Real-World Experience Treating Pediatric Epilepsy Patients With Cenobamate

IntroductionIn one third of all patients with epilepsy, seizure freedom is not achieved through anti-seizure medication (ASM). These patients have an increased risk of earlier death, poorer cognitive development, and reduced quality of life. Cenobamate (CNB) has recently been approved as a promising novel ASM drug for the treatment of adults with focal-onset epilepsy. However, there is little experience for its application in pediatric patients.MethodsIn a multicenter study we evaluated retrospectively the outcome of 16 pediatric patients treated “off label” with CNB.ResultsIn 16 patients with a mean age of 15.38 years, CNB was started at an age of 15.05 years due to DRE. Prior to initiation of therapy, an average of 10.56 (range 3–20) ASM were prescribed. At initiation, patients were taking 2.63 (range 1–4) ASM. CNB was increased by 0.47 ± 0.27mg/kg/d every 2 weeks with a mean maximum dosage of 3.1 mg/kg/d (range 0.89–7) and total daily dose of 182.81 mg (range 50–400 mg). Seizure freedom was achieved in 31.3% and a significant seizure reduction of >50% in 37.5%. Adverse events occurred in 10 patients with fatigue/somnolence as the most common. CNB is taken with high adherence in all but three patients with a median follow-up of 168.5 daysConclusionCenobamate is an effective ASM for pediatric patients suffering from drug-resistant epilepsy. In addition to excellent seizure reduction or freedom, it is well-tolerated. Cenobamate should be considered as a novel treatment for DRE in pediatric patients

Apoptosis as main cell death mechanism in the developing brain

Titelblatt und Inhaltsverzeichnis Einleitung Fragestellungen der vorgestellten Arbeiten Eigene Forschungsergebnisse zur Pathophysiologie des unreifen Hirns Diskussion Zusammenfassung und Ausblick Danksagung Literatur Eidesstattliche VersicherungDas sich entwickelnde Gehirn der Saeugetiere ist gegenueber verschiedenen Noxen besonders vulnerabel und reagiert auf sie mit einem verstaerkten apoptotischen Zelltod. In verschiedenen Schaedigungsmodellen der neonatalen Ratte konnte diese besondere Empfindlichkeit des unreifen Gehirns nachgewiesen werden. Insbesondere nach einem Hirntrauma oder einer pharmakologischen Verminderung der neuronalen Aktivitaet durch Hemmung der Exzitation, Verstaerkung der Inhibition oder der Blockade spannungsabhaengiger Natriumkanaele ist eine apoptotische Neurodegeneration nachweisbar. Hirntraumen stellen bei Kindern bis zum 6. Lebensjahr eine der fuehrenden Ursachen der Morbiditaet und Mortalitaet dar. Der Nachweis des in diesem Lebensalter bei Nagetieren besonders ausgepraegten apoptotischen Zelltodes vermag moeglicherweise den schlechteren neurologischen Ausgang bei kleinen Kindern zu erklaeren. Die Aufklaerung der zugrundeliegenden Pathomechanismen einer Schaedigung des unreifen Gehirns kann zur Entwicklung neuroprotektiver Strategien fuehren. So konnte im Hirntrauma-Modell die Wirksamkeit des Pancaspase-Hemmers z-VAD-FMK bis zu 8 Stunden posttraumatisch belegt werden. Die Anwendung der Pharmaka zur Hemmung der neuronalen Aktivitaet ist beim Einsatz als Sedativum oder Antiepileptikum auch bei Schwangeren, Frueh- und Neugeborenen und Kindern bis zum 2. Lebensjahr mitunter unverzichtbar. Massnahmen zum Schutz des wachsenden Gehirns sind die Anwendung der proapoptotisch wirkenden Substanzen als Monopraeparat und in moeglichst niedrigen therapeutischen Blutkonzentrationen, wenn ihre Anwendung unbedingt notwendig erscheint. Die Entwicklung neuerer, weniger toxischer Medikamente oder die breitere Untersuchung der Wirksamkeit und Vertraeglichkeit bereits bei aelteren Kindern und Jugendlichen zugelassener Pharmaka, wie zum Beispiel des Topiramats oder Levetiracetams, bei Frueh- und Neugeborenen und im Saeuglingsalter koennten die Gabe schaedlicher Substanzen vermeiden helfen. Eine adjuvante Anwendung neuroprotektiv wirksamer Hormone wie zum Beispiel des Oestrogens oder des Erythropoietins bei Frueh- und Neugeborenen stellt eine weitere Option zum Schutz des unreifen Gehirns dar, wenn die Gabe bestimmter Sedativa oder Antiepileptika dringend indiziert ist. Die Ergebnisse aus den in dieser Arbeit vorgestellten Tierversuchen haben zur Aufklaerung einiger Pathomechanismen der Schaedigung des wachsenden Gehirns gefuehrt. Sehr wahrscheinlich spielen weitere Veraenderungen, Ereigniskaskaden und Prozesse eine Rolle bei der Verletzung des Gehirns: Die Hemmung der Synaptogenese, eine Aenderung der Reizschwelle fuer synaptische Prozesse oder eine negative Beeinflussung der Neurogenese in der Folge eines Insultes sind von mir nicht untersucht worden, sind aber an der Pathogenese einer Hirnschaedigung mitbeteiligt. Es konnte gezeigt werden, dass anders als im reifen Gehirn die Apoptose im unreifen Gehirn ganz wesentlich den neuropathologischen Ausgang einer Schaedigung mitbestimmt.Physiological cell death, a process by which redundant or unsuccessful neurons are deleted by apoptosis (cell suicide) from the developing central nervous system, has been recognized as a regular phenomenon in the developing brain. In recent studies we have shown that compounds which are used as sedatives, anesthetics or anticonvulsants in neonatal intensive care units, when administered to immature rodents during the period of the brain growth spurt, trigger widespread apoptotic neurodegeneration throughout the developing brain. Such compounds include drugs which alter physiologic synaptic activity, i.e. antagonists at N-methyl-D-aspartate (NMDA) receptors (ketamine, nitrous oxide), agonists at GABAA receptors (barbiturates, benzodiazepines, propofol) and sodium channel blockers (phenytoin, valproate). Similarly, oxygen, an agent widely used in neonatal and pediatric medicine, has the potential to trigger apoptotic cell death in the brain . The period of the brain growth spurt occurs in different species at different times relative to birth. In rats it occurs postnatally, but in humans it extends from the sixth month of gestation to several years after birth. Thus, there is a period in pre- and postnatal human development, lasting for several years, during which immature neurons are prone to commit suicide if exposed to intoxicating concentrations of drugs or oxygen. This information suggests that human infants may be susceptible to and actually sustain iatrogenic brain damage from treatments that are considered safe in older patients. Such mechanisms could potentially cause diffuse brain injury in early infancy and result in later cognitive and motor impairment. Although this evidence calls for caution with the use of pharmacologic agents and oxygen in neonatal and pediatric medicine, avoiding them is nearly impossible. Thus, the search for adjunctive neuroprotective measures that will prevent or ameliorate toxicity of anticonvulsants, anesthetic drugs and oxygen for the developing human brain is highly warranted. Trauma to the developing brain constitutes a poorly explored field. Some recent studies attempting to model and study pediatric head trauma, the leading cause of death and disability in the pediatric population, revealed interesting aspects and potential targets for future research. Trauma triggers both excitotoxic and apoptotic neurodegeneration in the developing rat brain. Apoptotic neurodegeneration contributes in an age-dependent fashion to neuronal injury following head trauma, with the immature brain being exceedingly sensitive. Targeting the downstream effectors of neuronal apoptosis in the acute phase of the insult may have therapeutic potential in the treatment of traumatic injury to the immature brain. Antiapoptotic therapies may give cells enough time to establish intrinsic protection systems and restore cellular homeostasis and function

Hodgkin Lymphoma Cell Lines and Tissues Express mGluR5: A Potential Link to Ophelia Syndrome and Paraneoplastic Neurological Disease

Ophelia syndrome is characterized by the coincidence of severe neuropsychiatric symptoms, classical Hodgkin lymphoma, and the presence of antibodies to the metabotropic glutamate 5 receptor (mGluR5). Little is known about the pathogenetic link between these symptoms and the role that anti-mGluR5-antibodies play. We investigated lymphoma tissue from patients with Ophelia syndrome and with isolated classical Hodgkin lymphoma by quantitative immunocytochemistry for mGluR5-expression. Further, we studied the L-1236, L-428, L-540, SUP-HD1, KM-H2, and HDLM-2 classical Hodgkin lymphoma cell lines by FACS and Western blot for mGluR5-expression, and by transcriptome analysis. mGluR5 surface expression differed significantly in terms of receptor density, distribution pattern, and percentage of positive cells. The highest expression levels were found in the L-1236 line. RNA-sequencing revealed more than 800 genes that were higher expressed in the L-1236 line in comparison to the other classical Hodgkin lymphoma cell lines. High mGluR5-expression was associated with upregulation of PI3K/AKT and MAPK pathways and of downstream targets (e.g., EGR1) known to be involved in classical Hodgkin lymphoma progression. Finally, mGluR5 expression was increased in the classical Hodgkin lymphoma-tissue of our Ophelia syndrome patient in contrast to five classical Hodgkin lymphoma-patients without autoimmune encephalitis. Given the association of encephalitis and classical Hodgkin lymphoma in Ophelia syndrome, it is possible that mGluR5-expression in classical Hodgkin lymphoma cells not only drives tumor progression but also triggers anti-mGluR5 encephalitis even before classical Hodgkin lymphoma becomes manifest