Language lateralization represented by spatiotemporal mapping of magnetoencephalography.

BACKGROUND AND PURPOSE: Determination of hemispheric language dominance is critical for planning epilepsy surgery. We assess the usefulness of spatiotemporal source analysis of magnetoencephalography for determining language laterality. MATERIALS AND METHODS: Thirty-five patients with epilepsy were studied. The patients performed a semantic word-processing task during MEG recording. Epochs containing language-related neuromagnetic activity were averaged after preprocessing. The averaged data between 250 and 550 ms after stimulus were analyzed by using dynamic statistical parametric mapping. ROIs were obtained in the opercular and triangular parts of the inferior frontal gyrus, superior temporal gyrus, and supramarginal gyrus in both hemispheres. We calculated laterality indices according to 1) dSPM-amplitude method, based on the amplitude of activation in the ROIs, and 2) dSPM-counting method, based on the number of unit dipoles with activation over a threshold in the ROIs. The threshold was determined as half of the maximum value in all ROIs for each patient. A LI ≥0.10 or ≤-0.10 was considered left- or right-hemisphere dominance, respectively; a LI between -0.10 and 0.10 was considered bilateral. All patients underwent an intracarotid amobarbital procedure as part of presurgical evaluation. RESULTS: The dSPM-counting method demonstrated laterality consistent with the IAP in 32 of 35 patients (91.4%), the remaining 3 (8.6%) demonstrated bilateral language representation, whereas the dSPM-amplitude method showed 18 (51.4%) concordant and 17 (48.6%) bilateral. No laterality opposite to the IAP was found. CONCLUSIONS: Spatiotemporal mapping of language lateralization with the dSPM-counting method may reduce the necessity for an IAP in as many as 90% of patients.

Rufinamide for the treatment of epileptic spasms.

OBJECTIVE: The purpose of this study was to determine the safety and efficacy of rufinamide for treatment of epileptic spasms. METHODS: We retrospectively reviewed patients treated with rufinamide for epileptic spasms from January 2009 to March 2010. Age, presence of hypsarrhythmia, change in seizure frequency following rufinamide initiation, and side effects were assessed. Patients who had a ≥ 50% reduction in spasm frequency were considered responders. RESULTS: Of all 107 children treated with rufinamide during the study period, 38 (36%) had epileptic spasms. Median patient age was 7 years (range: 17 months to 23). One patient had hypsarrhythmia at the time of treatment with rufinamide, and 9 other patients had a history of hypsarrhythmia. Median starting dose of rufinamide was 9 mg/kg/day (range: 2-18) and median final treatment dose was 39 mg/kg/day (range: 8-92). All patients were receiving concurrent antiepileptic drug therapy, with the median number of antiepileptic drugs being 3 (range: 2-6). Median duration of follow-up since starting rufinamide was 171 days (range: 10-408). Responder rate was 53%. Median reduction in spasm frequency was 50% (interquartile range=-56 to 85%, P<0.05). Two patients (5%) achieved a >99% reduction in spasms. Rufinamide was discontinued in 7 of 38 patients (18%) because of lack of efficacy, worsening seizures, or other side effects. Minor side effects were reported in 14 of 38 patients (37%). CONCLUSIONS: Rufinamide appears to be a well-tolerated and efficacious adjunctive therapeutic option for children with epileptic spasms. A prospective study is warranted to validate our observations.

Higher evening antiepileptic drug dose for nocturnal and early-morning seizures.

We describe 17 children with nocturnal or early-morning seizures who were switched to a proportionally higher evening dose of antiepileptic drugs and were retrospectively reviewed for seizure outcome and side effects. Of 10 children with unknown etiology, clinical presentation was consistent with nocturnal frontal lobe epilepsy (NFLE) in 5 and benign epilepsy with centrotemporal spikes (BECTS) in 3. After a mean follow-up of 5.3 months, 15 patients were classified as responders; 11 of these became seizure free (5 NFLE, 1 BECTS, 5 with structural lesions) and 4 (2 BECTS, 2 with structural lesions) experienced 75-90% reductions in seizures. Among two nonresponders, seizures in one had failed to resolve with epilepsy surgery. Nine subjects (53%) received monotherapy after dose modification, and none presented with worsening of seizures. Two complained of transient side effects (fatigue/somnolence). Differential dosing led to seizure freedom in 64.7% (11/17) of patients, and 88.2% (15/17) experienced ≥ 50% reductions in seizures.

Magnetoencephalographic mapping of interictal spike propagation: a technical and clinical report.

Distinguishing propagated epileptic activity from primary epileptic foci is of critical importance in presurgical evaluation of patients with medically intractable focal epilepsy. We studied an 11-year-old patient with complex partial epilepsy by using simultaneous magnetoencephalography (MEG) and electroencephalography (EEG). In EEG, bilateral interictal discharges appeared synchronous, whereas MEG source analysis suggested propagation of spikes from the right to the left frontal lobe.

The value of multichannel MEG and EEG in the presurgical evaluation of 70 epilepsy patients.

OBJECTIVE: To evaluate the sensitivity of a simultaneous whole-head 306-channel magnetoencephalography (MEG)/70-electrode EEG recording to detect interictal epileptiform activity (IED) in a prospective, consecutive cohort of patients with medically refractory epilepsy that were considered candidates for epilepsy surgery. METHODS: Seventy patients were prospectively evaluated by simultaneously recorded MEG/EEG. All patients were surgical candidates or were considered for invasive EEG monitoring and had undergone an extensive presurgical evaluation at a tertiary epilepsy center. MEG and EEG raw traces were analysed individually by two independent reviewers. RESULTS: MEG data could not be evaluated due to excessive magnetic artefacts in three patients (4%). In the remaining 67 patients, the overall sensitivity to detect IED was 72% (48/67 patients) for MEG and 61% for EEG (41/67 patients) analysing the raw data. In 13% (9/67 patients), MEG-only IED were recorded, whereas in 3% (2/67 patients) EEG-only IED were recorded. The combined sensitivity was 75% (50/67 patients). CONCLUSION: Three hundred and six-channel MEG has a similarly high sensitivity to record IED as EEG and appears to be complementary. In one-third of the EEG-negative patients, MEG can be expected to record IED, especially in the case of lateral neocortical epilepsy and/or cortical dysplasia.

Topiramate and metabolic acidosis in pediatric epilepsy.

PURPOSE: Topiramate (TPM) has been widely used as an adjunctive therapy for treating epilepsy. TPM is reported to have multiple mechanisms of action, including inhibition of carbonic anhydrase, which may result in metabolic acidosis from decreased serum bicarbonate (HCO3-). METHODS: Clinical data from 30 children who received TPM as adjunctive therapy for medically refractory epilepsy were reviewed at Children's Hospital, Boston. Serum HCO3- levels were assessed before, during, and after discontinuing TPM (n = 9). When multiple data were available, mean values were used for analysis. RESULTS: Of the 30 patients, 21 had a >10% decrease in HCO3- levels. The mean decrease in HCO3- among the 21 patients was 4.7 mEq/L, and maximum was 10 mEq/L. No clinical symptoms occurred, and HCO3- supplement was not needed, except for one patient who developed tachypnea from worsened acidosis after prolonged status epilepticus during a suspected viral illness. Among the 21 patients, TPM was discontinued in seven children because of a lack of efficacy, and in two because of anorexia. After discontinuing TPM, the serum HCO3- returned to the previous level before starting TPM in all nine. CONCLUSIONS: Decreased HCO3- levels occurred in the majority of patients reviewed, usually only to a small to moderate extent, but by 8 and 10 mEq/L in two cases. In patients at risk for acidosis, the decrease in HCO3- may cause significant consequences, such as severe acidosis or renal calculi. Monitoring HCO3- levels before and during TPM therapy may be indicated, especially with conditions that predispose to acidosis.

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.

Transparahippocampal selective amygdalohippocampectomy in children and adolescents: efficacy of the procedure and cognitive morbidity in patients.

OBJECT: Unilateral resection of the hippocampus and amygdala can be used to treat medically intractable mesial temporal lobe seizures. To date seizure outcome and the extent of cognitive morbidity have been unknown in children following the transparahippocampal variation of selective amygdalohippocampectomy (TSA), which prompted the present prospective study. METHODS: Preoperative examinations and outcomes in 22 consecutive children and adolescents who underwent TSA were studied. Cognitive and psychological morbidity were assessed using standard neuropsychological instruments. The authors evaluated relationships between seizure control and cognitive morbidity and 13 and nine clinical variables, respectively. Seizure control was achieved in 11 (65%) of 17 patients (>2 years follow up). Among 13 clinical variables, the only preoperative finding that had a significant bearing on seizure control was the presence of unilateral hypometabolism, which could be observed on [18F]fluorodeoxyglucose-positron emission tomography scans (p<0.001). Patients with seizure control showed significant improvements in verbal and full scale intelligence quotients (both p = 0.05). Patients with longer preoperative durations of seizures exhibited more cognitive impairment that persisted postoperatively. Cognitive outcome analysis based on nine clinical factors revealed no significant difference in cognitive parameters postoperatively, except that significant improvement occurred in rote verbal memory scores among patients who underwent right-sided TSA (p = 0.01). Individually, 81% of the children achieved significant improvement in at least one of seven cognitive parameters, and 52% had stable or improved scores in all parameters. CONCLUSIONS: The results indicate that TSA is a safe effective approach for the treatment of medically intractable mesial temporal lobe seizures in children with minimum effect on cognitive morbidity. Given that the literature suggests that children suffer progressive cognitive morbidity from persistent seizures, the results of this study support early surgical intervention for this group of children.

New antiepileptic drugs in children: which ones for which seizures?

Until 1993, carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), and valproate (VPA) accounted for the great majority of the prescriptions written for the treatment of epilepsy. Since 1993, five antiepileptic drugs (AEDs) have been released in the United States, and at least three additional drugs are expected to be released by the end of the year 2000. As a group, these newer drugs differ from the established drugs in terms of their pharmacokinetics, interaction potential, and adverse effects. In addition, any one of the newer drugs may achieve seizure control in situations in which an established drug had not. The newer drugs certainly represent a welcome addition to the existing options for the treatment of epilepsy in children. However, the availability of several new AEDs represents a therapeutic dilemma for the clinician because optimal use of these drugs has not yet been established. This is particularly true in children because (i) newer drugs are often studied less frequently in children, (ii) pharmacokinetics in children differ from those in adults, (iii) children may have different adverse effects, and (iv) children have a broader spectrum of various seizure types and epilepsy syndromes. In the first part of this review, the clinical pharmacology of the currently available newer AEDs is discussed individually, with special emphasis on data in children. In particular, pharmacokinetics, interactions, dosage and titration, efficacy spectrum, and adverse effect profile is discussed for each drug. In the second part, an attempt is made to determine the place for the newer drugs in the treatment of the different pediatric seizures and epilepsy syndromes.

Pharmacokinetic properties of current antiepileptic drugs: what improvements are needed?

The pharmacokinetics of antiepileptic drugs (AEDs) largely determine their ability to achieve and maintain concentrations that maximize their efficacy and safety. The term "pharmacokinetics" encompasses the quantitative assessment of changes of drug concentrations over time as a function of absorption, distribution, and elimination. Interaction among AEDs, and between AEDs and other classes of drugs, can result in undesirable drug levels. The pharmacokinetic properties of AEDs considered to be clinically most relevant include complete or constant bioavailability, availability of a parenteral formulation, elimination half-life or preparation suitable for once- or twice-daily dosing, linear elimination kinetics, no autoinduction of enzymatic biotransformation, and lack of pharmacokinetic interactions with other drugs. Both established AEDs (carbamazepine, phenytoin, valproate, phenobarbital, and primidone) and newer AEDs (oxcarbazepine, felbamate, gabapentin, lamotrigine, topiramate, tiagabine) are evaluated in terms of these properties. None of the currently marketed AEDs combines all of these desirable pharmacokinetic characteristics. However some of the newer AEDs have more favorable pharmacokinetic profiles. The main improvements needed are limited or no pharmacokinetic interactions, preparations suitable for once- or twice-daily administration, and availability of parenteral formulations.

Pharmacokinetics and pharmacodynamics of topiramate.

In the treatment of children with epilepsy, the role of topiramate has been expanding gradually. The main factor that has contributed to this trend is the relatively large body of information that has accumulated on the clinical pharmacology of topiramate in children, including its broad-spectrum efficacy, pediatric pharmacokinetics, side-effect profile, and safety. It has also become increasingly apparent with time that topiramate, in contrast to other broad-spectrum antiepileptic drugs used in children, does not seem to be associated with a significant risk of any serious or life-threatening adverse effects. The present review summarizes the available evidence related to the clinical pharmacology of topiramate in children and provides an update on its known mechanisms of action. Finally, available experimental data on the neuroprotective effect of topiramate are reviewed because of their considerable clinical potential in the treatment of children and newborns.

A retarded boy with seizures precipitated by stepping into the bath water.

This report describes the unusual case of a boy with partial deletion in the proximal region of a long arm of chromosome 2 and reflex epilepsy. Seizures with identical onset were precipitated predictably by two independent triggers, micturition and immersion of the feet in tepid or hot water. A seizure precipitated by immersion could be reproduced under video and EEG monitoring. The EEG seizure onset was in the central midline region.

Pharmacokinetics and metabolism of topiramate.

The pharmacokinetics and pharmacokinetic interactions of topiramate (TPM) in humans have been studied quite extensively. The available information on TPM pharmacokinetics is derived from studies that were specifically designed for this purpose. In contrast to most conventional antiepileptic drugs, the pharmacokinetic profile of TPM combines most of the properties that are desirable for an antiepileptic drug. Topiramate is rapidly absorbed, with a high bioavailability that is not affected by concomitant food intake. The volume of distribution is 0.6-0.8 l/kg, suggesting distribution into total body water. The binding of TPM to serum proteins is low, which precludes the displacement interactions that are seen between highly bound drugs such as valproate and phenytoin. The elimination kinetics of TPM are strictly linear and, accordingly, there is a linear relationship between maintenance dose and steady-state plasma levels. Topiramate is excreted predominantly by the kidneys as unmetabolized drug. This is generally associated with lower interpatient variability in elimination kinetics. Approximately 20% of orally administered TPM is metabolized in the liver and this fraction may increase up to 50% in the presence of enzyme-inducing drugs, such as phenytoin or carbamazepine. During chronic ingestion of TPM, there is no clinically significant accumulation of any active metabolite, even in patients taking enzyme-inducing drugs. The elimination half-life of TPM is relatively long and does not require more frequent than twice-daily dosing. Finally, TPM has a relatively low potential for drug interactions. The clinically significant pharmacokinetic interactions between TPM and other antiepileptic drugs are limited to an increase in the clearance of TPM when inducing drugs such as phenytoin or carbamazepine are added. TPM has little or no effect on the pharmacokinetics of other antiepileptic drugs, but it can increase the clearance of the estrogenic component of oral contraceptives by up to 30%.

Antiepileptic drugs, learning, and behavior in childhood epilepsy.

Cognitive and behavioral impairments are found more often among epileptic children than among their peers. The cause of these impairments is multifactorial. Identifying the relative contribution of antiepileptic drugs (AEDs) to these problems has been the object of a large number of clinical investigations. This area of research has been characterized by an unusually high number of methodological challenges and pitfalls. Accordingly, results have often been inconsistent and contradictory, except for the more obvious observations that can be derived from clinical experience. Overall, the effects of AEDs on cognition and behavior in children have been overrated in the past. More recent research has benefited from the methodological lessons of previous studies and it suggests that the majority of children taking AEDs do not experience clinically relevant cognitive of behavioral adverse effects from these medications. In addition, some of the newer AEDs may indeed have a better cognitive profile. Nevertheless, clinical experience must be used to identify the subgroup of children who remain at risk for significant and clinically relevant cognitive and behavioral adverse effects of AEDs.

New antiepileptic drugs.

The current developments in the availability of new antiepileptic drugs (AEDs) are unprecedented. After a period of many years during which no new AED became available, 5 new AEDs were introduced in the United States between 1993 and 1997, and 2 more are expected to be approved soon. These new drugs are a most welcome addition to the therapeutic options in the treatment of epilepsy, but they also create a dilemma for the clinician because their individual places and their optimal use in the treatment of various forms of epilepsy are yet to be determined. This review serves to summarize the main characteristics of the newer AEDs.

Temporal lobe epilepsy in infants and children.

Temporal lobe epilepsy in adults and adolescents is a fairly homogeneous syndrome, both in terms of seizure semiology and in terms of its pathology, and it has been studied extensively. Temporal lobe epilepsy in infants and young children has begun to receive increasing attention in recent years, and a different clinico-pathological picture has emerged. Clinically, the concept of complex partial seizures, which may be useful in adults, is difficult to apply to infants, since it is often not possible to assess impairment of consciousness in this age group. The main distinctive features of complex partial seizures of temporal lobe origin in infants are (1) a predominance of behavioral arrest with possible impairment of consciousness, (2) no identifiable aura, (3) automatisms that are discrete and mostly orofacial, (4) more prominent convulsive activity, and (5) a longer duration (more than 1 min). In addition, seizures of temporal lobe origin in infants may appear clinically generalized, such as infantile spasms or generalized tonic seizures, or can occasionally represent a benign syndrome. The neuropathological findings of temporal lobe epilepsy in infants differ even more than the clinical seizure semiology. In contrast to adult and adolescent patients, mesial temporal sclerosis is a rare finding in infants, in whom the pathological abnormalities associated with seizures of temporal lobe origin consist mostly of dysplasias, migrational disorders, hamartomas, and low-grade tumors such as gangliogliomas. Mesial temporal sclerosis is seen more often in older children than in infants, and its pathogenesis remains a subject of controversy.

Rapid switchover to carbamazepine using pharmacokinetic parameters.

PURPOSE: The standard practice of switching patients to carbamazepine (CBZ) involves initiating a low dose and raising it by small increments until the desired dose is reached, to avoid intolerable adverse effects (AE). In a pilot study, a protocol using single-dose kinetic studies was developed to switch patients to CBZ through rapid-dose increments and to manage concurrent rapid taper of the previous antiepileptic drugs (AEDs) without causing AE. The purpose of this prospective study was (a) to reassess whether a rapid switchover to CBZ could be done with minimal or no AE and without causing an increase in seizures; (b) to determine whether the maintenance dose of CBZ predicted at the time of the single-dose kinetic study can yield the desired concentration at steady state (Css); and (c) to determine the degree to which the calculated maintenance dose of CBZ will need to be adjusted after the previous AED has been discontinued for a four-week period. METHODS: Twenty-five patients taking phenytoin (PHT) and/ or phenobarbital (PB) and/or primidone (PRM) underwent a rapid switchover to CBZ following a 10 mg/kg single-dose kinetic study (day 1) which allowed calculation of a maintenance dose necessary to yield a mean Css of 10.2 (+/-2.2) mg/l. On day 2, patients received a CBZ dose equivalent to 10 mg/kg + 200 mg; thereafter, they underwent daily dose increments of 200 mg until the calculated maintenance dose was reached. Dose increments were modified in the case of AE. Concurrent tapering of the previous AED was started as of day 1: PHT by 100 mg/day, while PB and PRM were stopped on day 1; PB was restarted before patients were to be discharged from the hospital if a PB serum concentration above 10 mg/l was identified at that time. Pharmacokinetic data and occurrence of AE were compared between the two groups at the time of the single-dose kinetic study, at the completion of the switchover to CBZ, and 4 weeks after discontinuation of the previous AED. RESULTS: All patients completed the switchover to CBZ within a mean time period of 6 days (+/-2), reaching a mean maintenance dose of 1,639 mg/day (+/-370) which yielded a mean Css of 11.3 (+/-3.2) mg/l. The maintenance dose had to be lowered by 20.4% (+/-8.3) in 59% of patients within the four-week period following discontinuation of at least one of the previous AEDs. None of the patients experienced an increase in seizure frequency relative to baseline. Fifteen (60%) patients had no AE; five (20%) experienced AE of mild severity. AE rated as moderately severe (n = 4) or severe (n = 1) occurred in patients with a static encephalopathy (p = 0.02, Fisher's exact test) and among patients > or =55 years (p = 0.017, Fisher's exact test). CONCLUSIONS: A rapid switch-over to CBZ from PHT, PB, or PRM can be carried out safely with no, or minimal, AE in young adults, unless they suffer from static encephalopathy.

Felbamate.

The development and release of felbamate is characterized by several relatively unique features. Felbamate was submitted to innovative and unconventional clinical trials. It was the first antiepileptic drug (AED) to be tested in a double-blind fashion in patients withdrawn from AEDs for presurgical video/electroencephalogram (EEG) monitoring. In addition, felbamate was the first AED to be tested in double-blind monotherapy trials. Felbamate was also the first drug to be tested in a placebo-controlled trial in children with the Lennox-Gastaut syndrome. When it was first released in North America in 1993, felbamate was the first new antiepileptic drug in 15 years. Finally, after 1 year of being very successfully marked as a drug devoid of the adverse effects of other AEDs, felbamate came very close to being completely withdrawn from the market, because of several cases of fatal bone marrow aplesia and liver toxicity. At the present time, the main indication for felbamate is in children with Lennox-Gastaut syndrome, and similar forms of epilepsy, who failed to respond to other AEDs.

New antiepileptic drugs.

For many years, the medical treatment of epilepsy was based on the use of the same few drugs, which were chosen according to the seizure type in a fairly standardized manner. In the recent past, there have been several changes, and more are expected in the near future. Since 1993, three new antiepileptic drugs have been released in the United States, and two more are expected to be released before the end of 1997. Because the full spectrum of efficacy and side effects of these drugs has not yet been established, the present management of epilepsy requires a larger degree of flexibility, and it is necessary to become acquainted with the new drugs and to follow closely new reports on the experience with new drugs. This is particularly true for the management of epilepsy in children, because controlled studies in children tend to be completed later than those in adults and antiepileptic drug use in children is often "off label." The present review of newer antiepileptic drug consists of a brief summary of background information on each drug, followed by a closer analysis of recently published papers. Information on pediatric use is reviewed, when available. The new antiepileptic drugs selected for discussion are gabapentin, lamotrigine, felbamate, vigabatrin, and topiramate.