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

Abstract 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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Pain and small-fiber affection in hereditary neuropathy with liability to pressure palsies (HNPP)

Scandinavian Journal of Pain ◽

10.1515/sjpain-2019-0090 ◽

2019 ◽

Vol 20 (1) ◽

pp. 61-68

Author(s):

Tore Thomas Dukefoss ◽

Inge Petter Kleggetveit ◽

Tormod Helås ◽

Ellen Jørum

Keyword(s):

Healthy Subjects ◽

Nerve Fibers ◽

Hereditary Neuropathy ◽

Detection Thresholds ◽

Axon Reflex ◽

Thermal Thresholds ◽

C Fibers ◽

Small Fiber ◽

Pressure Palsies ◽

Small Nerve

AbstractBackground and aimsHereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal – dominant hereditary neuropathy caused by a deficiency in the peripheral protein PMP-22, due to deletion on chromosome 17p11,2 or in some rare cases point mutations in the PMP-22 gene. The clinical picture is characterized by recurrent mononeuropathies in nerves which frequently may be exposed to pressure, such as the median, ulnar, radial and peroneal nerves or also a more general neuropathy. Although pain is reported to be an unusual clinical symptom, there have been reports of pain in a surprisingly high proportion of these patients. Since pain may be explained by mechanisms in afferent small unmyelinated C- nerve fibers, an assessment of the function of small nerve fibers has been requested. The purpose of the present study was to investigate the presence of pain and the possible affection of afferent small nerve-fibers, A-δ and C-fibers, by quantitative sensory testing (QST)-assessment of thermal thresholds, as well as quantitative sudomotor axon reflex (QSART), a quantitative, validated assessment of efferent postganglionic sumodotor function. QST values were compared to values of age- and sex matched healthy subjects.MethodsThe 19 patients were investigated clinically, with an emphasis on pain characteristics, with nerve conduction studies (NCS) of major nerves in upper- and lower extremity, small fiber testing (QST, measurement of thermal thresholds) and with QSART.ResultsA total of 10 patients reported numbness in some extremity, suggesting entrapment of individual nerves as well as a general neuropathy, as verified by NCS in nine patients. A total of 15 patients had findings compatible with a general polyneuropathy. A total of eight patients reported pain, seven patients with pain in the feet, described as burning, aching, shooting and six with severe pathological QST values, mainly cold detection, but also four patients with elevated thresholds to warmth. Four of the patients had signs of a severe sensory neuropathy on NCS, with no sural findings. One patient had only pain in the arms, with only minor changes on NCS and with normal QST-values. Cold detection thresholds (CD) were significantly elevated (reduced sensibility) on the dorsum of the foot (mean of two feet), in patients [26.0 °C (19.7–28.0)] as compared with healthy subjects [28.6 °C (27.4–29.6) p = 0.000]. There were also significantly elevated warmth detection thresholds (WD) in feet in patients 39.5 °C (36.4–42.9) compared to healthy subjects [37.7 °C (36.1–39.4) p = 0.048]. However, there were no significant differences in QST values between patients with and without pain.ConclusionsOf a total of 19 patients with verified HNPP, eight patients (42.1%) suffered from neuropathic pain, mainly in both feet.ImplicationsDue to the high percentage of pain in HNPP, it is important not to disregard this diagnosis in a patient presenting with pain. Since there are no significant differences in QST values in patients with and without pain, routine QST studies in HNPP do not seem necessary.

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Quantitative Sudomotor Axon Reflex and Related Tests

Clinical Neurophysiology ◽

10.1093/med/9780190259631.003.0036 ◽

2016 ◽

pp. 628-634

Author(s):

Phillip A. Low

Keyword(s):

Nerve Fibers ◽

Clinical Applications ◽

Screening Tests ◽

Response To Treatment ◽

Dynamic Tests ◽

Axon Reflex ◽

Sudomotor Function ◽

Distal Nerve ◽

Definition Of ◽

Small Nerve

Small distal nerve fibers are often selectively involved in some patients with axonal neuropathies (distal small-fiber neuropathy). One method of testing the integrity of these small nerve fibers is to study the postganglionic sympathetic sudomotor “C” fiber function. The application of noninvasive, sensitive, quantitative, and dynamic tests of sudomotor function significantly enhances the ability to quantitate one aspect of the autonomic deficit. The quantitative sudomotor axon reflex test (QSART) has an important role in clinical applications to better definition of the course of neuropathy, its response to treatment, and further exploration of sudomotor physiology. Simpler methods are available as screening tests. This chapter reviews the use of methods to measure sudomotor fiber function.

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Abnormal skin biopsy for intraepidermal nerve fibers: When “Decreased small nerve fibers” is not “Small fiber neuropathy”

Microsurgery ◽

10.1002/micr.22372 ◽

2015 ◽

Vol 35 (7) ◽

pp. 505-506 ◽

Cited By ~ 3

Author(s):

A. Lee Dellon

Keyword(s):

Skin Biopsy ◽

Nerve Fibers ◽

Small Fiber Neuropathy ◽

Small Fiber ◽

Small Nerve

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Sudomotor Dysfunction

Seminars in Neurology ◽

10.1055/s-0040-1713847 ◽

2020 ◽

Vol 40 (05) ◽

pp. 560-568

Author(s):

William P. Cheshire

Keyword(s):

Diagnostic Marker ◽

Heat Stroke ◽

Sympathetic Skin Response ◽

Sweat Test ◽

Axon Reflex ◽

Sudomotor Function ◽

Small Fiber ◽

Skin Response ◽

Patient At Risk ◽

Thermoregulatory Sweat Test

AbstractDisorders of sudomotor function are common and diverse in their presentations. Hyperhidrosis or hypohidrosis in generalized or regional neuroanatomical patterns can provide clues to neurologic localization and inform neurologic diagnosis. Conditions that impair sudomotor function include small fiber peripheral neuropathy, sudomotor neuropathy, myelopathy, α-synucleinopathies, autoimmune autonomic ganglionopathy, antibody-mediated hyperexcitability syndromes, and a host of medications. Particularly relevant to neurologic practice is the detection of postganglionic sudomotor deficits as a diagnostic marker of small fiber neuropathies. Extensive anhidrosis is important to recognize, as it not only correlates with symptoms of heat intolerance but may also place the patient at risk for heat stroke when under conditions of heat stress. Methods for assessing sudomotor dysfunction include the thermoregulatory sweat test, the quantitative sudomotor axon reflex test, silicone impressions, and the sympathetic skin response.

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Characterization of small nerve fibers in painful distal symmetric polyneuropathy and healthy controls

Scandinavian Journal of Pain ◽

10.1016/j.sjpain.2015.04.015 ◽

2015 ◽

Vol 8 (1) ◽

pp. 51

Author(s):

P. Karlsson ◽

S. Haroutounian ◽

M. Polydefkis ◽

J.R. Nyengaard ◽

T.S. Jensen

Keyword(s):

Nerve Fiber ◽

Quantitative Sensory Testing ◽

Nerve Fibers ◽

Healthy Controls ◽

Sensory Testing ◽

Fiber Morphology ◽

Small Fiber ◽

Intraepidermal Nerve Fiber Density ◽

Distal Symmetric Polyneuropathy ◽

Small Nerve

AbstractAimsThe introduction of skin biopsies to examine small nerve fiber morphology together with functional measures such as quantitative sensory testing (QST) has led to an improvement in diagnosing patients with small fiber neuropathy (SFN). Quantification of intraepidermal nerve fiber density (IENFD) is an important measure in SFN. However, the relationship between structure and function is not straightforward and the morphological and functional fiber characteristics are still unclear. This study aimed to combine structural and functional measurements to improve the diagnosis of distal symmetric polyneuropathy and small fiber involvement. Additionally, we investigated whether patients and healthy controls have differential patterns of correlations between structural and functional nerve measurements.Methods17 patients with painful distal symmetric polyneu-ropathy (DSP) and 19 controls underwent comprehensive small fiber assessments that included quantitative sensory testing, response to topical capsaicin and analysis of skin biopsy samples (IENFD, epidermal and dermal nerve fiber length densities (eNFLD, dNFLD) and swellings).ResultsDSP patients had reduced sensitivity to cold and heat, diminished capsaicin response, and lower IENFD, eNFLD and dNFLD (all p < 0.0003).The correlation between structural and functional parameters was better in controls than in DSP. A diagnostic approach of combined IENFD and eNFLD utilization, increased DSP diagnostic sensitivity from 82.0% to 100% and specificity from 84.0% to 89.5%.ConclusionsA correlation is found between functional and structural small fiber parameters for DSP and controls, and an approach to improve diagnostic accuracy in DSP is suggested.

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Topical Phenytoin Cream Reduces Burning Pain Due to Small Fiber Neuropathy in Sarcoidosis

Journal of Anesthesia & Pain Medicine ◽

10.33140/japm/02/01/00004 ◽

2017 ◽

Vol 2 (1) ◽

Keyword(s):

Sleep Disturbances ◽

Nerve Fibers ◽

Small Fiber Neuropathy ◽

Patient Case ◽

Burning Pain ◽

Small Fiber ◽

Minute Period ◽

Single Blind ◽

Placebo Cream ◽

Small Nerve

We present a patient case of burning pain and sleep disturbances due to small fiber neuropathy (SFN) in sarcoidosis, treated successfully by topically applied phenytoin 10% cream. Using a single blind, placebo-controlled response test, the patient identified that within a 10 minute period phenytoin 10% cream provided a pain reduction of 50%, while placebo cream did not reduce pain at all. Subsequently, the patient was prescribed phenytoin 10% cream and used this cream for several weeks. Burning pain was reduced by 50% to 60%, resulting in a much improved sleep. The onset of analgesia starts around five minutes after the application of phenytoin 10% cream and in this case lasts for around 20 hours. Plasma levels of phenytoin, measured in 15 comparable patients were below the level of detection, ruling out systemic analgesia. Our hypothesis is that topical phenytoin influences epidermal targets such as nociceptors, small nerve fibers and keratinocytes, all which play a role in the pathogenesis of pain in SFN.

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Diagnosing small fiber neuropathy in clinical practice: a deep phenotyping study

Therapeutic Advances in Neurological Disorders ◽

10.1177/17562864211004318 ◽

2021 ◽

Vol 14 ◽

pp. 175628642110043

Author(s):

Nadine Egenolf ◽

Caren Meyer zu Altenschildesche ◽

Luisa Kreß ◽

Katja Eggermann ◽

Barbara Namer ◽

...

Keyword(s):

Neurological Examination ◽

Punch Biopsy ◽

Small Fiber Neuropathy ◽

Fiber Density ◽

Axon Reflex ◽

Small Fiber ◽

Corneal Confocal Microscopy ◽

Intraepidermal Nerve Fiber Density ◽

Number Of Patients ◽

Skin Punch Biopsy

Background and aims: Small fiber neuropathy (SFN) is increasingly suspected in patients with pain of uncertain origin, and making the diagnosis remains a challenge lacking a diagnostic gold standard. Methods: In this case–control study, we prospectively recruited 86 patients with a medical history and clinical phenotype suggestive of SFN. Patients underwent neurological examination, quantitative sensory testing (QST), and distal and proximal skin punch biopsy, and were tested for pain-associated gene loci. Fifty-five of these patients additionally underwent pain-related evoked potentials (PREP), corneal confocal microscopy (CCM), and a quantitative sudomotor axon reflex test (QSART). Results: Abnormal distal intraepidermal nerve fiber density (IENFD) (60/86, 70%) and neurological examination (53/86, 62%) most frequently reflected small fiber disease. Adding CCM and/or PREP further increased the number of patients with small fiber impairment to 47/55 (85%). Genetic testing revealed potentially pathogenic gene variants in 14/86 (16%) index patients. QST, QSART, and proximal IENFD were of lower impact. Conclusion: We propose to diagnose SFN primarily based on the results of neurological examination and distal IENFD, with more detailed phenotyping in specialized centers.

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