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This prospective observational study evaluated the long-term EEG changes in children treated with everolimus (EVO) for refractory TSC-associated epilepsy. Changes in EEG-abnormalities were related to developmental outcomes.Thirteen children treated with EVO were examined for EEG-recorded seizures and interictal epileptic discharges (IED) during a 72-hour-video-EEG-monitoring, which was performed at baseline and repeated at follow-up intervals of at least 9 months. Antiseizure medication was left unchanged for at least 27 months. Changes in cognitive developmental parameters were related to reduction of seizures and IED at the last monitoring.We found a significant reduction of recorded seizures and IED during sleep at the first as well as the last follow-up recording. The reduction of IED was especially prominent during sleep. For patients who continued for more than one monitoring under EVO (n = 8), number of seizures further decreased. In patients with developmental examination (n = 9), we observed that only (nearly) full cessation of IED was related to acquisition of new skills.In children with TSC, EVO was effective in reducing recorded seizures and IED; long-term EVO treatment led to a more pronounced reduction and an improvement of nocturnal IED even when the patient was initially not seizure-free. Cessation of IED in children with developmental improvement may point to the importance of healthy sleep for cognition.

Das Thema SUDEP („sudden unexpected death in epilepsy“) ist in den letzten Jahren auch in Bezug auf Kinder und Jugendliche mit Epilepsie zunehmend in den Fokus geraten. Die Datenlage ist fur diese Altersgruppe allerdings sehr heterogen. Dies erschwert ein Beratungsgesprach mit den Eltern. Einordnung der unterschiedlichen Fallzahlen zum Thema „SUDEP bei Kindern und Jugendlichen“ als Grundlage fur Gesprache mit Patienten und ihren Eltern. Systematische Literaturrecherche in PubMed, Sichtung und Zusammenstellung der relevanten padiatrischen Literatur. Unterscheidung von 3 Typen von Studien: populationsbasierte Studien, Arbeiten auf Basis von Patienten mit Epilepsien und Arbeiten auf Basis von Todesfallen. Anschliesende Zusammenstellung der Arbeiten und Einordnung der unterschiedlichen Pravalenzzahlen z. B. anhand methodischer Unterschiede. Es waren 3 populationsbasierte Arbeiten, 13 monozentrische Studien an Epilepsiepatienten und 8 Publikationen unter Hinzuziehung von Todesfallregistern zu finden. Die Haufigkeitsangaben fur SUDEP im Kindesalter schwanken von 1,3 bis 14,5 pro 10.000 Patientenjahre. Es existiert keine Studie im padiatrischen Bereich mit mehr als 20 Betroffenen. Die Studien weisen deutliche methodische Unterschiede auf, die eine Vergleichbarkeit erheblich erschweren. Dies erklart auch zumindest teilweise die unterschiedlichen Ergebnisse und daraus resultierenden Einschatzungen. Eine Vergleichbarkeit der publizierten Daten ist aufgrund fehlender Angaben zur altersgruppenbezogenen Pravalenz von Epilepsien im Untersuchungskollektiv schwierig. Ergebnisse beruhen nicht selten auf Annahmen der Autoren zur Pravalenz oder extrapolierten Daten. Die Angaben zur Pravalenz von Epilepsien schwanken, was gerade bei sehr niedrigen Fallzahlen eine erhebliche Auswirkung auf die Haufigkeit z. B. von SUDEP haben kann. Unabhangig von der angewandten Methodik sind die in den Studien angegebenen Fallzahlen fur die Population von Kindern mit Epilepsie gering. Bestimmte Atiologien und/oder Epilepsiesyndrome gehen mit einem erhohten Risiko einher. Es sind jedoch auch SUDEP-Falle bei fur gewohnlich gutartig verlaufenden Epilepsieformen beschrieben worden.

Background and ObjectiveThe spectrum of myelin oligodendrocyte glycoprotein (MOG) antibody–associated disorder (MOGAD) comprises monophasic diseases such as acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), and transverse myelitis and relapsing courses of these presentations. Persistently high MOG antibodies (MOG immunoglobulin G [IgG]) are found in patients with a relapsing disease course. Prognostic factors to determine the clinical course of children with a first MOGAD are still lacking. The objective of the study is to assess the clinical and laboratory prognostic parameters for a risk of relapse and the temporal dynamics of MOG‐IgG titers in children with MOGAD in correlation with clinical presentation and disease course.MethodsIn this prospective multicenter hospital-based study, children with a first demyelinating attack and complete data set comprising clinical and radiologic findings, MOG-IgG titer at onset, and clinical and serologic follow-up data were included. Serum samples were analyzed by live cell-based assay, and a titer level of ≥1:160 was classified as MOG-IgG–positive.ResultsOne hundred sixteen children (f:m = 57:59) with MOGAD were included and initially diagnosed with ADEM (n = 59), unilateral ON (n = 12), bilateral ON (n = 16), myelitis (n = 6), neuromyelitis optica spectrum disorder (n = 8) or encephalitis (n = 6). The median follow-up time was 3 years in monophasic and 5 years in relapsing patients. There was no significant association between disease course and MOG-IgG titers at onset, sex, age at presentation, or clinical phenotype. Seroconversion to MOG-IgG–negative within 2 years of the initial event showed a significant risk reduction for a relapsing disease course. Forty-two/one hundred sixteen patients (monophasic n = 26, relapsing n = 16) had serial MOG-IgG testing in years 1 and 2 after the initial event. In contrast to relapsing patients, monophasic patients showed a significant decrease of MOG-IgG titers during the first and second years, often with seroconversion to negative titers. During the follow-up, MOG-IgG titers were persistently higher in relapsing than in monophasic patients. Decrease in MOG-IgG of ≥3 dilution steps after the first and second years was shown to be associated with a decreased risk of relapses. In our cohort, no patient experienced a relapse after seroconversion to MOG-IgG–negative.DiscussionIn this study, patients with declining MOG-IgG titers, particularly those with seroconversion to MOG-IgG–negative, are shown to have a significantly reduced relapse risk.

Purpose To investigate the efficacy and tolerability of long-term treatment with Everolimus (EVO) in patients with tuberous sclerosis complex (TSC) and therapy-resistant epilepsy in a compassionate use trial. Methods After a 3-month baseline, patients were treated with EVO. Treatment was divided into treatment phases each lasting at least 9 months. Patients started with one of three target serum levels. In case of insufficient seizure control, subsequent treatment phases with other target serum levels followed. The accompanying antiseizure medication (ASM) remained stable during the baseline phase and for at least the initial three treatment phases. We evaluated changes in seizure frequency and seizure-free days compared to baseline for each patient (Cox-Stuart-test). Results Fifteen patients were followed up for up to 10 years (minimum 0.6 years, median 5.8 years). Twelve patients (80%) experienced a significant reduction in seizure frequency or an increase in seizure-free days: Six (40%) patients became seizure-free and four patients (26.7%) remained seizure free for > 7 years, of which three required no additional ASM. All participants reported at least one adverse effect, the vast majority (92.5%) of which were mild or moderate. Conclusion Long-term treatment with EVO was highly efficacious, safe and well tolerated. While EVO can be a therapeutic option for therapy-resistant epilepsy in TSC, it can take a long time for seizure relief to manifest.

Context 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting This was a multicenter retrospective study using information collected from 3 predominant centers. Patients A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder., Canadian Institutes of Health Research [201610PJT-377869, MOP-G2-341146-159133-BRIDG]; Fondation Les Amis d'Elliot; Leuco-Action; Fondation Lueur d'Espoir pour Ayden; Fondation le Tout pour Loo; Reseau de Medecine Genetique Appliquee of the Fonds de Recherche du Quebec-Sante; Compute Canada; Fonds de Recherche du Quebec en Sante (FRQS) Doctoral Scholarship; Fondation du Grand defi Pierre Lavoie Doctoral Scholarship; McGill Faculty of Medicine F. S.B. Miller Fellowship; Research Institute of the McGill University Health Centre Desjardins Studentship in Child Health Research; Directorate of Higher Education Overseas Scholarship-Dikti Scholarship, Ministry of National Education, Republic of Indonesia; CIHR [201603PJT-148695]; BC Children's Hospital Foundation through its intramural Investigator Grant Award Program (IGAP); National Institute for Neurological Disorders and Stroke [R01NS082094]; Jakob Kamens Chair in Translational Neurotherapeutics; Fonds de Recherche du Quebec-Sante (FRQS); Canadian Institutes of Health Research; European Reference Network for Rare Neurological Disorders (ERN-RND) [739510], This study was supported by grants from the Canadian Institutes of Health Research (201610PJT-377869, MOP-G2-341146-159133-BRIDG), Fondation Les Amis d'Elliot, Leuco-Action, Fondation Lueur d'Espoir pour Ayden, Fondation le Tout pour Loo, and Reseau de Medecine Genetique Appliquee of the Fonds de Recherche du Quebec-Sante to G. Bernard. This research was enabled in part by support provided by Compute Canada (www.computecanada.ca).S.Perrier is supported by the Fonds de Recherche du Quebec en Sante (FRQS) Doctoral Scholarship, the Fondation du Grand defi Pierre Lavoie Doctoral Scholarship, the McGill Faculty of Medicine F. S.B. Miller Fellowship, and the Research Institute of the McGill University Health Centre Desjardins Studentship in Child Health Research. F. K.C. is a recipient of the Directorate of Higher Education Overseas Scholarship-Dikti Scholarship, Ministry of National Education, Republic of Indonesia. W.T. G. received funding from the CIHR (201603PJT-148695) and is supported by the BC Children's Hospital Foundation through its intramural Investigator Grant Award Program (IGAP). B.L. F. was supported by the National Institute for Neurological Disorders and Stroke (R01NS082094). A.V. receives funding from the Jakob Kamens Chair in Translational Neurotherapeutics. G. Bernard has received a Research Scholar Junior 1 award from the Fonds de Recherche du Quebec-Sante (FRQS) (2012-2016) and the New Investigator Salary Award from the Canadian Institutes of Health Research (2017-2022). I.K.M., M. Synofzik, D. Tonduti, B.P.v.d.W., M.S. V.d.K., and N.I.W. are members of the European Reference Network for Rare Neurological Disorders (ERN-RND), project ID 739510.

ObjectiveTo describe the clinical and genetic findings in a cohort of individuals with bathing epilepsy, a rare form of reflex epilepsy.MethodsWe investigated by Sanger and targeted resequencing the SYN1 gene in 12 individuals from 10 different families presenting with seizures triggered primarily by bathing or showering. An additional 12 individuals with hot-water epilepsy were also screened.ResultsIn all families with bathing epilepsy, we identified 8 distinct pathogenic or likely pathogenic variants and 2 variants of unknown significance in SYN1, 9 of which are novel. Conversely, none of the individuals with hot-water epilepsy displayed SYN1 variants. In mutated individuals, seizures were typically triggered by showering or bathing regardless of the water temperature. Additional triggers included fingernail clipping, haircutting, or watching someone take a shower. Unprovoked seizures and a variable degree of developmental delay were also common.ConclusionBathing epilepsy is genetically distinct reflex epilepsy caused mainly by SYN1 mutations.

Purpose Focal cortical dysplasia (FCD) is the major cause of focal intractable epilepsy in childhood. Here we analyze the factors influencing the success of surgical treatment in a large cohort of children with histologically ascertained FCD. Method A retrospective study of the effects of FCD type, surgical intervention, and age at surgery in a pediatric cohort. Results A total of 113 patients (71 male; mean age at surgery 10.3 years; range 0–18) were analyzed; 45 had undergone lesionectomy, 42 lobectomy, 18 multi-lobectomy, and eight hemispherotomy. Complete seizure control (Engel Ia) was achieved in 56% after two years, 52% at five years, and 50% at last follow-up (18–204 months). Resections were more extensive in younger patients (40% of the surgeries affecting more than one lobe in patients aged nine years or younger vs. 22% in patients older than nine years). While resections were more limited in older children, their long-term outcome tended to be superior (42% seizure freedom in patients aged nine years or younger vs. 56% in patients older than nine years). The outcome in FCD I was not significantly inferior to that in FCD II. Conclusions Our data confirm the long-term efficacy of surgery in children with FCD and epilepsy. An earlier age at surgery within this cohort did not predict a better long-term outcome, but it involved less-tailored surgical approaches. The data suggest that in patients with an unclear extent of the dysplastic area, later resections may offer advantages in terms of the precision of surgical-resection planning.

Die Pravalenz von Kopfschmerzen bei Kindern und Jugendlichen ist hoch. Da ein Teil dieser Kopfschmerzen moglicherweise auf eine funktionelle Storung der oberen Halswirbelgelenke zuruckzufuhren ist, konnte manuelle Therapie effektiv sein. Kontrollierte Therapiestudien fehlen weitgehend, daher wurde ein hausliches Selbsthilfeprogramm mit einer einmaligen Manualtherapie verglichen. Insgesamt wurden 67 Kinder im Alter von 6 bis 17 Jahren untersucht und behandelt. Einschlusskriterien waren mindestens 1 Kopfschmerzereignis pro Woche innerhalb von 30 aufeinanderfolgenden Tagen und der Nachweis einer signifikanten Bewegungsstorung der oberen Halswirbelsaule (HWS). Die Kinder wurden in 2 Behandlungsgruppen randomisiert: Eine Gruppe fuhrte Entspannungs- und Ablenktechniken durch, die andere erhielt eine einmalige manuelle Intervention. Die taglichen Kopfschmerzereignisse, Kopfschmerzdauer und -starke, Medikamenteneinnahme sowie Ausfall von Freizeitaktivitat und Schulbesuch wurden 30 Tage vor und nach der Behandlung dokumentiert. Beide Therapieverfahren zeigten zum Zeitpunkt der Folgeuntersuchung eine hochsignifikante Reduktion der Kopfschmerzereignisse. Zwischen beiden Verfahren bestand kein statistisch relevanter Unterschied, aber es gab einen Trend zu einem wirksameren Ansprechen der Manipulation. Die anderen Parameter zeigten ebenfalls signifikante Besserungen, aber es waren keine statistisch relevanten Unterschiede zwischen beiden Verfahren zu erkennen. Gemessen an der Haufigkeit der alternativen Behandlungen erscheint eine einmalige manuelle Masnahme von Vorteil, erfordert allerdings spezielle therapeutische Fertigkeiten des Anwenders. Sie kann im Einzelfall sinnvoll sein, wenn standardisierte Behandlungsformen langfristig nicht wirksam sind.

BACKGROUND Although multilobar resections correspond to one-fifth of pediatric epilepsy surgery, there are little data on long-term seizure control. OBJECTIVE To investigate the long-term seizure outcomes of children and adolescents undergoing multilobar epilepsy surgery and identify their predictors. METHODS In this retrospective study, we considered 69 consecutive patients that underwent multilobar epilepsy surgery at the age of 10.0 ± 5.0 yr (mean ± SD). The magnetic resonance imaging revealed a lesion in all but 2 cases. Resections were temporo-parieto(-occipital) in 30%, temporo-occipital in 41%, parieto-occipital in 16%, and fronto-(temporo)-parietal in 13% cases. Etiologies were determined as focal cortical dysplasia in 67%, perinatal or postnatal ischemic lesions in 23%, and benign tumors in 10% of cases. RESULTS At last follow-up of median 9 yr (range 2.8-14.8), 48% patients were seizure free; 33% were off antiepileptic drugs. 10% of patients, all with dysplastic etiology, required reoperations: 4 of 7 achieved seizure freedom. Seizure recurrence occurred mostly (80%) within the first 6 mo. Among presurgical variables, only an epileptogenic zone far from eloquent cortex independently correlated with significantly higher rates of seizure arrest in multivariate analysis. Among postsurgical variables, the absence of residual lesion and of acute postsurgical seizures was independently associated with significantly higher rates of seizure freedom. CONCLUSION Our study demonstrates that multilobar epilepsy surgery is effective regarding long-term seizure freedom and antiepileptic drug withdrawal in selected pediatric candidates. Epileptogenic zones–and lesions–localized distant from eloquent cortex and, thus, fully resectable predispose for seizure control. Acute postsurgical seizures are critical markers of seizure recurrence that should lead to prompt reevaluation.

Bilateral optic neuritis (bilON) is a rare clinical presentation often thought to be associated with relapsing disorders such as neuromyelitis optica spectrum disorders (NMOSD) or multiple sclerosis (MS).To characterize the clinical, radiological phenotype and antibody status of children presenting with bilON.Retrospective multicenter study on children with bilON age18 years with a first episode aquired demyelinating syndrome (ADS), cMRI, AQP4- and serum MOG-antibody status and follow-up data were collected.30 patients (f:m = 15:15, median age 8.0y) with bilON met the inclusion criteria. 22/30 (73%) were MOG-positive (median: 1:1280, range: 1:160-1:1520). No patient showed AQP4-abs. 4/30 patients (13%), all with high MOG-abs titers, had recurrent episodes. No patient developed MS. Improvement after IVMP was observed in most patients (26/30; 87%). Outcome was favorable with no sequelae in 22/30 patients. Serial MOG-abs titers tested in 15/22 patients decreased to a median of 1:160 (range: 0-1:640) over a period of 31 months (range: 2-141 months) in 14/15 (93%) patients. MR imaging showed a predominantly anterior affection of the visual system in seropositive patients with bilateral intraorbital lesions in 68% (15/22), compared to 25% in MOG-negative patients (2/8).Pediatric bilON is associated with high MOG-abs titers in combination with anterior involvement of the visual system. Despite severe loss of vision, the majority of patients shows distinct recovery after IVMP.

The natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care and development of targeted treatments. Nusinersen was the first drug approved for the treatment of all SMA patients. The transfer of clinical trial data into a real-life environment is challenging, especially regarding the advice of patients and families to what extent they can expect a benefit from the novel treatment. We report the results of a modified Delphi consensus process among child neurologists from Germany, Austria and Switzerland about the indication or continuation of nusinersen treatment in children with SMA type 1 based on different clinical case scenarios.

Background Although the majority of children undergoing epilepsy surgery are younger than 3 yr at epilepsy manifestation, only few actually receive surgical treatment in early childhood. Past studies have, however, suggested that earlier intervention may correlate with superior developmental outcomes. Objective To identify predictors for long-term seizure freedom and cognitive development following epilepsy surgery in the first 3 yr of life and determine the appropriate timing for surgical treatment in this age group. Methods We retrospectively analyzed the data of 48 consecutive children aged 1.1 ± 0.7 yr at surgery. Results Final surgeries comprised 52% hemispherotomies, 13% multilobar, and 35% intralobar resections. Etiology included cortical malformations in 71%, peri- or postnatal ischemic lesions in 13%, and benign tumor or tuberous sclerosis in 8% each. At last follow-up (median 4.3, range 1-14.3 yr), 60% of children remained seizure-free: 38% had discontinued antiepileptic drugs. Intralobar lesionectomy resulted more often in seizure control than multilobar or hemispheric surgery. Postsurgical seizure freedom was determined by the completeness of resection. Early postsurgical seizures were key markers of seizure recurrence. Presurgical adaptive and cognitive developmental status was impaired in 89% children. Longer epilepsy duration and larger lesion extent were detrimental to presurgical development, which, in turn, determined the postsurgical developmental outcome. Conclusion Our study demonstrates that epilepsy surgery in very young children is safe as well as efficient regarding long-term seizure freedom and antiepileptic drug cessation in selected candidates. Longer epilepsy duration is the only modifiable predictor of impaired adaptive and cognitive development, thus supporting early surgical intervention.

Objective There is increasing awareness of neuronal autoantibodies and their impact on the pathogenesis of epilepsy. We investigated children with focal epilepsy in order to provide an estimate of autoantibody frequency within a pediatric population without prima facie evidence of encephalitis using a broad panel of autoantibodies. This was done to assess the specificity of antibodies and to see whether antibodies might be of modifying influence on the course of focal epilepsies. Method We searched for autoantibodies in 124 patients with focal epilepsy (1–18 years; mean 10; 6 years). Sera were tested using a broad panel of surface and intracellular antigens. Results We found autoantibodies in 5/124 patients (4%): high-positive GAD65 antibodies ( n = 1), low-positive GAD65 antibodies ( N = 1), VGKC complex antibodies not reactive with LGI1 or CASPR2 ( n = 3). We did not find any distinctive features distinguishing antibody positive patients from those without antibodies. Conclusions The antibodies found in this cohort are probably neither disease-specific nor pathogenic. This has been suggested before for these antigenic targets. Moreover, they do not seem to modify disease severity in the antibody-positive epilepsy patients.

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.

Background Although frontal lobe resections account for one-third of intralobar resections in pediatric epilepsy surgery, there is a dearth of information regarding long-term seizure freedom, overall cognitive and adaptive functioning. Objective To identify outcome predictors and define the appropriate timing for surgery. Methods We retrospectively analyzed the data of 75 consecutive patients aged 10.0 ± 4.9 yr at surgery that had an 8.1 yr mean follow-up. Results Etiology comprised focal cortical dysplasia (FCD) in 71% and benign tumors in 16% cases. All patients but one had a magnetic resonance imaging-visible lesion. At last follow-up, 63% patients remained seizure-free and 37% had discontinued antiepileptic drugs. Presurgical predictors of seizure freedom were a shorter epilepsy duration, strictly regional epileptic discharges in electroencephalography (EEG), and an epileptogenic zone and/or lesion distant from eloquent cortex. Postsurgical predictors were the completeness of resection and the lack of early postoperative seizures or epileptic discharges in EEG. Higher presurgical overall cognitive and adaptive functioning was related to later epilepsy onset and to a sublobar epileptogenic zone and/or lesion. Following surgery, scores remained stable in the majority of patients. Postsurgical gains were determined by higher presurgical performance and tumors vs FCD. Conclusion Our findings highlight the favorable long-term outcomes following frontal lobe epilepsy surgery in childhood and adolescence and underline the importance of early surgical intervention in selected candidates. Early postsurgical relapses and epileptic discharges in EEG constitute key markers of treatment failure and should prompt timely reevaluation. Postsurgical overall cognitive and adaptive functioning is stable in most patients, whereas those with benign tumors have higher chances of improvement.

Summary 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.

Aims To investigate seizure and developmental outcomes following epilepsy surgery in very young children and determine their predictive factors. Methods We retrospectively reviewed the clinical data, surgical variables, and outcomes of 30 children under 3 years of age that underwent resection for refractory focal epilepsy in our institution in 2001–2011. Results Seizure onset was in the first year of life in 27 (90%) cases and mean age at surgery was 20 months (range 5–33.6). Pathology consisted of cortical malformations in 24 (80%) cases, glioneuronal tumour and infarction with or without cortical dysplasia in three (10%) cases each. Morbidity was comparable with older paediatric cohorts. At 1–11.6 year follow-up (mean 4.1) 21 of 30 (70%) children achieved seizure freedom (Engel I), six (20%) demonstrated worthwhile improvement (Engel II/III) and three (10%) did not benefit from surgery (Engel IV). Intralobar lesionectomy more often resulted in seizure freedom than multilobar or hemispheric surgery. The abundance of non-regional interictal and ictal EEG findings did not preclude seizure freedom. Presurgical developmental impairment was established in 25 of 28 (89%) children; its severity correlated with longer epilepsy duration and determined postoperative developmental outcome. Developmental progress was established in 26 out of 28 (93%) children following surgery, showing stabilized trajectories rather than catch-up. Conclusions Resective surgery in very young children is safe and effective in terms of seizure control and developmental progress. Our findings underline the importance of early intervention in order to timely stop seizures and their deleterious effects on the developing brain.

SummaryObjective We aimed to investigate the long-term seizure outcome of children and adolescents who were undergoing epilepsy surgery in the parietooccipital cortex and determine their predictive factors. Methods We retrospectively analyzed the data of 50 consecutive patients aged 11.1 (mean) ± 5.1 (standard deviation) years at surgery. All patients but one had a magnetic resonance imaging (MRI)–visible lesion. Resections were parietal in 40%, occipital in 32%, and parietooccipital in 28% cases; 24% patients additionally underwent a resection of the posterior border of the temporal lobe. Etiology included focal cortical dysplasia in 44%, benign tumors (dysembryoplastic neuroepithelial tumor, ganglioglioma, angiocentric glioma, and pilocystic astrocytoma) in 32%, peri- or postnatal ischemic lesions in 16%, and tuberous sclerosis in 8% cases. Results At last follow-up (mean 8 years, range 1.5–18 years), 60% patients remained seizure-free (Engel class I): 30% had discontinued and 20% had reduced antiepileptic drugs. Most seizure recurrences (71%) occurred within the first 6 months, and only three patients presented with seizures ≥2 years after surgery. Independent predictors of seizure recurrence included left-sided as well as parietal epileptogenic zones and resections. Longer epilepsy duration to surgery was identified as the only modifiable independent predictor of seizure recurrence. Significance Our study demonstrates that posterior cortex epilepsy surgery is highly effective in terms of lasting seizure control and antiepileptic drug cessation in selected pediatric candidates. Most importantly, our data supports the early consideration of surgical intervention in children and adolescents with refractory posterior cortex epilepsy.

In the presurgical evaluation of children and juvenile patients with refractory focal epilepsy, the main challenge is to localize the point of seizure onset as precisely as possible. We compared results of the conventional electroencephalography-functional magnetic resonance imaging (EEG-fMRI) analysis with those obtained with a newly developed method using voltage maps of average interictal epileptiform discharges (IEDs) recorded during clinical long-term monitoring and with the results of the electric source imaging (ESI).

Aim To investigate the neuronal networks in children with tuberous sclerosis complex (TS) undergoing treatment with Everolimus. Methods Sleep and wake electroencephalography (EEG) before and one year after the start of the treatment with Everolimus were investigated in 13 patients with TS. To investigate functional and effective connectivity within the network generating the delta and theta activity in the background sleep and wake EEG, the methods of dynamic imaging of coherent sources (DICS) and renormalized partial directed coherence (RPDC) were applied. Results Sources before the treatment . Independent of location of the tubera and severity of epilepsy, delta activity in the background EEG pattern in patients with TS was associated with the sources in the medial prefrontal cortex, the supplementary motor area and the putamen during sleep. Theta waves during sleep were associated with sources in the prefrontal cortex, sensory cortex, hippocampus and the thalamus. The sources of delta frequency during wakefulness were identified at the posterior parietal cortex, the parahippocampal gyrus and the Broca area. Sources at theta frequency were found at the sensorymotor cortex, the prefrontal cortex, the primary visual cortex and the thalamus at awake state. Sources after the treatment. The sources one year after the start of the therapy, for both delta and delta frequencies were located in the same areas as before, however with a significantly weaker strength of coherence. The RPDC analysis at baseline showed strong bidirectional connections between described sources. The RPDC analyses after the one year of treatment showed significantly weaker unidirectional connections within the described network. At the follow up patients were grouped in two groups; group 1: five patients with >50% reduction of seizures and spike wave index, group 2: eight patients with Conclusion The current study described the neuronal network in children with severe epilepsies due to TS. Regardless of the locations of the tubera the DICS analyses showed a complex network of cortical and subcortical sources with strong bidirectional connections. The described network was significantly weaker after one year under the treatment with Everolimus and appears to be characteristic for the children with TS and severe epilepsy.

Objective Most studies on seizure detection systems focus more on the effectiveness of devices than on their practicability in and impact on everyday life. Our study investigated the impact of a technical monitoring system on subjective quality of sleep and the lives of affected families. Furthermore, we evaluated the impact of anxiety levels on seizure monitoring and vice versa. Methods Forty-three patients with newly diagnosed epilepsy were included. Initially, the families decided whether they did (group 1, n = 27) or did not (group 2, n = 16) want to use a monitoring device. In group 1, patients were randomly assigned to using Epi-Care® (group 1A, n = 14) or an audio baby monitor (group 1B, n = 13). Quality of life was assessed at two points (t1, at the start of the study and t2, at 5–7 months of follow-up) using the SF-12, Kindl-R, and “Familien-Belastungs-Fragebogen” (German version of the “Impact on Family Scale”). In addition, parental anxiety was measured using the State–Trait Anxiety-Inventory, and subjective quality of sleep was measured using the Pittsburgh Sleep Quality Index. Statistical analysis focused on the possible differences between groups 1 and 2 that may influence parents' decisions and the effects of the presence and types of technical monitoring over time. Results Anxiety levels were not significantly different between the groups with and without monitoring (group 1 vs. group 2). We also found no statistically significant, substantial baseline differences between the Epi-Care® and audio baby monitor groups, with at least medium effect sizes (group 1A vs. group 1B). Parents' health-related mental quality of life measured via the SF-12 increased significantly over time in all groups. By tendency, the fear of further seizures as well as the frequency of cosleeping arrangements in the monitoring group decreased during the study and approached the stable values of the control group. Significance Individual parental anxiety levels are not crucial in the decision regarding the use of a monitoring device. A monitoring system may help some families in certain aspects of daily life. During the first months following a diagnosis of epilepsy, quality of life increases independently of the use of a monitoring system.

We report a case of a 9-year-old boy with normal cognitive and neurological status. Pharmacoresistant epilepsy started at 2 years of age when he woke up from sleep with epigastric painful sensations. During the course, somatosensory seizures with pain in the legs and, from 3.2 years on, gelastic seizures and dyscognitive seizures occurred. High-resolution magnetic resonance image (MRI) of the brain revealed bilateral independent hypothalamic hamartomas in the supramamillary region. After presurgical evaluation, a decision for an endoscopic resection of the bigger, right-sided hamartoma was made. Seizures improved transiently after surgery (Engel 3a). However, no significant improvement was noted 6 months after surgery. As the only negative consequence, a marked weight gain followed surgery. Cognitive functions remained stable. On the basis of this case, we discuss the therapeutic options for this rare condition which include resection of the contralateral hamartoma or stereotactic laser ablation.

Background Reoperations account for >10% in pediatric epilepsy surgery cohorts, and they are especially relevant in young children with catastrophic epilepsy. Objective To determine surgical outcomes and their predictive factors in reoperations for refractory epilepsy in childhood. Methods We retrospectively analyzed presurgical findings, resections, and outcomes of 23 consecutive children who underwent reoperations from 2000 to 2011. Results Etiology included cortical dysplasia with/without glioneuronal tumor in 19 patients (83%), sole glioneuronal tumor in 2, and tuberous sclerosis and Rasmussen encephalitis in 1 each. The reasons for the failure of the initial surgery were functional considerations in 8 (35%), incorrect delineation of the epileptogenic zone in 8 (35%), and resection not performed as initially planned in 7 (30%) cases. Final procedures included 8 (35%) intralobar, 8 (35%) multilobar resections, and 7 (30%) hemispherotomies. Following reoperations, 14 (61%) patients were seizure free, 6 (26%) showed significant or worthwhile improvement, and 3 (13%) did not respond to surgery. Six of 8 patients who underwent the first resection before the age of 3 years, 6 of 8 whose first resection was limited by functional considerations, and all 7 with hemispherotomy as the final resection achieved seizure freedom after reoperation. Conclusion Reoperation is particularly beneficial for selected children with refractory epilepsy associated with cortical dysplasia that did not respond to an initial limited and/or early resection but achieved seizure freedom after extensive procedures. When indicated, reoperation should be performed at the youngest possible age to profit from higher functional plasticity in compensating for neurological deficit.

Background Tuberous Sclerosis Complex (TSC) is an often severe neurodevelopmental disorder caused by overactivation of the mTOR pathway due to mutations in either the TSC1 or TSC2 genes. Seizures are the primary cause of neurologic morbidity and often refractory. The mTOR inhibitor everolimus was recently approved for the treatment of giant cell astrocytomas and renal angiomyolipomas in TSC. Whether everolimus has any direct effect on epilepsy in TSC is not known. Methods Within the framework of a compassionate use trial, we evaluated the safety and efficacy of everolimus in seven patients with TSC and intractable epilepsy. We evaluated seizure frequency, seizure-free days and adverse effects including standard laboratory parameters. Seizure frequency was analysed in each patient using a non-parametric test for trend and using a Generalized Estimating Equations Model in the total patient group. The observation period was continued for nine months. Results One patient discontinued the medication at the beginning of the observation period due to side effects (flushing). In the remaining 6 patients, we observed a reduction of seizures in 4/6 patients with a reduction of 25–100%. In addition, the percentage of seizure-free days increased in 3/4 of these patients. In 2/6 patients, no alteration of seizure frequency was noted. We observed an increase of mild infections and an increase of triglycerides and various liver function tests. We did not encounter life-threatening infections or other side effects of everolimus. Interpretation In some patients with TSC, everolimus may have an anticonvulsant effect with a reduction in seizure frequency and increase of seizure-free days. Everolimus was well tolerated, with adverse effects similar to those reported in previous studies.

Summary Purpose To evaluate the seizure control and developmental outcomes after hemispherotomy for refractory epilepsy in childhood and to identify their predictive factors. Methods We retrospectively studied the clinical courses and outcomes of 52 children with refractory epilepsy who underwent hemispherotomy in the Epilepsy Center Freiburg between 2002 and 2011. Key Findings Mean age at epilepsy onset was 1.8 years (range 0–8 years) and mean age at surgery was 6.7 years (range 6 months–18 years). The underlying etiology was congenital in 22 (42%) children, acquired in 24 (46%), and progressive in 6 (12%). At final follow-up of 1–9.8 years (mean 3.3), 43 children (83%) were seizure-free. Seizure outcome was not correlated to etiology, with the exception of hemimegalencephaly that was linked to poor seizure control. Presurgical development was impaired in all but one child. Postsurgical development highly correlated with presurgical development. Patients with acquired or progressive etiology, later epilepsy onset, and subsequent later surgery exhibited higher presurgical developmental status that substantially determined postoperative developmental outcome. Improved postsurgical development was determined by acquired etiology and seizure freedom off antiepileptic drugs. Significance In our study, most of the selected children and adolescents achieved seizure freedom, including those with congenital etiology. Developmental outcomes, however, were superior in patients with acquired etiology and older age at surgery, underscoring that it is never too late to reap the benefits of this procedure in terms of both epilepsy and development.

In the presurgical evaluation of children and juvenile patients with refractory focal epilepsy, the main challenge is to localize the point of seizure onset as precisely as possible. We compared results of the conventional electroencephalography-functional magnetic resonance imaging (EEG-fMRI) analysis with those obtained with a newly developed method using voltage maps of average interictal epileptiform discharges (IEDs) recorded during clinical long-term monitoring and with the results of the electric source imaging (ESI).Simultaneous EEG-fMRI was recorded in nine patients (ages 1.5-17.5 years) undergoing presurgical evaluation. The postoperative outcome and resected area were compared with the following: the localizations of blood oxygen-level dependent (BOLD) signal changes associated with IEDs, which were identified by visual inspection changes using SPM5 software (Analysis I); BOLD signal changes related to IED topography, which was characterized using spike-specific voltage maps of average IED recorded outside the MR scanner during clinical long-term monitoring (Analysis II); as well as results of EEG source analysis based on the distributed linear local autoregressive average (LAURA) algorithm using the Cartool software by Denis Brunet (Analysis III).All nine patients had postoperative outcome Engel class I-IIb (postoperative time 6-26 months). The analysis I revealed an IED-related area of activation within the resection area in 3 (33%) of 9 patients, analysis II was able to reliably localize the source of epileptic activity in 4 (44%) of 9 patients, and analysis III rendered results concordant with the postoperative resection site in all nine patients.The localization of seizure onset based on EEG-fMRI may be a useful adjunct in the preoperative evaluation but also has some deficits that impair the reliability of results. In contrast, EEG source analysis is clearly a more credible method for epileptic focus localization in children with refractory epilepsies. It seems likely that the analysis based on IED topography (Analysis II) may increase sensitivity and reliability of EEG-fMRI in some patients. However, the benefit from this innovative method in children is rather limited compared with adults.

Summary Background Duchenne muscular dystrophy is a rare X-linked progressive disease characterised by loss of ambulation at about age 10 years, with death in early adulthood due to respiratory and cardiac insufficiency. Steroids are effective at slowing the progression of muscle weakness; however, their use is limited by side-effects, prompting the search for alternatives. We assessed the effect of ciclosporin A as monotherapy and in combination with intermittent prednisone for the treatment of ambulant patients with this disorder. Methods Our study was a parallel-group, placebo-controlled, double-blind, multicentre trial at trial sites of the German muscular dystrophy network, MD-NET, over 36 months. Ambulant patients with Duchenne muscular dystrophy who were aged 5 years or older were randomly assigned to receive either ciclosporin A (3·5–4·0 mg/kg per day) or matching placebo. Allocation was done centrally with computer-generated random numbers. Patients and investigators were masked to the allocated treatment. After 3 months of treatment, both groups were also given intermittent prednisone for a further 12 months (0·75 mg/kg, alternating 10 days on with 10 days off). All patients who received at least one dose of study drug or placebo were included in the primary analysis. The primary outcome measure was manual muscle strength measured on the Medical Research Council (MRC) scale. This trial is registered with the German clinical trial register DRKS, number DRKS00000445. Findings 77 patients were randomly assigned to the ciclosporin A group and 76 to the placebo group; 73 patients on ciclosporin A and 73 on placebo received at least one dose and were available for efficacy analyses. 3 months of treatment with ciclosporin A alone did not show any significant improvement in primary outcome measures (mean change in the proportion of a possible total MRC score [%MRC] was −2·6 [SD 6·0] for patients on ciclosporin A and −0·8 [4·9] for patients on placebo; adjusted group difference estimate −0·88, 97·5% CI −2·6 to 0·9; p=0·26). The combination of ciclosporin A with intermittent steroids was not better than intermittent steroids alone over 12 months (mean change in %MRC was 0·7 [7·1] for patients on ciclosporin A and −0·3 [7·9] for patients on placebo; adjusted group difference estimate −0·85, −3·6 to 1·9; p=0·48). Numbers of adverse events (75 in patients on ciclosporin A and 74 on placebo) and serious adverse events (four with ciclosporin A and four with placebo) did not differ significantly between groups. Interpretation Ciclosporin A alone or in combination with intermittent prednisone does not improve muscle strength or functional abilities in ambulant boys with Duchenne muscular dystrophy, but is safe and well tolerated. Funding German Federal Ministry of Education and Research, Action Benni and co eV, Novartis Pharma AG, and Deutsche Gesellschaft fur Muskelkranke eV.

Generalized spike and wave discharges (GSW) are often accompanied by transitory cognitive impairment (TCI). As a possible neurophysiological correlate of TCI, activation in the thalamus and deactivation in the frontoparietal brain regions associated with GSW were discussed in previous studies which used simultaneous recordings of EEG and functional MRI (EEG-fMRI) in patients with absence epilepsy. We report on a girl having GSW up to 10 seconds without any clinical concomitants. The girl underwent an EEG-fMRI investigation with simultaneous behavioral testing (continuous performance task). Although GSW repeatedly occurred during the task, no TCI was observed. EEG-fMRI revealed bilateral deactivation in frontoparietal brain areas and activation in the thalamus in association with GSWs. This study challenges the relation between cognitive impairment during absences and the characteristic pattern of thalamic activation and deactivation in frontoparietal areas associated with GSW.

Twenty-six Austrian, Dutch, German, and Swiss epilepsy centers were asked to report on use of the Wada test (intracarotid amobarbital procedure, IAP) from 2000 to 2005 and to give their opinion regarding its role in the presurgical diagnosis of epilepsy. Sixteen of the 23 centers providing information had performed 1421 Wada tests, predominantly the classic bilateral procedure (73%). A slight nonsignificant decrease over time in Wada test frequency, despite slightly increasing numbers of resective procedures, could be observed. Complication rates were relatively low (1.09%; 0.36% with permanent deficit). Test protocols were similar even though no universal standard protocol exists. Clinicians rated the Wada test as having good reliability and validity for language determination, whereas they questioned its reliability and validity for memory lateralization. Several noninvasive functional imaging techniques are already in use. However, clinicians currently do not want to rely solely on noninvasive functional imaging in all patients.