ADHD in childhood epilepsy: Clinical determinants of severity and of the response to methylphenidate
Attention-deficit/hyperactivity disorder (ADHD) is commonly observed in children with epilepsy. However, factors associated with the development of ADHD and which might help to guide its therapeutic management, remain an issue of debate.Methods
We conducted a multicenter prospective observational study that included children, aged 6–16 years, with both epilepsy and ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. After inclusion, patients entered a 12–16 week follow-up period during which they were either treated with methylphenidate or they did not receive specific ADHD treatment. ADHD was evaluated with the ADHD Rating Scale-IV.Results
One hundred sixty-seven patients were included, of which 91 were seizure-free during the preinclusion baseline period. At inclusion, the ADHD Rating Scale-IV total score was 30.4 ± (standard deviation) 9.2, the inattentive subscore was 17.3 ± 4.4, and the hyperactive subscore was 13.2 ± 6.6. We did not detect any difference of ADHD Rating Scale-IV scores across patients' age or gender, age at epilepsy onset, epilepsy syndrome, seizure frequency, or number of ongoing antiepileptic drugs. Methylphenidate was initiated in 61 patients, including 55 in whom a follow-up evaluation was available. At the last follow-up, 41 patients (75%) treated with methylphenidate and 39 (42%) of those who did not received ADHD therapy demonstrated ≥25% decrease of ADHD Rating Scale-IV total score (p < 0.001). Response to methylphenidate was greater in girls but was not influenced by any epilepsy-related variables.Significance
We did not detect any epilepsy-related factor associated with the severity of ADHD. Twenty-five percent of patients did not respond to methylphenidate. A better understanding of the pathologic process that underlies ADHD development in childhood epilepsy might be required to improve therapeutic strategies.
Corpus callosotomy is a palliative neurosurgical treatment for patients with either generalized or multifocal refractory epilepsy and injurious drop attacks. This report aims to systematically review the pediatric literature.Methods
Medline, Embase, Web of Knowledge, and Scopus were searched systematically for published articles on treatment outcomes of corpus callosotomy for refractory epilepsy. Studies were included if the patient population was younger than 18 at the time of surgery and median follow-up was >1 year. Studies were excluded if resective surgery was also performed.Results
A total of 12 articles met inclusion criteria. All articles were retrospective case series, with the exception of one being a prospectively designed retrospective case series. There was very little agreement among authors on the definition of a good seizure outcome. Articles that used the Engel classification found that 88.2% of total corpus callosotomy patients had a worthwhile reduction in seizures compared with 58.6% of patients who underwent anterior corpus callosotomy (p < 0.05). Drop attacks improved from corpus callosotomy more than other generalized seizure types. Reported complications were minor in all but one patient, and one death was reported. Transient disconnection syndrome was significantly more likely in total corpus callosotomy than in anterior corpus callosotomy (12.5% vs. 0%; p < 0.05). Improvements in quality of life, behavior, and intelligence/development quotient, as well as parental satisfaction, were generally correlated with seizure outcome. There was no postcallosotomy change in the number of antiepileptic drugs.Significance
Total corpus callosotomy was significantly more likely to result in a reduction in seizures. Anterior corpus callosotomy was unlikely to result in disconnection syndrome. Although all of the papers drew a similar conclusion, the quality of evidence was low. At best, the evidence raises the hypothesis that corpus callosotomy is a safe and effective treatment for refractory generalized epilepsy. It is clear that a case–control or randomized trial is warranted.
This is the first of a two-part primer on the genetics of the epilepsies within the Genetic Literacy Series of the Genetics Commission of the International League Against Epilepsy. In Part 1, we cover the foundations of epilepsy genetics including genetic epidemiology and the range of genetic variants that can affect the risk for developing epilepsy. We discuss various epidemiologic study designs that have been applied to the genetics of the epilepsies including population studies, which provide compelling evidence for a strong genetic contribution in many epilepsies. We discuss genetic risk factors varying in size, frequency, inheritance pattern, effect size, and phenotypic specificity, and provide examples of how genetic risk factors within the various categories increase the risk for epilepsy. We end by highlighting trends in epilepsy genetics including the increasing use of massive parallel sequencing technologies.
Adjunctive perampanel in adolescents with inadequately controlled partial-onset seizures: A randomized study evaluating behavior, efficacy, and safety
The noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel was shown in phase III trials to be an effective and well-tolerated adjunctive treatment for partial-onset seizures. In adolescents, it is necessary to characterize cognitive, neuropsychological, and behavioral side effects of antiepileptic drugs (AEDs). The current analysis focuses on behavioral outcomes, efficacy, and safety of perampanel in adolescents.Methods
Adolescents (12–17 years) on a stable regimen of 1–3 AEDs for partial-onset seizures were randomized (2:1 ratio) to receive up to 12 mg/day perampanel or placebo. Alongside efficacy, cognitive, and neuropsychological assessments, behavioral outcomes were measured with the Child Behavior Checklist (CBCL) before and after a 19-week titration and maintenance phase.Results
Of the randomized patients, 85 received perampanel and 48 received placebo. Median reduction in seizure frequency from baseline was 58.0% for perampanel and 24.0% for placebo (p = 0.079). More patients had seizure frequency reduced by 50% after perampanel (n = 49 [59.0%]) than placebo (n = 17 [37.0%]; p = 0.0144). Changes in behavior were minimal, and there were no differences between groups on competency (p = 0.619) or problems (p = 0.174). A greater proportion of placebo patients were classified in the CBCL “clinical” range for competency at end of treatment, whereas the number in the perampanel group remained unchanged. The overall safety profile was similar to that reported previously for perampanel; most frequently reported adverse events (AEs) were dizziness (26 patients [30.6% vs. 14.6% placebo]), somnolence (13 patients [15.3% vs. 4.2%]), and headache (nine patients [10.6% vs. 14.6%]). Aggression was reported in seven patients receiving perampanel (8.2% vs. 2.1% placebo); two of these were serious AEs, with neither requiring treatment discontinuation.Significance
Adjunctive perampanel is efficacious and well tolerated in adolescents with partial-onset seizures, and appears to have no clinically important impact on behavior measured using the CBCL.
Cortical high-frequency oscillations (HFOs; 100–500 Hz) play a critical role in the pathogenesis of epilepsy; however, whether they represent a true epileptogenic process remains largely unknown. HFOs have been recorded in the human cortex but their network dynamics during the transitional period from interictal to ictal phase remain largely unknown. We sought to determine the high-frequency network dynamics of these oscillations in patients with epilepsy who were undergoing intracranial electroencephalographic recording for seizure localization.Methods
We applied a graph theoretical analysis framework to high-resolution intracranial electroencephalographic recordings of 24 interictal and 24 seizure periods to identify the spatiotemporal evolution of community structure of high-frequency cortical networks at rest and during multiple seizure episodes in patients with intractable epilepsy.Results
Cortical networks at all examined frequencies showed temporally stable community architecture in all 24 interictal periods. During seizure periods, high-frequency networks showed a significant breakdown of their community structure, which was characterized by the emergence of numerous small nodal communities, not limited to seizure foci and encompassing the entire recorded network. Such network disorganization was observed on average 225 s before the electrographic seizure onset and extended on average 190 s after termination of the seizure. Gamma networks were characterized by stable community dynamics during resting and seizure periods.Significance
Our findings suggest that the modular breakdown of high-frequency cortical networks represents a distinct functional pathology that underlies epileptogenesis and corresponds to a cortical state of highest propensity to generate seizures.
Safety and tolerability of adjunctive brivaracetam as intravenous infusion or bolus in patients with epilepsy
An intravenous (IV) formulation of brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, has been developed. We investigated the safety, tolerability, and pharmacokinetics of adjunctive IV BRV administered as a bolus or infusion to adults with epilepsy.Methods
A phase III, multicenter, randomized, four-arm, parallel-group study (NCT01405508) of patients aged 16–70 years with focal or generalized epilepsy uncontrolled by 1–2 antiepileptic drugs was undertaken. The study comprised a 7-day baseline period, a 7-day double-blind run-in period (oral BRV 200 mg/day or placebo [PBO] twice daily [BID]), and 4.5-day open-label evaluation period (IV BRV 200 mg/day BID; 2-min bolus or 15-min infusion, total nine doses). Patients were randomized 1:1:1:1 PBO/BRV bolus; PBO/BRV infusion; BRV/BRV bolus; BRV/BRV infusion. Safety and tolerability were assessed using adverse events, electrocardiography, vital signs, and laboratory assessments. BRV plasma concentrations were measured before and 15 min after the first and last IV doses.Results
Of the 105 patients randomized (53.3% women; 77.1% white; mean [standard deviation; SD] age 41.6 [12.2] years), 103 (98.1%) completed the study. Treatment-emergent adverse event (TEAE) incidence during IV BRV was similar whether IV BRV was initiated first (70.6%) or followed oral BRV (66.0%), and whether it was administered as a bolus (71.2%) or infusion (65.4%). Injection-related TEAEs were reported by 9.6% of patients following bolus and 11.5% following infusion. No serious TEAEs were reported. IV BRV plasma concentrations were higher after the first dose in the conversion groups than initiation groups, and slightly higher in the bolus arm than the infusion arm; concentrations were similar in all patients after the last IV dose.Significance
IV BRV was generally well tolerated, with similar tolerability as a bolus or infusion and independent of de novo administration or as conversion from oral BRV tablets. IV BRV may be an option for patients who are unable to receive oral BRV.
To describe the phenomenology of monitored sudden unexpected death in epilepsy (SUDEP) occurring in the interictal period where death occurs without a seizure preceding it.Methods
We report a case series of monitored definite and probable SUDEP where no electroclinical evidence of underlying seizures was found preceding death.Results
Three patients (two definite and one probable) had SUDEP. They had a typical high SUDEP risk profile with longstanding intractable epilepsy and frequent generalized tonic–clonic seizures (GTCS). All patients had varying patterns of respiratory and bradyarrhythmic cardiac dysfunction with profound electroencephalography (EEG) suppression. In two patients, patterns of cardiorespiratory failure were similar to those seen in some patients in the Mortality in Epilepsy Monitoring Units Study (MORTEMUS).Significance
SUDEP almost always occur postictally, after GTCS and less commonly after a partial seizure. Monitored SUDEP or near-SUDEP cases without a seizure have not yet been reported in literature. When nonmonitored SUDEP occurs in an ambulatory setting without an overt seizure, the absence of EEG information prevents the exclusion of a subtle seizure. These cases confirm the existence of nonseizure SUDEP; such deaths may not be prevented by seizure detection–based devices. SUDEP risk in patients with epilepsy may constitute a spectrum of susceptibility wherein some are relatively immune, death occurs in others with frequent GTCS with one episode of seizure ultimately proving fatal, while in others still, death may occur even in the absence of a seizure. We emphasize the heterogeneity of SUDEP phenomena.
Determining the disability adjusted life years lost to childhood and adolescence epilepsy in southeast Nigeria: An exploratory study
Sudden unexpected death in epilepsy (SUDEP) is the most common cause of epilepsy-related mortality. We hypothesized that electrocardiography (ECG) features may distinguish SUDEP cases from living subjects with epilepsy. Using a matched case–control design, we compared ECG studies of 12 consecutive cases of SUDEP over 10 years and 22 epilepsy controls matched for age, sex, epilepsy type (focal, generalized, or unknown/mixed type), concomitant antiepileptic, and psychotropic drug classes. Conduction intervals and prevalence of abnormal ventricular conduction diagnosis (QRS ≥110 msec), abnormal ventricular conduction pattern (QRS <110 msec, morphology of incomplete right or left bundle branch block or intraventricular conduction delay), early repolarization, and features of inherited cardiac channelopathies were assessed. Abnormal ventricular conduction diagnosis and pattern distinguished SUDEP cases from matched controls. Abnormal ventricular conduction diagnosis was present in two cases and no controls. Abnormal ventricular conduction pattern was more common in cases than controls (58% vs. 18%, p = 0.04). Early repolarization was similarly prevalent in cases and controls, but the overall prevalence exceeded that of published community-based cohorts.
Scrub typhus is an emerging infection, and there is little information about status epilepticus (SE) in scrub typhus. We report the clinical spectrum and outcome of SE in scrub typhus. In a 3-year prospective hospital-based observational study, all scrub typhus patients with SE were included. Scrub typhus was diagnosed by immunochromatography assay. SE was defined if convulsions lasted longer than 5 min. The patients' demographic, clinical, computed tomography (CT), magnetic resonance imaging (MRI), and electroencephalography (EEG) findings were noted. Response to antiepileptic drugs (AEDs) and outcome at 1 month and 1 year were recorded. Between 2012 and 2014, there were 66 patients with scrub typhus admitted with central nervous system (CNS) involvement, 10 (15.2%) of whom had SE (generalized convulsions in 5, secondary generalized in one). The median age of the patients was 34 (range 18–71) years and seven were female. The duration of SE ranged between 10 min and 48 h. SE responded to one AED in five patients, two AEDs in three patients, and more than two AEDs in two patients. Cranial MRI findings were normal. All patients recovered completely with doxycycline by 1 month and AED was withdrawn by 8 months in all. Although 15% patients with scrub typhus may have SE, they have good outcome.
Patients who have sustained brain injury or had developmental brain lesions present a non-negligible risk for developing delayed epilepsy. Finding therapeutic strategies to prevent development of epilepsy in at-risk patients represents a crucial medical challenge. Noncoding microRNA molecules (miRNAs) are promising candidates in this area. Indeed, deregulation of diverse brain-specific miRNAs has been observed in animal models of epilepsy as well as in patients with epilepsy, mostly in temporal lobe epilepsy (TLE). Herein we review deregulated miRNAs reported in epilepsy with potential roles in key molecular and cellular processes underlying epileptogenesis, namely neuroinflammation, cell proliferation and differentiation, migration, apoptosis, and synaptic remodeling. We provide an up-to-date listing of miRNAs altered in epileptogenesis and assess recent functional studies that have interrogated their role in epilepsy. Last, we discuss potential applications of these findings for the future development of disease-modifying therapeutic strategies for antiepileptogenesis.
Dravet syndrome (DS) is a rare and therapy-resistant epilepsy syndrome. A retrospective analysis of add-on fenfluramine treatment in 12 patients with DS was published in 2012 and provided evidence of a meaningful long-term response. Herein we present the results of a subsequent 5-year prospective observation of this original cohort. Ten patients with a mean current age of 24 years were followed prospectively from 2010 until 2014. The mean current dose of fenfluramine was 0.27 mg/kg/day, with a mean treatment duration of 16.1 years. Seizure frequency was derived from a seizure diary. Cardiac examinations and assessments of clinical effectiveness and adverse events were performed at least annually. Three patients were seizure-free for the entire 5 years, and an additional four patients experienced seizure-free intervals of at least 2 years. Fenfluramine was generally well-tolerated. Two patients had mild (stable) valve thickening on the last echocardiography that was deemed clinically insignificant. No patient had any clinical or echocardiographic signs of pulmonary hypertension. These findings support the long-term control of convulsive seizures by low-dose fenfluramine while being well tolerated in this cohort of patients with DS. After up to 27 years of treatment, no patient has developed any clinical signs or symptoms of cardiac valvulopathy or pulmonary hypertension.