Cannabidiol for the treatment of Lennox-Gastaut syndrome and Dravet syndrome: experts' recommendations for its use in clinical practice in Spain. / Cannabidiol para el tratamiento del síndrome de Lennox-Gastaut y del síndrome de Dravet: recomendaciones de expertos sobre su uso en la práctica clínica en España.

INTRODUCTION: Cannabidiol (CBD) is one of the main components of the cannabis plant that has demonstrated anti-epileptic seizure effect. Following its clinical development, in September 2019 the European Medicines Agency approved its indication for the adjunctive therapy of epileptic seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS), combined with clobazam (CLB), in patients of 2 years of age and older. AIM: To establish recommendations on the use of plant-derived highly purified CBD on which Spanish experts have reached consensus for the treatment of epilepsy in patients with DS and LGS based on their clinical experience and the scientific evidence. DEVELOPMENT: Consensus meeting with the participation of four Spanish neurologists and neuropediatric who are experts in epilepsy secondary to DS and LGS and with clinical experience in the use and management of CBD. They discussed on several topics, including posology (starting dose, dose escalation schema), efficacy (assessment of outcomes and indications for treatment withdrawal), and safety (evaluation, drug-drug interactions, adverse events management). CONCLUSIONS: In order to optimise CBD treatment, a slow dose escalation (= 4 weeks) is recommended until the maximum recommended dose or the desire effect is reached. It is also recommended that the concomitant antiseizure medications (ASMs) be reduced in case of adverse events due to interactions, and that the treatment continues for at least 6 months if it is well tolerated. The efficacy and safety of CBD must be assessed individually, considering the benefits and risks for individual patients.

TITLE: Cannabidiol para el tratamiento del síndrome de Lennox-Gastaut y del síndrome de Dravet: recomendaciones de expertos sobre su uso en la práctica clínica en España.Introducción. El cannabidiol (CBD) es uno de los componentes principales de la planta del cannabis que ha demostrado efecto ante las crisis epilépticas. Tras su desarrollo clínico, obtuvo su aprobación por la Agencia Europea del Medicamento en septiembre de 2019 para el tratamiento de las crisis epilépticas asociadas con el síndrome de Lennox-Gastaut (SLG) y el síndrome de Dravet (SD), en combinación con el clobazam (CLB), en pacientes a partir de los dos años. Objetivo. Establecer unas recomendaciones de manejo del CBD derivado de la planta altamente purificado consensuadas por expertos españoles en el tratamiento de la epilepsia para su uso en pacientes con SD y SLG, basándose en su experiencia clínica y en la evidencia científica. Desarrollo. Reunión de consenso de un grupo de cuatro neurólogos y neuropediatras españoles expertos en el manejo de la epilepsia asociada al SD y el SLG y con experiencia clínica en el uso de CBD. Se debatió sobre diferentes áreas, incluyendo la posología (dosis de inicio, pauta de escalada), la eficacia (valoración de resultados e indicaciones para la suspensión del tratamiento) y la seguridad (evaluación, interacciones entre fármacos, manejo de efectos adversos). Conclusiones. Para optimizar el tratamiento con CBD, se recomienda una pauta lenta de escalada de dosis (de cuatro semanas o más) hasta alcanzar la dosis máxima recomendada o el efecto deseado, reducir los fármacos anticrisis epilépticas concomitantes si aparecen efectos adversos por interacciones y mantener el tratamiento al menos seis meses si se tolera. La eficacia y la seguridad del CBD deben evaluarse de forma individual, considerando el beneficio y el riesgo para cada paciente.

New therapeutic approach in Dravet syndrome and Lennox-Gastaut syndrome with cannabidiol. / Cannabidiol en los síndromes de Dravet y Lennox-Gastaut: un nuevo abordaje terapéutico.

INTRODUCTION: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are two serious epileptic syndromes with paediatric onset which are refractory to therapy and are associated with an important increase in mortality rates and comorbidities compared to the general population. These pathologies have a strong impact on the lives of patients and their families, because they undergo multiple pharmacological therapies (many of them without specific indication), with frequent changes due to poor efficacy and associated adverse effects. The specialists who care for these patients highlight unmet needs and the lack of specific, safe and effective treatments for better management of the syndrome. DEVELOPMENT: A group of four neurologists specializing in epilepsy has met to review the scientific literature and evaluate the efficacy and safety of oral solution cannabidiol in the treatment of these syndromes, both in randomized clinical trials (CT) and in some observational studies. CONCLUSIONS: Cannabidiol is positioned as an innovative therapy that allows better control of epileptic seizures and comorbidities of DS and LGS, furthermore its efficacy and safety have been evaluated in more than 700 patients. In CTs, cannabidiol significantly reduced the percentage of convulsive seizures and drop seizures compared to placebo in patients with DS and LGS respectively, which could improve their quality of life and that of their family members. The most frequent adverse effects reported were somnolence and decreased appetite. Elevated liver aminotransferase levels were also reported, especially in patients given concomitant sodium valproate. This therapy may allow better control of the epileptic seizures associated with these syndromes.

TITLE: Cannabidiol en los síndromes de Dravet y Lennox-Gastaut: un nuevo abordaje terapéutico.Introducción. Los síndromes de Dravet (SD) y Lennox-Gastaut (SLG) son dos síndromes epilépticos graves y de inicio en la edad pediátrica, refractarios al tratamiento, asociados a un notable incremento en las tasas de mortalidad y comorbilidades respecto a la población general. Suponen un fuerte impacto en la vida de los pacientes y sus familiares, ya que los pacientes están sometidos a múltiples terapias farmacológicas (muchas sin indicación específica), con cambios frecuentes debido a la escasa eficacia y a los efectos adversos. Los especialistas que les atienden destacan las necesidades no cubiertas y la falta de tratamientos específicos, seguros y eficaces para un mejor manejo de la enfermedad. Desarrollo. Se ha reunido un grupo formado por cuatro neurólogos especialistas en epilepsia para hacer una revisión de la literatura científica y evaluar los resultados de eficacia y seguridad de la solución oral de cannabidiol en el tratamiento de estos síndromes, tanto en ensayos clínicos aleatorizados como en diversos estudios observacionales. Conclusiones. El cannabidiol se sitúa como una terapia innovadora que permite un mejor control de las crisis epilépticas y comorbilidades del SD y el SLG; además, su eficacia y seguridad han sido evaluadas en más de 700 pacientes. En los ensayos clínicos redujo significativamente el porcentaje de crisis convulsivas y de caída en comparación con placebo en los pacientes con SD y SLG, respectivamente, y puede mejorar su calidad de vida y la de sus familiares. Los efectos adversos más frecuentes fueron la somnolencia y la disminución del apetito. También se notificaron niveles elevados de aminotransferasas hepáticas, especialmente en pacientes tratados concomitantemente con ácido valproico. Esta terapia podría permitir un mejor control de las crisis epilépticas asociadas a estas patologías.

Epilepsia resistente a fármacos. Concepto y alternativas terapéuticas / Drug-resistant epilepsy: Definition and treatment alternatives

Introducción: El dolor es un síntoma muy frecuente en los pacientes con síndrome de Guillain-Barré, con una intensidad de moderada a severa en la mayoría de los casos; puede persistir luego de la resolución de la enfermedad. Objetivo: Identificar la terapia analgésica más apropiada para el manejo del dolor en los pacientes con síndrome de Guillain-Barré. Material y métodos: Se realizó una búsqueda y selección sistemática de los artículos científicos sobre el tratamiento del dolor en pacientes con síndrome de Guillain-Barré publicados entre enero de 1985 y diciembre de 2012. Se incluyeron solo ensayos clínicos aleatorizados, doble ciego, que evaluaron el efecto de los medicamentos en el tratamiento del dolor en estos pacientes. Resultados: Cuatro artículos cumplieron los criterios de inclusión. Uno evaluó el uso de gabapentina, otro, el de carbamazepina, otro comparó el uso de gabapentina y carbamazepina, y el último evaluó el uso de metilprednisolona. Tanto carbamazepina como gabapentina fueron útiles en el manejo del dolor. En el estudio que comparó carbamazepina y gabapentina, los pacientes presentaron menor intensidad del dolor con el uso de este último. La metilprednisolona no mostró un efecto positivo en la reducción del dolor. Los datos publicados no permitieron la realización de un metaanálisis. Conclusiones: No hay evidencia sólida en el momento actual para recomendar una opción terapéutica específica ante este problema. Es necesaria la realización de futuros estudios clínicos que incluyan un mayor número de pacientes, por un tiempo más prolongado, que individualicen los tipos de dolor por pacientes y midan objetivamente la intensidad de este

Introduction: Pain is a common symptom in patients with Guillain-Barre syndrome. Intensity is moderate to severe in most cases and pain may persist after resolution of the disease. Objective: Identify the most appropriate analgesic therapy for pain management in patients with Guillain-Barre syndrome. Material and methods: Systematic review and selection of scientific articles on treatment of pain in Guillain-Barre syndrome patients, published between January 1985 and December 2012. We included only randomised, double-blind, controlled trials assessing the effectiveness of drugs for pain management in these patients. Results: Four articles met the inclusion criteria. One evaluated the use of gabapentin, another evaluated carbamazepine, a third compared gabapentin to carbamazepine, and the last evaluated use of methylprednisolone. Both carbamazepine and gabapentin were useful for pain management. Patients experienced lower-intensity pain with gabapentin treatment in the study comparing that drug to carbamazepine. Methylprednisolone was not shown to be effective for reducing pain. The published data did not permit completion of a meta-analysis. Conclusions: There is no robust evidence at present that would point to a single treatment option for this disorder. Further clinical studies of larger patient samples and with a longer duration are needed to characterise types of pain for each patient and measure pain intensity in an objective way

Drug-resistant epilepsy: definition and treatment alternatives.

INTRODUCTION: Drug-resistant epilepsy affects 25% of all epileptic patients, and quality of life decreases in these patients due to their seizures. Early detection is crucial in order to establish potential treatment alternatives and determine if the patient is a surgical candidate. DEVELOPMENT: PubMed search for articles, recommendations published by major medical societies, and clinical practice guidelines for drug-resistant epilepsy and its medical and surgical treatment options. Evidence and recommendations are classified according to the criteria of the Oxford Centre for Evidence-Based Medicine (2001) and the European Federation of Neurological Societies (2004) for therapeutic actions. CONCLUSIONS: Identifying patients with drug-resistant epilepsy is important for optimising drug therapy. Experts recommend rational polytherapy with antiepileptic drugs to find more effective combinations with fewer adverse effects. When adequate seizure control is not achieved, a presurgical evaluation in an epilepsy referral centre is recommended. These evaluations explore how to resect the epileptogenic zone without causing functional deficits in cases in which this is feasible. If resective surgery is not achievable, palliative surgery or neurostimulation systems (including vagus nerve, trigeminal nerve, or deep brain stimulation) may be an option. Other treatment alternatives such as ketogenic diet may also be considered in selected patients.

A reporter system for replication-competent gammaretroviruses: the inGluc-MLV-DERSE assay.

Although novel retroviral vectors for use in gene-therapy products are reducing the potential for formation of replication-competent retrovirus (RCR), it remains crucial to screen products for RCR for both research and clinical purposes. For clinical-grade gammaretrovirus-based vectors, RCR screening is achieved by an extended S(+)L(-) or marker-rescue assay, whereas standard methods for replication-competent lentivirus detection are still in development. In this report, we describe a rapid and sensitive method for replication-competent gammaretrovirus detection. We used this assay to detect three members of the gammaretrovirus family and compared the sensitivity of our assay with well-established methods for retrovirus detection, including the extended S(+)L(-) assay. Results presented here demonstrate that this assay should be useful for gene-therapy product testing.

Advancement of physical process by mental activation: a prospective controlled study.

According to the literature, patients who are significantly impaired by physical mobility limitations can be rehabilitated if the patient's working memory is used to capacity. The conclusion that periodic mental activity improves physical rehabilitation should be evaluated. This is a prospective, controlled, and randomized open study of patients who underwent a total hip arthroplasty (THA). Sixteen patients who played the video game Dr. Kawashima's Brain Training: How Old Is Your Brain? were compared in terms of rehabilitation progress to 16 individuals who did not play. Harris Hip and Merle d'Aubigné scores were evaluated 1 d preoperation and again 12 +/- 1 d postoperation. Preoperation, no significant differences in hip scores between the gaming and control groups were found (median Harris Hip score: 39 vs 33, respectively, p = 0.304; median Merle D'Aubigné score: 12 vs 9, respectively, p = 0.254). Postoperation, there were significant differences between the gaming and control groups (median Harris Hip score: 76.0 vs 56.5, respectively, p = 0.001; median Merle D'Aubigné score: 16.0 vs 13.5, respectively, p = 0.014). Within both groups, the posttest scores significantly improved; however, the increase for the gaming group was greater for both measures. Because the influence of age, sex, and level of education can be excluded, it can be assumed that mental activities can improve physical rehabilitation after THA.

New concepts for dynamic plant uptake models.

Models for the prediction of chemical uptake into plants are widely applied tools for human and wildlife exposure assessment, pesticide design and for environmental biotechnology such as phytoremediation. Steady-state considerations are often applied, because they are simple and have a small data need. However, often the emission pattern is non-steady. Examples are pesticide spraying, or the application of manure and sewage sludge on agricultural fields. In these scenarios, steady-state solutions are not valid, and dynamic simulation is required. We compared different approaches for dynamic modelling of plant uptake in order to identify relevant processes and timescales of processes in the soil-plant-air system. Based on the outcome, a new model concept for plant uptake models was developed, approximating logistic growth and coupling transpiration to growing plant mass. The underlying system of differential equations was solved analytically for the inhomogenous case, i.e. for constant input. By superposition of the results of n periods, changes in emission and input data between periods are considered. This combination allows to mimic most input functions that are relevant in practice. The model was set up, parameterized and tested for uptake into growing crops. The outcome was compared with a numerical solution, to verify the mathematical structure.

Early diagnosis and treatment of atrioventricular block in the fetus exposed to maternal anti-SSA/Ro-SSB/La antibodies: a prospective, observational, fetal kinetocardiogram-based study.

BACKGROUND: A fetus exposed to maternal anti-SSA/Ro or anti-SSB/La antibodies (or both) may develop complete atrioventricular block (AVB), which results in high prenatal and postnatal morbidity and mortality. Until recently, only high-grade AVB could be diagnosed in utero. The tissue velocity-based fetal kinetocardiogram (FKCG) enables accurate measurement of AV conduction time and diagnosis of low-grade AVB. In the present multicenter observational study, we used FKCG to detect first-degree AVB in fetuses at risk. METHODS AND RESULTS: FKCG was performed in 70 fetuses of 56 mothers who were positive for anti-SSA/Ro and/or anti-SSB/La. Fetuses were monitored with weekly FKCG from 13 to 24 weeks' gestation, followed by monthly assessments until delivery in unaffected fetuses and weekly assessments in affected fetuses. AV conduction in 70 at-risk and 109 normal fetuses was compared. FKCG was obtained readily in all fetuses; 6 showed first-degree AVB (AV conduction time >2 z scores above normal mean) at 21 to 34 gestational weeks. Immediate maternal treatment with dexamethasone resulted in normalization of AV conduction in all affected fetuses within 3 to 14 days. AV conduction time in the remaining 64 untreated fetuses remained normal throughout gestation. The ECG PR interval immediately after birth was normal in all affected newborns. No child developed AVB or cardiomyopathy in the subsequent 1- to 6-year (median 4-year) follow-up. CONCLUSIONS: The present findings suggest that an FKCG can detect first-degree AVB in the fetus exposed to maternal anti-SSA/Ro or anti-SSB/La antibodies (or both). Dexamethasone given on detection was associated with normalized AV conduction in fetuses with first-degree AVB. No fetus in the present study developed complete prenatal or postnatal AVB.

Mutant murine leukemia virus Gag proteins lacking proline at the N-terminus of the capsid domain block infectivity in virions containing wild-type Gag.

We have investigated the properties of murine leukemia virus Gag mutants in which the p12-CA cleavage site is altered. In one mutant, the cleavage is blocked; in the other, the conserved proline at the N-terminus of CA has been replaced with glycine. No infectivity was detected in either mutant. Mutant particles cannot synthesize full-length DNA upon infecting permissive cells. Particles composed of a mixture of wild-type and mutant proteins have severely impaired infectivity. These mixed particles are defective in their ability to synthesize DNA upon infection, but this defect is less severe than the loss of infectivity. Thus, proteins lacking the correct N-terminus of CA inhibit DNA synthesis and also interfere with formation or integration of a full-length, normal provirus. The results imply that CA proteins function as part of a large, highly organized structure in reverse transcription and apparently at a later step as well.

NT-proBNP as a marker for persistent cardiac disease in children with history of dilated cardiomyopathy and myocarditis.

Children with myocarditis and dilated cardiomyopathy may recover clinically and echocardiographically. Plasma levels of the N-terminal segment of B-type natriuretic peptide prohormone (NT-proBNP), a sensitive marker for cardiac dysfunction, may reflect residual cardiac damage in these patients. The purpose of this study was to evaluate NT-proBNP status in pediatric patients with a history of myocarditis and dilated cardiomyopathy. Cardiac evaluation was performed and the levels of NT-proBNP were measured in 23 children who had a history of myocarditis or dilated cardiomyopathy. NT-proBNP levels were also measured in 56 age-matched control children. Nine of the 23 patients had evidence of left ventricular dysfunction (DCM group), whereas 14 had none (recovery). NT-proBNP levels were higher in the DCM group (3154 +/- 2858 pg/ml) than in the recovery group (122 +/- 75 pg/ml, p < 0.001) and the control group (113 +/- 96 pg/ml, p < 0.001). There was no difference between the recovery and the control groups (p = 0.45), and none of the recovered patients had a NT-proBNP level higher than the upper limit of normal. The area under the receiver operating characteristics curve for the diagnosis of persistent left ventricular dysfunction was 0.984. NT-proBNP levels correlated with echocardiographically derived shortening fraction and with clinical score. NT-proBNP is a good marker for persistent left ventricular dysfunction in children who have had myocarditis or cardiomyopathy. In this group of patients, NT-proBNP levels are normal in children who recover echocardiographically, suggesting no residual hemodynamic abnormalities.

Tetralogy of Fallot with pulmonic atresia with cyclic occlusion of an associated aortic sinus of Valsalva-pulmonary artery window.

A first case of an unusual aortopulmonary window with tetralogy of Fallot associated with pulmonary atresia is presented. The aortopulmonary window was at the aortic sinus of Valsalva. The left aortic leaflet prevented pulmonary hypertension by occluding the window in systole.

[Clinical experiences with pregabalin in the treatment of focal epilepsies]. / Experiencia clínica de la pregabalina en el tratamiento de las epilepsias focales.

INTRODUCTION: Pregabalin is an antiepileptic drug recently approved in the European Union for add-on therapy of focal epilepsy. A review of its clinical and pharmacological characteristics is, therefore, appropriate. DEVELOPMENT: This drug, which binds to a subunit of voltage-dependent calcium channels in neuronal membranes, has a favourable pharmacokinetic profile. Pregabalin administered in two or three divided doses was compared to placebo in three double-blind randomised multicenter clinical trials, including 1,052 patients with focal epilepsy not controlled with other antiepileptic drugs. Results of these studies showed efficacy at doses of 150 mg per day, and a dose-response relationship up to doses of 600 mg per day. At the highest dose, mean seizure reduction for pregabalin was 44.3 to 54%, a significant reduction compared to placebo (p < or =0.0001), and a response rate of 43.5 to 51% (p < or =0.001). In one of these studies 12% of patients treated with pregabalin at 600 mg per day were seizure free for the last month of therapy while another study demonstrated its efficacy when used on a twice daily schedule. Subsequent open studies demonstrated a sustained efficacy of the drug. The most common adverse events were dizziness, somnolence, ataxia, asthenia, and weight gain. Withdrawal from controlled studies due to adverse effects was 15.3% in patients treated with pregabalin, compared with 6.15% in those receiving placebo. CONCLUSION: Pregabalin favourable pharmacokinetic profile, in addition to its good tolerability and remarkable efficacy make this new antiepileptic drug an attractive option for the treatment of focal epilepsies.

Experiencia clínica de la pregabalina en el tratamiento de las epilepsias focales / Clinical experiences with pregabalin in the treatment of focal epilepsies

Introducción. La pregabalina es un fármaco recientemente aprobado en la Unión Europea para el uso como terapia añadida en el tratamiento de epilepsias focales. Su reciente introducción en España justifica esta revisión sobre su perfil antiepiléptico. Desarrollo. Este fármaco posee unas atractivas características farmacocinéticas y actúa sobre una subunidad de canales del calcio voltajedependientes. La pregabalina, administrada en dos o tres tomas diarias, se comparó con placebo en tres ensayos multicéntricos, aleatorizados y doble ciego que incluyeron a 1.052 pacientes con epilepsia parcial no controlada con otros fármacos. Los resultados demostraron que era eficaz a partir de una dosis de 150 mg/día y que había una clara relación dosis/respuesta hasta los 600 mg/día. En esta última dosis, la pregabalina producía una reducción de la frecuencia de crisis de 44,3-54% que resultaba muy significativa frente al grupo placebo (p≤0,0001). Asimismo, la tasa de respondedores era de 43,5-51% (p≤0,001). En uno de estos estudios, el 12% de los pacientes tratados con 600 mg/día de pregabalina no sufrieron crisis durante el último mes de tratamiento, mientras que otro estudio demostró su eficacia cuando se administró en dos tomas al día. Estudios posteriores confirmaron los resultados de los primeros ensayos. Los efectos secundarios observados con mayor frecuencia han sido: mareo, somnolencia, ataxia, astenia y aumento de peso. En estudios controlados, el porcentaje de retiradas por efectos secundarios fue del 15,3% para quienes tomaban pregabalina frente al 6,1% en los tratados con placebo. Conclusión. Sus favorables propiedades farmacocinéticas, su tolerabilidad generalmente buena y su destacable eficacia convierten a la pregabalina en una atractiva incorporación al ya extenso arsenal disponible para el tratamiento de las epilepsias focales

Introduction. Pregabalin is an antiepileptic drug recently approved in the European Union for add-on therapy of focal epilepsy. A review of its clinical and pharmacological characteristics is, therefore, appropriate. Development. This drug, which binds to a subunit of voltage-dependent calcium channels in neuronal membranes, has a favourable pharmacokinetic profile. Pregabalin administered in two or three divided doses was compared to placebo in three double-blind randomised multicenter clinical trials, including 1,052 patients with focal epilepsy not controlled with other antiepileptic drugs. Results of these studies showed efficacy at doses of 150 mg per day, and a dose-response relationship up to doses of 600 mg per day. At the highest dose, mean seizure reduction for pregabalin was 44.3 to 54%, a significant reduction compared to placebo (p≤0.0001), and a response rate of 43.5 to 51% (p≤0.001). In one of these studies 12% of patients treated with pregabalin at 600 mg per day were seizure free for the last month of therapy while another study demonstrated its efficacy when used on a twice daily schedule. Subsequent open studies demonstrated a sustained efficacy of the drug. The most common adverse events were dizziness, somnolence, ataxia, asthenia, and weight gain. Withdrawal from controlled studies due to adverse effects was 15.3% in patients treated with pregabalin, compared with 6.15% in those receiving placebo. Conclusion. Pregabalin favourable pharmacokinetic profile, in addition to its good tolerability and remarkable efficacy make this new antiepileptic drug an attractive option for the treatment of focal epilepsies

[Safety of levetiracetam as adjunctive therapy in epilepsy: the SKATE trial in Spain]. / Seguridad del levetiracetam como tratamiento adyuvante en la epilepsia: el estudio SKATE en España.

AIM: To continue assessing safety and to evaluate the efficacy of levetiracetam and to assess the optimal dose in community based practice. PATIENTS AND METHODS: Single-arm, open label, multicenter, observational and prospective trial lasting 16-22 weeks. Criteria for inclusion: patients > 16 years experiencing epilepsy with partial seizures taking at least one concomitant antiepileptic drug. The initial dose was 1,000 mg/day, up to the maximal dose of 3,000 mg/day. Safety evaluation was adverse events reporting. Efficacy evaluation were reduction in seizure frequency; QOLIE-10 questionnaire and global evaluation scale of disease severity. RESULTS: Of the 342 subjects, 296 (86.5%) completed the treatment period. 103 subjects (30.1%) experienced at least one adverse event. The most frequently adverse events reported were somnolence (11.7%), dizziness (5.8%) and headache (3.5%). The events were majority (93.1%) of mild to moderate intensity. The median percent reduction in partial seizure frequency per week was 55%. 51.2% of patients experienced a reduction 50% in partial seizure frequency. Similar results were observed for total seizures. An increase of QOLIE-10 total score was observed (10.2 +/- 17.8). A total of 63.5% patients were rated as having moderate or marked improvement in their disease severity. CONCLUSIONS: These data confirm and provide additional support of levetiracetam safety and efficacy demonstrated in phase III trials.

N-terminal pro-B-type natriuretic peptide: reference plasma levels from birth to adolescence. Elevated levels at birth and in infants and children with heart diseases.

AIM: Determination of plasma levels of N-terminal pro-B-type natriuretic peptide (N-BNP) in infants and children with and without heart diseases. METHODS: Plasma N-BNP was measured in 78 infants and children without heart disease and in 55 infants and children with heart disease causing volume and pressure overload. Heart diseases included chronic dilated cardiomyopathy, acute left ventricular dysfunction, and congenital cardiac anomalies resulting in left and right ventricular volume or pressure overload. The Mann-Whitney rank-sum test and the ANOVA for ranks test were used to compare two or more groups, respectively. RESULTS: N-BNP levels were elevated in the first days of life but were not significantly different in children from 4 mo to 15 y old. The upper limit in children older than 4 mo with no heart disease was 349 pg/ml. In patients with heart disease, N-BNP levels were significantly higher than in control children (p < 0.0001). CONCLUSION: N-BNP levels are elevated in the first days of life and are stable from age 4 mo to adolescence. Elevated N-BNP levels reflect cardiac dysfunction in infants and children.

Seguridad del levetiracetam como tratamiento adyuvante en la epilepsia: el estudio SKATE en España / Safety of levetiracetam as adjunctive therapy in epilepsy: the SKATE trial in spain

Objetivo. Confirmar la seguridad y obtener mayor información acerca de la eficacia del levetiracetam, así como determinar la dosis óptima en la práctica clínica diaria. Pacientes y métodos. Estudio abierto, multicéntrico, observacional y prospectivo con un período de seguimiento de 16-22 semanas. Criterios de inclusión: pacientes > 16 años, con epilepsia con crisis parciales y que tomaran al menos un fármaco antiepiléptico concomitante. Dosis inicial de 1.000 mg/día, que podía aumentarse hasta un máximo de 3.000 mg/día. Evaluación de la seguridad mediante notificación de acontecimientos adversos. Evaluación de la eficacia por la reducción en la frecuencia de crisis, cuestionario QOLIE-10 y escala de evaluación global de la gravedad de la enfermedad. Resultados. De los 342 pacientes, 296 (86,5 por ciento) completaron el tratamiento. 103 pacientes (30,1 por ciento) notificaron algún acontecimiento adverso. Los más frecuentes fueron somnolencia (11,7 por ciento), mareos (5,8 por ciento) y cefaleas (3,5 por ciento). La mayoría de acontecimientos adversos fueron de intensidad leve-moderada. La mediana del porcentaje de reducción en la frecuencia de crisis parciales fue del 55 por ciento. El 51,2 por ciento de los pacientes experimentó una reducción 50 por ciento de la frecuencia semanal de las crisis parciales. Resultados similares se observaron para las crisis totales. Se observó un aumento de la puntuación total del QOLIE-10 (10,2 ñ 17,8). El 63,5 por ciento de pacientes se valoró con una mejoría moderada-notable en la gravedad de su enfermedad. Conclusión. El estudio confirma y aporta información adicional sobre la seguridad y la eficacia del levetiracetam demostradas en los ensayos en fase III (AU)

Aim. To continue assessing safety and to evaluate the efficacy of levetiracetam and to assess the optimal dose in community based practice. Patients and methods. Single-arm, open label, multicenter, observational and prospective trial lasting 16-22 weeks. Criteria for inclusion: patients > 16 years experiencing epilepsy with partial seizures taking at least one concomitant antiepileptic drug. The initial dose was 1,000 mg/day, up to the maximal dose of 3,000 mg/day. Safety evaluation was adverse events reporting. Efficacy evaluation were reduction in seizure frequency; QOLIE-10 questionnaire and global evaluation scale of disease severity. Results. Of the 342 subjects, 296 (86.5%) completed the treatment period. 103 subjects (30.1%) experienced at least one adverse event. The most frequently adverse events reported were somnolence (11.7%), dizziness (5.8%) and headache (3.5%). The events were majority of mild to moderate intensity. The median percent reduction in partial seizure frequency per week was 55%. 51.2% of patients experienced a reduction ≥ 50% in partial seizure frequency. Similar results were observed for total seizures. An increase of QOLIE-10 total score was observed (10.2 ± 17.8). A total of 63.5% patients were rated as having moderate or marked improvement in their disease severity. Conclusions. These data confirm and provide additional support of levetiracetam safety and efficacy demonstrated in phase III trials (AU)

Use of tissue velocity imaging in the diagnosis of fetal cardiac arrhythmias.

BACKGROUND: Precise diagnosis of cardiac arrhythmias in the fetus is crucial for a managed therapeutic approach. However, many technical, positional, and gestational age-related limitations may render conventional methods, such as M-mode and Doppler flow methodologies, or newer techniques, such as fetal electrocardiography or magnetocardiography, difficult to apply, or these techniques may be unsuitable for the diagnosis of fetal arrhythmias. METHODS AND RESULTS: In this prospective study, we describe a novel method based on raw scan-line tissue velocity data acquisition and analysis. The raw data are available from high-frame-rate 2D tissue velocity images and allow simultaneous sampling of right and left atrial and ventricular wall velocities to yield precise temporal analysis of atrial and ventricular events. Using this timing data, a ladder diagram-like "fetal kinetocardiogram" was developed to diagram and diagnose arrhythmias and to provide true intervals. This technique was feasible and fast, yielding diagnostic results in all 31 fetuses from 18 to 38 weeks of gestation. Analysis of various supraventricular and ventricular arrhythmias was readily obtained, including arrhythmias that conventional methods fail to diagnose. CONCLUSIONS: The fetal kinetocardiogram opens a new window to aid in the diagnosis and understanding of fetal arrhythmias, and it provides a tool for studying the action of antiarrhythmic drugs and their effects on electrophysiological conduction in the fetal heart.

Cost implications of introducing an alternative treatment for patients with osteoarthritis of the knee in a managed care setting.

OBJECTIVES: To illustrate the current cost of treating osteoarthritis (OA) of the knee and to demonstrate potential savings associated with the new treatment modality of viscosupplementation in a managed care setting. STUDY DESIGN: Pharmacoeconomic model with inputs obtained from peer-reviewed medical literature, clinical trial data, clinical expert opinion, and claims data. METHODS: A spreadsheet-based model was developed to define a treatment pathway for OA of the knee, illustrate the current costs of treating patients with the condition, and demonstrate the potential savings associated with introduction of Hylan G-F 20. A hypothetical cohort of patients categorized as having mild, moderate, or severe OA of the knee was followed over a 3-year time period. The analysis was conducted from the perspective of a managed care plan with a large Medicare population. RESULTS: The 3-year savings associated with adding 1 or more courses of Hylan G-F 20 therapy to the standard treatment pathway for OA of the knee was $8,810,771. The total savings per OA patient receiving Hylan G-F 20 was $4706. The number of total knee replacements (TKRs) avoided was 808. The model was highly sensitive to the durability of Hylan G-F 20; increasing and decreasing durability within a reasonable range resulted in 3-year savings of $9,131,879 and $2,012,082, respectively. CONCLUSIONS: Hylan G-F 20 has proven to be an effective treatment for patients with OA of the knee. Appropriate use of Hylan G-F 20 could delay the need for TKRs and generate savings in the managed care setting.