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Talrijke onderzoeken hebben aangetoond dat de kwaliteit van leven van mensen met medicatieresistente epilepsie aanzienlijk kan worden verbeterd als ze, indien mogelijk, worden behandeld door middel van epilepsiechirurgie. Er bestaat in Nederland echter een substantiële onderverwijzing voor een prechirurgisch evaluatietraject, waardoor medicatieresistente patiënten met epilepsie minder kans hebben om aanvalsvrij te worden.

Rationale: Diagnostic criteria for possible or definite autoimmune limbic encefalitis include brain abnormalities of the medial temporal lobe(s) in MRIs (Lancet Neurol. 2016 Apr;15(4):391–404). Although some objective measures to identify those abnormalities, i.e. swelling of amygdala/hippocampus or increased signal in the fluid attenuated inversion recovery (FLAIR) scans are reported (e.g., Epilepsia. 2013 Sep;54(9):1679-87), a visual inspection of the MRI is still clinical standard. In this research, a open and free to download software is developed (analyseMRI), for autonomous and complete objective volumetric and intensity analysis of the hippocampus, amygdala and cerebral cortex simultaneously. Methods: Based on the FreeSurfer package (http://surfer.nmr.mgh.harvard.edu) a freeware software has been developed using Matlab (http://mathworks.com) to analyse segmented 3D T1-weighted and coregisterd 3D FLAIR series. From the masked structural scan, after specifying the isotropic voxel dimension, the volume of the structure is determined. From the masked FLAIR scan a voxel intensity analysis is performed. First, the intensities are normalized. From here, statistical information such as intensity mean, mode, variance and standard deviation are reported. For universality, also the relative volumes and intensity parameters are determined, relative to the corresponding hemisphere’s cerebral white matter parameter. A limbic encephalitis suspicion is formed as follows: presence of significant volumetric increase in combination with hyperintensity indicated the onset of limbic encephalitis, a following significant volumetric decrease indicates atrophy. From 20 healthy controls a scans were taken previously. The software compares the patient’s parameters to this control average and reports the comparison results. Additionally, if a patient’s volume deviates at least two standard deviations from the control average, this is reported as a significant volume deviation. Next, the software reports the absolute volumes of the structures. Finally, the software checks whether there is clear one-sided hyperintensity in the hippocampi of amygdalae, by comparing the relative intensity mode and standard deviations. A one-sided hyperintensity is characterized by an increased relative intensity mode and simultaneously decreased intensity standard deviation on a structure, compared to the other hemisphere’s corresponding structure. Results: In general, (relative) volumetric increases combined with hyperintensity of the hippocampi and amygdalae, as well as volumetric decreases of the cerebral cortex as a whole, were detected in 5 patients diagnosed with definite limbic encephalitis. In addition, 21 potential limbic encephalitis patients were analyzed. Significant volumetric deviations were found in 48%, one-sided hyperintensities in the FLAIR-signal were found in 76%. Conclusions: To objectify inspection of T1-weighted and FLAIR MRI scans in patients with potential autoimmune limbic encephalitis, a software (analyseMRI) was developed to yield a fast, automatic analysis of MRI scans. As a result, this software produces per patient a waring for a suspicion of limbic encephalitis.

Topiramate (TPM) is effective for treating epilepsy, but executive dysfunction is a common side effect that could significantly affect everyday life. Additionally, previous studies have suggested that patients might be unaware of these changes.To evaluate a rapid TPM titration scheme for the early detection of adverse cognitive side effects.In this retrospective study, we assessed changes in objective cognitive performance (EpiTrackUsing Bayesian statistics, analyses revealed decisive evidence of a negative effect on cognitive performance when TPM was introduced (BF 31480000000) independent of the titration speed (BF 0.739). When using a fast titration rate, deficits in executive function increased from a baseline of 53.1 to 73.5% at follow-up, and 55.1% experienced a statistically significant intraindividual decline. When using the standard titration scheme, impairments increased from 52.2 to 65.2%, with an intraindividual deterioration found in 52.2% of the patients.Physicians might be able to detect adverse cognitive side effects sooner in epilepsy patients if TPM is administered using a faster titration rate while applying repeated cognitive assessments within days. This approach might help prevent any unnoticed intolerance and eventual negative consequences for the patient. Therefore, we recommend monitoring early on for adverse changes instead of withholding a potentially effective treatment option because of anticipated side effects.

In der Differenzialdiagnostik anfallsartig auftretender Ereignisse konnen Handyvideos ein wichtiger diagnostischer Baustein sein. Ziel dieser Ubersichtsarbeit ist es, anhand einer Literaturrecherche und Expertenmeinungen darzulegen, welchen Nutzen und welche Herausforderungen Handyvideos in der Diagnostik anfallsartig auftretender Ereignisse haben. Herausforderungen ergeben sich in der Sicherstellung einer ausreichenden Qualitat zur Erfassung und Darstellung der Anfalle und in juristischen Aspekten der Erstellung, Speicherung und Ubermittlung des Videos. Eine Verbesserung der diagnostischen Aussagekraft von Videos durch optimierte Anfallsaufzeichnung kann am ehesten durch Aufklarung und Anleitung von Angehorigen erfolgen. Fur die sichere Datenubermittlung eignen sich gesicherte Webplattformen, die sowohl das direkte Hochladen des Videos vom Handy des Patienten als auch Arzten und Kliniken den Zugriff hierauf erlauben. Eine in Schottland entwickelte DSGVO-konforme Videoplattform konnte zeigen, dass ein routinemasiger Einsatz von Handvideos in der Differenzialdiagnostik von anfallsartig auftretenden Ereignissen fur Arzte sehr hilfreich ist und durch Vermeidung weiterer diagnostischer Prozeduren Kosten reduziert.

Brain : a journal of neurology (2022). doi:10.1093/brain/awac119, Published by Oxford Univ. Press, Oxford

Epilepsy surgery still lacks an operational method for finding the epileptogenic zone (EZ) or the minimal amount of tissue that has to be resected in order to leave the patient seizure-free. Here we propose a method for predicting the result of a resection from data collected before the eventual resection, therefore allowing an optimal surgical planning. Our major hypothesis is that focal generalized epilepsies are caused by sub-systems with excessive afferent connectivity to and from the rest of the neuronal tissue. To address the issue of delineating the EZ before the actual resection, we propose a paradigm performing "virtual surgery" on the matrix of connectivity between local EEG measurements. The virtual resection removes not only the nodes covered by the suspected EZ and their connections but also subtracts the influence of these nodes on the rest of connectivity. The residual connectivity is then compared to the original one and a significant decrease indicate that the resection contains the EZ or at least large part of it. We tested this approach on a computational model of spatially distributed bi-stable units that provides a generic model of focal epileptic neuronal system. In the modelled cases of epileptic system with spreading seizures, we found that the removal of the EZ can be predicted by significant decrease of the residual connectivity after performing virtual resection. This decrease commensurate with the increase of the epileptic threshold (the ground truth) . The method also predicts the actual change of connectivity after removing the nodes from the model dynamics. In addition we tested our techniques against the "naive" virtual resection which is based on simply removing the corresponding nodes from the connectivity measure. The findings in this work can be exploited to increase the efficiency and accuracy of pre-surgical epileptogenic zone localization in cases of focal epileptic seizure onsets.

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.

To determine the efficacy of immunotherapy in limbic encephalitis (LE) associated epilepsies with autoantibodies against intracellular antigens in the forms of paraneoplastic autoantibodies versus glutamic acid decarboxylase 65 (GAD)-autoantibodies.Eleven paraneoplastic-antibodies+ and eleven age- and gender-matched GAD-antibodies+ patients with LE were compared regarding EEG, seizure frequency, MRI volumetry of the brain, and cognition. All patients received immunotherapy with corticosteroids add-on to antiepileptic therapy. A few patients underwent additional interventions like immunoglobulins or immunoadsorption.Immunotherapy led to a significantly greater proportion of seizure-free patients in the paraneoplastic antibodies+(55%) as compared to GAD-antibodies+(18%) patients (p0.05). Impaired cognition was evident initially (total cognitive performance score based on attentional-executive function, figural/verbal memory and word fluency) in 100% of the paraneoplastic-antibodies+ and 73% of the GAD-antibodies+ group. After therapy, cognition improved significantly in the paraneoplastic-antibodies+, but not in the GAD-antibodies+ patients (p0.05). Cognitive change did not correlate with the change in the number of antiepileptic drugs over time. MRI showed larger and unchanged volumes of the amygdala, presubiculum and subiculum in GAD-antibodies+as compared to paraneoplastic-antibodies+patients (p0.05) over time.Our data provide evidence of a beneficial effect of immunotherapy added to antiepileptic drugs on seizure frequency and cognition only in the paraneoplastic-antibodies+ subgroup of LE presenting autoantibodies against intracellular antigens.

Die Resektion epileptogener Lasionen ist ein etabliertes Behandlungsverfahren pharmakoresistenter fokaler Epilepsien. In eloquenten Arealen ist das Risiko eines dauerhaften neurologischen Defizits jedoch sehr hoch. In solchen Fallen konnte die neuromodulatorische Wirkung einer niedrig dosierten (nicht ablativen) hoch prazisen Bestrahlung umschriebener Lasionen eine Alternative darstellen. Sieben Patienten mit pharmakoresistenter fokaler Epilepsie infolge (vermuteter) fokaler kortikaler Dysplasie in eloquenten Arealen wurden in einem individuellen Therapieversuch risikoadaptiert mittels niedrig dosierter stereotaktischer Radiochirurgie (SRS) oder hypofraktionierter stereotaktischer Strahlentherapie (hfSRT) behandelt. Zwei Patienten wurden mittels hfSRT (Randdosis 36 Gy), funf mittels SRS (Randdosis 13 Gy) behandelt. Beim letzten Follow-up (im Mittel 21,3 ± 7,9 Monate) waren zwei Patienten seit mehr als zwolf Monaten anfallsfrei. Von den verbleibenden Patienten hat sich die Anfallskontrolle bei zwei Patienten gebessert und blieb bei drei Patienten unverandert. Bei keinem Patienten wurden Nebenwirkungen oder neurologische Defizite beobachtet. In dieser Fallserie zeigte die Behandlung von eloquent lokalisierten epileptogenen Lasionen mittels SRS oder hfSRT keine negativen Effekte und ein akzeptables Anfallsoutcome. Ein langerer postinterventioneller Beobachtungszeitraum muss abgewartet werden, um den neuromodulatorischen Effekt der Bestrahlung endgultig bewerten zu konnen. Unsere vorlaufigen Ergebnisse rechtfertigen jedoch die Initiierung einer groseren prospektiven Studie zur Beantwortung der Frage, ob eine niedrig dosierte hoch fokussierte stereotaktische Bestrahlung eine Therapieoption fur Lasionen in eloquenten Hirnarealen darstellt.

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.

Objectives Whether and when to immunologically treat epilepsy patients with suggested autoantibody (AB)-negative limbic encephalitis (LE) is clinically challenging. Therefore, we evaluated the clinical outcome and eventual outcome predictors of immunotherapy in a group of AB-negative patients with recent-onset temporal lobe epilepsy (TLE), magnetic resonance imaging (MRI) indicators of LE, subjective cognitive decline, and/or psychiatric symptoms. Methods This retrospective, observational, uncontrolled study monitored 28 TLE patients with suggested AB-negative LE along with methylprednisolone immunotherapy. Results All patients had seizures, amygdala and/or -hippocampal enlargement, subjective cognitive decline and/or behavioral problems. Eighty-six percent (24/28) were impaired in executive or memory functions, 39% (10/25) depressed, 81% were on antiepileptic drugs when pulse therapy started. After a median follow-up of 18 months, 46% (13/28) of the patients were seizure free (>2 months), 48% (13/27) showed MRI improvements (amygdala and/or hippocampal volume reduction), cognition improved in 57% (16/28), worsened in 32% (9/28), mood improved in 14% (4/25), and deteriorated in 11% (3/25). Immunotherapy was discontinued in 75% (21/28). Clinical changes did not correlate to each other. Outcomes could not be predicted. Conclusion Immunological treatment of suggested AB-negative LE showed reasonable seizure control, MRI and cognitive improvements. Treatment success was not predictable from clinical features, nor definitely attributable to immunological treatment. Lacking biomarkers for the reliable diagnosis of AB-negative LE, we suggest that in presence of mild manifestations, and after initiating antiepileptic drug therapy, negative dynamics in MRI, seizures, cognition, and behavior should be documented before immunosuppressive treatment is initiated.

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 36Gy) and four with SRS (marginal dose 13Gy). Clinical target volume (CTV) ranged from 0.70ccm to 4.32ccm. 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.

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.

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.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.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.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.

Summary 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

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 6–7 years 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.

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.

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.

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.

SummaryObjective 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 (

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., Rasmussen Encephalitis is a rare neurological disease accompanied by inflammation and T cell infiltration in the brain. Here the authors show that the severity of this disease correlates with clonal CD8 T cell expansion.

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.

Frontiers in neurology 6, 130 (2015). doi:10.3389/fneur.2015.00130, Published by Frontiers Research Foundation, Lausanne

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.

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.

Summary: Purpose: Sulthiame is a carbonic anhydrase (CA) inhibitor with an anticonvulsant effect in the treatment of benign and symptomatic focal epilepsy in children. The aim of the study was to elucidate the mode of action of sulthiame with respect to possible changes of intracellular pH (pHi) that might develop along with sulthiame’s anticonvulsant properties. Methods: The effects of sulthiame (a) on pHi of 2,7-bis(2carboxyethyl)-5(6)-carboxyfluorescein-acetoxymetyl ester (BCECF-AM) loaded CA3 neurones as well as (b) on epileptiform activity (induced by 50 M 4-aminopyridine) were compared with those of the CA inhibitors acetazolamide and benzolamide. Results: In the majority of neurons, sulthiame (1.0–1.5 mM; n 8) as well as the membrane permeant acetazolamide (0.5– 1.0 mM; n 6) reversibly decreased pHi by 0.18 ± 0.05 (SD) and 0.17 ± 0.10 (SD) pH units, respectively, within 10 min. The poor membrane permeant benzolamide (1.0–2.0 mM) had no influence on pHi (n 8). Sulthiame (1.0–2.5 mM) and acetazolamide (1.0–2.0 mM) reversibly reduced the frequency of action potentials and epileptiform bursts after 10–15 min (n 9, n 7), whereas benzolamide (1.0–2.0 mM) had no effect (n 6). Conclusions: The results suggest that sulthiame acts as a membrane-permeant CA inhibitor whose beneficial effect on epileptiform activity results at least in part from a modest intracellular acidosis of central neurons. Key Words: Sulthiame—Intracellular pH—Benzolamide—Acetazolamide— Carbonic anhydrase inhibitor.

Background and Purpose — Plasticity in extended, parallel, or reciprocal operating networks is well recognized. Changes in neuronal activity after lesions to distinct localized structures, such as the primary visual cortex, are less well characterized. We investigated the cortical reorganization in patients with poststroke visual field defects using blood oxygen level–dependent functional MRI. Methods — Brain activation was measured in 7 patients with a single occipital cortical lesion and partially recovered hemianopia and in 7 age-matched control subjects. Differences in activation between rest and visual hemifield stimulation were assessed with statistical parametric mapping (SPM’99). Results — In normal subjects, significant activation was found in the contralateral primary visual cortex and bilaterally in the extrastriate cortex. During hemifield stimulation of the unaffected side of stroke patients, a similar pattern was found compared with that seen in control subjects. During stimulation of the hemianopic side, bilateral activation was seen within the extrastriate cortex, stronger in the ipsilateral hemisphere. The primary visual cortex was not significantly activated in either hemisphere during stimulation of the hemianopic side. Conclusions — Visual field defects after stroke are associated with bilateral activation of the extrastriate visual cortex. This pattern of activation indicates altered neuronal activity in the visual system. Further investigation is necessary to determine the relationship between functional reorganization and recovery of lost visual function after poststroke hemianopia.

The theory of deterministic chaos addresses simple deterministic dynamics in which nonlinearity gives rise to complex temporal behavior. Although biological neuronal networks such as the brain are highly complicated, a number of studies provide growing evidence that nonlinear time series analysis of brain electrical activity in patients with epilepsy is capable of providing potentially useful diagnostic information. In the present study, this analysis framework was extended by introducing a new measure ξ , designed to discriminate between nonlinear deterministic and linear stochastic dynamics. For the evaluation of its discriminative power, ξ was extracted from intracranial multi-channel EEGs recorded during the interictal state in 25 patients with unilateral mesial temporal lobe epilepsy. Strong indications of nonlinear determinism were found in recordings from within the epileptogenic zone, while EEG signals from other sites mainly resembled linear stochastic dynamics. In all investigated cases, this differentiation allowed to retrospectively determine the side of the epileptogenic zone in full agreement with results of the presurgical workup.

Summary:Several recent studies emphasize the high value of nonlinear EEG analysis particularly for improved characterization of epileptic brain states. In this review the authors report their work to increase insight into the spatial and temporal dynamics of the epileptogenic process. Specifically

We investigate several quantifiers of the electroencephalogram (EEG) signal with respect to their ability to indicate depth of anesthesia. For 17 patients anesthetized with Sevoflurane, three established measures (two spectral and one based on the bispectrum), as well as a phase space based nonlinear correlation index were computed from consecutive EEG epochs. In absence of an independent way to determine anesthesia depth, the standard was derived from measured blood plasma concentrations of the anesthetic via a pharmacokinetic/pharmacodynamic model for the estimated effective brain concentration of Sevoflurane. In most patients, the highest correlation is observed for the nonlinear correlation index D*. In contrast to spectral measures, D* is found to decrease monotonically with increasing (estimated) depth of anesthesia, even when a "burst-suppression" pattern occurs in the EEG. The findings show the potential for applications of concepts derived from the theory of nonlinear dynamics, even if little can be assumed about the process under investigation., Comment: 7 pages, 5 figures

Summary: Purpose: Nonlinear EEG analysis is valuable in characterizing the spatiotemporal dynamics of the epilepto-genic process in mesial temporal lobe epilepsy. We examined the ability of the measure neuronal complexity loss (L*) to characterize the primary epileptogenic area of neocortical lesional epilepsies during the interictal state. Methods: Spatial distribution of L* (L* map) was extracted from electrocorticograms (n = 52) recorded during presurgical assessment via subdural 64-contact grid electrodes covering lesions in either frontal, parietal, or temporal neocortex in 15 patients. The exact location of recording contacts on the brain surface was identified by matching a postimplant lateral x-ray of the skull with a postoperatively obtained sagittal MRI scan. Reprojecting L* maps onto the subject's brain surface allowed us to compare the spatial distribution of L* with the resection range of the extended lesionectomy. Results: In each of the six patients who became seizure-free, maximum values of L* were restricted to recording sites coinciding with the area of resection. In contrast, L* maps of most patients who had no benefit from the resection indicated a more widespread extent or the existence of additional, probably autonomous, foci. The mean of L* values obtained from recording sites outside the area of resection correctly distinguished 13 patients (86.7 %) with respect to seizure outcome. Conclusions: Relevant information obtained from long-lasting interictal electrocorticographic recordings can be compressed to a single L* map that contributes to a spatial characterization of the primary epileptogenic area. In neocortical lesional epilepsies, L* allows for identification and characterization of epileptogenic activity and thus provides an additional diagnostic tool for presurgical assessment.

Recent studies have shown that time windowed extraction of nonlinear parameters like an effective correlation dimension from intracranially recorded EEG of epileptic patients often allows to detect and identify an unequivocal “pre-ictal phase” preceding an epileptic seizure. In another study, however, such an anticipation could not be made. These conflicting findings may indicate that observed changes in nonlinear parameters probably depend on the type of elementary mechanisms underlying epileptic processes and/or the spatial distribution of neurons primarily involved in generation of epileptiform discharges. To test the existence of such dependencies, the transition from normal to epileptiform activity (EA) of CA3-neurons in hippocampal slices was analyzed in four epilepsy models, using a time windowed computation of an effective correlation dimension. Indeed, in xanthine and penicillin models, signal complexity in intracellular recordings was reduced before manifestation of paroxysmal depolarization shifts (PDS), whereas a preceding loss of complexity was missing in low-magnesium and veratridine models. These findings indicate that interictal-like EA is predictable only in some epilepsy models.

We developed an optimized algorithm that allows computation of auto- and cross-correlation integrals from single channel time series without restricting the range of hypersphere radii and embedding dimensions. Optimization was achieved by eliminating any multiple computation of subsets entering the distance function in the time-delay reconstruction of the phase space repeatedly for increasing embedding dimensions; this is most effective when using the maximum norm. Compared to more naive implementations an improvement of 2–3 was achieved, depending on the type of workstation, the operating system, and the compiler. An additional optimization for 80×86 assembly language allows torun the algorithm on a standard personal computer as fast as on a workstation. In contrast to other implementations, the execution speed of this algorithm is nearly unaffected by the type of underlying data. Thus, it is optimal for real-time analyses.

Aggravation of focal epileptic seizures in adults is common after the antiepileptic drug (AED) therapy is initiated. Sometimes aggravation is mimicked by clustering of the seizures. Therefore, it is always necessary to analyze the patient's history and therapy carefully before drawing any conclusions. It is likely that a paradoxical aggravation of epileptic seizures can be attributed to the given AED and is sometimes, but only rarely, due to drug interactions.

Objectives: To characterize the cellular autoimmune response in patients with γ-aminobutyric acid (GABA) B receptor antibody–associated limbic encephalitis (GABA B -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 GABA B -R LE and one case of paraneoplastic GABA B -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 GABA B -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 GABA B -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 GABA B -R LE.

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.

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. Ann Neurol 2011

The present study investigated the co-localization of musical and linguistic syntax processing in the human brain. EEGs were recorded from subdural electrodes placed on the left and right perisylvian cortex. The neural generators of the early potentials elicited by syntactic errors in music and language were localized by means of distributed source modeling and compared within subjects. The combined results indicated a partial overlap of the sources within the bilateral superior temporal gyrus, and, to a lesser extent, in the left inferior frontal gyrus, qualifying these areas as shared anatomic substrates of early syntactic error detection in music and language.