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This prospective observational study focuses on developmental outcomes in the treatment of tuberous sclerosis complex (TSC) with everolimus (EVO). Fourteen children/adolescents aged 1.7-13.07 and one adult aged 31 years, all with TSC and refractory epilepsy participated. All were treated with EVO for 3-70 months (md: 37). Development/adaptive functioning were evaluated at baseline with follow-up in 11 patients; all patients were assessed during the course of treatment. Our exploratory analyses included factors contributing to developmental impairment and change from baseline to last evaluation. The majority of patients showed severe developmental impairment (86%). Patients with a higher age at inclusion, duration of epilepsy, and number of previous antiepileptic drugs (AEDs) showed lower developmental levels. Earlier onset of epilepsy and a higher number of current AEDs were associated with worse adaptive functioning. At their last examination, four patients were seizure-free (27%), and four experienced a reduction of seizures >50% (27%). With treatment, (slight) increase was seen in absolute values of developmental age (DA) regarding both development and adaptive functioning. Yet, when accounting for age, decrease was seen in both assessments. While developmental disorders were prominent, we observed an overall progression at a slower pace. Despite a positive effect on seizure occurrence, treatment with EVO did not reverse developmental problems in the observation period of this study., Competing Interests: Declaration of competing interest NEK has received honoraria for a speaking engagement by Novartis (Nürnberg, Germany). CR has no conflicts of interest. US has received honoraria for lectures and scientific advice from Desitin Arzneimittel GmbH, Dibropharm, Shire, Viropharma, Zogenix. GW obtained honoraria for speaking engagements from Desitin (Hamburg, Germany) and Novartis (Nürnberg, Germany). He gave scientific advice for PTC Therapeutics (Frankfurt, Germany). Work on this article was initiated by the authors and conducted independently of Novartis. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: BECTS (benign childhood epilepsy with centrotemporal spikes) is associated with characteristic EEG findings. This study examines the influence of anti-convulsive treatment on the EEG., Methods: In a randomized controlled trial including 43 children with BECTS, EEGs were performed prior to treatment with either Sulthiame or Levetiracetam as well as three times under treatment. Using the spike-wave-index, the degree of EEG pathology was quantified. The EEG before and after initiation of treatment was analyzed. Both treatment arms were compared and the EEG of the children that were to develop recurrent seizures was compared with those that were successfully treated., Results: Regardless of the treatment agent, the spike-wave-index was reduced significantly under treatment. There were no differences between the two treatment groups. In an additional analysis, the EEG characteristics of the children with recurrent seizures differed statistically significant from those that did not have any further seizures., Conclusion: Both Sulthiame and Levetiracetam influence the EEG of children with BECTS. Persistent EEG pathologies are associated with treatment failures., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: This non-interventional study was conducted to evaluate the efficacy and tolerability of intravenous lacosamide (LCM-iv) under routine conditions in daily clinical practice as a prospective registry., Methods: Patients with any type of seizure or epilepsy syndrome were recruited in 16 neurological and neuropediatric centers in Germany if the treating physician decided to administer LCM-iv for any reason. Observation time per patient was 10 days with daily documentation of LCM-iv administration, type and frequency of seizures, currently used drugs and doses, and adverse events. Treatment efficacy, tolerability, and handling of LCM-iv were assessed using a five-step scale., Results: In 119 patients treating physicians classified epilepsies as focal in 66.1% and generalized in 17.4% (16.5% unclassifiable). Most common etiologies of seizures were tumors (36.1%) and cerebrovascular diseases (21.8%). Reasons for LCM-iv treatment included preparation for surgery (25.2%), convulsive (24.4%) and non-convulsive (18.5%) status epilepticus (SE), series of seizures (16.0%), gastrointestinal causes (5.9%), and acute seizures (4.2%). The median dose of LCM-iv was 300mg per day. In 45 of 64 patients (70.3%) with SE or series of seizures, epileptic activity ceased during observation time. Five patients showed abnormalities in ECG prior to the infusion and one patient afterwards, but during infusion no abnormalities were reported. Treating physicians rated efficacy and tolerability as very good or good in 77.6% and 93.1% of patients, respectively., Conclusions: This large and independent multicenter registry on the use of LCM-iv in clinical practice demonstrates that LCM-iv is well-tolerated and highly efficacious when given in emergency situations, including patients experiencing SE. It is advisable to perform an electrocardiogram prior to LCM-iv administration., (Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: Most common clinical studies with antiepileptic drugs do not reflect medical everyday practice due to their strict in- and exclusion criteria and specifications of treatment regimens. Here we present a large non-interventional registry with the intention to evaluate the spectrum of applications in daily use and the efficacy and tolerability of intravenously given levetiracetam (LEV-iv)., Methods: In a prospective approach of 17 neurological and neuropediatric centres in Germany LEV-iv treated patients of all ages were included over a period of 10 months. The observational period was 10 days with daily documentation of LEV-iv administration, type and frequency of seizures, currently used drugs and doses, and adverse events (AEs). In addition, treatment efficacy and tolerability were assessed by patients and physicians at study end as well as practicability of LEV-iv using a five-step scale., Results: In 95 patients LEV-iv was administered, 93 were included into the analysis. The median LEV-iv dose was 1500 mg (range 110-6000 mg) per day. Median age was 66 years (range 0.7-90.3 years). The majority of patients (n=70, 75%) suffered from status epilepticus (SE, n=55, 59%) and acute seizure clusters (n=15, 16%). Of those with SE, 41 patients (75%) had SE for the first time. Acute seizure clusters and SE terminated in 83% after LEV-iv administration. A total of 29 adverse events were reported in 17 of the 95 patients from the safety set. Ten of these were at least possibly related to LEV-iv treatment. Slight decrease of blood pressure during the infusion (3 patients each) was captured most frequently. No serious side effect was observed. Physicians rated the efficacy and tolerability of LEV-iv treatment as good or very good in 78% and 82% of the cases, respectively., Conclusion: In this large observational study of everyday practise the use of LEV-iv exhibited a remarkable good response and tolerability in patients with acute onset seizures (mostly SE). Further randomized controlled studies, like the established status epilepticus trial (ESET) are needed to confirm these findings., (Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: Focal cortical dysplasia (FCD) is currently recognized as the most common cause of neocortical pharmacoresistant epilepsy. Epilepsy surgery has become an increasingly successful treatment option. Herein, the largest patient cohort reported to date is analyzed regarding long-term outcome and factors relevant for long-term seizure control., Methods: Two hundred eleven children and adults undergoing epilepsy surgery for histologically proven FCD and a follow-up period of 2-12 years were analyzed regarding the longitudinal course of seizure control, effects of FCD type, localization, magnetic resonance imaging (MRI), timing of surgery, and postoperative antiepileptic treatment., Results: After 1 year, Engel class I outcome was achieved in 65% of patients and the percentage of seizure-free patients remained stable over the following (up to 12) years. Complete resection of the assumed epileptogenic area, lower age at surgery, and unilobar localization were positive prognostic indicators of long-term seizure freedom. Seizure recurrence was 12% after the first year, whereas 8% achieved late seizure freedom either following additional introduction of antiepileptic drugs (AEDs) (4%), a reoperation (2%), or a running down phenomenon (2%). Thirty-nine percent of patients had a reduction of AED from polytherapy to monotherapy or a complete cessation of AED treatment. Late seizure relapse was seen in nine patients during reduction of AEDs (i.e., in 12% of all patients with AED tapering); in four of them seizures persisted after reestablishment of antiepileptic medication., Significance: Postoperative long-term seizure outcome was favorable in patients with FCD and remained stable in 80% of patients after the first postoperative year. Several preoperative factors revealed to be predictive for the postoperative outcome and may help in the preoperative counseling of patients with FCD and in the selection of ideal candidates for epilepsy surgery., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Dravet syndrome (DS) is a rare, severe childhood epilepsy syndrome that imposes a substantial burden on patients and their caregivers. This study evaluated health-care utilization over a 2-year period in patients with DS at an outpatient clinic of a German epilepsy center. Data on the course of epilepsy, anticonvulsant treatment, and direct costs were recorded using the electronic seizure diary Epivista and patients' files. We enrolled 13 patients with DS (6 females, mean age: 12.3±7.5 years) between 2007 and 2010 and evaluated them during a 1-year baseline. All patients had drug-resistant epilepsy and their seizures failed to improve with a mean number of 6.7±3.4 anticonvulsants. They had an overall mean seizure frequency of 102.1 seizures per year (median: 31, range: 3-538) with 43.2 GTCSs per year (median: 14, range: 0-228). We estimated the annual total direct costs at €6506±3974 (range: €1174-11,783) per patient with hospitalization (68.9% of total direct costs) as the major cost factor ahead of costs for anticonvulsants (24.0%). For the 1-year follow-up period, less severely affected patients were continued on conventional anticonvulsants (n=4) or switched to adjunctive treatment with stiripentol and clobazam (n=9). In the latter group, six patients (67%) were long-term responders, with between 25% and 100% seizure reduction with respect to either GTCSs or the overall seizure frequency. This reduction in seizure frequency was associated with a shift in the distribution of cost components towards higher medication costs and decreased hospitalization costs. The total direct costs increased by 42.7%, mainly due to the newly introduced stiripentol, with an annual cost of €6610. This study showed that direct costs of patients with DS were above the average European costs of drug-resistant epilepsy in children. Treatment with new anticonvulsants resulted in reduction of seizures and inpatient admissions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Myoclonic astatic epilepsy (MAE, Doose syndrome) is a difficult to treat idiopathic generalized epilepsy of early childhood. MAE frequently shows the course of an epileptic encephalopathy and may result in permanent cognitive impairment. Systematic analyses on clinical effects of different AED combinations are still needed. The purpose of our study was to analyze the therapeutic effect of adjunctive lamotrigine (LTG) in pharmacoresistant MAE patients., Patients and Methods: In an exploratory, retrospective study, 10 pharmacoresistant MAE patients were included who had been admitted to the Northern German Epilepsy Center between 07/2007 and 12/2010 and had been treated with LTG. Documentation was performed with the electronic seizure diary Epivista. A total observation period of 32 weeks was defined: 8-week 'pre LTG treatment phase' (before starting with LTG), 16-week 'titration phase' (starting with very low LTG doses), 8-week 'follow-up phase'. Seizure frequency, medication and adverse events were extracted from the electronic diary and evaluated in each particular patient. The individual reduction of seizure frequency per day was defined as primary outcome variable. Additionally, a dose-effect-relationship was analyzed for each patient., Results: Six out of ten patients were seizure free during the follow-up phase. Statistical analysis indicated a significant seizure reduction in seven patients at follow-up compared to the pre LTG treatment phase. Seizure frequency did not significantly decrease in two patients and increased in one patient. A significant relationship between seizure frequency per day and LTG dosage during titration and follow-up phase could be demonstrated in nine patients. Group statistics using the exact Wilcoxon test revealed a significant reduction in seizure frequency (p = 0.049, two-sided)., Conclusion: Our data provide evidence that adjunctive LTG is an eligible therapeutic option for the treatment of pharmacoresistant MAE and encourage further prospective studies to verify this observation., (Copyright © 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background: Antiepileptic treatment response has been suggested to be modulated by genetic polymorphisms of drug efflux transporters, in particular ABCB1. Recently, we found a significant association of ABCC2 -24C>T with nonresponse, primarily in the context of generalized epilepsy. Moreover, ABCC2 1249G>A was reported to alter transmembranal carbamazepine transport. Therefore, we aimed to confirm the association of ABCC2 variants with pharmacotherapy-resistance in Caucasians mainly affected by partial epilepsy., Patients and Methods: A total of 208 patients (114 male; age: 11.3±5.9 years) were genotyped for three putatively functionally relevant polymorphisms of ABCC2 (-24C>T, 1249G>A, 3972C>T). Genotype and haplotype frequencies were compared between responders and nonresponders to first-line antiepileptic treatment., Results: Carriers of the ABCC2 1249G>A variant (417V>I) were more frequent among responders [odds ratio (OR)=2.68 (1.25-5.78); P=0.010]. This association remained significant after adjusting for age, sex and seizure type, [OR=2.88 (1.23-6.73); P=0.015]. The impact of 1249G>A was more pronounced among 64 patients receiving carbamazepine or oxcarbazepine (P=0.005), but nonsignificant in patients receiving other anticonvulsants. ABCC2 -24C>T and 3972C>T showed lack of association to therapy response. Haplotype analyses revealed that haplotype H2 containing solely the 1249A variant allele was more frequent in the responder group [OR=2.98 (1.38-6.44); P=0.004]., Discussion: These data argue for a greater probability of antiepileptic drug response among carriers of the ABCC2 1249A variant that is associated with reduced carbamazepine transport. Although we could not confirm an impact of ABCC2 -24C>T, these results suggest that ABCC2 genotype may also modulate the response to anticonvulsants besides the extensively studied ABCB1 (P-glycoprotein).

Purpose: Patients with idiopathic generalized epilepsies (IGEs) often present with interictal spike-wave discharges (SWDs) at rest (spontaneous SWDs), during hyperventilation, and in response to photic stimulation (photoparoxysmal response or PPR). Valproic acid (VPA) is a first-line antiepileptic drug for therapy of patients with IGE. Herein we investigated the effect of VPA on all three types of SWDs in children and adolescents with IGE., Methods: Routine electroencephalography (EEG) during wakefulness, which was recorded before VPA monotherapy and up to four times during the first year of the VPA treatment, was analyzed retrospectively. For the analysis of the VPA effect on spontaneous SWDs and SWDs under hyperventilation, the number and duration of SWDs were counted. SWDs under intermittent photo stimulation (IPS) were classified according to the extent of propagation (grading). Response to VPA treatment (rest/hyperventilation) was defined as a disappearance of SWDs within the year after VPA introduction., Key Findings: Eighty-four patients (37 male and 47 female, mean age 9.5 ± 4.1 years) exhibited spontaneous SWDs or SWDs under hyperventilation. From this sample, 34 patients exhibited the PPR (7 male and 27 female, mean age 10.1 ± 3.9 years). A significant reduction in the number and duration of spontaneous SWDs and SWDs under hyperventilation was observed in the first 6 weeks of treatment (p ≤ 0.001, corrected, 87.3% responders). This effect remained stable over the 1 year observation period. Concerning PPR, only 4 (12.9%) of 31 patients were classified as responders. The difference between groups of patients with spontaneous/induced SWDs and PPR according to the number of responders was significant (p<0.001)., Significance: This study provides evidence that the effect of VPA on SWDs differs dependent on the types of SWDs. In the majority of patients, spontaneous SWDs and SWDs induced by hyperventilation disappeared, whereas the PPR mostly remained under VPA treatment. These results point to different pathogenetic mechanisms underlying the spontaneous and the evoked generalized epileptic activity in the EEG., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Voltage-gated calcium channels are key elements in regulating neuronal excitability and are thus of central importance in the pathogenesis of various forms of epilepsies. Among these, absence epilepsies represent about 10% of epileptic seizures in humans. They are electroencephalographically characterized by bilateral synchronous spike-wave discharge activity associated with loss or severe impairment of consciousness. Extensive studies during the last decades revealed that pathophysiologically increased oscillatory activity, i.e., hyperoscillation within the reticulothalamocortical circuitry, is the electrophysiological correlate of absence epilepsy, with extrathalamocortical structures, e.g., brainstem and cerebellum, projecting to the thalamocortical circuitry, thereby modulating its activity. Voltage-gated calcium channels are one of the central players regulating the transition from tonic to rebound burst-firing modes in both thalamic relay and reticular thalamic nucleus neurons, the burst-firing mode being the substrate of the thalamocortical oscillation. Thus, pharmacological interference with these channels enables effective control of spike-wave discharge activity in patients suffering from absence seizures. In this review, we summarize the medical history of absence epilepsies, their classification and terminology, the diagnostic armamentarium available today and the etiopathogenesis of absences. Finally, various antiepileptic drugs that have been proven to or are supposed to exert anti-absence effects are discussed with respect to their pharmacodynamics and pharmacokinetics.

Objective: We aimed to evaluate the association of non-response to antiepileptic pharmacotherapy with the frequency of variant alleles in the drug transporter genes ABCB1 and ABCC2 or in the CYP2C locus in young patients with epilepsy and an independent cohort of adults with drug-refractory epilepsy., Methods: A total of 221 pediatric or adolescent Caucasian patients with epilepsy (105 females; age: 14.5+/-6.54 years) were genotyped for nine putatively functionally relevant ABCB1, ABCC2, CYP2C8, CYP2C9, and CYP2C19 polymorphisms. In addition, 70 adult patients (35 females, age: 41.9+/-11.5 years) with drug-refractory epilepsy who had earlier undergone neurosurgical therapy were genotyped and partly (n = 22) investigated for hippocampal ABCB1 and ABCC2 mRNA expression. Finally, 242 healthy volunteers (167 females, age: 27.0+/-6.77 years) from the same region were included as controls., Results: The young cohort consisted of 103 (46.6%) responders and 118 (53.4%) non-responders to the first-line anticonvulsant. Carriers of the putatively low-expression ABCC2 -24T variant were significantly overrepresented among non-responders [odds ratio (OR) 2.15 (1.16-3.99); P = 0.016)]. This overrepresentation was confirmed by comparing young responders with adult drug-refractory patients [OR 3.36 (1.71-6.59); P<0.001]. Conversely, ABCB1 genotype distribution did not significantly differ between young responders and non-responders or adult drug-refractory patients. Excluding patients with febrile convulsions, heterozygous CYP2C8*4 [OR 0.35 (0.13-0.95); P = 0.038] and CYP2C9*3 [OR 0.34 (0.14-0.81); P = 0.015] variant allele carriers were underrepresented among non-responders. ABCC2 -24C>T genotype did not affect hippocampal ABCC2 expression, but was associated with increased ABCB1 expression (P = 0.034)., Conclusion: These data suggest a higher risk of antiepileptic drug failure in ABCC2 -24T allele carriers possibly because of compensatory upregulation of ABCB1.

Status epilepticus is a frequent neurologic emergency that is refractory to benzodiazepines and phenytoin in 60% to 70% of cases. Patients commonly require management in an intensive care unit incorporating aggressive treatment with intravenous anaesthetics. Treatment guidelines commonly comment on initial pharmacologic management in detail, as they can refer to data from randomised controlled trials. In contrast, recommendations for the management of refractory status epilepticus often are sparse, as they rely on data from retrospective or uncontrolled prospective studies only. Since status epilepticus is refractory in every third patient, a critical analysis of the available data and a review focussing on the further management of this condition are urgently needed. The Koenigstein Team, a panel of expert epileptologists and neuropediatricians, discussed at its 31(st) meeting in March 2006 the clinical and experimental aspects and implicit prognostic variables of refractory status epilepticus. Here we present the results of that discussion and state recommendations from a neurologic and neuropediatric perspective for current und future management of refractory status epilepticus.

Sulthiame is a carbonic anhydrase inhibitor that is widely used to treat partial and myoclonic seizures. In 11 healthy adults, we applied transcranial magnetic stimulation (TMS) to the primary motor cortex. Using a cross-over study design, we found that a single oral dose of sulthiame (5 mg/kg) produced a significant increase of resting motor threshold relative to placebo. No other TMS measure of corticomotor excitability was altered after a single dose of sulthiame. The selective increase in motor threshold suggests that sulthiame produces its antiepileptic effect by reducing the axonal excitability of cortical neurons.

Lamotrigine is a broadly effective antiepileptic drug in mono- and add-on therapy for children and adolescents with focal and generalized epilepsies. Some epileptologists consider lamotrigine as the drug of primary choice in older school children and adolescents because of its good tolerability (no increase of body weight, no impairment of cognitive functions, due to new data probably no teratogenic properties). Lamotrigine can be used with good efficacy in numerable epilepsy diseases, such as tuberous sclerosis, juvenile neuronal lipofuscinosis and Rett syndrome. The first studies show that lamotrigine is also effective in children under 2 years of age. For therapy of difficult-to-treat epilepsies the combination of lamotrigine with valproate has proved as especially useful. This clinical observation is supported by new results of animal experiments. The dose-dependant and typical CNS side effects vertigo, ataxia, nausea, tremor and diplopia are found most frequently. The rate of allergic skin rashes which was very high before 1998 has decreased markedly by new dosage guidelines and is now as low as in older antiepileptic drugs. Lamotrigine does not impair cognitive functions, especially not memory and language. It has mood-stabilizing features and may improve quality of life. In animal experiments lamotrigine shows antiepileptogenic and neuroprotective effects.

Provocation of various seizure types including epileptic negative myoclonus and generalised atonic seizures is rarely observed in children treated with carbamazepine (CBZ). Provocation of the latter seizure types by oxcarbazepine (OXC) is not described in the literature. We report a four year-old boy with symptomatic epilepsy caused by left-sided cerebral atrophy of unknown origin who developed numerous daily drop attacks when exposed to OXC. Polygraphic analysis revealed secondary generalised precentral sharp-slow waves frequently associated with a silent period lasting for 100-150 ms in the electromyogram recorded from the deltoid and neck muscles. These seizures stopped promptly within 36 hours after discontinuation of OXC. This case demonstrates that OXC, similar to CBZ, can provoke epileptic negative myoclonus in some children with focal epilepsies. [Published with videosequences].

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