Neu-horizons: neuroprotection and therapeutic use of riluzole for the prevention of oxaliplatin-induced neuropathy-a randomised controlled trial.

TRIAL DESIGN: Peripheral neuropathy is a commonly reported adverse effect of oxaliplatin treatment, representing a significant limitation which may require discontinuation of effective therapy. The present study investigated the neuroprotective potential of riluzole in patients undergoing oxaliplatin treatment in a randomised-controlled trial comparing riluzole and placebo-control. METHODS: Fifty-two patients (17 females, 58.1 ± 12.7 years) receiving oxaliplatin treatment were randomised into either a treatment (50 mg riluzole) or lactose placebo group. The primary outcome measure was the total neuropathy score-reduced (TNSr). Secondary outcome measures include nerve excitability measures, 9-hole pegboard and FACT-GOG NTX questionnaire. Patients were assessed at baseline, pre-cycle 10 or 12, 4-week and 12-week post-treatment. RESULTS: Both the treatment and placebo groups developed objective and patient reported evidence of neurotoxicity over the course of oxaliplatin treatment, although there were no significant differences across any parameters between the two groups. However, across follow-up assessments, the treatment group experienced greater neuropathy, represented by a higher TNSr score at 4-week post-chemotherapy of 8.3 ± 2.7 compared with 4.6 ± 3.6 (p = 0.032) which was sustained at 12-week post-treatment (p = 0.089). Similarly, patients in the treatment group reported worse symptoms with a FACT-GOG NTX score of 37.4 ± 10.2 compared with 43.3 ± 7.4 (p = 0.02) in the placebo group at 4-week post-treatment. CONCLUSION: This study is the first to provide an objective clinical investigation of riluzole in oxaliplatin-induced peripheral neuropathy employing both functional and neurophysiological measures. Although the recruitment target was not reached, the results do not show any benefit of riluzole in minimising neuropathy and may suggest that riluzole worsens neuropathy associated with oxaliplatin treatment.

Chemotherapy-induced peripheral neurotoxicity: a critical analysis.

With a 3-fold increase in the number of cancer survivors noted since the 1970s, there are now over 28 million cancer survivors worldwide. Accordingly, there is a heightened awareness of long-term toxicities and the impact on quality of life following treatment in cancer survivors. This review will address the increasing importance and challenge of chemotherapy-induced neurotoxicity, with a focus on neuropathy associated with the treatment of breast cancer, colorectal cancer, testicular cancer, and hematological cancers. An overview of the diagnosis, symptomatology, and pathophysiology of chemotherapy-induced peripheral neuropathy will be provided, with a critical analysis of assessment strategies, neuroprotective approaches, and potential treatments. The review will concentrate on neuropathy associated with taxanes, platinum compounds, vinca alkaloids, thalidomide, and bortezomib, providing clinical information specific to these chemotherapies.

Multimodal quantitative examination of nerve function in colorectal cancer patients prior to chemotherapy.

INTRODUCTION: Given recent findings of subclinical sensory deficits in colorectal cancer patients before oxaliplatin treatment, in the current study we aimed to identify evidence of subclinical peripheral neuropathy on multimodal testing before chemotherapy commencement. METHODS: Clinical, functional, and neurophysiological assessments were undertaken in 93 colorectal cancer patients before chemotherapy. RESULTS: There was no neurophysiological evidence of neuropathy, with 92 of 93 sural sensory values within normative reference values for age and no significant abnormalities detected in nerve conduction or nerve excitability studies. Clinical neurological assessment revealed 75.9% of patients with no signs or symptoms, 10.3% with reduction in distal vibration or pinprick sensitivity, and 6.9% with reduction in ankle reflexes only. There was no difference in manual dexterity (using the 9-hole peg-board test) compared with normative data. DISCUSSION: The present study has established a low likelihood of significant distal symmetrical polyneuropathy in colorectal cancer patients before initiation of chemotherapy. Muscle Nerve 57: 615-621, 2018.

Cardiometabolic health and risk of amyotrophic lateral sclerosis.

INTRODUCTION: Patients diagnosed with amyotrophic lateral sclerosis (ALS) generally have a limited medical history and a normal body mass index, raising the possibility of a premorbid ALS phenotype. METHODS: The prevalence of cardiometabolic factors was analyzed in 58 ALS patients via comprehensive cardiovascular assessments and compared with Australian population norms. RESULTS: ALS patients had good cardiac fitness and no reported cardiovascular events. Average blood pressure, heart rate, PR interval, and corrected QT interval were in the normal range. There were significantly fewer obese women in the ALS cohort (13.6%, P < 0.05) and more men with a normal body mass index than in the general population (47.2%, P < 0.001). The percentage of individuals who had never smoked was greater for the ALS cohort (55.8%, P ≤ 0.001), and the prevalence of dyslipidemia was lower (38.7%) compared with the general population (74.4%, P < 0.001). CONCLUSION: ALS patients had good cardiometabolic health, with evidence of a reduced vascular risk profile. Muscle Nerve 56: 721-725, 2017.

Short-term peripheral nerve stimulation ameliorates axonal dysfunction after spinal cord injury.

There is accumulating evidence that peripheral motor axons deteriorate following spinal cord injury (SCI). Secondary axonal dysfunction can exacerbate muscle atrophy, contribute to peripheral neuropathies and neuropathic pain, and lead to further functional impairment. In an attempt to ameliorate the adverse downstream effects that developed following SCI, we investigated the effects of a short-term peripheral nerve stimulation (PNS) program on motor axonal excitability in 22 SCI patients. Axonal excitability studies were undertaken in the median and common peroneal nerves (CPN) bilaterally before and after a 6-wk unilateral PNS program. PNS was delivered percutaneously over the median nerve at the wrist and CPN around the fibular head, and the compound muscle action potential (CMAP) from the abductor pollicis brevis and tibialis anterior was recorded. Stimulus intensity was above motor threshold, and pulses (450 µs) were delivered at 100 Hz with a 2-s on/off cycle for 30 min 5 days/wk. SCI patients had consistently high thresholds with a reduced CMAP consistent with axonal loss; in some patients the peripheral nerves were completely inexcitable. Nerve excitability studies revealed profound changes in membrane potential, with a "fanned-in" appearance in threshold electrotonus, consistent with membrane depolarization, and significantly reduced superexcitability during the recovery cycle. These membrane dysfunctions were ameliorated after 6 wk of PNS, which produced a significant hyperpolarizing effect. The contralateral, nonstimulated nerves remained depolarized. Short-term PNS reversed axonal dysfunction following SCI, may provide an opportunity to prevent chronic changes in axonal and muscular function, and may improve rehabilitation outcomes.

Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory neuropathy, classically characterised by a slowly progressive onset and symmetrical, sensorimotor involvement. However, there are many phenotypic variants, suggesting that CIDP may not be a discrete disease entity but rather a spectrum of related conditions. While the abiding theory of CIDP pathogenesis is that cell-mediated and humoral mechanisms act together in an aberrant immune response to cause damage to peripheral nerves, the relative contributions of T cell and autoantibody responses remain largely undefined. In animal models of spontaneous inflammatory neuropathy, T cell responses to defined myelin antigens are responsible. In other human inflammatory neuropathies, there is evidence of antibody responses to Schwann cell, compact myelin or nodal antigens. In this review, the roles of the cellular and humoral immune systems in the pathogenesis of CIDP will be discussed. In time, it is anticipated that delineation of clinical phenotypes and the underlying disease mechanisms might help guide diagnostic and individualised treatment strategies for CIDP.

Continuous subcutaneous insulin infusion preserves axonal function in type 1 diabetes mellitus.

BACKGROUND: Diabetic peripheral neuropathy is a common and debilitating complication of diabetes mellitus. Although strict glycaemic control may reduce the risk of developing diabetic peripheral neuropathy, the neurological benefits of different insulin regimens remain relatively unknown. METHODS: In the present study, 55 consecutive patients with type 1 diabetes mellitus underwent clinical neurological assessment. Subsequently, 41 non-neuropathic patients, 24 of whom were receiving multiple daily insulin injections (MDII) and 17 receiving continuous subcutaneous insulin infusion (CSII), underwent nerve excitability testing, a technique that assesses axonal ion channel function and membrane potential in human nerves. Treatment groups were matched for glycaemic control, body mass index, disease duration and gender. Neurophysiological parameters were compared between treatment groups and those taken from age and sex-matched normal controls. RESULTS: Prominent differences in axonal function were noted between MDII-treated and CSII-treated patients. Specifically, MDII patients manifested prominent abnormalities when compared with normal controls in threshold electrotonus (TE) parameters including depolarizing TE(10-20ms), undershoot and hyperpolarizing TE (90-100 ms) (P < 0.05). Additionally, recovery cycle parameters superexcitability and subexcitability were also abnormal (P < 0.05). In contrast, axonal function in CSII-treated patients was within normal limits when compared with age-matched controls. The differences between the groups were noted in cross-sectional analysis and remained at longitudinal follow-up. CONCLUSIONS: Axonal function in type 1 diabetes is maintained within normal limits in patients treated with continuous subcutaneous insulin infusion and not with multiple daily insulin injections. This raises the possibility that CSII therapy may have neuroprotective potential in patients with type 1 diabetes.

Paclitaxel-induced neuropathy: potential association of MAPT and GSK3B genotypes.

BACKGROUND: Paclitaxel treatment produces dose-limiting peripheral neurotoxicity, which adversely affects treatment and long-term outcomes. In the present study, the contribution of genetic polymorphisms to paclitaxel-induced neurotoxicity were assessed in 21 patients, focusing on polymorphisms involved in the tau-microtubule pathway, an important target of paclitaxel involved in neurotoxicity development. METHODS: Polymorphisms in the microtubule-associated protein tau (MAPT) gene (haplotype 1 and rs242557 polymorphism) and the glycogen synthase kinase-3ß (GSK3ß) gene (rs6438552 polymorphism) were investigated. Neurotoxicity was assessed using neuropathy grading scales, neurophysiological studies and patient questionnaires. RESULTS: A significant relationship between the GSK-3B rs6438552 polymorphism and paclitaxel-induced neurotoxicity was evident. CONCLUSIONS: Polymorphisms in tau-associated genes may contribute to the development of paclitaxel-induced neurotoxicity, although larger series will be necessary to confirm these findings.

Transynaptic changes evident in peripheral axonal function after acute cerebellar infarct.

The cerebellum has a vital role in fine motor control of the limbs. Consequently, downstream changes in peripheral axonal function may develop following a cerebellar infarct, in part, to adapt to the resultant impairment. The present study investigated changes in excitability in ipsilateral and contralateral upper limb peripheral motor axons in patients with acute cerebellar infarct to determine whether plastic changes may have functional relevance. Peripheral nerve excitability studies and detailed clinical assessments of functional impairment were undertaken in 13 patients with acute unilateral cerebellar infarct within 1 week of ictus. Changes were followed longitudinally over 1 year at 3, 6 and 12 months with results compared to 15 age-matched control subjects. Immediately following stroke, there were significant alterations in peripheral nerve excitability parameters in the upper limbs of patients compared to controls that were most evident in the more severely impaired group. There were significant correlations between excitability indices and functional scores in the entire cohort that demonstrated greater changes in axonal function associated with more impairment. Peripheral excitability trended towards normal over the study period in the context of clinical improvement. Following an acute cerebellar infarct, changes were observed in peripheral motor axons bilaterally that were more pronounced in patients with severe functional impairment. The peripheral changes may represent a functionally relevant plastic process reflecting altered activity to adapt to the disability of the stroke.

Axonal dysfunction, dysmyelination, and conduction failure in hereditary neuropathy with liability to pressure palsies.

INTRODUCTION: Patients with hereditary neuropathy with liability to pressure palsies (HNPP) manifest with episodes of focal paresis when exposed to mechanical stress, although the basis for vulnerability to conduction block remains relatively unexplained. METHODS: Axonal excitability techniques were utilized to provide insights into pathophysiological mechanisms in 13 HNPP patients, stimulating median motor and sensory axons at the wrist. RESULTS: In HNPP, distal latencies were prolonged, and motor and sensory amplitudes were reduced. Threshold was increased. Depolarizing and hyperpolarizing electrotonus was greater, and resting current-threshold slope was reduced. There were greater threshold changes in superexcitability, and refractoriness was decreased. CONCLUSIONS: Taken together, excitability testing in patients with HNPP established axonal hyperpolarization in both motor and sensory axons that may be attributable to changes in nerve architecture. In turn, the hyperpolarized resting membrane potential in HNPP may be a major predisposing factor for development of conduction block with mechanical stresses.

Axonal excitability as an early biomarker of nerve involvement in hereditary transthyretin amyloidosis.

OBJECTIVES: The treatment of hereditary transthyretin amyloidosis polyneuropathy (ATTRv-PN) has been revolutionised by genetic therapies, with dramatic improvements in patient outcomes. Whilst the optimal timing of treatment initiation remains unknown, early treatment is desirable. Consequently, the aim of the study was to develop biomarkers of early nerve dysfunction in ATTRv-PN. METHODS: Ulnar motor and sensory axonal excitability studies were prospectively undertaken on 22 patients with pathogenic hereditary transthyretin amyloid (ATTRv) gene variants, 12 with large fibre neuropathy (LF+) and 10 without (LF-), with results compared to age- and sex-matched healthy controls. RESULTS: In motor axons we identified a continuum of change from healthy controls, to LF- and LF+ ATTRv with progressive reduction in hyperpolarising threshold electrotonus (TEh40(10-20 ms): p = 0.04, TEh40(20-40 ms): p = 0.01 and TEh40(90-10 ms): p = 0.01), suggestive of membrane depolarisation. In sensory axons lower levels of subexcitability were observed on single (SubEx) and double pulse (SubEx2) recovery cycle testing in LF+ (SubEx: p = 0.015, SubEx2: p = 0.015, RC(2-1): p = 0.04) suggesting reduced nodal slow potassium conductance, which promotes sensory hyperexcitability, paraesthesia and pain. There were no differences in sensory or motor excitability parameters when comparing different ATTRv variants. CONCLUSIONS: These progressive changes seen across the disease spectrum in ATTRv-PN suggest that axonal excitability has utility to identify early and progressive nerve dysfunction in ATTRv, regardless of genotype. SIGNIFICANCE: Axonal excitability is a promising early biomarker of nerve dysfunction in ATTRv-PN.

Evolution of peripheral nerve function in humans: novel insights from motor nerve excitability.

While substantial alterations in myelination and axonal growth have been described during maturation, their interactions with the configuration and activity of axonal membrane ion channels to achieve impulse conduction have not been fully elucidated. The present study utilized axonal excitability techniques to compare the changes in nerve function across healthy infants, children, adolescents and adults. Multiple excitability indices (stimulus-response curve, strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle) combined with conventional neurophysiological measures were investigated in 57 subjects (22 males, 35 females; age range 0.46-24 years), stimulating the median motor nerve at the wrist. Maturational changes in conduction velocity were paralleled by significant alterations in multiple excitability parameters, similarly reaching steady values in adolescence. Maturation was accompanied by reductions in threshold (P < 0.005) and rheobase (P = 0.001); depolarizing and hyperpolarizing electrotonus progressively reduced (P < 0.001), or 'fanned-in'; resting current-threshold slope increased (P < 0.0001); accommodation to depolarizing currents prolonged (P < 0.0001); while greater threshold changes in refractoriness (P = 0.001) and subexcitability (P < 0.01) emerged. Taken together, the present findings suggest that passive membrane conductances and the activity of K(+) conductances decrease with formation of the axo-glial junction and myelination. In turn, these functional alterations serve to enhance the efficiency and speed of impulse conduction concurrent with the acquisition of motor skills during childhood, and provide unique insight into the evolution of postnatal human peripheral nerve function. Significantly, these findings bring the dynamics of axonal development to the clinical domain and serve to further illuminate pathophysiological mechanisms that occur during development.

Axonal dysfunction prior to neuropathy onset in type 1 diabetes.

BACKGROUND: The present study was undertaken to determine whether there were changes evident in axonal membrane function prior to the onset of neuropathy in patients with type 1 and type 2 diabetes. METHODS: From a cohort of 110 consecutive referrals, nerve excitability was investigated in 40 diabetic patients without clinical evidence of neuropathy (20 type 1 diabetic patients and 20 type 2 diabetic patients). Groups were matched for gender, disease duration and HbA(1c). Studies were also undertaken in two control groups, younger controls and older controls, matched for age and gender with the diabetic cohorts. RESULTS: Subjects with type 1 diabetes demonstrated significant nerve excitability abnormalities when compared with younger normal controls. Specifically, type 1 subjects showed a significant reduction at multiple time points in both depolarising and hyperpolarising threshold electrotonus. Additionally, the relative refractory period was prolonged (type 1, 3.19 ms; younger normal controls, 3.0 ms; p < 0.05) and superexcitability was reduced (type 1, -23.12%; younger normal controls, -26.37%; p < 0.05), consistent with axonal membrane depolarisation. Correlations were identified in type 1 patients between disease duration and nerve excitability parameters, including the relative refractory period (r = -0.533, p < 0.05). In contrast, only minor non-specific changes were noted in the type 2 group. DISCUSSION: This study provides clear evidence of altered axonal function in patients with type 1 diabetes in the absence of clinical neuropathy. These findings suggest that altered axonal membrane potential may precede neuropathy onset in type 1 diabetes and as such may indicate a window of opportunity to intervene and potentially reverse axonal membrane dysfunction before the development of irreversible neuropathy.

Motor cortex excitability in acute cerebellar infarct.

Limited evidence to date has demonstrated changes in excitability that develops over the contralateral motor cortex after a cerebellar infarct. As such, the present study investigated changes in excitability over the contra- (contraM1) and ipsilateral motor cortices (ipsiM1), in patients with acute cerebellar infarct, to determine whether the changes may have functional relevance. Paired-pulse transcranial magnetic stimulation, combined with detailed clinical assessment, was undertaken in ten patients presenting with acute unilateral cerebellar infarct. Studies were undertaken within 1 week of ictus and followed longitudinally at 3-, 6-, and 12-month periods. Comparisons were made with 15 age-matched controls. Immediately following a stroke, short-interval intracortical inhibition (SICI) was significantly reduced over the contraM1 in all patients (P = 0.01), while reduced over the ipsiM1 in those with severe functional impairment (P = 0.01). Moreover, ipsiM1 SICI correlated with impairment (r = 0.69, P = 0.03), such that less SICI was observed in those patients with most impairment. Cortical excitability changes persisted over the follow-up period in the context of clinical improvement. Following an acute cerebellar infarct, excitability abnormalities develop over both motor cortices, more prominently in patients with severe functional impairment. The cortical changes, particularly over the ipsilateral motor cortex, may represent a functionally relevant plastic process that may guide future therapeutic strategies to better facilitate recovery.

Botulinum toxin modulates cortical maladaptation in post-stroke spasticity.

INTRODUCTION: Maladaptive plasticity involving the unaffected hemisphere (UH) in stroke patients may contribute to post-stroke deficits, including spasticity. We investigated the central and peripheral effects of botulinum toxin in post-stroke spasticity to determine whether there is modulation of cortical processes in the UH. METHODS: Transcranial magnetic stimulation and peripheral nerve excitability studies were undertaken in 5 stroke patients with upper limb spasticity before (T1) and 6 weeks after (T2) botulinum injection. RESULTS: Transcranial magnetic stimulation demonstrated inexcitable motor cortices of the affected hemisphere at T1 and T2, and short-interval intracortical inhibition (SICI) in the UH was significantly reduced at T1. At T2, SICI in the UH increased significantly compared with T1, normalizing to controls, and was found to be associated with clinical improvements in spasticity. Peripheral excitability parameters were unchanged after injection. CONCLUSION: Cortical excitability changes were demonstrated in UH, suggesting that the clinical benefits of botulinum toxin relate to modulation of abnormal central reorganization (maladaptive plasticity) in post-stroke spasticity.

Impaired energy-dependent processes underlie acute lead neuropathy.

INTRODUCTION: The mechanisms of lead neuropathy remain unexplained. A 48-year-old painter presented after undertaking a 3-week project of paint removal without the use of a protective mask. Two weeks later, he developed fasciculations, weakness, and muscle wasting. Nerve conduction studies demonstrated a motor neuropathy. A high serum lead level was identified, leading to a diagnosis of acute lead neuropathy. METHODS: To investigate the pathophysiology, nerve excitability studies were undertaken acutely and in convalescence. Studies were undertaken at baseline and after the induction of limb ischemia. RESULTS: Prominent abnormalities of excitability were noted, including a rightward shift of stimulus-response curves, reduction in depolarizing threshold electrotonus, and increased refractoriness. These changes became more severe with limb ischemia, and there was abolition of the superexcitable period and increased refractoriness. CONCLUSIONS: We identified prominent changes in nerve excitability in lead neuropathy. The results suggest that there is impairment of axonal energy-dependent processes in lead neuropathy.

Adaptation of motor function after spinal cord injury: novel insights into spinal shock.

The mechanisms underlying spinal shock have not been clearly defined. At present, clinical assessment remains the mainstay to describe progression through spinal shock following traumatic spinal cord injury. However, nerve excitability studies in combination with conventional nerve conduction and clinical assessments have the potential to investigate spinal shock at the level of the peripheral axon. Therefore, peripheral motor axon excitability was prospectively and systematically evaluated in more than 400 studies of 11 patients admitted to hospital after traumatic spinal cord injury, with cord lesions above T9 (nine cervical, two thoracic). Recordings commenced within 15 days of admission from the median nerve to abductor pollicis brevis in the upper limb and the common peroneal nerve to tibialis anterior in both lower limbs, and were continued until patient discharge from hospital. Excitability was assessed using threshold tracking techniques and recordings were compared with data from healthy controls. In addition, concurrent clinical measures of strength, serum electrolytes and nerve conduction were collected. High threshold stimulus-response relationships were apparent from the early phase of spinal shock that coincided with depolarization-like features that reached a peak on Day 16.9 (± 2.7 standard error) for the common peroneal nerve and Day 11.8 (± 2.0 standard error) for the median nerve. Overall, changes in the common peroneal nerve were of greater magnitude than for the median nerve. For both nerves, the most significant changes were in threshold electrotonus, which was 'fanned in', and during the recovery cycle superexcitability was reduced (P < 0.001). However, refractoriness was increased only for the common peroneal nerve (P < 0.05). Changes in the spinal injured cohort could not be explained on the basis of an isolated common peroneal nerve palsy. By the time patients with spinal injury were discharged from hospital between Days 68 and 215, excitability for upper and lower limbs had returned towards normative values, but not for all parameters. Electrolyte levels and results for nerve conduction studies remained within normal limits throughout the period of admission. Contrary to prevailing opinion, these data demonstrate that significant changes in peripheral motor axonal excitability occur early during spinal shock, with subsequent further deterioration in axonal function, before recovery ensues.

Dysfunction of axonal membrane conductances in adolescents and young adults with spinal muscular atrophy.

Spinal muscular atrophy is distinct among neurodegenerative conditions of the motor neuron, with onset in developing and maturing patients. Furthermore, the rate of degeneration appears to slow over time, at least in the milder forms. To investigate disease pathophysiology and potential adaptations, the present study utilized axonal excitability studies to provide insights into axonal biophysical properties and explored correlation with clinical severity. Multiple excitability indices (stimulus-response curve, strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle) were investigated in 25 genetically characterized adolescent and adult patients with spinal muscular atrophy, stimulating the median motor nerve at the wrist. Results were compared with 50 age-matched controls. The Medical Research Council sum score and Spinal Muscular Atrophy Functional Rating Scale were used to define the strength and motor functional status of patients with spinal muscular atrophy. In patients with spinal muscular atrophy, there were reductions in compound muscle action potential amplitude (P < 0.0005) associated with reduction in stimulus response slope (P < 0.0005), confirming significant axonal loss. In the patients with mild or ambulatory spinal muscular atrophy, there was reduction of peak amplitude without alteration in axonal excitability; in contrast, in the non-ambulatory or severe spinal muscular atrophy cohort prominent changes in axonal function were apparent. Specifically, there were steep changes in the early phase of hyperpolarization in threshold electrotonus (P < 0.0005) that correlated with clinical severity. Additionally, there were greater changes in depolarizing threshold electrotonus (P < 0.0005) and prolongation of the strength-duration time constant (P = 0.001). Mathematical modelling of the excitability changes obtained in patients with severe spinal muscular atrophy supported a mixed pathology comprising features of axonal degeneration and regeneration. The present study has provided novel insight into the pathophysiology of spinal muscular atrophy, with identification of functional abnormalities involving axonal K(+) and Na(+) conductances and alterations in passive membrane properties, the latter linked to the process of neurodegeneration.

Impact of oxaliplatin-induced neuropathy: a patient perspective.

INTRODUCTION: Dose-limiting neurotoxicity is a major side effect of oxaliplatin treatment, producing initial acute neurotoxicity and chronic neuropathy with increasing exposure. The improvement in survival for patients with early-stage colorectal cancer treated with oxaliplatin has highlighted the need for valid and reliable assessment of peripheral neuropathy. OBJECTIVES: The objective of this paper was to explore neuropathic symptoms in oxaliplatin-treated patients as assessed using different methods. METHODS: Consecutive symptomatic patients reporting peripheral neuropathy after oxaliplatin chemotherapy for colorectal cancer were interviewed using a semi-structured clinical interview. Neurotoxicity was also assessed using the National Cancer Institute Common Toxicity Criteria scale (clinician-rated), patient 'self-report' questionnaires (PNQ), nerve conduction and clinical assessment. RESULTS: Twenty patients were assessed, 12.6 ± 2.8 months after treatment cessation (mean cumulative oxaliplatin dose, 789 mg/m(2)). In 40% of patients, neurotoxicity necessitated early cessation of treatment. Only 10% of patients were designated by clinicians with severe neurotoxicity, whilst, in contrast, patient interviews and self-report questionnaires described significant physical limitations due to neuropathic symptoms in 60% of patients. The majority (85%) of patients had objective evidence of sensory neuropathy with nerve conduction studies. Reports from clinical interviews were strongly correlated with patient self-assessment (Pearson coefficient = 0.790, p < 0.0005). CONCLUSION: Given the discrepancies in symptom prevalence highlighted by these findings, the monitoring of oxaliplatin-induced neurotoxicity would benefit from more informative clinical assessment, with inclusion of patient-reported outcome measures. Such an approach would be beneficial in a clinical trial setting to monitor the efficacy of interventions and in prospective studies of survivorship to determine the true burden of peripheral neuropathy in oxaliplatin-treated patients.

Differences in nerve excitability properties across upper limb sensory and motor axons.

OBJECTIVE: The excitability of motor and sensory axons of the main upper limb nerves were compared to characterise the differences between nerves and provide a guide for future studies in human diseases with median neuropathy at the wrist. METHODS: Axonal excitability studies were undertaken on median and ulnar motor (APB and ADM) and sensory axons (D2 and D5) and the superficial radial axons (D1) using a threshold tracking technique. RESULTS: Compared to the median, ulnar motor axons had reduced early depolarising threshold electrotonus (TEd40(10-20 ms) p = 0.02) and superexcitability (p = 0.03). The ulnar sensory axons required a stronger stimulus (p = 0.02) and had a larger rheobase (p = 0.02) than median axons, but were otherwise comparable. The superficial radial axons were "fanned-in" compared to median, and to a lesser degree ulnar axons, with greater resting I/V slope. Mathematical modelling of the radial and median sensory axons suggested that a 15.1% reduction in conductances between nodal and internodal compartments accounted for 82% of this discrepancy. CONCLUSIONS: The excitability parameters of motor and sensory axons are most comparable between median and ulnar nerves. SIGNIFICANCE: The present study demonstrates the feasibility of, and provides normative data for, axonal excitability recordings of the radial and ulnar nerves. We suggest the use of ulnar recordings as an alternative to the median nerve in the setting of compressive neuropathy at the wrist.