Holger Lerche

University of Tuebingen, Tübingen, Baden-Württemberg, Germany

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Publications (174)982.66 Total impact

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    ABSTRACT: We previously reported nonlinear correlations between verbal episodic memory performance and BOLD signal in memory fMRI in healthy subjects. The purpose of the present study was to examine this observation in patients with left mesial temporal lobe epilepsy (mTLE) who often experience memory decline and need reliable prediction tools before epilepsy surgery with hippocampectomy. Fifteen patients with left mTLE (18-57years, nine females) underwent a verbal memory fMRI paradigm. Correlations between BOLD activity and neuropsychological data were calculated for the i) hippocampus (HC) as well as ii) extrahippocampal mTL structures. Memory performance was systematically associated with activations within the right HC as well as with activations within the left extrahippocampal mTL regions (amygdala and parahippocampal gyrus). As hypothesized, the analyses revealed cubic relationships, with one peak in patients with marginal memory performance and another peak in patients with very good performance. The nonlinear correlations between memory performance and activations might reflect the compensatory recruitment of neural resources to maintain memory performance in patients with ongoing memory deterioration. The present data suggest an already incipient preoperative reorganization process of verbal memory in non-amnesic patients with left mTLE by simultaneously tapping the resources of the right HC and left extrahippocampal mTL regions. Thus, in the preoperative assessment, both neuropsychological performance and memory fMRI should be considered together. Copyright © 2014 Elsevier Inc. All rights reserved.
    Epilepsy & Behavior 12/2014; 42C:78-85. · 2.06 Impact Factor
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    ABSTRACT: Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent de novo mutation, c.959G>A (p.Arg320His), in KCNC1 was identified as a new major cause for PME. Eleven unrelated exome-sequenced (13%) and two affected individuals in a secondary cohort (7%) had this mutation. KCNC1 encodes KV3.1, a subunit of the KV3 voltage-gated potassium ion channels, which are major determinants of high-frequency neuronal firing. Functional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect. Ten cases had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6 and SERPINI1). Identification of mutations in PRNP, SACS and TBC1D24 expand their phenotypic spectra to PME. These findings provide insights into the molecular genetic basis of PME and show the role of de novo mutations in this disease entity.
    Nature genetics. 11/2014;
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    ABSTRACT: Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na(+) channels in interneurons and persistent Na(+) currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca(2+) imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation.
    The Journal of neuroscience : the official journal of the Society for Neuroscience. 11/2014; 34(45):14874-89.
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    ABSTRACT: Febrile seizures affect 2–4% of all children and have a strong genetic component. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.
    Nature Genetics 11/2014; advance online publication. · 35.21 Impact Factor
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    ABSTRACT: We report a consanguineous family with 2 affected individuals whose clinical symptoms closely resembled MERRF (myoclonus epilepsy with ragged red fibers) syndrome including severe myoclonic epilepsy, progressive spastic tetraparesis, progressive impairment of vision and hearing, as well as progressive cognitive decline.
    Neurology 10/2014; · 8.30 Impact Factor
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    ABSTRACT: Electroencephalography (EEG) and magnetoencephalography (MEG) are widely used to localize brain activity and their spatial resolutions have been compared in several publications. While most clinical studies demonstrated higher accuracy of MEG source localization, simulation studies suggested a more accurate EEG than MEG localization for the same number of channels. However, studies comparing real MEG and EEG data with equivalent number of channels are scarce. We investigated 14 right-handed healthy subjects performing a motor task in MEG, high-density-(hd-) EEG and fMRI as well as a somatosensory task in MEG and hd-EEG and compared source analysis results of the evoked brain activity between modalities with different head models. Using individual head models, hd-EEG localized significantly closer to the anatomical reference point obtained by fMRI than MEG. Source analysis results were least accurate for hd-EEG based on a standard head model. Further, hd-EEG and MEG localized more medially than fMRI. Localization accuracy of electric source imaging is dependent on the head model used with more accurate results obtained with individual head models. If this is taken into account, EEG localization can be more accurate than MEG localization for the same number of channels.
    Brain Topography 10/2014; · 3.67 Impact Factor
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    ABSTRACT: 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 “classical” epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10−4), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.
    The American Journal of Human Genetics 09/2014; · 11.20 Impact Factor
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    ABSTRACT: Medicinal plants used for the treatment of epilepsy are potentially a valuable source of novel anti-epileptic small molecules. To identify anticonvulsant secondary metabolites, we performed an in vivo, zebrafish-based screen of medicinal plants used in Southeast Asia for the treatment of seizures. Solanum torvum Sw. (Solanaceae) was identified as having significant anticonvulsant activity in zebrafish larvae with seizures induced by the GABAA antagonist pentylenetetrazol (PTZ). This finding correlates well with the ethnomedical use of this plant in the Philippines, where a water decoction of S. torvum leaves is used to treat epileptic seizures. HPLC microfractionation of the bioactive crude extract, in combination with the in vivo zebrafish seizure assay, enabled the rapid localization of several bioactive compounds that were partially identified on-line by UHPLC-TOF-MS as steroid glycosides. Targeted isolation of the active constituents from the methanolic extract enabled the complete de novo structure identification of the six main bioactive compounds that were also present in the traditional preparation. To partially mimic the in vivo metabolism of these triterpene glycosides, their common aglycone was generated by acid hydrolysis. The isolated molecules exhibited significant anticonvulsant activity in zebrafish seizure assays. These results underscore the potential of zebrafish bioassay-guided microfractionation to rapidly identify novel bioactive small molecules of natural origin.
    ACS Chemical Neuroscience 08/2014; · 3.87 Impact Factor
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    ABSTRACT: 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 loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). Methods: We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p<1·66 × 10–8. Findings: We included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10–10), implicating SCN1A, and at 4p15.1 (p=5·44 × 10–9), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10–9), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. Interpretation: This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the ultimate aim of assisting in disease classification and prognosis. The data suggest that specific loci can act pleiotropically raising risk for epilepsy broadly, or can have effects limited to a specific epilepsy subtype. Future genetic analyses might benefit from both lumping (ie, grouping of epilepsy types together) or splitting (ie, analysis of specific clinical subtypes).
    The Lancet Neurology 07/2014; · 23.92 Impact Factor
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    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) 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 CNVs at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5 - 30.1 Mb) in 393 unrelated patients with typical (n=339) and atypical (ARE; n=54) RE compared with the prevalence in 65046 European population controls (5/393 cases vs 32/65046 controls; Fisher's exact test P=2.83 x 10(-6), OR=26.2, 95% CI: 7.9 - 68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n=330) and genetic generalized epilepsies (n=1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P=2.1 x 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical Rolandic epilepsy.
    Human Molecular Genetics 06/2014; · 7.69 Impact Factor
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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; · 10.23 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
  • Snezana Maljevic, Holger Lerche
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    ABSTRACT: Several potassium channel genes have been implicated in different neurological disorders including genetic and acquired epilepsy. Among them, KCNQ2 and KCNQ3, coding for KV7.2 and KV7.3 voltage-gated potassium channels, present an example how genetic dissection of an epileptic disorder can lead not only to a better understanding of disease mechanisms but also broaden our knowledge about the physiological function of the affected proteins and enable novel approaches in the antiepileptic therapy design. In this chapter, we focus on the neuronal KV7 channels and associated genetic disorders-channelopathies, in particular benign familial neonatal seizures, epileptic encephalopathy, and peripheral nerve hyperexcitability (neuromyotonia, myokymia) caused by KCNQ2 or KCNQ3 mutations. Furthermore, strategies using KV7 channels as targets or tools for the treatment of epileptic diseases caused by neuronal hyperexcitability are being addressed.
    Progress in brain research 01/2014; 213C:17-53. · 4.19 Impact Factor
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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
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    ABSTRACT: Susac's Syndrome (SS) consists of the triad of encephalopathy, branch retinal artery occlusions (BRAO) and hearing loss (HL). Histopathologically, SS is characterised by a microangiopathy, and some observations suggest that an immune-mediated damage of endothelial cells might play a role. These findings also implicate a similarity between SS and other autoimmune diseases, most notably juvenile dermatomyositis (JDM). However, SS and JDM are commonly thought to affect distinct and non-overlapping sets of organs, and it is currently not clear how these specificities arise. Moreover, in the absence of clinical trials, some authors suggest that therapeutic approaches in SS should rely onthe model of other autoimmune diseases such as JDM. Here, we report a case of SS in a 32-year-old pregnant woman. She initially was admitted to the hospital with subacute severe encephalopathy and multifocal neurologic signs. As cranial magnetic resonance imaging (MRI) revealed multifocal white matter lesions including the corpus callosum, erroneously a diagnosis of multiple sclerosis (MS) was made, and intravenous methylprednisolone (IVMP) therapy was initiated. A few days later, an exanthema appeared on the trunk and extremities, which was diagnosed as livedo racemosa (LR). Several weeks later, the patient was readmitted to the clinic with an obscuration of her left visual hemifield and a bilateral HL. Ophthalmologic examination revealed extensive ischemic damage to both retinae. Now the correct diagnosis of SS was established, based on the above triad of clinical symptoms in conjunction with typical MRI and fundoscopic findings. When SS was diagnosed, the standard therapy with intravenous cyclophosphamide (IVCTX) was not instituted because of a significant risk of permanent infertility. Instead, sustained control of disease activity could be achieved with a therapeutic regime combining prednisolone, intravenous immunoglobulins (IVIG), mycophenylate mofetil (MM), and methotrexate (MTX). An association with LR has only been described in very few cases of SS before and further underlines the pathogenetic relationship between SS and other autoimmune diseases such as JDM. In young women with SS and the desire for a child the combination of MM and MTX may represent a reasonable alternative to IVCTX.
    BMC Neurology 11/2013; 13(1):185. · 2.56 Impact Factor

Publication Stats

4k Citations
982.66 Total Impact Points


  • 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
    • Hertie-Institute for Clinical Brain Research
      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
  • 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
  • 2008–2009
    • 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