Looking for early and non-invasive markers: possible role of LEPs
Aims: To study laser-evoked potentials (LEPs) in patients with type 2 diabetes (T2DM), compared to controls (C), and to analyze the associations between LEPs changes and cardiovascular autonomic reflex tests (CARTs), in the T2DM group.
Methods: Thirty three patients with T2DM and 33 age-matched C were retrospectively enrolled. LEPs (diameter 5 mm, duration 5 ms, wavelength 1.4 µm, energy max 6 J) were collected from hands and feet stimulation, in both groups. The subjects were asked to rate the intensity of the stimulus to detect the threshold able to activate Aδ fibers and to elicit a pinprick sensation (at least 4 on NRS). LEPs were recorded by EMG, positioning electrodes on the frontal area, the vertex area and the temporal area. Peak latency and peak-to-peak amplitude of the N2-P2 vertex complex were measured. The T2DM group underwent blood sample evaluation, clinical examination (ankle reflexes, vibratory perception threshold, 10 g monofilament sensitivity), MNSI and DN4 questionnaire. The four CARTs were performed. Correlation analysis was implemented among LEP results and clinical, laboratory variables and CARTs.
Results: N2/P2 complex amplitude was significantly reduced in T2DM compared to C, with greater involvement in the lower limbs (mean Amp 14.5 ± 4.7 uV vs. 21.1 ± 8.7 uV , p = 0.001). LEP amplitude reduction was associated with elevated HbA1c levels (p=0.01) and longer disease duration (p=0.02). Only a near-significant correlation between abnormal LEP results and Valsalva Maneuver was observed (p=0.07).
Conclusions: LEP alterations are detectable in T2DM, also in early stages. No significant correlations between LEP alteration and CARTs were found.
Comments: The idea of finding an early and non-invasive marker for neuropathy is certainly an ambitious goal. Previous studies already described LEPs as a sensitive biomarker for early small-fiber neuropathy in diabetes (Ragé M et al J Neurol. 2011;258:1852-64), leading to consider them as a less invasive alternative to skin biopsy, despite their moderate sensitivity (78%) and specificity (81%) (Di Stefano G et al Pain. 2017;158:1100-1107). In this study, the significant difference observed between LEPs of T2DM group compared to controls, in particular in the lower limbs, endorse the ability of this procedure to identify nociceptor loss secondary to a length-dependent disease. Furthermore, the significant correlations with higher disease duration and HbA1c levels (well-known risk factors for the development of diabetic neuropathy) corroborate the hypothesis that cumulative exposure to hyperglycemia could favour and accelerate small-fiber dysfunction. Although no significant results were found between LEPs and CARTs, the slight significant correlation with the Valsalva Maneuver suggests that this relationship deserves further investigation.
Certainly, these results are influenced by some limitations, such as the retrospective design of this study and, mostly, the small sample size, which did not allow for an adequate number of patients to study different subgroups (distinguishing for example patients with or without peripheral neuropathy or painful neuropathy). However, LEPs provided interesting preliminary data. Its connection with CAN deserves further investigation.
Marika Menduni
Reference. Borin GU, Aventaggiato M, Bittante C, Cacciatori V, Segatti A, Concon E, Devigili G, Bonora E, Zoppini G, Squintani GM. Laser-Evoked Potentials in the Early Diagnosis of Diabetic Neuropathy and Their Association with Cardiovascular Autonomic Reflex Tests: A Retrospective Observational Study in Patients with Type 2 Diabetes. Brain Sci. 2026 Mar 31;16(4):390. doi: 10.3390/brainsci16040390. PMID: 42041800; PMCID: PMC13115508.
