An exploratory study to investigate potential sensory biomarkers of chemotherapy-induced and diabetic peripheral neuropathy
Author(s)
Narayanaswamy, Hema Malini
Type
Thesis
Abstract
Aims: Identification of neurophysiological or skin innervation biomarkers which can be used to assess and monitor progression of diabetic sensory polyneuropathy (DPN) and chemotherapy-induced neuropathy (CIPN). Sensitive and robust measures are needed to detect changes in the relatively short duration of clinical trials aimed to modify progression of neuropathy.
Methods: 40 patients with DPN were studied longitudinally over 1 year, and 33 patients with CIPN in a cross-sectional study. Clinical assessments, questionnaires, quantitative sensory testing, histamine-induced skin flare, nerve conduction studies and contact heat evoked potentials were measured. Repeat skin biopsies were performed at a 6 month interval to quantify intra- (IENF) and sub-epidermal (SENF) nerve fibres immunoreactive for PGP 9.5 (pan-neuronal marker), TRPV1 (heat and capsaicin receptor) and GAP-43 (marker of regenerating fibres) in the DPN group, and at baseline in the CIPN group.
Results: There was no change in symptoms and sensory tests in the DPN group. However, there was a significant reduction in IENF and SENF for both PGP 9.5 and TRPV1 fibres in the second DPN skin biopsy (n = 29 had repeat biopsy). GAP- 43 fibres were present in the dermis and remained unchanged. Patients in the CIPN group had less painful neuropathy, but similar abnormalities on examination and sensory tests. Despite this, a preserved number of IENF and SENF were seen in the CIPN group, with abnormal morphology. This has not been reported previously. Conclusion: PGP 9.5 and TRPV1-immunoreactive nerve fibres in sequential skin biopsies provide objective markers of progression of neuropathy, while the preserved GAP 43-immunoreactive fibres may detect enhanced regeneration. Novel findings in the CIPN group suggest prevention of degeneration and restoration of function should be the treatment strategy, rather than enhancing regeneration.
Methods: 40 patients with DPN were studied longitudinally over 1 year, and 33 patients with CIPN in a cross-sectional study. Clinical assessments, questionnaires, quantitative sensory testing, histamine-induced skin flare, nerve conduction studies and contact heat evoked potentials were measured. Repeat skin biopsies were performed at a 6 month interval to quantify intra- (IENF) and sub-epidermal (SENF) nerve fibres immunoreactive for PGP 9.5 (pan-neuronal marker), TRPV1 (heat and capsaicin receptor) and GAP-43 (marker of regenerating fibres) in the DPN group, and at baseline in the CIPN group.
Results: There was no change in symptoms and sensory tests in the DPN group. However, there was a significant reduction in IENF and SENF for both PGP 9.5 and TRPV1 fibres in the second DPN skin biopsy (n = 29 had repeat biopsy). GAP- 43 fibres were present in the dermis and remained unchanged. Patients in the CIPN group had less painful neuropathy, but similar abnormalities on examination and sensory tests. Despite this, a preserved number of IENF and SENF were seen in the CIPN group, with abnormal morphology. This has not been reported previously. Conclusion: PGP 9.5 and TRPV1-immunoreactive nerve fibres in sequential skin biopsies provide objective markers of progression of neuropathy, while the preserved GAP 43-immunoreactive fibres may detect enhanced regeneration. Novel findings in the CIPN group suggest prevention of degeneration and restoration of function should be the treatment strategy, rather than enhancing regeneration.
Date Issued
2011
Date Awarded
2012-03
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Anand, Praveen
Sponsor
Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD)
Creator
Narayanaswamy, Hema Malini
Publisher Department
Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Medicine (Research) MD (Res)