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Giulio Ferrari, Nambi Nallasamy, Heather Downs, Reza Dana, Anne Louise Oaklander; Corneal Nerve Imaging As A Biomarker For Paclitaxel-induced Peripheral Neuropathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):293.
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Small-fiber polyneuropathies (SFPN) are an increasingly common cause of chronic pain and sensory loss from common conditions including diabetes, HIV, and neurotoxicity. We used a common and dose-limiting cancer chemotherapeutic agent, paclitaxel, to evaluate the potential of measuring corneal innervation to assess presence and severity of SFPN. Parallel assessment of epidermal innervation was also made from distal-limb skin biopsies, which is the current standard diagnostic method and provided positive controls.
6 week-old male C57/BL6 mice (n=10; 10; 16 respectively) were administered paclitaxel at 5, 10, or 20mg/kg given as one intraperitoneal dose. C57/BL6 untreated mice (n=14) provided controls. Mice were sacrificed 2 weeks later; tissues harvested for immunohistochemistry comprised 2 mm punch skin-biopsies from their hind paws, corneas and trigeminal ganglia. After fixation and sectioning, skin-biopsies and ganglia were immunolabeled against PGP 9.5, the standard marker used for clinical diagnosis of small-fiber polyneuropathy. Corneal axons were labeled with anti-beta-3 tubulin antibody. Epidermal nerve fibers (ENF) were quantitated by a single blinded morphometrist using consensus methods for clinical diagnosis, and the total length of all corneal axons was digitally measured using an automated Matlab-based program. Trigeminal ganglia sections were qualitatively assessed for gross anatomic difference between groups. ANOVA was used to evaluate differences between groups.
Skin biopsies revealed expected dose-responsive losses of ENF (P<0.0001) as did corneal samples (P<0.0001). The ganglia showed a similar pattern of neural body rarefaction.
This study suggests that the SFPN caused by paclitaxel chemotherapy affects corneal as well as distal-limb innervation in mice. Not only presence, but severity of SFPN was detectable in the cornea; post-hoc analysis found significantly different corneal-nerve densities between all dosage groups (P<0.0001). Given the increasing availability of non-invasive and repeatable clinical examination of humans by in-vivo corneal confocal microscopy, corneal nerve assessments might provide a valuable new tool with which to evaluate small-fiber polyneuropathies.
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