Abnormal Corticospinal Excitability in Patients with Disorders of Consciousness

BackgroundTranscranial magnetic stimulation (TMS) has been frequently used to explore changes in the human motor cortex in different conditions, while the extent of motor cortex reorganization in patients in vegetative state (VS) (now known as unresponsive wakefulness syndrome, UWS) and minimally conscious (MCS) states due to severe brain damage remains largely unknown.Objective/hypothesisIt was hypothesized that cortical motor excitability would be decreased and would correlate to the level of consciousness in patients with disorders of consciousness.MethodsCorticospinal excitability was assessed in 47 patients (24 VS/UWS and 23 MCS) and 14 healthy controls. The test parameters included maximal peak-to-peak M-wave (M_max), F-wave persistence, peripheral and central motor conduction times, sensory (SEP) and motor evoked (MEP) potential latencies and amplitudes, resting motor threshold (RMT), stimulus/response curves, and short latency afferent inhibition (SAI). TMS measurements were correlated to the level of consciousness (assessed using the Coma Recovery Scale-Revised).ResultsOn average, the patient group had lower M_max, lower MEP and SEP amplitudes, higher RMTs, narrower stimulus/response curves, and reduced SAI compared to the healthy controls (P < 0.05). The SAI alterations were correlated to the level of consciousness (P < 0.05).ConclusionsThe findings demonstrated the impairment of the cortical inhibitory circuits in patients with disorders of consciousness. Moreover, the significant relationship was found between cortical inhibition and clinical consciousness dysfunction.     

Application of ED-optimality to screening experiments for analgesic compounds in an experimental model of neuropathic pain

In spite of the evidence regarding high variability in the response to evoked pain, little attention has been paid to its impact on the screening of drugs for inflammatory and neuropathic pain. In this study, we explore the feasibility of introducing optimality concepts to experimental protocols, enabling estimation of parameter and model uncertainty. Pharmacokinetic (PK) and pharmacodynamic data from different experiments in rats were pooled and modelled using nonlinear mixed effects modelling. Pain data on gabapentin and placebo-treated animals were generated in the complete Freund??s adjuvant model of neuropathic pain. A logistic regression model was applied to optimise sampling times and dose levels to be used in an experimental protocol. Drug potency (EC₅₀) and interindividual variability (IIV) were considered the parameters of interest. Different experimental designs were tested and validated by SSE (stochastic simulation and estimation) taking into account relevant exposure ranges. The pharmacokinetics of gabapentin was described by a two-compartment PK model with first order absorption (CL?=?0.159?l?h^?1, V₂?=?0.118?l, V₃?=?0.253?l, Ka?=?0.26?h^?1, Q?=?1.22?l?h^?1). Drug potency (EC₅₀) for the anti-allodynic effects was estimated to be 1400?ng?ml^?1. Protocol optimisation improved bias and precision of the EC50 by 6 and 11.9.?%, respectively, whilst IIV estimates showed improvement of 31.89 and 14.91?%, respectively. Our results show that variability in behavioural models of evoked pain response leads to uncertainty in drug potency estimates, with potential impact on the ranking of compounds during screening. As illustrated for gabapentin, ED-optimality concepts enable analysis of discrete data taking into account experimental constraints.     

Dosing rationale for fixed-dose combinations in children: shooting from the hip?

In this investigation we evaluate the relevance of a model-based approach for pharmacokinetic (PK) bridging and dose selection of drug combinations in children. The fixed-dose combination of atovaquone (ATV) and proguanil (PGN) was used for illustration purposes. A population PK model was developed for each compound using plasma concentration data from adult and pediatric patients. PK parameter estimates were subsequently used to simulate drug exposure in children treated with different dose levels of these drugs. We show that, contrary to common practice, different dose ratios may be required across age groups in order to achieve target exposure levels comparable to adults. This example illustrates the effects of covariate interactions, specifically the ones involving body weight (BW) and ethnicity, on the PK of drugs. A model-based approach is critical for dose selection and the rational use of drug combinations in children. Flexible rather than fixed-dose ratios may be needed to ensure comparable target exposure in bridging studies.     

Integration of pharmacogenetics and pharmacogenomics in drug development: implications for regulatory and medical decision making in pediatric diseases

This article aims to provide an overview of the current situation regarding pharmacogenetic and pharmacogenomic (PG) studies in pediatrics, with a special focus on the role of PG data in the regulatory decision-making process. Despite the gap in pharmacogenetic research due to the lack of translational studies in adults and children, several technologies exist in drug development and biomarkers validation, which could supply valuable information concerning labeling and dosing recommendations. If performed under strict good clinical practice quality criteria, such findings could be included in the submission package of new chemical entities and used as additional information for prescribers, supporting further evaluation and understanding of the efficacy and safety profile of new medicines. Even though regulatory authorities may be aware of the potential role of PG in medical practice and guidances are available about the integration of PG in drug development, most data obtained from PG studies are not used by prescribers. The challenge is to better understand whether PG markers can be used to assess potential differences in drug response during the clinical program, so PG data can be integrated into the regulatory decision-making process, enabling the introduction of labeling information that promotes optimal dosing in the pediatric population.     

CAG repeat length and clinical features in three Italian families with spinocerebellar ataxia type 2 (SCA2): early impairment of Wisconsin Card Sorting Test and saccade velocity

We report on the clinical, neuropsychological, neurophysiological, computerized eye movement, magnetic resonance imaging (MRI) and molecular findings from 17 individuals affected with spinocerebellar ataxia type 2 (SCA2) belonging to three families. The average age at onset of the symptoms was 35.6, 11.9 (mean, SD) years. The mean age at onset of the symptoms in the parents was 44.8, 8.2 years, and in the offspring it was 28.7, 7.2 years. In 12 parent-child pairs, the mean anticipation was –15.75, 9.1 years (range –8.1 to –23.3 years, t = –4.9, P = < 0.002). The mutated SCA2 alleles ranged from 38 to 42 CAG repeats, while the normal alleles ranged from 22 to 24 repeats, with 97% of the alleles having 22 repeats. Small differences in the number of CAG repeats influenced the age at onset and rate of progression of the disease considerably. Indeed, patients presenting with their first symptom at an age of 35 years or later with a slower course of the disease harboured between 38 and 39 repeats. In contrast, patients carrying ≥ 40 CAG repeats manifested the disease prior to 30 years of age and had a faster disease progression toward incapacity. The presenting symptom was always gait ataxia. Slow saccades occured from the beginning of the disease despite normal delay, accuracy and smooth pursuit eye movements. The neuropsychological study showed early and selective impairment of conceptual reasoning ability, as detected by the Wisconsin Card Sorting Test (WCST). It is noteworthy that a significant mutual relationship was observed between performance on the WCST and saccade velocity. All of these findings favour the hypothesis that the disease process of SCA2 in regions other than the cerebellum and brain stem affects severely and early those cortical structures involved in the control of both visually guided saccades and WCST performance. Received: 13 October 1997 Received in revised form: 23 February 1998 Accepted: 20 March 1998     

Lumbosacral spinal evoked potentials in patients with multiple sclerosis

Lumbosacral spinal evoked potentials were recorded percutaneously in 22 MS patients with spinal symptoms and in 24 age-matched normal volunteers. Latencies, durations, and areas of waves R and A (level S1) as well as S and P2 (level Th12) were analyzed. The most significant result observed in the MS group was a reduction of the ratio between the areas of P2 and S. The reduction was strongly correlated with intensity of spasticity, but not with other clinical features. The P2/S ratio can thus be proposed as an electrophysiologic measure of spasticity.     

Weaning from ventilator after cardiac operation using the Ciaglia percutaneous tracheostomy.

OBJECTIVE: To determine the predictors of weaning from mechanical ventilation after cardiac operation with the Ciaglia percutaneous dilatational tracheostomy (PDT) in our preliminary experience in the use of this technique. METHODS: We prospectively analysed 33 consecutive patients (mean age 70.9+/-12.7 years) who underwent PDT in our intensive care unit after cardiac operation. The investigation involved preoperative and postoperative clinical status, operative procedure, indication and timing for PDT. RESULTS: PDT was performed after a mean time of 7.7+/-5.0 consecutive days of translaryngeal intubation. Twenty-four (73%) patients were weaned from ventilator after a mean time of mechanical ventilation of 15.8+/-9.1 days. Time point of PDT was the only predictor of ventilator weaning (P=0.0029): there was significant association between PDT performed before the seventh consecutive day of translaryngeal intubation (early PDT) and successful weaning from ventilator (P=0.01; odds ratio=11.2, 95% confidence interval=1.2-104.3). Among the patients weaned from ventilator, those who underwent early PDT had significantly shorter times of mechanical ventilation, and intensive care unit and hospital stays than patients with later PDT (P=0.035, 0.011 and 0.0073, respectively). Nine (27%) patients died of their underlying disease while still being mechanically ventilated; another six (18%) spontaneously breathing but still incannulated patients died afterward. No major PDT-related complications were observed. Two minor peristomal bleedings and one self-resolving subcutaneous emphysema were recorded. CONCLUSIONS: Early PDT was a safe and effective method to wean from mechanical ventilation the cardiosurgical patients of this series.