Publications by authors named "Guido Widman"

32 Publications

Specific B- and T-cell populations are associated with cognition in patients with epilepsy and antibody positive and negative suspected limbic encephalitis.

J Neurol 2021 Feb 20;268(2):455-466. Epub 2020 Aug 20.

Department of Epileptology, University Hospital Bonn, Building 83 Venusberg-Campus 1, 53127, Bonn, Germany.

Objective: Neuropsychological impairments are major symptoms of autoimmune limbic encephalitis (LE) epilepsy patients. In LE epilepsy patients with an autoimmune response against intracellular antigens as well as in antibody-negative patients, the antibody findings and magnetic resonance imaging pathology correspond poorly to the clinical features. Here, we evaluated whether T- and B-cells are linked to cognitive impairment in these groups.

Methods: In this cross-sectional, observational, case-controlled study, we evaluated 106 patients with adult-onset epilepsies with a suspected autoimmune etiology. We assessed verbal and visual memory, executive function, and mood in relation to the presence or absence of known auto-antibodies, and regarding T- and B-cell activity as indicated by flow cytometry (fluorescence-activated cell sorting = FACS, peripheral blood = PB and cerebrospinal fluid = CSF).

Results: 56% of the patients were antibody-negative. In the other patients, auto-antibodies were directed against intracellular antigens (GAD65, paraneoplastic: 38%), or cellular surface antigens (LGI1/CASPR2/NMDA-R: 6%). Excluding LGI1/CASPR2/NMDA-R, the groups with and without antibodies did not differ in disease features, cognition, or mood. CD4+ T-cells and CD8+ T-cells in blood and CD4+ T-cells in CSF were prominent in the auto-antibody positive group. Regression analyses indicated the role education, drug load, amygdala and/or hippocampal pathology, and CD4+ T-cells play in verbal memory and executive function. Depressed mood revealed no relation to flow cytometry results.

Conclusion: Our results indicate a link between T- and B-cell activity and cognition in epilepsy patients with suspected limbic encephalitis, thus suggesting that flow cytometry results can provide an understanding of cognitive impairment in LE patients with autoantibodies against intracellular antigens.
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http://dx.doi.org/10.1007/s00415-020-10158-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880943PMC
February 2021

CD19+ B-cells in autoantibody-negative limbic encephalitis.

Epilepsy Behav 2020 05 18;106:107016. Epub 2020 Mar 18.

Department of Epileptology, University of Bonn Medical Center, Venusberg - Campus 1, 53127 Bonn, Germany.

Purpose: Flow cytometry helps to elucidate the cellular immune repertoire's mechanisms in patients with temporal lobe epilepsy (TLE) due to limbic encephalitis (LE) subcategories and carries potential significance for subtype-specific treatment.

Methods: We enrolled 62 patients with TLE due to LE associated with no autoantibodies (n = 40), neural autoantibodies (n = 22), as well as autoantibodies against intracellular antigens (n = 15/22). All patients underwent neuropsychological testing, brain magnetic resonance imaging (MRI), electroencephalography (EEG) recordings, and peripheral blood (PB) and cerebrospinal fluid (CSF) investigations including flow cytometry.

Results: CD19+ B-cells were increased in the PB and CSF of patients with antibody-negative LE compared with those associated with antibodies against intracellular antigens (Kruskal-Wallis one way analysis of variance (ANOVA) on ranks with Dunn's test, p < 0.05). There were no differences in CD138+ B-cells, CD4+ T-cells, human leukocyte antigen - DR isotype (HLA-DR+) CD4+ T-cells, CD8+ T-cells, and HLA-DR+ CD8+ T-cells in the CSF between groups with LE. The blood-brain barrier is more often impaired in patients with antibody-negative LE than in LE with antibodies against intracellular antigens (chi-square test, p < 0.05). In addition, we detected no correlations between immune cell subsets and clinical or paraclinical parameters in patients with antibody-negative and intracellular antibody-positive LE.

Conclusions: The increase of CD19+ B-cells in the CSF and frequent signs of dysfunctional blood-brain barrier in patients with antibody-negative rather than intracellular antibody-positive LE suggest that CD19+ B-cells play a role in antibody-negative encephalitis although their pathogenic role in the central nervous system (CNS) immunity because of missing correlations between immune cells and clinical and paraclinical parameters remains unknown. Further studies are required to evaluate the usefulness of these B-cells as a biomarker for the stratification of treatment strategies.
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http://dx.doi.org/10.1016/j.yebeh.2020.107016DOI Listing
May 2020

Low CSF CD4/CD8+ T-cell proportions are associated with blood-CSF barrier dysfunction in limbic encephalitis.

Epilepsy Behav 2020 01 14;102:106682. Epub 2019 Dec 14.

Department of Epileptology, University of Bonn Medical Center, Venusberg - Campus 1, 53127 Bonn, Germany.

Purpose: Investigating immune cells in autoimmune limbic encephalitis (LE) will contribute to our understanding of its pathophysiology and may help to develop appropriate therapies. The aim of the present study was to analyze immune cells to reveal underlying immune signatures in patients with temporal lobe epilepsy (TLE) with LE.

Methods: We investigated 68 patients with TLE with LE compared with 7 control patients with TLE with no signs of LE screened from 154 patients with suspected LE. From the patients with TLE-LE, we differentiated early seizure onset (<20 years, n = 9) and late seizure onset group (≥20 years, n = 59) of patients. Patients underwent neuropsychological assessment, electroencephalography (EEG), brain magnetic resonance imaging (MRI), and peripheral blood (PB) and cerebrospinal fluid (CSF) analysis including flow cytometry.

Results: We identified a higher CD4/8+ T-cell ratio in the PB in all patients with TLE-LE and in patients with late-onset TLE-LE each compared with controls (Kruskal-Wallis one-way ANOVA (analysis of variance) with Dunn's test, p < 0.05). Moreover, a lower CD4/CD8+ T-cell ratio is detected in all patients with TLE-LE with blood-CSF barrier dysfunction, unlike in those with none (Kruskal-Wallis one-way ANOVA with Dunn's test, p < 0.05).

Conclusions: These findings suggest that the proportion of CD4+ and CD8+ T-cells in the CSF of patients with LE associated with blood-CSF barrier dysfunction plays a potential role in CNS (central nervous system) inflammation in these patients. Thus, flow cytometry as a methodology reveals novel insights into LE's genesis and symptomatology. The CD4/8+ T-cell ratio in PB as a biomarker for LE requires further investigation.
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http://dx.doi.org/10.1016/j.yebeh.2019.106682DOI Listing
January 2020

Epilepsy monitoring units can be safe places; a prospective study in a large cohort.

Epilepsy Behav 2020 01 28;102:106718. Epub 2019 Nov 28.

Department of Clinical Neurophysiology, Stichting Epilepsie Instellingen Nederland (SEIN), the Netherlands.

Objective: No international guideline is available for minimum safety measures at epilepsy monitoring units (EMUs), although recommendations for preferred practices exist. These are mostly based on expert opinion, without evidence of effectiveness. We do not apply all of these preferred practices at our EMU setting. We audited adverse events and diagnostic utility at our EMU over one year.

Methods: From May 2018 to May 2019, we prospectively collected data concerning adverse events and diagnostic utility of all EMU admissions (noninvasive video-electroencephalogram (EEG) recordings); during these admissions, individuals can be ambulant within their EMU room.

Results: There were 1062 admissions comprising 1518 EMU days. In 2% of the admissions, a complication occurred, mostly a fall without injury (n = 6). In almost half of the falls, this was from the bed. Complications occurred most often during admissions for presurgical evaluation. Antiseizure medication (ASM) was tapered in 86% of presurgical cases, but no serious injury occurred, and occurring seizures were effectively treated with intranasal midazolam if needed.

Conclusions: The overall adverse event rate was low. Falls are the most common adverse event comparable with previously published fall rates at other EMUs where people are restricted to their bed. We showed that restricted ambulation at a well-monitored EMU is not necessary and possibly unwanted. No serious injury due to tapering of ASM occurred, and intranasal midazolam was shown to be effective as acute seizure treatment.
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http://dx.doi.org/10.1016/j.yebeh.2019.106718DOI Listing
January 2020

Critical remark on the "heart rate differential method"/"HR-diff" parameter.

Epilepsia 2019 12 21;60(12):2530-2531. Epub 2019 Nov 21.

Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands.

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http://dx.doi.org/10.1111/epi.16393DOI Listing
December 2019

Cancer frequency detected by positron emission tomography-computed tomography in limbic encephalitis.

Epilepsy Behav 2018 Dec 6;89:105-111. Epub 2018 Nov 6.

Department of Epileptology, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.

Objective: Paraneoplastic limbic encephalitis (LE) occurs frequently with considerable variability according to literature reports. We thus determined the cancer frequency in mixed LE subtypes sharing the diagnosis of temporal lobe epilepsy (TLE).

Methods: All patients underwent magnetic resonance imaging (MRI) of the brain, electroencephalography (EEG) recordings, neuropsychological testing, immunohistochemistry, and clinical examination together with whole body 2-fluor-2-desoxy-d-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) to detect cancer in this observatory study.

Results: Ninety-three patients (median: 52 years) with TLE due to autoimmune LE were investigated. Cancer was detected in the FDG-PET/CTs of 3 out of 93 (3.2%) patients with LE. Cancer was diagnosed upon, 5 years earlier and 5 years after FDG-PET/CT in 7 of 93 (7.5%) of all patients with LE. The cancer frequency in those patients was significantly lower than that reported in the largest series of patients with LE associated with and without different antibodies (7.5% vs. 23.5%, Bootstrap test, p < 0.05), but was indistinguishable from the estimated age-dependent cancer frequency in the German regional North-Rhine-Westfalian population without LE in 2014 (Chi-square test: p = 0.2).

Conclusions: Our findings reveal that the cancer frequency in patients with TLE with LE detected by FDG-PET/CT is low and not different from the age-dependent natural cancer occurrence in a regional population.
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http://dx.doi.org/10.1016/j.yebeh.2018.09.043DOI Listing
December 2018

Pre- and long-term postoperative courses of hippocampus-associated memory impairment in epilepsy patients with antibody-associated limbic encephalitis and selective amygdalohippocampectomy.

Epilepsy Behav 2018 02 16;79:93-99. Epub 2017 Dec 16.

Department of Epileptology, University of Bonn, Sigmund Freud Str. 25, 53127 Bonn, Germany.

Objective: Limbic encephalitis (LE) is defined by mesiotemporal lobe structure abnormalities, seizures, memory, and psychiatric disturbances. This study aimed to identify the long-term clinical and neuropsychological outcome of selective amygdalohippocampectomy (sAH) in drug-resistant patients with temporal lobe epilepsy due to known or later diagnosed subacute LE not responding to immunotherapy associated with neuronal autoantibodies.

Methods: In seven patients with temporal lobe epilepsy due to antibody positive LE (glutamic acid decarboxylase (GAD65): n=5; voltage-gated potassium channel complex (VGKC), N-methyl d-aspartate receptor (NMDAR): n=1; Ma-2/Ta: n=1) sAH (6 left, 1 right) was performed. Those patients underwent repeated electroencephalography (EEG) recordings, magnetic resonance imaging (MRI) volumetry of the amygdala and hippocampus, and neuropsychological examinations and were followed up for 6-7years on average.

Results: Verbal memory and figural memory were affected in 57% of patients at baseline and 71% at the last follow-up. At the last follow-up, 14% of the patients had declined in verbal memory and figural memory. We observed improved memory in 43% of patients regarding figural memory, but not in a single patient regarding verbal memory. Repeated evaluations across the individual courses reveal cognitive and MRI dynamics that appear to be unrelated to surgery and drug treatment. Three of the seven patients with LE with different antibodies (NMDAR: n=1, Ma-2/Ta: n=1 and GAD65: n=1) achieved persistent seizure freedom along with no accelerated memory decline after surgery. Two of the five GAD65-antibody patients positive with LE showed progressive memory decline and a long-term tendency to contralateral hippocampus atrophy.

Conclusions: While memory demonstrated some decline in the long run, what is most important is that a progressive decline in memory is seldom found after sAH in patients with LE. Moreover, the dynamics in performance and MRI before and after surgery reveal disease dynamics independent of surgery. Selective amygdalohippocampectomy can lead to seizure freedom, but should be considered as a last resort treatment option for drug-resistant patients with temporal lobe epilepsy due to LE. Particular caution is recommended in patients with GAD65-LE.
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http://dx.doi.org/10.1016/j.yebeh.2017.10.033DOI Listing
February 2018

Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery.

N Engl J Med 2017 10;377(17):1648-1656

From the Departments of Neuropathology (I.B., G.H., R.C., K.K.) and Neurosurgery (K.R.) and the Epilepsy Center (H. Hamer, H.S.), University Hospital Erlangen, Erlangen, the Epilepsy Center Bethel, Krankenhaus Mara, Bielefeld (C.G.B., M.P.), the Departments of Epileptology (C.E., G.W.) and Neuropathology (A.B.), University of Bonn Medical Center, and Medical Faculty, University of Bonn (J.S.), Bonn, the Neuropediatric Clinic, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth (T.P., H. Holthausen, M.K., P.A.W.), the Epilepsy Center Berlin-Brandenburg, Berlin (H.J.M.), the Epilepsy Center (G.H., A.S.-B.) and Department of Neurosurgery (J.Z., D.H.H.), University Hospital, and the Department of Neuroradiology, Medical Center-University of Freiburg, and Faculty of Medicine, University of Freiburg (H.U.) Freiburg, Kork Epilepsy Center, Kehl-Kork (B.J.S., T.B.), the Departments of Neuropathology (S.V.) and Neurology (U.R.), University Hospital Greifswald, Greifswald, the Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen (H.L., Y.W.), the Department of Neurology, University of Ulm, Ulm (H.L., Y.W.), the Epilepsy Center, Department of Neurology, Ludwig-Maximilians-University Hospital, Munich (S.N., E.H., P.A.W.), Sächsisches Epilepsiezentrum Radeberg, Radeberg (T.M., M.L.), Epilepsy Center Frankfurt Rhine-Main and the Department of Neurology, Goethe University, Frankfurt am Main (F.R., A.H.), the Epilepsy Center Hessen-Marburg, Philipps-University Marburg, Marburg (F.R., A.H.), and the Department of Social Medicine, Occupational and Environmental Dermatology, Heidelberg University, Heidelberg (T.L.D.) - all in Germany; the Clinical Epileptology and Experimental Neurophysiology Unit (R.S.) and the Department of Neurophysiology, Epilepsy Center (G.A.), IRCCS Foundation, Neurological Institute C. Besta, and the Claudio Munari Epilepsy Surgery Center, Niguarda Hospital (L.T., G.L.R.), Milan, and the Pediatric Neurology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Florence (R.G., C.B.) - all in Italy; Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery (K.P.B., F.L.), and the Department of (Neuro)Pathology (E.A.), University Medical Center Utrecht, Utrecht, the Department of Neurosurgery, VU University Medical Center (J.C.B.), and the Department of (Neuro)Pathology, Academic Medisch Centrum, University of Amsterdam (E.A., A.M.), and the Department of (Neuro)Pathology, VU University Medical Center (E.A., A.M.), Amsterdam, Stichting Epilepsie Instellingen Nederland, Heemstede (E.A.), and the Department of Neurosurgery, Academic Center for Epileptology, Maastricht University Medical Center, Maastricht (O.S.) - all in the Netherlands; the Department of Neurosurgery, Sainte-Anne Hospital, and Paris Descartes University, Paris (F.C.), the Department of Neurology, Michallon Hospital, GIN INSERM Unité 836, Grenoble Alpes University, Grenoble (P. Kahane), and the Department of Clinical Epileptology, Sleep Disorders and Functional Neurology in Children, University Hospitals of Lyon, and the Brain Dynamics and Cognition team, Lyon Neurosciences Research Center, Lyon (A.A., A.U.-C.) - all in France; the Departments of Neuropathology (M.T.) and Clinical and Experimental Epilepsy (M.C.W., S.M.S., J.S.D., A.W.M.), UCL Institute of Neurology, and the Developmental Biology and Cancer Programme (T.S.J.) and Developmental Neurosciences Program (J.H.C.), UCL-Great Ormond Street Institute of Child Health, and the Department of Histopathology, Great Ormond Street Hospital for Children (T.S.J.), London, and Young Epilepsy, Lingfield (J.H.C.) - all in the United Kingdom; the Departments of Neurology (C.Ö.) and Pathology (B.O.), Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey; the Department of Pediatric Neurology, Motol Epilepsy Center, Charles University in Prague, and the 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic (P. Krsek); the Department of Anatomical Pathology, Hospital Pedro Hispano, Matosinhos (M.H.), and the Laboratory of Neuropathology, Department of Neurosciences, Hospital de Santa Maria-Centro Hospitalar de Lisboa Norte, Lisbon (J.P.) - both in Portugal; the Epilepsy Unit, Child Neurology Department, Hospital San Juan de Dios, Barcelona (A.A., A.U.-C.); the Department of Pediatrics, Medical University Vienna, Vienna (M.F., A.M.), the Departments of Neurology (E.T.) and Neurosurgery (P.A.W.), Christian Doppler Medical Center, Paracelsus Medical University, Center for Cognitive Neuroscience, Salzburg, and the Department of Neurology I, Neuromed Campus, Kepler Universitätsklinikum, Linz (T.J.O.) - all in Austria; the Swiss Epilepsy Center and Department of Neurology, University Hospital, Zurich, Switzerland (T.G.); the Department of Neurology, Hospital Ruber Internacional, Madrid (A.G.-N., R.T.D.); and the Neurosurgical Department (B.Z.) and Epilepsy Monitoring Unit (K.G.), St. Luke's Hospital, Thessaloniki, Greece.

Background: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy.

Methods: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%).

Results: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients.

Conclusions: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).
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http://dx.doi.org/10.1056/NEJMoa1703784DOI Listing
October 2017

Non-paraneoplastic limbic encephalitis and central nervous HHV-6B reactivation: Causality or coincidence?

Neuropathology 2016 Aug 15;36(4):376-80. Epub 2016 Jan 15.

Department of Neurology / Pathology, Oslo University Hospital, Oslo, Norway.

Autoantibody-related encephalopathies represent an important differential diagnosis in adult onset epilepsy. Here, we report the case of a 25-year-old patient with new-onset epilepsy and psychotic syndrome, who underwent biopsy resection for etiological classification. MRI analysis and neuropathological examination showed a T-lymphocytic dominated encephalitis with involvement of the limbic system. An indirect immunohistochemistry approach identified autoantibodies against glutamic acid decarboxylase (GAD) in cerebral spinal fluid and serum, which were confirmed by affinity purification / mass spectrometry analysis. Further examinations revealed evidence of chromosomally integrated human herpes virus type 6B (HHV-6B). However, astrocytic expression of HHV-6 lytic protein was detected by double immunofluorescence analysis. The cerebral expression of HHV-6 antigen, a clinical improvement under antiviral therapy as well as an initial finding of HHV-6 IgM antibodies strongly argue for an additional active HHV-6B infection. Review of the literature reveals singular reports of patients with GAD antibody-positive limbic encephalitis and central nervous system infections with HHV-6B. Since herpes simplex virus encephalitis has been recently reported as a trigger of N-methyl-D-aspartate receptor antibody encephalitis, it is tempting to speculate that HHV-6B infections may trigger a non-paraneoplastic form of limbic encephalitis in a parallel cascade.
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http://dx.doi.org/10.1111/neup.12283DOI Listing
August 2016

Suspected new-onset autoimmune temporal lobe epilepsy with amygdala enlargement.

Epilepsia 2016 09 15;57(9):1485-94. Epub 2016 Jul 15.

Department of Epileptology, University of Bonn, Bonn, Germany.

Objective: Recent reports define temporal lobe epilepsy with amygdala enlargement (TLE-AE) as a distinct electroclinical syndrome comparable to TLE with hippocampal sclerosis. In this retrospective observational study, we present the largest consecutive series of patients with new-onset TLE-AE to date and describe clinical characteristics and seizure outcome, and we aim to explore underlying autoimmune mechanisms within this syndrome.

Methods: We reviewed all consecutive patients between 2004 and 2014 at our tertiary epilepsy center at the University of Bonn, Germany, with new-onset (<5 years) TLE-AE, negative serum antibody (ab) test results, and with available follow-up data for at least 12 months.

Results: We identified 40 patients (23 male) with TLE-AE with a median age at epilepsy onset of 51 years (range 10-73) and a median disease duration of 11 months (range 0.5-55) at first presentation. At follow-up, 50% of the entire cohort achieved seizure freedom. Of interest, patients with remittent features of AE at follow-up (N = 24) had a superior outcome compared to those with stable magnetic resonance imaging (MRI) features of AE (N = 16): 17 (71%) of 24 were seizure-free for at least 6 months compared to 3 (19%) of 16, respectively (p = 0.003). MRI volumetry confirmed significantly enlarged amygdalae in TLE-AE in relation to healthy controls, and additionally showed significantly greater volume reductions in patients with remittent AE compared to those with stable AE.

Significance: TLE-AE is a clinical syndrome beginning mostly in middle age, and in addition to its known association with ab-positive limbic encephalitis, it occurs in an ab-negative condition. Remission of AE in the course of the disease could be identified as a predictor for a favorable clinical outcome and is suspicious of an autoimmune etiology, although we could not confirm this hypothesis unequivocally with currently available noninvasive diagnostic tools.
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http://dx.doi.org/10.1111/epi.13471DOI Listing
September 2016

Evidence of a pathogenic role for CD8(+) T cells in anti-GABAB receptor limbic encephalitis.

Neurol Neuroimmunol Neuroinflamm 2016 Jun 29;3(3):e232. Epub 2016 Apr 29.

Departments of Neurology (K.S.G., K.B., C.M., M.H., H.W., S.G.M., H.L., C.C.G., N.M.) and Clinical Radiology (W.S.), and Institute of Physiology I-Neuropathophysiology (S.G.M.), University of Münster; Departments of Epileptology (G.W., C.E.E.) and Neuropathology (K.M.v.L., A.J.B.), University of Bonn; Epilepsy Center Hamburg (M.L.), Evangelisches Krankenhaus Alsterdorf, Hamburg; and Department of Neuropathology (M.G.), University of Hamburg, Germany.

Objectives: To characterize the cellular autoimmune response in patients with γ-aminobutyric acid (GABA)B receptor antibody-associated limbic encephalitis (GABAB-R LE).

Methods: Patients underwent MRI, extensive neuropsychological assessment, and multiparameter flow cytometry of peripheral blood and CSF.

Results: We identified a series of 3 cases of nonparaneoplastic GABAB-R LE and one case of paraneoplastic GABAB-R LE associated with small cell lung cancer. All patients exhibited temporal lobe epilepsy, neuropsychological deficits, and MRI findings typical of LE. Absolute numbers of CD19(+) B cells, CD138(+) CD19(+) plasma cells, CD4(+) T cells, activated HLADR(+) CD4(+) T cells, as well as CD8(+) T cells and HLADR(+) CD8(+) T cells did not differ in peripheral blood but were elevated in CSF of patients with GABAB-R LE compared to controls. Augmented absolute numbers of CD138(+) CD19(+) plasma cells and activated HLADR(+) CD8(+) T cells in CSF corresponded to higher overall neuropsychological and memory deficits in patients with GABAB-R LE. A histologic specimen of one patient following selective amygdalohippocampectomy revealed perivascular infiltrates of CD138(+) plasma cells and CD4(+) T cells, whereas cytotoxic CD8(+) T cells were detected within the brain parenchyma in close contact to neurons.

Conclusion: Our data suggest a pathogenic role for CD8(+) T cells in addition to the established role of plasma cell-derived autoantibodies in GABAB-R LE.
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http://dx.doi.org/10.1212/NXI.0000000000000232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853055PMC
June 2016

CD8(+) T-cell pathogenicity in Rasmussen encephalitis elucidated by large-scale T-cell receptor sequencing.

Nat Commun 2016 Apr 4;7:11153. Epub 2016 Apr 4.

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

Rasmussen encephalitis (RE) is a rare paediatric epilepsy with uni-hemispheric inflammation and progressive neurological deficits. To elucidate RE immunopathology, we applied T-cell receptor (TCR) sequencing to blood (n=23), cerebrospinal fluid (n=2) and brain biopsies (n=5) of RE patients, and paediatric controls. RE patients present with peripheral CD8(+) T-cell expansion and its strength correlates with disease severity. In addition, RE is the only paediatric epilepsy with prominent T-cell expansions in the CNS. Consistently, common clones are shared between RE patients, who also share MHC-I alleles. Public RE clones share Vβ genes and length of the CDR3. Rituximab/natalizumab/basiliximab treatment does not change TCR diversity, stem cell transplantation replaces the TCR repertoire with minimal overlap between donor and recipient, as observed in individual cases. Our study supports the hypothesis of an antigen-specific attack of peripherally expanded CD8(+) lymphocytes against CNS structures in RE, which might be ameliorated by restricting access to the CNS.
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http://dx.doi.org/10.1038/ncomms11153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822013PMC
April 2016

Low-dose radiosurgery or hypofractionated stereotactic radiotherapy as treatment option in refractory epilepsy due to epileptogenic lesions in eloquent areas - Preliminary report of feasibility and safety.

Seizure 2016 Mar 27;36:57-62. Epub 2016 Feb 27.

Department of Epileptoloy, University Hospital of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.

Purpose: The eradication of epileptogenic lesions (e.g. focal cortical dysplasia) can be used for treatment of drug-resistant focal epilepsy, but in highly eloquent cortex areas it can also lead to a permanent neurological deficit. In such cases the neuromodulation effect of low-dose high-precision irradiation of circumscribed lesions may represent an alternative therapy.

Method: A total of 10 patients with eloquent localized lesions causing pharmacoresistant focal epilepsy were prospectively identified. After informed consent, six patients agreed and were treated with risk adapted low-dose radiosurgery (SRS) or hypofractionated stereotactic radiotherapy (hfSRT). Comprehensive data concerning treatment modalities and outcome after short-term follow up (mean=16.3 months) were prospectively collected and evaluated.

Results: From the six patients, two patients were treated with hfSRT (marginal dose 36 Gy) and four with SRS (marginal dose 13 Gy). Clinical target volume (CTV) ranged from 0.70 ccm to 4.32 ccm. The short-term follow-up ranged from 6 to 27 months. There were no side effects or neurological deficits after treatment. At last available follow-up two patients were seizure-free, one of them being off antiepileptic drugs. The seizure frequency improved in one and remained unchanged in three patients.

Conclusion: Treatment of eloquent localized epileptogenic lesions by SRS and hfSRT showed no adverse events and an acceptable seizure outcome in this small prospective patient series. The relatively short-term follow-up comprises one of the study's drawbacks and therefore a longer follow-up should be awaited in order to evaluate the neuromodulation effect of the treatment. These preliminary results may however justify the initiation of a larger prospective trial investigating whether focused low-dose stereotactic irradiation could be an option for lesions in eloquent brain areas.
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http://dx.doi.org/10.1016/j.seizure.2016.02.010DOI Listing
March 2016

Serum from a Patient with GAD65 Antibody-Associated Limbic Encephalitis Did Not Alter GABAergic Neurotransmission in Cultured Hippocampal Networks.

Front Neurol 2015 28;6:189. Epub 2015 Aug 28.

Department of Epileptology, University Hospital Bonn , Bonn , Germany ; Center for Rare Diseases Bonn (ZSEB), University Hospital Bonn , Bonn , Germany.

Background: Glutamate decarboxylase is an intracellular enzyme converting glutamate into GABA. Antibodies (abs) to its isoform GAD65 were described in limbic encephalitis and other neurological conditions. The significance of GAD65 abs for epilepsy is unclear, but alterations of inhibitory GABAergic neurotransmission may be involved. Here, we investigated the effects of the serum of a female patient suffering from GAD65 ab-associated LE on GABAA currents in cultured hippocampal networks.

Methods: Spontaneous or evoked post-synaptic GABAA currents were measured in cultured hippocampal neurons prepared from embryonic mice after 11-21 days in vitro using the patch-clamp technique in the whole-cell mode after incubation with serum of a healthy control or the LE-patient at a final concentration of 1% for 5-8 h.

Results: Properties of miniature inhibitory post-synaptic currents were not different in cultures treated with control and LE-serum. Likewise, paired-pulse ratio of evoked GABAA currents as a measure of release probability was not different in both conditions. Evoked GABAA currents were significantly depressed during 10 Hz stimulation without significant differences between control and LE-serum treated cultures.

Conclusion: In our experimental paradigms, serum of a patient with confirmed GAD65 ab-associated LE had no apparent effect on GABAergic neurotransmission in murine-cultured hippocampal networks. These results challenge the view that the presence of GAD65 abs invariably compromise inhibitory network function.
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http://dx.doi.org/10.3389/fneur.2015.00189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551833PMC
September 2015

Treating a GAD65 Antibody-Associated Limbic Encephalitis with Basiliximab: A Case Study.

Front Neurol 2015 3;6:167. Epub 2015 Aug 3.

Department of Epileptology, University of Bonn , Bonn , Germany.

Background: Antibodies (ABs) against the 65-kDa isoform of the intracellular enzyme glutamate decarboxylase (GAD65) have been found in limbic encephalitis (LE) and other neurological conditions. The direct significance of anti-GAD65-ABs for epilepsy is unclear. However, in histological preparations from biopsies of resective epilepsy surgeries, predominantly cytotoxic T-lymphocytes were detected making close contacts to neurons. Activated T-lymphocytes can, in turn, be selectively controlled by therapeutic interleukin-2 receptor Abs, such as basiliximab.

Case Presentation: We report of a 25-year-old male patient with epilepsy since the age of 18 and displaying clinical signs of LE and a high titer of GAD65 ABs in cerebrospinal fluid (CSF) and serum. Monthly, repetitive, intravenous cortisone pulse therapies that were initially administered for 6 months failed to improve his condition. Subsequent flow-cytometry analysis of CSF showed especially an increased fraction of activated HLA-DR(+) CD8(+) T-lymphocytes (fCD8(+)TL) when compared to controls. Thus, a second, intravenous cortisone pulse therapy with an additional basiliximab dose of 20 mg/month was started. After 3 months, the fCD8(+)TL in the CSF normalized; after 6 months, the psychological impulse-control deficits normalized; and after 11 months the patient was seizure free. However, 7 weeks later, seizures and, later on, psychological deficits recurred and fCD8(+)TL was once again present in the CSF. Flumazenil PET, magnetic resonance imaging-volumetry, and neuropsychological changes during therapy are described.

Conclusion: The correlation of the fCD8(+)TL in the CSF with clinical and paraclinical measures of disease activity combined with the unambiguous response to basiliximab strongly argues in favor of the putative pathogenic role fCD8(+)TL in anti-GAD65 LE. The clinical relapse at the end of the observation period might be due to the formation of human anti-drug ABs, a well-known complication of therapy with chimeric ABs.
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http://dx.doi.org/10.3389/fneur.2015.00167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522569PMC
August 2015

Loss of Autonoetic Awareness of Recent Autobiographical Episodes and Accelerated Long-Term Forgetting in a Patient with Previously Unrecognized Glutamic Acid Decarboxylase Antibody Related Limbic Encephalitis.

Front Neurol 2015 9;6:130. Epub 2015 Jun 9.

Department of Epileptology, University of Bonn , Bonn , Germany.

We describe a 35-year-old male patient presenting with depressed mood and emotional instability, who complained about severe anterograde and retrograde memory deficits characterized by accelerated long-term forgetting and loss of autonoetic awareness regarding autobiographical memories of the last 3 years. Months before he had experienced two breakdowns of unknown etiology giving rise to the differential diagnosis of epileptic seizures after various practitioners and clinics had suggested different etiologies such as a psychosomatic condition, burnout, depression, or dissociative amnesia. Neuropsychological assessment indicated selectively impaired figural memory performance. Extended diagnostics confirmed accelerated forgetting of previously learned and retrievable verbal material. Structural imaging showed bilateral swelling and signal alterations of temporomesial structures (left >right). Video-EEG monitoring revealed a left temporal epileptic focus and subclincal seizure, but no overt seizures. Antibody tests in serum and liquor were positive for glutamic acid decarboxylase antibodies. These findings led to the diagnosis of glutamic acid decarboxylase antibody related limbic encephalitis. Monthly steroid pulses over 6 months led to recovery of subjective memory and to intermediate improvement but subsequent worsening of objective memory performance. During the course of treatment, the patient reported de novo paroxysmal non-responsive states. Thus, antiepileptic treatment was started and the patient finally became seizure free. At the last visit, vocational reintegration was successfully in progress. In conclusion, amygdala swelling, retrograde biographic memory impairment, accelerated long-term forgetting, and emotional instability may serve as indicators of limbic encephalitis, even in the absence of overt epileptic seizures. The monitoring of such patients calls for a standardized and concerted multilevel diagnostic approach with repeated assessments.
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http://dx.doi.org/10.3389/fneur.2015.00130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460811PMC
June 2015

Large-scale analysis of viral nucleic acid spectrum in temporal lobe epilepsy biopsies.

Epilepsia 2015 Feb 20;56(2):234-43. Epub 2014 Dec 20.

Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.

Objective: Chronic inflammatory processes are important promotors of temporal lobe epilepsy (TLE) development. Based on human herpesvirus 6 (HHV-6) DNA detection in brain tissue from patients with TLE, an association of persistent viral infection with TLE has been discussed. Individual studies reported increased HHV-6 DNA in patients with clinical signs of previous inflammatory brain reaction, that is, febrile seizures or meningoencephalitis. However, detection rates vary considerably between different studies. Here we performed a large-scale analysis of viral DNA/RNA spectrum in high-quality TLE biopsies. In addition to all Herpesviridae, we addressed potentially relevant neurotropic RNA viruses.

Methods: DNA and RNA were extracted from 346 fresh-frozen tissue samples removed by epilepsy surgery. Real-time polymerase chain reaction (PCR) and nested PCR were performed for Herpesviridae and RNA viruses, respectively. Clinical data were analyzed for earlier signs of inflammatory brain reactions. Fresh-frozen hippocampal tissue samples from patients without chronic central nervous system (CNS) disease served as controls (n = 62). Seven previous PCR studies with overall 178 TLE patients were additionally analyzed regarding a correlation of clinical parameters and HHV-6 detection.

Results: PCR revealed HHV-6B DNA in 34 specimens (9.8%) from TLE patients. HHV-6B DNA was also present in eight control samples (12.9%; p > 0.05), but showed a lower virus concentration (p < 0.001). Other herpesviruses and RNA viruses were virtually absent. In patients with clinical signs of previous brain inflammation, HHV-6B DNA was observed in 15.0%, whereas only 6.3% of the samples from patients without febrile seizures or meningoencephalitis were positive for HHV-6B DNA (p < 0.05). A meta-analysis of the eight HHV-6 PCR studies revealed similar results.

Significance: This biopsy-based study shows no differences in frequency of HHV-6B DNA detection between TLE patients and controls. These results do not support the hypothesis of a persistent HHV-6B infection as a major pathogenetic factor in TLE. However, the higher virus load in TLE patients and the increased detection rate of HHV-6B DNA in patients with previous inflammatory brain reactions require further investigations.
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http://dx.doi.org/10.1111/epi.12890DOI Listing
February 2015

Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors.

J Neurol Neurosurg Psychiatry 2013 Jan 7;84(1):62-9. Epub 2012 Nov 7.

Department of Neurology, University of Bonn, Bonn, Germany.

Objectives: The objective of this preliminary study was to explore long-term changes in neurobehavioral parameters, brain morphology and electroencephalography of sepsis patients who received intensive care compared to non-septic intensive care unit (ICU) patients.

Methods: Two-centre follow-up study 6-24 months after discharge from hospital using published norms and existing databases of healthy controls for comparison. Patients included 25 septic and 19 non-septic ICU survivors who were recruited from two ICUs of a university and community hospital. Measurements used include brain morphology, standard electroencephalography, cognition and psychiatric health and health-related quality of life.

Results: Sepsis survivors showed cognitive deficits in verbal learning and memory and had a significant reduction of left hippocampal volume compared to healthy controls. Moreover, sepsis and to some extent non-septic ICU patients had more low-frequency activity in the EEG indicating unspecific brain dysfunction. No differences were found in health-related quality of life, psychological functioning or depressive symptoms, and depression could be ruled out as a confounding factor.

Conclusions: This study demonstrates permanent cognitive impairment in several domains in both septic and non-septic ICU survivors and unspecific brain dysfunction. In the sepsis group, left-sided hippocampal atrophy was found compared to healthy controls. Further study is needed to clarify what contribution sepsis and other factors at the ICU make to these outcomes. Specific neuroprotective therapies are warranted to prevent persisting brain changes in ICU patients.
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http://dx.doi.org/10.1136/jnnp-2012-302883DOI Listing
January 2013

Co-localizing linguistic and musical syntax with intracranial EEG.

Neuroimage 2013 Jan 20;64:134-46. Epub 2012 Sep 20.

Max Planck Institute for Human Cognitive and Brain Sciences, Stephanstraße 1a, 04103 Leipzig, Germany.

Despite general agreement on shared syntactic resources in music and language, the neuroanatomical underpinnings of this overlap remain largely unexplored. While previous studies mainly considered frontal areas as supramodal grammar processors, the domain-general syntactic role of temporal areas has been so far neglected. Here we capitalized on the excellent spatial and temporal resolution of subdural EEG recordings to co-localize low-level syntactic processes in music and language in the temporal lobe in a within-subject design. We used Brain Surface Current Density mapping to localize and compare neural generators of the early negativities evoked by violations of phrase structure grammar in both music and spoken language. The results show that the processing of syntactic violations relies in both domains on bilateral temporo-fronto-parietal neural networks. We found considerable overlap of these networks in the superior temporal lobe, but also differences in the hemispheric timing and relative weighting of their fronto-temporal constituents. While alluding to the dissimilarity in how shared neural resources may be configured depending on the musical or linguistic nature of the perceived stimulus, the combined data lend support for a co-localization of early musical and linguistic syntax processing in the temporal lobe.
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http://dx.doi.org/10.1016/j.neuroimage.2012.09.035DOI Listing
January 2013

Memory modulation by weak synchronous deep brain stimulation: a pilot study.

Brain Stimul 2013 May 24;6(3):270-3. Epub 2012 Aug 24.

Department of Epileptology, University of Bonn, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany.

Zero-lag phase synchronization of EEG activity has been reported to be a central mechanism accompanying long-term memory formation. In this pilot study, we examined the effects of synchronous low-amplitude stimulation of the rhinal cortex and the hippocampus in eleven temporal lobe epilepsy patients. The impact of in-phase stimulation (zero lag) on long-term memory encoding of words was contrasted with anti-phase (180° phase lag) and sham stimulation. We hypothesized more correctly remembered words for the in-phase compared to the sham condition and fewer correctly remembered words for the anti-phase vs. the sham condition. Indeed, we observed a trend for a linear condition effect for correctly remembered words, which is in accordance to our prediction (in-phase > sham > anti-phase). This finding suggests that even weak synchronous deep brain stimulation of rhinal cortex and hippocampus may modulate memory performance, while clear evidence for an enhancement of memory by this kind of deep brain simulation is still lacking.
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http://dx.doi.org/10.1016/j.brs.2012.08.001DOI Listing
May 2013

Antiepileptic drugs and vitamin B6 plasma levels in adult patients.

Epilepsy Res 2012 Aug 30;101(1-2):182-4. Epub 2012 Mar 30.

Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, Zurich, Switzerland.

Treatment with several antiepileptic drugs (AED) is associated with lower serum concentrations of folate or vitamin B12. This prospective monocenter study analyzed vitamin B6 blood levels in 400 serial patients with epilepsy, AED-treated (n=385), untreated (n=15) and healthy controls (n=233). The mean plasma vitamin B6 levels of the AED-treated (12.1±10.1; p=0.093) and the untreated patients (15.6±12.4; p=0.664) were not significantly different from the controls (13.9±15.2). These observations do not support the hypothesis that vitamin B6 blood levels are influenced by AED treatment.
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http://dx.doi.org/10.1016/j.eplepsyres.2012.03.002DOI Listing
August 2012

Antiepileptic drugs interact with folate and vitamin B12 serum levels.

Ann Neurol 2011 Feb 19;69(2):352-9. Epub 2011 Jan 19.

Department of Neurology, University Hospital Zurich, Switzerland.

Objective: Antiepileptic drugs (AEDs) are important for the treatment of epilepsy, psychiatric diseases, and pain syndromes. Small studies have suggested that AED treatment reduces serum levels of folate and vitamin B12.

Methods: This prospective monocenter study aimed at testing the hypothesis that AED treatment is associated with folate and vitamin B12 serum levels in a large population. A total of 2730 AED-treated and 170 untreated patients with epilepsy and 200 healthy individuals were enrolled.

Results: Treatment with carbamazepine, gabapentin, oxcarbazepine, phenytoin, primidone, or valproate was associated with lower mean serum folate levels or with a higher frequency of folate levels below the reference range in comparison with the entire group of patients, untreated patients, or controls. Treatment with phenobarbital, pregabalin, primidone, or topiramate was associated with lower vitamin B12 levels compared with the entire group of patients. Vitamin B12 serum levels were higher in patients treated with valproate compared with the entire group of patients, untreated patients, and healthy controls. Folate or vitamin B12 levels below the reference range were associated with higher mean corpuscular volume (MCV) and higher homocysteine plasma levels. Vitamin substitution for 3 months in 141 patients with folate or vitamin B12 levels below the reference range yielded normal vitamin levels in 95% of the supplemented patients and reduced MCV and homocysteine plasma levels.

Interpretation: Treatment with most of the commonly used AEDs is associated with reduced folate or vitamin B12 serum levels and is a risk factor for hyperhomocysteinemia. Oral substitution is effective to restore vitamin, MCV, and homocysteine levels.
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http://dx.doi.org/10.1002/ana.22229DOI Listing
February 2011

Voluntary brain regulation and communication with electrocorticogram signals.

Epilepsy Behav 2008 Aug 20;13(2):300-6. Epub 2008 May 20.

Institute of Environmental Medicine and Clinical Hygiene, University Medical Center Freiburg, Freiburg, Germany.

Brain-computer interfaces (BCIs) can be used for communication in writing without muscular activity or for learning to control seizures by voluntary regulation of brain signals such as the electroencephalogram (EEG). Three of five patients with epilepsy were able to spell their names with electrocorticogram (ECoG) signals derived from motor-related areas within only one or two training sessions. Imagery of finger or tongue movements was classified with support-vector classification of autoregressive coefficients derived from the ECoG signals. After training of the classifier, binary classification responses were used to select letters from a computer-generated menu. Offline analysis showed increased theta activity in the unsuccessful patients, whereas the successful patients exhibited dominant sensorimotor rhythms that they could control. The high spatial resolution and increased signal-to-noise ratio in ECoG signals, combined with short training periods, may offer an alternative for communication in complete paralysis, locked-in syndrome, and motor restoration.
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http://dx.doi.org/10.1016/j.yebeh.2008.03.014DOI Listing
August 2008

Classifying EEG and ECoG signals without subject training for fast BCI implementation: comparison of nonparalyzed and completely paralyzed subjects.

IEEE Trans Neural Syst Rehabil Eng 2006 Jun;14(2):183-6

Max Planck Institute for Biological Cybernetics, 72012 Tübingen, Germany.

We summarize results from a series of related studies that aim to develop a motor-imagery-based brain-computer interface using a single recording session of electroencephalogram (EEG) or electrocorticogram (ECoG) signals for each subject. We apply the same experimental and analytical methods to 11 nonparalysed subjects (eight EEG, three ECoG), and to five paralyzed subjects (four EEG, one ECoG) who had been unable to communicate for some time. While it was relatively easy to obtain classifiable signals quickly from most of the nonparalyzed subjects, it proved impossible to classify the signals obtained from the paralyzed patients by the same methods. This highlights the fact that though certain BCI paradigms may work well with healthy subjects, this does not necessarily indicate success with the target user group. We outline possible reasons for this failure to transfer.
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http://dx.doi.org/10.1109/TNSRE.2006.875548DOI Listing
June 2006

Improved spatial characterization of the epileptic brain by focusing on nonlinearity.

Epilepsy Res 2006 Apr 28;69(1):30-44. Epub 2006 Feb 28.

John von Neumann Institute for Computing, Forschungszentrum Jülich GmbH, Jülich, Germany.

An advanced characterization of the complicated dynamical system brain is one of science's biggest challenges. Nonlinear time series analysis allows characterizing nonlinear dynamical systems in which low-dimensional nonlinearity gives rise to complex and irregular behavior. While several studies indicate that nonlinear methods can extract valuable information from neuronal dynamics, others doubt their necessity and conjecture that the same information can be obtained using classical linear techniques. To address this issue, we compared these two concepts, but included furthermore a combination of nonlinear measures with surrogates, an approach that has been designed to specifically focus on nonlinearity. As a benchmark we used the discriminative power to detect the seizure-generating hemisphere in medically intractable mesial temporal lobe epilepsy. We analyzed intracranial electroencephalographic recordings from the seizure-free interval of 29 patients. While the performance of both linear and nonlinear measures was weak, if not insignificant, a very high performance was obtained by the use of surrogate-corrected measures. Focusing on nonlinearity by using a combination of nonlinear measures with surrogates appears as the key to a successful characterization of the spatial distribution of the epileptic process.
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http://dx.doi.org/10.1016/j.eplepsyres.2005.12.004DOI Listing
April 2006

Are there physical risk factors for psychogenic non-epileptic seizures in patients with epilepsy?

Seizure 2003 Dec;12(8):561-7

Academic Unit of Neurology, Division of Genomic Medicine, University of Sheffield, Royal Hallanshire Hospital, Glossop Road, Sheffield S10 2JF, UK.

Unlabelled: Patients with epilepsy may have additional psychogenic non-epileptic seizures (PNES). It has been suggested that PNES are more common if patients with epilepsy are female, develop epilepsy later in life and have right-sided brain lesions. We examine whether these or other physical factors affect the risk of PNES in patients with epilepsy in a controlled study.

Methods: Ninety consecutive patients with PNES and concurrent epilepsy (PNES+E group) and 90 consecutive patients with epilepsy alone (epilepsy group) were compared with regard to the variables sex, age at onset of epilepsy, epilepsy type (focal/generalised), location and lateralisation of epileptogenic zone, aetiology of epilepsy, interictal epileptiform potentials, magnetic resonance imaging (MRI) abnormalities, neuropsychological (NPS) deficits and intelligence quotient (IQ).

Results: Female sex (P<0.001), abnormal visual memory (P=0.012), global NPS impairment (P=0.029), and low IQ category (P=0.005) were associated with a higher risk of PNES. Other variables did not differ between the groups.

Conclusions: In patients with epilepsy, female sex, poor visual memory or global neuropsychological underperformance and low IQ are associated with an increased risk of PNES. MRI changes, epileptiform EEG abnormalities and location of epileptogenic zone do not show a predilection for one hemisphere.
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http://dx.doi.org/10.1016/s1059-1311(03)00064-5DOI Listing
December 2003

Aggressive behavior of epilepsy patients in the course of levetiracetam add-on therapy: report of 33 mild to severe cases.

Epilepsy Behav 2003 Oct;4(5):537-47

Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud Strasse 25, 53105 Bonn, Germany.

Levetiracetam (LEV) was shown to be very efficacious and well tolerated as add-on therapy for refractory epilepsy. Here we report 33 patients with longstanding histories of epilepsy who experienced aggressive episodes during LEV therapy. This corresponds to 3.5% of LEV-treated patients as compared with less than 1% of patients not on LEV. Among these cases, 24 showed only moderate, partly transient irritability, with 10 patients requiring reduction or discontinuation of LEV. More strikingly, 9 patients displayed severe symptoms of aggression with physical violence and, in 2 cases, the need for psychiatric emergency treatment. One patient developed additional psychotic symptoms. We suggest that, specifically in patients with a previous history of aggression, behavioral tolerability of LEV should be carefully monitored.
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http://dx.doi.org/10.1016/j.yebeh.2003.07.008DOI Listing
October 2003

Digital photography and 3D MRI-based multimodal imaging for individualized planning of resective neocortical epilepsy surgery.

Epilepsia 2002 Dec;43(12):1543-50

Department of Epileptology, University of Bonn, Bonn, Germany.

Purpose: Invasive presurgical work up of pharmacoresistant epilepsies presumes integration of multiple diagnostic modalities into a comprehensive picture of seizure onset and eloquent brain areas. During resection, reliable transfer of evaluation results to the patient's individual anatomy must be made. We investigated the value of digital photography-based grid localization in combination with preoperative three-dimensional (3D) magnetic resonance imaging (MRI) for clinical routine.

Methods: Digital photographs of the exposed cortex were taken before and after grid placement. Location of electrode contacts on the cortex was identified and schematically indicated on native cortex prints. Accordingly, transfer of contact positions to a 3D MRI brain-surface rendering was carried out manually by using the rendering software. Results of the electrophysiologic evaluation were transferred to either electrode contact reproduction and co-registered with imaging-based techniques such as single-photon emission computed tomography (SPECT), positron emission tomography (PET), and functional MRI (fMRI).

Results: Digital photography allows precise and highly realistic documentation of electrode contact positions on the individual neocortical surface. Lesions underneath grids can be highlighted by semitransparent MRI surface rendering, and lobar boundaries can be identified. Because of integrating electrode contact positions into the postprocessed 3D MRI data set, imaging-based techniques can be codisplayed with the results of the electrophysiologic evaluation. Comparison with CT/MRI co-registration showed good accuracy of the method. However, grids not sewn to the dura at implantation can become subject to significant displacement.

Conclusions: Digital photography in combination with preimplantation 3D MRI allows the generation of reliable tailored resection plans in neocortical epilepsy surgery. The method enhances surgical safety and confidence.
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http://dx.doi.org/10.1046/j.1528-1157.2002.30002.xDOI Listing
December 2002

The natural history of Rasmussen's encephalitis.

Brain 2002 Aug;125(Pt 8):1751-9

Department of Epileptology, University of Bonn, Bonn, Germany.

Rasmussen's encephalitis (RE) is a chronic inflammatory disease of unknown origin, usually affecting one brain hemisphere. In the present study, a comprehensive assessment of the natural history of the disorder is presented. Seizure frequency, degree of hemiparesis and degree of cerebral hemiatrophy in 13 patients with histopathologically proven RE are analysed over the time course prior to resective epilepsy surgery or introduction of long-term immunosuppressive pharmacotherapy. For the assessment of the degree of cerebral hemiatrophy, on defined slices comprising the Sylvian fissure of hard copies of serial MRI investigations, the hemispheric ratio (HR) was determined. The data show an initial prodromal phase with an intermediate frequency of focal onset seizures and mostly no hemiparesis. The occurrence of this stage was mainly observed in the adolescent and adult patients. All patients went through an acute phase with a median duration of 8 months. During this stage, there were frequent simple partial motor seizures, development of hemiparesis and volume loss of the affected hemisphere. After this, the patients passed into a residual stage with a marked decrease in seizure frequency. Twelve months after the onset of the acute stage, the average HR was 0.72. These data allow an estimation of the prognosis of newly affected patients, and demonstrate that most of the brain damage in RE occurs during the first 8-12 months. These findings should be taken into consideration when future therapeutic approaches to RE are evaluated.
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http://dx.doi.org/10.1093/brain/awf176DOI Listing
August 2002

Valproate acidifies hippocampal CA3-neurons--a novel mode of action.

Eur Neuropsychopharmacol 2002 Aug;12(4):279-85

Rheinische Kliniken, Universitätsklinik für Psychiatrie und Psychotherapie, Virchowstrasse 174, D-45147 Essen, Germany.

Various hypotheses try to explain the anticonvulsive and mood stabilizing effects of valproate. Among them, amplification of GABAergic inhibition and reduction of membrane excitability is favored. Here we show that superfusion with 0.1-1 mM valproate induced a moderate intracellular acidification of BCECF-AM-loaded CA3-neurons (hippocampal slices, guinea pig) which was measured as the difference between intracellular pH before (baseline pH(i)) and during valproate treatment (deltapH(i)). In two groups of neurons treated with 1 mM and 0.1-0.5 mM, deltapH(i) values amounted to 0.20 +/- 0.10 and 0.10 +/- 0.04 (deltapH(i) +/- S.D.), respectively, suggesting a dependence on the used valproate-concentration. DeltapH(i) did not correlate with the baseline pH(i). Furthermore, the acidification seems to be independent from an activation of postsynaptic GABA-A receptors, as it was not influenced by 0.1 mM picrotoxin. Since our previous studies clearly demonstrated a reduction of membrane excitability during moderate intracellular acidification, we suggest that the valproate-mediated intracellular acidification may substantially contribute to its anticonvulsive and mood stabilizing properties.
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http://dx.doi.org/10.1016/s0924-977x(02)00023-8DOI Listing
August 2002
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