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Genetic variants in relevant genes coexisting with MRI lesions in children with drug‐resistant epilepsy (DRE) can negatively influence epilepsy surgery outcomes. Still, presurgical evaluation does not include genetic diagnostics routinely. Here, we report our presurgical evaluation algorithm that includes routine genetic testing. We analyzed retrospectively the data of 68 children with DRE operated at a mean age of 7.8 years (IQR: 8.1 years) at our center. In 49 children, genetic test results were available. We identified 21 gene variants (ACMG III: n = 7, ACMG IV: n = 2, ACMG V: n = 12) in 19 patients (45.2%) in the genes TSC1, TSC2, MECP2, DEPDC5, HUWE1, GRIN1, ASH1I, TRIO, KIF5C, CDON, ANKD11, TGFBR2, ATN1, COL4A1, JAK2, KCNQ2, ATP1A2, and GLI3 by whole‐exome sequencing as well as deletions and duplications by array CGH in six patients. While the results did not change the surgery indication, they supported counseling with respect to postoperative chance of seizure freedom and weaning of antiseizure medication (ASM). The presence of genetic findings leads to the postoperative retention of at least one ASM. In our cohort, the International League against Epilepsy (ILAE) seizure outcome did not differ between patients with and without abnormal genetic findings. However, in the 7/68 patients with an unsatisfactory ILAE seizure outcome IV or V 12 months postsurgery, 2 had an abnormal or suspicious genetic finding as a putative explanation for persisting seizures postsurgery, and 3 had received palliative surgery including one TSC patient. This study highlights the importance of genetic testing in children with DRE to address putative underlying germline variants as genetic epilepsy causes or predisposing factors that guide patient and/or parent counseling on a case‐by‐case with respect to their individual chance of postoperative seizure freedom and ASM weaning. Plain Language Summary: Genetic variants in children with drug‐resistant epilepsy (DRE) can negatively influence epilepsy surgery outcomes. However, presurgical evaluation does not include genetic diagnostics routinely. This retrospective study analyzed the genetic testing results of the 68 pediatric patients who received epilepsy surgery in our center. We identified 21 gene variants by whole‐exome sequencing as well as deletions and duplications by array CGH in 6 patients. These results highlight the importance of genetic testing in children with DRE to guide patient and/or parent counseling on a case‐by‐case with respect to their individual chance of postoperative seizure freedom and ASM weaning. [ABSTRACT FROM AUTHOR]

Although epilepsy surgery is the only curative therapeutic approach for lesional drug‐resistant epilepsy (DRE), there is reluctance to operate on infants due to a fear of complications. A recent meta‐analysis showed that epilepsy surgery in the first 6 months of life can achieve seizure control in about two thirds of children. However, robust data on surgical complications and postoperative cognitive development are lacking. We performed a retrospective multicenter study of infants who underwent epilepsy surgery in the first 6 months of life. 15 infants underwent epilepsy surgery at a median age of 134 days (IQR: 58) at four centers. The most common cause was malformation of cortical development, and 13 patients underwent a hemispherotomy. Two thirds required intraoperative red blood transfusions. Severe intraoperative complications occurred in two patients including death in one infant due to cardiovascular insufficiency. At a median follow‐up of 1.5 years (IQR: 1.8), 57% of patients were seizure‐free. Three patients where reoperated at a later age, resulting in 79% seizure freedom. Anti‐seizure medication could be reduced in two thirds, and all patients improved in their development. Our findings suggest that early epilepsy surgery can result in good seizure control and developmental improvement. However, given the perioperative risks, it should be performed only in specialized centers. [ABSTRACT FROM AUTHOR]

Focal cortical dysplasias (FCDs) are malformations of cortical development and one of the most common pathologies causing pharmacoresistant focal epilepsy. Resective neurosurgery yields high success rates, especially if the full extent of the lesion is correctly identified and completely removed. The visual assessment of magnetic resonance imaging does not pinpoint the FCD in 30%–50% of cases, and half of all patients with FCD are not amenable to epilepsy surgery, partly because the FCD could not be sufficiently localized. Computational approaches to FCD detection are an active area of research, benefitting from advancements in computer vision. Automatic FCD detection is a significant challenge and one of the first clinical grounds where the application of artificial intelligence may translate into an advance for patients' health. The emergence of new methods from the combination of health and computer sciences creates novel challenges. Imaging data need to be organized into structured, well‐annotated datasets and combined with other clinical information, such as histopathological subtypes or neuroimaging characteristics. Algorithmic output, that is, model prediction, requires a technically correct evaluation with adequate metrics that are understandable and usable for clinicians. Publication of code and data is necessary to make research accessible and reproducible. This critical review introduces the field of automatic FCD detection, explaining underlying medical and technical concepts, highlighting its challenges and current limitations, and providing a perspective for a novel research environment. [ABSTRACT FROM AUTHOR]

Objective: Some patients unexpectedly display an unfavorable cognitive course after epilepsy surgery subsequent to any direct cognitive sequelae of the surgical treatment. Therefore, we conducted in‐depth neuropathological examinations of resective specimens from corresponding patients to provide insights as to the underlying disease processes. Methods: In this study, cases with significant cognitive deterioration following a previous postoperative assessment were extracted from the neuropsychological database of a longstanding epilepsy surgical program. An extensive reanalysis of available specimens was performed using current, state‐of‐the‐art neuropathological examinations. Patients without cognitive deterioration but matched in regard to basic pathologies served as controls. Results: Among the 355 operated patients who had undergone more than one postoperative neuropsychological examination, 30 (8%) showed significant cognitive decline in the period after surgery. Of the 24 patients with available specimens, 71% displayed further neuropathological changes in addition to the typical spectrum (ie, hippocampal sclerosis, focal cortical dysplasias, vascular lesions, and low‐grade tumors), indicating (1) a secondary, putatively epilepsy‐independent neurodegenerative disease process; (2) limbic inflammation; or (3) the enigmatic pathology pattern of "hippocampal gliosis" without segmental neurodegeneration. In the controls, the matched individual principal epilepsy‐associated pathologies were not found in combination with the secondary pathology patterns of the study group. Interpretation: Our findings indicate that patients who unexpectedly displayed unfavorable cognitive development beyond any direct surgical effects show rare and very particular pathogenetic causes or parallel, presumably independent, neurodegenerative alterations. A multicenter collection of such cases would be appreciated to discern presurgical biomarkers that help with surgical decision‐making. ANN NEUROL 2023;93:536–550 [ABSTRACT FROM AUTHOR]

Objective: Rasmussen encephalitis (RE) is a progressive and destructive inflammatory disease of one hemisphere. Its cause is unknown. We investigated comorbidity and laterality factors that might predispose to RE. Methods: We retrospectively compared the histories of 160 RE patients to those with genetic generalized epilepsy (n = 154) and those with focal cortical dysplasia Type II (FCD II; n = 148). Results: The median/mean age at symptom onset in RE was 7/10 years (range = 1–53 years), and 58.1% of the patients were female. The female sex predominated in RE patients, with age > 7 years at disease manifestation. The left hemisphere was affected in 65.6%. Perinatal complications (preterm birth, twin pregnancies, early acquired brain lesions) were more frequent in RE than in control patients. Ipsilateral facial autoimmune conditions (scleroderma en coup de sabre, uveitis, or chorioretinitis) were only observed in RE patients (6.9%). Onset of RE was more frequently associated with fever than that of FCD II. In 33.1% of RE patients, ≥1 potential risk factor was found. Interestingly, 11.9% of patients had one‐sided early brain lesions or facial autoimmune lesions ipsilateral to subsequent RE; none had such a lesion contralaterally. Significance: Perinatal complications and facial autoimmune conditions may act as predisposing factors for RE. Fever might trigger RE manifestation. Further genetic or infectious contributors may be identified in the future. Single or combined hits may be required to elicit or facilitate the start of the disease. Ipsilateral early comorbid lesions or facial autoimmune processes might in part explain the enigmatic unilaterality of RE. [ABSTRACT FROM AUTHOR]

Objective: Direct pathogenic effects of autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GAD65) in autoimmune limbic encephalitis (LE) have been questioned due to its intracellular localization. We therefore hypothesized a pathogenic role for T cells. Methods: We assessed magnet resonance imaging, neuropsychological and peripheral blood, and CSF flow cytometry data of 10 patients with long‐standing GAD65‐LE compared to controls in a cross‐sectional manner. These data were related to each other within the GAD65‐LE group and linked to neuropathological findings in selective hippocampectomy specimen from another two patients. In addition, full‐resolution human leukocyte antigen (HLA) genotyping of all patients was performed. Results: Compared to controls, no alteration in hippocampal volume but impaired memory function and elevated fractions of activated HLADR+ CD4+ and CD8+ T cells in peripheral blood and cerebrospinal fluid were found. Intrathecal fractions of CD8+ T cells negatively correlated with hippocampal volume and memory function, whereas the opposite was true for CD4+ T cells. Consistently, antigen‐experienced CD8+ T cells expressed increased levels of the cytotoxic effector molecule perforin in peripheral blood, and perforin‐expressing CD8+ T cells were found attached mainly to small interneurons but also to large principal neurons together with wide‐spread hippocampal neurodegeneration. 6/10 LE patients harbored the HLA‐A*02:01 allele known to present the immunodominant GAD65114–123 peptide in humans. Interpretation: Our data suggest a pathogenic effect of CD8+ T cells and a regulatory effect of CD4+ T cells in patients with long‐standing GAD65‐LE. [ABSTRACT FROM AUTHOR]

Objective: Using multimodal imaging, we tested the hypothesis that patients after hemispherotomy recruit non‐primary motor areas and non‐pyramidal descending motor fibers to restore motor function of the impaired limb. Methods: Functional and structural MRI data were acquired in a group of 25 patients who had undergone hemispherotomy and in a matched group of healthy controls. Patients' motor impairment was measured using the Fugl‐Meyer Motor Assessment. Cortical areas governing upper extremity motor‐control were identified by task‐based functional MRI. The resulting areas were used as nodes for functional and structural connectivity analyses. Results: In hemispherotomy patients, movement of the impaired upper extremity was associated to widespread activation of non‐primary premotor areas, whereas movement of the unimpaired one and of the control group related to activations prevalently located in the primary motor cortex (all p ≤ 0.05, FWE‐corrected). Non‐pyramidal tracts originating in premotor/supplementary motor areas and descending through the pontine tegmentum showed relatively higher structural connectivity in patients (p < 0.001, FWE‐corrected). Significant correlations between structural connectivity and motor impairment were found for non‐pyramidal (p = 0.023, FWE‐corrected), but not for pyramidal connections. Interpretation: A premotor/supplementary motor network and non‐pyramidal fibers seem to mediate motor function in patients after hemispherotomy. In case of hemispheric lesion, the homologous regions in the contralesional hemisphere may not compensate the resulting motor deficit, but the functionally redundant premotor network. [ABSTRACT FROM AUTHOR]

Objective: To identify non‐EEG‐based signals and algorithms for detection of motor and non‐motor seizures in people lying in bed during video‐EEG (VEEG) monitoring and to test whether these algorithms work in freely moving people during mobile EEG recordings. Methods: Data of three groups of adult people with epilepsy (PwE) were analyzed. Group 1 underwent VEEG with additional devices (accelerometry, ECG, electrodermal activity); group 2 underwent VEEG; and group 3 underwent mobile EEG recordings both including one‐lead ECG. All seizure types were analyzed. Feature extraction and machine‐learning techniques were applied to develop seizure detection algorithms. Performance was expressed as sensitivity, precision, F1 score, and false positives per 24 hours. Results: The algorithms were developed in group 1 (35 PwE, 33 seizures) and achieved best results (F1 score 56%, sensitivity 67%, precision 45%, false positives 0.7/24 hours) when ECG features alone were used, with no improvement by including accelerometry and electrodermal activity. In group 2 (97 PwE, 255 seizures), this ECG‐based algorithm largely achieved the same performance (F1 score 51%, sensitivity 39%, precision 73%, false positives 0.4/24 hours). In group 3 (30 PwE, 51 seizures), the same ECG‐based algorithm failed to meet up with the performance in groups 1 and 2 (F1 score 27%, sensitivity 31%, precision 23%, false positives 1.2/24 hours). ECG‐based algorithms were also separately trained on data of groups 2 and 3 and tested on the data of the other groups, yielding maximal F1 scores between 8% and 26%. Significance: Our results suggest that algorithms based on ECG features alone can provide clinically meaningful performance for automatic detection of all seizure types. Our study also underscores that the circumstances under which such algorithms were developed, and the selection of the training and test data sets need to be considered and limit the application of such systems to unseen patient groups behaving in different conditions. [ABSTRACT FROM AUTHOR]

Objective: Transsylvian selective amygdalo‐hippocampectomy (tsSAHE) represents a generally recognized surgical procedure for drug‐resistant mesial temporal lobe epilepsy (mTLE). Although postoperative seizure freedom can be achieved in about 70% of tsSAHE, there is a considerable amount of patients with persisting postoperative seizures. This might partly be explained by differing extents of resection of various tsSAHE target volumes. In this study we analyzed the resected proportions of hippocampus, amygdala as well as piriform cortex in regard of postoperative seizure outcome. Methods: Between 2012 and 2017, 82 of 103 patients with mTLE who underwent tsSAHE at the authors' institution were included in the analysis. Resected proportions of hippocampus, amygdala and temporal piriform cortex as target structures of tsSAHE were volumetrically assessed and stratified according to favorable (International League Against Epilepsy (ILAE) class 1) and unfavorable (ILAE class 2–6) seizure outcome. Results: Patients with favorable seizure outcome revealed a significantly larger proportion of resected temporal piriform cortex volumes compared to patients with unfavorable seizure outcome (median resected proportional volumes were 51% (IQR 42–61) versus (vs.) 13 (IQR 11–18), P = 0.0001). Resected proportions of hippocampus and amygdala did not significantly differ for these groups (hippocampus: 81% (IQR 73–88) vs. 80% (IQR 74–92) (P = 0.7); amygdala: 100% (IQR 100–100) vs. 100% (IQR 100–100) (P = 0.7)). Interpretation: These results strongly suggest temporal piriform cortex to constitute a key target resection volume to achieve seizure freedom following tsSAHE. [ABSTRACT FROM AUTHOR]

Objective: To ascertain factors that are related to the antiepileptic drug load in epilepsy. Methods: In this cross‐sectional study, we analyzed a large cohort of conservatively treated patients with epilepsy (n = 1135) and a smaller homogeneous group of presurgical patients with neuropathologically confirmed unilateral hippocampal sclerosis (n = 91). Considered clinical variables comprised (1) presence of an underlying cerebral lesion, (2) onset and (3) duration of epilepsy, (4) seizure frequency, (5) generalized or focal to bilateral tonic‐clonic seizures, (6) ictal impairment of awareness, and (7) a history of convulsive status epilepticus. In the presurgical sample, we additionally considered (8) the degree of pathology (hippocampal neuronal cell densities) instead of (1) presence of a cerebral lesion and (9) an overall rating of epilepsy severity (GASE scale). Drug load was quantified as (a) the number of concomitant antiepileptic drugs (AEDs) and (b) the total defined daily dose (DDD). Results: Analyses disclosed only small correlations between clinical variables and drug load indices. In the conservatively treated cohort, the multiple regression analyses revealed that epilepsy onset, cerebral lesion, history of convulsive status epilepticus, and seizure frequency combined explained only 6%–10% of variance in drug load. Nearly the same variance (5%–8%) could be explained by duration of epilepsy alone. Degree of hippocampal pathology and the epilepsy severity ratings were not related to drug load indices. Significance: Clinical markers of epilepsy severity were only marginally associated with drug load. Findings rather indicate that patients seem to accumulate drugs due to the chronicity of epilepsy. Overall, the drug load remained largely unexplained. The findings nevertheless call for scrutinizing multidrug therapies in patients with long‐lasting epilepsies. [ABSTRACT FROM AUTHOR]

Inflammation plays a role in the pathogenesis of immune‐mediated epilepsy, but also in epilepsy of other etiology such as hippocampal sclerosis. This study aimed to characterize immune cell signatures in the peripheral blood (PB) and cerebrospinal fluid (CSF) in temporal lobe epilepsy (TLE) of different etiologies. We retrospectively evaluated CSF routine parameters and immune cell profiles using flow cytometry in a cohort of 51 patients and 45 age‐matched controls with functional disorders. Groups were comprised of patients with nonlesional TLE (n = 26), TLE due to hippocampal sclerosis (n = 14), or limbic encephalitis with antibodies against the 65‐kDa isoform of glutamic acid decarboxylase (GAD65‐LE; n = 11). TLE patients showed increased proportions of human leukocyte antigen–DR isotype (HLA‐DR)‐expressing CD4+ T lymphocytes in the CSF. Furthermore, they were characterized by a shift in monocyte subsets toward immature CD14lowCD16+ cells in the PB and blood/CSF‐barrier dysfunction. Whereas TLE patients in general showed similar immune cell profiles, patients with GAD65‐LE differed from other TLE patients by increased proportions of HLA‐DR–expressing CD8+ T lymphocytes and type 2/3 oligoclonal bands. These findings point to a role of innate and adaptive immunity in TLE. CSF parameters may help to discriminate epilepsy patients from controls and different forms of TLE from each other. [ABSTRACT FROM AUTHOR]

Limbic encephalitis (LE) forms a spectrum of autoimmune diseases involving temporal lobe epilepsy and memory impairment. Imaging features of LE are known to depend on the associated antibody and to occur on the brain network level. However, first studies investigating brain networks in LE have either focused on one distinct antibody subgroup or on distinct anatomical regions. In this study, brain graphs of 17 LE patients with autoantibodies against glutamic acid decarboxylase 65 (GAD‐LE), four LE patients with autoantibodies against leucine‐rich glioma‐inactivated 1, five LE patients with autoantibodies against contactin‐associated protein‐like 2, 26 age‐ and gender‐matched healthy control subjects, and 20 epilepsy control patients with hippocampal sclerosis were constructed based on T1‐weighted structural magnetic resonance imaging scans and diffusion tensor imaging. GAD‐LE showed significantly altered global network topology in terms of integration and segregation as compared to healthy controls and patients with hippocampal sclerosis (P <.01, analysis of variance with Tukey‐Kramer post hoc tests). Linear regression linked global network measures with amygdala volume and verbal memory performance (P <.05). Alterations of local network topology show serotype dependence in hippocampus, amygdala, insula, and various cortical regions. Our findings reveal serotype‐dependent patterns of structural connectivity and prove the relevance of in silico network measures on clinical grounds. [ABSTRACT FROM AUTHOR]

Objective: Assess occurrence of the dendritic spine scaffolding protein Drebrin as a pathophysiologically relevant autoantibody target in patients with recurrent seizures and suspected encephalitis as leading symptoms.Methods: Sera of 4 patients with adult onset epilepsy and suspected encephalitis of unresolved etiology and equivalent results in autoantibody screening were subjected to epitope identification. We combined a wide array of approaches, ranging from immunoblotting, immunoprecipitation, mass spectrometry, subcellular binding pattern analyses in primary neuronal cultures, and immunohistochemistry in brains of wild-type and Drebrin knockout mice to in vitro analyses of impaired synapse formation, morphology, and aberrant neuronal excitability by antibody exposure.Results: In the serum of a patient with adult onset epilepsy and suspected encephalitis, a strong signal at ∼70kDa was detected by immunoblotting, for which mass spectrometry revealed Drebrin as the putative antigen. Three other patients whose sera also showed strong immunoreactivity around 70kDa on Western blotting were also anti-Drebrin-positive. Seizures, memory impairment, and increased protein content in cerebrospinal fluid occurred in anti-Drebrin-seropositive patients. Alterations in cerebral magnetic resonance imaging comprised amygdalohippocampal T2-signal increase and hippocampal sclerosis. Diagnostic biopsy revealed T-lymphocytic encephalitis in an anti-Drebrin-seropositive patient. Exposure of primary hippocampal neurons to anti-Drebrin autoantibodies resulted in aberrant synapse composition and Drebrin distribution as well as increased spike rates and the emergence of burst discharges reflecting network hyperexcitability.Interpretation: Anti-Drebrin autoantibodies define a chronic syndrome of recurrent seizures and neuropsychiatric impairment as well as inflammation of limbic and occasionally cortical structures. Immunosuppressant therapies should be considered in this disorder. ANN NEUROL 2020;87:869-884. [ABSTRACT FROM AUTHOR]

Objective: To determine predictors of focal to bilateral tonic‐clonic seizures (FBTCS) during video–electroencephalography (EEG) monitoring (VEM). Methods: All adult patients undergoing presurgical VEM from 2014 to 2015 in the department of epileptology were eligible (N = 229). Those with refractory focal epilepsy and epileptic seizures recorded during VEM were analyzed (N = 188, Group 1). To assess the effects of antiepileptic drug (AED) taper, the total AED load was calculated as the sum of the ratios of prescribed daily dose and defined daily dose of all AEDs per VEM day and was correlated with the occurrence of focal seizures without bilateral tonic‐clonic seizures (FwoBTCS) and FBTCS. To validate the findings, data of patients undergoing VEM in 2004 and 2005 (Group 2, eligible N = 243, analyzed N = 203) were also investigated. Results: In Group 1, 53 patients had FBTCS and 135 patients had exclusively FwoBTCS during VEM. Reduced AED load at seizure onset was the most important modifiable risk factor for FBTCS (receiver‐operating characteristic [ROC]: area under the curve [AUC] = 0.78). Furthermore, the risk of FBTCS varied with the history and frequency of FBTCS prior to VEM. For instance, patients had a 50% risk of FBTCS by reducing the AED load to ~20% when no information about history of FBTCS was taken into account, to ~30% when a positive history of FBTCS was taken into account, and to ~50% when a high frequency of FBTCS prior to VEM was taken into account. These findings were largely replicated in Group 2 (59 patients with FBTCS and 144 exclusively with FwoBTCS). Significance: The risk of FTBCS during VEM depends on the history and frequency of FTBCS prior to VEM and is particularly associated with the extent of AED reduction. Our data underscore the need for appropriate tapering regimens in VEM units. [ABSTRACT FROM AUTHOR]

Objective: Tonic‐clonic seizures (TCS) lead to metabolic stress and changes in related blood markers. Such markers may indicate harmful conditions but can also help to identify TCS as a cause of transient loss of consciousness. In this study, we hypothesized that the alterations of circulating markers of metabolic stress depend on the clinical features of TCS. Methods: Ninety‐one adults undergoing video‐EEG monitoring participated in this prospective study. Electrolytes, renal parameters, creatine kinase (CK), prolactin (PRL), lactate, ammonia, glucose, and other parameters were measured at inclusion and different time points after TCS. Results: A total of 39 TCS were recorded in 32 patients (six generalized onset tonic‐clonic seizures in 6 and 33 focal to bilateral tonic‐clonic seizures in 26 patients). Shortly after TCS, mean lactate, ammonia, and PRL levels were significantly increased 8.7‐fold, 2.6‐fold, and 5.1‐fold, respectively, with levels of more than twofold above the upper limits of the normal (ULN) in 90%, 71%, and 70% of the TCS and returned to baseline levels within 2 hours. Only postictal lactate levels were significantly correlated with the total duration of the tonic‐clonic phase. In contrast, CK elevations above the ULN were found in three TCS (~10%) only with a peak after 48 hours. Immediately after the TCS, hyperphosphatemia occurred in one third of the patients, whereas hypophosphatemia was observed in one third 2 hours later. TCS led to subtle but significant alterations of other electrolytes, creatinine, and uric acid, whereas glucose levels were moderately increased. Significance: Lactate is a robust metabolic marker of TCS with elevations found in ~90% of cases within 30 minutes after seizure termination, whereas ammonia rises in ~ 70%, similarly to PRL. Phosphate levels show an early increase and a decrease 2 hours after TCS in a third of patients. CK elevations are rare after video‐EEG‐documented TCS, challenging its value as a diagnostic marker. [ABSTRACT FROM AUTHOR]

Summary: Rasmussen encephalitis (RE) is an immune‐mediated brain disease with progressive unihemispheric atrophy. Although it is regarded as a strictly one‐sided pathology, volumetric magnetic resonance imaging (MRI) studies have revealed atrophy in the so‐called unaffected hemisphere. In contrast to previous studies, we hypothesized that the contralesional hemisphere would show increased gray matter volume in response to the ipsilesional atrophy. We assessed the gray matter volume differences among 21 patients with chronic, late‐stage RE and 89 age‐ and gender‐matched healthy controls using voxel‐based morphometry. In addition, 11 patients with more than one scan were tested longitudinally. Compared to controls, the contralesional hemisphere of the patients revealed a higher cortical volume but a lower subcortical gray matter volume (all P < 0.001, unpaired t test). Progressive gray matter volume losses in bilateral subcortical gray matter structures were observed (P < 0.05, paired t test). The comparatively higher cortical volume in the contralesional hemisphere can be interpreted as a result of compensatory structural remodeling in response to atrophy of the ipsilesional hemisphere. Contralesional subcortical gray matter volume loss may be due to the pathology or its treatment. Because MRI provides the best marker for determining the progression of RE, an accurate description of its MRI features is clinically relevant. [ABSTRACT FROM AUTHOR]

Summary: Objective: Generalized convulsive seizures (GCS) are associated with high demands on the cardiovascular system, thereby facilitating cardiac complications. To investigate occurrence, influencing factors, and extent of cardiac stress or injury, the alterations and time course of the latest generation of cardiac blood markers were investigated after documented GCS. Methods: Adult patients with refractory epilepsy who underwent video–electroencephalography (EEG) monitoring along with simultaneous one‐lead electrocardiography (ECG) recordings were included. Cardiac biomarkers (cardiac troponin I [cTNI]; high‐sensitive troponin T [hsTNT]; N‐terminal prohormone of brain natriuretic peptide [NT‐proBNP]; copeptin; suppression of tumorigenicity‐2 [SST‐2]; growth differentiation factor 15, [GDF‐15]; soluble urokinase plasminogen activator receptor [suPAR]; and heart‐type fatty acid binding protein [HFABP]) and catecholamines were measured at inclusion and at different time points after GCS. Periictal cardiac properties were assessed by analyzing heart rate (HR), HR variability (HRV), and corrected QT intervals(QTc). Results: Thirty‐six GCS (6 generalized‐onset tonic–clonic seizures and 30 focal to bilateral tonic–clonic seizures) were recorded in 30 patients without a history of cardiac or renal disease. Postictal catecholamine levels were elevated more than twofold. A concomitant increase in HR and QTc, as well as a decrease in HRV, was observed. Elevations of cTNI and hsTNT were found in 3 of 30 patients (10%) and 6 of 23 patients (26%), respectively, which were associated with higher dopamine levels. Copeptin was increased considerably after most GCS, whereas SST‐2, HFABP, and GDF‐15 displayed only subtle variations, and suPAR was unaltered in the postictal period. Cardiac symptoms did not occur in any patient. Significance: The use of more sensitive biomarkers such as hsTNT suggests that signs of cardiac stress occur in about 25% of the patients with GCS without apparent clinical symptoms. SuPAR may indicate clinically relevant troponin elevations. Copeptin could help to diagnose GCS, but specificity needs to be tested. [ABSTRACT FROM AUTHOR]

The article discusses a study on the use of antiepileptic drug treatment and dementia risk factors. Noted is the progressive mental decline in the older people with dementia as well as the risk for higher doses of antiepileptic drugs (AEDs). Information is also provided on the epidemiological study of health care databases from Finland and Germany.

Neurosurgery is an underutilized treatment that can potentially cure drug-refractory epilepsy. Careful, multidisciplinary presurgical evaluation is vital for selecting patients and to ensure optimal outcomes. Advances in neuroimaging have improved diagnosis and guided surgical intervention. Invasive electroencephalography allows the evaluation of complex patients who would otherwise not be candidates for neurosurgery. We review the current state of the assessment and selection of patients and consider established and novel surgical procedures and associated outcome data. We aim to dispel myths that may inhibit physicians from referring and patients from considering neurosurgical intervention for drug-refractory focal epilepsies. Ann Neurol 2018;83:676-690. [ABSTRACT FROM AUTHOR]

Background Deep brain stimulation (DBS) of the human entorhinal area using 50 Hz pulses has revealed conflicting results regarding memory performance. Moreover, its impact on memory-related hippocampal potentials has not yet been investigated. Methods We recorded data from seven epilepsy patients implanted with depth electrodes in the entorhinal cortex, hippocampus, amygdala, and parahippocampal cortex. Entorhinal DBS (bipolar, biphasic 50 Hz pulses, on- and off-cycles of 15 s) was applied with low amplitude (0.1 mA) to resemble physiologic conditions. During DBS on- and off-periods, patients learned noun-color associations that were later tested. Results During entorhinal DBS we observed more positive deflections of event-related potentials (ranging from 700 to 950 ms) in the anterior hippocampus for the on- vs. off-condition. We detected no effects in the amygdala, mid hippocampus and parahippocampal cortex. On the behavioral level, no differences in memory performance (item and source memory) were apparent in the on- vs. off-condition, neither across all trials nor across patients. Discussion Our findings indicate that entorhinal DBS with low amplitude has an impact on memory encoding-related potentials within the anterior hippocampus, but not on memory performance per se. [ABSTRACT FROM AUTHOR]

Objective Autoimmune encephalitis is most frequently associated with anti- NMDAR autoantibodies. Their pathogenic relevance has been suggested by passive transfer of patients' cerebrospinal fluid ( CSF) in mice in vivo. We aimed to analyze the intrathecal plasma cell repertoire, identify autoantibody-producing clones, and characterize their antibody signatures in recombinant form. Methods Patients with recent onset typical anti- NMDAR encephalitis were subjected to flow cytometry analysis of the peripheral and intrathecal immune response before, during, and after immunotherapy. Recombinant human monoclonal antibodies (rhuMab) were cloned and expressed from matching immunoglobulin heavy- (IgH) and light-chain (IgL) amplicons of clonally expanded intrathecal plasma cells (cePc) and tested for their pathogenic relevance. Results Intrathecal accumulation of B and plasma cells corresponded to the clinical course. The presence of cePc with hypermutated antigen receptors indicated an antigen-driven intrathecal immune response. Consistently, a single recombinant human GluN1-specific monoclonal antibody, rebuilt from intrathecal cePc, was sufficient to reproduce NMDAR epitope specificity in vitro. After intraventricular infusion in mice, it accumulated in the hippocampus, decreased synaptic NMDAR density, and caused severe reversible memory impairment, a key pathogenic feature of the human disease, in vivo. Interpretation A CNS-specific humoral immune response is present in anti- NMDAR encephalitis specifically targeting the GluN1 subunit of the NMDAR. Using reverse genetics, we recovered the typical intrathecal antibody signature in recombinant form, and proved its pathogenic relevance by passive transfer of disease symptoms from man to mouse, providing the critical link between intrathecal immune response and the pathogenesis of anti- NMDAR encephalitis as a humorally mediated autoimmune disease. [ABSTRACT FROM AUTHOR]

Objectives To evaluate dose-response relationship of BGG492 as add-on therapy to 1-3 antiepileptic drugs in patients with partial-onset seizures and to investigate safety and tolerability of BGG492. Methods This was a 12-week, randomized, double-blind, placebo-controlled, phase II dose-titration study (core study) with a 30-week, flexible-dose, open-label extension. In the core study, patients were randomized (1:2) to placebo or BGG492 100 mg t.i.d. in cohort 1, and in cohort 2 patients were randomized (1:4) to placebo or BGG492 150 mg t.i.d. On completion of the core study, eligible patients entered the extension study. Primary outcome measures were total partial seizure frequency per 28 days (core study) and safety and tolerability (extension study). Results Overall, 93 patients were randomized (150 mg [n = 44]; 100 mg [n = 24]; placebo [n = 25]), and 81 (87.1%) completed the core study. Fifty-one patients entered and 43 (84.3%) completed the extension study. In the core study, no statistically significant dose-response trend among the BGG492 treatment groups (100 and 150 mg) was observed at the 4-week double-blind maintenance period (weeks 7-10); however, there was higher percent reduction in total partial seizure frequency in the BGG492 150 mg over placebo groups (37.32%; 95% confidence interval [CI] −18.90, 66.95). Dizziness, somnolence, and fatigue were the most common adverse events ( AEs), higher in the BGG492 150 mg group than in the 100 mg and placebo groups (dizziness: 14 [31.8%] vs. 3 [12.5%] and 1 [4.0%]; somnolence: 7 [15.9%] vs. 1 [4.2%] and 1 [4.0%]; fatigue: 5 [11.4%] vs. 1 [4.2%] and 1 [4.0%]). During the open-label extension study, 39 (76.5%) patients on BGG492 had AEs, and the most commonly experienced AEs were dizziness (14 [27.5%]) and somnolence (9 [17.6%]). Significance There was no significant dose-response trend in the BGG492 treatment groups (100 and 150 mg); however, higher percent reduction over placebo was observed in the BGG492 150 mg group. Safety and tolerability data were consistent with the known safety profile for BGG492, and no new safety risks were identified. [ABSTRACT FROM AUTHOR]

Objective Cardiorespiratory function alterations are commonly observed with epileptic seizures and may lead to syncope and sudden unexpected death in epilepsy ( SUDEP). Although most previous research has focused on controlling heart rate ( HR) and respiration, little is known about seizure-related regulation of systemic blood pressure ( BP). Herein, we have investigated whether the periictal modulation of systemic BP and HR depends on seizure characteristics. Methods Systemic arterial BP, HR, and peripheral capillary oxygen saturation ( SPO2) were continuously and noninvasively monitored using the ccNexfin device in those epilepsy patients undergoing video-electroencephalography ( EEG) telemetry. Data are given as mean ± standard deviation ( SD). Results Forty-five seizures in 37 patients were included. In focal seizures ( FS, n = 35), the mean arterial BP ( MAP) increased by 33 ± 35% and the HR by 53 ± 44%, whereas the SPO2 remained unaltered. The MAP and HR increases were significantly greater in FS with alterations in consciousness than in those without. For those FS that evolved to bilateral convulsive seizures ( BCS, n = 10), all of the ictal recordings were compromised by artifacts. However, 2 min after seizure cessation, the MAP was enhanced by only 16 ± 14% and returned to a baseline slightly below preictal levels after 5 min, whereas the HR was increased by 77 ± 33% and remained elevated throughout the postictal phase. Significance Periictal regulation of systemic BP and HR displays distinct patterns depending on the type of seizure with focal onset. These changes were unrelated to alterations in SPO2. The potential clinical implications of these findings are discussed in the article. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective Autoantibodies against glutamic acid decarboxylase ( GAD) and the voltage-gated potassium channel ( VGKC) complex are associated with distinct subtypes of limbic encephalitis regarding clinical presentation, response to therapy, and outcome. The aim of this study was to investigate white matter changes in these two limbic encephalitis subtypes by means of diffusion tensor imaging (DTI). Methods Diffusion data were obtained in 14 patients with GAD antibodies and 16 patients with VGKC-complex antibodies and compared with age- and gender-matched control groups. Voxelwise statistical analysis was carried out using tract-based spatial statistics. The results were furthermore compared with those of 15 patients with unilateral histologically confirmed hippocampal sclerosis and correlated with verbal and figural memory performance. Results We found widespread changes of fractional anisotropy and all diffusivity parameters in GAD-associated limbic encephalitis, whereas no changes were found in VGKC-complex-associated limbic encephalitis. The changes observed in the GAD group were even more extensive when compared against those of the hippocampal sclerosis group, although the disease duration was markedly shorter in patients with GAD antibodies. Correlation analysis revealed areas with a trend toward a negative correlation of diffusivity parameters with figural memory performance located mainly in the right temporal lobe in the GAD group as well. Significance The present study provides further evidence that, depending on the associated antibody, limbic encephalitis features clearly distinct imaging characteristics by showing widespread white matter changes in GAD-associated limbic encephalitis and preserved white matter integrity in VGKC-complex-associated limbic encephalitis. Furthermore, our results contribute to a better understanding of the specific pathophysiologic properties in these two subforms of limbic encephalitis by revealing that patients with GAD antibodies show widespread affections of white matter across various regions of the brain. In contrast to this, the inflammatory process seems to be more localized in VGKC-complex-associated limbic encephalitis, primarily affecting mesiotemporal gray matter. [ABSTRACT FROM AUTHOR]

Background Epilepsia partialis continua ( EPC) is defined as continuous myoclonic jerking of a body part of cortical origin and often resembles a movement disorder. Unfortunately, anti-epileptic therapy is frequently ineffective. Currently, the effect of botulinum neurotoxin (Bo NT) therapy in EPC is controversial. Methods We analyzed case histories, treatment protocols, and video documentation of 5 patients with EPC, who received Bo NT therapy in our movement disorders unit. The Unified Myoclonus Rating Scale was used to document treatment effects. Results In all patients, Bo NT treatment significantly reduced severity and frequency of myoclonus and led to pronounced improvement of speech and arm utilization, regardless of etiology or duration of EPC. Conclusion Bo NT represents a safe, effective treatment in EPC, offering long-term abatement of myoclonus. The substantial functional profit may hint at mechanisms beyond local impairment of neuromuscular transmission, such as modulation of maladaptive cortical plasticity, as observed in dystonia and poststroke spasticity. [ABSTRACT FROM AUTHOR]

Objective Antibody-associated limbic encephalitis ( LE) is an increasingly recognized cause of mostly adult-onset temporal lobe epilepsy. Magnetic resonance imaging ( MRI) typically shows volume and signal changes of the mesiotemporal structures. However, recent studies indicate that imaging characteristics depend on the type of the associated antibody. The aim of the present study was to investigate early and chronic gray matter ( GM) volume changes in LE by means of voxel-based morphometry ( VBM). Methods Optimized VBM analysis was applied to altogether 73 MRI volumes of 55 patients with antibody-associated LE. Based on the time point of MRI acquisition, patients were split into two separate groups to enable the evaluation of early (≤2 years after LE onset) and chronic (>2 years after LE onset) GM volume changes. In addition, separate analyses for the two most common LE subtypes in our study cohort, that is, glutamic acid decarboxylase ( GAD)-associated LE and voltage-gated potassium channel ( VGKC)-complex-associated LE were performed. Age- and gender-matched healthy subjects served as controls. Results Referring to the entire LE group, VBM revealed bi-amygdalar GM volume increase in the early disease stage. In the chronic disease stage, amygdala enlargement had resolved and we found GM volume reduction in the right cerebellar hemisphere. In the subgroup analysis, VBM showed corresponding bi-amygdalar GM volume increase in VGKC-complex-associated LE on early MRI, whereas no changes were found in GAD-associated LE. In the chronic disease stage, VBM revealed left frontal GM volume increase in VGKC-complex-associated LE and right frontoparietal GM volume reduction in GAD-associated LE. Significance The present study provides further evidence of a predominant affection of the amygdala in the early disease stage of LE, which resolves during the later course of the disease. Furthermore, our results show that LE features distinct imaging characteristics depending on the associated antibody and thus may contribute to a better pathophysiologic understanding of this disease. [ABSTRACT FROM AUTHOR]

Objective: Chronic inflammatory processes are important promotors of temporal lobe epilepsy (TLE) development. Based on human herpesvirus 6 (HHV-6)DNAdetection 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. 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. [ABSTRACT FROM AUTHOR]

Auditory stimulation with monaural or binaural auditory beats (i.e. sine waves with nearby frequencies presented either to both ears or to each ear separately) represents a non-invasive approach to influence electrical brain activity. It is still unclear exactly which brain sites are affected by beat stimulation. In particular, an impact of beat stimulation on mediotemporal brain areas could possibly provide new options for memory enhancement or seizure control. Therefore, we examined how electroencephalography ( EEG) power and phase synchronization are modulated by auditory stimulation with beat frequencies corresponding to dominant EEG rhythms based on intracranial recordings in presurgical epilepsy patients. Monaural and binaural beat stimuli with beat frequencies of 5, 10, 40 and 80 Hz and non-superposed control signals were administered with low amplitudes (60 dB SPL) and for short durations (5 s). EEG power was intracranially recorded from mediotemporal, temporo-basal and temporo-lateral and surface sites. Evoked and total EEG power and phase synchronization during beat vs. control stimulation were compared by the use of Bonferroni-corrected non-parametric label-permutation tests. We found that power and phase synchronization were significantly modulated by beat stimulation not only at temporo-basal, temporo-lateral and surface sites, but also at mediotemporal sites. Generally, more significant decreases than increases were observed. The most prominent power increases were seen after stimulation with monaural 40-Hz beats. The most pronounced power and synchronization decreases resulted from stimulation with monaural 5-Hz and binaural 80-Hz beats. Our results suggest that beat stimulation offers a non-invasive approach for the modulation of intracranial EEG characteristics. [ABSTRACT FROM AUTHOR]

In the recent past, various intrinsic connectivity networks (ICN) have been identified in the resting brain. It has been hypothesized that the fronto-parietal ICN is involved in attentional processes. Evidence for this claim stems from task-related activation studies that show a joint activation of the implicated brain regions during tasks that require sustained attention. In this study, we used functional magnetic resonance imaging (fMRI) to demonstrate that functional connectivity within the fronto-parietal network at rest directly relates to attention. We applied graph theory to functional connectivity data from multiple regions of interest and tested for associations with behavioral measures of attention as provided by the attentional network test (ANT), which we acquired in a separate session outside the MRI environment. We found robust statistical associations with centrality measures of global and local connectivity of nodes within the network with the alerting and executive control subfunctions of attention. The results provide further evidence for the functional significance of ICN and the hypothesized role of the fronto-parietal attention network. Hum Brain Mapp 35:1700-1709, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT Studies on hippocampal cell loss in epilepsy have produced diverging evidence as to which subfields are specifically related to memory. This may be due to rather small and often heterogeneous samples, or to different memory measures. Therefore, the current study examined hippocampal cell densities and memory in a large sample of patients with solely mesial temporal lobe epilepsy (mTLE), employing measures with proven sensitivity to mesiotemporal pathology. In 104 patients who had undergone epilepsy surgery for mTLE, we evaluated the role of segmental hippocampal cell loss and its underlying factor structure with regard to presurgical verbal and figural memory while controlling for side-of-surgery and hemispheric dominance. First of all, patients showed material-specific memory impairment concordant with the lateralization of epilepsy. Factor analysis of segmental cell loss revealed a single factor reflecting the overall integrity of the hippocampus. The overall pathological status of the left hippocampus correlated with verbal memory parameters ( r = 0.33-0.34, P < 0.05), especially when controlling for atypical hemispheric dominance ( r = 0.50-0.57, P < 0.01), and explained up to 33% of the observed variance. Further analyses revealed no superior role of a single subfield or cell loss pattern for memory performance. No systematic relations between neuronal cell densities of the right hippocampus and memory function were found, nor did left or right hippocampal pathology explain figural memory parameters. The results suggest that the overall pathological status of the left hippocampus - rather than a specific subfield pathology - is predictive for verbal memory in mTLE. The finding that figural memory parameters, although sensitive to right mTLE, were not related to neuronal cell densities of the right hippocampus, puts the left/right hippocampus verbal/nonverbal memory dichotomy into perspective. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24 h apart. The International League Against Epilepsy ( ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria. The task force proposed that epilepsy be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or who have remained seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years. 'Resolved' is not necessarily identical to the conventional view of 'remission or 'cure.' Different practical definitions may be formed and used for various specific purposes. This revised definition of epilepsy brings the term in concordance with common use. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . [ABSTRACT FROM AUTHOR]

Purpose Magnetic resonance imaging ( MRI) is a key technology in the presurgical evaluation of patients with epilepsy. Already at early outpatient stages it can contribute to the identification of patients who are, in the case of pharmacoresistance, good candidates for epilepsy surgery. Yet, 'standard head' MRI examinations often fail to displaying therapeutically relevant epileptogenic lesions. The purpose of this study is to identify an epilepsy-specific MRI protocol, which is likewise sensitive for even small epileptogenic lesions and economical enough to be applied outside specialized epilepsy centers. Methods Based on a large European presurgical epilepsy program comprising 2,740 patients we identified the spectrum of common epileptogenic lesions and determine the set of MRI sequences that are required for their reliable detection. Relying on a series of small, therapeutically particularly relevant lesions we determined the required slices thickness, slice angulations, and orientations for an epilepsy-specific MRI protocol. Key Findings Indispensable for early outpatient epilepsy specific MRI are fluid attenuated inversion recovery ( FLAIR), T2-weighted, T1-weighted, and hemosiderin/calcification-sensitive sequences. Slice thickness for T2 and FLAIR must not exceed 3 mm. The T1 image should be acquired in three-dimensional technique at 1 mm isotropic voxels size. For T2 and FLAIR, at least two slice orientations each must be demanded in hippocampal angulation. We suggest no adaption to a clinical focus hypothesis. The resulting 'essential 6' sequence protocol allows the detection of virtually all common epileptogenic lesion entities. Significance The creation of a broadly accepted and abundantly applied MRI protocol for epilepsy outpatients can contribute to improved and earlier identification of potential candidates for epilepsy surgery. Our systematic analysis of MRI requirements for the detection of epileptogenic lesions can serve as basis for protocol negotiations between epileptologists, radiologists, and health care funders. [ABSTRACT FROM AUTHOR]

Purpose Limbic encephalitis is an autoimmune-mediated disease leading to temporal lobe epilepsy, mnestic deficits, and affective disturbances. Magnetic resonance imaging ( MRI) usually shows signal and volume changes of the temporomesial structures. However, these abnormalities may be subtle, thereby hampering the diagnosis by conventional visual assessment. In the present study we evaluated the diagnostic value of a fully automated MRI postprocessing technique in limbic encephalitis and hippocampal sclerosis. Methods The MRI postprocessing was based largely on a recently described method allowing for an observer-independent quantification of the fluid-attenuated inversion recovery ( FLAIR) signal intensities of amygdala and hippocampus. A 95% confidence region was calculated from the FLAIR intensities of 100 healthy controls. We applied this analysis to the MRI data of 39 patients with antibody-associated limbic encephalitis and 63 patients with hippocampal sclerosis. Moreover, the results were compared to those of visual assessment by an experienced neuroradiologist. Key Findings The method detected limbic encephalitis and hippocampal sclerosis with a high sensitivity of 85% and 95%, respectively. The detection rate of the automated approach in limbic encephalitis was significantly superior to visual analysis (85% vs. 51%; p = 0.001), whereas no statistically significant difference for the detection rate in hippocampal sclerosis was found. Patients with limbic encephalitis had significantly higher absolute intensity values of the amygdala and a significantly higher percentage fell outside of the amygdalar confidence region compared to those with hippocampal sclerosis (79% vs. 27%; p < 0.001), whereas we found opposite results in the hippocampal analysis (38% vs. 95%; p < 0.001). Significance The FLAIR analysis applied in this study is a powerful tool to quantify signal changes of the amygdala and hippocampus in limbic encephalitis and hippocampal sclerosis. It significantly increases the diagnostic sensitivity in limbic encephalitis in comparison to conventional visual analysis. Furthermore, the method provides an interesting insight into the distinct properties of these two disease entities on MRI, indicating a predominant affection of the amygdala in limbic encephalitis, whereas the affection of the hippocampus is far less pronounced when compared to hippocampal sclerosis. [ABSTRACT FROM AUTHOR]

Purpose Precise outcome data about the surgical therapy of cerebral cavernous malformation (CCM)-associated epilepsy is scarce regarding different epilepsy types, surgical approach, and outcome. Long-term outcome in patients with CCM-associated epilepsy is analyzed in a large single-center series. Methods Seizure outcome data >24 months was available in 118 patients. The influence of different parameters of preoperative workup and surgical technique was analyzed with regard to seizure outcome. Key Findings The study cohort comprised 76 patients with drug-resistant epilepsy (DRE), 20 patients with chronic epilepsy that did not meet the definition of DRE, as well as 22 patients with sporadic seizures. Temporal localization of CCMs predisposed to develop DRE. Detailed epileptologic workup was performed in 85 patients; invasive monitoring was done in 23 (37%) of 76 DRE cases. In 84% of DRE cases more extensive resections were performed. Mean follow-up varied between 107 and 137 months for the three groups. Seizure freedom in DRE was 88%, in chronic epilepsy 80%, and in sporadic seizures was 91%. Longer symptom duration was associated with worse seizure outcome. Outcome of patients who underwent invasive monitoring was not worse. The outcome in CCM-associated DRE can be good if more extensive resections are used and if noninvasive and/or invasive presurgical epileptologic workup is used whenever indicated. DRE was considerably more frequent in the temporal lobe, suggesting that temporal localization predisposes development of DRE. Seizure freedom rates were stable over a long period. Significance Surgical therapy of CCM-associated seizures and epilepsy can be successful if different surgical techniques according to presurgical evaluation are realized. To prevent clinical worsening into DRE, surgical intervention in CCM-associated epilepsy may be considered early. [ABSTRACT FROM AUTHOR]

Several studies reported changes in white matter architecture following temporal lobe surgery in patients with temporal lobe epilepsy ( TLE) at short intervals after surgery. We investigated 20 patients with left-sided TLE using diffusion-imaging at two time points, that is, at 3-6 months and 12 months after surgery, to investigate postsurgical plasticity. We observed a loss of fiber tract integrity mainly in fiber tracts of the ipsilateral temporal lobe. Our data show that the remodeling of brain connectivity after surgical interventions continues for longer time periods. The functional implications of these plastic changes will have to be explored. [ABSTRACT FROM AUTHOR]

Purpose: Rasmussen encephalitis (RE) leads to progressive tissue and function loss of one brain hemisphere and often intractable epilepsy. This is the first randomized prospective treatment trial in RE. Methods: Germany-wide, patients with suspected recent-onset RE were recruited and if eligible randomized to tacrolimus or intravenous immunoglobulins (IVIGs). A loss of motor function or hemispheric volume by ≥15% (in patients >12 years at disease onset: ≥8%) led to study exit. Untreated patients served as a historical control group. Key Findings: Over 6.3 years, 21 patients with recent-onset RE were identified. Sixteen were randomized to tacrolimus (n = 9) or IVIG (n = 7). Immunotreated patients had a longer 'survival' than the historical controls. Neither treatment was more efficacious than the other. Two tacrolimus patients experienced serious adverse events. No immunotreated but several untreated patients developed intractable epilepsy. No patient with refractory epilepsy became treatment-responsive under immunotherapy. Significance: The countrywide incidence rate of diagnosed RE is estimated as 2.4 cases/107 people ≤ age 18/year. Treatment with tacrolimus or IVIG may slow down tissue and function loss and prevent development of intractable epilepsy. However, immunotherapy may 'arrest' patients in a dilemma state of pharmacoresistant epilepsy but too good function to be offered functional hemispherectomy. These compounds may therefore contribute to the therapeutic armamentarium for RE patients without difficult-to-treat epilepsies. [ABSTRACT FROM AUTHOR]

Purpose: Levetiracetam (LEV) is a highly effective antiepileptic agent. A clinically relevant psychiatric complication of LEV treatment, however, is the provocation of irritability and aggression. Recent behavioral research indicates that personality traits may predispose to these side effects. To assess the genetic basis of the adverse psychotropic profile of LEV, a candidate gene-based two-stage association study was conducted. Methods: Polymorphisms were a priori selected according to their relevance for impulsivity and reactive-impulsive aggression. Based on data from both stages, a Bonferroni-corrected joint meta-analysis was computed. Key Findings: Stage 1 analysis included 290 patients with epilepsy and revealed a higher load of adverse psychotropic side effects of LEV in patients carrying genetic variants associated with decreased dopaminergic activity: rs1611115 (dopamine-β-hydroxylase, DBH), rs4680 (catechol- O-methyltransferase, COMT), and rs1800497 (dopamine receptor D2-associated ANKK1 TAQ-1A). Stage II analysis including 100 patients with epilepsy, and joint meta-analysis confirmed the effect of the rs1800497 polymorphism (Bonferroni corrected significance of the joint meta-analysis, p = 0.0096). Significance: Confirming the suggestion from behavioral observations that patients might be predisposed to develop irritation and aggression under treatment with LEV, the findings provide first evidence of an association of genetic variation in dopaminergic activity and the risk for psychiatric complications of LEV treatment. Replication and further work is required to prove a true causal relationship. Overall, the pharmacogenomic approach to behavioral side effects may provide a future tool to predict adverse psychotropic effects related to antiepileptic drugs. [ABSTRACT FROM AUTHOR]

Purpose: In patients with pharmacoresistant focal-onset seizures, invasive presurgical workup can identify epilepsy surgery options when noninvasive workup has failed. Yet, the potential benefit must be balanced with procedure-related risks. This study examines risks associated with the implantation of subdural strip and grid, and intracerebral depth electrodes. Benefit of invasive monitoring is measured by seizure outcomes. Diagnostic procedures made possible by electrode implantation are described. Methods: Retrospective evaluation of invasive workups in 242 epilepsy surgery candidates and additional 18 patients with primary brain tumors implanted for mapping only. Complications are scaled in five grades of severity. A regression analysis identifies risk factors for complications. Outcome is classified according to Engel's classification. Key Findings: Complications of any type were documented in 23% of patients, and complications requiring surgical revision in 9%. We did not find permanent morbidity or mortality. Major risk factor for complications was the implantation of grids and the implantation of electrode assemblies comprising strip and grid electrodes. Depth electrodes were significantly correlated with a lower risk. Tumors were not correlated with higher complication rates. Chronic invasive monitoring of 3-40 days allowed seizure detection in 99.2% of patients with epilepsy and additional extensive mapping procedures. Patients with epilepsy with follow-up >24 months (n = 165) had an Engel class 1a outcome in 49.7% if epilepsy surgery was performed, but only 6.3% when surgery was rejected. Significance: The benefit of chronic invasive workup outweighs its risks, but complexity of implantations should be kept to a minimum. [ABSTRACT FROM AUTHOR]

Summary Purpose: Rasmussen encephalitis is a chronic immune-mediated disease leading to unilateral atrophy on magnetic resonance imaging (MRI) and progressive neurologic deficits. Until now, quantitative parameters describing the course of the disease on MRI require manual intervention and are, therefore, time-consuming and observer-dependent. Furthermore, regional atrophy differences cannot be evaluated with the previously published methods. In this study we present a fully automated volumetric approach applied to serial MRI scans of 12 patients with Rasmussen encephalitis. Methods: We retrospectively analyzed 12 patients with Rasmussen encephalitis with a disease onset between 2001 and 2008. All patients underwent a total of 66 serial MRI scans including a three-dimensional T1 data set. The volumetric analysis was based on standard procedures of the freely available software FMRIB Software Library (FSL) and required about 45 min per scan. Furthermore, planimetric analyses were performed on 51 scans as described previously. Key Findings: The relative and absolute volume loss of the affected hemisphere was significantly higher compared to the unaffected hemisphere. Referring to regional atrophy differences our results show that the frontal lobe and the insula were preferentially involved in the atrophic process. The degree of hemispheric, parietal, and occipital atrophy was negatively correlated with the age at disease onset, indicating a more aggressive and outspread disease in young children compared to adolescents. Volumetric hemispheric ratio and planimetric hemispheric ratio correlated significantly, but planimetric hemispheric ratio underestimated the real degree of hemiatrophy, especially in patients with predominant affections outside the frontoinsular region. Significance: The volumetric analysis presented here offers a precise assessment of the disease progression in Rasmussen encephalitis in an observer-independent and time-efficient manner and gives an interesting insight into the course of the disease on MRI. The degree of atrophy evaluated with this method correlates with clinical parameters and is comparable to atrophy rates in patients receiving immunotherapy in preceding planimetric MRI studies. [ABSTRACT FROM AUTHOR]

Summary Purpose: Intracerebral vascular malformations including cavernous angiomas (CAs) and arteriovenous malformations (AVMs) are an important cause of chronic pharmacoresistant epilepsies. Little is known about the pathogenetic basis of epilepsy in patients with vascular malformations. Intracerebral deposits of iron-containing blood products have been generally regarded as responsible for the strong epileptogenic potential of CAs. Here, we have analyzed whether blood-brain barrier (BBB) dysfunction and subsequent astrocytic albumin uptake, recently described as critical trigger of focal epilepsy, represent pathogenetic factors in vascular lesion-associated epileptogenesis. Methods: We examined the correlation between hemosiderin deposits, albumin accumulation, and several clinical characteristics in a series of 80 drug-refractory epilepsy patients with CAs or AVMs who underwent surgical resection. Analysis of clinical parameters included gender, age of seizure onset, epilepsy frequency, duration of epilepsy before surgery, and postoperative seizure outcome classification according to Engel class scale. Hemosiderin deposits in the adjacent brain tissue of the vascular lesion were semiquantitatively analyzed. Fluorescent double-immunohistochemistry using GFAP/albumin costaining was performed to study albumin extravasation. Key Findings: Our results suggest that a shorter duration of preoperative epilepsy is correlated with significantly better postsurgical outcome (p < 0.05), whereas no additional clinical or neuropathologic parameter correlated significantly with the postsurgical seizure situation. Intriguingly, we observed strong albumin immunoreactivity within the vascular lesion and in perilesional astrocytes (57.65 ± 4.05%), but not in different control groups. Significance: Our present data on albumin uptake in brain tissue adjacent to AVMs and CAs suggests BBB dysfunction and accumulation of albumin within astrocytes as a new pathologic feature potentially associated with the epileptogenic mechanism for vascular lesions and provides novel therapy perspectives for antiepileptogenesis in affected patients. [ABSTRACT FROM AUTHOR]

Abstract: An fMRI study was conducted with unfamiliar and familiar (strong and weak) brands to assess linguistic encoding and retrieval processes, and the use of declarative and experiential information, in brand evaluations. As expected, activations in brain areas associated with linguistic encoding were higher for unfamiliar brands, but activations in brain areas associated with information retrieval were higher for strong brands. Interestingly, weak brands were engaged simultaneously in both processes. Most importantly, activations of the pallidum, associated with positive emotions, for strong brands and activations of the insula, associated with negative emotions, for weak and unfamiliar brands suggested that consumers use experienced emotions rather than declarative information to evaluate brands. As a result, brand experiences should be considered a key driver of brand equity in addition to brand awareness and cognitive associations. [Copyright &y& Elsevier]

Summary Purpose: In patients with drug-refractory focal epilepsy, nonlesional magnetic resonance imaging (MRI) or discordant data of presurgical standard investigations leads to failure generating a sufficient hypothesis for electrode implantation or epilepsy surgery. The seizure-onset zone can be further investigated by subtraction ictal single-photon emission computed tomography (SPECT) coregistered to MRI (SISCOM). This is an observational study of a large consecutive cohort of patients undergoing prospective SISCOM to generate hypothesis for electrode implantation or site of epilepsy surgery. Methods: One hundred seventy-five consecutive patients undergoing presurgical evaluation with either nonlesional MRI or discordant data of standard investigations preventing the generation of hypothesis for seizure onset were evaluated with SISCOM. Results were compared to gold standard for seizure onset detection, either electrocorticography (ECoG) and/or postoperative outcome. Key Findings: One hundred thirty patients had successful SPECT injection. Hypothesis for electrode implantation/site of surgery was generated in 74 patients. Forty patients had gold standard comparison. Twenty-eight patients underwent resective surgery. SISCOM was concordant to site of surgery in 82%. An additional 12 patients underwent invasive EEG monitoring but were not suitable for surgery. SISCOM was concordant multifocal in 75%. Two years postsurgical follow-up of 26 patients showed favorable outcome in 22 (Engel class I and class II). Significance: SISCOM is a highly valuable diagnostic tool to localize the seizure-onset zone in nonlesional and extratemporal epilepsies. Outcome in this patient group was unexpectedly good, even in patients with nonlesional MRI. The high correlation with ECoG and site of successful surgery is a strong indicator that outcome prediction in this patient group should be adapted accordingly, which may encourage more patients to undergo electrode implantation and subsequent successful surgery. Statistical analysis showed that SISCOM with shorter duration of seizures, focal seizures, and lesional MRI was more likely to generate implantation hypothesis. [ABSTRACT FROM AUTHOR]

Summary Purpose: Focal cortical dysplasia type IIb (FCD IIb) lesions are highly epileptogenic and frequently cause pharmacoresistant epilepsy. Complete surgical resection leads to seizure freedom in most cases. However, the term 'complete' resection is controversial with regard to the necessity of performing resections of the subcortical zone, which is frequently seen in these lesions on magnetic resonance imaging (MRI). Methods: We retrospectively analyzed 50 epilepsy patients with histologically proven FCD IIb. The extent of surgical resection was determined by SPM5-based coregistration of the preoperative and postoperative MRI scans. Postoperative outcome was analyzed with regard to (1) the completeness of the resection of the cortical abnormality and (2) the completeness of the resection of the subcortical abnormality. Key Findings: Complete resection of the cortical abnormality led to postoperative seizure freedom (Engel class Ia) in 34 of 37 patients (92%), whereas incomplete cortical resection achieved this in only one of 13 patients (8%, p < 0.001). Among the patients with complete cortical resection, 36 had FCDs with a subcortical hyperintensity according to MRI. In this group, complete resection of the subcortical abnormality did not result in a better postoperative outcome than incomplete resection (90% vs. 93% for Engel class Ia, n.s.). Significance: Complete resection of the MRI-documented cortical abnormality in FCD IIb is crucial for a favorable postoperative outcome. However, resection of the subcortical hyperintense zone is not essential for seizure freedom. Therefore, sparing of the subcortical white matter may reduce the surgical risk of encroaching on relevant fiber tracts. In addition, these findings give an interesting insight into the epileptogenic propensity of different parts of these lesions. [ABSTRACT FROM AUTHOR]

The article offers information on a study conducted to analyze whether antiepilectic drugs (AEDs) have affect on serum levels of vitamin B12 and folate. The study included patients who suffered from epilepsy of the Department for Epileptology of the University Hospital Bonn in Germany. It mentions that the study conducted in Germany concluded that AEDS other than benzodiazepines and levetiracetam are associated with lower serum levels.

Deeper semantic processing of words leads to enhanced memory encoding (depth of processing effect). The left inferior prefrontal cortex (LIPC) and the left hippocampus are known to be involved in this effect. We tested the hypothesis that different semantic encoding processes contribute qualitatively differently to memory encoding. In a memory experiment using functional magnetic resonance imaging, we compared three different encoding tasks: a nonsemantic alphabetical, an animacy decision, and a size comparison tasks. Recognition memory was tested subsequently. We hypothesized that the size comparison task would activate brain areas involved in the processing of object features and that this would be associated with successful memory encoding. Results showed that the size comparison task led to significantly better memory encoding than the two other tasks. As with the animacy decision task, it led to stronger activation of the LIPC and left hippocampus than the nonsemantic task. Both regions also had stronger activations for later remembered than for nonremembered words. The size comparison task additionally led to stronger activation in the left anterior fusiform gyrus, which was also associated with successful memory encoding. We conclude that different types of semantic processing affect memory encoding based on distinguishable brain processes. Hum Brain Mapp, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Recent findings indicate that the hippocampus is not only crucial for long-term memory (LTM) encoding, but plays a role for working memory (WM) as well. In particular, it has been shown that the hippocampus is important for WM maintenance of multiple items or associations between item features. Previous studies using intracranial electroencephalography recordings from the hippocampus of patients with epilepsy revealed slow positive potentials during maintenance of a single item and during LTM encoding, but slow negative potentials during maintenance of multiple items. These findings predict that WM maintenance of multiple items interferes with LTM encoding, because these two processes are associated with slow potentials of opposing polarities in the hippocampus. Here, we tested this idea in a dual-task paradigm involving a LTM encoding task nested into a WM Sternberg task with either a low (one item) or a high (three items) memory load. In the high WM load condition, LTM encoding was significantly impoverished, and slow hippocampal potentials were more negative than in the low WM load condition. Time-frequency analysis revealed that a reduction of slow hippocampal activity in the delta frequency range supported LTM formation in the low load condition, but not during high WM load. Together, these findings indicate that multi-item WM and LTM encoding interfere within the hippocampus. [ABSTRACT FROM AUTHOR]

The presentation of rare target stimuli results in P300 scalp event-related potentials (ERPs). Generators of this ERP component were found in various brain areas, indicating that multiple cortical and subcortical areas subserve target detection. One of these structures is the mediotemporal lobe (MTL). In the hippocampus, large negative MTL-P300 potentials are usually observed, whereas reports concerning the rhinal cortex and subiculum are inconsistent. The aim of the present study was to investigate the topography of the mediotemporal P300. ERPs were recorded in epilepsy patients from multicontact depth electrodes, implanted along the longitudinal axis of MTL. Patients had to respond to rare visual target stimuli by a button press. ERP data from the nonfocal hemisphere of 53 patients were included in the analysis. Target detection resulted in large MTL-P300 potentials in the hippocampus and subiculum. Their latencies did not differ. The hippocampal P300 amplitude increased linearly from anterior to posterior hippocampal body (HB). In contrast, an inverse gradient with larger mean amplitudes in anterior parts was observed for the subiculum. Our results indicate two separate generators of the MTL-P300, one in the anterior subiculum and one in the posterior HB. Since latencies did not differ, a parallel activation via the entorhinal cortex might have initiated the simultaneous MTL-P300. Hippocampus and subiculum are essential parts of the MTL-memory system. Their function within target detection might be to maintain a template of previous stimuli for a comparison with incoming sensory stimuli. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The face inversion effect (FIE) refers to a disproportionate disruption of the processing of face information by inverting faces. We investigated the FIE in epilepsy patients by simultaneous intracranial and scalp recordings of event-related potentials (ERPs). In scalp recordings, a typical FIE on ERPs was observed with increased latencies and amplitudes of the positive counterpart of the occipito-temporal N170, namely, the vertex positive potential (VPP), in response to inverted faces. Similar amplitude and latency increases were revealed for the intracranial N200 recorded over face-sensitive and non-face-sensitive areas in the lateral occipital cortex, but not in the ventral temporal cortex. Peak latencies did not differ between the scalp VPP and intracranial N200. Findings indicate that the lateral occipital cortex but not the ventral temporal cortex contributes primarily to the FIE observed in scalp recordings. [ABSTRACT FROM AUTHOR]