Small-Fiber Neuropathy: An Etiology-Oriented Review

Overview

Journal Brain Sci

Publisher MDPI

Date 2025 Feb 26

PMID 40002491

Authors

Alessandro Furia

Rocco Liguori

Vincenzo Donadio

Affiliations

Soon will be listed here.

Abstract

Background: Small-fiber neuropathy (SFN), affecting Aδ or C nerve fibers, is characterized by alterations of pain and temperature sensation, as well as autonomic dysfunction. Its diagnosis may still remain challenging as methods specifically assessing small nerve fibers are not always readily available, and standard techniques for large-fiber neuropathies, such as electroneuromyography, yield negative results. Still, skin biopsy for epidermal innervation and quantitative sensory testing allow for diagnosis in the presence of a congruent clinical picture.

Objectives: Many different etiologies may underlie small-fiber neuropathy, of which metabolic (diabetes mellitus/impaired glucose tolerance) and idiopathic remain prevalent. The aim of this narrative review is to provide a general picture of SFN while focusing on the different etiologies described in the literature in order to raise awareness of the variegated set of different causes of SFN and promote adequate diagnostic investigation.

Methods: The term "Small-Fiber Neuropathy" was searched on the PubMed database with its different recognized etiologies: the abstracts of the articles were reviewed and described in the article if relevant for a total of 40 studies.

Results: Many different disorders have been associated with SFN, even though often in the form of case reports or small case series.

Conclusions: Idiopathic forms of SFN remain the most prevalent in the literature, but association with different disorders (e.g., infectious, autoimmune) should prompt investigation for SFN in the presence of a congruent clinical picture (e.g., pain with neuropathic features).

References

Catterall W, Yu F . Painful channels. Neuron. 2006; 52(5):743-4. DOI: 10.1016/j.neuron.2006.11.017. View

Raicher I, Ravagnani L, Correa S, Dobo C, Mangueira C, Macarenco R . Investigation of nerve fibers in the skin by biopsy: technical aspects, indications, and contribution to diagnosis of small-fiber neuropathy. Einstein (Sao Paulo). 2022; 20:eMD8044. PMC: 9262281. DOI: 10.31744/einstein_journal/2022MD8044. View

Giannoccaro M, Donadio V, Gomis Perez C, Borsini W, Di Stasi V, Liguori R . Somatic and autonomic small fiber neuropathy induced by bortezomib therapy: an immunofluorescence study. Neurol Sci. 2011; 32(2):361-3. DOI: 10.1007/s10072-010-0475-2. View

Tan C, Chen Y, Chen C, Chao C, Liou H, Hsieh S . Painful neuropathy due to skin denervation after metronidazole-induced neurotoxicity. J Neurol Neurosurg Psychiatry. 2010; 82(4):462-5. DOI: 10.1136/jnnp.2009.194118. View

Galosi E, Falco P, Di Pietro G, Leone C, Esposito N, De Stefano G . The diagnostic accuracy of the small fiber neuropathy symptoms inventory questionnaire (SFN-SIQ) for identifying pure small fiber neuropathy. J Peripher Nerv Syst. 2022; 27(4):283-290. PMC: 10092576. DOI: 10.1111/jns.12513. View

Moisset X, Bouhassira D, Avez Couturier J, Alchaar H, Conradi S, Delmotte M . Pharmacological and non-pharmacological treatments for neuropathic pain: Systematic review and French recommendations. Rev Neurol (Paris). 2020; 176(5):325-352. DOI: 10.1016/j.neurol.2020.01.361. View

Cox J, Reimann F, Nicholas A, Thornton G, Roberts E, Springell K . An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006; 444(7121):894-8. PMC: 7212082. DOI: 10.1038/nature05413. View

Mucke M, Cuhls H, Radbruch L, Baron R, Maier C, Tolle T . Quantitative sensory testing (QST). English version. Schmerz. 2016; 35(Suppl 3):153-160. DOI: 10.1007/s00482-015-0093-2. View

Orstavik K, Norheim I, Jorum E . Pain and small-fiber neuropathy in patients with hypothyroidism. Neurology. 2006; 67(5):786-91. DOI: 10.1212/01.wnl.0000234035.13779.4a. View

10.

Misery L, Brenaut E, Garrec R, Abasq C, Genestet S, Marcorelles P . Neuropathic pruritus. Nat Rev Neurol. 2014; 10(7):408-16. DOI: 10.1038/nrneurol.2014.99. View

11.

Yang Y, Wang Y, Li S, Xu Z, Li H, Ma L . Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet. 2004; 41(3):171-4. PMC: 1735695. DOI: 10.1136/jmg.2003.012153. View

12.

Rosenberg M, Tervo T, Immonen I, Muller L, Gronhagen-Riska C, Vesaluoma M . Corneal structure and sensitivity in type 1 diabetes mellitus. Invest Ophthalmol Vis Sci. 2000; 41(10):2915-21. View

13.

Lauria G, Majorana A, Borgna M, Lombardi R, Penza P, Padovani A . Trigeminal small-fiber sensory neuropathy causes burning mouth syndrome. Pain. 2005; 115(3):332-337. DOI: 10.1016/j.pain.2005.03.028. View

14.

Yates J, Devere T, Sakurai-Burton S, Santi B, McAllister C, Frank K . Case Report: Angiostrongylus cantonensis Infection Presenting as Small Fiber Neuropathy. Am J Trop Med Hyg. 2022; 107(2):367-369. PMC: 9393434. DOI: 10.4269/ajtmh.22-0199. View

15.

Faber C, Hoeijmakers J, Ahn H, Cheng X, Han C, Choi J . Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2011; 71(1):26-39. DOI: 10.1002/ana.22485. View

16.

Nascimento O . Leprosy neuropathy: clinical presentations. Arq Neuropsiquiatr. 2013; 71(9B):661-6. DOI: 10.1590/0004-282X20130146. View

17.

Cazzato D, Castori M, Lombardi R, Caravello F, Bella E, Petrucci A . Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes. Neurology. 2016; 87(2):155-9. PMC: 4940063. DOI: 10.1212/WNL.0000000000002847. View

18.

Gemignani F, Giovanelli M, Vitetta F, Santilli D, Bellanova M, Brindani F . Non-length dependent small fiber neuropathy. a prospective case series. J Peripher Nerv Syst. 2010; 15(1):57-62. DOI: 10.1111/j.1529-8027.2010.00252.x. View

19.

Devigili G, Rinaldo S, Lombardi R, Cazzato D, Marchi M, Salvi E . Diagnostic criteria for small fibre neuropathy in clinical practice and research. Brain. 2019; 142(12):3728-3736. PMC: 6906595. DOI: 10.1093/brain/awz333. View

20.

Anderson D, Beecher G, Power C, Bridgland L, Zochodne D . A neuropathic pain syndrome associated with hantavirus infection. J Neurovirol. 2017; 23(6):919-921. PMC: 7095002. DOI: 10.1007/s13365-017-0576-2. View