Use of Intravenous Immunoglobulin Therapy for Small Fiber Neuropathy: A Systematic Review of Current Clinical...

Small fiber neuropathy (SFN) is a clinically heterogeneous and difficult-to-manage condition for which intravenous immunoglobulin (IVIG) is increasingly used despite inconsistent evidence and substantial cost. We therefore systematically evaluated the clinical effectiveness of IVIG in SFN, with attention to the variation across etiological subtypes. In accordance with PRISMA 2020 guidelines, the review protocol was registered in PROSPERO (CRD420251247780). PubMed, Embase, and the Cochrane Library databases were searched from inception to 31 August 2025. Eligible studies included adults with clinically or histologically confirmed SFN receiving IVIG, reporting at least one predefined outcome. Two reviewers independently screened and extracted data. Risk of bias was assessed, and certainty of evidence was evaluated using GRADE. Due to heterogeneity, a narrative synthesis was performed. A total of seven studies (2 randomized controlled trials [RCTs], 5 observational studies) involving 165 IVIG-treated patients were included. RCTs in idiopathic or broadly defined SFN showed no significant benefit of IVIG over placebo in pain reduction, autonomic symptoms, quality of life, or intraepidermal nerve fiber density. In contrast, observational studies reported improvements in pain, autonomic function, and, in some cases, nerve fiber density, particularly in autoimmune-associated SFN subtypes. However, these studies were limited by small sample sizes, lack of controls, and high risk of bias. GRADE assessment indicated low to very low certainty of evidence across outcomes. Current evidence does not support routine IVIG use in SFN. Apparent benefits in selected immune-mediated subtypes remain inconclusive and warrant further research with biologically stratified, adequately powered trials.