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Abstract
This thesis examines the pathophysiology underlying chemotherapy-induced neurotoxicity. Oxaliplatin, utilised in the treatment of colorectal cancer, produces prominent neurotoxicity. Clinical and specialised neurophysiological studies were undertaken to determine the full spectrum of oxaliplatin-induced neuropathy. These studies demonstrated acute alterations in Na+ channel-related parameters in sensory axons post-infusion, suggesting that an acute Na+ channelopathy may contribute to the development of neuropathic symptoms. Patients were also assessed longitudinally, revealing a characteristic pattern of sensory axonal abnormalities, which developed progressively across treatment and occurred earlier than changes in conventional parameters of nerve function. Importantly, excitability abnormalities were predictive of neuropathy severity at treatment completion. Studies in a subset of oxaliplatin-treated patients with Lhermitte's phenomenon (electric shock-like sensations on neck flexion) confirmed that the extent of excitability change was associated with the severity of neuropathy. To further define mechanisms, studies were undertaken before and immediately following oxaliplatin infusion. These studies established that oxaliplatin affected transient Na+ channel inactivation processes more significantly than persistent Na+ channel conductances in both motor and sensory axons. Studies utilising natural activity to produce axonal hyperpolarization established that changes in the recovery cycle of excitability post-oxaliplatin were greatly enhanced. These studies established that oxaliplatin-induced changes were membrane-potential dependent, supporting the hypothesis that oxaliplatin modulates axonal Na+ channel inactivation. To examine the long-term sequelae of oxaliplatin treatment, follow-up studies were undertaken, revealing chronic sensory neuropathy in the majority of patients. Importantly, sensory axonal excitability measures prospectively obtained during treatment were predictive of neurological outcomes at long-term follow-up, confirming that excitability techniques provided a sensitive biomarker of oxaliplatin-induced neuropathy. To contrast these findings, a cohort of paclitaxel-treated patients were assessed, revealing an entirely different basis for neurotoxicity related to damaged axonal transport systems. Paclitaxel produced early and progressive changes in stimulus threshold and maximal sensory amplitudes in the absence of focal changes in individual axonal conductances. In conclusion, studies in this thesis have established abnormalities in selective axonal Na+ channel-dependent properties in oxaliplatin-treated patients which preceded the development of neuropathy. Axonal excitability techniques may be utilised as early and sensitive biomarkers of oxaliplatin-induced neurotoxicity, yielding important insight into pathophysiological mechanisms of neuropathy.