Variability in Serum Concentrations and Clinical Response in Artisanal Versus Pharmaceutical Cannabidiol Treatment of Pediatric Pharmacoresistant Epilepsy.

OBJECTIVE: We hypothesized that serum cannabidiol (CBD) concentrations would be higher in patients taking pharmaceutical- versus artisanal-CBD oil, and higher serum CBD concentrations would correlate with increased side effects and decreased seizure frequency. METHODS: This was a retrospective chart review. We included patients with pharmacoresistant epilepsy, treated with artisanal-CBD or pharmaceutical-CBD (Epidiolex), and with quantitative serum CBD concentrations. We tracked epilepsy diagnosis, artisanal-CBD dosage, pharmaceutical-CBD dose, serum CBD concentration, clobazam concentration, N-desmethylclobazam concentration, seizure history (frequency of motor seizures), response to medication (percentage reduction in motor seizures), and side effects. RESULTS: Forty-two patients met inclusion criteria. Mean serum CBD concentration was 51.1 ng/mL (artisanal group) and 124 ng/mL (pharmaceutical group) (p = 0.022). Patients receiving artisanal-CBD had no change in median overall seizures (IQR, -50% to 50%); the pharmaceutical-CBD group had median 50% reduction (IQR, -90% to no change) (p = 0.199). CONCLUSIONS: Pharmaceutical-CBD achieves higher serum CBD concentrations than artisanal-CBD in pediatric patients with refractory epilepsy. These higher CBD concentrations are associated with increased reported adverse effects, but no detectable difference in seizure frequency.

Spatiotemporal distribution and age of seizure onset in a pediatric epilepsy surgery cohort with cortical dysplasia.

OBJECTIVE: Focal Cortical Dysplasias (CD) are a common etiology of refractory pediatric epilepsy and are amenable to epilepsy surgery. We investigated the association of lesion volume and location to age of seizure onset among children with CD who underwent epilepsy surgery. METHODS: A retrospective study of epilepsy surgery patients with pathologically-confirmed CD. Regions of interest (ROI) determined preoperative lesion volumes on 1.5 T and 3 T T2 and SPGR MRIs, and location in 7 distributed neural networks. Descriptive and inferential statistics were used. RESULTS: Fifty-five patients were identified: 35 girls (56.5 %). Median age of seizure onset: 19.0 months (range 0.02 months - 16.0 years). Median age of surgery: 7.8 years (range 2.89 months - 24.45 years). CD were frontal (n = 21, 38 %); temporal (n = 15, 27 %); parietal (n = 10, 18 %); occipital (n = 3, 5%); multilobar (n = 6, 11 %). Frontal FCD had seizure onset < 1-year-old (P = 0.10); temporal lobe CD seizure onset was more likely > 5-years-old (P= 0.06). Median lesion volume for CD was 23.23 cm3 (range: 1.87-591.73 cm3). Larger CD lesions were associated with earlier epilepsy (P = 0.01, r = -0.16). We did not find that lesions proximal to early maturing cortical regions were associated with earlier seizure onset. We found an association with CD location in the default mode network (DMN) and age onset < 5years old (P = 0.03). Age of seizure onset was negatively correlated with percent of CD overlapping motor cortex (P = 0.001, r =-0.794) but not with CD overlap of the visual cortex (P = 0.35). There was no effect of CD type on age of epilepsy onset. SIGNIFICANCE: Larger CD lesions are associated with earlier onset epilepsy. CD most commonly occurs within the DMN and Limbic network, and DMN is associated with seizure onset before 5-years-old. Percent of CD overlapping motor cortex correlates with earlier seizure onset. These observations may reflect patterns of brain maturation or regional differences in clinical expression of seizures.

Differential antiseizure medication sensitivity of the Affective Reactivity Index: A randomized controlled trial in new-onset pediatric focal epilepsy.

BACKGROUND: Irritability is a adverse effect of many antiseizure medications (ASMs), but there are no validated measures currently available to characterize this behavioral risk. We examined both child and parent/guardian versions of the Affective Reactivity Index (ARI), a validated measure developed for application in adolescent psychiatry, to determine its sensitivity to ASM-related irritability. We hypothesized irritability increases associated with levetiracetam (LEV) but not lamotrigine (LTG) or oxcarbazepine (OXC). METHOD: The ARI was administered to 71 child and parent/guardian pairs randomized to one of three common ASMs (LEV, LTG, OXC) used to treat new-onset focal (localization-related) epilepsy. Subjects were recruited as part of a prospective multicenter, randomized, open-label, parallel group design. The ARI was administered at baseline prior to treatment initiation and again at 3 months after ASM initiation. RESULTS: There was a significant increase in ARI ratings for both child and parent/guardian ratings for LEV but not LTG or OXC when assessed 3 months after treatment initiation. When examined on the individual subject level using a criterion of at least a 3-point ARI increase, there was an increase associated with LEV for child ratings but not parent/guardian scores. CONCLUSION: Both child and parent/guardian versions of the ARI appear sensitive to medication-induced irritability associated with LEV on both the group and individual levels. The findings extend the applicability of ARI from characterizing the presence of clinical irritability as a psychiatric diagnostic feature to a more modifiable aspect of behavior change related to medication management and support its use in clinical trial applications.

Evaluation of Dry Sensors for Neonatal EEG Recordings.

PURPOSE: Neonatal seizures are a common neurologic diagnosis in neonatal intensive care units, occurring in approximately 14,000 newborns annually in the United States. Although the only reliable means of detecting and treating neonatal seizures is with an electroencephalography (EEG) recording, many neonates do not receive an EEG or experience delays in getting them. Barriers to obtaining neonatal EEGs include (1) lack of skilled EEG technologists to apply conventional wet electrodes to delicate neonatal skin, (2) poor signal quality because of improper skin preparation and artifact, and (3) extensive time needed to apply electrodes. Dry sensors have the potential to overcome these obstacles but have not previously been evaluated on neonates. METHODS: Sequential and simultaneous recordings with wet and dry sensors were performed for 1 hour on 27 neonates from 35 to 42.5 weeks postmenstrual age. Recordings were analyzed for correlation and amplitude and were reviewed by neurophysiologists. Performance of dry sensors on simulated vernix was examined. RESULTS: Analysis of dry and wet signals showed good time-domain correlation (reaching >0.8), given the nonsuperimposed sensor positions and similar power spectral density curves. Neurophysiologist reviews showed no statistically significant difference between dry and wet data on most clinically relevant EEG background and seizure patterns. There was no skin injury after 1 hour of dry sensor recordings. In contrast to wet electrodes, impedance and electrical artifact of dry sensors were largely unaffected by simulated vernix. CONCLUSIONS: Dry sensors evaluated in this study have the potential to provide high-quality, timely EEG recordings on neonates with less risk of skin injury.

Stable dosages of clobazam for Lennox-Gastaut syndrome are associated with sustained drop-seizure and total-seizure improvements over 3 years.

OBJECTIVE: To determine long-term safety and efficacy of adjunctive clobazam for patients with Lennox-Gastaut syndrome (LGS). METHODS: Eligible patients from two randomized controlled trials (Phase II OV-1002 and Phase III OV-1012) were able to enroll in open-label extension (OLE) study OV-1004 beginning in December 2005 and received clobazam until they discontinued (mandatory at 2 years for patients outside the United States) or until study completion in March 2012. Patients in the United States could have received clobazam for 6 years before it became commercially available. Efficacy assessments included changes in rates of drop seizures and total seizures, responder rates (≥50%, ≥75%, or 100% decreases in seizure frequency vs. baseline), sustained efficacy over time, concomitant antiepileptic drug (AED) use, and global evaluations. Safety assessments included exposure to clobazam, laboratory assessments, physical and neurologic examinations, vital sign monitoring, electrocardiography monitoring, and adverse event reporting. RESULTS: Of 267 patients who enrolled in the OLE, 188 (70%) completed the trial. Two hundred seven patients were from the United States, which was the only country in which patients could be treated with clobazam for >2 years. Forty-four patients were treated with clobazam for 5 years, and 11 for 6 years. Because of the low number of Year 6 patients, this group is not reported separately. Improvements in baseline seizure rates were very stable over the course of the study, with a median 85% decrease in drop seizures at Year 1, 87% at Year 2, 92% at Year 3, 97% at Year 4, and a 91% decrease for patients who had reached Year 5. Similar results were observed for total seizures (79% decrease at both Years 1 and 2, 82% decrease at Year 3, 75% decrease at Year 4, and 85% decrease at Year 5). Responder rates were also stable for the duration of the trial. Of patients who had achieved a ≥50% decrease in median drop-seizure frequency from baseline to Month 3, 86% still had that degree of drop-seizure reduction at Year 3 (and 14% lost their initial responses), and 47% were drop-seizure-free. Most patients who had achieved drop-seizure freedom in the original controlled trials remained drop-seizure-free in the OLE. Based on parents' and physicians' ratings of global evaluations, 80% of patients were "very much improved" or "much improved" after 3 years. Of the 43 patients with concomitant AED data who were treated for 5 years, 30% increased, 19% decreased, and 51% had no change in numbers of AEDs versus their Week 4 regimens. The mean modal clobazam dosage was 0.90 mg/kg/day at Year 1 and 0.97 mg/kg/day at Year 5, suggesting that study patients did not need significant increases in dosage over time. The safety profile was what would be expected for clobazam for LGS patients over a 5-year span, and no new safety concerns developed over time. SIGNIFICANCE: In this largest and longest-running trial in LGS, adjunctive clobazam sustained seizure freedom and substantial seizure improvements at stable dosages through 3 years of therapy in this difficult- to-treat patient population. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Psychiatric symptoms in children prior to epilepsy surgery differ according to suspected seizure focus.

PURPOSE: Children and adolescents with epilepsy have an overrepresentation of psychiatric illness. However, few studies in pediatrics have characterized specific psychiatric conditions associated with seizure localization. In addition, degree to which psychiatric illness may be more prominent in children refractory to standard medical treatment for epilepsy is not known. The aim of this study was to assess psychiatric symptoms in children with medically refractory epilepsy and ascertain whether symptoms were associated with specific localization. METHODS: Case records were reviewed for 40 children with medically refractory epilepsy at the time of their referral for presurgical evaluation. Patients received a clinical psychiatric evaluation and parents completed the Child Behavioral Checklist (CBCL). Seizure localization was verified by pediatric epileptologists, and suitability for surgical procedures was verified by neurosurgical specialists. Groups were compared based on localization of seizure foci, either in the temporal lobe or predominantly extratemporal. KEY FINDINGS: The majority of the sample had psychiatric diagnoses and behavior problems, well beyond the level reported in chronic epilepsy populations. In addition, children with temporal lobe seizure foci had more CBCL behavioral problem categories rated in the clinically significant range, and also were more likely to have clinical diagnoses of depression. SIGNIFICANCE: Routine psychiatric evaluation prior to epilepsy surgery may be important for pediatric patients with medically refractory epilepsy. Psychiatric illness, particularly depression, may be especially prominent for those with temporal lobe seizure foci.

The effect of seizure focus on regional language processing areas.

PURPOSE: To determine the effect of seizure focus location within the left hemisphere on the expression of regional language dominance. METHODS: In this cross-sectional study we investigated 90 patients (mean age 23.3 ± 12.9 years) with left hemisphere focal epilepsy (mean age onset 11.7 ± 8.3 years). Eighteen patients had a frontal lobe focus and 72 had a temporal lobe focus (43 mesial; 29 neocortical). Subjects performed an auditory word definition language paradigm using 3 Tesla blood oxygen level dependent (BOLD) EPI functional magnetic resonance imaging (fMRI). Data were analyzed in SPM2. Regional laterality indices (LIs) for inferior frontal gyrus (IFG), and Wernicke's area (WA), were calculated using a bootstrap method. Categorical language dominance and mean LI were analyzed. KEY FINDINGS: Mean WA LI was lower for subjects with a mesial temporal focus compared with a frontal focus (p = 0.04). There was a greater proportion of atypical language in WA for subjects with a mesial temporal focus compared with a frontal focus (χ(2) = 4.37, p = 0.04). WA LI did not differ for subjects with a neocortical focus compared with a mesial focus or a frontal focus. Mean IFG LI and proportion of atypical language in IFG were similar across seizure focus groups. Age and age of onset were not correlated with mean laterality in WA or IFG. Epilepsy duration tended to be negatively correlated with WA LI (r = -0.18, p = 0.10), but not IFG LI. SIGNIFICANCE: Temporal lobe foci have wide-ranging effects on the distributed language system. In contrast, the effects of a frontal lobe focus appear restricted to anterior rather than posterior language processing areas.

Herbs in epilepsy: evidence for efficacy, toxicity, and interactions.

Herbs and dietary supplements enjoy widespread use in the treatment of epilepsy although supportive data yielding efficacy and safety are lacking. Ten specific products, American hellebore, betony, blue cohosh, kava, mistletoe, mugwort, pipsissiwa, skullcap, valerian, and melatonin, have either multiple-cited recommendations for use in epilepsy or a rationale for antiepileptic action and are discussed in detail. These items paradoxically often have a proconvulsant effect in addition to potentially serious adverse effects. Herb-drug interactions also occur at the level of the P450 hepatic enzyme system of drug catabolism and the P-glycoprotein transport system regulating the entry of exogenous compounds into the vasculature or blood-brain barrier. Thus, significant pharmacokinetic interactions may occur, in addition to pharmacodynamic interactions and proconvulsant effects of alternative medications themselves. Patients should be inquired as to the nature of any alternative medicine products they are using, with the view that these products may be reasonable if traditional antiepileptic drug therapy is continued, potential adverse effects of the alternative agents are monitored, and the alternative and traditional agents do not conflict.

Novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy.

OBJECTIVE: To characterize a novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy. DESIGN: Genomic DNA was isolated from blood and submitted for commercial testing. The identified missense mutation was confirmed in brain DNA obtained at autopsy. Genomic DNA from the brain of the proband was analyzed by comparative genome hybridization, and the coding exons of SCN9A were amplified. Quantitation studies of the mutant transcript were performed. SETTING: Children's National Medical Center and Yale University School of Medicine. PROBAND: A full-term female infant who experienced seizure onset at age 10 weeks, with progression of hemiclonic, apneic, and multifocal migrating partial seizures leading to recurrent status epilepticus and death at age 9 months. MAIN OUTCOME MEASURES: Electroencephalographic and magnetic resonance imaging results, quantitative RNA expression, and secondary mutation test results. RESULTS: The heterozygous missense mutation c.C5006C>A was identified by sequencing genomic DNA from blood and was confirmed in brain DNA. The resulting amino acid substitution p.A1669E alters an evolutionarily conserved residue in an intracellular linker of domain 4 of the SCN1A sodium channel protein Na(v)1.1. The mutant transcript is found to be expressed at levels comparable to the wild-type allele in brain RNA. No variation in copy number was detected in the chromosome region 2q24 containing SCN1A or elsewhere in the genome. No mutations were detected in the linked sodium channel gene SCN9A, which has been reported to act as a modifier of SCN1A mutations. CONCLUSION: This report expands the spectrum of SCN1A epileptic channelopathies to include malignant migrating partial seizures of infancy.

Failure of a vagus nerve stimulator following a nearby lightning strike.

We recently reported our experience with implanted vagus nerve stimulators (VNS) in 62 children over a 7-year period. Here, we present a case of a VNS that successfully reduced the number and severity of seizures in a patient with an unusual seizure pattern, and failed to function shortly after a lightning storm. To our knowledge, the failure of VNS or any implantable electrical devices by lightning has not been reported in the literature. This mechanism of electrical interference, while unusual, may require more attention as these devices are expected to be used more frequently.

Clobazam in the treatment of Lennox-Gastaut syndrome.

PURPOSE: This randomized, double-blind, dose-ranging study evaluated safety and efficacy of clobazam (CLB) as adjunctive therapy for drop seizures in patients with Lennox-Gastaut syndrome (LGS). METHODS: Sixty-eight patients with LGS aged 2-26 years were administered CLB (low dose = target 0.25 mg/kg/day; high dose = target 1.0 mg/kg/day). The study consisted of 4-week baseline, 3-week titration, and 4-week maintenance periods, followed by a 3-week taper or continuation in an open-label study. Seizure frequency was recorded in a diary by the parent/caregiver throughout the study. RESULTS: Weekly drop seizure rates were significantly reduced from baseline in both the high-dose and low-dose groups; the reduction was significantly greater in the high-dose group. A significantly greater proportion of patients in the high-dose group experienced reductions in drop seizures of >or=25%, >or=50%, and >or=75% compared to the low-dose group; more patients in the high-dose group experienced a 100% reduction, but the difference was not significant. Nondrop seizures were also reduced in a dose-dependent manner. In both investigator and parent/caregiver global evaluations, patients in the high-dose group showed significantly greater improvements in overall symptoms compared to low-dose CLB. Adverse events were generally mild or moderate, and were similar between dose groups. Five serious adverse events were reported in four patients, but in no case was CLB discontinued. CONCLUSIONS: Clobazam was well tolerated and reduced drop seizure rates; high-dose CLB was more effective than low-dose CLB. Other seizure types were also reduced.

Open-label, long-term safety study of zonisamide administered to children and adolescents with epilepsy.

BACKGROUND: Zonisamide is licensed in the EU and USA for the adjunctive treatment of partial-onset seizures in adults but there are few data about its use in children. AIMS: To assess the long-term safety and efficacy of zonisamide in children and adolescents. METHODS: Zonisamide-naïve patients (n=109, aged 3-15 years, weight >or=12.5 kg) with a clinical diagnosis of epilepsy (>or=4 seizures/month, receiving 1-2 antiepileptic drugs [AEDs] daily) received zonisamide once or twice daily in an open-label trial. The starting dose was 1mg/kg/day, increased by 2 mg/kg/day every 1-2 weeks at the investigator's discretion to an initial maximum of 12 mg/kg/day. The occurrence of adverse events (AEs) was the primary safety measure. Efficacy was measured via the reductions in seizure frequency and via investigator- and carer-rated global assessment ratings. RESULTS: The mean dose received was 8.5 mg/kg/day. Of the 109 children, 52 (48%) completed 15 months' treatment. Treatment-related AEs, mostly mild-to-moderate in severity, were reported by 58 patients. Seven patients discontinued due to treatment-related AEs. Serious AEs (pancreatitis, decreased sweating, and vertigo) were reported by three patients. A significant (p=0.033) median reduction in 'all seizure' frequency of 2.60 seizures per week was observed. Additionally, a significant (p=0.029) median reduction of 1.80 seizures/week in 'complex partial' seizures was reported. Improvements in investigator- and carer-rated global assessments were noted. CONCLUSIONS: Zonisamide treatment was generally well tolerated and was associated with significant reductions in seizure frequency in this pediatric population with a variety of both partial and generalized medically refractory epilepsy syndromes.

Cerebral MRI abnormalities associated with vigabatrin therapy.

PURPOSE: Investigate whether patients on vigabatrin demonstrated new-onset and reversible T(2)-weighted magnetic resonance imaging (MRI) abnormalities. METHODS: MRI of patients treated during vigabatrin therapy was reviewed, following detection of new basal ganglia, thalamus, and corpus callosum hyperintensities in an infant treated for infantile spasms. Patients were assessed for age at time of MRI, diagnosis, duration, and dose, MRI findings pre-, on, and postvigabatrin, concomitant medications, and clinical correlation. These findings were compared to MRI in patients with infantile spasms who did not receive vigabatrin. RESULTS: Twenty-three patients were identified as having MRI during the course of vigabatrin therapy. After excluding the index case, we detected new and reversible basal ganglia, thalamic, brainstem, or dentate nucleus abnormalities in 7 of 22 (32%) patients treated with vigabatrin. All findings were reversible following discontinuation of therapy. Diffusion-weighted imaging (DWI) was positive with apparent diffusion coefficient (ADC) maps demonstrating restricted diffusion. Affected versus unaffected patients, respectively, had a median age of 11 months versus 5 years, therapy duration 3 months versus 12 months, and dosage 170 mg/kg/day versus 87 mg/kg/day. All affected patients were treated for infantile spasms; none of 56 patients with infantile spasms who were not treated with vigabatrin showed the same abnormalities. DISCUSSION: MRI abnormalities attributable to vigabatrin, characterized by new-onset and reversible T(2)-weighted hyperintensities and restricted diffusion in thalami, globus pallidus, dentate nuclei, brainstem, or corpus callosum were identified in 8 of 23 patients. Young age and relatively high dose appear to be risk factors.

Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy.

PURPOSE: Vigabatrin used to treat infantile spasms (IS) has been associated with transient magnetic resonance imaging (MRI) abnormalities. We carried out a retrospective review to better characterize the frequency of those abnormalities in IS and in children and adults treated with vigabatrin for refractory complex partial seizures (CPS). METHODS: Medical records and 332 cranial MRIs from 205 infants (aged 16 years) with CPS were re-reviewed. Prespecified MRI abnormalities were defined as any hyperintensity on T(2)-weighted or fluid-attenuated inversion-recovery (FLAIR) sequences with or without diffusion restriction not readily explained by a radiographically well-characterized pathology. MRIs were read by two neuroradiologists blinded to treatment group. The incidence and prevalence of MRI abnormalities associated with vigabatrin were estimated. RESULTS: Among infants with IS, the prevalence of prespecified MRI abnormalities was significantly higher among vigabatrin-treated versus vigabatrin-naive subjects (22% vs. 4%; p < 0.001). Of nine subjects in the prevalence population with at least one subsequent determinate MRI, resolution of MRI abnormalities occurred in six (66.7%)-vigabatrin was discontinued in four. Among adults and children treated with vigabatrin for CPS, there was no statistically significant difference in the incidence or prevalence of prespecified MRI abnormalities between vigabatrin-exposed and vigabatrin-naive subjects. DISCUSSION: Vigabatrin is associated with transient, asymptomatic MRI abnormalities in infants treated for IS. The majority of these MRI abnormalities resolved, even in subjects who remained on vigabatrin therapy.

Misidentification of vagus nerve stimulator for intravenous access and other major adverse events.

The vagus nerve stimulator has become a standard modality for intractable pediatric epilepsy. We reviewed our experience with major adverse events, after accidental puncture of a stimulator wire by an emergency room physician seeking intravenous access to treat status epilepticus. The Children's National Medical Center database was reviewed for patients undergoing vagus nerve stimulator placement between January 1988 and June 2006. Patient characteristics, duration of therapy, and treatment-limiting adverse events were noted. Of 62 patients implanted over 8 years, 22 (35%) had adverse events which led to a change in therapy. Adverse events included prominent drooling, coughing, throat discomfort, dysphagia, wound infection, difficulty breathing, vomiting, vocal-cord weakness, lead failure, and iatrogenic (piercing of wire; surgical clipping of wire during revision). Eight patients required nonroutine surgical intervention (13%). There were two unusual case presentations. In a 13-year-old boy with status epilepticus at an outlying emergency department, the stimulator line was pierced in search of intravenous access. In a 25-year-old housepainter, neck paresthesias upon right lateral neck turning were attributed to insufficient strain relief. Treatment-limiting adverse events occurred in approximately one-third of patients. Unanticipated adverse events included misidentification of the wire for intravenous access, clipping of the wire during surgical dissection, and cervical dysesthesias associated with head-turning.

Zonisamide for the treatment of myoclonic seizures in progressive myoclonic epilepsy: an open-label study.

PURPOSE: To examine the safety and efficacy of zonisamide in treating myoclonic seizures associated with progressive myoclonic epilepsy (PME), in an open-label setting. METHODS: Thirty patients with refractory PME (aged > or = 5 years), who were taking up to three antiepileptic drugs, received adjunctive zonisamide (< or = 6 mg/kg/day) therapy for 16 weeks. Myoclonic seizures were recorded daily over a 24-hour period or in 10-minute epochs in the morning, afternoon, and evening. Safety was assessed via adverse events (AEs); efficacy was measured by the percentage of patients experiencing a > or = 50% decrease in myoclonic seizure frequency from baseline. RESULTS: Treatment-related AEs, experienced by 53% (n = 16/30) of patients, led to five patients discontinuing zonisamide. The most common AEs were decreased appetite, somnolence, and asthenia. Overall, 36% of patients (n = 10/28) had a > or = 50% reduction in myoclonic seizure frequency. CONCLUSIONS: These results suggest that zonisamide may be useful in the treatment of patients with PME. However, due to the size and open-label character of this study, further research is required.

Prospective assessment of levetiracetam pharmacokinetics during dose escalation in 4- to 12-year-old children with partial-onset seizures on concomitant carbamazepine or valproate.

PURPOSE: To assess the multiple-dose pharmacokinetics of levetiracetam and its major metabolite ucb L057 in children with partial-onset seizures and determine whether it is affected by adjunctive carbamazepine or valproate. To correlate levetiracetam concentrations in plasma and saliva and to assess its safety and clinical response. METHODS: Design was an open-label, multicenter study. Twenty-one children (4-12 years old) with epilepsy taking carbamazepine (13) or valproate (8) received adjunctive levetiracetam. Levetiracetam was initiated at 20 mg/(kg day) and titrated at 2-week intervals to 40 and then 60 mg/(kg day). Twelve-hour pharmacokinetics were determined at the end of each 2-week period. Efficacy was estimated from the partial seizure frequency per week and Global Evaluation Scale. RESULTS: Levetiracetam was rapidly absorbed following oral dosing, with median t(max) of 0.5 h. Dose proportional increases were observed for C(max) and AUC((0-12)) over the dose range; t(1/2) was 4.9 h. Pharmacokinetics of levetiracetam and ucb L057 were not markedly different with concomitant carbamazepine or valproate; clearance was only 7-13% faster and AUC was decreased by only 15-24% in those on carbamazepine compared to valproate. Levetiracetam did not affect trough carbamazepine or valproate. Concentration in saliva and plasma were strongly correlated. Seizure frequency declined by 50% or more in 43% of subjects in the intent-to-treat population (n=21) and in 56% of those with seizures at baseline (n=16). Marked or moderate improvement occurred in 80% and 75% of patients based on Global Evaluation Scale ratings by investigators and parents/guardians, respectively. Levetiracetam was well tolerated. CONCLUSION: Levetiracetam exhibits simple pharmacokinetics in children, with rapid absorption and dose-proportional kinetics. Small but not clinically relevant differences were observed between subjects receiving carbamazepine and valproate, suggesting significant dose adjustment is usually not necessary. This substantiates prior assessments that levetiracetam clearance is higher in children than adults, necessitating a higher dose in children on a mg/kg basis, and suggests it is useful add-on therapy for children with partial-onset seizures regardless of baseline therapy.

The benefits of a camp designed for children with epilepsy: evaluating adaptive behaviors over 3 years.

OBJECTIVE: Children with epilepsy attending a condition-specific overnight camp were evaluated for behavioral changes over 3 consecutive years, using a modification of the Vineland Adaptive Behavioral Scale. METHODS: Trained counselors completed pre- and postcamp assessments for each camper. Repeated-measures MANOVA was used to analyze effects of the camp experience for each year, with respect to gender and age. Repeated-measures ANOVA was conducted to evaluate long-term effects from year-to-year comparisons for return campers, following three successive camp experiences. RESULTS: A significant change in social interaction was observed over 3 years. Despite some decline at the start of camp in consecutive years, the overall trend for return campers suggests a positive cumulative impact of continued camp participation, with improvements in the domains of social interaction, responsibility, and communication. CONCLUSION: A condition-specific camp designed for children with epilepsy can improve adaptive behaviors and social interactions. Overall net gains appear to increase over time, suggesting additional benefits for return campers.

Clinical experience with anticonvulsant medication in pediatric epilepsy and comorbid bipolar spectrum disorder.

Anticonvulsant drugs are first-line treatments for both bipolar mood disorder and epilepsy; however, few studies have explored treatment options when these disorders co-occur. The aim of this study was to identify bipolar disorder symptoms common in pediatric epilepsy and to determine whether anticonvulsant monotherapy might be a practical treatment consideration. A retrospective chart review identified 38 children with bipolar spectrum disorder and epilepsy comorbidity. Two mental health clinicians independently assessed psychiatric diagnoses, symptoms, and assigned retrospective CGI-I ratings for psychiatric symptoms. Common bipolar symptoms included impulsivity, psychomotor agitation, and explosive rage. Forty-two medication trials with 11 different anticonvulsants were identified. Of the 30 instances in which anticonvulsant monotherapy was attempted, carbamazepine, divalproex sodium, lamotrigine, and oxcarbazepine were associated with better psychiatric CGI-I ratings than other monotherapies (P<0.01). Results suggest that in many cases, selected anticonvulsants appeared to simultaneously treat both epilepsy and mood disorder. Controlled trials are necessary to further ascertain optimal anticonvulsant usage.