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Objective: To update the 2004 American Academy of Neurology (AAN) guideline for treating new-onset focal or generalized epilepsy (GE) with second- and third-generation antiepileptic drugs (AEDs). Methods: The 2004 AAN criteria was used to systematically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. Results: Several second-generation AEDs are effective for new-onset focal epilepsy. Data are lacking on efficacy in new-onset generalized tonic–clonic seizures, juvenile myoclonic epilepsy, or juvenile absence epilepsy, and on efficacy of third-generation AEDs in new-onset epilepsy. Recommendations: Lamotrigine (LTG) should (Level B) and levetiracetam (LEV) and zonisamide (ZNS) may (Level C) be considered in decreasing seizure frequency in adults with new-onset focal epilepsy. LTG should (Level B) and gabapentin (GBP) may (Level C) be considered in decreasing seizure frequency in patients ≥60 years with new-onset focal epilepsy. Unless there are compelling adverse-effect–related concerns, ethosuximide (ETS) or valproic acid (VPA) should be considered before LTG to decrease seizure frequency in treating absence seizures in childhood absence epilepsy (Level B). No high-quality studies suggest clobazam, eslicarbazepine, ezogabine, felbamate, GBP, lacosamide, LEV, LTG, oxcarbazepine, perampanel, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, or ZNS is effective in treating new-onset epilepsy because no high-quality studies exist in adults of various ages. A recent FDA strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years old and perampanel as monotherapy received FDA approval.

Objective: To update the 2004 American Academy of Neurology (AAN) guideline for managing treatment-resistant (TR) epilepsy with second- and third-generation antiepileptic drugs (AEDs). Methods: 2004 criteria were used to systematically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. Results: Forty-two articles were included. Recommendations: The following are established as effective to reduce seizure frequency (Level A): immediate-release pregabalin and perampanel for TR adult focal epilepsy (TRAFE); vigabatrin for TRAFE (not first-line treatment; rufinamide for Lennox–Gastuat syndrome (LGS) (add-on therapy). The following should be considered to decrease seizure frequency (Level B): lacosamide, eslicarbazepine, and extended-release topiramate for TRAFE (ezogabine production discontinued); immediate- and extended-release lamotrigine for generalized epilepsy with TR generalized tonic–clonic (GTC) seizures in adults; levetiracetam (add-on therapy) for TR childhood focal epilepsy (TRCFE) (1 month to 16 years), TR GTC seizures, and TR juvenile myoclonic epilepsy; clobazam for LGS (add-on therapy); zonisamide for TRCFE (6–17 years); oxcarbazepine for TRCFE (1 month to 4 years). The text presents Level C recommendations. AED selection depends on seizure/syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. This evidence-based assessment informs AED prescription guidelines for TR epilepsy and indicates seizure types and syndromes needing more evidence. A recent FDA strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years of age and perampanel as monotherapy received FDA approval.

ObjectiveTo update the 2004 American Academy of Neurology (AAN) guideline for treating new-onset focal or generalized epilepsy with second- and third-generation antiepileptic drugs (AEDs).MethodsThe 2004 AAN criteria were used to systematically review literature (January 2003–November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength.ResultsSeveral second-generation AEDs are effective for new-onset focal epilepsy. Data are lacking on efficacy in new-onset generalized tonic-clonic seizures, juvenile myoclonic epilepsy, or juvenile absence epilepsy, and on efficacy of third-generation AEDs in new-onset epilepsy.RecommendationsLamotrigine (LTG) should (Level B) and levetiracetam (LEV) and zonisamide (ZNS) may (Level C) be considered in decreasing seizure frequency in adults with new-onset focal epilepsy. LTG should (Level B) and gabapentin (GBP) may (Level C) be considered in decreasing seizure frequency in patients ≥60 years of age with new-onset focal epilepsy. Unless there are compelling adverse effect–related concerns, ethosuximide or valproic acid should be considered before LTG to decrease seizure frequency in treating absence seizures in childhood absence epilepsy (level B). No high-quality studies suggest clobazam, eslicarbazepine, ezogabine, felbamate, GBP, lacosamide, LEV, LTG, oxcarbazepine, perampanel, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, or ZNS is effective in treating new-onset epilepsy because no high-quality studies exist in adults of various ages. A recent Food and Drug Administration (FDA) strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years old and perampanel as monotherapy received FDA approval.

Background Clobazam has been used in clinical practice as an adjunctive treatment for diverse seizure types and epilepsy syndromes. We evaluated the efficacy and safety of clobazam in a large sample of patients with refractory epilepsy at a tertiary pediatric center. Methods We retrospectively reviewed patients treated with clobazam between January 2001 and July 2013 who had a follow-up visit at least one month after starting clobazam. Response was defined as ≥50% reduction in seizure frequency compared with baseline seizure frequency during the 3 months before the introduction of clobazam. We examined the relationship between dose range and response rate. Results Four-hundred twenty-five patients were prescribed clobazam, of whom 300 (median age 9.1 years, interquartile range 4.7-13.3 years) had follow-up data greater than 1 month. Median follow-up was 5 months (interquartile range 3-11 months). Response to treatment with clobazam was observed in 203 of 300 (67.7%) patients, of whom 84 (28%) became seizure-free. The median starting dose was 0.2 (interquartile range 0.13-0.33) mg/kg/day with a target dose of 0.48 (0.26-0.80) mg/kg/day. Twenty-seven (9%) patients discontinued clobazam, 16 (59.3%) because adverse effects, 10 (37%) because of a lack of efficacy, and one (3.7%) because of a combination of adverse effects and lack of efficacy. The most common adverse effects were tiredness in 44 of 300 (14.6%) and mood or behavioral changes in 23 (7.7%). Conclusions Clobazam is a well-tolerated antiepileptic drug with good response rates in pediatric patients with refractory epilepsy.

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.

SummaryHemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged, malformed cerebral hemisphere, typically causing epilepsy that requires surgical resection. We studied resected HMG tissue to test whether the condition might reflect somatic mutations affecting genes critical to brain development. We found that two out of eight HMG samples showed trisomy of chromosome 1q, which encompasses many genes, including AKT3, a gene known to regulate brain size. A third case showed a known activating mutation in AKT3 (c.49G→A, creating p.E17K) that was not present in the patient's blood cells. Remarkably, the E17K mutation in AKT3 is exactly paralogous to E17K mutations in AKT1 and AKT2 recently discovered in somatic overgrowth syndromes. We show that AKT3 is the most abundant AKT paralog in the brain during neurogenesis and that phosphorylated AKT is abundant in cortical progenitor cells. Our data suggest that somatic mutations limited to the brain could represent an important cause of complex neurogenetic disease.

Hypothalamic hamartomas present with isolated fits of ictal laughter (gelastic epilepsy) or a combination of gelastic and other types of seizures. Many of these patients also suffer from cognitive decline, neuropsychiatric comorbidities and precocious puberty. Although there is a large body of anecdotal evidence about hypothalamic hamartomas and gelastic seizures, many questions still remain to be answered. For instance, which specific hypothalamic regions are most affected by the location of hamartomas causing laughing versus other types of seizures? Does the neuroanatomical localization of the lesions differ in cases with only gelastic seizures or a combination of gelastic and other types of seizures? Does the location of the lesions correlate with the presence of precocious puberty, and does the type of lesion influence the severity or the type of seizures? In a retrospective review of clinical and structural neuroimaging data from 100 cases of gelastic epilepsy and hypothalamic hamartoma, we aimed to address these questions by analysing the clinical presentation and the neuroanatomical features of the hypothalamic lesions in these patients. Our findings suggest that in all 100 cases, lesions were centred at the level of the mammillary bodies in the posterior hypothalamus. Compared with the patients with pure gelastic seizures (n = 32), those with gelastic and other types of seizures (n = 68) had significantly longer duration of epilepsy (P < 0.001), whereas age of seizure onset, the volume of lesions and the proximity to the mammillary bodies were not different between the two groups. In contrast, patients with cognitive or developmental impairment and those with precocious puberty had significantly larger lesions involving the anterior and posterior hypothalamus.

We report our pediatric experience with lacosamide, a new antiepileptic drug, approved by the US Food and Drug Administration as adjunctive therapy in focal epilepsy in patients more than 17 years old. We retrospectively reviewed charts for lacosamide use and seizure frequency outcome in patients with focal epilepsy (Wilcoxon signed rank test). Sixteen patients (7 boys) were identified (median dose 275 mg daily, 4.7 mg/kg daily; mean age 14.9 years, range 8-21 years). Patients were receiving a median of 2 antiepileptic drugs (interquartile range [IQR] 1.7-3) in addition to having undergone previous epilepsy surgery (n=3), vagus nerve stimulation (n=9), and ketogenic diet (n=3). Causes included structural (encephalomalacia and diffuse encephalitis, 1 each; stroke in 2) and genetic abnormalities (Aarskog and Rett syndromes, 1 each) or cause not known (n=10). Median seizure frequency at baseline was 57 per month (IQR 7-75), and after a median follow-up of 4 months (range 1-13 months) of receiving lacosamide, it was 12.5 per month (IQR 3-75), (P

We describe our experience with intraoperative electroencephalography in moyamoya surgery, a method to monitor for ischemic changes during the procedure and to minimize the risk of intraoperative and perioperative stroke. Case records and intraoperative electroencephalography recordings of all patients (n = 220) treated with surgical revascularization for moyamoya (pial synangiosis) performed for 14 years (1994-2008) were reviewed. Electroencephalographic slowing occurred in 100 cases (45.5%), and was persistent in nine cases (9%). Slowing coincided with specific operative manipulations, most commonly while suturing the donor vessel to the pia, and during closure of the craniotomy. Slowing generally occurred bilaterally, independently of the side of intervention. The presence, length, and severity of slowing were not predictive of perioperative ischemic events. We present additional data on intraoperative electroencephalography with a modified montage to accommodate the craniotomy. Although not predictive of perioperative ischemic events in this series, electroencephalographic changes were correlated with specific operative interventions, and revealed global responses to unilateral manipulation. These findings suggest that prospective analyses of this technique may elucidate additional methods of predicting (and possibly preventing) perioperative ischemic events.

Rufinamide is a new antiepileptic drug recently approved as adjunctive treatment for generalized seizures in Lennox-Gastaut syndrome. We undertook a retrospective analysis of 77 patients with refractory epilepsy and receiving rufinamide to evaluate the drug's efficacy, tolerability, safety, and dosing schedules. It appeared efficacious in diverse epilepsy syndromes, with the highest responder rate in focal cryptogenic epilepsies (81.1% of patients with >50% response rate), and in diverse seizure types, with the highest responder rate in tonic/atonic and partial seizures (48.6% and 46.7% of patients with >50% response rate, respectively). Rufinamide was well tolerated: only 13% of patients developed side effects necessitating drug withdrawal. These findings suggest that rufinamide may possess good efficacy and tolerability, and that its efficacy may extend to epilepsy syndromes beyond Lennox-Gastaut, including both partial and generalized epilepsy syndromes.

The newer antiepileptic drugs (AEDs) provide more therapeutic options and overall improved safety and tolerability for patients. To provide the best care, physicians must be familiar with the latest tolerability and safety data. This is particularly true in children, given there are relatively fewer studies examining the effects of AEDs in children compared with adults. Since we now have significant paediatric literature on each of these agents, we provide a comprehensive and current literature review of the newer AEDs, focusing on safety and tolerability data in children and adolescents. Because the safety profiles in children differ from those in adults, familiarity with this literature is important for child neurologists and other paediatric caregivers. We have organized the data by organ system for each AED for easier reference.

The purpose of this study is to assess the accuracy of spatiotemporal source analysis of magnetoencephalography (MEG) and scalp electroencephalography (EEG) for representing the propagation of frontotemporal spikes in patients with partial epilepsy. This study focuses on frontotemporal spikes, which are typically characterized by a preceding anterior temporal peak followed by an ipsilateral inferior frontal peak. Ten patients with frontotemporal spikes on MEG/EEG were studied. We analyzed the propagation of temporal to frontal epileptic spikes on both MEG and EEG independently by using a cortically constrained minimum norm estimate (MNE). Spatiotemporal source distribution of each spike was obtained on the cortical surface derived from the patient's MRI. All patients underwent an extraoperative intracranial EEG (IEEG) recording covering temporal and frontal lobes after presurgical evaluation. We extracted source waveforms of MEG and EEG from the source distribution of interictal spikes at the sites corresponding to the location of intracranial electrodes. The time differences of the ipsilateral temporal and frontal peaks as obtained by MEG, EEG and IEEG were statistically compared in each patient. In all patients, MEG and IEEG showed similar time differences between temporal and frontal peaks. The time differences of EEG spikes were significantly smaller than those of IEEG in nine of ten patients. Spatiotemporal analysis of MEG spikes models the time course of frontotemporal spikes as observed on IEEG more adequately than EEG in our patients. Spatiotemporal source analysis may be useful for planning epilepsy surgery, by predicting the pattern of IEEG spikes.

The purpose of this study is to assess the clinical value of spatiotemporal source analysis for analyzing ictal magnetoencephalography (MEG). Ictal MEG and simultaneous scalp EEG was recorded in five patients with medically intractable frontal lobe epilepsy. Dynamic statistical parametric maps (dSPMs) were calculated at the peak of early ictal spikes for the purpose of estimating the spatiotemporal cortical source distribution. DSPM solutions were mapped onto a cortical surface, which was derived from each patient's MRI. Equivalent current dipoles (ECDs) were calculated using a single-dipole model for comparison with dSPMs. In all patients, dSPMs tended to have a localized activation, consistent with the clinically determined ictal onset zone, whereas most ECDs were considered to be inappropriate sources according to their goodness-of-fit values. Analyzing ictal MEG spikes by using dSPMs may provide useful information in presurgical evaluation of epilepsy.

PRO: In the past decade, genotyping has started to help the neurologic practitioner treat patients with three types of epilepsy causing mutations, namely (1) SCN1A, a sodium channel gene mutated in Dravet's sporadic severe myoclonic epilepsy of infancy (SMEI and SMEB); (2) laforin (dual specificity protein phosphatase) and malin (ubiquitin E3 ligase) in Lafora progressive myoclonic epilepsy (PME); and (3) cystatin B in Unverricht-Lundborg type of PME. Laforin, malin, and cystatin B are non-ion channel gene mutations that cause PME. Genotyping ensures accurate diagnosis, helps treatment and genetic counseling, psychological and social help for patients and families, and directs families to organizations devoted to finding cures for specific epilepsy diseases. In SCN1A and cystatin B mutations, treatment with sodium channel blockers (phenytoin, carbamazepine, oxcarbazepine, lamotrigine) should be avoided. Because of early and correct diagnosis by genotyping of SCN1A mutations, the avoidance of sodium channel blockers, and aggressive treatment of prolonged convulsive status, there is hope that Dravet's syndrome may not be as severe as observed in all past reports. Genotyping also identifies nonsense mutations in Lafora PME. Nonsense mutations can be corrected by premature stop codon readthrough drugs such as gentamicin. The community practitioner together with epilepsy specialists in PME can work together and acquire gentamicin (Barton-Davis et al., 1999) for "compassionate use" in Lafora PME, a generalized lysosome multiorgan storage disorder that is invariably fatal. In Unverricht-Lundborg PME, new cohorts with genotyped cystatin B mutations have led to the chronic use of antioxidant N-acetylcysteine and combination valproate clobazam or clonazepam plus antimyoclonic drugs topiramate, zonisamide, piracetam, levetiracetam, or brivaracetam. These cohorts have minimal ataxia and no dementia, questioning whether the syndrome is truly progressive. In conclusion, not only is genotyping a prerequisite in the diagnosis of Dravet's syndrome and the progressive myoclonus epilepsies, but it also helps us choose the correct antiepileptic drugs to treat seizures in Dravet's syndrome and Unverricht-Lundborg PME. Genotyping also portends a brighter future, helping us to reassess the true course, severity, and progressive nature of Dravet's syndrome and Unverricht-Lundborg PME and helping us craft a future curative treatment for Dravet's syndrome and Lafora disease. Without the genotyping diagnosis of epilepsy causing mutations we are stuck with imprecise diagnosis and symptomatic treatment of seizures. CON: Genotyping of epilepsy may help to better understand the genetics of epilepsy, to establish an etiology in a patient with epilepsy, to provide genetic counseling, and to confirm a clinical diagnosis. However, critical analysis reveals that genotyping does not contribute to an improved treatment for the patients. In order to improve treatment, genotyping would have to (1) improve our ability to select the drug of choice for a given epilepsy or epileptic syndrome; (2) improve our ability to predict the individual risk of adverse reactions to certain drugs; (3) improve our ability to avoid unnecessary treatments or treatments that could aggravate seizures. Many example illustrate the lack of impact of genetic information on the treatment outcome: we do not treat Dravet syndrome more successfully since SCN1A testing became available; we do not treat Lafora disease more successfully since testing for laforin and malin became available; we do not need to know the genetic nature of Unverricht-Lundborg disease or test for the cystatin B mutation in order to select or avoid certain drugs; we do not treat Rett syndrome more successfully since MECP2 testing became available; we do not treat JME more successfully since we know its genetic origin; we do not treat autosomal dominant nocturnal frontal lobe epilepsy more successfully since we know its genetic origin and can test for its mutation. The clinical characteristics as well as the response to treatment of these epilepsy syndromes have been well established before genotyping became available. It can not be argued that genotyping is necessary for establishing a diagnosis or ensure accurate diagnosis. Since not all individuals with given syndromes have been shown to have the corresponding mutation, the clinical diagnosis must have been based on well-established clinical criteria. In addition, the presence or absence of the mutation in a given patient has never been shown to specifically predict the response to any form of treatment, positive or negative. Finally, the appropriate psychological and social help in a given patient will not depend on the identification of a mutation. This does not leave any role for genotyping in epilepsy for the sole reason of improving treatment of the patient. Claiming that the result of genotyping predicts optimal treatment in certain epilepsies is equivalent to stating that genotyping for diabetes has become available and that, based on this breakthrough, insulin can now be selected as the treatment of choice in those who test positive.

Although no randomized studies have demonstrated a positive impact of therapeutic drug monitoring (TDM) on clinical outcome in epilepsy, evidence from nonrandomized studies and everyday clinical experience does indicate that measuring serum concentrations of old and new generation antiepileptic drugs (AEDs) can have a valuable role in guiding patient management provided that concentrations are measured with a clear indication and are interpreted critically, taking into account the whole clinical context. Situations in which AED measurements are most likely to be of benefit include (1) when a person has attained the desired clinical outcome, to establish an individual therapeutic concentration which can be used at subsequent times to assess potential causes for a change in drug response; (2) as an aid in the diagnosis of clinical toxicity; (3) to assess compliance, particularly in patients with uncontrolled seizures or breakthrough seizures; (4) to guide dosage adjustment in situations associated with increased pharmacokinetic variability (e.g., children, the elderly, patients with associated diseases, drug formulation changes); (5) when a potentially important pharmacokinetic change is anticipated (e.g., in pregnancy, or when an interacting drug is added or removed); (6) to guide dose adjustments for AEDs with dose-dependent pharmacokinetics, particularly phenytoin.

Epilepsy is one of the most common neurological disorders of childhood, and antiepileptic drugs represent the main component of its treatment. The current emphasis in epilepsy treatment is to improve quality of life, not only by suppressing seizure, but also by minimizing the side effects of medications. The last 15 years have been characterized by significant advances in the development of new agents that have helped us to get closer to this goal. Knowledge of the essential properties, key indications and interactions of each antiepileptic drug will help to optimize efficacy and reduce adverse reactions. Age is also a determining factor of the epilepsy phenotype and its treatment. This review addresses the principles of pediatric epilepsy treatment, summarizes the profile of each of the commonly used antiepileptic drugs, and provides a treatment paradigm for particular seizures and epilepsy syndromes of childhood.

Interictal fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) is a component of the presurgical evaluation of patients with medically intractable epilepsy, including patients with malformations of cortical development. The authors describe 3 cases of focal cortical malformations that displayed asymmetrically higher uptake on FDG-PET performed in the interictal state in patients undergoing evaluation for possible focal resection for refractory localization-related epilepsy. The evaluation included routine and prolonged video electroencephalography (EEG), magnetic resonance imaging (MRI), interictal FDG-PET with concurrent EEG, and single-photon emission computed tomography (SPECT). All 3 patients had focal cortical malformations on MRI corresponding to regions of asymmetrically higher uptake on FDG-PET. EEG confirmed that the FDG-PET studies were performed in the interictal state. The lesions included a large region of subcortical heterotopia in the right frontal lobe, a left temporal lobe dysplasia, and a region of subcortical heterotopia in the right occipital lobe. In both patients with subcortical heterotopia, there were other focal regions of cortical malformation that were not associated with abnormal or asymmetric uptake on FDG-PET. Previous reports describe decreased uptake on interictal PET in most cases of focal cortical malformations. Normal to increased uptake has been reported with band heterotopia. The authors demonstrate that other types of focal malformations of cortical development, including focal subcortical heterotopia and lobar dysplasia, can be associated with asymmetrically higher uptake on interictal FDG-PET.

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.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.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).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.

OBJECTIVES. The objectives of this study were to delineate the etiologic profile and neurodevelopmental outcome of neonatal seizures in the current era of neonatal intensive care and to identify predictors of neurodevelopmental outcome in survivors.METHODS. Eighty-nine term infants with clinical neonatal seizures underwent neurologic examination, electroencephalography (EEG), neuroimaging, and extensive diagnostic tests in the newborn period. After discharge, all infants underwent regular neurologic evaluations and, at 12 to 18 months, formal neurodevelopmental testing. We tested the prognostic value of seizure etiology, neurologic examination, EEG, and neuroimaging.RESULTS. Etiology was found in 77 infants. Global cerebral hypoxia-ischemia, focal cerebral hypoxia-ischemia, and intracranial hemorrhage were most common. Neonatal mortality was 7%; 28% of the survivors had poor long-term outcome. Association between seizure etiology and outcome was strong, with cerebral dysgenesis and global hypoxia-ischemia associated with poor outcome. Normal neonatal period/early infancy neurologic examination was associated with uniformly favorable outcome at 12 to 18 months; abnormal examination lacked specificity. Normal/mildly abnormal neonatal EEG had favorable outcome, particularly if neonatal neuroimaging was normal. Moderate/severely abnormal EEG, and multifocal/diffuse cortical or primarily deep gray matter lesions, had a worse outcome.CONCLUSIONS. Mortality associated with neonatal seizures has declined although long-term neurodevelopmental morbidity remains unchanged. Seizure etiology and background EEG patterns remain powerful prognostic factors. Diagnostic advances have changed the etiologic distribution for neonatal seizures and improved accuracy of outcome prediction. Global cerebral hypoxia-ischemia, the most common etiology, is responsible for the large majority of infants with poor long-term outcome.

Antiepileptic drugs may paradoxically worsen seizure frequency or induce new seizure types in some patients with epilepsy. The mechanisms of seizure aggravation by antiepileptic drugs are mostly unknown and may be related to specific pharmacodynamic properties of these drugs. This article provides a review of the various clinical circumstances of seizure exacerbation and aggravation of epilepsy by antiepileptic drugs as well as a discussion of possible mechanisms underlying the occasional paradoxical effect of these drugs. Antiepileptic drug-induced seizure aggravation can occur virtually with all antiepileptic medications. Drugs that aggravate seizures are more likely to have only one or two mechanisms of action, either enhanced gamma-aminobutyric acid-mediated transmission or blockade of voltage-gated sodium channels. Antiepileptic drug-induced seizure exacerbation should be considered and the accuracy of diagnosis of the seizure type should be questioned whenever there is seizure worsening or the appearance of new seizure types after the introduction of any antiepileptic medication.

Summary: Purpose: To describe a distinct asymmetrical pattern of cortical malformation with large focal malformations of cortical development (MCDs) and contralateral periventricular nodular heterotopia (PNH). Methods: We identified three patients with epilepsy and focal EEG abnormalities. Each patient underwent 1.5-Tesla magnetic resonance imaging (MRI) to obtain sagittal T1-weighted, axial fluid-attenuated inversion recovery (FLAIR), fast spin-echo (FSE) T2-weighted, and coronal fast spin-echo inversion recovery (FSEIR) T2-weighted images; coronal spoiled gradient recalled (SPGR) T1-weighted images were obtained in two cases. Results: Patient 1, an 18-year-old right-handed man, had a 4-year history of intractable seizures. MRI revealed a right frontal subcortical heterotopia (SH) and a single left anterior PNH. Patient 2, a 10-year-old left-handed boy, had a 4-year history of epilepsy. MRI revealed a large region of SH in the left temporal, parietal, and occipital lobes and three right-sided PNH. Patient 3, a 16-month-old girl, had medically refractory infantile spasms. MRI revealed a large MCD in the left parietal lobe with contiguous underlying periventricular heterotopia as well as a small contralateral PNH. Conclusions: These cases together illustrate a distinct asymmetrical pattern of a large focal MCD with small contralateral PNH. The asymmetrical involvement of the two hemispheres suggests that the stage of maximal disruption of cortical development may differ between the two hemispheres. Further study into the mechanisms underlying such asymmetrical patterns of cortical malformation should enhance our understanding of cortical development as well as hemispheric lateralization.

This study compares a reduced electrode montage (9 electrodes) with the full 10/20 electrode montage for the ability to detect and characterize neonatal seizures and background electroencephalographic (EEG) characteristics, utilizing new digital technology allowing "remontage" of previously acquired records. A total of 151 neonatal EEG records were retrospectively and blindly analyzed by two readers. Records were first analyzed for seizure number, topography, duration, and characteristics of EEG background using the reduced montage, before reanalysis with the full montage. One hundred eighty-seven seizures were identified in 31 ictal recordings using the full montage. Using the reduced montage, 166 seizures were identified in 30 records. The sensitivity and specificity of the reduced montage for detecting electrographic seizures was 96.8% and 100% respectively. In only one patient's record, the single seizure was missed altogether. For grading background abnormalities, the sensitivity and specificity of reduced montage was 87% and 80%. Although there are inherent weaknesses in reduced montages with respect to both underestimation and overestimation of seizure number, a nine-electrode reduced montage can be a sensitive tool for identification of neonatal seizures and assessment of background characteristics of neonatal electroencephalography.

Antiepileptic drugs are often used for the treatment of both epilepsy and a wide range of behavioral and psychiatric disorders. The treatment of patients with epilepsy has been the proving ground for antiepileptic drugs, not only with respect to their efficacy in the treatment of seizures but also for clarifying their dose-related and idiosyncratic adverse events. This information has been useful in treating patients with behavioral and psychiatric disorders. Indeed, the number of prescriptions written for many antiepileptic drugs for nonepileptic uses far exceeds those written for the same drugs for epilepsy. Because patients with chronic epilepsy have a higher incidence of axis I psychiatric disorders, physicians can choose an antiepileptic drug to treat both the epilepsy and psychiatric comorbidity in selected patients. Guided by the principles of evidence-based medicine as outlined by the American Academy of Neurology and the American Academy of Pediatrics, this article reviews the application of antiepileptic drugs for epilepsy and behavioral and psychiatric disorders in children. (J Child Neurol 2004;19(Suppl 1):S39-S48).

The aim of this study was to study risperidone use in pediatric patients with comorbid epilepsy and psychiatric disorders.We retrospectively reviewed the outpatient psychopharmacology medical records of patients with epilepsy, aged 19 and younger, who received risperidone for psychiatric disorders.Twenty-one (21) youths (mean age, 12.0 +/- 4.2 years) met our criteria for review. Mean risperidone dosage was 2.4 +/- 3.5 mg/day. Target symptoms included severe aggression, severe agitation, psychosis, and self-injurious behavior. Diagnoses included attention-deficit hyperactivity disorder (ADHD), learning disorder, and impulse control disorder. Seizure type was partial complex in 12 patients, generalized in 6 patients, neonatal in 1 patient, myoclonic in 1 patient, and unclassified in 1 patient. The average number of previous psychotropic trials was 3.5 +/- 3.0. Using a definition of response of a Clinical Global Impressions (CGI) improvement score of 2 or less, 15 patients (71%) were considered responders. Adverse effects were none to slight in 16 patients, moderate in 4 patients, and severe in 1 patient. Seizures did not worsen in any patient.Risperidone was associated with a clinically significant global improvement, without seizure exacerbation in youths with epilepsy and psychiatric disorders. Despite the limitations of the study design, the 71% responder rate is noteworthy in this treatment-refractory group.

Objective: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide—reviewed in the order in which these agents received approval by the US Food and Drug Administration) in the treatment of children and adults with newly diagnosed partial and generalized epilepsies.Methods: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until September 2002, with selected manual searches up until 2003.Results: There is evidence either from comparative or dose-controlled trials that gabapentin, lamotrigine, topiramate, and oxcarbazepine have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. There is also evidence that lamotrigine is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking.Conclusions: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes where more evidence is necessary.

Although treatment of epilepsy easily evolves into a situation of overtreatment, reversing the process can be difficult and time consuming. Benefits of reducing overtreatment may include a decrease in side effects, better seizure control, a simplification in the medication regimen, improved compliance, and reduced costs. The risks include seizure exacerbation due to withdrawal or due to loss of protection. Reversal of pharmacokinetic interactions may also lead to seizure aggravation or to drug toxicity. When reducing overtreatment, there are three main challenges: to select the drugs that should be eliminated, to choose an appropriate rate of reduction, and to anticipate reversible pharmacokinetic interactions that can have clinically significant consequences. Overall, there is a lack of published data to properly support recommendations for implementing reduction of overtreatment. This is particularly the case in the pediatric population and for the newer antiepileptic drugs.

Summary: 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.

Purpose This study aimed to evaluate lexical retrieval, presurgery and postsurgery, among children and adolescents who had undergone temporal lobe resection for intractable epilepsy and to compare outcomes in patients whose surgery involved the left temporal lobe or the right temporal lobe. Materials and methods A retrospective chart review identified 36 patients from a major pediatric epilepsy treatment center who had undergone temporal lobe resection (21 underwent left temporal lobe resection; 15 underwent right temporal lobe resection) for intractable epilepsy and who had completed neuropsychological testing that included a measure of confrontation naming (Boston Naming Test, BNT) and verbal fluency (Delis–Kaplan Executive Function System (D-KEFS) Fluency) prior to and after surgery. Linear mixed effects regression models were used to evaluate presurgery and postsurgery changes and to compare the left temporal lobe resection group with the right temporal lobe resection group. Principal results Confrontation naming performance declined after left, but not right, temporal lobe resection (p Major conclusions Left temporal lobe resection for intractable epilepsy is associated with a decline in lexical retrieval. The risk of decline in specific language functions following surgery involving the left temporal lobe should be incorporated in the counseling of patients and families in decision-making with regard to surgery.

Summary Objective Reports of studies evaluating rufinamide as an add-on therapy in children and adolescents with refractory epilepsy are restricted to a few publications. Prospective multicenter studies including children and adults have yielded important information about several types of epilepsies and syndromes. We evaluated the use of rufinamide in a single pediatric center with a large cohort and long-term follow-up period. Methods We retrospectively included patients taking rufinamide from November 2008 to March 2013. Response was defined by a seizure reduction of ≥50% compared to baseline. Results Three hundred patients with a median age of 9.1 years (range 0.4–29.6 years) were reviewed. Median follow-up was 9 months (range 1–37 months). Epilepsy etiology was classified as genetic (23.7%), structural/metabolic (41%), and unknown cause (35.3%). Overall, rufinamide treatment led to a median seizure frequency reduction of 59.2% from responders to baseline. Seizure reduction was greater in patients with genetic etiology compared to structural/metabolic (66.2% vs. 45.5% responders, p = 0.005). Rufinamide was discontinued in 110 (36.7%) of 300 patients: 63 (21%) due to unsatisfactory response, 47 (15.7%) due to side effects, and in 18 (6%) of those due to both. Most common adverse effects were sleepiness, vomiting, mood changes, nausea, and loss of appetite. Median time to loss of efficacy was 11.6 months (range 3–28 months). Significance Rufinamide provides satisfactory seizure reduction as an adjunctive treatment in refractory epilepsy. Results need to be interpreted in the setting of data acquisition, including inherent biases of retrospective studies. Patients with a known genetic etiology may have better responses than patients with structural/metabolic etiology. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

article i nfo Keywords: Epilepsy Seizures ADHD Stimulant Methylphenidate Amphetamine Pharmacotherapy Comorbidity To retrospectively examine response to stimulant treatment in patients with epilepsy and ADHD symptoms as predicted by seizure freedom for six months, use of methylphenidate (MPH) versus amphetamine (AMP) preparations, cognitive level, and medical records were searched for patients under the age of 18 with epilepsy and ADHD symptoms treated with MPH or AMP (n = 36, age = 10.4 ± 3.5; male = 67%). "Responders" had a CGI-improvement score of ≤2 and did not stop medication because of adverse effects. "Worsened" patients discontinued medication because of agitation/emotional lability. Seizure freedom did not predict treatment response. Lower cognitive level was associated with increased rate of worsening (p = 0.048). No patients who were seizure-free at the start of the medication trial experienced an increase in seizures. Of the patients having seizures at the start of trial, one patient on MPH and two patients on AMP had increased seizures during the trial. Seizures returned to baseline frequency or less after stimulant discontinuation or anticon- vulsant adjustment. Methylphenidate was associated with a higher response rate, with 12 of 19 given MPH (0.62 ± 0.28 mg/kg/day) compared with 4 of 17 given AMP (0.37 ± 0.26 mg/kg/day) responding (p = 0.03). Methylphenidate treatment and higher cognitive level were associated with improved treatment outcome, while seizure freedom had no clear effect. Confidence in these findings is limited by the study's small, open-label, and uncontrolled design.

This chapter will review methodology of single photon emission computed tomography (SPECT) and positron emission tomography (PET), radiopharmaceuticals, imaging instrumentation, image fusion, and clinical applications in children. Both SPECT and PET can depict regional cerebral perfusion, glucose metabolism, and other functions and provide images of the location, quantification, and biokinetics of radiopharmaceutical agents. In addition, these techniques can detect rapid changes due to normal brain activity in different functional conditions or those caused by pharmacologic or cognitive stimulation. Improvements in the production and distribution of 18F-FDG and better PET systems have facilitated the widespread use of PET. Advances in imaging systems and data processing in SPECT have resulted in systems that are simpler to operate and that yield 3D images of high functional and anatomic resolution.

Electrode grids on the cortical surface of epileptic patients provide a unique opportunity to observe brain activity with high temporal–spatial resolution and high signal-to-noise ratio during a cognitive task. Previous work showed that large-amplitude theta frequency oscillations occurred intermittently during a maze navigation task, but it was unclear whether theta related to the spatial or working memory components of the task. To determine whether theta occurs during a nonspatial task, we made recordings while subjects performed the Sternberg working memory task. Our results show event-related theta and reveal a new phenomenon, the cognitive “gating” of a brain oscillation: at many cortical sites, the amplitude of theta oscillations increased dramatically at the start of the trial, continued through all phases of the trial, including the delay period, and decreased sharply at the end. Gating could be seen in individual trials and varying the duration of the trial systematically varied the period of gating. These results suggest that theta oscillations could have an important role in organizing multi-item working memory.

Prader-Willi syndrome is a chromosomal disorder caused by absence of expression of the paternal active genes in the 15q11∼q13 chromosome region; it is associated with an increased incidence of epilepsy and narcolepsy. Presented here is the case of a 2.5-year-old boy with Prader-Willi syndrome and a history of neonatal superior sagittal sinus thrombosis with new onset of atonic seizures with electrographic onset from the parasagittal region. It is postulated that microscarring from neonatal venous sinus thrombosis, history of febrile seizures, and Prader-Willi syndrome are factors predisposing him to epilepsy. The importance of video electroencephalography with electromyography electrodes is emphasized for Prader-Willi syndrome patients with drop episodes, to differentiate cataplexy from seizures. This being a novel report of a Prader-Willi syndrome patient with atonic seizures, the literature on seizure semiology among patients with Prader-Willi syndrome is reviewed.

To investigate the correlation between spike propagation represented by spatiotemporal source analysis of magnetoencephalographic (MEG) spikes and surgical outcome in patients with temporal lobe epilepsy.Thirty-seven patients were divided into mesial (n=27) and non-mesial (n=10) groups based on the presurgical evaluation. In each patient, ten ipsilateral spikes were averaged, and spatiotemporal source maps of the averaged spike were obtained by using minimum norm estimate. Regions of interest (ROIs) were created including temporoparietal, inferior frontal, mesial temporal, anterior and posterior part of the lateral temporal cortex. We extracted activation values from the source maps and the threshold was set at half of the maximum activation at the peak latency. The leading and propagated areas of the spike were defined as those ROIs with activation reaching the threshold at the earliest and at the peak latencies, respectively. Surgical outcome was assessed based on Engel's classification. Binary variables were created from leading areas (restricted to the anterior and mesial temporal ROIs or not) and from propagation areas (involving the temporoparietal ROI or not), and for surgical outcome (Class I or not). Fisher's exact test was used for significance testing.In total and mesial group, restricted anterior/mesial temporal leading areas were correlated with Class I (p0.05). Temporoparietal propagation was correlated with Class II-IV (p0.05). For the non-mesial group, no significant relation was found.Spike propagation patterns represented by spatiotemporal source analysis of MEG spikes may provide useful information for prognostic implication in presurgical evaluation of epilepsy.

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. (J Child Neurol 2000;15:S27-S30).

Low-frequency repetitive transcranial magnetic stimulation (rTMS) is emerging as a therapeutic tool for patients with intractable epilepsy. Although seizures during treatment have been reported as adverse events in some patients, the nature and severity of seizures that may be provoked by low-frequency rTMS in patients with epilepsy have not been extensively studied. Accordingly, this article documents seizures in patients (n = 5) with intractable epilepsy and average seizure frequency greater than one per day who underwent 1-Hz rTMS for seizure suppression. We report three observations in the present case series: (1) in each instance the in-session seizure was typical in semiology to the patient’s habitual seizures, (2) the duration of each documented seizure was either the same as or shorter than the patients’ baseline seizures, and (3) the overall neurological outcome on follow-up was not affected by the in-session seizures. More data will be required for valid conclusions with respect to safety and tolerability of low-frequency rTMS in patients with epilepsy, but it is noteworthy from our perspective that seizures during rTMS in this series were similar to the patients’ habitual seizures, occurred in patients with epilepsy with baseline seizure frequency exceeding one per day, and did not correlate with a poor neurological outcome or with absence of clinical response to rTMS.

A 13-year-old boy with Lennox-Gastaut syndrome characterized by absence, myoclonic, complex-partial, and secondarily generalized tonic-clonic seizures, presents with progressive obtundation and loss of motor and verbal skills over a 2-day period. Initial evaluation revealed therapeutic phenytoin serum concentrations. This article discusses the differential diagnosis and management approach used in this setting, as well as the appropriate interpretation of antiepileptic drug serum concentrations.

Until 1993, six antiepileptic drugs (phenytoin, phenobarbital, primidone, ethosuximide, carbamazepine, and valproate) accounted for the overwhelming majority of prescriptions written for the treatment of epilepsy. Among those, only valproate was truly a broad-spectrum drug, with some or good efficacy against all seizure types. Since 1993, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, zonisamide, and pregabalin were approved in the United States for the treatment of epilepsy. All were initially tested and approved as add-on treatment of partial-onset seizures, with or without secondary generalization. The era that began in 1993 was characterized not only by a new generation of antiepileptic drugs, but also by controlled trials in specific epileptic syndromes and in seizure types other than partial onset. From these trials, a gradually expanding pattern of a broader antiepileptic efficacy spectrum has emerged for several of the newer drugs, although some of them still retain a narrow spectrum, such as gabapentin, tiagabine, oxcarbazepine, and pregabalin (table). View this table: Table Current FDA-approved indications of newer antiepileptic drugs The Lennox-Gastaut syndrome is a generalized epilepsy that is notoriously refractory to treatment. In a trial reported in 1993, felbamate was the first drug ever to be submitted to a controlled trial in this syndrome, and it was found to be superior to placebo, in particular against the most debilitating drop attacks.1 Following this lead, subsequent similar placebo-controlled trials in this syndrome demonstrated the efficacy of lamotrigine2 and then topiramate.3 Another generalized seizure type, absence seizures, was shown in a controlled trial to respond to lamotrigine.4 Generalized tonic-clonic seizures (GTCS) are …

SUMMARY: 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.

We studied nine cases of focal cortical dysplasia (FCD) by MRI, with surface-rendered 3D reconstructions. One case was also examined using single-voxel proton MR spectroscopy (MRS). The histological features were reviewed and correlated with the MRI findings. The gyri affected by FCD were enlarged and the signal of the cortex was slightly increased on T1-weighted images. The gray-white junction was indistinct. Signal from the subcortical white matter was decreased on T1- and increased on T2-weighted images in most cases. Contrast enhancement was seen in two cases. Proton MRS showed a spectrum identical to that of normal brain.

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.

Summary: 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 singledose 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) andor 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) mgA. On day 2, patients received a CBZ dose equivalent to 10 mgkg + 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 mgA 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 2–55 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.

This chapter covers the main steps involved in the initiation of antiepileptic drug therapy. Aspects covered specifically include the decision whether or not to initiate treatment, the selection process of a drug of first choice for a given patient with a particular seizure type or epilepsy syndrome, and the process of initiating therapy with the selected drug of first choice. Suggested choices of antiepileptic drugs by seizure type or epilepsy syndrome are summarized in a table. In an appendix, these drugs are reviewed individually with regard to their clinical use. The emphasis is on initial dose, dosage escalation, common and serious adverse effects, baseline evaluation, monitoring of therapy, and relevant drug interactions.