Quantitative Evaluation of Medial Temporal Lobe Morphology in Children with Febrile Status Epilepticus: Results of the FEBSTAT Study.

BACKGROUND AND PURPOSE: The pathogenesis of febrile status epilepticus is poorly understood, but prior studies have suggested an association with temporal lobe abnormalities, including hippocampal malrotation. We used a quantitative morphometric method to assess the association between temporal lobe morphology and febrile status epilepticus. MATERIALS AND METHODS: Brain MR imaging was performed in children presenting with febrile status epilepticus and control subjects as part of the Consequences of Prolonged Febrile Seizures in Childhood study. Medial temporal lobe morphologic parameters were measured manually, including the distance of the hippocampus from the midline, hippocampal height:width ratio, hippocampal angle, collateral sulcus angle, and width of the temporal horn. RESULTS: Temporal lobe morphologic parameters were correlated with the presence of visual hippocampal malrotation; the strongest association was with left temporal horn width (P < .001; adjusted OR, 10.59). Multiple morphologic parameters correlated with febrile status epilepticus, encompassing both the right and left sides. This association was statistically strongest in the right temporal lobe, whereas hippocampal malrotation was almost exclusively left-sided in this cohort. The association between temporal lobe measurements and febrile status epilepticus persisted when the analysis was restricted to cases with visually normal imaging findings without hippocampal malrotation or other visually apparent abnormalities. CONCLUSIONS: Several component morphologic features of hippocampal malrotation are independently associated with febrile status epilepticus, even when complete hippocampal malrotation is absent. Unexpectedly, this association predominantly involves the right temporal lobe. These findings suggest that a spectrum of bilateral temporal lobe anomalies are associated with febrile status epilepticus in children. Hippocampal malrotation may represent a visually apparent subset of this spectrum.

Balancing clinical benefits of vigabatrin with its associated risk of vision loss.

Vigabatrin is an effective and well-tolerated antiepileptic drug (AED) for the treatment of refractory complex partial seizures (rCPS) and infantile spasms (IS), but its benefits must be evaluated in conjunction with its risk of retinopathy with the development of peripheral visual field defects (pVFDs). Vigabatrin should be considered for rCPS if a patient has failed appropriate trials of other AEDs or is not a suitable candidate for other AEDs, is not an optimal surgical candidate, and continues to experience debilitating effects from seizures. Vigabatrin is indicated as monotherapy for pediatric patients with IS. Its efficacy in achieving improved seizure control should be apparent within 12 weeks in patients with rCPS and within 2-4 weeks after attaining appropriate dosage for patients with IS. Because 12 weeks is well less than the known time of onset of visual defects, the risk of developing pVFDs may be minimized by discontinuing vigabatrin early during the course of therapy for patients with inadequate response. Appropriate vision screening is recommended at baseline, every 3 months during continued vigabatrin treatment, and at 3-6 months after discontinuation (if therapy has spanned more than a few months). If a pVFD is detected at any point and the decision is made to discontinue therapy, the pVFD is not likely to progress after discontinuation of vigabatrin. Although some patients will be at risk of retinopathy, vigabatrin is an appropriate treatment option for patients who achieve substantial clinical benefit, especially given the severe consequences of rCPS and uncontrolled IS. While retinopathy with the development of pVFDs is a serious adverse event, it is not life-threatening and its risk can be effectively managed.

The occurrence and characteristics of auras in a large epilepsy cohort.

OBJECTIVES: Despite several studies, estimates of the frequency with which auras occur in conjunction with epilepsy continue to be imprecise. The aim of this study was to assess the occurrence and characteristics of auras in a large population-based epilepsy cohort. MATERIALS AND METHODS: Subjects with verified epilepsy were recruited from population-based twin registries in the USA, Denmark and Norway. Using a structured interview in which a list of auras was provided, subjects were asked about the warning symptoms preceding their epileptic attacks. RESULTS: 31% of the total sample (n = 1897) and 39% of those with active epilepsy (n = 765) had experienced an aura. Six percent reported more than one type. Non-specified auras were most frequently reported (35%), followed by somatosensory (11%) and vertiginous (11%). While the majority of those reporting auras (59%) had focal epilepsies, auras of a mostly non-specific nature were experienced by 13% of those with generalized epilepsies. CONCLUSION: Auras serve an important purpose in that they may prevent seizure-related injuries and could provide an indication as to where the seizures originate. The occurrence of auras often is underestimated, especially in children and those with learning disabilities.

Phenomenology of prolonged febrile seizures: results of the FEBSTAT study.

BACKGROUND: Febrile status epilepticus (FSE) has been associated with hippocampal injury and subsequent mesial temporal sclerosis and temporal lobe epilepsy. However, little is known about the semiology of FSE. METHODS: A prospective, multicenter study of the consequences of FSE included children, aged 1 month through 5 years, presenting with a febrile seizure lasting 30 minutes or more. Procedures included neurologic history and examination and an MRI and EEG within 72 hours. All information related to seizure semiology was reviewed by three epileptologists blinded to MRI and EEG results and to subsequent outcome. Inter-rater reliability was assessed by the kappa statistic. RESULTS: Among 119 children, the median age was 1.3 years, the mean peak temperature was 103.2 degrees F, and seizures lasted a median of 68.0 minutes. Seizure duration followed a Weibull distribution with a shape parameter of 1.68. Seizures were continuous in 52% and behaviorally intermittent (without recovery in between) in 48%; most were partial (67%) and almost all (99%) were convulsive. In one third of cases, FSE was unrecognized in the emergency department. Of the 119 children, 86% had normal development, 24% had prior febrile seizures, and family history of febrile seizures in a first-degree relative was present in 25%. CONCLUSIONS: Febrile status epilepticus is usually focal and often not well recognized. It occurs in very young children and is usually the first febrile seizure. Seizures are typically very prolonged and the distribution of seizure durations suggests that the longer a seizure continues, the less likely it is to spontaneously stop.

Rapid infusion with valproate sodium is well tolerated in patients with epilepsy.

Many IV antiepileptic drugs administered in emergency situations to patients with prolonged seizures have serious adverse effects. For this reason, the authors conducted a multicenter, open-label, prospective, dose-escalation study of IV valproate sodium administered to patients with epilepsy at rates of infusion of up to 6 mg/kg/minute and doses of up to 30 mg/kg. Valproate sodium had no clinically significant negative effects on blood pressure and pulse rate and caused only mild-to-moderate, reversible adverse events.

Practice parameter: medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society.

OBJECTIVE: To determine the current best practice for treatment of infantile spasms in children. METHODS: Database searches of MEDLINE from 1966 and EMBASE from 1980 and searches of reference lists of retrieved articles were performed. Inclusion criteria were the documented presence of infantile spasms and hypsarrhythmia. Outcome measures included complete cessation of spasms, resolution of hypsarrhythmia, relapse rate, developmental outcome, and presence or absence of epilepsy or an epileptiform EEG. One hundred fifty-nine articles were selected for detailed review. Recommendations were based on a four-tiered classification scheme. RESULTS: Adrenocorticotropic hormone (ACTH) is probably effective for the short-term treatment of infantile spasms, but there is insufficient evidence to recommend the optimum dosage and duration of treatment. There is insufficient evidence to determine whether oral corticosteroids are effective. Vigabatrin is possibly effective for the short-term treatment of infantile spasm and is possibly also effective for children with tuberous sclerosis. Concerns about retinal toxicity suggest that serial ophthalmologic screening is required in patients on vigabatrin; however, the data are insufficient to make recommendations regarding the frequency or type of screening. There is insufficient evidence to recommend any other treatment of infantile spasms. There is insufficient evidence to conclude that successful treatment of infantile spasms improves the long-term prognosis. CONCLUSIONS: ACTH is probably an effective agent in the short-term treatment of infantile spasms. Vigabatrin is possibly effective.

A double-blind, placebo-controlled study of remacemide hydrochloride in patients with refractory epilepsy following pre-surgical assessment.

This multicentre, randomised, double-blind, placebo-controlled, parallel-group study investigated the efficacy, safety and pharmacokinetics of remacemide hydrochloride in adult patients ( n= 59) with refractory epilepsy, undergoing reduced or discontinued antiepileptic drug (AED) usage, as part of an evaluation for epilepsy surgery. On discontinuation or reduction of maintenance AEDs, patients received remacemide hydrochloride, up to 600 mg daily, or placebo, for up to ten days or until they experienced a fourth complex partial (CPS) or a generalised tonic-clonic (GTC) seizure. Pre- and post-study blood and urine samples were taken for analysis. Remacemide hydrochloride showed a significantly ( P= 0.045) longer median time to fourth seizure compared with placebo (6.8 vs. 3.8 days). Median nine-day seizure counts were significantly ( P= 0.0327) lower with remacemide hydrochloride than placebo (6.2 vs. 12.8). Eleven remacemide hydrochloride patients and six placebo patients completed ten days' treatment. Remacemide and desglycinyl metabolite levels were lower in patients receiving concomitant carbamazepine or phenytoin than in those receiving non-inducing AEDs or remacemide hydrochloride alone. No serious adverse events occurred; all patients receiving remacemide hydrochloride completed the study. Remacemide hydrochloride was well tolerated and showed significant therapeutic activity in this patient population.

Tiagabine (gabitril) experience in children.

Tiagabine (TGB) is indicated as adjunctive therapy for partial seizures in adults and children aged 12 years and older. Double-blind, placebo-controlled studies of TGB treatment are under way in younger children with various forms of epilepsy. The results of pediatric pharmacokinetic trials indicate patterns similar to those seen in adults. An open-label study was conducted in the United States in 31 children with refractory complex partial seizures, with doses escalated every 2 weeks by 0.25 mg/kg up to a maximal daily dose of 1 mg/kg. Twenty-nine patients were treated with TGB for >1 year; 26 completed the study, of whom 18 were receiving monotherapy at study completion. A European dose-escalation study evaluated TGB (0.25-1.5 mg/kg/day) as add-on therapy in 52 children aged 2-15 years. TGB appeared to be more effective in localization-related epilepsy syndromes, with 17 of 23 patients with localization-related epilepsy having a 33% median reduction of seizure rate compared with baseline in the fourth month of treatment, and six patients having > or =50% seizure rate reduction. In this study, myoclonic seizures and spasms showed a poor response as opposed to encouraging findings reported by other groups with these seizure types. The adverse effect profile of TGB in children with epilepsy is similar to that in adults. In the U.S. study, most common adverse events were related to the central nervous system (CNS) and decreased over time. In the European study, mostly mild to moderate adverse events, including asthenia (19%), nervousness (19%), dizziness (17%), and somnolence (17%), were reported by 83% of TGB-treated children (39% of children reported adverse events during the single-blind placebo period). In summary, preliminary pediatric data with TGB suggest particular efficacy against epilepsy characterized by partial seizures or other syndromes, and further investigation is warranted.

Utility of electroencephalography in the pediatric emergency department.

To assess the role of electroencephalography (EEG) in the pediatric emergency department, we reviewed the records of all patients having an EEG in the pediatric emergency department of our hospital between 1995 and 1997. EEG findings, clinical presentations, and follow-up data were analyzed, and patients were distributed into three groups according to clinical presentation: group 1 included patients with new-onset seizures, group 2 included patients with known epilepsy presenting with worsening seizures and altered mentation, and group 3 comprised patients with acute confusional states. Overall, 56 patients with 57 EEGs were included. In group 1 (n = 36), 20 (55.6%) had an abnormal EEG. The risk of recurrence was much higher in children with abnormal EEGs (80% vs. 31%) (P < .01). In retrospect, among all of the patients receiving the diagnosis of epilepsy, 76% had an abnormal emergency department EEG. Four in group 2 (n = 14) and one in group 3 (n = 7) were proven to have nonconvulsive status epilepticus and were treated accordingly. No patients in group 1 had nonconvulsive status epilepticus. Ongoing seizures were promptly excluded in the remainder. The EEG directly contributed to the diagnosis in 84% of all referrals in the pediatric emergency department, either being abnormal and leading to a diagnosis of a seizure disorder or confirming low suspicion for seizures. Thus, a prompt EEG should be considered in children with new-onset seizures and unexplained altered consciousness.

Short-term outcomes of children with febrile status epilepticus.

Febrile status epilepticus (SE) represents the extreme end of the complex febrile seizure spectrum. If there are significant sequelae to febrile seizures, they should be more common in this group. We have prospectively identified 180 children aged 1 month to 10 years who presented with febrile SE over a 10-year period in Bronx, New York, and Richmond, Virginia. They were compared with 244 children who presented with their first febrile seizure (not SE) in a prospective study done in the Bronx. The mean age of the children with febrile SE was 1.92 years, and of the comparison group, 1.85 years. Duration of SE was 30-59 min in 103 (58%), 60-119 min in 43 (24%), and > or =120 min in 34 (18%). Focal features were present in 64 (35%) of cases. There were no deaths and no cases of new cognitive or motor handicap. Children with febrile SE were more likely to be neurologically abnormal (20% vs. 5%; p < 0.001), to have a history of neonatal seizures (3% vs. 0; p = 0.006) and a family history of epilepsy (11% vs. 5%; p = 0.05) and less likely to have a family history of febrile seizures (15% vs. 27%; p = 0.01) than were children in the comparison group. The short-term morbidity and mortality of febrile SE are low. There are differences in the types of children who have febrile SE compared with those who experience briefer febrile seizures. Long-term follow-up of this cohort may provide insight into the relationship of prolonged febrile seizures and subsequent mesial temporal sclerosis.

Pharmacokinetic study of levetiracetam in children.

PURPOSE: The pharmacokinetics of the novel antiepileptic drug (AED) levetiracetam and its major metabolite, ucb L057, were studied in children with partial seizures in a multicenter, open-label, single-dose study. METHODS: Twenty-four children (15 boys, nine girls), 6 to 12 years old, received a single dose of levetiracetam (20 mg/kg) as an adjunct to their stable regimen of a single concomitant AED, followed by a 24-h pharmacokinetic evaluation. RESULTS: In children, the half-lives of levetiracetam and its metabolite ucb L057 were 6.0 +/- 1.1 and 8.1 +/-2.7 hours, respectively. The Cmax and area under the curve (AUC) of levetiracetam equated for a 1-mg/kg dose were lower in children (Cmax, norm=1.33 plus minus 0.35 microg/ml; AUCnorm=12.4 +/- 3.5 microg/h/ml) than in adults (Cmax, norm=1.38 +/- 0.05 microg/ml; AUCnorm=11.48 +/- 0.63 microg/h/ml), whereas the renal clearance was higher. The apparent body clearance (1.43 +/- 0.36 ml/min/kg) was approximately 30-40% higher in children than in adults. Levetiracetam was generally well tolerated. CONCLUSIONS: On the basis of these data, a daily maintenance dose equivalent to 130-140% of the usual daily adult maintenance dosage (1,000-3,000 mg/day) in two divided doses, on a weight-normalized level (mg/kg/day) is initially recommended. Clinical efficacy trials in children are ongoing with dosages of 20 to 60 mg/kg/day.

Treatment of epilepsy in the multiply handicapped.

The medical management of epilepsy in the multi-handicapped patient requires careful evaluation, classification, and pharmacologic treatment. It is estimated that 20-40% of patients with mental retardation and cerebral palsy have epilepsy. This review reports the clinical trial data and personal experience related to the use of newer AEDs in the chronic management of epilepsy syndromes in children and adults, as well as information available on the treatment of seizures in individuals with mental retardation and associated handicaps. Furthermore, clusters of seizures, prolonged seizures and status epilepticus are more commonly seen in the multiply handicapped and mentally retarded population and require special attention. The new antiepileptic drugs felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide show specific advantage in some multiply handicapped patients, be it for seizure control or medication tolerance. Furthermore, new modalities of treatment for prolonged seizures allow better efficacy both outside of hospital and within hospital facilities. The treatment of epilepsy in multi-handicapped and retarded adults and children has significantly advanced in the past few years, and much of this improvement can be attributed to improved knowledge and monitoring of new antiepileptic drugs. Conventional anticonvulsants remain first line therapy for most clinicians, but newer AEDs must broaden the therapeutic option and do allow improved therapy for some multiply handicapped patients.

Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, add-on trial.

This is a multicenter, open-label, add-on trial, investigating the safety and efficacy of ganaxolone (GNX) in a population of children with refractory infantile spasms, or with continuing seizures after a prior history of infantile spasms. A total of 20 children aged 7 months to 7 years were enrolled in this dose-escalation study, after baseline seizure frequencies were established. Concomitant antiepilepsy drugs were maintained throughout the study period. The dose of GNX was progressively increased to 36 mg/kg/d (or to the maximally tolerated dose) over a period of 4 weeks, then maintained for 8 weeks before tapering and discontinuation. Seizure diaries were maintained by the families, and spasm frequency was compared with the baseline period. The occurrence of adverse events was clinically monitored, and global evaluations of seizure severity and response to treatment were obtained. A total of 16 of the 20 subjects completed the study, 15 of whom had refractory infantile spasms at the time of study enrollment. Spasm frequency was reduced by at least 50% in 33% of these subjects, with an additional 33% experiencing some improvement (25-50% reduction in spasm frequency). Ganaxolone was well tolerated, and adverse events attributed to GNX were generally mild. Ganaxolone was safe and effective in treating this group of refractory infantile spasms patients in an open-label, add-on trial. Further investigation with randomized, controlled study design is warranted.

Treatment of epilepsy in the new millennium.

Treatment options for epilepsy have increased markedly since 1990, when only carbamazepine, phenytoin, phenobarbital, primidone, and valproate were used commonly for partial and secondarily generalized seizures. Those with primary generalized seizures received ethosuximide or valproate. Over the past decade, however, additional agents have been introduced, with the promise of improved seizure control and minimal side effects. The new antiepileptic drugs (AEDs)-felbamate, gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin and oxcarbazepine-have demonstrated superior efficacy for some with refractory epilepsy. In addition, the new agents frequently are better tolerated when used as monotherapy or adjunctive therapy. The optimal place for the new AED will require additional studies and careful postmarketing surveillance and assessments. Although these AEDs offer benefits, not all patients with epilepsy have responded. Thus, the search for new AEDs continues.

Overview of childhood epilepsy and epileptic syndromes and advances in therapy.

Seizures have a variety of etiologies and manifestations. Descriptions of various epiletic seizures as well as electroencephalographic findings have led to a unifying international classification of epileptic seizures and epilepsy syndromes. The development of this classification system and the emergence of several new antiepiletic drugs have led to progress in the refractory pediatric patient particularly disorders which are traditionally difficult to treat such as infantile spasms and the Lennox-Gastaut Syndrome. However, there is limited data regarding optimal use in children. The childhood epilepsy syndromes are reviewed as well as the newer antiepileptic drug treatments - felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide. Efficacy data and toxicity are discussed from both the adult, and when available, pediatric data.