Publications by authors named "Stjepana Kovac"

58 Publications

Dietary conjugated linoleic acid links reduced intestinal inflammation to amelioration of CNS autoimmunity.

Brain 2021 May;144(4):1152-1166

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.

A close interaction between gut immune responses and distant organ-specific autoimmunity including the CNS in multiple sclerosis has been established in recent years. This so-called gut-CNS axis can be shaped by dietary factors, either directly or via indirect modulation of the gut microbiome and its metabolites. Here, we report that dietary supplementation with conjugated linoleic acid, a mixture of linoleic acid isomers, ameliorates CNS autoimmunity in a spontaneous mouse model of multiple sclerosis, accompanied by an attenuation of intestinal barrier dysfunction and inflammation as well as an increase in intestinal myeloid-derived suppressor-like cells. Protective effects of dietary supplementation with conjugated linoleic acid were not abrogated upon microbiota eradication, indicating that the microbiome is dispensable for these conjugated linoleic acid-mediated effects. Instead, we observed a range of direct anti-inflammatory effects of conjugated linoleic acid on murine myeloid cells including an enhanced IL10 production and the capacity to suppress T-cell proliferation. Finally, in a human pilot study in patients with multiple sclerosis (n = 15, under first-line disease-modifying treatment), dietary conjugated linoleic acid-supplementation for 6 months significantly enhanced the anti-inflammatory profiles as well as functional signatures of circulating myeloid cells. Together, our results identify conjugated linoleic acid as a potent modulator of the gut-CNS axis by targeting myeloid cells in the intestine, which in turn control encephalitogenic T-cell responses.
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http://dx.doi.org/10.1093/brain/awab040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105041PMC
May 2021

Patients with a relapsing course of steroid-responsive encephalopathy associated with autoimmune thyroiditis exhibit persistent intrathecal CD4+ T-cell activation.

Eur J Neurol 2021 Apr 17;28(4):1284-1291. Epub 2020 Dec 17.

Department of Neurology with Institute of Translational Neurology, University Hospital Muenster, Muenster, Germany.

Background And Purpose: Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a rare condition defined by encephalopathy with acute or subacute onset, the presence of serum anti-thyroid antibodies, and reasonable exclusion of alternative causes. Despite having strong response towards corticosteroid treatment, some patients exhibit a chronic-relapsing course and require long-term immunosuppression. Markers for early identification of those patients are still absent. Thus, we aimed to characterise clinical as well as laboratory parameters of our local SREAT cohort.

Methods: We retrospectively evaluated a cohort of 22 SREAT patients treated in our hospital from January 2014.

Results: A total of 14 patients with a monophasic disease course and eight patients with multiple relapses were identified. Neither baseline characteristics nor routine cerebrospinal fluid (CSF) parameters were able to distinguish between those patient groups. Flow cytometry following initial relapse therapy showed treatment-resistant sequestration of activated CD4+ T cells in patients with a relapsing disease course, whereas other lymphocyte subsets showed uniform changes. Such changes were also present in long-term follow-up CSF examination.

Conclusion: Our findings indicate a potential biomarker for risk stratification in patients with SREAT. Currently, it remains unclear whether the observed two phenotypes are different spectra of SREAT or represent separate diseases in terms of pathophysiology.
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http://dx.doi.org/10.1111/ene.14657DOI Listing
April 2021

A role for TASK2 channels in the human immunological synapse.

Eur J Immunol 2021 02 18;51(2):342-353. Epub 2020 Dec 18.

Department of Neurology, Westfälische Wilhelms-Universität, Münster, Germany.

The immunological synapse is a transient junction that occurs when the plasma membrane of a T cell comes in close contact with an APC after recognizing a peptide from the antigen-MHC. The interaction starts when CRAC channels embedded in the T cell membrane open, flowing calcium ions into the cell. To counterbalance the ion influx and subsequent depolarization, K 1.3 and KCa3.1 channels are recruited to the immunological synapse, increasing the extracellular K concentration. These processes are crucial as they initiate gene expression that drives T cell activation and proliferation. The T cell-specific function of the K channel family member TASK2 channels and their role in autoimmune processes remains unclear. Using mass spectrometry analysis together with epifluorescence and super-resolution single-molecule localization microscopy, we identified TASK2 channels as novel players recruited to the immunological synapse upon stimulation. TASK2 localizes at the immunological synapse, upon stimulation with CD3 antibodies, likely interacting with these molecules. Our findings suggest that, together with K 1.3 and KCa3.1 channels, TASK2 channels contribute to the proper functioning of the immunological synapse, and represent an interesting treatment target for T cell-mediated autoimmune disorders.
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http://dx.doi.org/10.1002/eji.201948269DOI Listing
February 2021

Blood and cerebrospinal fluid immune cell profiles in patients with temporal lobe epilepsy of different etiologies.

Epilepsia 2020 10 7;61(10):e153-e158. Epub 2020 Sep 7.

Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.

Inflammation plays a role in the pathogenesis of immune-mediated epilepsy, but also in epilepsy of other etiology such as hippocampal sclerosis. This study aimed to characterize immune cell signatures in the peripheral blood (PB) and cerebrospinal fluid (CSF) in temporal lobe epilepsy (TLE) of different etiologies. We retrospectively evaluated CSF routine parameters and immune cell profiles using flow cytometry in a cohort of 51 patients and 45 age-matched controls with functional disorders. Groups were comprised of patients with nonlesional TLE (n = 26), TLE due to hippocampal sclerosis (n = 14), or limbic encephalitis with antibodies against the 65-kDa isoform of glutamic acid decarboxylase (GAD65-LE; n = 11). TLE patients showed increased proportions of human leukocyte antigen-DR isotype (HLA-DR)-expressing CD4 T lymphocytes in the CSF. Furthermore, they were characterized by a shift in monocyte subsets toward immature CD14 CD16 cells in the PB and blood/CSF-barrier dysfunction. Whereas TLE patients in general showed similar immune cell profiles, patients with GAD65-LE differed from other TLE patients by increased proportions of HLA-DR-expressing CD8 T lymphocytes and type 2/3 oligoclonal bands. These findings point to a role of innate and adaptive immunity in TLE. CSF parameters may help to discriminate epilepsy patients from controls and different forms of TLE from each other.
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http://dx.doi.org/10.1111/epi.16688DOI Listing
October 2020

Could the 2017 ILAE and the four-dimensional epilepsy classifications be merged to a new "Integrated Epilepsy Classification"?

Seizure 2020 May 5;78:31-37. Epub 2020 Mar 5.

Neurocenter Bellevue, Zurich, Switzerland.

Over the last few decades the ILAE classifications for seizures and epilepsies (ILAE-EC) have been updated repeatedly to reflect the substantial progress that has been made in diagnosis and understanding of the etiology of epilepsies and seizures and to correct some of the shortcomings of the terminology used by the original taxonomy from the 1980s. However, these proposals have not been universally accepted or used in routine clinical practice. During the same period, a separate classification known as the "Four-dimensional epilepsy classification" (4D-EC) was developed which includes a seizure classification based exclusively on ictal symptomatology, which has been tested and adapted over the years. The extensive arguments for and against these two classification systems made in the past have mainly focused on the shortcomings of each system, presuming that they are incompatible. As a further more detailed discussion of the differences seemed relatively unproductive, we here review and assess the concordance between these two approaches that has evolved over time, to consider whether a classification incorporating the best aspects of the two approaches is feasible. To facilitate further discussion in this direction we outline a concrete proposal showing how such a compromise could be accomplished, the "Integrated Epilepsy Classification". This consists of five categories derived to different degrees from both of the classification systems: 1) a "Headline" summarizing localization and etiology for the less specialized users, 2) "Seizure type(s)", 3) "Epilepsy type" (focal, generalized or unknown allowing to add the epilepsy syndrome if available), 4) "Etiology", and 5) "Comorbidities & patient preferences".
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http://dx.doi.org/10.1016/j.seizure.2020.02.018DOI Listing
May 2020

Structured testing during seizures: A practical guide for assessing and interpreting ictal and postictal signs during video EEG long term monitoring.

Seizure 2019 Nov 31;72:13-22. Epub 2019 Aug 31.

Department of Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Department of Clinical and Experimental Epilepsy, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.

Background: Ictal and postictal testing carried out in long-term epilepsy monitoring units is often sub-optimal. Recently, a European consensus protocol for testing patients during and after seizures was developed by a joint taskforce of the International League Against Epilepsy - Commission on European Affairs and the European Epilepsy Monitoring Unit Association.

Aim: Using this recently developed standardised assessment battery as a framework, the goal of this narrative review is to outline the proposed testing procedure in detail and explain the rationale for each individual component, focusing on the underlying neurobiology. This is intended to serve as an educational resource for staff working in epilepsy monitoring units.

Methods: A literature review of PubMed was performed; using the search terms "seizure", "ictal", "postictal", "testing", "examination", and "interview". Relevant literature was reviewed and relevant references were chosen. The work is presented as a narrative review.

Results: The proposed standardised assessment battery provides a comprehensive and user-friendly format for ictal-postictal testing, and examines consciousness, language, motor, sensory, and visual function.

Conclusion: The standardised approach proposed has the potential to make full use of data recorded during video EEG increasing the diagnostic yield with regards to lateralisation and localisation, aiding both presurgical and diagnostic studies.
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http://dx.doi.org/10.1016/j.seizure.2019.08.008DOI Listing
November 2019

Combination antioxidant therapy prevents epileptogenesis and modifies chronic epilepsy.

Redox Biol 2019 09 19;26:101278. Epub 2019 Jul 19.

UCL Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N, UK. Electronic address:

Many epilepsies are acquired conditions following an insult to the brain such as a prolonged seizure, traumatic brain injury or stroke. The generation of reactive oxygen species (ROS) and induction of oxidative stress are common sequelae of such brain insults and have been shown to contribute to neuronal death and the development of epilepsy. Here, we show that combination therapy targeting the generation of ROS through NADPH oxidase inhibition and the endogenous antioxidant system through nuclear factor erythroid 2-related factor 2 (Nrf2) activation prevents excessive ROS accumulation, mitochondrial depolarisation and neuronal death during in vitro seizure-like activity. Moreover, this combination therapy prevented the development of spontaneous seizures in 40% of animals following status epilepticus (70% of animals were seizure free after 8 weeks) and modified the severity of epilepsy when given to chronic epileptic animals.
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http://dx.doi.org/10.1016/j.redox.2019.101278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692059PMC
September 2019

Seizure-induced shoulder dislocations - Case series and review of the literature.

Seizure 2019 Aug 20;70:38-42. Epub 2019 Jun 20.

Department of Neurology, University of Münster, Münster, Germany. Electronic address:

Purpose: We aimed to identify clinical characteristics of patients with shoulder dislocations caused by an epileptic seizure.

Methods: In our retrospective analysis, we identified 15 patients, recorded over an 8-year period, who were diagnosed with shoulder dislocations in the setting of a bilateral tonic-clonic seizure.

Results: Patients were almost exclusively male (13/15) and drug-naïve patients suffering their first or second seizure (14/15). Epilepsy was diagnosed in five of these 14 patients after further diagnostic tests, four patients were diagnosed with a provoked or acute symptomatic seizure and five patients with an unprovoked seizure. Treatment with anticonvulsant drugs (AED) was initiated in 10/15 patients after the first seizure, without recommendation for tapering, although long-term treatment was retrospectively judged to be appropriate for only four of those cases. Posterior dislocations - usually rare - were seen in 12/15 patients and often required complex orthopedic interventions.

Conclusions: We conclude that in particular posterior shoulder dislocations are often caused by a first seizure and should always raise the suspicion of an epileptic seizure even in the absence of a clear history. AED treatment likely has a protective effect against this type of injury, even if seizure-freedom is not achieved.
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http://dx.doi.org/10.1016/j.seizure.2019.06.025DOI Listing
August 2019

Seizures and epilepsy in multiple sclerosis: epidemiology and prognosis in a large tertiary referral center.

J Neurol 2019 Jul 8;266(7):1789-1795. Epub 2019 May 8.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149, Münster, Germany.

Background: Seizures and epilepsy may substantially add to the burden of disease in multiple sclerosis (MS), whereas the exact prevalence and prognosis of seizures and epilepsy in patients with MS remains largely unknown.

Objectives: We aimed to investigate the epidemiology and prognosis of seizures and epilepsy in MS.

Methods: We retrospectively analyzed a cohort of 4078 MS patients from a single tertiary referral clinic.

Results: After excluding 37 patients with unconfirmed MS and alternative seizure etiologies, we found seizures attributable to MS in 1.5% and epilepsy in 0.9% of patients. 40.4% of patients with a follow-up of at least twelve months experienced only a single seizure and 59.6% had recurring seizures. 39% of patients with recurrent seizures were considered drug-resistant, with 9.7% experiencing status epilepticus. Seizure recurrence after a first seizure depended significantly on the MS subtype and was seen more often if the first seizure occurred simultaneously with a MS relapse than in the absence of a relapse.

Conclusion: Our study shows a lower number of seizures and epilepsy in MS than previously reported. While a single seizure in MS usually has a good prognosis, relapse-associated seizures and established epilepsy in MS may not be as benign as previously assumed.
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http://dx.doi.org/10.1007/s00415-019-09332-xDOI Listing
July 2019

Cell injury and receptor expression in the epileptic human amygdala.

Neurobiol Dis 2019 04 24;124:416-427. Epub 2018 Dec 24.

Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran; Department of Neurology with Institute of Translational Neurology, Westfälische Wilhelms-Universität Münster, Germany; Department of Neurosurgery, Westfälische Wilhelms-Universität Münster, Germany; Epilepsy research center, Westfälische Wilhelms-Universität Münster, Germany; Department of Neuroscience, Mashhad University of Medical Sciences, Iran. Electronic address:

Neuropathological findings in the amygdala obtained from patients with mesial temporal lobe epilepsy (MTLE) indicate varying degrees of histopathological alterations, such as neuronal loss and gliosis. The mechanisms underlying cellular damage in the amygdala of patients with MTLE have not been fully elucidated. In the present study, we assess cellular damage, determine the receptor expression of major inhibitory and excitatory neurotransmitters, and evaluate the correlation between the expression of various receptors and cell damage in the basolateral complex and the centromedial areas in the amygdala specimens resected during brain surgery on 30 patients with medically intractable MTLE. Our data reveal an increased rate of cell damage and apoptosis as well as decreased expression levels of several GABAergic receptor subunits (GABARα1, GABARβ3, and GABABR1) and GAD in the amygdalae obtained during epilepsy surgery compared to autopsy specimens. Analyses of the expression of glutamate excitatory receptor subunits (NR1, NR2B, mGluR1α, GluR1, and GluR2) reveal no significant differences between the epileptic amygdalae and autopsy control tissues. Furthermore, the increased occurrence of apoptotic cells in the amygdala is negatively correlated with the reduced expression of the studied GABAergic receptor subunits and GAD but is not correlated with the expression of excitatory receptors. The present data point to the importance of GABAergic neurotransmission in seizure-induced cell injury in the amygdala of patients with MTLE and suggest several GABA receptor subunits as potential druggable target structures to control epilepsy and its comorbid disorders, such as anxiety.
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http://dx.doi.org/10.1016/j.nbd.2018.12.017DOI Listing
April 2019

Human T cells in silico: Modelling dynamic intracellular calcium and its influence on cellular electrophysiology.

J Immunol Methods 2018 10 3;461:78-84. Epub 2018 Jul 3.

Department of Neurology with Institute of Translational Neurology, Albert-Schweitzer-Campus 1, Building A1, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany. Electronic address:

A network of ion currents influences basic cellular T cell functions. After T cell receptor activation, changes in highly regulated calcium levels play a central role in triggering effector functions and cell differentiation. A dysregulation of these processes might be involved in the pathogenesis of several diseases. We present a mathematical model based on the NEURON simulation environment that computes dynamic calcium levels in combination with the current output of diverse ion channels (K1.3, K3.1, K channels (TASK1-3, TRESK), VRAC, TRPM7, CRAC). In line with experimental data, the simulation shows a strong increase in intracellular calcium after T cell receptor stimulation before reaching a new, elevated calcium plateau in the T cell's activated state. Deactivation of single ion channel modules, mimicking the application of channel blockers, reveals that two types of potassium channels are the main regulators of intracellular calcium level: calcium-dependent potassium (K3.1) and two-pore-domain potassium (K) channels.
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http://dx.doi.org/10.1016/j.jim.2018.06.020DOI Listing
October 2018

Correction to: Impaired Bioenergetics in Mutant Mitochondrial DNA Determines Cell Fate during Seizure-Like Activity.

Mol Neurobiol 2019 Jan;56(1):335

Department of Molecular Neuroscience, UCL, London, UK.

The original version of this article unfortunately contained mistake. The author's family name "Kov ac" was written with space thus this should be corrected to "Kovac".
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http://dx.doi.org/10.1007/s12035-018-1110-0DOI Listing
January 2019

Impaired Bioenergetics in Mutant Mitochondrial DNA Determines Cell Fate During Seizure-Like Activity.

Mol Neurobiol 2019 Jan 27;56(1):321-334. Epub 2018 Apr 27.

Department of Molecular Neuroscience, UCL, London, UK.

Mutations in genes affecting mitochondrial proteins are increasingly recognised in patients with epilepsy, but the factors determining cell fate during seizure activity in these mutations remain unknown. Fluorescent dye imaging techniques were applied to fibroblast cell lines from patients suffering from common mitochondrial mutations and to age-matched controls. Using live cell imaging techniques in fibroblasts, we show that fibroblasts with mutations in the mitochondrial genome had reduced mitochondrial membrane potential and NADH pools and higher redox indices, indicative of respiratory chain dysfunction. Increasing concentrations of ferutinin, a Ca ionophore, led to oscillatory Ca signals in fibroblasts resembling dynamic Ca changes that occur during seizure-like activity. Co-monitoring of mitochondrial membrane potential (ΔΨ) changes induced by ferutinin showed accelerated membrane depolarisation and cell collapse in fibroblasts with mutations in the mitochondrial genome when compared to controls. Ca flash photolysis using caged Ca confirmed impaired Ca handling in fibroblasts with mitochondrial mutations. Findings indicate that intracellular Ca levels cannot be compensated during periods of hyperexcitability, leading to Ca overload and subsequent cell death in mitochondrial diseases.
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http://dx.doi.org/10.1007/s12035-018-1078-9DOI Listing
January 2019

Phenotypes, genotypes, and the management of paroxysmal movement disorders.

Dev Med Child Neurol 2018 06 30;60(6):559-565. Epub 2018 Mar 30.

Department of Molecular Neuroscience, Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London, UK.

As a consequence of the genomic revolution, a large number of publications describing paroxysmal movement disorders have been published in the last few years, shedding light on their molecular pathology. Routine gene testing is not necessary to guide treatment for typical forms of paroxysmal kinesigenic dyskinesia (PKD), paroxysmal nonkinesigenic dyskinesia (PNKD), and episodic ataxia type 1 or 2. It can, however, be helpful in the management of atypical or complex cases, especially for genetic counselling, treatment strategies, and the offer of preimplantation genetic diagnosis. Antiepileptic drugs remain the treatment of choice for PKD and episodic ataxia type 1, benzodiazepines are often useful for PNKD, and episodic ataxia type 2 benefits from acetazolamide regardless of the genetic etiology.

What The Paper Adds: A growing number of genes have been associated with classic and newly described paroxysmal movement disorders. Paroxysmal movement disorders share common mechanisms and clinical features with other neurological paroxysmal phenomena including epilepsy and migraine.
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http://dx.doi.org/10.1111/dmcn.13744DOI Listing
June 2018

KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy.

Brain 2018 05;141(5):1390-1403

UCL Institute of Neurology, University College London, Queen Square, London WC1N, UK.

Hippocampal sclerosis is a common acquired disease that is a major cause of drug-resistant epilepsy. A mechanism that has been proposed to lead from brain insult to hippocampal sclerosis is the excessive generation of reactive oxygen species, and consequent mitochondrial failure. Here we use a novel strategy to increase endogenous antioxidant defences using RTA 408, which we show activates nuclear factor erythroid 2-related factor 2 (Nrf2, encoded by NFE2L2) through inhibition of kelch like ECH associated protein 1 (KEAP1) through its primary sensor C151. Activation of Nrf2 with RTA 408 inhibited reactive oxygen species production, mitochondrial depolarization and cell death in an in vitro model of seizure-like activity. RTA 408 given after status epilepticus in vivo increased ATP, prevented neuronal death, and dramatically reduced (by 94%) the frequency of late spontaneous seizures for at least 4 months following status epilepticus. Thus, acute KEAP1 inhibition following status epilepticus exerts a neuroprotective and disease-modifying effect, supporting the hypothesis that reactive oxygen species generation is a key event in the development of epilepsy.
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http://dx.doi.org/10.1093/brain/awy071DOI Listing
May 2018

Uncensored EEG: The role of DC potentials in neurobiology of the brain.

Prog Neurobiol 2018 Jun - Aug;165-167:51-65. Epub 2018 Feb 8.

Department of Neurology and Institute of Translational Neurology, Westfälische Wilhelms-Universität Münster, Germany; Epilepsy Research Center, Westfalische Wilhelms-University Münster, Münster, Germany; Department of Neurosurgery, Westfalische Wilhelms-University Münster, Münster, Germany; Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran; Department of Neuroscience, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Brain direct current (DC) potentials denote sustained shifts and slow deflections of cerebral potentials superimposed with conventional electroencephalography (EEG) waves and reflect alterations in the excitation level of the cerebral cortex and subcortical structures. Using galvanometers, such sustained displacement of the EEG baseline was recorded in the early days of EEG recordings. To stabilize the EEG baseline and eliminate artefacts, EEG was performed later by voltage amplifiers with high-pass filters that dismiss slow DC potentials. This left slow DC potential recordings as a neglected diagnostic source in the routine clinical setting over the last few decades. Brain DC waves may arise from physiological processes or pathological phenomena. Recordings of DC potentials are fundamental electro-clinical signatures of some neurological and psychological disorders and may serve as diagnostic, prognostic, and treatment monitoring tools. We here review the utility of both physiological and pathological brain DC potentials in different aspects of neurological and psychological disorders. This may enhance our understanding of the role of brain DC potentials and improve our fundamental clinical and research strategies for brain disorders.
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http://dx.doi.org/10.1016/j.pneurobio.2018.02.001DOI Listing
February 2019

NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody.

Ann Clin Transl Neurol 2017 11 3;4(11):768-783. Epub 2017 Oct 3.

Department of Neurology Medical Faculty Heinrich Heine University Düsseldorf Düsseldorf Germany.

Objective: Autoimmune encephalitis is most frequently associated with anti-NMDAR autoantibodies. Their pathogenic relevance has been suggested by passive transfer of patients' cerebrospinal fluid (CSF) in mice in vivo. We aimed to analyze the intrathecal plasma cell repertoire, identify autoantibody-producing clones, and characterize their antibody signatures in recombinant form.

Methods: Patients with recent onset typical anti-NMDAR encephalitis were subjected to flow cytometry analysis of the peripheral and intrathecal immune response before, during, and after immunotherapy. Recombinant human monoclonal antibodies (rhuMab) were cloned and expressed from matching immunoglobulin heavy- (IgH) and light-chain (IgL) amplicons of clonally expanded intrathecal plasma cells (cePc) and tested for their pathogenic relevance.

Results: Intrathecal accumulation of B and plasma cells corresponded to the clinical course. The presence of cePc with hypermutated antigen receptors indicated an antigen-driven intrathecal immune response. Consistently, a single recombinant human GluN1-specific monoclonal antibody, rebuilt from intrathecal cePc, was sufficient to reproduce NMDAR epitope specificity in vitro. After intraventricular infusion in mice, it accumulated in the hippocampus, decreased synaptic NMDAR density, and caused severe reversible memory impairment, a key pathogenic feature of the human disease, in vivo.

Interpretation: A CNS-specific humoral immune response is present in anti-NMDAR encephalitis specifically targeting the GluN1 subunit of the NMDAR. Using reverse genetics, we recovered the typical intrathecal antibody signature in recombinant form, and proved its pathogenic relevance by passive transfer of disease symptoms from man to mouse, providing the critical link between intrathecal immune response and the pathogenesis of anti-NMDAR encephalitis as a humorally mediated autoimmune disease.
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http://dx.doi.org/10.1002/acn3.444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682115PMC
November 2017

Metabolic and Homeostatic Changes in Seizures and Acquired Epilepsy-Mitochondria, Calcium Dynamics and Reactive Oxygen Species.

Int J Mol Sci 2017 Sep 8;18(9). Epub 2017 Sep 8.

Department of Neurology, University of Münster, 48149 Münster, Germany.

Acquired epilepsies can arise as a consequence of brain injury and result in unprovoked seizures that emerge after a latent period of epileptogenesis. These epilepsies pose a major challenge to clinicians as they are present in the majority of patients seen in a common outpatient epilepsy clinic and are prone to pharmacoresistance, highlighting an unmet need for new treatment strategies. Metabolic and homeostatic changes are closely linked to seizures and epilepsy, although, surprisingly, no potential treatment targets to date have been translated into clinical practice. We summarize here the current knowledge about metabolic and homeostatic changes in seizures and acquired epilepsy, maintaining a particular focus on mitochondria, calcium dynamics, reactive oxygen species and key regulators of cellular metabolism such as the Nrf2 pathway. Finally, we highlight research gaps that will need to be addressed in the future which may help to translate these findings into clinical practice.
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http://dx.doi.org/10.3390/ijms18091935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618584PMC
September 2017

Gabapentin prevents cortical spreading depolarization-induced disinhibition.

Neuroscience 2017 Oct 12;361:1-5. Epub 2017 Aug 12.

Epilepsy Research Center, Westfälische Wilhelms-Universität Münster, Germany; Department of Neurosurgery, Westfälische Wilhelms-Universität Münster, Germany; Department of Neurology, Westfälische Wilhelms-Universität Münster, Germany; Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran; Department of Neuroscience, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Cortical spreading depolarization (CSD) has an important role in brain diseases such as stroke, subarachnoid hemorrhage, migraine with aura, and epilepsy. Several anti-epileptic drugs (AEDs) are used to treat paroxysmal brain diseases and are thus known to suppress CSD. One of these AEDs is gabapentin (GBP) which has been traditionally used for treatment of some CSD-related neurological diseases. We applied intra- and extracellular recordings to investigate the effect of CSD on inhibitory post synaptic potentials (IPSPs) and synaptic properties of rodent neocortex after application of GBP. Application of GBP after CSD increased the amplitude of IPSPs. In addition, GBP inhibited induction of long-term potentiation after CSD. These data support an effect of GBP on GABA-mediated inhibition in the late hyperexcitable phase of CSD. Modulations of synaptic properties and post-CSD GABAergic function are likely GBP's mechanisms of action in CSD-related disorders. These mechanisms could be targeted for further drug discovery in CSD-related diseases.
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http://dx.doi.org/10.1016/j.neuroscience.2017.08.009DOI Listing
October 2017

Treating refractory post-herpetic anti--methyl-d-aspartate receptor encephalitis with rituximab.

Oxf Med Case Reports 2017 Jul 3;2017(7):omx034. Epub 2017 Jul 3.

Department of Neurology, University of Münster, Münster, Germany.

Herpes simplex virus-1 has been identified as the trigger factor in certain cases of NMDA-receptor autoimmune encephalitis. We report on a 67-year-old female patient, who was severely affected by post-herpetic NMDA-receptor autoimmune encephalitis. Her symptoms did not improve under methylprednisolone pulse therapy and plasma exchange under acyclovir prophylaxis. She received protein A immunoadsorption and a long-term immunosuppression with rituximab. Under treatment, activated T-cells as well as B- and plasma cells decreased in peripheral blood and cerebrospinal fluid, and anti-NMDA-R IgG titers in serum and cerebrospinal fluid declined with near complete cessation of intrathecal autoantibody synthesis. The patient regained near complete independence and profoundly improved on formal neuropsychological assessment. Despite reduction of antiviral defense through of lowered activated T cells and concomitantly decreasing HSV-specific IgG antibodies, no evidence of viral reactivation was detected.
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http://dx.doi.org/10.1093/omcr/omx034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495011PMC
July 2017

Apoptosis Following Cortical Spreading Depression in Juvenile Rats.

Mol Neurobiol 2018 May 13;55(5):4225-4239. Epub 2017 Jun 13.

Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran.

Repetitive cortical spreading depression (CSD) can lead to cell death in immature brain tissue. Caspases are involved in neuronal cell death in several CSD-related neurological disorders, such as stroke and epilepsy. Yet, whether repetitive CSD itself can induce caspase activation in adult or juvenile tissue remains unknown. Inducing repetitive CSD in somatosensory cortices of juvenile and adult rats in vivo, we thus aimed to investigate the effect of repetitive CSD on the expression caspase-3, caspase-8, caspase-9, and caspase-12 in different brain regions using immunohistochemistry and western blotting techniques. Higher numbers of dark neurons and TUNEL-positive cells were observed in the hippocampal CA1 and CA3 regions as well as in the entorhinal and somatosensory cortices after CSD in juvenile rats. This was accompanied by higher expressions of caspase-3, caspase-8, and caspase-9. Caspase-12 levels remained unchanged after CSD, suggesting that endoplasmic reticulum stress is not involved in CSD-triggered apoptosis. Changes in caspase expression were paralleled by a decrease of procaspase-3, procaspase-8, and procaspase-9 in juvenile rat brain tissue subjected to CSD. In contrast, repetitive CSD in adult rats did not result in the upregulation of caspase signaling. Our data points to a maturation-dependent vulnerability of brain tissue to repetitive CSD with a higher degree of apoptotic damage and caspase upregulation observed in juvenile tissue. Findings suggest a key role of caspase signaling in CSD-induced cell death in the immature brain. This implies that anti-apoptotic treatment may prevent CSD-related functional deficits in the immature brain.
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http://dx.doi.org/10.1007/s12035-017-0642-zDOI Listing
May 2018

Astrocyte-mediated inflammation in cortical spreading depression.

Cephalalgia 2018 04 3;38(4):626-638. Epub 2017 Apr 3.

1 Shefa Neuroscience Research Center, Khatam-Alanbia Hospital, Tehran, Iran.

Background Cortical spreading depression (CSD) related diseases such as migraine, cerebrovascular diseases, and epilepsy have been associated with reactive astrocytosis, yet the mechanisms of these tissue changes remain unclear. CSD-induced inflammatory response has been proposed to play a role in some neurological disorders and thus may also contribute to reactive astrocytosis. Methods Using ex vivo brain slices and in vitro astrocytic cultures, we aimed to characterize CSD related changes in astrocytes and markers of inflammation by immunocyto- and immunohistochemistry. CSD was induced by application of KCl (3 mol/l) on neocortical tissues. The application of KCl was repeated weekly over the course of four weeks. Results CSD induced an increase in the mean number and volume of astrocytes in rat brain tissue when compared to controls, whereas no changes in neuronal numbers and volumes were seen. These cell-type specific changes, suggestive of reactive astrocytosis, were paralleled by an increased expression of protein markers indicative of astrocytes and neuroinflammation in ex vivo brain slices of animals undergoing CSD when compared to sham-treated controls. Cultured astrocytes showed an increased expression of the immune modulatory enzyme indoleamine 2,3-dioxygenase and an elevated expression of the pro-inflammatory markers, IL-6, IL-1β, and TNFα in addition to increased levels of toll like receptors (TLR3 and TLR4) and astrocytic markers after induction of CSD. Conclusion These findings indicate that CSD related reactive astrocytosis is linked to an upregulation of inflammatory markers. Targeting inflammation with already approved and available immunomodulatory treatments may thus represent a strategy to combat or ameliorate CSD-related disease.
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http://dx.doi.org/10.1177/0333102417702132DOI Listing
April 2018

Developmental changes in Notch1 and NLE1 expression in a genetic model of absence epilepsy.

Brain Struct Funct 2017 Aug 16;222(6):2773-2785. Epub 2017 Feb 16.

Shefa Neuroscience Research Centre, Khatam Alanbia Hospital, Tehran, Iran.

Childhood absence epilepsy (CAE) is an epilepsy syndrome with seizures occurring in the early childhood, highlighting that seizures susceptibility in CAE is dependent on brain development. The Notch 1 signalling pathway is important in brain development, yet the role of the Notch1 signalling pathway in CAE remains elusive. We here explored Notch1 and its modulator notchless homologue 1 (NLE1) expression in WAG/Rij and control rats using immunohistochemistry. Functional Notch 1 effects were assessed in WAG/Rij rats in vivo. WAG/Rij rats lack the developmental increase in cortical Notch1 and NLE 1 mRNA expression seen in controls, and Notch 1 and NLE1 mRNA and protein expression were lower in somatosensory cortices of WAG/Rij rats when compared to controls. This coincided with an overall decreased cortical GFAP expression in the early development in WAG/Rij rats. These effects were region-specific as they were not observed in thalamic tissues. Neuron-to-glia ratio as a marker of the impact of Notch signalling on differentiation was higher in layer 4 of somatosensory cortex of WAG/Rij rats. Acute application of Notch 1 agonist Jagged 1 suppressed, whereas DAPT, a Notch antagonist, facilitated spike and wave discharges (SWDs) in WAG/Rij rats. These findings point to Notch1 as an important signalling pathway in CAE which likely shapes architectural organization of the somatosensory cortex, a region critically involved in developmental epileptogenesis in CAE. More immediate effects of Notch 1 signalling are seen on in vivo SWDs in CAE, pointing to the Notch 1 pathway as a possible treatment target in CAE.
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http://dx.doi.org/10.1007/s00429-017-1371-9DOI Listing
August 2017

Carvacrol after status epilepticus (SE) prevents recurrent SE, early seizures, cell death, and cognitive decline.

Epilepsia 2017 02 13;58(2):263-273. Epub 2017 Jan 13.

UCL Institute of Neurology, University College London, London, United Kingdom.

Objective: Carvacrol is a naturally occurring monoterpenic phenol that has been suggested to have an action at transient receptor potential cation subfamily M7 (TRPM7) channels, γ-aminobutyric acid (GABA receptors, and sodium channels, and has been shown to be antiinflammatory. Carvacrol is neuroprotective in models of cerebral ischemia in vivo and in vitro, probably through its action at TRPM7 channels. We therefore aimed to determine the effect of carvacrol on status epilepticus (SE), chronic epilepsy, cell death, and post-SE cognitive decline.

Methods: We performed long-term, continuous wireless electroencephalography (EEG) monitoring in vivo in rats who underwent perforant path stimulation (PPS) to induce SE and were then randomized to treatment with carvacrol or saline. We also evaluated TRPM7 receptor expression and quantified seizure-induced cell death. The alternating T-maze paradigm was used to assess memory function.

Results: Immunostaining showed that TRPM7 channels are widely expressed in neurons within the hippocampus. We found that carvacrol inhibited recurrent SE and early seizures in vivo, but had no detectable effect in the hippocampus on paired-pulse inhibition or the fiber volley, indicating that it was not acting through sodium channel inhibition or GABA receptors. Although the development and severity of chronic epilepsy were not altered by carvacrol, cognitive decline was significantly improved in animals treated with carvacrol. In keeping with preserved memory functions in animals treated with carvacrol, carvacrol had a protective effect against SE-induced cell death in CA1 and hilus, the hippocampal regions most affected by cell loss in the PPS epilepsy model.

Significance: Carvacrol, a naturally occurring inhibitor of TRPM7 channels, is a novel, promising treatment to prevent early recurrence of SE, SE-related neuronal damage, and cognitive decline.
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http://dx.doi.org/10.1111/epi.13645DOI Listing
February 2017

Invasive epilepsy surgery evaluation.

Seizure 2017 Jan 21;44:125-136. Epub 2016 Oct 21.

Department of Clinical and Experimental Epilepsy, University College London, Institute of Neurology, Queen Square, London, UK; Department of Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. Electronic address:

Intracranial EEG (iEEG) recordings are widely used for the work up of pharmacoresistant epilepsy. Different iEEG recording techniques namely subdural grids, strips, depth electrodes and stereoencephalography (SEEG) are available with distinct limitations and advantages. Epilepsy centres mastering multiple techniques apply them in an individualised patient approach. These tools are used to map the seizure onset zone which is pivotal in approximating the epileptogenic zone, i.e. the zone which is indispensable for the generation of seizures and when resected will render the patient seizure free. Besides, the implanted electrodes can be used to define eloquent cortex through direct cortical stimulation. Different clinical scenarios exist which favour one iEEG recording technique over the other. Proximity of the presumed epileptogenic zone to eloquent cortex, for example, is a clinical scenario which may favour grid electrodes over SEEG. We here review the indication for iEEG for the work-up of patients suffering from pharmacoresistant epilepsy. In addition, we provide a description of the recording techniques focussing on the main techniques used: grid electrodes, depth electrodes and stereoencephalography. We then outline different clinical scenarios and the preferred technical approach for intracranial recordings in these scenarios. Finally, we highlight which advances have been made in the field of iEEG and which advances are in the pipeline waiting to be established for clinical use. This review provides the clinician with an update on the diagnostic use of intracranial EEG for epilepsy surgery and thus aids in understanding patient selection for this technique which may ultimately improve referral patterns.
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http://dx.doi.org/10.1016/j.seizure.2016.10.016DOI Listing
January 2017

Drop attacks, falls and atonic seizures in the Video-EEG monitoring unit.

Seizure 2015 Nov 15;32:4-8. Epub 2015 Aug 15.

Department of Clinical and Experimental Epilepsy, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK; Department of Neurology, University of Muenster, Münster, Germany. Electronic address:

Purpose: We set out to determine clinical and EEG features of seizures presenting with falls, epileptic drop attacks and atonia in the video EEG monitoring unit.

Methods: We searched the video EEG monitoring reports over a 5-year-period for the terms "drop", "fall" and "atonic".

Results: Seizures presenting as epileptic drop attacks, falls or atonia were found in 23/1112 (2%) admissions. About half of the patients suffering from these seizure types had developmental delay and learning difficulties and in half of the patients a lesion was seen on MRI which was often frontal. The presumed epileptogenic zone was frontal in many cases (43%), unclear with regards to a region or multifocal in 48% and posterior temporal/occipital in 2 patients (9%). EEG patterns recorded were paroxysmal fast activity, spike and wave discharges and EEG attenuation. Seizure related falls were seen in 8 cases (34%) with injuries recorded during Video EEG monitoring in half of those.

Conclusion: Clinical and EEG features outlined here can help the clinician to recognise patients at risk for these devastating seizure types.
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http://dx.doi.org/10.1016/j.seizure.2015.08.001DOI Listing
November 2015

Predictors for being offered epilepsy surgery: 5-year experience of a tertiary referral centre.

J Neurol Neurosurg Psychiatry 2016 Feb 2;87(2):209-11. Epub 2015 May 2.

UCL Institute of Neurology, UCL, London, UK Jules Thorne Telemetry Unit, National Hospital for Neurology and Neurosurgery, London, UK.

Objectives: To define factors that predict whether patients with pharmacoresistant focal epilepsy are offered epilepsy surgery (including invasive EEG) and the main reasons for not proceeding with these after non-invasive presurgical evaluation.

Methods: We retrospectively analysed data from 612 consecutive patients with focal epilepsy admitted to a video-EEG Telemetry Unit for presurgical evaluation, and used a multivariate logistic regression model to assess the predictive value of factors for being offered potentially curative surgery.

Results: In the multivariate analysis, bilateral lesions on MRI (OR: 0.10; 95% CI 0.03 to 0.24), no lesion (OR: 0.33; 95% CI 0.22 to 0.49) or extratemporal lobe epilepsy (OR: 0.30; 95% CI 0.20 to 0.45) were the only factors that significantly reduced the probability of being offered surgery. 32% of patients who were offered epilepsy surgery decided against proceeding.

Conclusions: There was a low chance (<10%) of being offered surgery if there were bilateral lesions on MRI and extratemporal lobe epilepsy. Patients should be given advice on the risk/benefit ratio and of realistic outcomes of epilepsy surgery; this may help reduce the number of patients who refuse surgery after comprehensive workup.
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http://dx.doi.org/10.1136/jnnp-2014-310148DOI Listing
February 2016

Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus.

Nat Commun 2015 Jan 23;6:6031. Epub 2015 Jan 23.

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.

Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Here we employ systems genetics approaches to characterize the genetic regulation of pathophysiological pathways in human temporal lobe epilepsy (TLE). Using surgically acquired hippocampi from 129 TLE patients, we identify a gene-regulatory network genetically associated with epilepsy that contains a specialized, highly expressed transcriptional module encoding proconvulsive cytokines and Toll-like receptor signalling genes. RNA sequencing analysis in a mouse model of TLE using 100 epileptic and 100 control hippocampi shows the proconvulsive module is preserved across-species, specific to the epileptic hippocampus and upregulated in chronic epilepsy. In the TLE patients, we map the trans-acting genetic control of this proconvulsive module to Sestrin 3 (SESN3), and demonstrate that SESN3 positively regulates the module in macrophages, microglia and neurons. Morpholino-mediated Sesn3 knockdown in zebrafish confirms the regulation of the transcriptional module, and attenuates chemically induced behavioural seizures in vivo.
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http://dx.doi.org/10.1038/ncomms7031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627576PMC
January 2015