Neuropathological Insights into Unexpected Cognitive Decline in Epilepsy.

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.

A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies.

Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P < 5 × 10-8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10-16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187-0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (>90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10-4, OR = 2.5, 95%CI = 1.499-4.157) and DRB1*04:01 allele (P = 8.3 × 10-5, OR = 2.4, 95%CI = 1.548-3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles.

Artificial intelligence for the detection of focal cortical dysplasia: Challenges in translating algorithms into clinical practice.

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.

Correction: Representation of abstract semantic knowledge in populations of human single neurons in the medial temporal lobe.

[This corrects the article DOI: 10.1371/journal.pbio.3000290.].

Family Burden and Epilepsy Surgery in Children with Drug-Resistant Epilepsy.

INTRODUCTION: Family burden (FB) in pediatric patients with drug-resistant epilepsy (DRE) is significantly higher than that in children with non-DRE. Epilepsy surgery is an established approach to treat DRE, and this study examines the impact of pediatric epilepsy surgery on FB. METHODS: We retrospectively analyzed data of families and pediatric patients with focal structural DRE treated with epilepsy surgery at our epilepsy center from April 2018 to November 2021. We examined the relationship between cognitive, behavioral, and epilepsy-specific data and the FB measured with the German version of the Impact on Family Scale before and after epilepsy surgery. RESULTS: The study cohort included 31 children with DRE at a mean age of 9 years at surgery (range = 0-16) and a mean epilepsy duration of 3 years (range = 0-14). Cognitive impairment correlated with FB in children with DRE prior to surgery. At the last assessment, 14.5 months (mean, range = 6-24) after epilepsy surgery, 87.2% of patients were seizure-free, FB values had decreased by 75.0%, and behavioral problems had decreased by 85,7%. Cognitive functions remained stable following epilepsy surgery. CONCLUSION: In children with DRE, epilepsy surgery reduces FB. Given the considerable impact of families on the development and wellbeing of their children, the impact of epilepsy surgery should be communicated to affected families.

Rasmussen encephalitis: Predisposing factors and their potential role in unilaterality.

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.

Representation of abstract semantic knowledge in populations of human single neurons in the medial temporal lobe.

Sensory experience elicits complex activity patterns throughout the neocortex. Projections from the neocortex converge onto the medial temporal lobe (MTL), in which distributed neocortical firing patterns are distilled into sparse representations. The precise nature of these neuronal representations is still unknown. Here, we show that population activity patterns in the MTL are governed by high levels of semantic abstraction. We recorded human single-unit activity in the MTL (4,917 units, 25 patients) while subjects viewed 100 images grouped into 10 semantic categories of 10 exemplars each. High levels of semantic abstraction were indicated by representational similarity analyses (RSAs) of patterns elicited by individual stimuli. Moreover, pattern classifiers trained to decode semantic categories generalised successfully to unseen exemplars, and classifiers trained to decode exemplar identity more often confused exemplars of the same versus different categories. Semantic abstraction and generalisation may thus be key to efficiently distill the essence of an experience into sparse representations in the human MTL. Although semantic abstraction is efficient and may facilitate generalisation of knowledge to novel situations, it comes at the cost of a loss of detail and may be central to the generation of false memories.

Shape description and volumetry of hippocampus and amygdala in temporal lobe epilepsy - A beneficial combination with a clinical perspective.

Shape-based markers have entered the field of morphometric neuroimaging analysis as a second mainstay alongside conventional volumetric approaches. We aimed to assess the added value of shape description for the analysis of lesional and autoimmune temporal lobe epilepsy (TLE) focusing on hippocampus and amygdala. We retrospectively investigated MRI and clinical data from 65 patients with lesional TLE (hippocampal sclerosis (HS) and astrogliosis) and from 62 patients with limbic encephalitis (LE) with serologically proven autoantibodies. Surface reconstruction and volumetric segmentation were performed with FreeSurfer. For the shape analysis, we used BrainPrint, a tool that utilizes eigenvalues of the Laplace-Beltrami operator on triangular meshes to calculate intra-subject asymmetry. Psychometric tests of memory performance were ascertained, to evaluate clinical relevance of the shape descriptor. The potential benefit of shape in addition to volumetric information for classification was assessed by five-fold repeated cross validation and logistic regression. For the LE group, the best performing classification model consisted of a combination of volume and shape asymmetry (mean AUC = 0.728), the logistic regression model was significantly improved considering both modalities instead of just volume asymmetry. For lesional TLE, the best model only considered volumetric information (mean AUC = 0.867). Shape asymmetry of the hippocampus was largely associated with verbal memory performance only in LE patients (OR = 1.07, p = 0.02). For lesional TLE, shape description is robust, but redundant when compared to volumetric approaches. For LE, in contrast, shape asymmetry as a complementary modality significantly improves the detection of subtle morphometric changes and is further associated with memory performance, which underscores the clinical relevance of shape asymmetry as a novel imaging biomarker.

Drebrin Autoantibodies in Patients with Seizures and Suspected Encephalitis.

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.

Predictors of focal to bilateral tonic-clonic seizures during long-term video-EEG monitoring.

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.

Does the accumulated antiepileptic drug load in chronic epilepsy reflect disease severity?

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.

Structural network topology in limbic encephalitis is associated with amygdala enlargement, memory performance and serostatus.

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.

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

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 CD14low CD16+ cells in the PB and blood/CSF-barrier dysfunction. Whereas TLE patients in general showed similar immune cell profiles, patients with GAD65-LE differed from other TLE patients by increased proportions of HLA-DR-expressing CD8+ T lymphocytes and type 2/3 oligoclonal bands. These findings point to a role of innate and adaptive immunity in TLE. CSF parameters may help to discriminate epilepsy patients from controls and different forms of TLE from each other.

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

PURPOSE: Flow cytometry helps to elucidate the cellular immune repertoire's mechanisms in patients with temporal lobe epilepsy (TLE) due to limbic encephalitis (LE) subcategories and carries potential significance for subtype-specific treatment. METHODS: We enrolled 62 patients with TLE due to LE associated with no autoantibodies (n = 40), neural autoantibodies (n = 22), as well as autoantibodies against intracellular antigens (n = 15/22). All patients underwent neuropsychological testing, brain magnetic resonance imaging (MRI), electroencephalography (EEG) recordings, and peripheral blood (PB) and cerebrospinal fluid (CSF) investigations including flow cytometry. RESULTS: CD19+ B-cells were increased in the PB and CSF of patients with antibody-negative LE compared with those associated with antibodies against intracellular antigens (Kruskal-Wallis one way analysis of variance (ANOVA) on ranks with Dunn's test, p < 0.05). There were no differences in CD138+ B-cells, CD4+ T-cells, human leukocyte antigen - DR isotype (HLA-DR+) CD4+ T-cells, CD8+ T-cells, and HLA-DR+ CD8+ T-cells in the CSF between groups with LE. The blood-brain barrier is more often impaired in patients with antibody-negative LE than in LE with antibodies against intracellular antigens (chi-square test, p < 0.05). In addition, we detected no correlations between immune cell subsets and clinical or paraclinical parameters in patients with antibody-negative and intracellular antibody-positive LE. CONCLUSIONS: The increase of CD19+ B-cells in the CSF and frequent signs of dysfunctional blood-brain barrier in patients with antibody-negative rather than intracellular antibody-positive LE suggest that CD19+ B-cells play a role in antibody-negative encephalitis although their pathogenic role in the central nervous system (CNS) immunity because of missing correlations between immune cells and clinical and paraclinical parameters remains unknown. Further studies are required to evaluate the usefulness of these B-cells as a biomarker for the stratification of treatment strategies.

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

PURPOSE: Investigating immune cells in autoimmune limbic encephalitis (LE) will contribute to our understanding of its pathophysiology and may help to develop appropriate therapies. The aim of the present study was to analyze immune cells to reveal underlying immune signatures in patients with temporal lobe epilepsy (TLE) with LE. METHODS: We investigated 68 patients with TLE with LE compared with 7 control patients with TLE with no signs of LE screened from 154 patients with suspected LE. From the patients with TLE-LE, we differentiated early seizure onset (<20 years, n = 9) and late seizure onset group (≥20 years, n = 59) of patients. Patients underwent neuropsychological assessment, electroencephalography (EEG), brain magnetic resonance imaging (MRI), and peripheral blood (PB) and cerebrospinal fluid (CSF) analysis including flow cytometry. RESULTS: We identified a higher CD4/8+ T-cell ratio in the PB in all patients with TLE-LE and in patients with late-onset TLE-LE each compared with controls (Kruskal-Wallis one-way ANOVA (analysis of variance) with Dunn's test, p < 0.05). Moreover, a lower CD4/CD8+ T-cell ratio is detected in all patients with TLE-LE with blood-CSF barrier dysfunction, unlike in those with none (Kruskal-Wallis one-way ANOVA with Dunn's test, p < 0.05). CONCLUSIONS: These findings suggest that the proportion of CD4+ and CD8+ T-cells in the CSF of patients with LE associated with blood-CSF barrier dysfunction plays a potential role in CNS (central nervous system) inflammation in these patients. Thus, flow cytometry as a methodology reveals novel insights into LE's genesis and symptomatology. The CD4/8+ T-cell ratio in PB as a biomarker for LE requires further investigation.

Getting the best outcomes from epilepsy surgery.

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.

Morphometric MRI findings challenge the concept of the "unaffected" hemisphere in Rasmussen encephalitis.

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.

Blood markers of cardiac stress after generalized convulsive seizures.

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.

Evidence for peri-ictal blood-brain barrier dysfunction in patients with epilepsy.

Epilepsy has been associated with a dysfunction of the blood-brain barrier. While there is ample evidence that a dysfunction of the blood-brain barrier contributes to epileptogenesis, blood-brain barrier dysfunction as a consequence of single epileptic seizures has not been systematically investigated. We hypothesized that blood-brain barrier dysfunction is temporally and anatomically associated with epileptic seizures in patients and used a newly-established quantitative MRI protocol to test our hypothesis. Twenty-three patients with epilepsy undergoing inpatient monitoring as part of their presurgical evaluation were included in this study (10 females, mean age ± standard deviation: 28.78 ± 8.45). For each patient, we acquired quantitative T1 relaxation time maps (qT1) after both ictal and interictal injection of gadolinium-based contrast agent. The postictal enhancement of contrast agent was quantified by subtracting postictal qT1 from interictal qT1 and the resulting ΔqT1 was used as a surrogate imaging marker of peri-ictal blood-brain barrier dysfunction. Additionally, the serum concentrations of MMP9 and S100, both considered biomarkers of blood-brain barrier dysfunction, were assessed in serum samples obtained prior to and after the index seizure. Fifteen patients exhibited secondarily generalized tonic-clonic seizures and eight patients exhibited focal seizures at ictal injection of contrast agent. By comparing ΔqT1 of the generalized tonic-clonic seizures and focal seizures groups, the anatomical association between ictal epileptic activity and postictal enhancement of contrast agent could be probed. The generalized tonic-clonic seizures group showed significantly higher ΔqT1 in the whole brain as compared to the focal seizures group. Specific analysis of scans acquired later than 3 h after the onset of the seizure revealed higher ΔqT1 in the generalized tonic-clonic seizures group as compared to the focal seizures group, which was strictly lateralized to the hemisphere of seizure onset. Both MMP9 and S100 showed a significantly increased postictal concentration. The current study provides evidence for the occurrence of a blood-brain barrier dysfunction, which is temporally and anatomically associated with epileptic seizures. qT1 after ictal contrast agent injection is rendered as valuable imaging marker of seizure-associated blood-brain barrier dysfunction and may be measured hours after the seizure. The observation of the strong anatomical association of peri-ictal blood-brain barrier dysfunction may spark the development of new functional imaging modalities for the post hoc visualization of brain areas affected by the seizure.

Parents' view of the cognitive outcome one year after pediatric epilepsy surgery.

OBJECTIVES: The cognitive outcome of pediatric epilepsy surgery has mainly been examined on the basis of standardized tests. Here, we analyzed the outcome in six cognitive domains from the parents' view. METHODS: Included were consecutive surgical pediatric patients whose parents filled-in a comprehensive questionnaire on cognitive problems in children and adolescents (Kognitive Probleme bei Kindern und Jugendlichen (KOPKIJ); Gleissner et al. 2006) at the preoperative baseline (T1) as well as twelve months thereafter (T2). All children also underwent standard neuropsychological assessments at T1 and T2. RESULTS: Parents of 96 patients provided pre- and postoperative KOPKIJ data. Overall, 80% of the children became seizure-free at the follow-up. Group means indicated a strong positive effect of time on KOPKIJ and neuropsychological performance. We found postoperative improvements in five out of six cognitive domains (language, memory, executive functions, attention, school; unchanged: visuospatial abilities). Individually, improvements were twice as likely as declines. However, 33 patients (35%) experienced significant decline in at least one cognitive domain. Later onset of epilepsy resulted in better performance but had no effect on change scores. Seizure-free status, lower antiseizure drug load, and stronger drug reduction after surgery contributed to postoperative cognitive improvements as perceived by the parents; no other effects of clinical factors were obtained (e.g., localization/lateralization). Despite their similar outcome patterns, change scores as derived from parental ratings and neuropsychological assessment were not correlated. CONCLUSIONS: Parents acknowledged the overall positive neurocognitive development after pediatric epilepsy surgery as previously shown by standardized tests. Seizure freedom and lower antiseizure drug load contributed to the beneficial cognitive outcome. Even if cognitive improvements outweighed declines, a risk for cognitive decline with impact on everyday functioning does exist.