Quantitative Pilomotor Axon Reflex Test

Siepmann, Timo; Gibbons, Christopher H.; Illigens, Ben Min-Woo; Lafo, Jacob; Brown, C M; Freeman, Roy

doi:10.1001/archneurol.2012.1092

Cited by 29 publications

(17 citation statements)

References 11 publications

(15 reference statements)

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“…Thus, the potential reaches the distal fiber endings in a skin region adjacent to the area of stimulation ("indirect area"). Thereby, a local response of the innervated organ is elicited, i.e., dilation of arterial skin vessels, sweating, or piloerection [16][17][18]. The axon-reflex can be elicited by iontophoresis of cholinergic agents in vasomotor or sudomotor fibers, adrenergic agents in pilomotor fibers, respectively, as well as by thermal, mechanic, or electric stimuli.…”

Section: Introductionmentioning

confidence: 99%

Assessment of cutaneous axon-reflex responses to evaluate functional integrity of autonomic small nerve fibers

et al. 2020

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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.

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Section: Introductionmentioning

confidence: 99%

Assessment of cutaneous axon-reflex responses to evaluate functional integrity of autonomic small nerve fibers

et al. 2020

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“…Iontophoresis of phenylephrine is used to induce axon-reflex-mediated piloerection as previously described (24). Briefly, a drug delivery capsule electrode (LI-611, Perimed, Sweden) is affixed on the testing area on the dorsal forearm.…”

Section: Methods and Anticipated Resultsmentioning

confidence: 99%

“…Whereas the sudomotor axon-reflex response is a postganglionic cholinergic function, pilomotor erection is executed via postganglionic noradrenergic fibers (17, 24). …”

Section: Introductionmentioning

confidence: 99%

“…First, we demonstrated that iontophoretic stimulation of cutaneous adrenergic small fibers with phenylephrine elicits axon-reflex-mediated pilomotor erection (goose bumps) in an indirect region surrounding the area of direct stimulation, which can be evaluated using the Quantitative Pilomotor Axon-Reflex Test (QPART) (24). In another investigation of pilomotor function in patients with PD versus healthy control subjects, we showed that functional integrity of pilomotor nerve fibers is impaired in early stages of PD and correlates negatively with severity of autonomic symptoms (25).…”

Section: Introductionmentioning

confidence: 99%

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Cutaneous Autonomic Pilomotor Testing to Unveil the Role of Neuropathy Progression in Early Parkinson’s Disease (CAPTURE PD): Protocol for a Multicenter Study

et al. 2017

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BackgroundIn 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/designA 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.DiscussionWe 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 registrationTRN .

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“…The most widely used application includes iontophoresis of acetylcholine using a predefined current and dosage. Similarly, axon-reflex responsivity can be assessed in sudomotor nerve fibers via cholinergic and in pilomotor fibers via adrenergic stimulation 21,22. Research has shown that sudomotor axon-reflex function is impaired in PD and impairment increases in severity with increasing disease stage 23.…”

Section: Limitations and Challengesmentioning

confidence: 99%

Alpha-synuclein in cutaneous small nerve fibers

Siepmann¹,

Illigens²,

Barlinn³

2016

NDT

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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.

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Quantitative Pilomotor Axon Reflex Test

Cited by 29 publications

References 11 publications

Assessment of cutaneous axon-reflex responses to evaluate functional integrity of autonomic small nerve fibers

Assessment of cutaneous axon-reflex responses to evaluate functional integrity of autonomic small nerve fibers

Cutaneous Autonomic Pilomotor Testing to Unveil the Role of Neuropathy Progression in Early Parkinson’s Disease (CAPTURE PD): Protocol for a Multicenter Study

Alpha-synuclein in cutaneous small nerve fibers

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