Valproate in children with newly diagnosed idiopathic generalized epilepsy.

OBJECTIVES: Sparse information on dose-response characteristics for initial antiepileptic drug monotherapy in children with idiopathic generalized epilepsy (IGE) is available. The aim of this study is to characterize the therapeutic dose of valproate in children with newly diagnosed IGE. MATERIALS AND METHODS: Effect of initial valproate monotherapy and doses associated with seizure freedom were examined in consecutive children with IGE identified from a New Onset Seizure Clinic. RESULTS: Of 84 patients identified, 48 (57%) became seizure-free on valproate monotherapy and another 10 patients became seizure-free but discontinued VPA because of adverse effects. The mean dose in seizure-free children was 15.7 mg/kg/day and over 95% of IGE patients will respond below 25 mg/kg/day. CONCLUSIONS: Half of children became seizure-free on valproate monotherapy and did so at modest doses.

Assessing quality and normalization of microarrays: case studies using neurological genomic data.

BACKGROUND: Genomic analysis using microarray tools has the potential benefit of enhancing our understanding of neurological diseases. The analysis of these data is complex due to the large amount of data generated. Many tools have been developed to assist with this, but standard methods of analysis of these tools have not been established. OBJECTIVE: This study analyzed the sensitivity and specificity of different analytical methods for gene identification and presents a standardized approach. METHODS: Affymetrix HG-U133 plus 2.0 microarray datasets from two neurological diseases - chronic migraine and new-onset epilepsy - were used as source data and methods of analysis for normalization of data and identification of gene changes were compared. Housekeeping genes were used to identify non-specific changes and gender related genes were used to identify specific changes. RESULTS: Initial normalization of data revealed that 5-10% of the microarray were potential outliers due to technical errors. Two separate methods of analysis (dChip and Bioconductor) identified the same microarray chips as outliers. For specificity and sensitivity testing, performing a per-gene normalization was found to be inferior to standard preprocessing procedures using robust multichip average analysis. CONCLUSIONS: Technical variation in microarray preprocessing may account for chip-to-chip and batch-to-batch variations and outliers need to be removed prior to analysis. Specificity and sensitivity of the final results are best achieved following this identification and removal with standard genomic analysis techniques. Future tools may benefit from the use of standard tools of measurement.

Factors associated with treatment delays in pediatric refractory convulsive status epilepticus.

OBJECTIVE: To identify factors associated with treatment delays in pediatric patients with convulsive refractory status epilepticus (rSE). METHODS: This prospective, observational study was performed from June 2011 to March 2017 on pediatric patients (1 month to 21 years of age) with rSE. We evaluated potential factors associated with increased treatment delays in a Cox proportional hazards model. RESULTS: We studied 219 patients (53% males) with a median (25th-75th percentiles [p25-p75]) age of 3.9 (1.2-9.5) years in whom rSE started out of hospital (141 [64.4%]) or in hospital (78 [35.6%]). The median (p25-p75) time from seizure onset to treatment was 16 (5-45) minutes to first benzodiazepine (BZD), 63 (33-146) minutes to first non-BZD antiepileptic drug (AED), and 170 (107-539) minutes to first continuous infusion. Factors associated with more delays to administration of the first BZD were intermittent rSE (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.14-2.09; p = 0.0467) and out-of-hospital rSE onset (HR 1.5, 95% CI 1.11-2.04; p = 0.0467). Factors associated with more delays to administration of the first non-BZD AED were intermittent rSE (HR 1.78, 95% CI 1.32-2.4; p = 0.001) and out-of-hospital rSE onset (HR 2.25, 95% CI 1.67-3.02; p < 0.0001). None of the studied factors were associated with a delayed administration of continuous infusion. CONCLUSION: Intermittent rSE and out-of-hospital rSE onset are independently associated with longer delays to administration of the first BZD and the first non-BZD AED in pediatric rSE. These factors identify potential targets for intervention to reduce time to treatment.

Expanding first-line therapy options for children with partial seizures.

Carbamazepine and phenytoin are considered first-line therapies for children with partial seizures on the basis of the adult Veterans Administration studies, open-label controlled and uncontrolled pediatric studies, and clinical experience. Although many new antiepileptic drugs (AEDs) have demonstrated efficacy in controlled trials in adults with partial seizures, additional issues must be examined before these new AEDs are considered as first-line therapy for children with partial seizures. This article proposes three criteria for assessing the suitability of a new AED as first-line therapy for pediatric partial seizures: (a) demonstrated efficacy against pediatric partial seizures in two or more randomized, double-blind controlled trials involving patients less than 12 years old (with at least one of the trials utilizing a monotherapy design); (b) a favorable safety profile in monotherapy trials and no severe idiosyncratic reactions; and (c) ease of use in children across a wide range of ages. On the basis of these criteria, two new AEDs, oxcarbazepine (OXC) and topiramate (TPM), are suitable for consideration. OXC has demonstrated efficacy in monotherapy and adjunctive therapy in pediatric partial seizures, along with good tolerability and the ability to be titrated rapidly. TPM has also demonstrated efficacy and tolerability in pediatric partial seizures but should be titrated slowly. In addition, gabapentin (GBP) can be considered as first-line therapy for pediatric partial seizures if the preliminary analysis of a monotherapy trial is confirmed. There are not yet enough data on efficacy to support consideration of lamotrigine, tiagabine, felbamate, levetiracetam, or zonisamide as first-line therapy for pediatric partial seizures.

Topiramate therapy of epilepsy associated with Angelman's syndrome.

Angelman's syndrome, a genetic disorder involving a defect in the DNA coding for subunits of the gamma-aminobutyric acid (GABA) type A receptor, often is associated with intractable epilepsy. Topiramate is a novel anticonvulsant that enhances GABAergic neurotransmission. Five children with Angelman's syndrome and epilepsy were treated with topiramate for clinical indications. The drug was effective and well tolerated, possibly because of its GABAergic properties. Further studies are necessary to confirm and elucidate this observation.

A double-blind, randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children. Topiramate YP Study Group.

OBJECTIVE: To evaluate the efficacy and safety of topiramate 6 mg/kg/day in children (age 2 to 16 years) as adjunctive therapy for uncontrolled partial-onset seizures with or without secondarily generalized seizures in a multicenter, randomized, double-blind, placebo-controlled trial. METHODS: Patients with at least six partial-onset seizures during the 8-week baseline phase were treated with either topiramate (n = 41) or placebo (n = 45) for 16 weeks. RESULTS: Topiramate-treated patients had a greater median percent reduction from baseline in average monthly partial-onset seizure rate than placebo-treated patients (33.1% versus 10.5%, p = 0.034), a greater proportion of treatment responders (i.e., patients with a > or = 50% seizure rate reduction; 16 of 41 [39%] versus 9 of 45 [20%], p = 0.080), and patients with a > or = 75% seizure rate reduction (7 of 41 [17%] versus 1 of 45 [2%], p = 0.019), and better parental global evaluations of improvement in seizure severity (p = 0.019). Emotional lability (12% versus 4%), fatigue (15% versus 7%), difficulty with concentration or attention (12% versus 2%), and forgetfulness/impaired memory (7% versus 0%) were more frequent among topiramate-treated than placebo-treated patients. Most treatment-emergent adverse events were mild or moderate in severity. No topiramate-treated patients discontinued the study due to adverse events. CONCLUSIONS: Topiramate was safe and effective in the treatment of partial-onset seizures in children.

A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Topiramate YL Study Group.

OBJECTIVE: To evaluate the efficacy and safety of topiramate as adjunctive therapy for Lennox-Gastaut syndrome in a multicenter, double-blind, placebo-controlled trial. BACKGROUND: Conventional antiepileptic drugs are frequently ineffective against multiple-seizure types of Lennox-Gastaut syndrome. METHODS: Ninety-eight patients >1 year to <30 years of age, with slow spike-and-wave patterns on EEG, seizure types including drop attacks, and either a history of or active atypical absence seizures, were assigned to an 11-week, double-blind treatment phase with either topiramate or placebo. Topiramate was titrated to target doses of approximately 6 mg/kg/d. RESULTS: For drop attacks, the most severe seizures associated with this syndrome, the median percentage reduction from baseline in average monthly seizure rate was 14.8% for the topiramate group and -5.1% (an increase) for the placebo group (p = 0.041). Topiramate-treated patients demonstrated greater improvement in seizure severity than did placebo-treated patients based on parental global evaluations (p = 0.037). The percentage of patients with a > or = 50% reduction from baseline in major seizures (drop attacks and tonic-clonic seizures) was greater in the topiramate group (15/46 or 33%) than in the control group (4/50 or 8%; p = 0.002). The most common adverse events in both groups were CNS related; there were no discontinuations from topiramate therapy due to adverse events. CONCLUSIONS: Topiramate adjunctive therapy was effective in reducing the number of drop attacks and major motor seizures and in improving seizure severity as determined by parental global evaluation.

Adjunctive therapy with oxcarbazepine in children with partial seizures. The Oxcarbazepine Pediatric Study Group.

OBJECTIVE: To evaluate the safety and efficacy of oxcarbazepine (OXC) as adjunctive therapy in children with inadequately controlled partial seizures on one or two concomitant antiepileptic drugs (AEDs). BACKGROUND: OXC has shown antiepileptic activity in several comparative monotherapy trials in newly diagnosed patients with epilepsy, and in a placebo-controlled monotherapy trial in hospitalized patients evaluated for epilepsy surgery. DESIGN: A total of 267 patients were evaluated in a multicenter, randomized, placebo-controlled trial consisting of three phases: 1) a 56-day baseline phase (patients maintained on their current AEDs); 2) a 112-day double-blind treatment phase (patients received either OXC 30-46 mg/kg/day orally or placebo); and 3) an open-label extension phase. Data are reported only from the double-blind treatment phase; the open-label extension phase is ongoing. METHODS: Children (3 to 17 years old) with inadequately controlled partial seizures (simple, complex, and partial seizures evolving to secondarily generalized seizures) were enrolled. RESULTS: Patients treated with OXC experienced a significantly greater median percent reduction from baseline in partial seizure frequency than patients treated with placebo (p = 0.0001; 35% versus 9%, respectively). Forty-one percent of patients treated with OXC experienced a > or =50% reduction from baseline in partial seizure frequency per 28 days compared with 22% of patients treated with placebo (p = 0.0005). Ninety-one percent of the group treated with OXC and 82% of the group treated with placebo reported > or =1 adverse event; vomiting, somnolence, dizziness, and nausea occurred more frequently (twofold or greater) in the group treated with OXC. CONCLUSION: OXC adjunctive therapy administered in a dose range of 6 to 51 mg/kg/day (median 31.4 mg/kg/day) is safe, effective, and well tolerated in children with partial seizures.

Acquired neuropathologic lesions associated with the hypoplastic left heart syndrome.

This study details the type, frequency, clinical presentation, and etiologic associations of acquired brain lesions in 40 infants with the hypoplastic left heart syndrome encountered during a 52-month interval. Detailed postmortem neuropathologic examinations showed that 55% of the infants were free of acquired brain lesions. However, the other 45% had combinations of hypoxic-ischemic lesions and intracranial hemorrhage. Central nervous system perfusion and glucose-oxygen delivery appeared to be important factors in the occurrence of hypoxic-ischemic lesions or intracranial hemorrhage, whereas acidosis and hypercarbia were not. Cerebral necrosis may be a predisposing factor for a major intracranial hemorrhage. A duration of cardiopulmonary bypass with hypothermic total circulatory arrest longer than 40 minutes was associated with a higher incidence of acquired neuropathology. These results indicate that the majority of infants with hypoplastic left heart syndrome are free of acquired neuropathology and suggest practical ways to reduce the risks in the others.

Congenital brain anomalies associated with the hypoplastic left heart syndrome.

This study details the type, frequency, and clinical presentation of developmental brain anomalies in 41 infants with the hypoplastic left heart syndrome encountered during a 52-month interval. Overall, 29% of the infants had either a major or minor central nervous system abnormality. Overt central nervous system malformations, including 3 cases of agenesis of the corpus callosum and 1 case of holoprosencephaly, were seen in 4 infants (10%). Micrencephaly (brain weight at autopsy more than 2 SDs below the mean for age) was found in 27% of the infants. An immature cortical mantle was seen in 21% of the study group. Seven infants (17%) had specific recognizable patterns of malformation. The absence of dysmorphic physical features did not preclude overt or subtle central nervous system malformations. Conversely, the presence of dysmorphic features did not reliably indicate an underlying brain anomaly. Infants who had hypoplastic left heart syndrome as one of multiple nonneurologic malformations were more likely to have micrencephaly than those infants with hypoplastic left heart syndrome as an isolated abnormality. Occurrence of developmental neuropathology was elevated in those infants with hypoplastic left heart syndrome who did not have a recognizable pattern of malformation but who were small for gestational age, microcephalic, or had ocular abnormalities. Infants with hypoplastic left heart syndrome deserve careful genetic, opthalmologic, and neurologic evaluations, imaging of their intracranial anatomy, and long-term neurologic follow-up.

Neurologic complications of pediatric heart transplantation.

OBJECTIVE: To determine the type and frequency of acquired neurologic complications in survivors of pediatric heart transplantation (HT). DESIGN: Retrospective study. SETTING: Tertiary care children's hospital. PARTICIPANTS: Fourteen survivors of 17 consecutive patients who underwent HT during a 60-month period beginning in January 1986. INTERVENTIONS: None. MEASUREMENTS OR MAIN RESULTS: Three distinct subgroups of patients who had undergone HT were identified: six infants with uncorrected hypoplastic left heart syndrome (HLHS), three infants with HLHS who had undergone previous stage 1 Norwood repair, and eight older children with end-stage cardiomyopathy. Fourteen (82%) of 17 children were alive at follow-up. Only one patient (7%) had a significant acquired neurologic deficit (left temporal lobe stroke with subsequent seizures in an infant with uncorrected HLHS). The remaining subjects had normal results of post-HT neurologic examinations (n = 7), minor post-HT neurologic abnormalities (n = 3), no significant change in preexisting neurologic abnormalities (n = 1), or normal neurologic status by report (n = 2). The minor neurologic abnormalities noted post-HT were dysmetria, tremor, and absent reflexes. No episodes of choreoathetosis or cyclosporine-related seizures were seen. CONCLUSIONS: Pediatric HT is associated with both a high survival rate and a low incidence of severe acquired neurologic deficits despite a significant incidence of severe systemic and metabolic derangements in the pretransplantation and posttransplantation periods. In infants with HLHS, HT seems to carry a lower incidence of severe neurologic morbidity (12%) than other surgical treatments.

Short-term and long-term memory in early temporal lobe dysfunction.

Following medial temporal damage, mature humans are impaired in retaining new information over long delays but not short delays. The question of whether a similar dissociation occurs in children was addressed by testing children (ages 7-16) with unilateral temporal lobe epilepsy (TLE) and controls on short- and long-term memory tasks, including a spatial delayed response task (SDR). Early-onset TLE did not affect performance on short delays on SDR, but it did impair performance at the longest delay (60 s), similar to adults with unilateral medial temporal damage. In addition, early-onset TLE affected performance on pattern recall, spatial span, and verbal span with rehearsal interference. No differences were found on story recall or on a response inhibition task.

Oxcarbazepine in the treatment of epilepsy.

Oxcarbazepine is a new antiepileptic drug (AED) that has been registered in more than 50 countries worldwide since 1990 and recently received approval in the United States and the European Union. Oxcarbazepine is a keto analog of carbamazepine and has a more favorable pharmacokinetic profile. It is rapidly absorbed after oral administration and undergoes rapid and almost complete reductive metabolism to form the pharmacologically active 10-monohydroxy derivative. Oxcarbazepine exhibits linear pharmacokinetics, no autoinduction, and minimal interaction with other AEDs. Ten controlled trials demonstrated that oxcarbazepine is safe and efficacious in the treatment of partial seizures across a wide range of ages (children to adults), situations (recent onset to treatment-resistant epilepsy), and uses (monotherapy and adjunctive therapy). The most common treatment-emergent adverse events are related to the central nervous system. Treatment-emergent hyponatremia (defined as serum sodium level < 125 mEq/L) occurred in 3% of patients treated with oxcarbazepine in clinical trials. According to the efficacy and safety profile established in the controlled trials, oxcarbazepine represents an important new treatment option indicated for monotherapy and adjunctive therapy in adults with partial seizures and as adjunctive therapy in children aged 4 years or older with partial seizures. Although structurally similar to carbamazepine, significant differences exist in the pharmacokinetics, drug interaction potential, adverse-effect profile, and dosage and titration between these two agents, and they should be considered distinct therapeutic agents.

Felbamate in the treatment of acquired epileptic aphasia.

A previously healthy six year old boy developed severe receptive and expressive aphasia, multifocal epileptiform discharges, and refractory clinical seizures consistent with acquired epileptic aphasia. The patient experienced complete seizure control and almost complete return of language skills following the addition of felbamate. This is the first case of successful treatment of acquired epileptic aphasia using felbamate.

Topiramate in the catastrophic epilepsies of childhood.

Several epileptic syndromes that occur during childhood are characterized by severe treatment-resistant seizures, progressive loss of higher intellectual functions, and characteristic electroencephalographic abnormalities. These catastrophic epileptic syndromes include epileptic encephalopathy with diffuse slow spike waves (Lennox-Gastaut syndrome), West syndrome, progressive myoclonic epilepsies, and electrical status epilepticus during sleep. This article summarizes each syndrome and reviews the most recent information concerning the effectiveness of topiramate with respect to each condition. Suggestions are offered to help clinicians maximize topiramate's efficacy and tolerability in patients suffering with these syndromes. Overall, topiramate is a valuable antiepileptic medication in the treatment of catastrophic pediatric epileptic syndromes.

Adequacy of routine EEG examinations in neonates with clinically suspected seizures.

This study identified the clinical and electroencephalographic (EEG) characteristics that distinguished neonates with EEG-confirmed seizures from those without, in order to assess the adequacy of routine short-term EEG examinations in neonates with clinically suspected seizures. Two different subgroups of tracings were analyzed: EEGs performed on therapeutically paralyzed (TP+) neonates and EEGs performed on non-therapeutically paralyzed (TP-) neonates. The rate of electrographic seizures, abnormal EEG background activity, and excessive sharp EEG transients (SETs) was significantly more common in the tracings performed on TP- neonates. In lethargic/comatose TP- neonates with clinically suspected seizures and abnormal EEG background activity, the rate of EEGs with excessive SETs (implying a "lowered seizure threshold") occurred equally in tracings with or without documented electrographic seizures. Consequently, we suspect that routine EEGs may be inadequate to electrographically confirm suspected seizures in some TP- neonates due to a large sampling error. In contrast, routine 40-minute EEGs are probably adequate to seek evidence of electrographic seizure activity in TP+ neonates because their seizure rate is low and most do not display background abnormalities or excessive SETs.

Complications and costs of treatment of refractory generalized convulsive status epilepticus in children.

Multiple case series in the literature suggest that benzodiazepines and barbiturates are highly efficacious at stopping seizures. Apparent differences in mortality might not be due solely to drug effect. In this systematic review of the medical literature, we assessed the complications and costs of treatment of refractory status epilepticus in 111 children who met strict inclusion criteria, as part of an effort to provide an evidenced-based recommendation for optimal therapy. All children treated with barbiturates required mechanical ventilation, versus 13% of patients treated with benzodiazepines. Benzodiazepine treatment was associated with pressor use in 3.5% of cases, versus 35% with barbiturate treatment. Midazolam treatment was for the shortest duration and allowed the most rapid return to consciousness. Differences in mean 24-hour drug costs were small compared to savings produced by shorter length of treatment and return to consciousness. Benzodiazepines appear to have higher drug costs but lower complications and overall costs than barbiturates.

Cushing's ulcer as a consequence of adrenocorticotropic hormone administration for infantile spasms.

Adrenocorticotropic hormone (ACTH) is the treatment of choice for infantile spasms despite its multiple side effects. This case represents a previously unreported side effect, peptic ulceration, occurring during ACTH treatment of infantile spasms. Two pathophysiologic mechanisms are proposed and examined. A direct effect of ACTH on the duodenum is considered but deemed unlikely. Alternatively, the combination of the patient's communicating hydrocephalus and ACTH's central effects is proposed to have led to increased intracranial pressure and a Cushing's ulcer. The need for pretreatment neuroimaging and H2-receptor antagonist use during ACTH therapy in all cases, along with gastrin level measurements in selected cases, is recommended.

Abnormal magnetic resonance images in hemorrhagic shock and encephalopathy syndrome.

Hemorrhagic shock and encephalopathy syndrome is an acute childhood illness that involves the rapid onset of multisystem failure, including central nervous system, renal, cardiovascular, hepatic, and hematologic dysfunction, and often leads to death or serious neurologic damage. We report the first case of a child with hemorrhagic shock and encephalopathy in which magnetic resonance imaging was used to define the cortical hemorrhagic involvement.

Efficacy and mortality in treatment of refractory generalized convulsive status epilepticus in children: a meta-analysis.

There is no consensus on the choice of drug treatment for refractory generalized convulsive status epilepticus in children. The objective of this meta-analysis of the published literature was to determine the effects of drug treatments on efficacy (seizure cessation) and mortality in children with this condition, controlling for potential confounding factors. One hundred eleven children, treated with diazepam, midazolam, thiopental, pentobarbital, or isoflurane, met strict inclusion criteria. Diazepam was significantly less efficacious than other treatments (P = .006) stratifying for etiology. Overall mortality was 20% in symptomatic cases and 4% in idiopathic cases (P = .038). Mortality was less frequent in midazolam-treated patients (P = .021) stratifying for etiology. Midazolam appears to be a good choice for initial treatment of refractory generalized convulsive status epilepticus in children, but the attribution of differences in efficacy and mortality solely to drug effect is not possible based on the published literature.