Pathology of Small Fiber Neuropathy: Skin Biopsy for the Analysis of Nociceptive Nerve Fibers

BackgroundRetrospective investigation of the somatosensory profile and prediction of histologic small fiber neuropathy (SFN) in postural orthostatic tachycardia syndrome (POTS) was performed using quantitative sensory testing (QST) as a standardized noninvasive test.MethodsIn this investigation, full data sets from 30 patients (age: 34.03 ± 10.82 years, n = 6 males), including results of autonomic function testing, norepinephrine values, skin biopsy, and QST, were retrospectively analyzed. The QST data were compared with healthy controls (HCs) (age: 34.20 ± 10.5 years, n = 6 males, t test: 0.95).ResultsThe evaluation of all QST parameters in POTS compared with HCs yielded differences in all thermal parameters (cold detection threshold: p < 0.05, warm detection threshold: p < 0.001, thermal sensory limen: p < 0.001, cold pain threshold: p < 0.05, and heat pain threshold: p < 0.001) and in paradoxical heat sensations (p < 0.05). Differences in nonpainful stimuli (mechanical detection threshold: p < 0.05 and vibration detection threshold: p < 0.001) were also detected. All patients who had clinical signs of SFN in combination with impairment of small fibers in QST also had SFN on skin biopsy.ConclusionThese results suggest that a non–region-specific SFN in POTS compared with controls can be detected by noninvasive QST that predicts histologic small fiber pathology.

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Ca2+ toxicity due to reverse Na+/Ca2+ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation

Journal of Neurophysiology ◽

10.1152/jn.00195.2015 ◽

2015 ◽

Vol 114 (3) ◽

pp. 1554-1564 ◽

Cited By ~ 24

Author(s):

M. Estacion ◽

B. P. S Vohra ◽

S. Liu ◽

J. Hoeijmakers ◽

C. G. Faber ◽

...

Keyword(s):

Nerve Fibers ◽

Small Fiber Neuropathy ◽

Missense Mutations ◽

Sodium Calcium Exchanger ◽

Drg Neurons ◽

Persistent Currents ◽

Burning Pain ◽

Reverse Mode ◽

Small Fiber ◽

High K

Gain-of-function missense mutations in voltage-gated sodium channel Nav1.7 have been linked to small-fiber neuropathy, which is characterized by burning pain, dysautonomia and a loss of intraepidermal nerve fibers. However, the mechanistic cascades linking Nav1.7 mutations to axonal degeneration are incompletely understood. The G856D mutation in Nav1.7 produces robust changes in channel biophysical properties, including hyperpolarized activation, depolarized inactivation, and enhanced ramp and persistent currents, which contribute to the hyperexcitability exhibited by neurons containing Nav1.8. We report here that cell bodies and neurites of dorsal root ganglion (DRG) neurons transfected with G856D display increased levels of intracellular Na+ concentration ([Na+]) and intracellular [Ca2+] following stimulation with high [K+] compared with wild-type (WT) Nav1.7-expressing neurons. Blockade of reverse mode of the sodium/calcium exchanger (NCX) or of sodium channels attenuates [Ca2+] transients evoked by high [K+] in G856D-expressing DRG cell bodies and neurites. We also show that treatment of WT or G856D-expressing neurites with high [K+] or 2-deoxyglucose (2-DG) does not elicit degeneration of these neurites, but that high [K+] and 2-DG in combination evokes degeneration of G856D neurites but not WT neurites. Our results also demonstrate that 0 Ca2+ or blockade of reverse mode of NCX protects G856D-expressing neurites from degeneration when exposed to high [K+] and 2-DG. These results point to [Na+] overload in DRG neurons expressing mutant G856D Nav1.7, which triggers reverse mode of NCX and contributes to Ca2+ toxicity, and suggest subtype-specific blockade of Nav1.7 or inhibition of reverse NCX as strategies that might slow or prevent axon degeneration in small-fiber neuropathy.

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Low Sensitivity of Skin Biopsy in Diagnosing Small Fiber Neuropathy in Chinese Americans

Journal of Clinical Neuromuscular Disease ◽

10.1097/cnd.0000000000000223 ◽

2018 ◽

Vol 20 (1) ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

Peter Jin ◽

Ling Cheng ◽

Ming Chen ◽

Lan Zhou

Keyword(s):

Skin Biopsy ◽

Chinese Americans ◽

Small Fiber Neuropathy ◽

Small Fiber ◽

Low Sensitivity

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Small Fiber Neuropathy

Seminars in Neurology ◽

10.1055/s-0039-1688977 ◽

2019 ◽

Vol 39 (05) ◽

pp. 570-577 ◽

Cited By ~ 4

Author(s):

Lan Zhou

Keyword(s):

Skin Biopsy ◽

Lifestyle Modification ◽

Specific Treatment ◽

Small Fiber Neuropathy ◽

Fiber Density ◽

Small Fiber ◽

Intraepidermal Nerve Fiber Density ◽

Associated Conditions ◽

Density Evaluation

AbstractSmall fiber neuropathy (SFN) is common, and can be associated with many medical conditions. The majority of the patients with SFN suffer from painful paresthesia which can negatively impact their quality of life. Skin biopsy with intraepidermal nerve fiber density evaluation is the gold standard diagnostic test. Autonomic function testing is useful when autonomic symptoms are present. Screening for associated conditions should be done in every patient, even when a known underlying associated condition is present, before the neuropathy evaluation. Etiology-specific treatment, lifestyle modification, and pain control are the key elements of SFN management. This article will review the clinical presentation, skin biopsy procedure, utility of diagnostic tests, associated conditions, management, and prognosis of SFN.

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Limitations of Skin Biopsy in the Assessment of Isolated Small Fiber Neuropathy (P03.207)

Neurology ◽

10.1212/wnl.78.1_meetingabstracts.p03.207 ◽

2012 ◽

Vol 78 (Meeting Abstracts 1) ◽

pp. P03.207-P03.207 ◽

Cited By ~ 1

Author(s):

V. Lawson ◽

P. Mongiovi ◽

W. Arnold

Keyword(s):

Skin Biopsy ◽

Small Fiber Neuropathy ◽

Small Fiber

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