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Pain, agitation and delirium are common during critical illness and are associated with many adverse consequences. A key aim of critical care is the facilitation of a calm, comfortable patient who can interact with their family and staff. Intensive care unit (ICU) patients frequently have pain from a variety of sources, many of which are not readily appreciated or actively managed. This article explores the challenges of assessing pain in the ICU and outlines methods that can be used to better identify and manage pain in this patient group. Agitation in ICU is often multifactorial, with many of its sources under-recognized. We will discuss the potential reasons that ICU patients become agitated, methods for measuring agitation and the actions that can be taken to alleviate it. Although the use of sedative and anxiolytic drugs is common in the ICU, their use is not without risks. This article will outline these risks, the variety of drugs available and how to use these drugs to a targeted effect. We will also explore delirium, its risk factors, precipitants and associated morbidity and mortality. This article will discuss how to diagnose delirium and the methods used to prevent and manage it.

Convulsive status epilepticus (CSE) is the most common neurological emergency in children and the second most common neurological emergency in adults. Mortality is low, but morbidity, including neuro-disability, learning difficulties, and a de-novo epilepsy, may be as high as 22%. The longer the duration of CSE, the more difficult it is to terminate, and the greater the risk of morbidity. Convulsive status epilepticus is usually managed using specific national or local algorithms. The first-line treatment is administered when a tonic-clonic or focal motor clonic seizure has lasted five minutes (impending or premonitory CSE). Second-line treatment is administered when the CSE has persisted after two doses of a first-line treatment (established CSE). Randomised clinical trial (RCT) evidence supports the use of benzodiazepines as a first-line treatment of which the most common are buccal or intra-nasal midazolam, rectal diazepam and intravenous lorazepam. Alternative drugs, for which there are considerably less RCT data, are intra-muscular midazolam and intravenous clonazepam. Up until 2019, phenobarbital and phenytoin (or fosphenytoin) were the preferred second-line treatments but with no good supporting RCT evidence. Robust RCT data are now available which has provided important information on second-line treatments, specifically phenytoin (or fosphenytoin), levetiracetam and sodium valproate. Lacosamide is an alternative second-line treatment but with no supporting RCT evidence. Current evidence indicates that first, buccal or intranasal midazolam or intravenous lorazepam are the most effective and the most patient and carer-friendly first-line anti-seizure medications to treat impending or premonitory CSE and second, that there is no difference in efficacy between levetiracetam, phenytoin (or fosphenytoin) or sodium valproate for the treatment of established CSE. Pragmatically, levetiracetam or sodium valproate are preferred to phenytoin (or fosphenytoin) because of their ease of administration and lack of serious adverse side-effects, including potentially fatal cardiac arrhythmias. Sodium valproate must be used with caution in children aged three and under because of the rare risk of hepatotoxicity and particularly if there is an underlying mitochondrial disorder.

Summary When developing a new medicine for children, the potential to extrapolate from adult efficacy data is well recognized. However, significant assumptions about the similarity of adults and children are needed for extrapolations to be biologically plausible. One such assumption is that of similar exposure–response (E–R-) relationships. Motivated by applications to antiepileptic drug development, we consider how data that are available from existing trials of adults and adolescents can be used to quantify prior uncertainty about whether E–R-relationships are similar in adults and younger children. A Bayesian multivariate meta-analytic model is fitted to existing E–R-data and adjusted for external biases that arise because these data are not perfectly relevant to the comparison of interest. We propose a strategy for eliciting expert prior opinion on external biases. From the bias-adjusted meta-analysis, we derive prior distributions quantifying our uncertainty about the degree of similarity between E–R-relationships for adults and younger children. Using these we calculate the prior probability that average pharmacodynamic responses in adults and younger children, both on placebo and at an effective concentration, are sufficiently similar to justify a complete extrapolation of efficacy data. A simulation study is performed to evaluate the operating characteristics of the approach proposed.

BackgroundAlternatives to prospective informed consent enable the conduct of paediatric emergency and critical care trials. Research without prior consent (RWPC) involves practitioners approaching parents after an intervention has been given and seeking consent for their child to continue in the trial. As part of an embedded study in the ‘Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus in children’ (EcLiPSE) trial, we explored how practitioners described the trial and RWPC during recruitment discussions, and how well this information was understood by parents. We aimed to develop a framework to assist trial conversations in future paediatric emergency and critical care trials using RWPC.MethodsQualitative methods embedded within the EcLiPSE trial processes, including audiorecorded practitioner–parent trial discussions and telephone interviews with parents. We analysed data using thematic analysis, drawing on the Realpe et al (2016) model for recruitment to trials.ResultsWe analysed 76 recorded trial discussions and conducted 30 parent telephone interviews. For 19 parents, we had recorded trial discussion and interview data, which were matched for analysis. Parental understanding of the EcLiPSE trial was enhanced when practitioners: provided a comprehensive description of trial aims; explained the reasons for RWPC; discussed uncertainty about which intervention was best; provided a balanced description of trial intervention; provided a clear explanation about randomisation and provided an opportunity for questions. We present a seven-step framework to assist recruitment practice in trials involving RWPC.ConclusionThis study provides a framework to enhance recruitment practice and parental understanding in paediatric emergency and critical care trials involving RWPC. Further testing of this framework is required.

Background Convulsive status epilepticus is the most common neurological emergency in children. Its management is important to avoid or minimise neurological morbidity and death. The current first-choice second-line drug is phenytoin (Epanutin, Pfizer Inc., New York, NY, USA), for which there is no robust scientific evidence. Objective To determine whether phenytoin or levetiracetam (Keppra, UCB Pharma, Brussels, Belgium) is the more clinically effective intravenous second-line treatment of paediatric convulsive status epilepticus and to help better inform its management. Design A multicentre parallel-group randomised open-label superiority trial with a nested mixed-method study to assess recruitment and research without prior consent. Setting Participants were recruited from 30 paediatric emergency departments in the UK. Participants Participants aged 6 months to 17 years 11 months, who were presenting with convulsive status epilepticus and were failing to respond to first-line treatment. Interventions Intravenous levetiracetam (40 mg/kg) or intravenous phenytoin (20 mg/kg). Main outcome measures Primary outcome – time from randomisation to cessation of all visible signs of convulsive status epilepticus. Secondary outcomes – further anticonvulsants to manage the convulsive status epilepticus after the initial agent, the need for rapid sequence induction owing to ongoing convulsive status epilepticus, admission to critical care and serious adverse reactions. Results Between 17 July 2015 and 7 April 2018, 286 participants were randomised, treated and consented. A total of 152 participants were allocated to receive levetiracetam and 134 participants to receive phenytoin. Convulsive status epilepticus was terminated in 106 (70%) participants who were allocated to levetiracetam and 86 (64%) participants who were allocated to phenytoin. Median time from randomisation to convulsive status epilepticus cessation was 35 (interquartile range 20–not assessable) minutes in the levetiracetam group and 45 (interquartile range 24–not assessable) minutes in the phenytoin group (hazard ratio 1.20, 95% confidence interval 0.91 to 1.60; p = 0.2). Results were robust to prespecified sensitivity analyses, including time from treatment commencement to convulsive status epilepticus termination and competing risks. One phenytoin-treated participant experienced serious adverse reactions. Limitations First, this was an open-label trial. A blinded design was considered too complex, in part because of the markedly different infusion rates of the two drugs. Second, there was subjectivity in the assessment of ‘cessation of all signs of continuous, rhythmic clonic activity’ as the primary outcome, rather than fixed time points to assess convulsive status epilepticus termination. However, site training included simulated demonstration of seizure cessation. Third, the time point of randomisation resulted in convulsive status epilepticus termination prior to administration of trial treatment in some cases. This affected both treatment arms equally and had been prespecified at the design stage. Last, safety measures were a secondary outcome, but the trial was not powered to demonstrate difference in serious adverse reactions between treatment groups. Conclusions Levetiracetam was not statistically superior to phenytoin in convulsive status epilepticus termination rate, time taken to terminate convulsive status epilepticus or frequency of serious adverse reactions. The results suggest that it may be an alternative to phenytoin in the second-line management of paediatric convulsive status epilepticus. Simple trial design, bespoke site training and effective leadership were found to facilitate practitioner commitment to the trial and its success. We provide a framework to optimise recruitment discussions in paediatric emergency medicine trials. Future work Future work should include a meta-analysis of published studies and the possible sequential use of levetiracetam and phenytoin or sodium valproate in the second-line treatment of paediatric convulsive status epilepticus. Trial registration Current Controlled Trials ISRCTN22567894 and European Clinical Trials Database EudraCT number 2014-002188-13. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 58. See the NIHR Journals Library website for further project information.

IntroductionAntiepileptic drugs (AEDs) are the mainstay of epilepsy treatment. Over the past 20 years, a number of new drugs have been approved for National Health Service (NHS) use on the basis of information from short-term trials that demonstrate efficacy. These trials do not provide information about the longer term outcomes, which inform treatment policy. This trial will assess the long-term clinical and cost-effectiveness of the newer treatment levetiracetam and zonisamide.Methods and analysisThis is a phase IV, multicentre, open-label, randomised, controlled clinical trial comparing new and standard treatments for patients with newly diagnosed epilepsy. Arm A of the trial randomised 990 patients with focal epilepsy to standard AED lamotrigine or new AED levetiracetam or zonisamide. Arm B randomised 520 patients with generalised epilepsy to standard AED sodium valproate or new AED levetiracetam. Patients are recruited from UK NHS outpatient epilepsy, general neurology and paediatric clinics. Included patients are aged 5 years or older with two or more spontaneous seizures requiring AED monotherapy, who are not previously treated with AEDs. Patients are followed up for a minimum of 2 years. The primary outcome is time to 12-month remission from seizures. Secondary outcomes include time to treatment failure (including due to inadequate seizure control or unacceptable adverse reactions); time to first seizure; time to 24-month remission; adverse reactions and quality of life. All primary analyses will be on an intention to treat basis. Separate analyses will be undertaken for each arm. Health economic analysis will be conducted from the perspective of the NHS to assess the cost-effectiveness of each AED.Ethics and disseminationThis trial has been approved by the North West-Liverpool East REC (Ref. 12/NW/0361). The trial team will disseminate the results through scientific meetings, peer-reviewed publications and patient and public involvement.Trial registration numbersEudraCT 2012-001884-64; ISRCTN30294119.

BackgroundKey challenges to the successful conduct of The Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus in children (EcLiPSE) trial were identified at the pre-trial stage. These included practitioner anxieties about conducting research without prior consent (RWPC), inexperience in conducting an ED-led trial and use of a medication that was not usual ED practice. As part of an embedded study, we explored parent and practitioner experiences of recruitment, RWPC and conduct of the trial to inform the design and conduct of future ED-led trials.MethodsA mixed-methods study within a trial involving (1) questionnaires and interviews with parents of randomised children, (2) interviews and focus groups with EcLiPSE practitioners and (3) audio-recorded trial discussions. We analysed data using thematic analysis and descriptive statistics as appropriate.ResultsA total of 143 parents (93 mothers, 39 fathers, 11 missing information) of randomised children completed a questionnaire and 30 (25 mothers, 5 fathers) were interviewed. We analysed 76 recorded trial recruitment discussions. Ten practitioners (4 medical, 6 nursing) were interviewed, 36 (16 medical, 20 nursing) participated in one of six focus groups. Challenges to the success of the trial were addressed by having a clinically relevant research question, pragmatic trial design, parent and practitioner support for EcLiPSE recruitment and research without prior consent processes, and practitioner motivation and strong leadership. Lack of leadership negatively affected practitioner engagement and recruitment. EcLiPSE completed on time, achieving its required sample size target.ConclusionsSuccessful trial recruitment and conduct in a challenging ED-led trial was driven by trial design, recruitment experience, teamwork and leadership. Our study provides valuable insight from parents and practitioners to inform the design and conduct of future trials in this setting.

The epilepsies of childhood are a markedly heterogeneous group of diseases with different presentations, outcomes and aetiologies. There is no single, gold-standard investigation that will unequivocally diagnose an epilepsy. The range of aetiologies includes genetic, structural brain malformations and metabolic; in many, there may be a combination of causes. Despite major advances in neuro-imaging and genetics, a cause will not be identified in approximately 40% of all children with epilepsies. This article outlines the available investigations and provides a practical and structured approach on their most effective use in the childhood epilepsies.

To compare the de novo incidence of Panayiotopoulos syndrome (PS, early-onset childhood occipital epilepsy) and a common epilepsy syndrome, benign epilepsy with centro-temporal spikes (BECTS), in children and young people.The incidence of PS and BECTS was recorded over 16 months in a population of children and young people (aged16 years) living within a specific geographic area and epilepsy network within the North West of England and North Wales and the catchment area of the tertiary paediatric epilepsy centre. Monthly data collection proformas were circulated to the paediatricians and paediatric neurologists responsible for the evaluation of epilepsy in children within this area. This also included monthly reminders of the electro-clinical criteria for these syndromes. EEGs were undertaken in the neurophysiology department of the tertiary paediatric epilepsy centre. The departmental EEG database on all16 year olds that underwent an EEG during the study period was examined to identify additional patients that may not have been reported via a proforma-reporting system.The incidence of PS and BECTS was found to be 0.8 and 6.1 per 100,00016 year olds, respectively. The ages at seizure onset and diagnosis were similar for BECTS and PS.This study is the first to determine a comparative incidence of PS and BECTS. The findings suggest BECTS is eight times more common than PS and that the incidence of PS is lower than previously suggested.

ObjectiveTo evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome.MethodsPatients aged 4–10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol). Safety assessments were clinical laboratory tests, physical examinations, vital signs, ECGs, adverse events (AEs), seizure frequency, and suicidality.ResultsThirty-four patients were randomized (10, 8, and 9 to the 5, 10, and 20 mg/kg/d CBD groups, and 7 to placebo); 32 (94%) completed treatment. Exposure to CBD and its metabolites was dose-proportional (AUC0–t). CBD did not affect concomitant AED levels, apart from an increase in N-CLB (except in patients taking stiripentol). The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury and all recovered. No other clinically relevant safety signals were observed.ConclusionsExposure to CBD and its metabolites increased proportionally with dose. An interaction with N-CLB was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. CBD resulted in more AEs than placebo but was generally well-tolerated.Classification of evidenceThis study provides Class I evidence that for children with Dravet syndrome, CBD resulted in more AEs than placebo but was generally well-tolerated.

Purpose Paediatric Epilepsy surgery in the UK has recently been centralised in order to improve expertise and quality of service available to children. Video EEG monitoring or telemetry is a highly specialised and a crucial component of the pre-surgical evaluation. Although many Epilepsy Monitoring Units work to certain standards, there is no national or international guideline for paediatric video telemetry. Methods Due to lack of evidence we used a modified Delphi process utilizing the clinical and academic expertise of the clinical neurophysiology sub-specialty group of Children's Epilepsy Surgical Service (CESS) centres in England and Wales. This process consisted of the following stages I: Identification of the consensus working group, II: Identification of key areas for guidelines, III: Consensus practice points and IV: Final review. Statements that gained consensus (median score of either 4 or 5 using a five-point Likerttype scale) were included in the guideline. Results Two rounds of feedback and amendments were undertaken. The consensus guidelines includes the following topics: referral pathways, neurophysiological equipment standards, standards of recording techniques, with specific emphasis on safety of video EEG monitoring both with and without drug withdrawal, a protocol for testing patient's behaviours, data storage and guidelines for writing factual reports and conclusions. All statements developed received a median score of 5 and were adopted by the group. Conclusion Using a modified Delphi process we were able to develop universally-accepted video EEG guidelines for the UK CESS. Although these recommendations have been specifically developed for the pre-surgical evaluation of children with epilepsy, it is assumed that most components are transferable to any paediatric video EEG monitoring setting.

Aim Phenytoin is the recommended second-line intravenous anticonvulsant in the management of paediatric convulsive status epilepticus (CSE). Anecdotal data suggest levetiracetam may be as effective as, and safer than phenytoin. The aim of this trial was to compare the effectiveness and safety of both drugs in CSE. Methods A superiority and open-label, randomised controlled trial (RCT) undertaken in 30 Emergency Departments in the UK. Participants were aged 6 months to Results Consent was obtained for 286 (152 levetiracetam, 134 phenytoin) randomised and treated participants between July 2015 and April 2018 comprising the primary outcome analysis. Median time (IQR) from randomisation to CSE-cessation was 35 min (20-NA) in the levetiracetam and 45 min (24-NA) in the phenytoin-treated group (adjusted Hazard Ratio 1.17 [95% CI 0.87–1.57; p=0.3). CSE was terminated in 106 (69.6%) of the levetiracetam, and 86 (64.2%) of the phenytoin-treated group. Sensitivity analysis showed no difference between groups using time from start of infusion to CSE-cessation. Five serious adverse events occurred in four participants, one of which was considered related to the drug (severe hypotension in a phenytoin-treated participant). No serious, new or unexpected reactions were observed with levetiracetam. Conclusion No statistically significant difference was detected between treatments but results, robust across sensitivity analyses, favoured levetiracetam. Serious adverse events were low for both treatments although there are known concerns with the safety profile of phenytoin. This trial suggests levetiracetam be considered as an alternative to phenytoin as the first-choice, second-line treatment of CSE in children.

Aims Challenges to the success of ‘The Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus in children (EcLiPSE)’ trial included: practitioner anxieties about research without prior consent (‘deferred consent’), including how parents would react to being informed their child had already been randomised into the trial; inexperience in conducting an Emergency Department led trial in a paediatric neurological emergency; and use of an anti-epileptic medication (Levetiracetam), which was not the standard medication in this clinical setting. This was a nested study within EcLiPSE that aimed to explore parent and practitioner experiences to inform trial recruitment and conduct. Methods A mixed method study involving interviews, focus groups and questionnaires with EcLiPSE practitioners and questionnaires and interviews with parents of randomised children. Qualitative data were anonymised and analysed thematically. Quantitative data were cleaned and analysed using descriptive statistics and chi-square test for trend. We present key themes identified from data synthesis. Results One hundred and forty three parents (93 mothers, 39 fathers, 11 missing parent information) of randomised children completed a questionnaire and 30 (25 mothers, 5 fathers) were interviewed. Ten practitioners (4 medical, 6 nursing) were interviewed, 36 (16 medical, 20 nursing) participated in one of six focus groups and 199 (117 medical, 78 nursing, 3 ‘other’) completed a questionnaire in the final phase of EcLiPSE. Practitioners highly valued bespoke site training, a clinically important research question and simple trial design. These factors, alongside recruitment experience and leadership, were found to facilitate practitioner ‘buy in’, commitment and ultimately, trial success. Parents supported the trial and understood why consent had been sought after treatment had been given. EcLiPSE was completed on time, achieving its recruitment target. Conclusions Our study provides valuable insight into factors that helped to facilitate successful conduct and recruitment to a challenging emergency department led trial. The results will hopefully facilitate future research in paediatric emergency departments.

Background EcLiPSE (Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus in children) is a randomised controlled trial (RCT) in the United Kingdom. Challenges to success include the need to immediately administer an intervention without informed consent and changes in staffing during trial conduct, mainly due to physician rotations. Using literature on parents’ perspectives and research without prior consent (RWPC) guidance, we developed an interactive training package (including videos, simulation and question and answer sessions) and evaluated its dissemination and impact upon on practitioners’ confidence in recruitment and consent. Methods Questionnaires were administered before and immediately after training followed by telephone interviews (mean 11 months later), focus groups (mean 14 months later) and an online questionnaire (8 months before trial closure). Results One hundred and twenty-five practitioners from 26/30 (87%) participating hospitals completed a questionnaire before and after training. We conducted 10 interviews and six focus groups (comprising 36 practitioners); 199 practitioners working in all recruiting hospitals completed the online questionnaire. Before training, practitioners were concerned about recruitment and consent. Confidence increased after training for explaining (all scale 0–5, 95% CIs above 0 and p values

Objective evidence is limited for the value of transition programs for youth with chronic illness moving from pediatric to adult care; however, such programs intuitively "make sense". We describe the strengths and weaknesses of a variety of transition programs from around the world for adolescents with epilepsy. Consequences of poorly organized transition beyond suboptimal seizure control may include an increased risk of sudden unexpected death in epilepsy (SUDEP), poor psychological and social outcome, and inadequate management of comorbidities. The content of transition programs for those with normal intelligence differs from those with intellectual disability, but both groups may benefit from an emphasis on sporting activities. Concerns that may interfere with optimal transition include lack of nursing or social work services, limited numbers of adult neurologists/epileptologists confident in the treatment of complex pediatric epilepsy problems, institutional financial support, and time constraints for pediatric and adult physicians who treat epilepsy and the provision of multidisciplinary care. Successful programs eventually need to rely on a several adult physicians, nurses, and other key healthcare providers and use novel approaches to complex care. More research is needed to document the value and effectiveness of transition programs for youth with epilepsy to persuade institutions and healthcare professionals to support these ventures.

Objective:\ud \ud Many different gene families are currently being investigated for their potential role in epilepsy and in the response to antiepileptic drugs. A common research challenge is identifying the members of a gene family that are most significantly dysregulated within the human epileptic focus, before taking them forward for resource‐intensive functional studies. Published data about transcriptomic changes within the human epileptic focus remains incomplete. A need exists for an accurate in silico system for the prediction of dysregulated genes within the epileptic focus. We present such a bioinformatic system. We demonstrate the validity of our approach by applying it to the solute carrier (SLC) gene family. There are >400 known SLCs. SLCs have never been systematically studied in epilepsy.\ud Methods:\ud \ud Using our in silico system, we predicted the SLCs likely to be dysregulated in the epileptic focus. We validated our in silico predictions by identifying ex vivo the SLCs dysregulated in epileptic foci, and determining the overlap between our in silico and ex vivo results. For the ex vivo analysis, we used a custom oligonucleotide microarray containing exon probes for all known SLCs to analyze 24 hippocampal samples obtained from surgery for pharmacoresistant mesial temporal lobe epilepsy and 24 hippocampal samples from normal postmortem controls.\ud Results:\ud \ud There was a highly significant (p < 9.99 × 10−7) overlap between the genes identified by our in silico and ex vivo strategies. The SLCs identified were either metal ion exchangers or neurotransmitter transporters, which are likely to play a part in epilepsy by influencing neuronal excitability.\ud Significance:\ud \ud The identified SLCs are most likely to mediate pharmacoresistance in epilepsy by enhancing the intrinsic severity of epilepsy, but further functional work will be needed to fully evaluate their role. Our successful in silico strategy can be adapted in order to prioritize genes relevant to epilepsy from other gene families.

Purpose: To use a physiologically based pharmacokinetic (PBPK) modelling system to predict the serum levels achieved by two different intravenous loading doses of phenytoin. Methods: A phenytoin pharmacokinetic model was used in the SimcypTM population-based ADME simulator, simulating 100 children age 2-10 years receiving intravenous phenytoin (18 and 20 mg/kg). Visual checks were used to evaluate the predictive performance of the candidate model. Results: Loading with doses of 18 mg/kg, blood levels were sub-therapeutic in 22/100 (concentration at 2 h post infusion (C2h) 20 mg/mL). Loading with 20 mg/kg, the percentages were 15, 59, and 26, respectively. Increasing from 18 to 20 mg/kg increased the mean C2h from 16.0 to 17.9 μg/mL, and the mean AUC from 145 to 162 μg/mL/h. A C2h > 30 μg/mL was predicted in 4% and 8% of children in the 18 and 20 mg/kg doses, with 3% predicted to have a C2h > 40 μg/mL following either dose. For maintenance doses, a 1st dose of 2.5 or 5 mg/kg (intravenous) given at 12 h (after either 18 or 20 mg/kg loading) gives the highest percentages of 10-20 μg/mL serum concentrations. For sub-therapeutic concentrations following intravenous loading (20 mg/kg), a 1st maintenance dose (intravenous) of 10 mg/kg will achieve therapeutic concentrations in 93%. Conclusion: Use of PBPK modelling suggests that children receiving the 20 mg/kg intravenous loading dose are at slightly increased risk of supra-therapeutic blood levels. Ideally, therapeutic drug monitoring is required to monitor serum concentrations, although the dose regime suggested by the BNFc appear appropriate.

Cerebral palsy (CP) is an umbrella term that defines a group of non-progressive, but often changing, syndromes of motor impairment secondary to lesions or anomalies of the brain arising in the early stages of its development.1 2 The characteristic clinical feature that is common to all CP syndromes is the presence of pyramidal or extrapyramidal signs. CP is neither a specific disease nor a pathological or aetiological entity, and importantly the term CP does not—and should not—necessarily imply or identify a specific cause. The prevalence of CP ranges from 1.5 to 2.5 per 1000 live births, with the risk highest among very preterm and low birthweight babies. However, the majority of children with CP are born at or near term gestation. Causes of CP include perinatal hypoxic-ischaemic encephalopathy, intra- or periventricular haemorrhage, cerebral dysgenesis, and intracranial infection. The CP syndromes may be classified by the predominant type of motor disturbance, including, for example, diplegia, tetraplegia, hemiplegia, dyskinesia, and ataxia, although frequently the overall clinical picture is not always pure. Finally, the aetiologies for these different syndromes tend to be quite distinct. Once a diagnosis of CP has been made on the basis of the child's symptoms and signs, each child should undergo appropriate evaluation and investigation to try and establish a cause and specifically to determine whether it is of prenatal, perinatal, or postnatal origin. Investigation is indicated even when there has been evidence of a preceding neurological event during the perinatal period or infancy, because some of these children may have an underlying neurological or metabolic disorder which may have made them more vulnerable to the stresses of delivery and extrauterine life. Finally, it is important that all children with a diagnosis of CP should be followed up, and when no obvious cause has been identified or there …

Background: cancellation of planned surgery impacts substantially on patients and health systems. This study describes the incidence and reasons for cancellation of inpatient surgery in the UK NHS. Methods: we conducted a prospective observational cohort study over 7 consecutive days in March 2017 in 245 NHS hospitals. Occurrences and reasons for previous surgical cancellations were recorded. Using multilevel logistic regression, we identified patient- and hospital-level factors associated with cancellation due to inadequate bed capacity. Results: we analysed data from 14 936 patients undergoing planned surgery. A total of 1499 patients (10.0%) reported previous cancellation for the same procedure; contemporaneous hospital census data indicated that 13.9% patients attending inpatient operations were cancelled on the day of surgery. Non-clinical reasons, predominantly inadequate bed capacity, accounted for a large proportion of previous cancellations. Independent risk factors for cancellation due to inadequate bed capacity included requirement for postoperative critical care [odds ratio (OR)=2.92; 95% confidence interval (CI), 2.12–4.02; PConclusions: a significant proportion of patients presenting for surgery have experienced a previous cancellation for the same procedure. Cancer surgery is relatively protected, but bed capacity, including postoperative critical care requirements, are significant risk factors for previous cancellations.

BACKGROUND: Tonic‐clonic convulsions and convulsive status epilepticus (currently defined as a tonic‐clonic convulsion lasting at least 30 minutes) are medical emergencies and require urgent and appropriate anticonvulsant treatment. International consensus is that an anticonvulsant drug should be administered for any tonic‐clonic convulsion that has been continuing for at least five minutes. Benzodiazepines (diazepam, lorazepam, midazolam) are traditionally regarded as first‐line drugs and phenobarbital, phenytoin and paraldehyde as second‐line drugs. This is an update of a Cochrane Review first published in 2002 and updated in 2008. OBJECTIVES: To evaluate the effectiveness and safety of anticonvulsant drugs used to treat any acute tonic‐clonic convulsion of any duration, including established convulsive (tonic‐clonic) status epilepticus in children who present to a hospital or emergency medical department. SEARCH METHODS: For the latest update we searched the Cochrane Epilepsy Group's Specialised Register (23 May 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 23 May 2017), MEDLINE (Ovid, 1946 to 23 May 2017), ClinicalTrials.gov (23 May 2017), and the WHO International Clinical Trials Registry Platform (ICTRP, 23 May 2017). SELECTION CRITERIA: Randomised and quasi‐randomised trials comparing any anticonvulsant drugs used for the treatment of an acute tonic‐clonic convulsion including convulsive status epilepticus in children. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and extracted data. We contacted study authors for additional information. MAIN RESULTS: The review includes 18 randomised trials involving 2199 participants, and a range of drug treatment options, doses and routes of administration (rectal, buccal, nasal, intramuscular and intravenous). The studies vary by design, setting and population, both in terms of their ages and also in their clinical situation. We have made many comparisons of drugs and of routes of administration of drugs in this review; our key findings are as follows: (1) This review provides only low‐ to very low‐quality evidence comparing buccal midazolam with rectal diazepam for the treatment of acute tonic‐clonic convulsions (risk ratio (RR) for seizure cessation 1.25, 95% confidence interval (CI) 1.13 to 1.38; 4 trials; 690 children). However, there is uncertainty about the effect and therefore insufficient evidence to support its use. There were no included studies which compare intranasal and buccal midazolam. (2) Buccal and intranasal anticonvulsants were shown to lead to similar rates of seizure cessation as intravenous anticonvulsants, e.g. intranasal lorazepam appears to be as effective as intravenous lorazepam (RR 0.96, 95% CI 0.82 to 1.13; 1 trial; 141 children; high‐quality evidence) and intranasal midazolam was equivalent to intravenous diazepam (RR 0.98, 95% CI 0.91 to 1.06; 2 trials; 122 children; moderate‐quality evidence). (3) Intramuscular midazolam also showed a similar rate of seizure cessation to intravenous diazepam (RR 0.97, 95% CI 0.87 to 1.09; 2 trials; 105 children; low‐quality evidence). (4) For intravenous routes of administration, lorazepam appears to be as effective as diazepam in stopping acute tonic clonic convulsions: RR 1.04, 95% CI 0.94 to 1.16; 3 trials; 414 children; low‐quality evidence. Furthermore, we found no statistically significant or clinically important differences between intravenous midazolam and diazepam (RR for seizure cessation 1.08, 95% CI 0.97 to 1.21; 1 trial; 80 children; moderate‐quality evidence) or intravenous midazolam and lorazepam (RR for seizure cessation 0.98, 95% CI 0.91 to 1.04; 1 trial; 80 children; moderate‐quality evidence). In general, intravenously‐administered anticonvulsants led to more rapid seizure cessation but this was usually compromised by the time taken to establish intravenous access. (5) There is limited evidence from a single trial to suggest that intranasal lorazepam may be more effective than intramuscular paraldehyde in stopping acute tonic‐clonic convulsions (RR 1.22, 95% CI 0.99 to 1.52; 160 children; moderate‐quality evidence). (6) Adverse side effects were observed and reported very infrequently in the included studies. Respiratory depression was the most common and most clinically relevant side effect and, where reported, the frequency of this adverse event was observed in 0% to up to 18% of children. None of the studies individually demonstrated any difference in the rates of respiratory depression between the different anticonvulsants or their different routes of administration; but when pooled, three studies (439 children) provided moderate‐quality evidence that lorazepam was significantly associated with fewer occurrences of respiratory depression than diazepam (RR 0.72, 95% CI 0.55 to 0.93). Much of the evidence provided in this review is of mostly moderate to high quality. However, the quality of the evidence provided for some important outcomes is low to very low, particularly for comparisons of non‐intravenous routes of drug administration. Low‐ to very low‐quality evidence was provided where limited data and imprecise results were available for analysis, methodological inadequacies were present in some studies which may have introduced bias into the results, study settings were not applicable to wider clinical practice, and where inconsistency was present in some pooled analyses. AUTHORS' CONCLUSIONS: We have not identified any new high‐quality evidence on the efficacy or safety of an anticonvulsant in stopping an acute tonic‐clonic convulsion that would inform clinical practice. There appears to be a very low risk of adverse events, specifically respiratory depression. Intravenous lorazepam and diazepam appear to be associated with similar rates of seizure cessation and respiratory depression. Although intravenous lorazepam and intravenous diazepam lead to more rapid seizure cessation, the time taken to obtain intravenous access may undermine this effect. In the absence of intravenous access, buccal midazolam or rectal diazepam are therefore acceptable first‐line anticonvulsants for the treatment of an acute tonic‐clonic convulsion that has lasted at least five minutes. There is no evidence provided by this review to support the use of intranasal midazolam or lorazepam as alternatives to buccal midazolam or rectal diazepam.

Importance: Antibodies to myelin oligodendrocyte glycoprotein IgG (MOG-IgG) are increasingly detected in patients with non–multiple sclerosis–related demyelination, some of whom manifest a neuromyelitis optica (NMO) phenotype. Cortical involvement, encephalopathy, and seizures are rare in aquaporin 4 antibody (AQP4-IgG)–related NMO in the white European population. However, the authors encountered several patients with seizures associated with MOG-IgG disease. Objective: To compare incidence of seizures and encephalitis-like presentation, or both between AQP4-IgG–positive and MOG-IgG–positive patients. Design, Setting, and Participants: Retrospective case series of all patients who were seropositive for MOG-IgG (n = 34) and the last 100 patients with AQP4-IgG disease (NMO spectrum disorder) seen in the NMO service between January 2013 and December 2016, and analysis was completed January 4, 2017. All patients were seen in a tertiary neurological center, The Walton Centre NHS Foundation Trust in Liverpool, England. Main Outcomes and Measures: The difference in seizure frequency between the AQP4-IgG–positive and MOG-IgG–positive patient groups was determined. Results: Thirty-four patients with MOG-IgG disease (20 female) with a median age at analysis of 30.5 years (interquartile range [IQR], 15-69 years), and 100 AQP4-IgG–positive patients (86 female) with a median age at analysis of 54 years (IQR, 12-91 years) were studied. Most patients were of white race. Five of the 34 patients with MOG-IgG (14.7%) had seizures compared with 1 patient with AQP4-IgG (2-sided P

We conducted a literature review of the intensive care unit-acquired weakness syndromes (critical illness polyneuropathy, critical illness myopathy and critical illness neuromyopathy) with the primary objective of determining their incidence as a combined group. Studies were identified through MEDLINE, Embase, Cochrane Database and article reference list searches and were included if they evaluated the incidence of one or more of these conditions in an adult intensive care unit population. The incidence of an intensive care unit-acquired weakness syndrome in the included studies was 40% (1080/2686 patients, 95% confidence interval 38–42%). The intensive care unit populations included were heterogeneous though largely included patients receiving mechanical ventilation for seven or more days. Additional prespecified outcomes identified that the incidence of intensive care unit-acquired weakness varied with the diagnostic technique used, being lower with clinical (413/1276, 32%, 95% CI 30–35%) compared to electrophysiological techniques (749/1591, 47%, 95% CI 45–50%). Approximately a quarter of patients were not able to comply with clinical evaluation and this may be responsible for potential underreporting of this condition.

Aims Variations from informed consent (known as deferred consent or research without prior consent-RWPC) enable paediatric critical care research to proceed by allowing consent to be sought after a child has received an investigational intervention. The first UK trials conducted in this setting show high levels of recruitment, yet children and young people (CYP) were rarely involved in recruitment discussions, often because they were too young or too poorly. We aimed to explore CYP’s views on RWPC and identify methods of involving them in decisions about their participation in critical care research. Methods Qualitative interview study involving 14 CYP (aged 7 to 15 years) with chronic health conditions and experience of paediatric emergency care treatment in the 12 months prior to interview. Results CYP were keen to be included in critical care research without prior consent if doctors viewed the trial intervention to be safe and of potential benefit to participants and others. All CYP felt that they have the right to be informed and have a say about their participation in a trial as soon as they had recovered. CYP suggest methods to help practitioners and parents facilitate RWPC discussions with children, including videos, cartoons, websites and leaflets. Conclusion CYP support research without prior consent in life threatening situations and provide examples of how multimedia resources could be used to engage and involve children in decisions about participation in research when they have recovered.

There has been considerable evolution in epilepsy healthcare for children over the last decade in the United Kingdom. There has been no single explanation for this. The development of national clinical guidelines, locally delivered but nationally designed educational programmes, nation-wide clinical audit, clinical networks and development of designated services have all had complimentary roles in enabling the implementation of national recommendations for the development of epilepsy care. These models may be applicable to other healthcare settings outside the UK.

Purpose Prescription errors are a common and potentially hazardous problem and may cause patient harm. This review evaluates all new anti-epileptic drug (AED) outpatient prescriptions over one year and reviews the subject literature. Methods A 12-month retrospective review of all outpatient prescriptions of AEDs within a large Children's Hospital. Copies of all prescriptions were obtained from the Trust's Pharmacy. The evaluation included the completeness of the required information, prescribing errors and the need for pharmacist intervention before the drug could be dispensed. It did not address the severity of prescribing errors or the potential harm to the patient. Results Two hundred and sixty two new prescriptions were evaluated. Incomplete prescriptions (that omitted at least one piece of required information) were found in 72.1%. The most common omission was the dose strength (mg/ml) or actual dose (mg) of the AED. No clinical diagnosis was documented in 62.6% and in 22%, only the word ‘epilepsy', was stated with no reference to the epilepsy syndrome or seizure type. Pharmacist intervention was required in approximately 17% (approximately 1 in 6) of all prescriptions before the AED could be dispensed. Conclusion This review highlights the importance of clinical information on prescriptions and that incomplete or poor documentation may contribute to prescribing errors. It also emphasises the importance of pharmacists in the identification and correction or resolution of potential prescribing errors. There is a need to develop a well-validated measure to assess the severity of prescribing errors that will better address their clinical significance and risk.

PurposeTo investigate whether genetic variants in inflammation-related genes are associated with increased risk of childhood-onset febrile seizures.MethodTagging single nucleotide polymorphisms (SNPs) from 19 inflammation-related candidate genes were identified and genotyped on the Sequenom platform in a sample of Caucasian childhood-onset febrile seizures cases (n=98) compared to ethnicity, age and gender matched febrile controls presenting without seizures (n=123). Tests for allelic association were carried out using PLINK. SNPs generating empirical P-values (P

Purpose To survey the current transitional epilepsy services in tertiary paediatric neurology centres in the UK within the principles of transitional care for young people with epilepsy. Methods An online web-based questionnaire was sent to the lead epilepsy clinicians in tertiary paediatric neurology centres on behalf of the British Paediatric Epilepsy Group, the specialist epilepsy group of the British Paediatric Neurology Association (BPNA). A transition clinic was defined as a ‘ clinic or service that provided joint paediatric and adult supervision of care from paediatric to adult services '. Results Twenty-three centres were approached of which18 responded and 15 of which provided auditable data. The clinics were held between three and 12 times per year, mostly in the afternoon and sited equally between the paediatric and adult centre. Approximately three to five new, and three to eight follow up patients were seen in each clinic. Most clinics accepted new referrals with a minimum age of 14 and a maximum of 20 years. Most young people were seen only once in a transition clinic before then being promoted into the adult epilepsy service. Very few clinics accepted direct referrals from the GP. Adult, slightly more than the paediatric team provided out-of-hospital advice after the young person was seen in the transition clinic. Conclusions Young people with epilepsy are a challenging, but interesting group and their care at this time may have a potentially irreversible impact on their life. Their progress from paediatric to adult services should be a dynamic, gradual and smoothly transitioned process to optimise their care. Although recommended by the National Institute for Health and Clinical Excellence (NICE) and the National Services Framework (NSF), the findings of this survey would suggest an un-met need of this population.

Migrating partial seizures of infancy, also known as epilepsy of infancy with migrating focal seizures, is a rare early infantile epileptic encephalopathy with poor prognosis, presenting with focal seizures in the first year of life. A national surveillance study was undertaken in conjunction with the British Paediatric Neurology Surveillance Unit to further define the clinical, pathological and molecular genetic features of this disorder. Fourteen children with migrating partial seizures of infancy were reported during the 2 year study period (estimated prevalence 0.11 per 100 000 children). The study has revealed that migrating partial seizures of infancy is associated with an expanded spectrum of clinical features (including severe gut dysmotility and a movement disorder) and electrographic features including hypsarrhythmia (associated with infantile spasms) and burst suppression. We also report novel brain imaging findings including delayed myelination with white matter hyperintensity on brain magnetic resonance imaging in one-third of the cohort, and decreased N-acetyl aspartate on magnetic resonance spectroscopy. Putaminal atrophy (on both magnetic resonance imaging and at post-mortem) was evident in one patient. Additional neuropathological findings included bilateral hippocampal gliosis and neuronal loss in two patients who had post-mortem examinations. Within this cohort, we identified two patients with mutations in the newly discovered KCNT1 gene. Comparative genomic hybridization array, SCN1A testing and genetic testing for other currently known early infantile epileptic encephalopathy genes (including PLCB1 and SLC25A22) was non-informative for the rest of the cohort.

Data from clinical trials in adults, extrapolated to predict benefits in paediatric patients, could result in fewer or smaller trials being required to obtain a new drug licence for paediatrics. This article outlines the place of such extrapolation in the development of drugs for use in paediatric epilepsies. Based on consensus expert opinion, a proposal is presented for a new paradigm for the clinical development of drugs for focal epilepsies. Phase I data should continue to be collected in adults, and phase II and III trials should simultaneously recruit adults and paediatric patients aged above 2 years. Drugs would be provisionally licensed for children subject to phase IV collection of neurodevelopmental safety data in this age group. A single programme of trials would suffice to license the drug for use as either adjunctive therapy or monotherapy. Patients, clinicians and sponsors would all benefit from this new structure through cost reduction and earlier access to novel treatments. Further work is needed to elicit the views of patients, their parents and guardians as appropriate, regulatory authorities and bodies such as the National Institute for Health and Care Excellence (UK).

Infantile spasms, and specifically within the context of West syndrome , is one of the most common epileptic encephalopathies to occur in early infancy. Early recognition and treatment can improve neurodevelopmental outcome in some cases, although the underlying aetiology is probably the most important prognostic factor in both spasm suppression and developmental outcome. Corticosteroids, either adrenocorticotrophic hormone (ACTH) or prednisolone, and vigabatrin are currently the preferred first-line treatment options. Vigabatrin is the treatment of choice when the underlying cause is tuberous sclerosis complex (TSC). Emerging evidence suggests that a combination of steroid and vigabatrin may be more effective in the suppression of spasms and resolution of hypsarrhythmia, the electro-encephalographic signal of spasms. Several other anti-epileptic drugs (AEDs) (levetiracetam, nitrazepam, sodium valproate, topiramate, zonisamide) are usually used as add-on or adjunctive treatment in refractory cases. Pyridoxine (or pyridoxal phosphate) and the ketogenic diet are established treatment options in refractory cases. There is some evidence that neuro-active steroids, including ganaxolone, may be effective; however, clinical trials undertaken intermittently for over a decade have yet to prove their efficacy, not only for the suppression of infantile spasms but also for the resolution of hypsarrhythmia, which may be as important as seizure control in developmental outcome in these children. Insights into developing novel treatment options have emerged from rodent models of infantile spasms, and research is continuing into the efficacy of rapamycin in improving outcomes in infantile spasms. This review provides a brief overview of the existing scientific literature around treatment options and outlines emerging newer treatment options in infantile spasms.

Objective: To study rituximab in pediatric neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD) and the relationship between rituximab, B cell repopulation, and relapses in order to improve rituximab monitoring and redosing. Methods: Multicenter retrospective study of 16 children with NMO/NMOSD receiving ≥2 rituximab courses. According to CD19 counts, events during rituximab were categorized as “repopulation,” “depletion,” or “depletion failure” relapses (repopulation threshold CD19 ≥10 × 10 6 cells/L). Results: The 16 patients (14 girls; mean age 9.6 years, range 1.8–15.3) had a mean of 6.1 events (range 1–11) during a mean follow-up of 6.1 years (range 1.6–13.6) and received a total of 76 rituximab courses (mean 4.7, range 2–9) in 42.6-year cohort treatment. Before rituximab, 62.5% had received azathioprine, mycophenolate mofetil, or cyclophosphamide. Mean time from rituximab to last documented B cell depletion and first repopulation was 4.5 and 6.8 months, respectively, with large interpatient variability. Earliest repopulations occurred with the lowest doses. Significant reduction between pre- and post-rituximab annualized relapse rate (ARR) was observed ( p = 0.003). During rituximab, 6 patients were relapse-free, although 21 relapses occurred in 10 patients, including 13 “repopulation,” 3 “depletion,” and 4 “depletion failure” relapses. Of the 13 “repopulation” relapses, 4 had CD19 10–50 × 10 6 cells/L, 10 had inadequate monitoring (≤1 CD19 in the 4 months before relapses), and 5 had delayed redosing after repopulation detection. Conclusion: Rituximab is effective in relapse prevention, but B cell repopulation creates a risk of relapse. Redosing before B cell repopulation could reduce the relapse risk further. Classification of evidence: This study provides Class IV evidence that rituximab significantly reduces ARR in pediatric NMO/NMOSD. This study also demonstrates a relationship between B cell repopulation and relapses.

Purpose To report the effectiveness and safety of intravenous levetiracetam in the treatment of children with acute repeated seizures, and status epilepticus in a children's hospital. Methods This two-year observational study evaluated all in-patients who received intravenous levetiracetam to treat acute repeated seizures (ARS) or convulsive and non-convulsive status epilepticus (SE). Information was collected on seizure type, epilepsy syndrome and underlying cause, the initial loading dose of intravenous levetiracetam, its effectiveness and safety and whether the patient remained on the drug at final follow-up. Analysis was descriptive. Results Fifty-one patients aged 0.2–18.8 (mean 7.1) years were evaluated, including 45 with acute ARS or SE and six unable to continue their usual orally administered anti-epileptic medication. The median initial dose of levetiracetam was 14.4 (range 5–30)mg/kg in the 45 patients treated for acute seizures and SE. Twenty three of the 39 (59%) patients with ARS became and remained seizure-free. Levetiracetam terminated status in three of four (75%) patients with convulsive, and the two patients with non-convulsive status epilepticus. Aggressive behaviour occurred in three children, one of whom discontinued treatment. Forty-two patients (81%), including 34 of the 45 patients (76%) treated for ARS or SE remained on levetiracetam at the time of final follow-up, between two and 18 months after receiving the drug. Conclusion This observational study has confirmed previous data that intravenous levetiracetam seems to be effective and safe in the treatment of acute repeated seizures and status epilepticus. A randomised clinical trial is justified to determine whether intravenous levetiracetam should replace intravenous phenytoin as the first long-acting anticonvulsant in the management of acute repetitive seizures and status epilepticus.

The majority of patients now survive their intensive care unit (ICU) stay. Unfortunately, follow-up of survivors has found weakness acquired during the ICU stay to be a major contributor to morbidity and impaired quality of life post-ICU.

Purpose Sulthiame is an old antiepileptic drug primarily used in a few European countries for the treatment of benign epilepsy of childhood with central temporal spikes. Other studies suggest that it might be effective in children and adults with a range of refractory seizure types. Methods A retrospective case note review was undertaken to evaluate the efficacy and safety of sulthiame as adjunctive therapy in children with refractory epilepsies. Results Twenty patients (10 female) were evaluated, aged 10.7 (range 2.1–17) years. The median duration of treatment with sulthiame was 18 (range 2–37) months. Fifty five percent of patients showed at least a 50% reduction in seizure frequency and two patients were seizure-free at the end of follow-up. Patients with focal seizures responded best. Seven patients reported side effects, leading to withdrawal of the drug in two (10%). Conclusion Sulthiame was reasonably effective and well-tolerated in a heterogeneous group of 20 children with refractory epilepsies. Although an ‘old' antiepileptic drug it should be considered in a similar population.

The National Institute for Health and Clinical Excellence (NICE) in Clinical Guideline 83: Rehabilitation after critical illness has set challenging recommendations regarding the routine evaluation for, and provision of, rehabilitation within critical care units. There is no published information regarding current practice in the UK. To establish current practice in Scotland we undertook a telephone survey of all 23 Scottish ICU lead clinicians and physiotherapists − 96% of lead clinicians and 100% of lead physiotherapists completed the survey. Routine assessment for physical (median two (IQR 1–3 [range 0–4])) and non-physical sequelae (median zero (IQR 0–2 [range 0–5])) is low. Aproximately half of ICUs (52%) provide an individualised, structured rehabilitation programme, 32% include activities of daily living and all provide low intensity rehabilitation (eg limb stretching and positioning exercises). There are significant differences (all p

Dravet syndrome is an epilepsy syndrome of infantile onset, frequently caused by SCN1A mutations or deletions. Its prevalence, long-term evolution in adults and neuropathology are not well known. We identified a series of 22 adult patients, including three adult post-mortem cases with Dravet syndrome. For all patients, we reviewed the clinical history, seizure types and frequency, antiepileptic drugs, cognitive, social and functional outcome and results of investigations. A systematic neuropathology study was performed, with post-mortem material from three adult cases with Dravet syndrome, in comparison with controls and a range of relevant paediatric tissue. Twenty-two adults with Dravet syndrome, 10 female, were included, median age 39 years (range 20–66). SCN1A structural variation was found in 60% of the adult Dravet patients tested, including one post-mortem case with DNA extracted from brain tissue. Novel mutations were described for 11 adult patients; one patient had three SCN1A mutations. Features of Dravet syndrome in adulthood include multiple seizure types despite polytherapy, and age-dependent evolution in seizure semiology and electroencephalographic pattern. Fever sensitivity persisted through adulthood in 11 cases. Neurological decline occurred in adulthood with cognitive and motor deterioration. Dysphagia may develop in or after the fourth decade of life, leading to significant morbidity, or death. The correct diagnosis at an older age made an impact at several levels. Treatment changes improved seizure control even after years of drug resistance in all three cases with sufficient follow-up after drug changes were instituted; better control led to significant improvement in cognitive performance and quality of life in adulthood in two cases. There was no histopathological hallmark feature of Dravet syndrome in this series. Strikingly, there was remarkable preservation of neurons and interneurons in the neocortex and hippocampi of Dravet adult post-mortem cases. Our study provides evidence that Dravet syndrome is at least in part an epileptic encephalopathy.

Background Neuromyelitis Optica (NMO) is a severe and rare inflammatory condition, where relapses are predictive of disability. Methods We describe a national paediatric NMO cohort9s clinical, MRI, outcome, and prognostic features in relation to Aquaporin-4 antibody (AQP4-Ab) status, and compared to a non NMO control cohort. Observations Twenty NMO cases (females=90%; AQP4-Ab positive=60%; median age=10.5yrs) with median follow-up=6.1yrs were compared to a national cohort sample of known sequential AQP4-Ab negative first episode CNS acquired demyelination cases (n=29; females=55%; all AQP4-Ab negative; median age=13.6yrs). At presentation, 40% NMO cases had unilateral optic neuritis (ON); 20% bilateral ON; 15% transverse myelitis (TM); 15% simultaneous TMO 10% Acute disseminated encephalomyelitis. At follow up, 55% had a clinical demyelinating episode involving the brain; 30% of cases had abnormal brain MRI at onset and 75% by follow up. NMO brain scan lesions compared to controls were large (>2 cm), acute lesions largely resolved on repeat imaging, and often showed T1 hypointense lesions. Mean time to relapse=0.76yrs (95% CI 0.43–1.1yrs) for AQP4-Ab positive vs 2.4yrs in AQP4-Ab negative cases (95% CI 1.1–3.6yrs). In AQP4-Ab positive cases, 10/12 had visual acuity Conclusions In children, NMO is associated with early recurrence and visual impairment in AQP4-Ab positivity and physical disability in AP4-Ab negative relapsing cases. Distinct MRI changes appear more commonly and earlier compared to adult NMO. Early AQP4-Ab testing may allow prompt immunomodulatory treatment to minimise disability.

Integrated care pathways are widely used for a range of medical and surgical conditions with the aim of providing a streamlined and unified approach to evidence-based care. They have been used for a number of years in the multidisciplinary management of adults with neurological conditions who are expected to require prolonged rehabilitation. Care pathways have been used in approximately 60 conditions at Alder Hey Children's Hospital over the past few years. This paper describes an experience of a care pathway for children with Guillain–Barré syndrome. As far as the authors are aware, this is the first care pathway to be used for children with a neurological disorder. Preliminary observations, which have yet to be formally audited, suggest that the pathway has benefited patient care and significantly improved patient documentation and interdisciplinary communication. It has also helped to reduce and minimize unnecessary variation from expected evidence-based management.

PurposeTo evaluate the effectiveness and tolerability of zonisamide in children with epilepsy.MethodRetrospective case note review of young people (less than 19 years) with epilepsy from three UK tertiary centres who received treatment with zonisamide and were followed up for a minimum of 12 months.ResultsFifty-seven children were included, aged 1.5–18.5 (median, 12) years. Thirty-three (57.9%) patients had generalised epilepsy, 21 (36.8%) focal epilepsy, and three (5.3%) a mixed, generalised and focal, epilepsy. Fifty-six of the 57 patients had been refractory to at least three previous antiepileptic drugs. The maintenance dose of zonisamide was [range (median)] 0.7–14 (5)mg/kg/day. The median duration of treatment for all patients was 12 (range 0.25–35) months. After 2 months of treatment, 51 patients remained on zonisamide, 18 (35.3%) of whom demonstrated a ≥50% reduction in seizure frequency. At the end of the follow-up period, there was a loss of effect for some patients. Thirteen (25.5%) of the 51 patients continued to demonstrate a ≥50% reduction in seizure frequency whilst two who had become seizure-free started having seizures again. Six (11.8%) had