Diagnostic Accuracy of The Water Immersion Wrinkle Test for Small Fiber Neuropathy

NCT07255573 | Completed

• 1 other identifier: 14202
• Study Type: observational
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

Small-fiber neuropathy (SFN) affects A-delta and C fibers and commonly presents with sensory symptoms and dysautonomia. Confirmation often relies on specialized tests such as quantitative sensory testing (QST) and sympathetic skin response (SSR). This prospective, single-center observational diagnostic-accuracy study will estimate the performance of the Water-Immersion Wrinkle Test (WIWT) for detecting SFN in adults evaluated by a neuromuscular service. The composite reference standard is specialist clinical assessment plus abnormality on ≥1 validated scale (Utah Early Neuropathy Scale \[UENS\] or modified Toronto Clinical Neuropathy Score \[mTCNS\]). The index procedure (WIWT) is standardized as follows: both hands immersed to at least the distal interphalangeal crease for 15 minutes; immersion begins at 43-44 °C with expected passive cooling of \~2 °C every 5 minutes; temperature measured at 0, 5, 10 and 15 minutes; no water is added or replaced during immersion. After gentle drying, standardized photographs are obtained and wrinkling grades (0-4) are recorded for digits 2-5; the bilateral summed score is classified abnormal \<24 and normal ≥24. Examiners for WIWT, QST, and SSR are mutually blinded. The primary outcome is WIWT sensitivity and specificity versus the composite reference at baseline. Secondary outcomes include ROC area under the curve (AUC), positive/negative predictive values, and inter- and intra-rater reliability (intraclass correlation coefficients). Recruitment is ongoing; anticipated primary completion: November 2025.

Conditions

Small-Fiber Neuropathy; Dysautonomia

Keywords

small-fiber neuropathy; dysautonomia; water-immersion wrinkle test; QST; SSR

Outcome Measures

Primary Outcomes (1)

• Sensitivity and specificity of WIWT (%) vs composite reference (clinical + UENS/mTCNS abnormality)

  WIWT scoring: Each fingertip (digits 2-5 of both hands) is graded 0-4 after immersion (0 = no wrinkling; 4 = marked wrinkling). Per-hand sum 0-16; bilateral sum 0-32 (higher = more wrinkling/normal sympathetic function). Threshold to define test result: bilateral sum \<24 = abnormal, ≥24 = normal. Procedure: Hands immersed 15 min, starting 43-44 °C with passive cooling ≈2 °C/5 min to \~37-38 °C; temperature checked at 0, 5, 10 min; no water added or replaced; standardized photographs scored by blinded raters. Reference standard: Neuromuscular specialist clinical assessment plus abnormality on ≥1 validated scale (UENS or mTCNS). Metrics: Sensitivity = TP/(TP+FN); Specificity = TN/(TN+FP); both reported as percent (%) with 95% CIs.

  Baseline (single visit; same-day completion of all tests)

Secondary Outcomes (5)

• ROC Area Under the Curve (AUC) for WIWT

  Baseline

• Positive and Negative Predictive Values (PPV, NPV) of WIWT

  Baseline

• Inter-rater Reliability of WIWT Wrinkle Scoring (ICC)

  Within 7 days (two image-rating sessions separated by 48 h-7 days).

• Intra-rater Reliability of WIWT Wrinkle Scoring (ICC)

  48 h-7 days between sessions.

• Comparative Diagnostic Performance: WIWT vs QST and SSR (AUC, Se/Sp)

  Baseline

Study Arms (2)

SFN Group

Adults evaluated in a tertiary neuromuscular clinic who, after baseline assessment, are classified as having small-fiber neuropathy (SFN) by the prespecified composite reference standard. The reference integrates (1) neuromuscular specialist clinical judgment (history and focused examination) and (2) abnormality on ≥1 validated scale (UENS or mTCNS) using published scoring rules. Group assignment is independent of WIWT, QST, or SSR results; these tests may be performed as index/comparator procedures but do not define cohort membership.

Control Group

Adults evaluated in a tertiary neuromuscular clinic who, after baseline assessment, are classified as No Small-Fiber Neuropathy (No SFN) by the prespecified composite reference. This cohort includes healthy adult volunteers with no neuropathic symptoms or signs, a normal neurological examination, and normal UENS and mTCNS scores per published rules. Group assignment is independent of WIWT, QST, or SSR results; these tests may be performed as index/comparator procedures but do not define cohort membership.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Adults evaluated at the Neuromuscular Department and Neurophysiology Laboratory of Hospital Británico de Buenos Aires (Argentina), a tertiary referral center. The source population includes consecutive clinic patients referred for assessment of suspected small-fiber neuropathy and healthy adult volunteers recruited from the hospital community. Recruitment occurs during routine outpatient activity; all index/comparator testing is performed on site.

You may qualify if:

• Age ≥ 18 years.
• Suspicion of small-fiber neuropathy based on history and/or physical examination by a neuromuscular neurology specialist.
• Sensory and motor nerve conduction studies within normal limits.
• Prior QST performed, regardless of result.
• Prior SSR performed, regardless of result.

You may not qualify if:

• Patients under 18 years.
• Individuals who do not wish to participate in the study or who decline informed consent.
• Patients with any contraindication to any of the aforementioned studies.
• Neurophysiological studies demonstrating large-fiber involvement.

Sponsors & Collaborators

• HOSPITAL BRITANICO DE BUENOS AIRES: lead

Study Sites (1)

Hospital Britanico de Buenos Aires

Buenos Aires, Buenos Aires F.D., 1428, Argentina

Location

Related Publications (17)

• Piedrafita Vico LA, Reisin R, Gonorazky S. Teaching NeuroImage: Absence of Wrinkles in Small Fiber Neuropathy. Neurology. 2022 Nov 22;99(21):962-963. doi: 10.1212/WNL.0000000000201320. Epub 2022 Sep 13. No abstract available.

  PMID: 36100436 BACKGROUND

• Clark CV, Pentland B, Ewing DJ, Clarke BF. Decreased skin wrinkling in diabetes mellitus. Diabetes Care. 1984 May-Jun;7(3):224-7. doi: 10.2337/diacare.7.3.224.

  PMID: 6734390 BACKGROUND

• Braham J, Sadeh M, Sarova-Pinhas I. Skin wrinkling on immersion of hands: a test of sympathetic function. Arch Neurol. 1979 Feb;36(2):113-4. doi: 10.1001/archneur.1979.00500380083013.

  PMID: 420620 BACKGROUND

• Teoh HL, Chow A, Wilder-Smith EP. Skin wrinkling for diagnosing small fibre neuropathy: comparison with epidermal nerve density and sympathetic skin response. J Neurol Neurosurg Psychiatry. 2008 Jul;79(7):835-7. doi: 10.1136/jnnp.2007.140947. Epub 2008 Feb 12.

  PMID: 18270233 BACKGROUND

• Wilder-Smith EP, Guo Y, Chow A. Stimulated skin wrinkling for predicting intraepidermal nerve fibre density. Clin Neurophysiol. 2009 May;120(5):953-8. doi: 10.1016/j.clinph.2009.03.011. Epub 2009 Apr 16.

  PMID: 19375384 BACKGROUND

• Wilder-Smith EP. Stimulated skin wrinkling as an indicator of limb sympathetic function. Clin Neurophysiol. 2015 Jan;126(1):10-6. doi: 10.1016/j.clinph.2014.08.007. Epub 2014 Sep 2.

  PMID: 25216595 BACKGROUND

• Cales L, Weber RA. Effect of water temperature on skin wrinkling. J Hand Surg Am. 1997 Jul;22(4):747-9. doi: 10.1016/s0363-5023(97)80141-4.

  PMID: 9260639 BACKGROUND

• Singleton JR, Bixby B, Russell JW, Feldman EL, Peltier A, Goldstein J, Howard J, Smith AG. The Utah Early Neuropathy Scale: a sensitive clinical scale for early sensory predominant neuropathy. J Peripher Nerv Syst. 2008 Sep;13(3):218-27. doi: 10.1111/j.1529-8027.2008.00180.x.

  PMID: 18844788 BACKGROUND

• Abraham A, Barnett C, Katzberg HD, Lovblom LE, Perkins BA, Bril V. Toronto Clinical Neuropathy Score is valid for a wide spectrum of polyneuropathies. Eur J Neurol. 2018 Mar;25(3):484-490. doi: 10.1111/ene.13533. Epub 2017 Dec 26.

  PMID: 29194856 BACKGROUND

• Galosi E, Falco P, Di Pietro G, Leone C, Esposito N, De Stefano G, Di Stefano G, Truini A. The diagnostic accuracy of the small fiber neuropathy symptoms inventory questionnaire (SFN-SIQ) for identifying pure small fiber neuropathy. J Peripher Nerv Syst. 2022 Dec;27(4):283-290. doi: 10.1111/jns.12513. Epub 2022 Oct 5.

  PMID: 36175394 BACKGROUND

• Bril V, Tomioka S, Buchanan RA, Perkins BA; mTCNS Study Group. Reliability and validity of the modified Toronto Clinical Neuropathy Score in diabetic sensorimotor polyneuropathy. Diabet Med. 2009 Mar;26(3):240-6. doi: 10.1111/j.1464-5491.2009.02667.x.

  PMID: 19317818 BACKGROUND

• Zilliox LA, Ruby SK, Singh S, Zhan M, Russell JW. Clinical neuropathy scales in neuropathy associated with impaired glucose tolerance. J Diabetes Complications. 2015 Apr;29(3):372-7. doi: 10.1016/j.jdiacomp.2015.01.011. Epub 2015 Feb 3.

  PMID: 25690405 BACKGROUND

• Novak P. Electrochemical skin conductance: a systematic review. Clin Auton Res. 2019 Feb;29(1):17-29. doi: 10.1007/s10286-017-0467-x. Epub 2017 Sep 26.

  PMID: 28951985 BACKGROUND

• Terkelsen AJ, Karlsson P, Lauria G, Freeman R, Finnerup NB, Jensen TS. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. Lancet Neurol. 2017 Nov;16(11):934-944. doi: 10.1016/S1474-4422(17)30329-0.

  PMID: 29029847 BACKGROUND

• Devigili G, Rinaldo S, Lombardi R, Cazzato D, Marchi M, Salvi E, Eleopra R, Lauria G. Diagnostic criteria for small fibre neuropathy in clinical practice and research. Brain. 2019 Dec 1;142(12):3728-3736. doi: 10.1093/brain/awz333.

  PMID: 31665231 BACKGROUND

• Gendre T, Lefaucheur JP, Nordine T, Baba-Amer Y, Authier FJ, Devaux J, Creange A. Characterizing Acute-Onset Small Fiber Neuropathy. Neurol Neuroimmunol Neuroinflamm. 2024 Mar;11(2):e200195. doi: 10.1212/NXI.0000000000200195. Epub 2024 Jan 3.

  PMID: 38170952 BACKGROUND

• Devigili G, Cazzato D, Lauria G. Clinical diagnosis and management of small fiber neuropathy: an update on best practice. Expert Rev Neurother. 2020 Sep;20(9):967-980. doi: 10.1080/14737175.2020.1794825. Epub 2020 Jul 23.

  PMID: 32654574 BACKGROUND

MeSH Terms

Conditions

Small Fiber Neuropathy; Autonomic Nervous System Diseases

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases

Study Officials

• Lucas A Piedrafita Vico, MD

  Hospital Británico de Buenos Aires

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 20, 2025
• First Posted: December 1, 2025
• Study Start: November 1, 2024
• Primary Completion: November 1, 2025
• Study Completion: November 20, 2025
• Last Updated: December 8, 2025

Record last verified: 2025-12

Locations

AR (1)