Ulrich Stephani

• Universitätsklinikum Schleswig - Holstein

This article presents a short report on a systematic review (SR) collating data on the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroids (CST) in children with epilepsies other than infantile epileptic spasm syndrome (IESS) which showed no response to antiseizure medication (ASM). The SR included retrospective and...

We conducted a systematic review investigating the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroids in children with epilepsies other than infantile epileptic spasm syndrome (IESS) that are resistant to anti‐seizure medication (ASM). We included retrospective and prospective studies reporting on more than five pat...

From a neurobiological standpoint, the question of consciousness centers on whether one or more structures in the brain play a role in the function of consciousness. That could be a single structure or brain area, or a network connecting different brain areas. Movements, sensations, emotions, vegetative regulations, all kinds of cognition and compl...

The Phospholipid Phosphatase Related 4 gene (PLPPR4, *607813) encodes the Plasticity-Related-Gene-1 (PRG-1) protein. This cerebral synaptic transmembrane-protein modulates cortical excitatory transmission on glutamatergic neurons. In mice, homozygous Prg-1 deficiency causes juvenile epilepsy. Its epileptogenic potential in humans was unknown. Thus,...

Childhood absence epilepsy (CAE), involves 3 Hz generalized spikes and waves discharges (GSWDs) on the electroencephalogram (EEG), associated with ictal discharges (seizures) with clinical symptoms and impairment of consciousness and subclinical discharges without any objective clinical symptoms or impairment of consciousness. This study aims to co...

Aim : 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. Methods : Thirteen children treated with EVO were examined for EEG-recorded seizures and interictal epileptic discharge...

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...

Mobile apps for the smartphone enable monitoring and treatment of medical conditions, such as epilepsy and to prevent complications in particular due to noncompliance and missing adherence. Data from smartphone applications can be used to support medical decision-making. An overview of the current status of medical apps in the healthcare system wit...

Objective Childhood absence epilepsy (CAE) is a disease with distinct seizure semiology and electroencephalographic (EEG) features. Differentiating ictal and subclinical generalized spikes and waves discharges (GSWDs) in the EEG is challenging, since they appear to be identical upon visual inspection. Here, spectral and functional connectivity (FC)...

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on ge...

Background and objective: The human brain displays rich and complex patterns of interaction within and among brain networks that involve both cortical and subcortical brain regions. Due to the limited spatial resolution of surface electroencephalography (EEG), EEG source imaging is used to reconstruct brain sources and investigate their spatial and...

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 treatedwith EVO for 3–70months (md: 37). Development/adaptive functio...

Importance Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. Objective To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet...

Background: Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the effica...

Epilepsien zählen weltweit zu den häufigsten neurologischen Erkrankungen. Je nach Schweregrad der Epilepsie können Betroffene ein nahezu unbeschwertes Leben führen oder große Einschränkungen ihrer Autonomie erleben. Charakteristisches Symptom sind wiederkehrende epileptische Anfälle, die aufgrund der Unvorhersehbarkeit des Zeitpunkts, an dem Anfäll...

Niedrige Serotonin- und Tryptophan-Konzentrationen im ZNS-Gewebe von Epilepsiepatienten weisen auf die mögliche pathophysiologische Bedeutung der serotoninergen Neurotransmission hin. Das serotoninerg wirkende Fenfluramin, ein nicht stimulierendes Amphetaminanalogon, wurde als Appetitzügler verwendet, bis es wegen schwerer kardiovaskulärer Nebenwir...

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilep...

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilep...

Objective To compare direct and indirect costs and quality of life (QoL) of pediatric and adult patients with Dravet syndrome (DS), with drug‐resistant epilepsy (DRE) and in seizure remission (SR), and their caregivers, in Germany. Methods Questionnaire responses from 93 DS patients and their caregivers were matched by age and gender with response...

Non-linear State space model , Cox-Stuart trend test

In this paper a nonlinear filtering algorithm for count time series is developed that takes the non-negativity of the data into account and preserves positive definiteness of the covariance matrices of the model. For this purpose, a recently proposed variant of Kalman Filtering based on Singular Value Decomposition is incorporated into Iterative Ex...

The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-...

Purpose: To identify factors correlating with poorer quality of life (QoL) in children and adolescents with epilepsy and regarding QoL and depression of their caregivers in Germany. Method: A cross-sectional multicenter study on QoL and depression was performed in two representative German states. Variance analysis, linear regression, and bivariat...

Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals...

Das Dravet-Syndrom beschreibt eine seltene, im ersten Lebensjahr beginnende und meist therapieschwierig verlaufende Epilepsieform des Kindesalters. Ursächlich sind bei ca. 80 % der Erkrankten Veränderungen des SCN1A-Gens, das für eine Untereinheit eines spannungsabhängigen Natriumkanals kodiert. Der Epilepsieverlauf erfordert meist eine medikamentö...

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 withi...

Objective Multifocal epileptic activity is an unfavourable feature of a number of epileptic syndromes (Lennox-Gastaut syndrome, West syndrome, severe focal epilepsies) which suggests an overall vulnerability of the brain to pathological synchronization. However, the mechanisms of multifocal activity are insufficiently understood. This explorative s...

the aim of this proof-of-concept work was to apply the spatiotemporal Kalman filter (STKF) algorithm to magnetocardiographic (MCG) recordings of the heart. Due to the lack of standardized software and pipelines for MCG source imaging, we needed to construct a pipeline for MCG forward modeling before we could apply the STKF method. In the forward mo...

Mutations in the ATP1A3 gene are known to cause alternating hemiplegia of childhood (AHC) and rapid-onset dystonia parkinsonism (RDP). Both conditions are childhood-onset neurological disorders with distinct symptoms and different times of onset. ATP1A3 has also been associated with CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atr...

Plasticity related gene 1 encodes a cerebral neuron-specific synaptic transmembrane protein that modulates hippocampal excitatory transmission on glutamatergic neurons. In mice, homozygous Prg1-deficiency results in juvenile epilepsy. Screening a cohort of 18 patients with infantile spasms (West syndrome), we identified one patient with a heterozyg...

Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB...

Zusammenfassung Epilepsien zählen zu den häufigsten neurologischen Erkrankungen mit etwa 600 000 Betroffenen in Deutschland. Symptome epileptischer Anfälle, die Vielzahl möglicher Epilepsieursachen und die unterschiedlichen Krankheitsverläufe erschweren sowohl die korrekte Diagnosestellung als auch die Auswahl einer geeigneten Therapie (Antikonvuls...

The clinical routine of non-invasive electroencephalography (EEG) is usually performed with 8-40 electrodes, especially in long-term monitoring, infants or emergency care. There is a need in clinical and scientific brain imaging to develop inverse solution methods that can reconstruct brain sources from these low-density EEG recordings. In this pro...

The reconstruction of brain sources from non-invasive electroencephalography (EEG) or magnetoencephalography (MEG) via source imaging can be distorted by information redundancy in case of high-resolution recordings. Dimensionality reduction approaches such as spatial projection may be used to alleviate this problem. In this proof-of-principle paper...

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox–Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients with IS or LGS. The contribution of autosomal recessi...

Objective: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. Methods: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutat...

Independent component analysis (ICA) is an approved method for (e.g., muscle) artifact removal in electroencephalography (EEG). But, as it creates only \(m \le n\) components from n signals, it may fail to clearly separate the artifacts. In order to keep the strengths of ICA and overcome its limitations, we extend ICA by state-space modeling (SSM),...

Objective: Childhood and Juvenile Absence Epilepsy account for 30% of all genetic generalized epilepsies with a strong genetic contribution. At the current state the genetic background remains to be resolved. The aim of this study was to identify disease associated transcripts pinpointing potential underlying disease mechanisms in patients with CA...

© 2017(The American Journal of Human Genetics 95, 360–370; October 2, 2014) In the list of consortium members for the Epilepsy Phenome/Genome Project, member Dina Amrom's name was misspelled as Amron. The authors regret the error.

Objective: The aim of our study was to investigate the neuronal networks underlying background oscillations of epileptic encephalopathy with continuous spikes and waves during slow sleep (CSWS). Methods: Sleep electroencephalography (EEG) studies before and after the treatment were investigated in 15 patients with CSWS. To investigate functional...

Background/Purpose: Gros-Selbeck et al1 compared psycho-physiological characteristics – such as electrodermal activity (EDA; 3) – of photoparoxysmal response (PPR) positive adolescents with their PPR-negative siblings. The PPR-positive sample showed significantly higher responses. The phasic part of EDA – skin conductance response (SCR), driven by...

Background: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what exten...

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...

Zusammenfassung. Im Jahre 1992 wurde die Zeitschrift „Kindheit und Entwicklung“ gegründet und zum führenden Publikationsorgan der Klinischen Kinderpsychologie in den deutschsprachigen Ländern etabliert. Themen der Pädiatrischen Psychologie, Kinderpsychiatrie, Kinderhilfe/Jugendhilfe wurden genauso publiziert wie Beiträge zur Kinderpsychotherapie, A...

The journal Kindheit und Entwicklung (Childhood and Development) was launched in 1992 and has established itself as the leading publication in the field of clinical child psychology in German-speaking countries. The journal has published issues on pediatric psychology, child psychiatry, and children's aid/child welfare as well as scientific papers...

The first mutations identified in SLC2A1, encoding the glucose transporter type 1 (GLUT1) protein of the blood-brain barrier, were associated with severe epileptic encephalopathy. Recently, dominant SLC2A1 mutations were found in rare autosomal dominant families with various forms of epilepsy including early onset absence epilepsy (EOAE), myoclonic...

At the sensor level many aspects, such as spectral power, functional and effective connectivity as well as relative-power-ratio ratio (RPR) and spatial resolution have been comprehensively investigated through both electroencephalography (EEG) and magnetoencephalography (MEG). Despite this, differences between both modalities have not yet been syst...

This authoritative work provides an in-depth treatment of state space methods, with a range of applications in neural and clinical data. Advanced and state-of-the-art research topics are detailed, including topics in state space analyses, maximum likelihood methods, variational Bayes, sequential Monte Carlo, Markov chain Monte Carlo, nonparametric...

To provide first data on the cost of epilepsy and cost-driving factors in children, adolescents, and their caregivers in Germany. A population-based, cross-sectional sample of consecutive children and adolescents with epilepsy was evaluated in the states of Hessen and Schleswig-Holstein (total of 8.796 million inhabitants) in all health care sector...

The discretization of the brain and the definition of the Laplacian matrix influence the results of methods based on spatial and spatio-temporal smoothness, since the Laplacian operator is used to define the smoothness based on the neighborhood of each grid point. In this paper, the results of low resolution electromagnetic tomography (LORETA) and...

The assumption of spatial-smoothness is often used to solve the bioelectric inverse problem during electroencephalographic (EEG) source imaging, e.g., in low resolution electromagnetic tomography (LORETA). Since the EEG data show a temporal structure, the combination of the temporal-smoothness and the spatial-smoothness constraints may improve the...

We propose an approach for the analysis of epileptic seizure count time series within a state space framework. Time-dependent dosages of several simultaneously administered anticonvulsants are included as external inputs. The method aims at distinguishing which temporal correlations in the data are due to the medications, and which correspond to an...

Recently, mutations and deletions in the GRIN2A gene have been identified to predispose to benign and severe idiopathic focal epilepsies (IFE), revealing a higher incidence of GRIN2A alterations among the more severe phenotypes. This study aimed to explore the phenotypic boundaries of GRIN2A mutations by investigating patients with the two most com...

Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We deter...

Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confide...

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 intr...

Objective This article aims to report the first clinical experiences concerning effectiveness and tolerability of perampanel (PER) in a pediatric population with refractory epilepsies. Patients and Methods This nonsponsored, observational, retrospective survey was conducted through collaboration with multiple centers in Europe. The clinical course...

Fever-associated syndromic epilepsies ranging from febrile seizures plus (FS+) to Dravet syndrome have a significant genetic component. However, apart from SCN1A mutations in >80% of patients with Dravet syndrome, the genetic underpinnings of these epilepsies remain largely unknown. Therefore, we performed a genome-wide screening for copy number va...

Active brain stimulation to abate epileptic seizures has shown mixed success. In spike-wave (SW) seizures, where the seizure and background state were proposed to coexist, single-pulse stimulations have been suggested to be able to terminate the seizure prematurely. However, several factors can impact success in such a bistable setting. The factors...

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.M...

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associa...

Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the “cl...

Wir zeigen den Fall eines Kleinkindes mit epileptischer Enzephalopathie ungeklärter Ätiologie mit Burst-Suppressions-EEG. Ziel dieser Studie ist es, die pathophysiologischen Mechanismen dieses schwerwiegenden Leidens unter Zuhilfenahme von EEG-Quellanalysen besser zu verstehen. Unsere Ergebnisse stehen im Einklang mit denen anderer Studien, die ein...

Background / Purpose: The aim of this study, was firstly to identify the two neuronal sources in the brain which show the highest dipole strength; caused by the multi-focal epileptic activity using the Minimum-norm (MN) inverse solution technique on a realistic head model. The second aim was to study the dynamics of these two source signals so as...

Background / Purpose: Burst suppression (B-S): an electroencephalogram (EEG) pattern characterized by the quasiperiodic alternant phases of a high voltage activity (burst) and electrical silence (suppression), is considered as a global state of profound brain inactivation. Burst suppression can occur during different conditions such as early-onse...

This chapter covers the syndromes of benign epilepsy with centrotemporal spikes (BECTS), nonlesional focal epilepsy in otherwise normal children (NLFN), and the genetic generalized epilepsies. BECTS is an epilepsy syndrome that always enters terminal remission before the general age of a planned transition of adolescents. This is also the case for...

Source localization of an epileptic seizure is becoming an important diagnostic tool in pre-surgical evaluation of epileptic patients. However, for localizing the epileptogenic zone precisely, the epileptic activity needs to be isolated from other activities that are not related to the epileptic source. In this study, we aim at an investigation of...

Background: The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loc...

Background / Purpose: The aim of this study was to investigate the dynamics of neuronal networks during focal seizures using dynamic imaging of coherent sources (DICS) ( Gross et al. 2001 ) and renormalized partial directed coherence (RPDC) ( Schelter et al. 2009 ). Ictal EEG recordings from a patient with drug resistant focal epilepsy, due to a...

A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies a...

The aim of this exploratory study was to investigate the relationship between focal interictal epileptiform discharges (IEDs), intellectual disability and cortical information processing in children with partial epilepsy. Two groups of patients - Group 1 (n = 9 patients) with focal IEDs and normal IQ and Group 2 (n = 10 patients) with focal IEDs an...

Hyperpolarization-activated, cyclic nucleotide–gated (HCN) channels contribute to cationic I h current in neurons and regulate the excitability of neuronal networks. Studies in rat models have shown that the Hcn1 gene has a key role in epilepsy, but clinical evidence implicating HCN1 mutations in human epilepsy is lacking. We carried out exome sequ...

Background: Atypical benign partial epilepsy/pseudo-Lennox syndrome (ABPE/PLS) and continues spike and wave during sleep (CSWS) belong to a spectrum of idiopathic focal epilepsy syndromes ranging from benign Rolandic epilepsy to more severe seizure disorders, which are commonly characterized by the association of various epileptic seizure types, a...

Die Systematik in der Medizin beinhaltet die Beschäftigung mit der Ätiologie, der Pathogenese/Pathophysiologie, der Symptomatik, der Diagnostik und der Therapie einer Erkrankung oder Erkrankungsgruppe als Kernaspekte allen ärztlichen Handelns.Zur Ätiologie: Schon Hippokrates hatte eine Erblichkeit von Epilepsie als somatischer Krankheit identifizie...

Epileptische Enzephalopathien (EE) gehören zu der Gruppe von Epilepsien, die mit ausgeprägten kognitiven Defiziten und Verhaltensstörungen infolge epileptischer Aktivität einhergehen. Trotz großer Bedeutung von EE für die Entwicklung des betroffenen Kindes und dessen psychosozialer Anpassung sind bislang Mechanismen kognitiver Defizite bei EE unzur...

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 w...

To identify neuronal networks underlying generalized spike and wave discharges (GSW) in myoclonic astatic epilepsy (MAE). Simultaneous EEG-fMRI recordings were performed in 13 children with MAE. Individual GSW-associated blood oxygenation level-dependent (BOLD) signal changes were analyzed in every patient. A group analysis was performed to determi...

Die myoklonisch-astatische Epilepsie (MAE, Doose-Syndrom, Epilepsie mit myoklonisch-atonischen Anfällen) ist ein seltenes, elektroklinisches Syndrom des frühen Kindesalters, das bei zuvor gesunden, normal entwickelten Kindern auftritt. Jungen sind häufiger betroffen (70 %). Pathognomonisch sind die myoklonisch-atonischen Anfälle (oft Sturzanfälle)....