Oxaliplatin induces hyperexcitability at motor and autonomic neuromuscular junctions through effects on voltage-gated sodium channels

Oxaliplatin, an effective cytotoxic treatment in combination with 5-fluorouracil for colorectal cancer, is associated with sensory, motor and autonomic neurotoxicity. Motor symptoms include hyperexcitability while autonomic effects include urinary retention, but the cause of these side-effects is unknown. We examined the effects on motor nerve function in the mouse hemidiaphragm and on the autonomic system in the vas deferens. In the mouse diaphragm, oxaliplatin (0.5 mM) induced multiple endplate potentials (EPPs) following a single stimulus, and was associated with an increase in spontaneous miniature EPP frequency. In the vas deferens, spontaneous excitatory junction potential frequency was increased after 30 min exposure to oxaliplatin; no changes in resting Ca(2+) concentration in nerve terminal varicosities were observed, and recovery after stimuli trains was unaffected.In both tissues, an oxaliplatin-induced increase in spontaneous activity was prevented by the voltage-gated Na(+) channel blocker tetrodotoxin (TTX). Carbamazepine (0.3 mM) also prevented multiple EPPs and the increase in spontaneous activity in both tissues. In diaphragm, beta-pompilidotoxin (100 microM), which slows Na(+) channel inactivation, induced multiple EPPs similar to oxaliplatin's effect. By contrast, blockers of K(+) channels (4-aminopyridine and apamin) did not replicate oxaliplatin-induced hyperexcitability in the diaphragm. The prevention of hyperexcitability by TTX blockade implies that oxaliplatin acts on nerve conduction rather than by effecting repolarisation. The similarity between beta-pompilidotoxin and oxaliplatin suggests that alteration of voltage-gated Na(+) channel kinetics is likely to underlie the acute neurotoxic actions of oxaliplatin.

Interobserver agreement of the Gross Motor Function Classification System in an ambulant population of children with cerebral palsy

Gross Motor Function Classification System (GMFCS) level was reported by three independent assessors in a population of children with cerebral palsy (CP) aged between 4 and 18 years (n=184; 112 males, 72 females; mean age 10y 10mo [SD 3y 7mo]). A software algorithm also provided a computed GMFCS level from a regional CP registry. Participants had clinical diagnoses of unilateral (n=94) and bilateral (n=84) spastic CP, ataxia (n=4), dyskinesia (n=1), and hypotonia (n=1), and could walk independently with or without the use of an aid (GMFCS Levels I-IV). Research physiotherapist (n=184) and parent/guardian data (n=178) were collected in a research environment. Data from the child's community physiotherapist (n=143) were obtained by postal questionnaire. Results, using the kappa statistic with linear weighting (?1w), showed good agreement between the parent/guardian and research physiotherapist (?1w=0.75) with more moderate levels of agreement between the clinical physiotherapist and researcher (?1w=0.64) and the clinical physiotherapist and parent/guardian (?1w=0.57). Agreement was consistently better for older children (>2y). This study has shown that agreement with parent report increases with therapists'experience of the GMFCS and knowledge of the child at the time of grading. Substantial agreement between a computed GMFCS and an experienced therapist (?1w=0.74) also demonstrates the potential for extrapolation of GMFCS rating from an existing CP registry, providing the latter has sufficient data on locomotor ability.