Cognitive development in children with medically intractable symptomatic focal epilepsies before and after epilepsy surgery

Die vorliegende Arbeit befasst sich mit der kognitiven Leistungsfähigkeit von Kindern mit symptomatisch-fokalen Epilepsien vor und nach einem epilepsiechirurgischen Eingriff. Wichtige, in der Literatur berichtete Einflussfaktoren auf Kognition bei Kindern mit Epilepsien sind das Alter bei Anfallsbeginn, hohe Anfallsfrequenz, antiepileptische Medikation und Dauer der Epilepsie. Weitere potentielle Einflussfaktoren mit weniger klaren Befunden stellen die Ätiologie sowie die Lokalisation und Lateralisation des epileptischen Fokus bzw. der Läsion bei Kindern mit symptomatischen Epilepsien dar. Hinsichtlich des postoperativen kognitiven Outcomes kommen aus theoretischen Überlegungen und aufgrund empirischer Befunde dem Anfallsoutcome, dem Alter bei Operation, der Länge des Nachuntersuchungszeitraums, dem Ausmaß der Resektion, der Dauer der Epilepsie vor dem Eingriff sowie der postoperativen Medikation eine besondere Bedeutung zu. 105 Kinder unter 16 Jahren wurden präoperativ und ein halbes sowie zwei Jahre postoperativ mit altersadäquaten Entwicklungs- bzw. Intelligenztests untersucht. Mittels Varianzanalysen wurden Gruppenunterschiede zwischen den verschiedenen Altersstufen, zwischen Kindern mit unterschiedlichen Ätiologien, Resektionsorten, frühem vs. späterem Anfallsbeginn, Mono- vs. Polytherapie, täglichen vs. nicht-täglichen Anfällen und unterschiedlichem Anfallsoutcome analysiert. Die Dauer der Epilepsie wurde als Kovariate berücksichtigt. Der präoperative Intelligenzquotient wurde von einem frühen Alter bei Beginn der Epilepsie sowie von medikamentöser Polytherapie negativ beeinflusst. Kinder mit Tumoren zeigten sich kognitiv weniger beeinträchtigt als Kinder mit anderen Ätiologien. Ein Zusammenhang zwischen hoher Anfallsfrequenz und niedrigerem kognitivem Niveau deutete sich an, wurde aber von Effekten der medikamentösen Therapie überlagert. Für die Gesamtgruppe wurde nach dem epilepsiechirurgischen Eingriff eine signifikante Verbesserung des IQs gefunden, die erst im mittelfristigen postoperativen Verlauf evident wurde. Das beste kognitive Outcome erzielten die Kinder, die nicht nur vollständig anfallsfrei waren, sondern zusätzlich auch keine epilepsietypischen Potentiale (ETPs) im postoperativen Routine-EEG aufwiesen. Dieser Effekt war besonders markant bei Kindern mit besonders hoher Anfallsbelastung vor der Operation. Kinder, die zum Zeitpunkt der Operation jünger als drei Jahre alt waren, zeigten einen Verlauf mit frühen Verlusten und mittelfristigen bedeutsamen Zugewinnen, der in den anderen Altersgruppen nicht beobachtet wurde. Die vorliegenden Daten sprechen für eine günstige Prognose für die mittelfristige kognitive Entwicklung von Kindern nach einem epilepsiechirurgischen Eingriff. Eine "Normalisierung" präoperativ gestörter Entwicklung ist nicht zu erwarten. Es bedarf weiterer Untersuchungen an homogenen Kollektiven von Kindern mit unterschiedlichen Ätiologien, Resektionsorten und Altersstufen, um relevante Einflussfaktoren genauer zu untersuchen. Zur endgültigen Bewertung der längerfristigen Prognose fehlen Untersuchungen an Erwachsenen, die im Kindesalter epilepsiechirurgisch behandelt wurden.This study deals with cognitive development in children with medically intractable symptomatic focal epilepsies before and after epilepsy surgery. Important factors influencing cognition in children with epilepsy are age at seizure onset, seizure frequency, antiepileptic medication and duration of epilepsy. Other potential factors whose impact on cognition is less well established include aetiology, localization and lateralization of the epileptic focus or lesion. Concerning cognitive outcome after epilepsy surgery, seizure control, age at surgery, length of follow-up, extent of resection, duration of epilepsy before surgery and postoperative medication are considered main influencing factors. 105 children who were younger than 16 years at surgery were assessed preopera-tively and six and 24 months after surgery with age appropriate developmental or intelligence tests. Group differences were analyzed between different age groups, aetiologies, localization of resection, early vs. later seizure onset, mono- vs. polytherapy, daily vs. not daily seizures and seizure outcome. Duration of epilepsy was included as a covariate. Preoperative IQ was significantly negatively influenced by early age at seizure onset and polytherapy. Children with tumours were less affected than children with other aetiologies. A tentative relationship between high seizure frequency and low cognitive level was masked by effects of polytherapy. After epilepsy surgery there was an increase in IQ for the group that reached statistical significance in the longer term (between first and second postoperative assessment). The best outcome was seen in the group of children who were seizure free and had no epileptiform acitivity in routine EEG. This effect was pronounced in children with very high preoperative seizure frequency. Children younger than three years at surgery showed a developmental trajectory with early losses and later substantial gains in IQ that was not seen in the other age groups. The data suggest a favourable prognosis for cognitive development after paediatric epilepsy surgery, at least for a follow-up period of two to three years. "Normalization" of preoperatively impaired cognitive development can't be expected. Further studies in homogeneous groups of children with different aetiologies, localization of resection and age groups are needed to further explore factors impacting postoperative cognitive development. Long-term prognosis requires studies of adults who underwent epilepsy surgery in childhood

DataSheet1_Concomitant inhibition of PI3K/mTOR signaling pathways boosts antiproliferative effects of lanreotide in bronchopulmonary neuroendocrine tumor cells.PDF

Introduction: Somatostatin analogues (SSAs) are commonly used in the treatment of hormone hypersecretion in neuroendocrine tumors (NETs), however the extent to which they inhibit proliferation is much discussed.Objective: We studied the antiproliferative effects of novel SSA lanreotide in bronchopulmonary NETs (BP-NETs). We focused on assessing whether pretreating cells with inhibitors for phosphatidylinositol 3-kinase (PI3K) and mammalian target for rapamycin (mTOR) could enhance the antiproliferative effects of lanreotide.Methods: BP-NET cell lines NCI-H720 and NCI-H727 were treated with PI3K inhibitor BYL719 (alpelisib), mTOR inhibitor everolimus and SSA lanreotide to determine the effect on NET differentiation markers, cell survival, proliferation and alterations in cancer-associated pathways. NT-3 cells, previously reported to express somatostatin receptors (SSTRs) natively, were used as control for SSTR expression.Results: SSTR2 was upregulated in NCI-H720 and NT-3 cells upon treatment with BYL719. Additionally, combination treatment consisting of BYL719 and everolimus plus lanreotide tested in NCI-H720 and NCI-H727 led to diminished cell proliferation in a dose-dependent manner. Production of proteins activating cell death mechanisms was also induced. Notably, a multiplexed gene expression analysis performed on NCI-H720 revealed that BYL719 plus lanreotide had a stronger effect on the downregulation of mitogens than lanreotide alone.Discussion/Conclusion: We report a widespread analysis of changes in BP-NET cell lines at the genetic/protein expression level in response to combination of lanreotide with pretreatment consisting of BYL719 and everolimus. Interestingly, SSTR expression reinduction could be exploited in therapeutic and diagnostic applications. The overall results of this study support the evaluation of combination-based therapies using lanreotide in preclinical studies to further increase its antiproliferative effect and ultimately facilitate its use in high-grade tumors.</p

First epileptic seizure and epilepsies in adulthood. Abridged version ofthe S2k guideline of the German Society for Neurology in cooperationwith the German Society for Epileptology

Holtkamp M, May T, Berkenfeld R, et al. Erster epileptischer Anfall und Epilepsien im Erwachsenenalter. Kurzfassung S2k-Leitlinie der Deutschen Gesellschaft für Neurologie in Zusammenarbeit mit der Deutschen Gesellschaft für Epileptologie. Clinical Epileptology. 2024.The new S2k guideline "First epileptic seizure and epilepsies in adulthood" provides recommendations on clinically relevant issues in five major topics: management of first epileptic seizures, pharmacotherapy, epilepsy surgery, complementary and supportive treatment, and psychosocial aspects. For the topic management of first epileptic seizures, the guideline provides recommendations on identifying the two major differential diagnoses, syncope and psychogenic non-epileptic seizure. The importance of additional examinations such as EEG, MRI and cerebrospinal fluid for syndromic classification and etiological allocation is discussed. Recommendations on neuropsychological and psychiatric screening tests are also given. The topic pharmacotherapy issues recommendations on antiseizure medication in monotherapy for focal, generalized and unclassified epilepsies; patient groups with special challenges such as the aged, women of childbearing potential and people with mental retardation are emphasized. Further issues are indications for measuring serum concentrations of antiseizure medication and possible risks of switching manufacturers. In the topic epilepsy surgery, indications for presurgical assessment and the multiple therapeutic approaches, such as resection, laser ablation, and neurostimulation are presented. Recommendations on postoperative management of patients, including rehabilitation and psychosocial counselling, are given. The topic complementary and supportive therapeutic approaches comprises recommendations on the diagnostics and treatment of common psychiatric comorbidities of epilepsy, such as anxiety disorder, depression and psychosis. Another important issue is the management of psychogenic non-epileptic seizures as a neuropsychiatric differential diagnosis or comorbidity of epileptic seizures. Furthermore, recommendations on the potential role of ketogenic diet and on acupuncture, homeopathy and other complementary approaches are made. The recommendations on psychosocial aspects comprise practical issues, such as fitness to drive a car, training and occupation, medical rehabilitation, sport, transition, patients' self-help, education programs for patients and next of kin, adherence, advise on SUDEP