By Mary L. Vo, MD, PharmD

Assistant Professor of Neurology, Weill Cornell Medical College

Dr. Vo reports she is an advisory board member for CSL Behring, is a consultant and advisory board member for Alexion Pharmaceuticals, and receives grant/research support from Takeda Pharmaceuticals.

SYNOPSIS: Multiple clinical tools have emerged to assess small fiber nerve dysfunction, but validated diagnostic criteria are needed to optimize diagnostic sensitivity, support clinical management, and facilitate patient selection for clinical trials.

SOURCE: Devigili G, Rinaldo S, Lombardi R, et al. Diagnostic criteria for small fibre neuropathy in clinical practice and research. Brain 2019;142:3728-3736.

Small fiber neuropathy (SFN) is a heterogenous condition characterized by impairment of Aδ and C nociceptive fibers involved in sensory perception to pain, temperature, and itch in addition to regulation of autonomic functions. Although various phenotypes have been described, a classic presentation is burning pain and paresthesias affecting the distal extremities. Given the clinical heterogeneity, symptom reporting alone is not reliable as a screening tool.1 Clinical examination findings can include lower temperature and pain perception in a distal gradient, although the exam can be normal in some patients. Nerve conduction studies are important to identify patients with large-fiber neuropathy but are normal in patients with isolated small fiber dysfunction.

Intraepidermal nerve fiber density (IENFD) and quantitative sensory testing (QST) are the most sensitive and commonly used diagnostic tools for SFN. IENFD obtained by skin biopsy of the distal leg is a reliable and widely used confirmatory test for SFN. Its diagnostic accuracy has been improved by availability of updated normative data.2 QST is designed to assess Aδ, Aβ, and C fiber sensory function and involves sequential application of thermal and mechanical stimuli to multiple standardized sites in the extremities while evaluating for abnormal sensation, allodynia, hyperalgesia, and aftersensation compared to published reference values.3 Thermoregulatory, autonomic, somatic, and sudomotor function tests have been developed to complement the clinical evaluation, but generally are limited to specialized centers. Validated diagnostic criteria combining clinical evaluation and diagnostic tools are needed to optimize diagnostic sensitivity, support clinical management, and facilitate patient selection for clinical trials.

Devigili et al compared the sensitivity of the Besta criteria4 and the NEURODIAB5 criteria for definite SFN. The Besta criteria require two objective clinical signs of small fiber impairment plus abnormal QST or IENFD. In contrast, the NEURODIAB criteria require the presence of a single clinical sign, a normal sural nerve conduction study, and either abnormal QST or IEFND. In the reappraisal portion of the study, the authors assessed historical clinical, IENFD, and QST data from 150 patients included in the original Besta study4 using updated IENFD reference values. Results showed a high level of agreement between the Besta and NEURODIAB criteria for definite SFN (area under the curve 0.98; 100% sensitivity; 98.5% specificity). The prospective validation study included 352 new and follow-up patients with suspected sensory neuropathy evaluated at a single Italian neurological center from January 2009 to September 2017. Symptom inventory questionnaires, detailed neurological exam, electrophysiologic testing, IENFD, and QST were obtained for all patients. A statistical analysis was performed using unpaired t-test and Mann-Whitney test to compare normally and non-normally distributed values, respectively. Paired t-test and Pearson R2 coefficient test were used to compare clinical exam to QST.

A total of 149 of 187 symptomatic patients without clinical or electrodiagnostic evidence of large fiber neuropathy satisfied the Besta criteria for definite SFN. An additional 34 patients were designated as possible SFN based on symptom reporting, but had normal clinical evaluation, IENFD, and QST testing. Four patients who had symptoms and abnormal QST also were deemed possible SFN. The NEURODIAB criteria was highly concordant with the Besta criteria (sensitivity 94.6%; specificity 99%), supporting the validity and reliability of the clinical assessment. Moreover, IENFD had higher sensitivity, specificity, and diagnostic efficacy compared to QST. At the time of follow-up, 29 of 98 patients with definite SFN were reclassified as having large fiber neuropathy or sensory neuronopathy. Eight patients with definite SFN based on abnormal QST and IENFD developed clinical exam abnormalities at the time of follow-up. Nineteen of 38 patients with possible SFN based on symptoms alone reported complete resolution and had a normal examination. Four patients with possible SFN based solely on abnormal QST also had normal clinical examinations and IENFD at follow-up. The combination of clinical examination, IENFD, and QST provides an accurate and reliable screen for SFN. Compared to QST, IENFD showed higher sensitivity, specificity, and diagnostic efficiency.


The high concordance between Besta and NEURODIAB highlight the reliability of a focused clinical exam as a screening tool for patients presenting with classical symptoms of SFN, particularly when at least two clinical signs are present. IENFD remains the most sensitive confirmatory test available for diagnosis of SFN. QST is a valid technique that can further increase diagnostic sensitivity for clinical research, but its clinical utility is limited by the technical and time-consuming nature of the test. The high reliability and sensitivity of the combined profile of clinical examination, QST, and IENFD would improve patient selection for clinical trials and serve as reliable outcome measures for future disease-modifying therapies.


  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.
  2. 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.
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  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.
  5. Tesfaye S, Boulton AJ, Dyck PJ, et al. Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010;33:2285-2293.