Therapy and Clinical Course in 52 Patients with PCDH19 Mutations

Effectiveness of the First Antiepileptic Drug in the Treatment of Pediatric Epilepsy

It has long been recognised that uncontrolled childhood epilepsy is detrimental to cognition and behaviour, impacting on a patient's ability to succeed academically. Patients who experience more frequent and serious seizures are at greater risk for cognitive decline, emphasising the need for more effective epilepsy treatments to bring seizures under control. That said, although more effective antiepileptic drugs (AEDs) have the potential to limit the impact of uncontrolled seizures on cognitive and behavioural function, recently it has been acknowledged that deficits in these functions may be caused by AEDs themselves. The cognitive and behavioural effects of older-generation AEDs have been determined largely from AE reporting rather than from specific assessment. Recently, clinical trials of newer-generation AEDs, such as topiramate, levetiracetam and perampanel, have included standardised neuropsychological tests as outcome measures to assess their impact on cognition and behaviour in children and adolescents. However, to understand how we may limit the cognitive and behavioural side effects of AEDs, it is necessary for us to gain a fuller, more accurate, characterisation of their true impact. Such insight will depend on sophisticated and standardised approaches to the design of AED clinical trials. This review provides a general overview of our current understanding of the impact of both epilepsy and AEDs on cognition and behaviour, before focusing on the AEDs for which more detailed assessment, using standardised cognitive and behavioural measures, has been undertaken. We will then go on to discuss the key elements in the design of future AED clinical trials to address current unmet needs.

Dalbavancin: First I.V. antibiotic for acute bacterial skin infections

Chapter 19 Metabolic Effects of AEDs: Impact on Body Weight, Lipids and Glucose Metabolism

Bone and calcium metabolism and antiepileptic drugs

Scopolamine-induced convulsions in fasted mice after food intake: effects of glucose intake, antimuscarinic activity and anticonvulsant drugs

Effects of lamotrigine and conventional antiepileptic drugs on amygdala- and hippocampal-kindled seizures in rats.

It is well-recognized that individuals with epilepsy have an increased risk of vertebral and nonvertebral fractures; this increased risk has been described to be secondary to an increased bone fragility and to an increased risk of falls. Osteoporosis is the most common bone disease which has been characterized by microarchitectural deterioration of trabecula and cortical bone mass with a decrease in bone mineral density and bone strength. Specific side effects of antiepileptic drugs (AEDs) on bone metabolism have been identified; recent research publications further characterized some of the specific side effects of AEDs on bone metabolism. It is the purpose of this review to describe recent advances on the knowledge of the effects of AEDs on bone metabolism and the cause of osteoporosis in the field of epilepsy. Recent literature demonstrates that the increased risk of fractures in the epileptic patient population is likely multifactorial and includes seizure activity, injuries from falls, decreased bone strength, adverse effects from AEDs. Reviewed publications suggest that the mechanism of adverse effects on bone metabolism may differ among different AEDs. The impact of vitamin D deficiency or its metabolism in the epileptic population has also been a concern of several reviewed publications. This is a review is of the recent epilepsy and osteoporosis literature published over the past 18 months, highlighting reports and studies concerning the cause, pathogenesis, and possible preventive measures and effects of AEDs on changes of bone metabolism, bone loss, and development of osteoporosis. In addition, we also reviewed articles focusing on issues of prevention and treatment of osteoporosis in individuals with epilepsy. We utilized the search engines of PubMed and Cochrane Reviews from January 2016 to June 2017.

To evaluate the effects of adjunctive pregabalin 300 mg/day versus placebo on polysomnographic (PSG) variables in patients with well controlled partial seizures and subjectively reported sleep disturbance. An exploratory, 4-week, double-blind, randomized study in patients with well controlled partial seizures on AED monotherapy and subjective sleep disturbance over the previous 6 months. Mean changes from baseline to endpoint in PSG and subjective sleep variables (MOS Sleep Scale, Groningen Sleep Questionnaire) in patients on adjunctive pregabalin 300 mg/day (n=8) were compared with patients on placebo (n=7). Baseline PSGs showed sleep fragmentation. Mean sleep efficiency improved significantly in both treatment groups in the mean baseline to endpoint change; there was no significant between-group difference. Pregabalin treatment was associated with a significant reduction in number of awakenings (p = 0.02), and improvement in wake time after sleep onset approached significance (p = 0.055), suggesting improvement in sleep continuity that was not observed in the placebo group. Pregabalin was also associated with significant improvements in the MOS sleep disturbance and sleep quantity subscales compared with placebo (p < or =0.03). There were no changes in self-reported seizure control. This exploratory pilot study suggests that pregabalin may improve sleep continuity in patients with clinically relevant sleep disturbance. The effect on disturbed sleep appears independent of seizure control. The effects of pregabalin on disturbed sleep and seizures and their interrelationships warrant further study.

In the first part of this essay, the "common wisdom" about Putnam and Merritt's contributions to the treatment of epilepsy was summarized (Rowland, 1982). Based on the history that has been presented here, how true are these "wisdoms"? Putnam and Merritt did devise "a simple and reliable method to test drugs of anticonvulsant effect" and they did show "that anticonvulsant effects in cats accurately predicted effects in humans," but others before them had done these same things. Dilantin, contrary to common wisdom, was not the first anticonvulsant drug to be tested in animals before it was given to human subjects; at least a year before, Cobb and his co-workers had done the same thing using vital dyes. However, Dilantin did represent the first time an anticonvulsant tested in animals was subsequently studied in a large series of patients. Nor were Putnam and Merritt the first to show that "anticonvulsant and sedative effects of drugs could be separated." Potassium borotartrate, ketogenic diet, ketone bodies, and vital dyes were anticonvulsive without necessarily being sedative. However, Putnam and Merritt were probably the first to make so explicit a statement to this effect. It may well have been this particular statement--and the fact that it was so well heard by other researchers--that represented their greatest achievement. In Kuhn's theory of scientific revolutions, the great step forward may not be so much the accumulation of evidence that the existing paradigm is not a feasible one, but rather the use of this evidence to form a new model or paradigm which is then accepted by normal science in such a fashion that the results prove to be productive. This, it would seem, is what Putnam and Merritt did. From it came their own major discovery, Dilantin, which, in Rowland's words, remains "a mainstay of treatment" for epilepsy up to the present time, and which "opened the way to the development of other anticonvulsant drugs."

Robust biomarkers for anti-epileptic drugs (AEDs) activity in the human brain are essential to increase the probability of successful drug development. The frequency analysis of electroencephalographic (EEG) activity, either spontaneous or evoked by transcranial magnetic stimulation (TMS-EEG) can provide cortical readouts for AEDs. However, a systematic evaluation of the effect of AEDs on spontaneous oscillations and TMS-related spectral perturbation (TRSP) has not yet been provided. We studied the effects of Lamotrigine, Levetiracetam, and of a novel potassium channel opener (XEN1101) in two groups of healthy volunteers. Levetiracetam suppressed TRSP theta, alpha and beta power, whereas Lamotrigine decreased delta and theta but increased the alpha power. Finally, XEN1101 decreased TRSP delta, theta, alpha and beta power. Resting-state EEG showed a decrease of theta band power after Lamotrigine intake. Levetiracetam increased theta, beta and gamma power, while XEN1101 produced an increase of delta, theta, beta and gamma power. Spontaneous and TMS-related cortical oscillations represent a powerful tool to characterize the effect of AEDs on in vivo brain activity. Spectral fingerprints of specific AEDs should be further investigated to provide robust and objective biomarkers of biological effect in human clinical trials.

Background: Epilepsy is commonly associated with reproductive endocrine disorders. These include polycystic ovary syndrome (PCOS), isolated components of this syndrome such as polycystic ovaries, hyperandrogenaemia, hypothalamic amenorrhoea, and functional hyperprolactinaemia....

Epilepsy and sleep are closely related, which is a hot research at home and abroad, the two of them influence each other.Sleep deprivation and sleep status can induce epilepticseizures; Epileptic seizures can lead to sleep disorders.We reviewed the interaction between epilepsy and sleep and the effects of antiepileptic drugs on sleep, which provide a new theoretical basis for improving sleep and improving the quality of life in patients with epilepsy and has important value to improve the level of prevention and treatment of epilepsy. Key words: Epilepsy; Sleep; Anti epileptic drugs

Febrile seizures occurring in a child older than one month during an episode of fever affect 2% to 4% of children in Great Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given during subsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs. To evaluate the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011. Issue 3); MEDLINE (1966 to May 2011); EMBASE (1966 to May 2011); Database of Abstracts of Reviews of Effectiveness (DARE) (May 2011). No language restrictions were imposed. We also contacted researchers in the field to identify continuing or unpublished studies. Trials using randomised or quasi-randomised patient allocation that compared the use of antiepileptic or antipyretic agents with each other, placebo or no treatment. Two review authors (RN and MO) independently applied pre-defined criteria to select trials for inclusion and extracted the pre-defined relevant data, recording methods for randomisation, blinding and exclusions. Outcomes assessed were seizure recurrence at 6, 12, 18, 24, 36 months and at age 5 to 6 years in the intervention and non-intervention groups, and adverse medication effects. The presence of publication bias was assessed using funnel plots. Thirty-six articles describing 26 randomised trials with 2740 randomised participants were included. Thirteen interventions of continuous or intermittent prophylaxis and their control treatments were analysed. Methodological quality was moderate to poor in most studies. We could not do a meta-analysis for eight of the 13 comparisons due to insufficient numbers of trials. No significant benefit for valproate, pyridoxine, intermittent phenobarbitone or ibuprofen versus placebo or no treatment was found; nor for diclofenac versus placebo followed by ibuprofen, acetominophen or placebo; nor for intermittent rectal diazepam versus intermittent valproate, nor phenobarbitone versus intermittent rectal diazepam.There was a significant reduction of recurrent febrile seizures with intermittent oral diazepam versus placebo with a relative risk (RR) of 0.67 (95% confidence interval (CI) 0.48 to 0.94) at 24 months), RR of 0.61 (95% CI 0.15 to 0.89) at 48 months, with no benefit at 6, 12 or 72 months. Phenobarbitone versus placebo or no treatment reduced seizures at 6, 12 and 24 months but not at 18 or 72 month follow up (RR 0.60, 95% CI 0.42 to 0.84 at 6 months; RR 0.59, 95% CI 0.46 to 0.75 at 12 months; and RR 0.65, 95% CI 0.49 to 0.88 at 24 months). Intermittent rectal diazepam versus no treatment or placebo also reduced seizures (RR 0.60, 95% CI 0.41 to 0.86 at 6 months; RR 0.65, 95% CI 0.49 to 0.87 at 12 months; RR 0.2, 95% CI 0.1 to 0.39 at 18 months; RR 0.36, 95% CI 0.18 to 0.71 at 36 months), with no benefit at 24 months. Intermittent clobazam compared to placebo at 6 months resulted in a RR of 0.09 (95% CI 0.02 to 0.30), an effect found against an extremely high (83.3%) recurrence rate in the controls and which is a result that needs replication.The recording of adverse effects was variable. Lower comprehension scores in phenobarbitone treated children were found in two studies. In general, adverse effects were recorded in up to some 30% of children in the phenobarbitone treated group and in up to 36% in benzodiazepine treated groups. Evidence of publication bias was found in the meta analyses of comparisons for phenobarbitone versus placebo (8 studies) at 12 months but not at 6 months (6 studies); and valproate versus placebo (4 studies) at 12 months; with too few studies to identify publication bias for the other comparisons. No clinically important benefits for children with febrile seizures were found for intermittent oral diazepam, phenytoin, phenobarbitone, intermittent rectal diazepam, valproate, pyridoxine, intermittent phenobarbitone or intermittent ibuprofen, nor for diclofenac versus placebo followed by ibuprofen, acetominophen or placebo. Adverse effects were reported in up to 30% of children. Apparent benefit for clobazam treatment in one recent trial needs to be replicated to be judged reliable. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management and, most importantly, the benign nature of the phenomenon.

Effect of antiepileptic drugs and reactive oxygen species on folate receptor 1 (FOLR1)-dependent 5-methyltetrahydrofolate transport