Etablierung eines Studiendesigns zur Untersuchung des Einflusses von Topiramat auf das Körpergewicht und den Insulin- und Fettstoffwechsel in tierexperimentellen Modellen der humanen Adipositas

Im Rahmen dieser Dissertation wurde ein Studiendesign etabliert, um den Einfluss von Topiramat auf die Zielparameter Körpergewicht sowie Futter- und Wasseraufnahme und den Insulin- und Fettstoffwechsel unter kohlenhydratreicher Ernährung zu evaluieren. Es wurden insgesamt 4 Versuchsreihen im Paarfütterungsdesign durchgeführt. Homozygote Zuckerratten und db/db Mäuse erhielten über 1 bis 4 Wochen eine Hochdosis-Topiramattherapie (100 mg/kg/d) über eine orogastrale Sonde. Die db/db Maus erwies sich als nicht robust genug für das zu etablierende Studiendesign. Bei den Zuckerratten zeigte Topiramat den bekannten akuten anorektischen Effekt. Im Verlauf wurde bei den behandelten Tieren eine Verlangsamung der Wachstumsgeschwindigkeit gegenüber den Placebotieren trotz höherer oder gleicher Futteraufnahme deutlich. Dies lässt auf Wirkmechanismen des Topiramats schliessen, die das Energiegleichgewicht der Tiere auf metabolischer Ebene beeinflussen. Als ein wichtiger metabolische Effekt konnte die bereits vorbeschriebene antidiabetische Wirkung beobachtet werden. Daneben konnte erstmals eine Verminderung der de novo Lipogeneserate im weißen Fettgewebe nachgewiesen werden. Dieser Befund lässt der Carboanhydrasehemmung durch Topiramat eine zentrale Bedeutung für die gewichtsreduzierende Wirkung zukommen und gibt Anlass zur Erforschung weiterer Hemmstoffe, die nach Möglichkeit eine höhere Spezifität für das weiße Fettgewebe aufweisen sollten

Checklist on the quality of the repetitive peripheral magnetic stimulation (rPMS) methods in research: An international Delphi study

An increasing number of clinical research studies have used repetitive peripheral magnetic stimulation (rPMS) in recent years to alleviate pain or improve motor function. rPMS is non-invasive, painless, and administrated over peripheral nerve, spinal cord roots, or a muscle using a coil affixed to the skin and connected to a rapid-rate magnetic stimulator. Despite the clinical impact and scientific interest, the methodological inconsistencies or incomplete details and findings between studies could make the rPMS demonstration difficult to replicate. Given the lack of guidelines in rPMS literature, the present study aimed at developing a checklist to improve the quality of rPMS methods in research. An international panel of experts identified among those who had previously published on the topic were enrolled in a two-round web-based Delphi study with the aim of reaching a consensus on the items that should be reported or controlled in any rPMS study. The consensual rPMS checklist obtained comprises 8 subject-related items (e.g., age, sex), 16 methodological items (e.g., coil type, pulse duration), and 11 stimulation protocol items (e.g., paradigm of stimulation, number of pulses). This checklist will contribute to new interventional or exploratory rPMS research to guide researchers or clinicians on the methods to use to test and publish rPMS after-effects. Overall, the checklist will guide the peer-review process on the quality of rPMS methods reported in a publication. Given the dynamic nature of a consensus between international experts, it is expected that future research will affine the checklist

Quality of life after brain injury in children and adolescents (QOLIBRI-KID/ADO)-The first disease-specific self-report questionnaire after traumatic brain injury

The subjective impact of the consequences of pediatric traumatic brain injury (pTBI) on different life dimensions should be assessed multidimensionally and as sensitively as possible using a disease-specific health-related quality of life (HRQoL) instrument. The development and psychometrics of the first such self-report questionnaire for children and adolescents after TBI are reported here. Focus group interviews with children, adolescents, and their parents, cognitive debriefing, item pool generation and reduction using Delphi expert panels were performed. The resulting version was psychometrically tested on 300 individuals aged 8–17 years. After item reduction based on factor analyses, differential item functioning, reliability, and validity were investigated. The final 35 items were associated with six scales (Cognition, Self, Daily Life and Autonomy, Social Relationships, Emotions, Physical Problems). Internal consistency and construct validity were satisfactory. Health-related Quality of life (HRQoL) was significantly lower in older and in female participants, as well as those with cognitive disabilities, anxiety, depression and post-concussion symptoms, than in comparative groups. The new QOLIBRI-KID/ADO is a comprehensive, multidimensional, reliable, and valid instrument, comparable in content and items to the QOLIBRI adult version. Therefore, disease-specific HRQoL can now be measured across the lifespan and may support the amelioration of treatment, care, rehabilitation, and daily life of children and adolescents after TBI.This research was funded by Dr. Senckenbergische Stiftung/Clementine Kinderhospital Dr. Christ‘sche Stiftungen (Germany), and Uniscientia Stiftung (Switzerland)

Migräne im Kindes- und Jugendalter — Ausblick auf innovative Behandlungsansätze im Rahmen multimodaler Therapiekonzepte

Although migraine is a~relevant health issue in children and adolescents, clinical care and research are still underrepresented and underfunded in this field. Quality of life can be significantly reduced when living with frequent episodes of pain. Due to the high level of vulnerability of the developing brain during adolescence, the risk of chronification and persistence into adulthood is high. In this narrative review, we describe the corner stones of a~patient-centered, multimodular treatment regimen. Further, an update on the pathophysiology of migraine is given considering the concept of a~periodically oscillating functional state of the brain in migraine patients (\textquotedblmigraine is a~brain state\textquotedbl). Besides central mechanisms, muscular structures with the symptoms of muscular pain, tenderness, or myofascial trigger points play an important role. Against this background, the currently available nonpharmacological and innovative neuromodulating approaches are presented focusing on the method of repetitive peripheral magnetic stimulation.Die Migräne ist auch im Kindes- und Jugendalter ein häufiges, aber in klinischer Versorgung und Wissenschaft oft unterrepräsentiertes Krankheitsbild. Gerade im Kindes- und Jugendalter bestehen relevante Einschränkungen der Lebensqualität durch das (häufige) Schmerzerfahren. Bedingt durch die entwicklungsspezifisch hohe Vulnerabilität des adoleszenten Gehirns besteht ein hohes Chronifizierungs- und Persistenzrisiko bis ins Erwachsenenalter hinein. In diesem Beitrag werden die Bestandteile eines patientenzentrierten, multimodalen Therapiekonzepts dargestellt. Darüber hinaus werden die aktuellsten Erkenntnisse zu den pathophysiologischen Grundlagen der Migräneerkrankung beleuchtet, nach denen Migräne durch einen sich phasenweise verändernden Funktionszustand des Gehirns entsteht (Stichwort: „migraine is a brain state“). Auch periphere Komponenten wie Muskelschmerzen, -verspannungen und -triggerpunkte spielen eine wichtige Rolle. Vor diesem Hintergrund werden nichtpharmakologische innovative Therapieansätze vorgestellt, die auf dem Prinzip der Neuromodulation beruhen, mit Fokus auf der repetitiven peripheren Magnetstimulation

A Multidimensional Approach to Assessing Factors Impacting Health-Related Quality of Life after Pediatric Traumatic Brain Injury

In the field of pediatric traumatic brain injury (TBI), relationships between pre-injury and injury-related characteristics and post-TBI outcomes (functional recovery, post-concussion depression, anxiety) and their impact on disease-specific health-related quality of life (HRQoL) are under-investigated. Here, a multidimensional conceptual model was tested using a structural equation model (SEM). The final SEM evaluates the associations between these four latent variables. We retrospectively investigated 152 children (8–12 years) and 148 adolescents (13–17 years) after TBI at the recruiting clinics or online. The final SEM displayed a fair goodness-of-fit (SRMR = 0.09, RMSEA = 0.08 with 90% CI [0.068, 0.085], GFI = 0.87, CFI = 0.83), explaining 39% of the variance across the four latent variables and 45% of the variance in HRQoL in particular. The relationships between pre-injury and post-injury outcomes and between post-injury outcomes and TBI-specific HRQoL were moderately strong. Especially, pre-injury characteristics (children’s age, sensory, cognitive, or physical impairments, neurological and chronic diseases, and parental education) may aggravate post-injury outcomes, which in turn may influence TBI-specific HRQoL negatively. Thus, the SEM comprises potential risk factors for developing negative post-injury outcomes, impacting TBI-specific HRQoL. Our findings may assist healthcare providers and parents in the management, therapy, rehabilitation, and care of pediatric individuals after TBI

Monogenic variants in dystonia: an exome-wide sequencing study

Background Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. Methods For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. Findings We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. Interpretation In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations