Holger Lerche

University of Tuebingen, Tübingen, Baden-Württemberg, Germany

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Publications (161)858.84 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in SLC2A1, encoding the glucose transporter type 1 (Glut1), cause a wide range of neurological disorders: (1) classical Glut1 deficiency syndrome (Glut1-DS) with an early onset epileptic encephalopathy including a severe epilepsy, psychomotor delay, ataxia and microcephaly, (2) paroxysmal exercise-induced dyskinesia (PED) and (3) various forms of idiopathic/genetic generalized epilepsies such as different forms of absence epilepsies. Up to now, focal epilepsy was not associated with SLC2A1 mutations. Here, we describe four cases in which focal seizures present the main or at least initial category of seizures. Two patients suffered from a classical Glut1-DS, whereas two individuals presented with focal epilepsy related to PED. We identified three novel SLC2A1 mutations in these unrelated individuals. Our study underscores that focal epilepsy can be caused by SLC2A1 mutations or that focal seizures may present the main type of seizures. Patients with focal epilepsy and PED should undergo genetic testing and can benefit from a ketogenic diet. But also individuals with pharmaco-resistant focal epilepsy and cognitive impairment might be candidates for genetic testing in SLC2A1.
    Journal of neurology. 07/2014;
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    ABSTRACT: Rolandic epilepsy (RE) and its atypical variants (atypical rolandic epilepsy, ARE) along the spectrum of epilepsy–aphasia disorders are characterized by a strong but largely unknown genetic basis. Two genes with a putative (ELP4) or a proven (SRPX2) function in neuronal migration were postulated to confer susceptibility to parts of the disease spectrum: the ELP4 gene to centrotemporal spikes and SRPX2 to ARE. To reexamine these findings, we investigated a cohort of 280 patients of European ancestry with RE/ARE for the etiological contribution of these genes and their close interaction partners. We performed next-generation sequencing and single-nucleotide polymorphism (SNP)–array based genotyping to screen for sequence and structural variants. In comparison to European controls we could not detect an enrichment of rare deleterious variants of ELP4, SRPX2, or their interaction partners in affected individuals. The previously described functional p.N327S variant in the X chromosomal SRPX2 gene was detected in two affected individuals (0.81%) and also in controls (0.26%), with some preponderance of male patients. We did not detect an association of SNPs in the ELP4 gene with centrotemporal spikes as previously reported. In conclusion our data do not support a major role of ELP4 and SRPX2 in the etiology of RE/ARE.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
    Epilepsia 06/2014; · 3.96 Impact Factor
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    Nature Genetics 05/2014; · 35.21 Impact Factor
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    ABSTRACT: Epileptic encephalopathies, including Dravet syndrome, are severe treatment-resistant epilepsies with developmental regression. We examined a mouse model based on a human β1 sodium channel subunit (Scn1a) mutation. Homozygous mutant mice shared phenotypic features and pharmaco-sensitivity with Dravet syndrome. Patch-clamp analysis showed that mutant subicular and layer 2/3 pyramidal neurons had increased action potential firing rates, presumably as a consequence of their increased input resistance. These changes were not seen in L5 or CA1 pyramidal neurons. This raised the concept of a regional seizure mechanism that was supported by data showing increased spontaneous synaptic activity in the subiculum but not CA1. Importantly, no changes in firing or synaptic properties of gamma-aminobutyric acidergic interneurons from mutant mice were observed, which is in contrast with Scn1a-based models of Dravet syndrome. Morphological analysis of subicular pyramidal neurons revealed reduced dendritic arborization. The antiepileptic drug retigabine, a K(+) channel opener that reduces input resistance, dampened action potential firing and protected mutant mice from thermal seizures. These results suggest a novel mechanism of disease genesis in genetic epilepsy and demonstrate an effective mechanism-based treatment of the disease.
    Brain 04/2014; · 9.92 Impact Factor
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    ABSTRACT: Perampanel (PER) has been approved by the European Medicines Agency (EMA) for adjunctive treatment of patients with partial-onset seizures from age 12 years on. It has been introduced to the market in Germany and Austria in 2012. This cross-sectional observational study summarizes the clinical experience of nine centers with adjunctive PER. Patients were consecutively followed from the initiation of PER on. Only patients with a minimum observational period of six months (in case of ongoing treatment) were recruited. Efficacy data reflect the preceding three months at last observation, tolerability data were assessed at the last observation carried forward. 281 patients were included. After six months 169 were still on PER so that a retention rate of 60% resulted. 43 patients were seizure-free for the preceding 3 months (15%). Overall incidence of adverse events was 52.0%. The leading adverse events were somnolence (24.6%) and dizziness (19.6%) followed by ataxia (3.9%), aggression (2.8%), nausea (2.5%) and irritability (2.1%). We conclude that adjunctive PER may lead to at least temporary freedom of seizures in some of these highly difficult-to-treat patients. Adverse events are not uncommon.
    Epilepsy research 03/2014; · 2.48 Impact Factor
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    ABSTRACT: Recent studies reported DEPDC5 loss-of-function mutations in different focal epilepsy syndromes. Here we identified one predicted truncation and two missense mutations in three independent children with Rolandic epilepsy (3/207). In addition, we identified three families with unclassified focal childhood epilepsies carrying predicted truncating DEPDC5 mutations (3/82). The detected variants were all novel, inherited, and present in all tested affected (11) as well as in seven unaffected family members indicating low penetrance. Our findings extend the phenotypic spectrum associated with mutations in DEPDC5 and suggest that Rolandic epilepsy, albeit rarely, and other non-lesional childhood epilepsies are among the associated syndromes. ANN NEUROL 2014. © 2014 American Neurological Association
    Annals of Neurology 03/2014; · 11.19 Impact Factor
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    ABSTRACT: The identification of valid biomarkers for outcome prediction of diseases and improvement of drug response, as well as avoidance of side effects is an emerging field of interest in medicine. The concept of individualized therapy is becoming increasingly important in the treatment of patients with epilepsy, as predictive markers for disease prognosis and treatment outcome are still limited. Currently, the clinical decision process for selection of an antiepileptic drug (AED) is predominately based on the patient's epileptic syndrome and side effect profiles of the AEDs, but not on effectiveness data. Although standard dosages of AEDs are used, supplemented, in part, by therapeutic monitoring, the response of an individual patient to a specific AED is generally unpredictable, and the standard care of patients in antiepileptic treatment is more or less based on trial and error. Therefore, there is an urgent need for valid predictive biomarkers to guide patient-tailored individualized treatment strategies in epilepsy, a research area that is still in its infancy. This review focuses on genomic factors as part of an individual concept for AED therapy summarizing examples that influence the prognosis of the disease and the response to AEDs, including side effects.
    Journal of the American Society for Experimental NeuroTherapeutics 02/2014; · 5.38 Impact Factor
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    ABSTRACT: Perampanel (PER) has been approved by the European Medicines Agency (EMA) for adjunctive treatment of patients with partial-onset seizures from age 12 years on. It has been introduced to the market in Germany and Austria in 2012. This cross-sectional observational study summarizes the clinical experience of nine centers with adjunctive PER. Patients were consecutively followed from the initiation of PER on. Only patients with a minimum observational period of six months (in case of ongoing treatment) were recruited. Efficacy data reflect the preceding three months at last observation, tolerability data were assessed at the last observation carried forward. 281 patients were included. After six months 169 were still on PER so that a retention rate of 60% resulted. 43 patients were seizure-free for the preceding 3 months (15%). Overall incidence of adverse events was 52.0%. The leading adverse events were somnolence (24.6%) and dizziness (19.6%) followed by ataxia (3.9%), aggression (2.8%), nausea (2.5%) and irritability (2.1%). We conclude that adjunctive PER may lead to at least temporary freedom of seizures in some of these highly difficult-to-treat patients. Adverse events are not uncommon.
    Epilepsy Research. 01/2014;
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    ABSTRACT: Objectives: Mutations inKCNQ2 and KCNQ3, encoding the voltage-gated potassium channels KV 7.2 and KV 7.3, are known to cause benign familial neonatal seizures mainly by haploinsufficiency. Here, we set out to determine the disease mechanism of seven de novo missense KCNQ2 mutations that were recently described in patients with a severe epileptic encephalopathy including pharmacoresistant seizures and pronounced intellectual disability. Methods: Mutations were inserted into the KCNQ2 cDNA. Potassium currents were recorded using two-microelectrode voltage clamping and surface expression was analyzed by a biotinylation assay in cRNA-injected Xenopus laevis oocytes. Results: We observed a clear loss-of-function for all mutations. Strikingly, five of seven mutations exhibited a drastic dominant-negative effect on wildtype KV 7.2 or KV 7.3 subunits, either by globally reducing current amplitudes (three pore mutations) or by a depolarizing shift of the activation curve (two voltage sensor mutations) decreasing potassium currents at the subthreshold level at which these channels are known to critically influence neuronal firing. One mutation significantly reduced surface expression. Application of retigabine, a recently marketed KV 7 channel opener, partially reversed these effects for the majority of analyzed mutations. Interpretation: The development of severe epilepsy and cognitive decline in children carrying five of the seven studied KCNQ2 mutations, can be related to a dominant-negative reduction of the resulting potassium current at subthreshold membrane potentials. Other factors such as genetic modifiers have to be postulated for the remaining two mutations. Retigabine or similar drugs may be used as a personalized therapy for this severe disease. (244 words) ANN NEUROL 2013. © 2013 American Neurological Association.
    Annals of Neurology 12/2013; · 11.19 Impact Factor
  • B. Zurek, H. Graessner, H. Lerche
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    ABSTRACT: IonNeurONet ist ein vom Bundesministerium für Bildung und Forschung (BMBF) gefördertes Verbundforschungsprojekt der Universitäten Tübingen und Ulm sowie der CeGaT GmbH, Tübingen, mit dem Ziel, die Erkrankungsmechanismen seltener neurologischer und ophthalmologischer Ionenkanalerkrankungen aufzuklären, die als Basis für die Entwicklung neuer Therapien dienen können. Der Aufbau eines klinischen Netzwerks soll die nationale Versorgung für diese seltenen und oftmals unerkannten Erkrankungen bereitstellen. Ein auf Next Generation Sequencing (NGS) basierends schnelles und effizientes genetisches Diagnostikwerkzeug wurde bereits entwickelt. Es wird fortlaufend durch neue Krankheitsgene, die mittels Exomsequenzierung identifiziert wurden, ergänzt. Weitere Teilprojekte beschäftigen sich mit detaillierten funktionellen physiologischen Studien in heterologen Expressionssystemen sowie in Muskel- und Nervenzellen. Das Projekt etabliert Plattformen für genetische und bioinformatische Analysen, automatisierte und detaillierte funktionelle Studien, intrazellulären Transport von Membranproteinen und induzierte pluripotente Stammzellen.
    Medizinische Genetik 12/2013; 25(4). · 0.09 Impact Factor
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    ABSTRACT: Dravet syndrome is a severe epilepsy syndrome characterized by infantile onset of therapy-resistant, fever-sensitive seizures followed by cognitive decline. Mutations in SCN1A explain about 75% of cases with Dravet syndrome; 90% of these mutations arise de novo. We studied a cohort of nine Dravet-syndrome-affected individuals without an SCN1A mutation (these included some atypical cases with onset at up to 2 years of age) by using whole-exome sequencing in proband-parent trios. In two individuals, we identified a de novo loss-of-function mutation in CHD2 (encoding chromodomain helicase DNA binding protein 2). A third CHD2 mutation was identified in an epileptic proband of a second (stage 2) cohort. All three individuals with a CHD2 mutation had intellectual disability and fever-sensitive generalized seizures, as well as prominent myoclonic seizures starting in the second year of life or later. To explore the functional relevance of CHD2 haploinsufficiency in an in vivo model system, we knocked down chd2 in zebrafish by using targeted morpholino antisense oligomers. chd2-knockdown larvae exhibited altered locomotor activity, and the epileptic nature of this seizure-like behavior was confirmed by field-potential recordings that revealed epileptiform discharges similar to seizures in affected persons. Both altered locomotor activity and epileptiform discharges were absent in appropriate control larvae. Our study provides evidence that de novo loss-of-function mutations in CHD2 are a cause of epileptic encephalopathy with generalized seizures.
    The American Journal of Human Genetics 11/2013; 93(5):967-75. · 11.20 Impact Factor
  • The American Journal of Human Genetics 11/2013; · 11.20 Impact Factor
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    ABSTRACT: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in people with chronic refractory epilepsy. Very rarely, SUDEP occurs in epilepsy monitoring units, providing highly informative data for its still elusive pathophysiology. The MORTEMUS study expanded these data through comprehensive evaluation of cardiorespiratory arrests encountered in epilepsy monitoring units worldwide. Between Jan 1, 2008, and Dec 29, 2009, we did a systematic retrospective survey of epilepsy monitoring units located in Europe, Israel, Australia, and New Zealand, to retrieve data for all cardiorespiratory arrests recorded in these units and estimate their incidence. Epilepsy monitoring units from other regions were invited to report similar cases to further explore the mechanisms. An expert panel reviewed data, including video electroencephalogram (VEEG) and electrocardiogram material at the time of cardiorespiratory arrests whenever available. 147 (92%) of 160 units responded to the survey. 29 cardiorespiratory arrests, including 16 SUDEP (14 at night), nine near SUDEP, and four deaths from other causes, were reported. Cardiorespiratory data, available for ten cases of SUDEP, showed a consistent and previously unrecognised pattern whereby rapid breathing (18-50 breaths per min) developed after secondary generalised tonic-clonic seizure, followed within 3 min by transient or terminal cardiorespiratory dysfunction. Where transient, this dysfunction later recurred with terminal apnoea occurring within 11 min of the end of the seizure, followed by cardiac arrest. SUDEP incidence in adult epilepsy monitoring units was 5·1 (95% CI 2·6-9·2) per 1000 patient-years, with a risk of 1·2 (0·6-2·1) per 10 000 VEEG monitorings, probably aggravated by suboptimum supervision and possibly by antiepileptic drug withdrawal. SUDEP in epilepsy monitoring units primarily follows an early postictal, centrally mediated, severe alteration of respiratory and cardiac function induced by generalised tonic-clonic seizure, leading to immediate death or a short period of partly restored cardiorespiratory function followed by terminal apnoea then cardiac arrest. Improved supervision is warranted in epilepsy monitoring units, in particular during night time. Commission of European Affairs of the International League Against Epilepsy.
    The Lancet Neurology 09/2013; · 23.92 Impact Factor
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    ABSTRACT: Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.
    Nature Genetics 08/2013; · 35.21 Impact Factor
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    ABSTRACT: Sporadic and familial hemiplegic migraines are rare paroxysmal disorders characterized by transient hemiparesis and headache. The distinction is based on whether other family members are affected. In 50% of cases, these migraines are caused by CACNA1 A missense mutations. We describe a patient with a particularly severe phenotype and a de novo R1349Q mutation on the CACNA1 A gene. The patient suffered from early-onset profound mental retardation, epileptic seizures, cerebellar ataxia, and progressive cerebellar atrophy. He experienced prolonged attacks of migraine with hemiparesis, seizures, altered consciousness, and fever resulting from minor head traumas. A prolonged hemiplegic attack improved following a 5-day treatment of 100 mg/d methylprednisolone. R1349Q mutation of the CACN1 A gene is associated with a severe phenotype. Corticoids might be beneficial in prolonged hemiplegic attacks.
    Pediatric Neurology 07/2013; · 1.42 Impact Factor
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    ABSTRACT: An international workshop on juvenile myoclonic epilepsy (JME) was conducted in Avignon, France in May 2011. During that workshop, a group of 45 experts on JME, together with one of the founding fathers of the syndrome of JME ("Janz syndrome"), Prof. Dr. Dieter Janz from Berlin, reached a consensus on diagnostic criteria and management of JME. The international experts on JME proposed two sets of criteria, which will be helpful for both clinical and scientific purposes. Class I criteria encompass myoclonic jerks without loss of consciousness exclusively occurring on or after awakening and associated with typical generalized epileptiform EEG abnormalities, with an age of onset between 10 and 25. Class II criteria allow the inclusion of myoclonic jerks predominantly occurring after awakening, generalized epileptiform EEG abnormalities with or without concomitant myoclonic jerks, and a greater time window for age at onset (6-25years). For both sets of criteria, patients should have a clear history of myoclonic jerks predominantly occurring after awakening and an EEG with generalized epileptiform discharges supporting a diagnosis of idiopathic generalized epilepsy. Patients with JME require special management because their epilepsy starts in the vulnerable period of adolescence and, accordingly, they have lifestyle issues that typically increase the likelihood of seizures (sleep deprivation, exposure to stroboscopic flashes in discos, alcohol intake, etc.) with poor adherence to antiepileptic drugs (AEDs). Results of an inventory of the different clinical management strategies are given. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?
    Epilepsy & Behavior 07/2013; 28 Suppl 1:S87-90. · 1.84 Impact Factor
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    [Show abstract] [Hide abstract]
    ABSTRACT: An international workshop on juvenile myoclonic epilepsy (JME) was conducted in Avignon, France in May 2011. During that workshop, a group of 45 experts on JME, together with one of the founding fathers of the syndrome of JME (“Janz syndrome”), Prof. Dr. Dieter Janz from Berlin, reached a consensus on diagnostic criteria and management of JME.The international experts on JME proposed two sets of criteria, which will be helpful for both clinical and scientific purposes.Class I criteria encompass myoclonic jerks without loss of consciousness exclusively occurring on or after awakening and associated with typical generalized epileptiform EEG abnormalities, with an age of onset between 10 and 25. Class II criteria allow the inclusion of myoclonic jerks predominantly occurring after awakening, generalized epileptiform EEG abnormalities with or without concomitant myoclonic jerks, and a greater time window for age at onset (6–25 years).For both sets of criteria, patients should have a clear history of myoclonic jerks predominantly occurring after awakening and an EEG with generalized epileptiform discharges supporting a diagnosis of idiopathic generalized epilepsy.Patients with JME require special management because their epilepsy starts in the vulnerable period of adolescence and, accordingly, they have lifestyle issues that typically increase the likelihood of seizures (sleep deprivation, exposure to stroboscopic flashes in discos, alcohol intake, etc.) with poor adherence to antiepileptic drugs (AEDs).Results of an inventory of the different clinical management strategies are given.This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?
    Epilepsy & Behavior 07/2013; 28(Supplement):S87-S90. · 1.84 Impact Factor
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    ABSTRACT: Objective: Episodic memory processes can be investigated using different functional MRI (fMRI) paradigms. The purpose of the present study was to examine correlations between neuropsychological memory test scores and BOLD signal changes during fMRI scanning using three different memory tasks. Method: Twenty-eight right-handed healthy subjects underwent three paradigms, (a) a word pair, (b) a space-labyrinth, and (c) a face-name association paradigm. These paradigms were compared for their value in memory quantification and lateralization by calculating correlations between the BOLD signals in the mesial temporal lobe and behavioral data derived from a neuropsychological test battery. Results: As expected, group analysis showed left-sided activation for the verbal, a tendency to right-sided activation for the spatial, and bilateral activation for the face-name paradigm. No linear correlations were observed between neuropsychological data and activation in the temporo-mesial region. However, we found significant u-shaped correlations between behavioral memory performance and activation in both the verbal and the face-name paradigms, that is, BOLD signal changes were greater not only among participants who performed best on the neuropsychological tests, but also among the poorest performers. The figural learning task did not correlate with the activations in the space-labyrinth paradigm at all. Conclusions: We interpreted the u-shaped correlations to be due to compensatory hippocampal activations associated with low performance when people try unsuccessfully to remember presented items. Because activation levels did not linearly increase with memory performance, the latter cannot be quantified by fMRI alone, but only be used in conjunction with neuropsychological testing. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
    Neuropsychology 07/2013; 27(4):402-16. · 3.58 Impact Factor
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    ABSTRACT: Missense mutations in SCN2A, encoding the brain sodium channel NaV 1.2, have been described in benign familial neonatal-infantile seizures (BFNIS), a self-limiting disorder, whereas several SCN2A de novo nonsense mutations have been found in patients with more severe phenotypes including epileptic encephalopathy. We report a family with BFNIS originating from Madagascar. Onset extended from 3 to 9 months of age. Interictal EEGs were normal. In two patients, ictal electroencephalography (EEG) studies showed partial seizure patterns with secondary generalization in one. Seizures remitted before 18 months of age, with or without medication. Intellectual development was normal. A novel missense mutation of SCN2A, c.4766A>G/p.Tyr1589Cys, was found in a highly conserved region of NaV 1.2 (D4/S2-S3). Functional studies using heterologous expression in tsA201 cells and whole-cell patch clamping revealed a depolarizing shift of steady-state inactivation, increased persistent Na(+) current, a slowing of fast inactivation and an acceleration of its recovery, thus a gain-of-function. Using an action potential waveform in a voltage-clamp experiment we indicated an increased inward Na(+) current at subthreshold voltages, which can explain a neuronal hyperexcitability. Our results suggest that this mutation induces neuronal hyperexcitability, resulting in infantile epilepsy with favorable outcome.
    Epilepsia 06/2013; · 3.96 Impact Factor

Publication Stats

4k Citations
858.84 Total Impact Points

Institutions

  • 2013–2014
    • University of Tuebingen
      • Department of Neurology
      Tübingen, Baden-Württemberg, Germany
    • University of Cologne
      • Cologne Center for Genomics (CCG)
      Köln, North Rhine-Westphalia, Germany
  • 2010–2014
    • Universitätsklinikum Tübingen
      Tübingen, Baden-Württemberg, Germany
    • Christian-Albrechts-Universität zu Kiel
      • Institute of Clinical Molecular Biology
      Kiel, Schleswig-Holstein, Germany
  • 2012–2013
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 2010–2013
    • Hertie-Institute for Clinical Brain Research
      Tübingen, Baden-Württemberg, Germany
  • 1993–2011
    • Universität Ulm
      • • Clinic of Neurology
      • • Clinic for Neurosurgery
      • • Institute of Applied Physiology
      Ulm, Baden-Wuerttemberg, Germany
  • 2009
    • University Medical Center Schleswig-Holstein
      Kiel, Schleswig-Holstein, Germany
    • University Medical Center Utrecht
      • Department of Medical Genetics
      Utrecht, Provincie Utrecht, Netherlands
    • Neurologische Klinik Westend
      Бад Вилдунген, Hesse, Germany
  • 2006–2007
    • Max-Delbrück-Centrum für Molekulare Medizin
      Berlín, Berlin, Germany
    • Technische Universität Dresden
      • Abteilung Neuroradiologie
      Dresden, Saxony, Germany
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 1999
    • Vanderbilt University
      Nashville, Michigan, United States