Background & Aims

Skin punch biopsy is a well-established method to determine intraepidermal nerve fiber density (IENFD) [1, 2]. Small fiber neuropathy (SFN), a sensory and painful neuropathy, is typically associated with a reduction of the IENFD [1]. Although skin punch biopsy is a widespread tool in SFN diagnostics, it is invasive and no gold-standard. Seeking a reliable non-invasive alternative by using readily available biomaterial, blood sphingolipids and amino acids are promising. Recent studies show sphingolipids and amino acids, which are structural components of neuronal membranes, to be involved in peripheral nerve impairment [3-5]. In our study, we aimed to analyze the blood sphingolipid profiles of patients with SFN and investigate their predictive value for skin innervation.

Methods

We recruited 79 patients with a medical history and a clinical phenotype suggestive of SFN. Patients underwent a skin punch biopsy taken from the distal leg to determine the IENFD. Based on the group median, the patient cohort was subdivided into patients with a low fiber density (LFD) and patients with a high fiber density (HFD). Venous blood was drawn after overnight fasting to determine the following parameters: plasma glucose, HbA1c, cholesterols (high (HDL) and low (LDL) density lipoprotein), and triglycerides (TG). We further analyzed plasma 1-deoxysphingolipids and the amino acids alanine, serine, and glycine as basic components of sphingolipid synthesis. We used receiver operating characteristic (ROC) curve analysis to calculate the predictive value of the mentioned parameters.

Results

Median IENFD at the lower leg of our patient group was 5.3 fibers/mm. 39/79 (49%) patients were defined as patients with LFD (median IENFD 2.2 [0 – 4.5] fibers/mm) and 40/79 (51%) as patients with HFD (median IENFD 7.1 [5.3 – 16.3] fibers/mm). Fasting plasma glucose (p < 0.001) and TG levels (p < 0.01) were higher in patients with LFD compared to HFD, while HDL was lower in patients with LFD compared to HFD (p < 0.001). Expression of 1- deoxysphingolipids was higher in patients with LFD than in patients with HFD (p < 0.01), while the expression of amino acids did not differ in subgroup comparison. 1-deoxysphingolipids correlated inversely with distal IENFD in patients with LFD (p < 0.01, r2 = 0.19). Highest predictive value for distal IENFD was reached for fasting plasma glucose (area under the curve (AUC) = 0.76) and 1-deoxysphingolipids (AUC = 0.71). Combined with HDL and TG levels, we achieved an accuracy of 80% to predict epidermal denervation.

Conclusions

We provide a comprehensive analysis of glucose, lipid parameters, and deoxysphingolipids in patients with SFN. Our data reveal correlations between distinct blood parameters and IENFD on skin punch biopsies. The high predictive accuracy reached by combining glucose, lipid, and deoxysphingolipids provides – additional to the typical medical history and the respective findings in clinical examination – a promising tool in diagnosing SFN.

References

1.Devigili, G., et al., The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain, 2008. 131(Pt 7): p. 1912-25.
2.Lauria, G., et al., EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy. Eur J Neurol, 2005. 12(10): p. 747-58.
3.Handzlik, M.K., et al., Insulin-regulated serine and lipid metabolism drive peripheral neuropathy. Nature, 2023. 614(7946): p. 118-124.
4.Penno, A., et al., Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem, 2010. 285(15): p. 11178-87.
5.Kramer, R., et al., Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy. Faseb j, 2015. 29(11): p. 4461-72.

Presenting Author

Luisa Kreß

Poster Authors

Luisa Kreß, Dr. med.

University Hospital Würzburg

Lead Author

Caren Meyer zu Altenschildesche

Department of Neurology, University Hospital Wuerzburg, Germany

Lead Author

Nadine Egenolf

Department of Neurology, University Hospital Wuerzburg, Germany

Lead Author

Thorsten Hornemann

Department of Biochemistry, University of Zurich, Switzerland

Lead Author

Nurcan Üçeyler

MD

Department of Neurology, University of Würzburg, Germany

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Neuropathic Pain - Peripheral