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.

Cutaneous autonomic small nerve fibers encompass unmyelinated C-fibers and thinly myelinated Aδ-fibers, which innervate dermal vessels (vasomotor fibers), sweat glands (sudomotor fibers), and hair follicles (pilomotor fibers). Analysis of their integrity can capture early pathology in autonomic neuropathies such as diabetic autonomic neuropathy or peripheral nerve inflammation due to infectious and autoimmune diseases. Furthermore, intraneural deposition of alpha-synuclein in synucleinopathies such as Parkinson’s disease can lead to small fiber damage. Research indicated that detection and quantitative analysis of small fiber pathology might facilitate early diagnosis and initiation of treatment. While autonomic neuropathies show substantial etiopathogenetic heterogeneity, they have in common impaired functional integrity of small nerve fibers. This impairment can be evaluated by quantitative analysis of axonal responses to iontophoretic application of adrenergic or cholinergic agonists to the skin. The axon-reflex can be elicited in cholinergic sudomotor fibers to induce sweating and in cholinergic vasomotor fibers to induce vasodilation. Currently, only few techniques are available to quantify axon-reflex responses, the majority of which is limited by technical demands or lack of validated analysis protocols. Function of vasomotor small fibers can be analyzed using laser Doppler flowmetry, laser Doppler imaging, and laser speckle contrast imaging. Sudomotor function can be assessed using quantitative sudomotor axon-reflex test, silicone imprints, and quantitative direct and indirect testing of sudomotor function. More recent advancements include analysis of piloerection (goose bumps) following stimulation of adrenergic small fibers using pilomotor axon-reflex test. We provide a review of the current literature on axon-reflex tests in cutaneous autonomic small fibers.

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.

In diesem Beitrag werden die wichtigsten Erkrankungen skizziert, die ätiologisch einer Small-Fiber-Neuropathie (SFN) zugrunde liegen können. Schwerpunkt des Artikels bildet die Charakterisierung der im klinischen Alltag bereits etablierten sowie der in der aktuellen klinischen Forschung untersuchten Verfahren zur Diagnostik einer kutanen autonomen Dysfunktion.

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.

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.

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.

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Introduction: Elevated arterial blood pressure (BP) increases the risk of intracerebral hemorrhage after intravenous (IV) thrombolysis with tPA in acute ischemic stroke (AIS). While arterial BP is usually monitored using intermittent oscillometric measurements with an upper arm cuff, the vascular unloading technique (VUT) provides non-invasive continuous BP monitoring with a finger cuff. Hypothesis: We hypothesized that VUT monitoring is feasible in AIS patients receiving IV tPA, is comparable to the standard technique, and allows detection of BP peaks that might be missed in oscillometric BP monitoring. Methods: We performed an interim analysis of an ongoing prospective method comparison study. AIS patients were simultaneously monitored over 24 h following IV tPA bolus using VUT and contralateral oscillometric BP assessment every 30 min. Results: We present interim data from 15 out of 24 AIS (4 m, 11 f; aged 72.5±14.9 y, mean±SD) receiving IV tPA. Nominal significance level was set to 0.029 in accordance with Pocock’s rule. Missing data were less than 5% for both techniques. There was a positive correlation between VUT and oscillometric BP assessment (Pearson’s correlation coefficient r=0.91, p<0.001 for systolic BP; and r=0.88, p<0.001 for diastolic BP). Bland-Altman analysis confirmed this agreement (figure 1). The mean difference between VUT and oscillometric BP measurements was 9.4±6.1 mmHg for systolic, and 4.5±3.0 mmHg for diastolic BP (p=n.s.). Peaks (systolic BP>180 or diastolic BP>110 mmHg) were detected by VUT monitoring (at least one episode≥5 min) in 12 patients, and by oscillometric BP assessment (≥one time point of measurement) in 7 patients (p<0.01). Conclusions: Our interim data suggest that VUT-based BP monitoring is feasible in AIS patients receiving IV tPA, and might be more sensitive than intermittent oscillometric BP assessment in detecting potentially harmful blood pressure peaks. Figure 1: Bland Altman plot