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

Multi-system neurological disease is common in patients with OPA1 mutations

Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal 'dominant optic atrophy plus' variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment

Neonatal seizures

In childhood, the risk for seizures is greatest in the neonatal period. Currently used therapies have limited efficacy. Although the treatment of neonatal seizures has not significantly changed in the past several decades, there has been substantial progress in understanding developmental mechanisms that influence seizure generation and responsiveness to anticonvulsants. This review includes an overview of current approaches to the diagnosis and treatment of neonatal seizures, identifies some of the critical factors that have limited progress, and highlights recent insights about the pathophysiology of neonatal seizures that may provide the foundation for better treatment. Ann Neurol 2007Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57360/1/21167_ftp.pd

Altering the trajectory of early postnatal cortical development can lead to structural and behavioural features of autism

<p>Abstract</p> <p>Background</p> <p>Autism is a behaviourally defined neurodevelopmental disorder with unknown etiology. Recent studies in autistic children consistently point to neuropathological and functional abnormalities in the temporal association cortex (TeA) and its associated structures. It has been proposed that the trajectory of postnatal development in these regions may undergo accelerated maturational alterations that predominantly affect sensory recognition and social interaction. Indeed, the temporal association regions that are important for sensory recognition and social interaction are one of the last regions to mature suggesting a potential vulnerability to early maturation. However, direct evaluation of the emerging hypothesis that an altered time course of early postnatal development can lead to an ASD phenotype remains lacking.</p> <p>Results</p> <p>We used electrophysiological, histological, and behavioural techniques to investigate if the known neuronal maturational promoter valproate, similar to that in culture systems, can influence the normal developmental trajectory of TeA <it>in vivo</it>. Brain sections obtained from postnatal rat pups treated with VPA <it>in vivo </it>revealed that almost 40% of cortical cells in TeA prematurely exhibited adult-like intrinsic electrophysiological properties and that this was often associated with gross cortical hypertrophy and a reduced predisposition for social play behaviour.</p> <p>Conclusions</p> <p>The co-manifestation of these functional, structural and behavioural features suggests that alteration of the developmental time course in certain high-order cortical networks may play an important role in the neurophysiological basis of autism.</p

Recommendations for the design of therapeutic trials for neonatal seizures

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from welldesigned clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population

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