Association between calcineurin inhibitor treatment and peripheral nerve dysfunction in renal transplant recipients.

Neurotoxicity is a significant clinical side effect of immunosuppressive treatment used in prophylaxis for rejection in solid organ transplants. This study aimed to provide insights into the mechanisms underlying neurotoxicity in patients receiving immunosuppressive treatment following renal transplantation. Clinical and neurophysiological assessments were undertaken in 38 patients receiving immunosuppression following renal transplantation, 19 receiving calcineurin inhibitor (CNI) therapy and 19 receiving a calcineurin-free (CNI-free) regimen. Groups were matched for age, gender, time since transplant and renal function and compared to normal controls (n = 20). The CNI group demonstrated marked differences in nerve excitability parameters, suggestive of nerve membrane depolarization (p < 0.05). Importantly, there were no differences between the two CNIs (cyclosporine A or tacrolimus). In contrast, CNI-free patients showed no differences to normal controls. The CNI-treated patients had a higher prevalence of clinical neuropathy and higher neuropathy severity scores. Longitudinal studies were undertaken in a cohort of subjects within 12 months of transplantation (n = 10). These studies demonstrated persistence of abnormalities in patients maintained on CNI-treatment and improvement noted in those who were switched to a CNI-free regimen. The results of this study have significant implications for selection, or continuation, of immunosuppressive therapy in renal transplant recipients, especially those with pre-existing neurological disability.

Mechanisms underlying chemotherapy-induced neurotoxicity and the potential for neuroprotective strategies.

Chemotherapy-induced neurotoxicity is a significant complication in the successful treatment of many cancers. Neurotoxicity may develop as a consequence of treatment with platinum analogues (cisplatin, oxaliplatin, carboplatin), taxanes (paclitaxel, docetaxel), vinca alkaloids (vincristine) and more recently, thalidomide and bortezomib. Typically, the clinical presentation reflects an axonal peripheral neuropathy with glove-and-stocking distribution sensory loss, combined with features suggestive of nerve hyperexcitability including paresthesia, dysesthesia, and pain. These symptoms may be disabling, adversely affecting activities of daily living and thereby quality of life. The incidence of chemotherapy-induced neurotoxicity appears critically related to cumulative dose and infusion duration, while individual risk factors may also influence the development and severity of neurotoxicity. Differences in structural properties between chemotherapies further contribute to variations in clinical presentation. The mechanisms underlying chemotherapy-induced neurotoxicity are diverse and include damage to neuronal cell bodies in the dorsal root ganglion and axonal toxicity via transport deficits or energy failure. More recently, axonal membrane ion channel dysfunction has been identified, including studies in patients treated with oxaliplatin which have revealed alterations in axonal Na(+) channels, suggesting that prophylactic pharmacological therapies aimed at modulating ion channel activity may prove useful in reducing neurotoxicity. As such, improved understanding of the pathophysiology of chemotherapy-induced neurotoxicity will inevitably assist in the development of future neuroprotective strategies and in the design of novel chemotherapies with improved toxicity profiles.

Nerve excitability changes in critical illness polyneuropathy.

Patients in intensive care units frequently suffer muscle weakness and atrophy due to critical illness polyneuropathy (CIP), an axonal neuropathy associated with systemic inflammatory response syndrome and multiple organ failure. CIP is a frequent and serious complication of intensive care that delays weaning from mechanical ventilation and increases mortality. The pathogenesis of CIP is not well understood and no specific therapy is available. The aim of this project was to use nerve excitability testing to investigate the changes in axonal membrane properties occurring in CIP. Ten patients (aged 37-76 years; 7 males, 3 females) were studied with electrophysiologically proven CIP. The median nerve was stimulated at the wrist and compound action potentials were recorded from abductor pollicis brevis muscle. Strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle (refractoriness, superexcitability and late subexcitability) were recorded using a recently described protocol. In eight patients a follow-up investigation was performed. All patients underwent clinical examination and laboratory investigations. Compared with age-matched normal controls (20 subjects; aged 38-79 years; 7 males, 13 females), CIP patients exhibited reduced superexcitability at 7 ms, from -22.3 +/- 1.6% to -7.6 +/- 3.1% (mean +/- SE, P approximately 0.0001) and increased accommodation to depolarizing (P < 0.01) and hyperpolarizing currents (P < 0.01), indicating membrane depolarization. Superexcitability was reduced both in patients with renal failure and without renal failure. In the former, superexcitability correlated with serum potassium (R = 0.88), and late subexcitability was also reduced (as also occurs owing to hyperkalaemia in patients with chronic renal failure). In patients without renal failure, late subexcitability was normal, and the signs of membrane depolarization correlated with raised serum bicarbonate and base excess, indicating compensated respiratory acidosis. It is inferred that motor axons in these CIP patients are depolarized, in part because of raised extracellular potassium, and in part because of hypoperfusion. The chronic membrane depolarization may contribute to the development of neuropathy.