Harmonizing Quality Improvement Metrics Across Global Trial Networks to Advance Paediatric Clinical Trials Delivery.

BACKGROUND: Despite global efforts to improve paediatric clinical trials, significant delays continue in paediatric drug approvals. Collaboration between research networks is needed to address these delays. This paper is a first step to promote interoperability between paediatric networks from different jurisdictions by comparing drivers for, and content of, metrics about clinical trial conduct. METHODS: Three paediatric networks, Institute for Advanced Clinical Trials for Children, the Maternal Infant Child and Youth Research Network and conect4children, have each developed metrics to address delays and create efficiencies. We identified the methodology by which each network identified metrics, described the metrics of each network, and mapped consistency to come to consensus about core metrics that networks could share. RESULTS: Metric selection was driven by site quality improvement in one network (11 metrics), by network performance in one network (13 metrics), and by both in one network (five metrics). The domains of metrics were research capacity/capability, site identification/feasibility, trial start-up, and recruitment/enrolment. The network driven by site quality improvement did not have indicators for capacity/capability or identification/feasibility. Fifteen metrics for trial start up and conduct were identified. Metrics related to site approvals were found in all three networks. The themes for metrics can inform the development of 'shared' metrics. CONCLUSION: We found disparity in drivers, methodology and metrics. Tackling this disparity will result in a unified approach to addressing delays in paediatric drug approvals. Collaborative work to define inter-operable metrics globally is outlined.

Evaluating Kidney Function Decline in Children with Chronic Kidney Disease Using a Multi-Institutional Electronic Health Record Database.

BACKGROUND: The objectives of this study were to use electronic health record data from a US national multicenter pediatric network to identify a large cohort of children with CKD, evaluate CKD progression, and examine clinical risk factors for kidney function decline. METHODS: This retrospective cohort study identified children seen between January 1, 2009, to February 28, 2022. Data were from six pediatric health systems in PEDSnet. We identified children aged 18 months to 18 years who met criteria for CKD: two eGFR values <90 and ≥15 ml/min per 1.73 m2 separated by ≥90 days without an intervening value ≥90. CKD progression was defined as a composite outcome: eGFR <15 ml/min per 1.73 m2, ≥50% eGFR decline, long-term dialysis, or kidney transplant. Subcohorts were defined based on CKD etiology: glomerular, nonglomerular, or malignancy. We assessed the association of hypertension (≥2 visits with hypertension diagnosis code) and proteinuria (≥1 urinalysis with ≥1+ protein) within 2 years of cohort entrance on the composite outcome. RESULTS: Among 7,148,875 children, we identified 11,240 (15.7 per 10,000) with CKD (median age 11 years, 50% female). The median follow-up was 5.1 (interquartile range 2.8-8.3) years, the median initial eGFR was 75.3 (interquartile range 61-83) ml/min per 1.73 m2, 37% had proteinuria, and 35% had hypertension. The following were associated with CKD progression: lower eGFR category (adjusted hazard ratio [aHR] 1.44 [95% confidence interval (95% CI), 1.23 to 1.69], aHR 2.38 [95% CI, 2.02 to 2.79], aHR 5.75 [95% CI, 5.05 to 6.55] for eGFR 45-59 ml/min per 1.73 m2, 30-44 ml/min per 1.73 m2, 15-29 ml/min per 1.73 m2 at cohort entrance, respectively, when compared with eGFR 60-89 ml/min per 1.73 m2), glomerular disease (aHR 2.01 [95% CI, 1.78 to 2.28]), malignancy (aHR 1.79 [95% CI, 1.52 to 2.11]), proteinuria (aHR 2.23 [95% CI, 1.89 to 2.62]), hypertension (aHR 1.49 [95% CI, 1.22 to 1.82]), proteinuria and hypertension together (aHR 3.98 [95% CI, 3.40 to 4.68]), count of complex chronic comorbidities (aHR 1.07 [95% CI, 1.05 to 1.10] per additional comorbid body system), male sex (aHR 1.16 [95% CI, 1.05 to 1.28]), and younger age at cohort entrance (aHR 0.95 [95% CI, 0.94 to 0.96] per year older). CONCLUSIONS: In large-scale real-world data for children with CKD, disease etiology, albuminuria, hypertension, age, male sex, lower eGFR, and greater medical complexity at start of follow-up were associated with more rapid decline in kidney function.

Pediatric Clinical Research Networks: Role in Accelerating Development of Therapeutics in Children.

BACKGROUND: Recent decades have seen many advances in policy and legislation that support the development of drugs used by neonates, infants, children, and young people. This review summarizes the characteristics and performance of networks capable of conducting studies needed to meet regulatory requirements and make advances in pediatric drug development. METHODS: Description of network goals and capabilities by network leaders. RESULTS: In the United States, Europe, Japan, and Canada, clinical research networks have been organized to meet the needs of biopharmaceutical and academic sponsors for timely access to high-quality sites, as well as to provide advice about drug development with regard to strategic and operational feasibility. Each network addresses the specificities of its context while working toward shared principles including standards and timelines; alignment of goals and processes, while not disturbing arrangements for conducting trials that work well; wide geographic coverage; all age groups and pediatric conditions; sources of funding; sites that compete on performance; performance monitoring for benchmarking, and opportunities to optimize the allocation of resources; and education and training for network members. Facilitation in interactions among these networks is based on a single point-of-contact for each; similar approaches to strategic and operational feasibility assessment, and site selection; and collaborative approaches to education and training. CONCLUSION: Within five years, clinical research networks will support the needs of biopharmaceutical and publicly funded pediatric drug development through locally appropriate and globally interoperable approaches.

Inclusion of Adolescents in Adult Clinical Trials: Report of the Institute for Advanced Clinical Trials for Children's Pediatric Innovation Research Forum.

Including adolescents in adult clinical trials can play an important role in making innovative new medicines available to children in a timelier fashion. Stakeholders involved in the processes leading to regulatory approval and labeling of new drugs recognize that challenges exist in involving adolescents and older children in clinical trials before the safety and efficacy of these drugs are established for adults. However, it has been possible to design and execute phase 3 trials that combine adults with adolescents which are medically and scientifically sound and ethically justified. Based on this experience and considerations of the medical and scientific, ethical, and operation-related matters, the 2019 Pediatric Innovation Research Forum advocated for the position that adolescents routinely be considered for enrollment in phase 3 clinical trials. The Forum also concluded that exclusion of adolescents in adult pivotal trials occur only when a thorough evaluation of the target disease and the potential benefit and risks of the study intervention supports a delay in their involvement until after completion of clinical trials in adults.

Efficacy and patient opinion of wet-wrap dressings using 0.1% triamcinolone acetonide ointment vs cream in the treatment of pediatric atopic dermatitis: A randomized split-body control study.

BACKGROUND: Wet wraps can be an effective means of improving atopic dermatitis (AD). Little research has been done regarding the comparative efficacy of topical steroid vehicles and patient preference. OBJECTIVE: This study aimed to compare the efficacy of 0.1% triamcinolone acetonide ointment vs cream used with wet wraps in pediatric patients with AD and to explore patient preference/opinion. METHODS: We performed a small, randomized, investigator-blind prospective study of 39 pediatric patients experiencing symmetric, bilateral AD flares. Patients were instructed to apply a topical steroid cream to one extremity and apply the same topical steroid in an ointment vehicle to the other extremity using the wet-wrap technique once or twice daily for 3 to 5 consecutive days. Patients were evaluated at a follow-up visit. RESULTS: Comparison of the change in Investigator's Global Assessment scores disclosed no significant difference between efficacy ratings of cream (mean difference = 0.72) and ointment (mean difference = 0.59) when used with wet wraps (P = 0.22). Although patients found the ointment more difficult to apply, they were more likely to prefer ointments for future prescriptions (P < 0.01). CONCLUSION: Patient preference of corticosteroid vehicle is what should ultimately drive treatment. In this small study, we found no difference in efficacy between triamcinolone acetonide wet wraps with cream vs ointment. Dermatologists should select the vehicle of the patient's choice as it may increase satisfaction with treatment.

Association Between Delusions of Infestation and Prescribed Narcotic and Stimulant Use.

OBJECTIVE: Patients diagnosed with delusions of infestation (DOI) at a psychodermatology clinic appeared to have a higher incidence of being prescribed narcotic or stimulant medications compared with the general dermatologic clinic population with chronic pruritic conditions. A retrospective study was conducted examining the correlation between patients with DOI and prescribed psychoactive medications. METHODS: Ninety-two patients with a diagnosis of DOI, seen at our University Psychodermatology Clinic, served as the study population. The comparison group (N=354) included dermatology patients seen at a dermatology clinic by the same dermatologist for itching, including adults seen for chronic pruritic conditions and contact dermatitis. For both groups, the reported use of any psychoactive prescription medications was noted. RESULTS: Patients with DOI were significantly more likely than other dermatology patients to receive prescriptions for narcotics [adjusted odds ratio (OR)=2.19; confidence interval (CI)=1.21-3.99) and stimulants (OR=5.44; CI=2.37-12.52). Patients with DOI were also more likely to be female (OR=2.49; CI=1.47-4.22) than patients who did not have such delusions. DISCUSSION: Few data are available concerning the etiology and management of DOI. Findings from this study indicated an association between the diagnosis of DOI and the prescribing of narcotics and stimulants, even when sex and age were taken into account. This information may be used to assist with the diagnosis of patients presenting with DOI and possible treatment options. It will be important to determine if these medications are a cause of the condition, or are merely correlated with other medical conditions.

Patterns of antiepileptic drug use in patients with potential refractory epilepsy in Texas Medicaid.

OBJECTIVES: Antiepileptic drug (AED) monotherapy is usually effective in 60% of the patients with epilepsy while the remaining patients have refractory epilepsy. This study compared treatment patterns (adherence, persistence, addition, and switching) associated with refractory and nonrefractory epilepsy. METHODS: Texas Medicaid claims from 09/01/07-12/31/13 were analyzed, and patients eligible for the study 1) were between 18 and 62 years of age, 2) had a prescription claim for an AED during the identification period (03/01/08-12/31/11) with no prior baseline AED use (6-month), and 3) had evidence of epilepsy diagnosis within 6 months of AED use. Based on AED use in the identification period, patients were categorized into "refractory" (≥3AEDs) and "nonrefractory" (<3AEDs) cohorts. The index date was the date of the first AED claim. Patients in both cohorts were matched 1:1 using propensity scoring and compared for adherence (proportion of days covered (PDC) ≥80% vs. <80%), persistence, addition (yes/no), and switching (yes/no) using multivariate conditional regression models. Conditional logistic regression and Cox proportional hazard models were used to address the study objectives. RESULTS: Of the 10,599 eligible patients, 2798 (26.5%) patients in the refractory cohort were matched to patients in the nonrefractory cohort. Patients in the refractory cohort had significantly higher (p < 0.005) mean (±Standard deviation (SD)) adherence (88.6% (±19.1%) vs. 77.0% ±â€¯(25.8%)) and persistence (328.0 (±87.3) days vs. 294.9 ±â€¯(113.4) days) as compared with patients in the nonrefractory cohort. Compared with patients with nonrefractory epilepsy, patients with refractory epilepsy were 3.6 times (odds ratio (OR) = 3.553; 95% confidence interval (CI) = 3.060-4.125; p < 0.0001) more likely to adhere to AEDs and had a 34.7% (hazard ratio (HR) = 0.653; 95% CI = 0.608-0.702; p < 0.0001) lower hazard rate of discontinuation of AEDs. Also, patients with refractory epilepsy were 3.7 times (OR = 3.723; 95% CI = 2.902-4.776; p < 0.0001) more likely to add an alternative AED and 3.6 times (OR = 3.591; 95% CI = 3.010-4.284; p < 0.0001) more likely to switch to an alternative AED. CONCLUSION: Patients with refractory epilepsy were significantly more likely to adhere and persist to AED regimen and were significantly more likely to add and switch to an alternative AED than patients with nonrefractory epilepsy.

Comparison of a rapid albuterol pathway with a standard pathway for the treatment of children with a moderate to severe asthma exacerbation in the emergency department.

OBJECTIVE: The objective of this study was to determine if a rapid albuterol delivery pathway with a breath-enhanced nebulizer can reduce emergency department (ED) length of stay (LOS), while maintaining admission rates and side effects, when compared to a traditional asthma pathway with a standard jet nebulizer. METHODS: Children aged 3-18 presenting to a large urban pediatric ED for asthma were enrolled if they were determined by pediatric asthma score to have a moderate to severe exacerbation. Subjects were randomized to either a standard treatment arm where they received up to 2 continuous albuterol nebulizations, or a rapid albuterol arm where they received up to 4 rapid albuterol treatments with a breath-enhanced nebulizer, depending on severity scoring. The primary endpoint was ED LOS from enrollment until disposition decision. Asthma scores, albuterol dose, side effects, and return visits were also recorded. RESULTS: A total of 50 subjects were enrolled (25 in each arm). The study LOS was shorter in the rapid albuterol group (118 vs. 163 minutes, p = 0.0002). When total ED LOS was analyzed, the difference was no longer statistically significant (192 vs. 203 minutes, p = 0.65). There were no statistically significant differences with respect to admission rates, asthma score changes, side effects, or return visits. CONCLUSION: A rapid albuterol treatment pathway that utilizes a breath-enhanced nebulizer is an effective alternative to traditional pathways that utilize continuous nebulizations for children with moderate to severe asthma exacerbations in the ED.

Look Who's Talking: Comparing Perceptions Versus Direct Observations in Family-Centered Rounds.

BACKGROUND AND OBJECTIVES: Family-centered rounds (FCR) are an important and recommended component of pediatric hospital care. This study compares direct observations versus perceptions and ideals of who talks during FCR. METHODS: A silent investigator observed FCR and noted who spoke, time in patient rooms, nurse and family presences, and patient information. After the observation period, the medical team was offered an anonymous survey regarding typical and ideal usage of time on FCR. Data analysis included general linear models and analysis of variance tests. RESULTS: Thirty rounding sessions involving 234 encounters of FCR over a 12-week period were analyzed. On average, teams spent 7 minutes in each patient room and approximately the same amount of time outside of the room. Attending physicians were the dominant medical speakers during rounds (30.8%), and nurses spoke the least (2%). When inside a patient room, there was no significant difference between the percentage of time that attending physicians spoke (25.6%) and that of families and patients (23.0%). The surveys revealed that the medical team consistently underestimated the percentage of time attending physicians talked and desired attending physicians to talk less. They also overestimated the time spent in the patient rooms, the time families talked, and nurse presence during rounds and desired an increase in each of these areas. CONCLUSIONS: The medical teams' perceptions of FCR do not reflect clinical observations. Medical teams believe and desire that attending physicians talk less and families and nurses talk more than observations reveal.

Emergence of the primary pediatric stroke center: impact of the thrombolysis in pediatric stroke trial.

BACKGROUND AND PURPOSE: In adult stroke, the advent of thrombolytic therapy led to the development of primary stroke centers capable to diagnose and treat patients with acute stroke rapidly. We describe the development of primary pediatric stroke centers through preparation of participating centers in the Thrombolysis in Pediatric Stroke (TIPS) trial. METHODS: We collected data from the 17 enrolling TIPS centers regarding the process of becoming an acute pediatric stroke center with capability to diagnose, evaluate, and treat pediatric stroke rapidly, including use of thrombolytic therapy. RESULTS: Before 2004, <25% of TIPS sites had continuous 24-hour availability of acute stroke teams, MRI capability, or stroke order sets, despite significant pediatric stroke expertise. After TIPS preparation, >80% of sites now have these systems in place, and all sites reported increased readiness to treat a child with acute stroke. Use of a 1- to 10-Likert scale on which 10 represented complete readiness, median center readiness increased from 6.2 before site preparation to 8.7 at the time of site activation (P≤0.001). CONCLUSIONS: Before preparing for TIPS, centers interested in pediatric stroke had not developed systematic strategies to diagnose and treat acute pediatric stroke. TIPS trial preparation has resulted in establishment of pediatric acute stroke centers with clinical and system preparedness for evaluation and care of children with acute stroke, including use of a standardized protocol for evaluation and treatment of acute arterial stroke in children that includes use of intravenous tissue-type plasminogen activator. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01591096.

Epigenetic analysis of neurocognitive development at 1 year of age in a community-based pregnancy cohort.

Multiple studies show that molecular genetic changes and epigenetic modifications affect the risk of cognitive disability or impairment. However, the role of epigenetic variation in cognitive development of neurotypical young children remains largely unknown. Using data from a prospective, community-based study of mother-infant pairs, we investigated the association of DNA methylation patterns in neonatal umbilical cord blood with cognitive and language development at 1 year of age. No CpG loci achieved genome-wide significance, although a small number of weakly suggestive associations with Bayley-III Receptive Communication scales were noted. While umbilical cord blood is a convenient resource for genetic analyses of birth outcomes, our results do not provide conclusive evidence that its use for DNA methylation profiling yields epigenetic markers that are directly related to postnatal neurocognitive outcomes at 1 year of age.

Extended-release antiepileptic drugs: a comparison of pharmacokinetic parameters relative to original immediate-release formulations.

Many antiepileptic drugs (AEDs) have short half-lives with large fluctuations in peak-to-trough plasma concentrations. Consequences of these pharmacokinetic (PK) properties may include adverse events (AEs) and breakthrough seizures, potentially leading to poor adherence. To address these challenges, newer formulations of these AEDs have been developed using unique extended-release (ER) technologies. These technologies extend the dosing interval such that dosing frequency can be minimized, which may improve patient adherence. Available ER formulations have the potential to minimize the spikes in maximum plasma concentrations (C(max) ) at steady-state that often contribute to AEs during treatment with immediate-release (IR) products. In so doing, tolerability advantages may lead to increased AED effectiveness by improving adherence and allowing higher doses if clinically indicated. Direct PK comparison studies of IR and ER formulations (e.g., carbamazepine, divalproate sodium, lamotrigine, oxcarbazepine, levetiracetam, and phenytoin) have found that dose-normalized ER formulations may or may not be bioequivalent to their IR counterparts, but most ER formulations have a lower fluctuation index ([C(max) -C(min) ]/C(avg) ) compared with the IR versions. This results in flatter concentration-time plots. Not all ER preparations improve the various PK parameters to the same extent, and PK nuances may impact the effectiveness, tolerability, and adherence rates of various ER formulations.

Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes: Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including antiepileptic drug (AED) teratogenicity and adverse perinatal outcomes. It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine (CBZ), and possibly compared to phenytoin (PHT) or lamotrigine (LTG). It is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. AED polytherapy probably contributes to the development of MCMs and reduced cognitive outcomes compared to monotherapy. Intrauterine exposure to VPA monotherapy probably reduces cognitive outcomes and monotherapy exposure to PHT or phenobarbital (PB) possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7. If possible, avoidance of VPA and AED polytherapy during the first trimester of pregnancy should be considered to decrease the risk of MCMs. If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered and avoidance of PHT and PB throughout pregnancy may be considered to prevent reduced cognitive outcomes.

Management issues for women with epilepsy--focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid and prenatal vitamin K use and the clinical implications of placental and breast-milk transfer of antiepileptic drugs (AEDs). The committee evaluated the available evidence based on a structured literature review and classification of relevant articles. Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in clinically important amounts. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentrations of lamotrigine, phenytoin, and, to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative (MHD). Supplementing WWE with at least 0.4 mg of folic acid before pregnancy may be considered. Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered, and monitoring of levetiracetam and oxcarbazepine (as MHD) levels may be considered. A paucity of evidence limited the strength of many recommendations.

Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): I. Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including the risk of pregnancy complications or other medical problems during pregnancy, change in seizure frequency, the risk of status epilepticus, and the rate of remaining seizure-free during pregnancy. The committee evaluated the available evidence according to a structured literature review and classification of relevant articles. For WWE who are taking antiepileptic drugs (AEDs), there is probably no substantially increased risk (>2 times expected) of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk (>1.5 times expected) of premature contractions or premature labor and delivery. There is possibly a substantially increased risk of premature contractions and premature labor and delivery during pregnancy for WWE who smoke. WWE should be counseled that seizure freedom for at least 9 months prior to pregnancy is probably associated with a high likelihood (84-92%) of remaining seizure-free during pregnancy. WWE who smoke should be counseled that they possibly have a substantially increased risk of premature contractions and premature labor and delivery.

Use of alteplase in childhood arterial ischaemic stroke: a multicentre, observational, cohort study.

BACKGROUND: The safety and efficacy of thrombolysis after acute stroke in children have not been established. Our aim was to describe current practices and results of the use of alteplase for acute arterial ischaemic stroke in children enrolled in an international pediatric stroke registry and to compare current practices with those published in case reports and with guidelines for the use of alteplase for adult stroke. METHODS: In this multicentre observational cohort study, we analysed the clinical features, the dosing and timing of treatment, and the short-term outcome in children treated with alteplase for acute arterial ischaemic stroke who were enrolled in the International Pediatric Stroke Study (IPSS) between January, 2003, and July, 2007. The findings from the IPSS were compared with published case reports for clinical features, adherence to adult guidelines for alteplase, and outcomes. FINDINGS: Of 687 children with acute arterial ischaemic stroke enrolled in the IPSS, 15 (2%) received alteplase: nine received intravenous alteplase and six received intra-arterial alteplase. The median time to treatment from stroke onset was 3.3 h (range 2.0-52.0 h) for intravenous alteplase and 4.5 h (3.8-24.0 h) for intra-arterial alteplase. Two patients died (one owing to massive infarction and brain herniation, and one owing to brainstem infarction). At discharge from hospital, one patient was healthy and 12 patients had neurological deficits. Intracranial haemorrhage after alteplase occurred in four of 15 patients, although none of the bleeding events was judged to be acutely symptomatic. When compared with ten patients reported in published articles who were given intravenous alteplase, the nine patients in the IPSS cohort were mostly younger, waited longer for treatment, and had worse outcomes, which suggests there is a publication bias towards short treatment intervals from symptom onset and favourable outcomes. INTERPRETATION: Children with acute stroke received alteplase infrequently and at time intervals that often deviated from adult guidelines. Although no alteplase-related deaths or symptomatic intracranial haemorrhage was reported, poor neurological outcome was common. Clinical trials to evaluate the dose and the safety and efficacy of alteplase are needed in childhood stroke.

Adolescent and caregiver experiences with epilepsy.

Epilepsy during adolescence can impede the development of psychosocial independence and typical biological maturational processes. We examined in parallel the experiences and perceptions of adolescent patients with epilepsy and their caregivers. Specifically, we focused on frequency and type of seizures, comorbid conditions, adherence to therapies, productivity, clinical and quality of life consequences of seizures, estimated use and content of seizure emergency plans, and the patient-physician relationship. Two cross-sectional online surveys were conducted among 153 adolescent patients with epilepsy and their respective caregivers. A total of 35% of adolescents indicated that they had been nonadherent to antiepileptic medications in the prior month. Adolescents scored significantly lower compared with their peers on quality-of-life measures. Adolescents and caregivers reported similarly on nearly all domains. An adolescent-centered epilepsy management program may help alleviate concerns and also help the adolescent independently manage their epilepsy as they transition into adulthood.

Rapid infusion of a loading dose of intravenous levetiracetam with minimal dilution: a safety study.

Intravenous antiepileptic drugs are required in patients needing urgent treatment or unable to take oral medication. The safety of intravenous levetiracetam has been established in prospective studies of adult epilepsy and healthy participants. The authors performed a prospective, single-center study to evaluate the safety of a rapid loading dose of intravenous levetiracetam. Patients were divided into 3 equal dosing groups (N = 15 each): 20, 40, and 60 mg/kg (corresponding to maximum doses of 1, 2, and 3 g). Electrocardiogram and safety assessment were performed during the infusion. Ages were 4 to 32 years. Postinfusion serum levetiracetam concentrations were 14 to 189 microg/mL. There were no significant changes in blood pressure, no local infusion site reactions, and no electrocardiogram abnormalities. The authors concluded that high serum levels of parenteral levetiracetam can be achieved rapidly and safely, in a small infusion volume. This finding has important implications for the treatment of status epilepticus.

Thrombolysis in acute childhood stroke: design and challenges of the thrombolysis in pediatric stroke clinical trial.

BACKGROUND: Although tissue plasminogen activator (tPA) has revolutionized the treatment of acute ischemic stroke in adults, no thrombolysis trials in childhood stroke have been conducted. Experience in adults cannot be applied to children due to fundamental age-related differences in coagulation systems, stroke pathophysiology and neuropharmacology. Obstacles to acute treatment trials in childhood stroke include delays in diagnosis and minimizing risk in a vulnerable population. STUDY DESIGN: Thrombolysis in Pediatric Stroke (TIPS) is an international multicenter study to assess the safety of intravenous tPA within 0-3 h and intra-arterial tPA within 3-6 h of onset of arterial ischemic stroke in childhood. Through the International Pediatric Stroke Study, 30 international centers will enroll a total of 48 patients: 24 will be treated with intravenous tPA (0.6, 0.75, 0.9, and 1.0 mg/kg) using the classical dose-finding method, and 24 will be treated with intra-arterial tPA (maximum 0.2, 0.3, 0.4, and 0.5 mg/kg) using a Bayesian dose-finding method. CONCLUSION: The TIPS trial will be the first clinical trial exploring the safety and feasibility of systemic and local thrombolytic therapy in childhood stroke and the obstacles in conducting such a trial.