CoChat
Sign Up
Cited by 72Hereditary Neurological DisordersPain Mechanisms and TreatmentsPeripheral Neuropathies and Disorders

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

Open access
Egenolf, Nadine, Altenschildesche, Caren Meyer zu, Kreß, Luisa, Eggermann, Katja, Namer, Barbara, Gross, Franziska, Klitsch, Alexander, Malzacher, Tobias +5 more·2021·Therapeutic Advances in Neurological Disorders
DOI 10.1177/17562864211004318PMC PMC8283814
Open this paper in CoChat — free account

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1177/17562864211004318

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Several healthy men in the control cohort had a reduced IENFD, as shown in previous studies, although all participants were screened negative for known causes of small fiber pathology.

    “Furthermore, several healthy men in our control cohort had a reduced IENFD as already shown in previous studies13,19 although all participants were screened negative for known causes of small fiber pathology.”

    From Pain and small fiber pathology in men with fibromyalgia syndrome (2024) · cites this paper as [13]

    The Results section (‘Four skin innervation patterns in SFN and healthy controls’; page unavailable) reports reduced distal IENFD in 29 of 180 healthy controls. The Methods section (‘Small fiber tests’; page unavailable) says the control cohort included men, but the paper does not say whether any of the controls with reduced IENFD were men. Its screening and exclusion criteria are described for patients, not for the healthy controls. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 38

  1. [1]Terkelsen AJ Karlsson P Lauria G, et al. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. Lancet Neurol 2017; 16: 934– 944. 29029847
  2. [2]Lacomis D. Small-fiber neuropathy. Muscle Nerve 2002; 26: 173– 188. 12210380
  3. [3]Stewart JD Low PA Fealey RD. Distal small fiber neuropathy: results of tests of sweating and autonomic cardiovascular reflexes. Muscle Nerve 1992; 15: 661– 665. 1324425
  4. [4]Devigili G Tugnoli V Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain 2008; 131: 1912– 1925. 18524793 PMC2442424
  5. [5]Devigili G Rinaldo S Lombardi R, et al. Diagnostic criteria for small fibre neuropathy in clinical practice and research. Brain 2019; 142: 3728– 3736. 31665231 PMC6906595
  6. [6]Haroutounian S Todorovic MS Leinders M, et al. Diagnostic criteria for idiopathic small fiber neuropathy: a systematic review. Muscle Nerve 2020; 63: 170– 177. 32989823
  7. [8]Joint Task Force of the EFNS and the PNS; Lauria G Hsieh ST, et al. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Peripher Nerv Syst 2010; 15: 79– 92. 20626771
  8. [9]Freeman R Gewandter JS Faber CG, et al. Idiopathic distal sensory polyneuropathy: ACTTION diagnostic criteria. Neurology 2020; 95: 1005– 1014. 33055271 PMC7734920
  9. [10]Bouhassira D Attal N Fermanian J, et al. Development and validation of the Neuropathic Pain Symptom Inventory. Pain 2004; 108: 248– 257. 15030944
  10. [11]Sommer C Richter H Rogausch JP, et al. A modified score to identify and discriminate neuropathic pain: a study on the German version of the Neuropathic Pain Symptom Inventory (NPSI). BMC Neurol 2011; 11: 104. 21861889 PMC3180265
  11. [12]Von Korff M Ormel J Keefe FJ, et al. Grading the severity of chronic pain. Pain 1992; 50: 133– 149. 1408309
  12. [14]Meyer TD Hautzinger M. Allgemeine Depressions-Skala (ADS) Normierung an Minderjährigen und Erweiterung zur Erfassung manischer Symptome (ADMS). Diagnostica 2001; 47: 208– 215.
  13. [15]Rolke R Baron R Maier C, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 2006; 123: 231– 243. 16697110
  14. [16]Magerl W Krumova EK Baron R, et al. Reference data for quantitative sensory testing (QST): refined stratification for age and a novel method for statistical comparison of group data. Pain 2010; 151: 598– 605. 20965658
  15. [17]Üçeyler N Kafke W Riediger N, et al. Elevated proinflammatory cytokine expression in affected skin in small fiber neuropathy. Neurology 2010; 74: 1806– 1813. 20513817
  16. [18]Lauria G Bakkers M Schmitz C, et al. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst 2010; 15: 202– 207. 21040142
  17. [19]Kreß L Hofmann L Klein T, et al. Differential impact of keratinocytes and fibroblasts on nociceptor degeneration and sensitization in small fiber neuropathy. Pain. Epub ahead of print 12 November 2020. DOI: 10.1097/j.pain.0000000000002122. 33196576 · DOI
  18. [20]Kalteniece A Ferdousi M Adam S, et al. Corneal confocal microscopy is a rapid reproducible ophthalmic technique for quantifying corneal nerve abnormalities. PLoS One 2017; 12: e0183040. 28817609 PMC5560560
  19. [21]Üçeyler N Zeller D Kahn AK, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain 2013; 136: 1857– 1867. 23474848
  20. [22]Lefaucheur JP Ahdab R Ayache SS, et al. Pain-related evoked potentials: a comparative study between electrical stimulation using a concentric planar electrode and laser stimulation using a CO2 laser. Neurophysiol Clin 2012; 42: 199– 206. 22632868
  21. [23]Hagbarth KE. Microelectrode recordings from human peripheral nerves (microneurography). Muscle Nerve Suppl 2002; 11: S28– 35. 12116283
  22. [24]Schmelz M Forster C Schmidt R, et al. Delayed responses to electrical stimuli reflect C-fiber responsiveness in human microneurography. Exp Brain Res 1995; 104: 331– 336. 7672025
  23. [25]Piscosquito G Provitera V Mozzillo S, et al. The analysis of epidermal nerve fibre spatial distribution improves the diagnostic yield of skin biopsy. Neuropathol Appl Neurobiol. Epub ahead of print 19 August 2020. DOI: 10.1111/nan.12651. 32750736 · DOI
  24. [26]Üçeyler N Vollert J Broll B, et al. Sensory profiles and skin innervation of patients with painful and painless neuropathies. Pain 2018; 159: 1867– 1876. 29863528
  25. [27]Scherens A Maier C Haussleiter IS, et al. Painful or painless lower limb dysesthesias are highly predictive of peripheral neuropathy: comparison of different diagnostic modalities. Eur J Pain 2009; 13: 711– 718. 18789872
  26. [29]Olausson H Lamarre Y Backlund H, et al. Unmyelinated tactile afferents signal touch and project to insular cortex. Nat Neurosci 2002; 5: 900– 904. 12145636
  27. [30]Morrison I Loken LS Minde J, et al. Reduced C-afferent fibre density affects perceived pleasantness and empathy for touch. Brain 2011; 134: 1116– 1126. 21378097
  28. [31]Tavakoli M Marshall A Pitceathly R, et al. Corneal confocal microscopy: a novel means to detect nerve fibre damage in idiopathic small fibre neuropathy. Exp Neurol 2010; 223: 245– 250. 19748505 PMC2938826
  29. [32]Özgül OS Maier C Enax-Krumova EK, et al. High test-retest-reliability of pain-related evoked potentials (PREP) in healthy subjects. Neurosci Lett 2017; 647: 110– 116. 28342940
  30. [33]Üçeyler N Kahn AK Kramer D, et al. Impaired small fiber conduction in patients with Fabry disease: a neurophysiological case-control study. BMC Neurol 2013; 13: 47. 23705943 PMC3672069
  31. [34]Thaisetthawatkul P Fernandes JAM Herrmann DN. Contribution of Qsart to the diagnosis of small fiber neuropathy. Muscle Nerve 2013; 48: 883– 888. 23649502
  32. [35]Kamel JT Vogrin SJ Knight-Sadler RJ, et al. Combining cutaneous silent periods with quantitative sudomotor axon reflex testing in the assessment of diabetic small fiber neuropathy. Clin Neurophys 2015; 126: 1047– 1053. 25449560
  33. [36]Berger MJ Kimpinski K. Test-retest reliability of quantitative sudomotor axon reflex testing. J Clin Neurophysiol 2013; 30: 308– 312. 23733097
  34. [37]Tavee JO Polston D Zhou L, et al. Sural sensory nerve action potential, epidermal nerve fiber density, and quantitative sudomotor axon reflex in the healthy elderly. Muscle Nerve 2014; 49: 564– 569. 23893404
  35. [38]de Greef BTA Hoeijmakers JGJ Gorissen-Brouwers CML, et al. Associated conditions in small fiber neuropathy - a large cohort study and review of the literature. Eur J Neurol 2018; 25: 348– 355. 29112785 PMC5814938
  36. [39]Brouwer BA Merkies ISJ Gerrits MM, et al. Painful neuropathies: the emerging role of sodium channelopathies. J Peripher Nerv Syst 2014; 19: 53– 65. 25250524
  37. [40]Castoro R Simmons M Ravi V, et al. SCN11A Arg225Cys mutation causes nociceptive pain without detectable peripheral nerve pathology. Neurol Genet 2018; 4: e255. 30046661 PMC6055356
  38. [41]Rage M Van Acker N Knaapen MWM, et al. Asymptomatic small fiber neuropathy in diabetes mellitus: investigations with intraepidermal nerve fiber density, quantitative sensory testing and laser-evoked potentials. J Neurol 2011; 258: 1852– 1864. 21472496

Cited by

Sorted by citations

Authors
Egenolf, N., Altenschildesche, C. M. Z., Kreß, L., Eggermann, K., Namer, B., Gross, F., Klitsch, A., Malzacher, T., Kampik, D., Malik, R. A., Kurth, I., Sommer, C., & Üçeyler, N.
Affiliations
  • University of Würzburg (DE)
  • RWTH Aachen University (DE)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • Weill Cornell Medical College in Qatar (QA)
Corresponding author
Üçeyler, Nurcan
ORCID
Venue
Therapeutic Advances in Neurological Disorders
Publisher
SAGE Publications
Published
2021-01
Volume
14
Pages
17562864211004318-17562864211004318
ISSN
  • 1756-2856 (ISSN-L)
  • 1756-2864
DOI
10.1177/17562864211004318
PMC
PMC8283814
OpenAlex
W3138292339
Cited by
72
References
3
Citations by year
2026: 6 · 2025: 16 · 2024: 17 · 2023: 14 · 2022: 15 · 2021: 4
FWCI
5.76
Type
journal article
Language
en
Update notices
correction (2021-07-31)
Open access
Licence
Locations
  • Therapeutic Advances in Neurological Disorders (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by-nc)
  • RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
  • OPUS FAU (Kooperativer Bibliotheksverbund Berlin-Brandenburg (KOBV), on behalf of the Universitätsbibliothek Erlangen-Nürnberg) (submittedVersion, cc-by-nc)
  • RWTH Publications (RWTH Aachen)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
Keywords
small fiber neuropathy, diagnosis, intraepidermal nerve fiber density, skin punch biopsy, corneal confocal microscopy, pain-related evoked potentials, quantitative sudomotor axon reflex test, quantitative sensory testing, genetic testing, phenotyping, neurological examination

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review