Assessing neuromuscular junction stability from stimulated EMG in children.

OBJECTIVE: We present our 9-year experience of stimulated EMG potential analysis using concentric electrodes (SPACE) to evaluate neuromuscular junction (NMJ) disorders in awake children. The technique uses high frequency filtration of stimulated motor unit potentials and applies peak detection software to estimate mean consecutive difference (MCD). METHODS: SPACE was carried out in orbicularis oculi of 878 children (377 girls; median age 47months) between 2007 and 2015, stimulating the facial nerve with a monopolar cathode. Mean MCD-index (MCD-I) was expressed as a ratio of the measured MCD to the upper normal limit. Diagnostic accuracy was calculated for primary NMJ disorders based on the 660 cases with clinical follow-up data. RESULTS: Primary NMJ disorders were present in 106 children, including 46 with genetically confirmed congenital myasthenic syndrome (CMS). Mean MCD-I was two times higher in children with primary NMJ disorders compared to others (205±108µs vs 94±38µs, p<0.005). After excluding children with neuronopathies, an MCD-I >100% had 84% sensitivity and 74% specificity for the primary NMJ disorders. Receiver operating characteristics (ROC) curve identified an MCD-I >115% as providing best diagnostic accuracy with sensitivity of 77% and specificity of 84%. CONCLUSION: SPACE is practicable and safe in unsedated children. SIGNIFICANCE: In combination with routine EMG, it has high diagnostic accuracy and can facilitate recognition of paediatric NMJ transmission disorders.

Statistical process control (SPC)--a simple objective method for monitoring seizure frequency and evaluating effectiveness of drug interventions in refractory childhood epilepsy.

INTRODUCTION: Objective assessment of seizure fluctuation in patients with refractory epilepsy in the clinical setting is difficult and subjective assessment may lead to inappropriate changes in medication. We therefore evaluated the utility of Statistical Process Control (SPC) charts as a simple objective clinical tool to demonstrate variability in seizure frequency and to assess the efficacy of drug interventions. METHODS: Total weekly seizure frequencies over 1 year were collected for 38 young people with refractory epilepsy. SPC I-charts were generated and Nelson's tests for "special" causes of variability applied. In a separate analysis, run charts were reviewed by two epileptologists blinded to clinical data who were asked to identify if and when drug interventions took place. RESULTS: The SPC charts showed that only seven out of 38 (18%) patients had stable seizure frequencies. In the others, they identified significant but short-lived increases in seizure frequency, which were followed by rapid return towards baseline independently of drug changes. A substantial reduction in seizure frequency was associated with a drug increase in only 5 (6.5%) instances. Inter-rater agreement on whether there were drug interventions and their timing was poor (κ=0.15, p=0.4). CONCLUSIONS: SPC I-charts have the potential to be used as a clinical tool to monitor seizure frequency and to evaluate efficacy of drug interventions in patients with refractory epilepsy. Epilepsy is commonly an unstable condition with fluctuations in seizure frequencies which are unpredictable and usually do not require a change in treatment. Positive responses to treatment changes are uncommon.

Abrogation of antibody-induced arthritis in mice by a self-activating viridin prodrug and association with impaired neutrophil and endothelial cell function.

OBJECTIVE: To test a novel self-activating viridin (SAV) prodrug that slowly releases wortmannin, a potent phosphoinositide 3-kinase inhibitor, in a model of antibody-mediated inflammatory arthritis. METHODS: The SAV prodrug was administered to K/BxN mice or to C57BL/6 (B6) mice that had been injected with K/BxN serum. Ankle thickness was measured, and histologic changes were scored after a 10-day disease course (serum-transfer arthritis). Protease activity was measured by a near-infrared imaging approach using a cleavable cathepsin-selective probe. Further near-infrared imaging techniques were used to analyze early changes in vascular permeability after serum injection, as well as neutrophil-endothelial cell interactions. Neutrophil functions were assessed using an oxidative burst assay as well as a degranulation assay. RESULTS: SAV prevented ankle swelling in mice with serum-transfer arthritis in a dose-dependent manner. It also markedly reduced the extent of other features of arthritis, such as protease activity and histology scores for inflammation and joint erosion. Moreover, SAV was an effective therapeutic agent. The underlying mechanisms for the antiinflammatory activity were manifold. Endothelial permeability after serum injection was reduced, as was firm neutrophil attachment to endothelial cells. Endothelial cell activation by tumor necrosis factor alpha was impeded by SAV, as measured by the expression of vascular cell adhesion molecule. Crucial neutrophil functions, such as generation of reactive oxygen species and degranulation of protease-laden vesicles, were decreased by SAV administration. CONCLUSION: A novel SAV prodrug proved strongly antiinflammatory in a murine model of antibody-induced inflammatory arthritis. Its activity could be attributed, at least in part, to the inhibition of neutrophil and endothelial cell functions.