Small‐fiber neuropathy (SFN) is a disorder of thinly myelinated Aδ and unmyelinated C fibers. SFN is clinically dominated by neuropathic pain and autonomic complaints, leading to a significant reduction in quality of life. According to international criteria, the diagnosis is established by the assessment of intraepidermal nerve fiber density and/or quantitative sensory testing. SFN is mainly associated with autoimmune diseases, sodium channel gene variants, diabetes mellitus, and vitamin B12 deficiencies, although in more than one half of patients no etiology can be identified. Recently, gain‐of‐function variants in the genes encoding for the Nav1.7, Nav1.8 and Nav1.9 sodium channel subunits have been discovered in SFN patients, enlarging the spectrum of underlying conditions. Sodium channel gene variants associated with SFN can lead to a diversity of phenotypes, including different pain distributions and presence or absence of autonomic symptoms. This suggests that SFN is part of a clinical continuum. New assessments might contribute to a better understanding of the cellular and molecular substrates of SFN and might provide improved diagnostic methods and trial designs in the future. Identification of the underlying mechanisms may inform the development of drugs that more effectively address neuropathic pain and autonomic symptoms of SFN.

BackgroundNeuropathic pain is common in peripheral neuropathy. Recent genetic studies have linked pathogenic voltage-gated sodium channel (VGSC) variants to human pain disorders. Our aims are to determine the frequency of SCN9A, SCN10A and SCN11A variants in patients with pure small fibre neuropathy (SFN), analyse their clinical features and provide a rationale for genetic screening.MethodsBetween September 2009 and January 2017, 1139 patients diagnosed with pure SFN at our reference centre were screened for SCN9A, SCN10A and SCN11A variants. Pathogenicity of variants was classified according to established guidelines of the Association for Clinical Genetic Science and frequencies were determined. Patients with SFN were grouped according to the VGSC variants detected, and clinical features were compared.ResultsAmong 1139 patients with SFN, 132 (11.6%) patients harboured 73 different (potentially) pathogenic VGSC variants, of which 50 were novel and 22 were found in ≥ 1 patient. The frequency of (potentially) pathogenic variants was 5.1% (n=58/1139) for SCN9A, 3.7% (n=42/1139) for SCN10A and 2.9% (n=33/1139) for SCN11A. Only erythromelalgia-like symptoms and warmth-induced pain were significantly more common in patients harbouring VGSC variants.Conclusion(Potentially) pathogenic VGSC variants are present in 11.6% of patients with pure SFN. Therefore, genetic screening of SCN9A, SCN10A and SCN11A should be considered in patients with pure SFN, independently of clinical features or underlying conditions.

Objective:This is the first double-blind, randomized, controlled trial evaluating the efficacy and safety of intravenous immunoglobulin (IVIg) versus placebo in patients with idiopathic small fiber neuropathy (I-SFN).Methods:Between July 2016 and November 2018, 60 Dutch patients with skin-biopsy proven idiopathic SFN randomly received a starting dose of IVIg (2 g/kg body weight) or matching placebo (0.9% saline). Subsequently, 3 additional infusions of IVIg (1 g/kg) or placebo were administered at 3-weekly intervals. The primary outcome was a 1-point change in Pain Intensity Numerical Rating Scale (PI-NRS) at 12 weeks compared to baseline.Results:Thirty patients received IVIg, and 30 received placebo. In both groups, 29 patients completed the trial. In 40% of patients receiving IVIg, the mean average pain was decreased with at least 1 point, compared to 30% of the patients receiving placebo (p-value 0.588, OR 1.56, 95%CI 0.53-4.53). No significant differences were found on any of the other pre-specified outcomes including general wellbeing, autonomic symptoms, and overall functioning and disability.Conclusions:This RCT showed that IVIg treatment had no significant effect on pain in patients with painful idiopathic SFN.