In Vivo Confocal Microscopy of the Cornea in Diagnosing Small Fibre Neuropathy: A Cross-Sectional Observational Study

<b>Objectives:</b> The aim of this study was to assess the accuracy of corneal in vivo confocal microscopy (IVCM) in the diagnostic process of small fibre neuropathy (SFN) compared to skin biopsy. <b>Methods:</b> This cross-sectional observational study was performed at the Eye Hospital and Institute of Neurophysiology, University Medical Centre Ljubljana, and included 35 patients with a clinical picture of SFN. All patients underwent a neurological exam that included an SFN questionnaire, standard skin biopsy, and ophthalmological assessment, including corneal IVCM. <b>Results:</b> Skin biopsy confirmed SFN in 14/35 patients (40%). These patients had a significantly shorter corneal nerve fibre length (CNFL) compared to those with negative biopsy (13.67 ± 2.99 mm/mm² vs. 16.27 ± 3.54 mm/mm², <i>p</i> = 0.030), as well as reduced corneal nerve branch density (CNBD) (36.68 ± 14.68 branches/mm² vs. 48.81 ± 17.83 branches/mm², <i>p</i> = 0.042). CNFL reduction below the 5th percentile was proven in 13/35 patients, yielding 64.3% sensitivity (95% CI: 35.1-87.2%) and 80.9% specificity (95% CI: 58.1-94.6%) compared to skin biopsy. In idiopathic SFN, negative IVCM results aligned with negative biopsies in 90% (95% CI: 55.5-99.8%) of cases. Meanwhile, in secondary SFN, positive IVCM results detected evidence of peripheral neurodegeneration in an additional 27.3% (95% CI: 6-61%) with negative skin biopsy. <b>Conclusion:</b> CNFL reduction in corneal IVCM demonstrated significant diagnostic value for SFN. Since skin biopsy findings do not always correspond with IVCM findings, corneal IVCM could be applied as a complementary tool to standard skin biopsy rather than as a replacement. It might be additionally useful for detecting patchy pattern presentations of SFN, excluding neuropathy in idiopathic SFN, and detecting neuropathy in biopsy-negative secondary SFN. In patients with positive IVCM, it could also be used as a primary tool for follow-up monitoring.