlusion (31.7%) displayed highest prevalence followed by diabetes (52.4%) and cardioembolism (19%). In very young patients, cardioembolism was the most prevalent etiology (27.3%). Risk profiles were similar between both age strata except for a higher prevalence of diabetes among the older cohort (31.8 vs. 63.4%, p = 0.01). Logistic regression identified diabetes as strongest predictor for association to the older strata (odds ratio = 4.2, 95% confidence interval = 1.2-14.1, p = 0.02). Conclusion: Cerebrovascular risk profiles and stroke etiologies in our cohort of young stroke patients differ from those of previous cohorts, suggesting the need for tailored prevention strategies that take into account local epidemiological data on cerebrovascular health.

Architecture of the Cutaneous Autonomic Nervous System.

The human skin is a highly specialized organ for receiving sensory information but also to preserve the body's homeostasis. These functions are mediated by cutaneous small nerve fibers which display a complex anatomical architecture and are commonly classified into cutaneous A-beta, A-delta and C-fibers based on their diameter, myelinization, and velocity of conduction of action potentials. Knowledge on structure and function of these nerve fibers is relevant as they are selectively targeted by various autonomic neuropathies such as diabetic neuropathy or Parkinson's disease. Functional integrity of autonomic skin nerve fibers can be assessed by quantitative analysis of cutaneous responses to local pharmacological induction of axon reflex responses which result in dilation of cutaneous vessels, sweating, or piloerection depending on the agent used to stimulate this neurogenic response. Sensory fibers can be assessed using quantitative sensory test. Complementing these functional assessments, immunohistochemical staining of superficial skin biopsies allow analysis of structural integrity of cutaneous nerve fibers, a technique which has gained attention due to its capacity of detecting pathogenic depositions of alpha-synuclein in patients with Parkinson's disease. Here, we reviewed the current literature on the anatomy and functional pathways of the cutaneous autonomic nervous system as well as diagnostic techniques to assess its functional and structural integrity.

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.

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.

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.

Neuropsychiatric symptoms in untreated Parkinson's disease.

Neuropsychiatric and cognitive symptoms are common in Parkinson's disease (PD) and may precede and exceed motor symptoms as major factors impacting disease course and quality of life. Neuropsychiatric symptoms (NPS) in PD are various and are attributed to pathologic changes within multiple brain regions, to psychological stress, and to adverse effects of dopamine replacement therapy. Sleep disorders and mood symptoms such as apathy, depression, and anxiety may antedate the development of motor symptoms by years, while other NPS such as impulse control disorders, psychosis, and cognitive impairment are more common in later stages of the disease. Few studies report on NPS in the early, untreated phase of PD. We reviewed the current literature on NPS in PD with a focus on the early, drug-naive stages of PD. Among these early disease stages, premotor and early motor phases were separately addressed in our review, highlighting the underlying pathophysiological mechanisms as well as epidemiological characteristics, clinical features, risk factors, and available techniques of clinical assessment.

Laser Doppler Assessment of Vasomotor Axon Reflex Responsiveness to Evaluate Neurovascular Function.

The vasomotor axon reflex can be evoked in peripheral epidermal nociceptive C-fibers to induce local vasodilation. This neurogenic flare response is a measure of C-fiber functional integrity and therefore shows impairment in patients with small fiber neuropathy. Laser Doppler flowmetry (LDF) and laser Doppler imaging (LDI) are both techniques to analyze vasomotor small fiber function by quantifying the integrity of the vasomotor-mediated axon reflex. While LDF assesses the flare response following acetylcholine iontophoresis with temporal resolution at a single defined skin point, LDI records flare responses with spatial and temporal resolution, generating a two-dimensional map of superficial blood flow. LDF is characterized by a high intra- and interindividual measurement variability, which is smaller in LDI due to its spatial resolution. Nevertheless, LDI still lacks standardized methods for image analysis. Consequently, use of the technique currently remains on an experimental level. Here, we sought to review the current literature on laser Doppler assessment of vasomotor function and discuss potential future applications of established techniques as well as those that are still experimental.

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.

Alpha-synuclein in cutaneous small nerve fibers.

Despite progression in the development of pharmacological therapy, treatment of alpha synucleinopathies, such as Parkinson's disease (PD) and some atypical parkinsonism syndromes, is still challenging. To date, our knowledge of the mechanisms whereby the pathological form of alpha-synuclein causes structural and functional damage to the nervous system is limited and, consequently, there is a lack of specific diagnostic tools to evaluate pathology in these patients and differentiate PD from other neurodegenerative proteinopathies. Recent studies indicated that alpha-synuclein deposition in cutaneous small nerve fibers assessed by skin biopsies might be a valid disease marker of PD and facilitate early differentiation of PD from atypical parkinsonism syndromes. This observation is relevant since early diagnosis may enable timely treatment and improve quality of life. However, challenges include the necessity of standardizing immunohistochemical analysis techniques and the identification of potential distinct patterns of intraneural alpha-synuclein deposition among synucleinopathies. In this perspective, we explore the scientific and clinical opportunities arising from alpha-synuclein assessment using skin biopsies. These include elucidation of the peripheral nervous system pathology of PD and other synucleinopathies, identification of novel targets to study response to neuroprotective treatment, and improvement of clinical management. Furthermore, we discuss future challenges in exploring the diagnostic value of skin biopsy assessment for alpha-synuclein deposition and implementing the technique in clinical practice.

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.

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.