1Prince of Wales Clinical School, University of New South Wales, 2Neuroscience Research Australia, University of New South Wales, 3School of Medical Sciences, University of New South Wales
Park, S. B., Lin, C. S. Y., Kiernan, M. C. Nerve Excitability Assessment in Chemotherapy-induced Neurotoxicity. J. Vis. Exp. (62), e3439, doi:10.3791/3439 (2012).
Chemotherapy-induced neurotoxicity is a serious consequence of cancer treatment, which occurs with some of the most commonly used chemotherapies1,2. Chemotherapy-induced peripheral neuropathy produces symptoms of numbness and paraesthesia in the limbs and may progress to difficulties with fine motor skills and walking, leading to functional impairment. In addition to producing troubling symptoms, chemotherapy-induced neuropathy may limit treatment success leading to dose reduction or early cessation of treatment. Neuropathic symptoms may persist long-term, leaving permanent nerve damage in patients with an otherwise good prognosis3. As chemotherapy is utilised more often as a preventative measure, and survival rates increase, the importance of long-lasting and significant neurotoxicity will increase.
There are no established neuroprotective or treatment options and a lack of sensitive assessment methods. Appropriate assessment of neurotoxicity will be critical as a prognostic factor and as suitable endpoints for future trials of neuroprotective agents. Current methods to assess the severity of chemotherapy-induced neuropathy utilise clinician-based grading scales which have been demonstrated to lack sensitivity to change and inter-observer objectivity4. Conventional nerve conduction studies provide information about compound action potential amplitude and conduction velocity, which are relatively non-specific measures and do not provide insight into ion channel function or resting membrane potential. Accordingly, prior studies have demonstrated that conventional nerve conduction studies are not sensitive to early change in chemotherapy-induced neurotoxicity4-6. In comparison, nerve excitability studies utilize threshold tracking techniques which have been developed to enable assessment of ion channels, pumps and exchangers in vivo in large myelinated human axons7-9.
Nerve excitability techniques have been established as a tool to examine the development and severity of chemotherapy-induced neurotoxicity10-13. Comprising a number of excitability parameters, nerve excitability studies can be used to assess acute neurotoxicity arising immediately following infusion and the development of chronic, cumulative neurotoxicity. Nerve excitability techniques are feasible in the clinical setting, with each test requiring only 5 -10 minutes to complete. Nerve excitability equipment is readily commercially available, and a portable system has been devised so that patients can be tested in situ in the infusion centre setting. In addition, these techniques can be adapted for use in multiple chemotherapies.
In patients treated with the chemotherapy oxaliplatin, primarily utilised for colorectal cancer, nerve excitability techniques provide a method to identify patients at-risk for neurotoxicity prior to the onset of chronic neuropathy. Nerve excitability studies have revealed the development of an acute Na+ channelopathy in motor and sensory axons10-13. Importantly, patients who demonstrated changes in excitability in early treatment were subsequently more likely to develop moderate to severe neurotoxicity11. However, across treatment, striking longitudinal changes were identified only in sensory axons which were able to predict clinical neurological outcome in 80% of patients10. These changes demonstrated a different pattern to those seen acutely following oxaliplatin infusion, and most likely reflect the development of significant axonal damage and membrane potential change in sensory nerves which develops longitudinally during oxaliplatin treatment10. Significant abnormalities developed during early treatment, prior to any reduction in conventional measures of nerve function, suggesting that excitability parameters may provide a sensitive biomarker.
1. Patient Preparation
2. Axonal Excitability Procedures
3. Axonal Excitability Protocols
4. Patient Assessment
5. Analysis and Interpretation
6. Representative Results
Examples of excitability results in a patient treated with oxaliplatin are provided. Immediately post-oxaliplatin infusion, acute changes in both sensory and motor excitability develop, suggestive of the development of a functional Na+ channelopathy10 -13. However, significant change in multiple excitability parameters develops progressively across oxaliplatin treatment only in sensory axons, with motor axons unaffected (Fig. 3), reflecting widespread sensory axonal damage and membrane potential change. This pattern matches the clinical expression of symptoms in chronic oxaliplatin-induced neurotoxicity. Excitability changes in sensory axons precedes reductions in peak amplitude as assessed using conventional nerve conduction techniques, and suggest that axonal excitability techniques may provide a sensitive assessment tool for early oxaliplatin-induced neurotoxicity.
Figure 1. Threshold electrotonus, depicting waveforms in response to prolonged subthreshold polarizing current (100 ms), with hyperpolarizing direction plotted in the bottom quadrant (blue) and depolarizing direction plotted in the upper quadrant (red). Below is the stimulus waveform applied to generate the threshold electrotonus response.
Figure 2. Recovery cycle of excitability, demonstrating the characteristic sequence of excitability changes following impulse conduction, with a period of reduced excitability (refractoriness) up to 3 ms following a supramaximal stimulus, followed by a period of increased excitability (superexcitability) peaking at 5-7 ms and subsequently reduced excitability (subexcitability). The paired pulse paradigm stimulus protocol is inset.
Figure 3. Excitability changes in sensory axons oxaliplatin-treated patients, with baseline recordings shown in black and post-treatment recordings shown in white, following 4-6 months of oxaliplatin treatment. These changes are thought to reflect widespread axonal damage and membrane potential change. A picture of the excitability set-up in the oncology setting is shown at left. Click here to view larger image.
Chemotherapy-induced neuropathy is a serious side effect of cancer treatment, which may affect treatment course and produce long-lasting patient disability. There is a lack of sensitive and objective assessment measures to specifically measure nerve dysfunction in chemotherapy treated patients. The clinical development of axonal excitability techniques has provided useful and predictive information for the assessment of chemotherapy-induced neurotoxicity. By providing information about ion channel function, resting potential, and axonal membrane function, these techniques enable insight into the pathophysiological processes underlying axonal dysfunction in cancer patients treated with chemotherapy. In addition, axonal excitability techniques have been demonstrated to be feasible in the clinical oncology setting, and a single test may be completed in 5-10 minutes.
In oxaliplatin-treated patients, axonal excitability techniques provide a sensitive biomarker which enables early identification of patients at risk of severe neurotoxicity. In comparison to conventional nerve conduction studies which identify oxaliplatin-induced nerve damage only after axonal loss has already occurred, axonal excitability studies provide predictive markers of nerve dysfunction prior to axonal loss. As such, axonal excitability studies may be utilised to provide assessment of nerve function in clinical trials of potential neuroprotective strategies, to objectively determine neuroprotective efficacy.
We have nothing to disclose.
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