Abstract
Background and purposeOxaliplatin-induced neuropathy (OIN) implies axonal damage of both small and large sensory nerve fibers. We aimed at comparing the neurophysiological changes occurred after treatment and the capability to recovery based on histological marker of re-innervation GAP-43.Methods48 patients with cancer were assessed before and after chemotherapy (at 3 months and 12 months if available). We recorded ulnar and sural sensory nerve action potentials (SNAP), determined quantitative sensory thresholds for warm and cold (WDT, CDT), pain thresholds and collected a distal biopsy of skin to assess the intra-epidermal nerve fiber density (IENFD) with PGP9.5 and GAP-43 markers (in a subgroup of 19 patients).ResultsIncreased WDT and CDT as well as diminished IENFD at distal leg were already found in 30% of oncologic patients before treatment. After oxaliplatin, there was a significant increase in thermal thresholds in 52% of patients, and a decrease of SNAP amplitude in the sural nerve in 67% patients. IENFD was reduced in 47% and remained unchanged in 37% after oxiplatin. The density of GAP-43 + fibers and GAP-43/PGP 9.5 ratio was similar before and after treatment showing that cutaneous re-innervation is preserved despite no clinical recovery was observed after one year.ConclusionNon-selective axonal loss affects sensory fibers in OIN. However, the presence of intra-epidermal regenerative sprouts detected by GAP-43 may reduce the impact of neurotoxicity in the small fibers with long-term sequelae mostly on myelinated nerve endings. Pre-oxaliplatin GAP-43 failed to identify patients with higher risk of damage or worse recovery after treatment.
Highlights
Peripheral sensory neurons and nerve fibers are vulnerable to oxaliplatin
We considered abnormal a mean sensory nerve action potentials (SNAP) amplitude value of < 5 μV for the antidromic sural and < 4 μV for the orthodromic ulnar nerve according to -2 SDs of previously published normative reference values from our institution in healthy subjects which were for male and female between 60 to 80 years old a mean sural SNAP of 12.6 ± 3.8 μV and mean ulnar SNAP of 12 ± 4 μV [19]
We found 6 out of 19 patients (32%) who had abnormal WDT at foot before-treatment and reduced intra-epidermal nerve fiber density (IENFD), which resulted of 4.0 ± 2.4 fibers/mm for PGP 9.5 and to GAP 43 marker it was 1.1 ± 0.4 fibers/mm (GAP-43/PGP 9.5 ratio of 0.4)
Summary
Peripheral sensory neurons and nerve fibers are vulnerable to oxaliplatin. Oxaliplatininduced neuropathy (OIN) is characterized by long-lasting loss of sensation, allodynia and other forms of neuropathic pain, with moderate interference in quality of life [3]. It is still unclear whether axonal damage affects predominantly small fibers or it is a non-selective damage of large and small fibers. Oxaliplatin-induced neuropathy (OIN) implies axonal damage of both small and large sensory nerve fibers. We recorded ulnar and sural sensory nerve action potentials (SNAP), determined quantitative sensory thresholds for warm and cold (WDT, CDT), pain thresholds and collected a distal biopsy of skin to assess the intra-epidermal nerve fiber density (IENFD) with PGP9.5 and GAP-43 markers (in a subgroup of 19 patients). Pre-oxaliplatin GAP-43 failed to identify patients with higher risk of damage or worse recovery after treatment
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