Efficacy of lisdexamfetamine dimesylate throughout the day in children and adolescents with attention-deficit/hyperactivity disorder: results from a randomized, controlled trial.

Lisdexamfetamine dimesylate (LDX) is a long-acting, prodrug stimulant therapy for patients with attention-deficit/hyperactivity disorder (ADHD). This randomized placebo-controlled trial of an optimized daily dose of LDX (30, 50 or 70 mg) was conducted in children and adolescents (aged 6-17 years) with ADHD. To evaluate the efficacy of LDX throughout the day, symptoms and behaviors of ADHD were evaluated using an abbreviated version of the Conners' Parent Rating Scale-Revised (CPRS-R) at 1000, 1400 and 1800 hours following early morning dosing (0700 hours). Osmotic-release oral system methylphenidate (OROS-MPH) was included as a reference treatment, but the study was not designed to support a statistical comparison between LDX and OROS-MPH. The full analysis set comprised 317 patients (LDX, n = 104; placebo, n = 106; OROS-MPH, n = 107). At baseline, CPRS-R total scores were similar across treatment groups. At endpoint, differences (active treatment - placebo) in least squares (LS) mean change from baseline CPRS-R total scores were statistically significant (P < 0.001) throughout the day for LDX (effect sizes: 1000 hours, 1.42; 1400 hours, 1.41; 1800 hours, 1.30) and OROS-MPH (effect sizes: 1000 hours, 1.04; 1400 hours, 0.98; 1800 hours, 0.92). Differences in LS mean change from baseline to endpoint were statistically significant (P < 0.001) for both active treatments in all four subscales of the CPRS-R (ADHD index, oppositional, hyperactivity and cognitive). In conclusion, improvements relative to placebo in ADHD-related symptoms and behaviors in children and adolescents receiving a single morning dose of LDX or OROS-MPH were maintained throughout the day and were ongoing at the last measurement in the evening (1800 hours).

Population pharmacokinetics of teicoplanin in children.

Teicoplanin is frequently administered to treat Gram-positive infections in pediatric patients. However, not enough is known about the pharmacokinetics (PK) of teicoplanin in children to justify the optimal dosing regimen. The aim of this study was to determine the population PK of teicoplanin in children and evaluate the current dosage regimens. A PK hospital-based study was conducted. Current dosage recommendations were used for children up to 16 years of age. Thirty-nine children were recruited. Serum samples were collected at the first dose interval (1, 3, 6, and 24 h) and at steady state. A standard 2-compartment PK model was developed, followed by structural models that incorporated weight. Weight was allowed to affect clearance (CL) using linear and allometric scaling terms. The linear model best accounted for the observed data and was subsequently chosen for Monte Carlo simulations. The PK parameter medians/means (standard deviation [SD]) were as follows: CL, [0.019/0.023 (0.01)] × weight liters/h/kg of body weight; volume, 2.282/4.138 liters (4.14 liters); first-order rate constant from the central to peripheral compartment (Kcp), 0.474/3.876 h(-1) (8.16 h(-1)); and first-order rate constant from peripheral to central compartment (Kpc), 0.292/3.994 h(-1) (8.93 h(-1)). The percentage of patients with a minimum concentration of drug in serum (Cmin) of <10 mg/liter was 53.85%. The median/mean (SD) total population area under the concentration-time curve (AUC) was 619/527.05 mg · h/liter (166.03 mg · h/liter). Based on Monte Carlo simulations, only 30.04% (median AUC, 507.04 mg · h/liter), 44.88% (494.1 mg · h/liter), and 60.54% (452.03 mg · h/liter) of patients weighing 50, 25, and 10 kg, respectively, attained trough concentrations of >10 mg/liter by day 4 of treatment. The teicoplanin population PK is highly variable in children, with a wider AUC distribution spread than for adults. Therapeutic drug monitoring should be a routine requirement to minimize suboptimal concentrations. (This trial has been registered in the European Clinical Trials Database Registry [EudraCT] under registration number 2012-005738-12.).

Lateral condyle fracture of the humerus in children treated with bioabsorbable materials.

The aim of this study was to compare clinical and radiological outcome of lateral condyle fracture of the elbow in children treated with bioabsorbable or metallic material. From January 2008 to December 2009, 16 children with similar fractures and ages were grouped according to the fixation material used. Children were seen at 3, 6, and 12 months and more than 4 years (mean 51.8 months) postoperatively. The clinical results were compared using the Mayo Elbow Performance Score (MEPS). Radiographic studies of the fractured and opposite elbow were assessed at last follow-up control. Twelve children had a sufficient followup and could be included in the study. Seven could be included in the traditional group and 5 in the bioabsorbable group. At 12 months, the MEPS was 100 for every child in both groups. Asymptomatic bony radiolucent visible tracks and heterotopic ossifications were noted in both groups. There were no significant differences in terms of clinical and radiological outcome between the two groups. The use of bioabsorbable pins or screws is a reasonable alternative to the traditional use of metallic materials for the treatment of lateral condyle fracture of the elbow in children.

Use of new biochemical plasmatic markers, plasma free and total metanephrines, for the diagnosis and follow-up of neuroblastoma in children with clinical correlation

Background: Neuroblastoma is a paediatrictumour derived from the neural crest. Biochemical diagnosis and follow up rely on quantitation of urinary catecholamines (dopamine and noradrenaline) and their metabolites vanillylmandelic acid (VMA) and homovanillic acid (HVA) (gold-standard). When combined, these analyses have a sensitivity of 95%. However, they are clearly limited by inaccuracy of urine collection in young children and normalisation of catecholamine concentrations by creatininuria. Recent development in biochemical diagnosis of pheochromocytoma, another neural crest tumour found in adults, shows that plasmatic measurement of methoxylated catecholamines called metanephrines are more sensitive and specific than other biomarkers. Moreover, a study to determine the reference intervals for metanephrines in a pediatric population has recently been completed. The aim of this work is to describe the role of metanephrines monitoring in the follow up of neuroblastoma. Method: This retrospective study included patients with neuroblastoma in whom the following parameters were determined: plasma free and total metanephrines, plasma catecholamines, 24h urinary catecholamines and metanephrines in absolute value and corrected by creatinine, VMA and HVA at the diagnosis and during treatment at the University Hospital of Lausanne (Switzerland). Eleven patients aged between the first day of life and 7 years old were followed between 2005 and 2012. Clinical outcome and biochemical concentrations of the analytes were correlated. Results: At diagnosis, plasma free and total normetanephrines and methoxytyramine have a sensitivity of 100% compared to 85% for the actual gold standard. Metanephrine remain below the upper reference limit as expected since these tumours do not produce adrenaline. The relationship between biochemical markers and clinical outcome is illustrated graphically. Plasma or urinary normetanephrine and methoxytyramine correlate better with the history of the patient than VMA and HVA, as evaluated by ordinal logistic regression. Concentrations of analytes in urine show a better correlation with clinical events when the results are corrected by creatininuria. Conclusion: Normetanephrine and methoxytyramine reflect disease history in neuroblastoma patients and could play a significant role in the follow up of this type of tumour. Formal studies in a sufficient number of patients are needed to confirm this preliminary observation.

Predicting Bacteremia in Children With Cancer and Fever in Chemotherapy-induced Neutropenia: Results of the Prospective Multicenter SPOG 2003 FN Study.

STUDY AIM:: To develop a score predicting the risk of bacteremia in cancer patients with fever and neutropenia (FN), and to evaluate its performance. METHODS:: Pediatric patients with cancer presenting with FN induced by nonmyeloablative chemotherapy were observed in a prospective multicenter study. A score predicting the risk of bacteremia was developed from a multivariate mixed logistic regression model. Its cross-validated predictive performance was compared with that of published risk prediction rules. RESULTS:: Bacteremia was reported in 67 (16%) of 423 FN episodes. In 34 episodes (8%), bacteremia became known only after reassessment after 8 to 24 hours of inpatient management. Predicting bacteremia at reassessment was better than prediction at presentation with FN. A differential leukocyte count did not increase the predictive performance. The reassessment score predicting future bacteremia in 390 episodes without known bacteremia used the following 4 variables: hemoglobin ≥90 g/L at presentation (weight 3), platelet count <50 G/L (3), shaking chills (5), and other need for inpatient treatment or observation according to the treating physician (3). Applying a threshold ≥3, the score-simplified into a low-risk checklist-predicted bacteremia with 100% sensitivity, with 54 episodes (13%) classified as low-risk, and a specificity of 15%. CONCLUSIONS:: This reassessment score, simplified into a low-risk checklist of 4 routinely accessible characteristics, identifies pediatric patients with FN at risk for bacteremia. It has the potential to contribute to the reduction of use of antimicrobials in, and to shorten the length of hospital stays of pediatric patients with cancer and FN.

Delayed diagnosis of acute ischemic stroke in children - a registry-based study in Switzerland.

QUESTIONS UNDER STUDY/PRINCIPLES: After arterial ischemic stroke (AIS) an early diagnosis helps preserve treatment options that are no longer available later. Paediatric AIS is difficult to diagnose and often the time to diagnosis exceeds the time window of 6 hours defined for thrombolysis in adults. We investigated the delay from the onset of symptoms to AIS diagnosis in children and potential contributing factors. METHODS: We included children with AIS below 16 years from the population-based Swiss Neuropaediatric Stroke Registry (2000-2006). We evaluated the time between initial medical evaluation for stroke signs/symptoms and diagnosis, risk factors, co-morbidities and imaging findings. RESULTS: A total of 91 children (61 boys), with a median age of 5.3 years (range: 0.2-16.2), were included. The time to diagnosis (by neuro-imaging) was <6 hours in 32 (35%), 6-12 hours in 23 (25%), 12-24 hours in 15 (16%) and >24 hours in 21 (23%) children. Of 74 children not hospitalised when the stroke occurred, 42% had adequate outpatient management. Delays in diagnosis were attributed to: parents/caregivers (n = 20), physicians of first referral (n = 5) and tertiary care hospitals (n = 8). A co-morbidity hindered timely diagnosis in eight children. No other factors were associated with delay to diagnosis. A total of 17 children were inpatients at AIS onset. CONCLUSIONS: One-third of children with AIS were diagnosed within six hours. Diagnostic delay was predominately caused by insufficient recognition of stroke symptoms. Increased public and expert awareness and immediate access to diagnostic imaging are essential. The ability of parents/caregivers and health professionals to recognise stroke symptoms in a child needs to be improved.

Mirror therapy in children with hemiplegia: a pilot study.

Mirror therapy, which provides the visual illusion of a functional paretic limb by using the mirror reflection of the non-paretic arm, is used in the rehabilitation of hemiparesis after stroke in adults. We tested the effectiveness and feasibility of mirror therapy in children with hemiplegia by performing a pilot crossover study in ten participants (aged 6-14 y; five males, five females; Manual Ability Classification System levels: one at level I, two at level II, four at level III, three at level IV) randomly assigned to 15 minutes of daily bimanual training with and without a mirror for 3 weeks. Assessments of maximal grasp and pinch strengths, and upper limb function measured by the Shriner's Hospital Upper Extremity Evaluation were performed at weeks 0 (baseline), 3, 6 (intervention), and 9 (wash-out). Testing of grasp strength behind the mirror improved performance by 15% (p=0.004). Training with the mirror significantly improved grasp strength (with mirror +20.4%, p=0.033; without +5.9%, p>0.1) and upper limb dynamic position (with mirror +4.6%, p=0.044; without +1.2%, p>0.1), while training without a mirror significantly improved pinch strength (with mirror +6.9%, p>0.1; without +21.9%, p=0.026). This preliminary study demonstrates the feasibility of mirror therapy in children with hemiplegia and that it may improve strength and dynamic function of the paretic arm.

Intensity modulated radiation therapy or stereotactic fractionated radiotherapy for infratentorial ependymoma in children: a multicentric study.

This study was to evaluate the treatment dosimetry, efficacy and toxicity of intensity modulated radiation therapy (IMRT) and fractionated stereotactic radiotherapy (FSRT) in the management of infratentorial ependymoma. Between 1999 and 2007, seven children (median age, 3.1 years) with infratentorial ependymoma were planned with either IMRT (3 patients) or SFRT (4 patients), the latter after conventional posterior fossa irradiation. Two children underwent gross total resection. Median prescribed dose was 59.4 Gy (range, 55.8-60). The median follow-up for surviving patients was 4.8 years (range, 1.3-8). IMRT (median dose, 59.4 Gy) and FSRT (median dose, 55.8 Gy) achieved similar optimal target coverage. Percentages of maximum doses delivered to the cochleae (59.5 vs 85.0% Gy; P = 0.05) were significantly inferior with IMRT, when compared to FSRT planning. Percentages of maximum doses administered to the pituitary gland (38.2 vs 20.1%; P = 0.05) and optic chiasm (38.1 vs 14.1%; P = 0.001) were, however, significantly higher with IMRT, when compared to FSRT planning. No recurrences were observed at the last follow-up. The estimated 3-year progression-free survival and overall survival were 87.5 and 100%, respectively. No grade >1 acute toxicity was observed. Two patients presented late adverse events (grade 2 hypoacousia) during follow-up, without cognitive impairment. IMRT or FSRT for infratentorial ependymomas is effective and associated with a tolerable toxicity level. Both treatment techniques were able to capitalize their intrinsic conformal ability to deliver high-dose radiation. Larger series of patients treated with these two modalities will be necessary to more fully evaluate these delivery techniques.

Mesure de la pression artérielle et dépistage de l'hypertension chez l'enfant. [Blood pressure measurement and screening of hypertension in children].

Children with elevated blood pressure are at risk of being hypertensive in adulthood and of developing complications such as ventricular hypertrophy. Obesity is a cause of hypertension. Because the prevalence of obesity is increasing, some authors argue that the systematic screening for hypertension in children and adolescents is justified for early prevention and treatment. Sex, age and height all influence children's blood pressure. When elevated blood pressure is identified, complementary investigations and treatment might be necessary. However, due to the difficulties of obtaining a valid estimate of blood pressure, to the moderate tracking of blood pressure from childhood to adulthood, and the rarity of hypertension cases in childhood, the usefulness of systematic screening of hypertension during childhood is still controversial. Un enfant dont la pression artérielle est élevée a un risque accru d'être hypertendu à l'âge adulte et de présenter des complications telles que l'hypertrophie ventriculaire gauche. L'augmentation de la prévalence de l'obésité justifierait selon certains auteurs le dépistage systématique de l'hypertension dès le plus jeune âge afin d'instaurer des mesures préventives ou curatives précoces. Les normes de pression dépendent du sexe, de l'âge et de la taille de l'enfant. En cas de pression élevée, des investigations complémentaires, voire un traitement, peuvent être indiqués. Au vu des difficultés pour obtenir une mesure fiable, des incertitudes entachant la valeur pronostique d'une pression artérielle élevée et de la rareté des cas d'hypertension, il n'y a pas de consensus sur l'utilité du dépistage systématique de l'hypertension durant l'enfance.

La thérapie actuelle du rhabdomyosarcome orbitaire de l'enfant [Update of orbital rhabdomyosarcoma therapy in children]

INTRODUCTION: Rhabdomyosarcoma is the most frequent primitive orbital malignant tumor in children. If the treatment is started as soon as possible after discovery of the disease, the vital prognosis is considerably better than otherwise. The goal of this paper is to present the new therapeutic protocol and to report our experience in this field. MATERIAL AND METHOD: During the past 35 years, 102 cases of orbital tumors were collected in children under 15 years of age: 5 cases of rhabdomyosarcoma were cared for in our department. At the time of tumor diagnosis, the age of our patients ranged from 3 weeks to 13 years. After a biopsy or excision biopsy, all our cases were treated by chemotherapy with or without radiotherapy. Medication was mostly vincristine, ifosfamide and actinomycine D. When the result of the treatment was not satisfactory, carboplatine and epirubicine, vincristine as well as ifosfamide were given. Radiotherapy was performed only in particular cases or in recurrences. CONCLUSION: Rhabdomyosarcoma is a highly malignant tumor. Although rare, it is the most frequent of malignant tumors in children. It is important to keep it in mind in order to perform a biopsy enabling quick diagnosis and treatment following the modern protocol giving the highest chances of survival to these patients: about 98% in 3 years.

Use of recombinant tissue plasminogen activator in children with meningococcal purpura fulminans: a retrospective study.

OBJECTIVE: Meningococcal disease causes septic shock with associated disseminated intravascular coagulation and hemorrhagic skin necrosis. In severe cases, widespread vascular thrombosis leads to gangrene of limbs and digits and contributes to morbidity and mortality. Uncontrolled case reports have suggested that thrombolytic therapy may prevent some complications, and the use of tissue plasminogen activator (t-PA) has been widespread. Our aim was to summarize the clinical outcome and adverse effects where systemic t-PA has been used to treat children with fulminant meningococcemia. DESIGN: International, multiple-center, retrospective, observational case note study between January 1992 and June 2000. SETTING: Twenty-four different hospitals in seven European countries and Australia. PATIENTS: A total of 62 consecutive infants and children with severe meningococcal sepsis in whom t-PA was used for the treatment of predicted amputations and/or refractory shock (40 to treat severe ischemia, 12 to treat shock, and ten to treat both). INTERVENTIONS: t-PA was administered with a median dose of 0.3 mg.kg(-1).hr(-1) (range, 0.008-1.13) and a median duration of 9 hrs (range, 1.2-83). MAIN RESULTS: Twenty-nine of 62 patients died (47%; 95% confidence interval, 28-65). Seventeen of 33 survivors had amputations (11 below knee/elbow or greater loss; six less severe). In 12 of 50 patients to whom t-PA was given for imminent amputation, no amputations were observed. Five developed intracerebral hemorrhages (five of 62, 8%; 95% confidence interval, 0.5-16). Of these five, three died, one developed a persistent hemiparesis, and one recovered completely. CONCLUSIONS: The high incidence of intracerebral hemorrhage in our study raises concerns about the safety of t-PA in children with fulminant meningococcemia. However, due to the absence of a control group in such a severe subset of patients, whether t-PA is beneficial or harmful cannot be answered from the unrestricted use of the drug that is described in this report. Our experience highlights the need to avoid strategies that use experimental drugs in an uncontrolled fashion and to participate in multiple-center trials, which are inevitably required to study rare diseases.

Follow-up of optic pathway gliomas in children with neurofibromatosis type 1.

Optic pathway gliomas (OPG) are found in about 15% of patients with neurofibromatosis Type 1 (NF-1). The natural history of OPG is not yet well documented. Treatment in cases with growing tumors is still controversial. Twenty-one patients with NF-1 and OPG, diagnosed over a 20-year period, and followed neuroradiologically and ophthalmologically for at least two years, were reevaluated. The diagnosis of OPG was made at a mean age of 7.1 years (range 0-14.5 years); six children were asymptomatic, 15 were symptomatic. The mean follow-up was 9.0 years (2.0-18.5 (years). In eight initially operated or biopsied patients (three optic nerve and five chiasmal gliomas) tumor regrowth was found in one patient without progression on subsequent follow-up. Improvement of visual acuity occurred in one child after operation of a large suprasellar tumor and deterioration in one patient after biopsy of a chiasmal glioma. The neuroradiological follow-up of the 13 not-operated and not-radiated patients (four optic nerve and nine chiasmal gliomas) was stable in 10, progressive in three, resulting in visual loss in one patient. In 11 children (52%) a second tumor outside the optic pathway was found at a mean age of 4.0 years after the diagnosis of an OPG. Until now they are mostly asymptomatic. Second site tumors were operated in two children because of rapid tumor growth, one child died of a brainstem tumor. OPG are a frequent complication in children with NF-1, appearing within the first decade.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk of mental disorders in children of parents with alcohol or heroin dependence: a controlled high-risk study.

Aim: To assess the specific effect of alcohol dependence (AD) or heroin dependence (HD) in patients and their spouses on the risk of psychopathology in their 276 6.0- to 17.9- year-old children (mean 11.3 years). Methods: The sample included 101 offspring of patients with AD, 23 of patients with HD, and 152 of medical controls, as well as their 2 parents. Participants were assessed using semistructured diagnostic interviews and family history reports by psychologists blind to patient diagnoses. Results: Children of HD and AD patients had largely elevated rates of recurrent major depressive disorder. Children of HD patients were also at an increased risk for attention deficit hyperactivity disorder and substance use disorders (SUD). There were interactions between SUD in the 2 parents to increase the risk of SUD in offspring. Conclusions: These results emphasize the need for prompt identification and treatment of these children and highlight the need to pay clinical attention not only to the patient, but also to the co-parent in order to optimize prevention in offspring.

Obesity in Switzerland: a critical assessment of prevalence in children and adults.

The objective was to analyze the situation in Switzerland regarding the prevalence of overweight or obesity in children, adolescents and adults. The data were compared with France, an adjacent much larger country. The results showed that there is a definitive lack of objective information in Switzerland on the prevalence of obesity at different ages. As in other European studies, the fact that many national surveys are classically based on subject interviews (self-reported weights and heights rather than measured values) implies that the overweight/obesity prevalence is largely underestimated in adulthood. For example, in a recent Swiss epidemiological study, the prevalence of obesity (BMI greater than 30 kg/m(2)) averaged 6-7% in young men and women (25-34 y), the prevalence being underestimated by a factor of two to three when body weight was self-reported rather than measured. This phenomenon has already been observed in previous European studies. It is concluded that National Surveys based on telephone interviews generally produce biased obesity prevalence results, although the direction of the changes in prevalence of obesity and its evolution with repeated surveys using strict standardized methodology may be evaluated correctly. Therefore, these surveys should be complemented by large-scale epidemiological studies (based on measured anthropomeric variables rather than declared) covering the different linguistic areas of Switzerland. An epidemiological body weight (BMI) monitoring surveillance system, using a harmonized methodology among European countries, would help to accurately assess differences in obesity prevalence across Europe without methodological bias. It will permit monitoring of the dynamic evolution of obesity prevalence as well as the development of appropriate strategies (taking into account the specificity of each country) for obesity prevention and treatment.