Functional connectivity of limbic system and prefrontal cortex years after pre-eclampsia: 7-Tesla functional magnetic resonance imaging study.

OBJECTIVE: Pre-eclampsia is a vascular complication of pregnancy, associated with a long-term risk of cerebrovascular and mental disorders. We explored whether formerly pre-eclamptic women exhibit differences in functional brain organization, especially in regions that may explain the commonly reported emotional symptoms and cognitive complaints even years after the pregnancy. METHODS: Formerly pre-eclamptic women and control women with a history of normotensive pregnancy underwent structural and functional 7-Tesla magnetic resonance imaging scans. Using graph theoretical analysis, the efficiency and clustering coefficient of the functional brain network were investigated. The study included local analysis focusing on particular brain structures, such as the limbic system and the prefrontal cortex, and global analysis of the whole cerebrum. Univariable and multivariable linear regression was used to investigate the relationship between brain network-related graph measures and the group (formerly pre-eclamptic or control). RESULTS: A total of 17 control parous women and 55 women with a history of pre-eclampsia were recruited. The time intervals between the index pregnancy and recruitment were 8.0 and 5.6 years for the two groups, respectively. Compared with control women, formerly pre-eclamptic women had higher local efficiency in the prefrontal cortex (P = 0.048) and anterior cingulate cortex (P = 0.03) but lower local efficiency and local clustering coefficient in the amygdala (P = 0.004 and P = 0.02, respectively) and parahippocampal cortex (P = 0.007 and P = 0.008, respectively). No differences were found in the global functional brain organization. CONCLUSIONS: Compared to controls with a history of normotensive pregnancy, formerly pre-eclamptic women displayed a different local functional brain organization. These differences in functional connectivity, especially in the limbic regions and the prefrontal cortex, are in line with the psychological and cognitive complaints reported commonly by women with a history of pre-eclampsia. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Blood-brain barrier leakage years after pre-eclampsia: dynamic contrast-enhanced 7-Tesla MRI study.

OBJECTIVE: Pre-eclampsia is a hypertensive complication of pregnancy that is associated with an increased risk of long-term cardiovascular and cerebrovascular disorders. Although the underlying mechanism of persistent susceptibility to cerebral complications after pre-eclampsia remains largely unclear, impaired blood-brain barrier (BBB) integrity has been suggested to precede several cerebrovascular diseases. In this study, we aimed to investigate the integrity of the BBB years after pre-eclampsia. METHODS: This was an observational study of premenopausal formerly pre-eclamptic women and controls with a history of normotensive pregnancy who underwent cerebral magnetic resonance imaging (MRI) at ultra-high field (7 Tesla) to assess the integrity of the BBB. Permeability of the BBB was determined by assessing leakage rate and fractional leakage volume of the contrast agent gadobutrol using dynamic contrast-enhanced MRI. BBB leakage measures were determined for the whole brain and lobar white and gray matter. Multivariable analyses were performed, and odds ratios were calculated to compare women with and those without a history of pre-eclampsia, adjusting for potential confounding effects of age, hypertension status at MRI and Fazekas score. RESULTS: Twenty-two formerly pre-eclamptic women (mean age, 37.8 ± 5.4 years) and 13 control women with a history of normotensive pregnancy (mean age, 40.8 ± 5.5 years) were included in the study. The time since the index pregnancy was 6.6 ± 3.2 years in the pre-eclamptic group and 9.0 ± 3.7 years in controls. The leakage rate and fractional leakage volume were significantly higher in formerly pre-eclamptic women than in controls in the global white (P = 0.001) and gray (P = 0.02) matter. Regionally, the frontal (P = 0.04) and parietal (P = 0.009) cortical gray matter, and the frontal (P = 0.001), temporal (P < 0.05) and occipital (P = 0.007) white matter showed higher leakage rates in formerly pre-eclamptic women. The odds of a high leakage rate after pre-eclampsia were generally higher in white-matter regions than in gray-matter regions. CONCLUSION: This observational study demonstrates global impairment of the BBB years after a pre-eclamptic pregnancy, which could be an early marker of long-term cerebrovascular disorders. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Cognition and quality of life in patients with poststroke epilepsy: A case-control study.

INTRODUCTION: Though seizures are a common complication after stroke, only little scientific evidence is available about the impact of epilepsy on cognitive functioning and quality of life in patients who have had a stroke. Therefore, we assessed these items in a case-control study. METHODS: We studied 36 patients with poststroke epilepsy (PSE) and 36 matched patients who have had a stroke without epilepsy using parts of the FePsy (the computerized visual searching task (CVST) for central information processing speed and a reaction time test), the mini-mental-state examination (MMSE), the EuroQol, the stroke-adapted Sickness Impact Profile questionnaire (SA-SIP-30), the Barthel index, the modified Rankin scale, and the National Institutes of Health stroke scale (NIHSS). RESULTS: Patients with PSE had significantly lower scores on the CVST and MMSE. Generic quality of life was the same in patients with poststroke epilepsy and patients with stroke only, however, the SA-SIP-30 showed a lower disease-specific quality of life in patients with poststroke epilepsy. The Barthel index showed no difference between both groups, but both the modified Rankin scale and the NIHSS were significantly higher in patients with poststroke epilepsy, indicating more disability and neurological impairment in patients with PSE. CONCLUSIONS: We found that PSE relates to impaired cognitive functioning, a lower disease-specific quality of life and more disability and neurological impairment. This underlines the importance of further clinical research in this field. This article is part of the Special Issue "Seizures & Stroke".

Medication use in poststroke epilepsy: A descriptive study on switching of antiepileptic drug treatment.

OBJECTIVE: Currently, as evidence-based guidelines are lacking, in patients with poststroke epilepsy (PSE), the choice of the first antiepileptic drug (AED) is left over to shared decision by the treating physician and patient. Although, it is not uncommon that patients with PSE subsequently switch their first prescribed AED to another AED, reasons for those switches are not reported yet. In the present study, we therefore assessed the reasons for switching the first prescribed AED in patients with PSE. METHOD: We gathered a hospital-based case series of 53 adult patients with poststroke epilepsy and assessed the use of AEDs, comedication, and the reasons for switches between AEDs during treatment. We also determined the daily drug dose (DDD) at the switching moment. RESULTS: During a median follow-up of 62 months (Interquartile range [IQR] 69 months), 21 patients (40%) switched their first prescribed AED. Seven patients switched AED at least once because of ineffectivity only or a combination of ineffectivity and side effects, whereas 14 patients switched AED at least once because of side effects only. The DDD was significantly (p < 0.001) higher in case of medication switches due to ineffectivity (median 1.20, IQR 0.33) compared to switching due to side effects (median 0.67, IQR 0.07). There was no difference in the use of comedication between the group that switched because of ineffectivity compared to the group that switched because of side effects. CONCLUSION: In our case series, up to 40% of patients with epilepsy after stroke needed to switch their first prescribed AED, mostly because of side effects in lower dosage ranges.

Classification of intellectual disability according to domains of adaptive functioning and between-domains discrepancy in adults with epilepsy.

BACKGROUND: In the Diagnostic and Statistical Manual of Mental Disorders-Fifth edition (DSM-5), the diagnostic criteria of intellectual disability (ID) include three domains of adaptive deficits: the conceptual, social and practical. Substantial intra-individual differences between domains can be considered an ID domain discrepancy. METHOD: We explored the associations between ID domains, discrepancies and epilepsy in 189 adults (mean age = 47.9; SD = 15.6). Each DSM-5 ID domain was assessed separately, using subscales of the Vineland II for the social and practical domains, and psychological instruments, including intelligence tests, for the conceptual domain. A set of standardised criteria is proposed to identify an ID domain discrepancy. RESULTS: An ID domain discrepancy seemed to be present in about one-third of subjects and was particularly present in subjects with moderate ID (53.4%). Impairment in the social domain was most often the reason for the discrepancy. The presence of a discrepancy was significantly related to a focal (localised) epilepsy type (OR = 2.3, P = .028) and a mixed seizure type (OR = 1.4, P = .009). Epilepsy characteristics that are indicative of a more severe and refractory epilepsy, including various seizure types, a high seizure frequency, a combined epilepsy type (both focal and generalised epilepsy) and an early age at onset, were significantly related to more severe impairments in conceptual, social and practical adaptive behaviour (all P values <.01). CONCLUSIONS: With a substantial proportion of the subjects who had both ID and epilepsy with an ID discrepancy, professionals should be aware of this and take all domains of ID into account when studying or working with this vulnerable population.

A randomized controlled trial of the ketogenic diet in refractory childhood epilepsy.

OBJECTIVE: To evaluate the efficacy and tolerability of the ketogenic diet (KD) during the first 4 months of a randomized controlled trial (RCT) in refractory epilepsy patients aged 1-18 years. METHODS: Children and adolescents with refractory epilepsy, not eligible for epilepsy surgery, were included. Following 1 month at baseline, patients were randomized to either the KD or to care as usual (CAU).Primary outcome is the proportion of patients with at least 50% reduction in seizure frequency at 4 months. Secondary outcomes are mean percentage of baseline seizures, seizure severity, and side effects. RESULTS: Fifty-seven patients were randomized; nine dropped out, leaving 48 for analysis (i.e., 26 KD, 22 CAU). In an intention-to-treat analysis, 13 patients (50%) treated with the KD and four patients (18.2%) of the CAU group were responders.Mean seizure frequency at 4 months compared to baseline, after removal of two outliers in the KD group, was significantly lower (P = 0.024) in the KD group (56%) (95% CI: 36-76) than in the CAU group (99%) (95% CI: 65-133%).Twice as many patients in the KD group had a relevant decrease in seizure severity score (P = 0.070).Patients treated with the KD had a significantly higher score for gastrointestinal symptoms (P = 0.021) without an increase in the total score of side effects. CONCLUSIONS: This trial provides class I evidence that the KD is an effective therapy in children and adolescents with refractory epilepsy compared with CAU. Most often reported side effects are gastrointestinal symptoms.The study has been registered with the Netherlands Trial Registry (NTR2498).

Cognitive deterioration in adult epilepsy: clinical characteristics of "Accelerated Cognitive Ageing".

OBJECTIVES: "Epileptic dementia" is reported in adults with childhood-onset refractory epilepsy. Cognitive deterioration can also occur in a "second-hit model". MATERIALS AND METHODS: We studied the clinical and neuropsychological characteristics of patients with cognitive deterioration (≥1 SD discrepancy between current IQ and premorbid IQ). Memory function, reaction time and processing speed were also evaluated. Analyses were performed to investigate which clinical characteristics correlated with cognitive deterioration. RESULTS: Twenty-seven patients were included with a mean age of 55.7 years old, an average age at epilepsy onset of 33.9 years and a mean duration of 21.8 years. Over 40% had experienced at least one status epilepticus. About 77.8% had at least one comorbid disease (most of (cardio)vascular origin). Cognitive deterioration scores were significant for both Performance IQ and Full Scale IQ, but not for Verbal IQ. Impairments in fluid functions primarily affected the IQ-scores. Memory was not impaired. Epilepsy factors explained 7% of the variance in deterioration, whereas 38% was explained by relatively low premorbid IQ and educational level, high age at seizure onset and older age. CONCLUSIONS: A subgroup of patients with localization-related epilepsy exhibits cognitive decline characterized by deterioration in PIQ and FSIQ, but with preserved higher order functions (VIQ and memory). Patients typically have epilepsia tarda, comorbid pathology, relatively low educational level and older age. These are factors known to increase the vulnerability of the brain by diminishing cognitive reserve. Cognitive deterioration may develop according to a stepwise "second-hit model", affecting and accelerating the cognitive ageing process.

Mental slowing in relation to epilepsy and antiepileptic medication.

OBJECTIVES: Slowing of the central information-processing speed (CIPS) is frequently observed in epilepsy as a consequence of epileptic seizures and/or antiepileptic drugs (AEDs). A variety of neuropsychological tests are used to asses this 'mental slowing,' but it is highly questionable whether the different tasks measure the same cognitive process. Also, it remains unspecified to which degree the various tasks are sensitive to seizure- or treatment-related factors, or both. METHODS: We used an open clinical non-comparative study design. The sample consisted of adult patients with cryptogenic localization-related epilepsy who performed different cognitive measures of CIPS and psychomotor speed (PmS). Clinical data about their seizures and antiepileptic drug treatment were collected from an electronic patient database. RESULTS: Eighty patients were included. CIPS tasks mutually correlated significantly, but did not correlate with measures of PmS (finger tapping and reaction time). Also, the CIPS tasks were differently affected by treatment and seizure effects. Processing of complex information is affected by tonic-clonic seizures, while less complex tasks are more sensitive for AED effects. CONCLUSIONS: CIPS tasks are mainly measuring central processing, and the psychomotor component of these tasks is negligible. We propose a psychometric continuum on which PmS and CIPS tasks are ordered with ascending complexity. The model shows that the tasks are affected differently by seizures, treatment, age, and education level. In neuropsychological practice, this continuum can be helpful in the detection of treatment and seizure effects on the CIPS in epilepsy.

Cognitive effects of lacosamide as adjunctive therapy in refractory epilepsy.

BACKGROUND: Lacosamide (LCM) is a novel antiepileptic drug (AED) with potential benefit as adjunctive treatment in patients with partial-onset seizures. As yet, limited information on cognitive effects of LCM is available, especially in real-life settings. AIMS: In this open clinical prospective study, the cognitive effects of LCM were evaluated when used as adjunctive antiepileptic therapy in patients with refractory epilepsy. METHODS: We included 33 patients aged between 16 and 74 years (mean: 37 years). All patients had a localization-related epilepsy. Patients were assessed at baseline before starting LCM treatment and during follow-up when the optimal clinical dose was achieved. MATERIALS: Subjective complaints were evaluated using the SIDAED; effects on cognition were evaluated using the computerized visual searching task (CVST). RESULTS: The CVST showed significant faster information processing reaction times at the second evaluation (P = 0.013), which was not correlated with seizure control, type of epilepsy, age, gender, drug load, number of concomitant drugs, dose or duration of LCM treatment. On the SIDAED, patients complained more about their cognitive function at the second evaluation (P = 0.005). For the SIDAED, a positive correlation at follow-up was found between the total severity score and higher age (r = 0.375, P = 0.031), but not with epilepsy factors or treatment characteristics. DISCUSSION/CONLUSION: Screening of the cognitive effects of LCM showed that LCM does not have negative effects on information processing speed. As this is the most sensitive function for cognitive side effects of AEDs, LCM does not seem to induce the common negative cognitive effects. Remarkably, patients complained more, especially about their cognitive function, which is possible the 'doing better, feeling worse phenomenon'.

Aetiology of cognitive impairment in children with frontal lobe epilepsy.

OBJECTIVES: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its aetiology is unknown. MRI scans often reveal no structural brain abnormalities that could explain the cognitive impairment. This does not exclude more subtle morphological abnormalities that can only be detected by automated morphometric techniques. AIMS: With these techniques, we investigate the relationship between cortical brain morphology and cognitive functioning in a cohort of children with FLE and healthy controls. MATERIALS AND METHODS: Thirty-four children aged 8-13 years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural brain MRI. Patients were grouped as cognitively impaired or unimpaired. Intracranial volume, white matter volume, lobular cortical volume, cortical thickness and volumes of cortex structures were compared between patients and controls, and potential correlations with cognitive status were determined. RESULTS: The group of cognitively impaired children with FLE had significantly smaller left temporal cortex volumes, specifically middle temporal grey matter volume and entorhinal cortex thickness. In addition, cognitively impaired children with FLE had smaller volumes of structures in the left and right frontal cortex, right temporal cortex and the left subcortical area. CONCLUSION: Cognitively impaired children with FLE have smaller volumes of various cortex structures within the frontal lobes and in extra-frontal regions, most notably temporal cortex volumes. These findings might well explain the broad scale of cognitive domains affected in children with FLE complicated by cognitive impairment and highlight that FLE impacts on areas beyond the frontal lobe.

Inter- and intraobserver agreement of seizure behavior scoring in the amygdala kindled rat.

INTRODUCTION: The Racine scale is a 5-point seizure behavior scoring paradigm used in the amygdala kindled rat. Though this scale has been applied widely in experimental epilepsy research, studies of reproducibility are rare. The aim of the current study was, therefore, to assess its interobserver variability and intraobserver variability. MATERIAL AND METHODS: A video database set was acquired in the course of amygdala kindling of 67 Wistar rats. Six blinded observers received scoring instructions and then viewed a set of 15 random videos (session #1). Next, each observer scored 379 to 1048 additional videos (session #2) and finally scored the same set of 15 videos again (session #3). Scores included the occurrence of seizures (yes or no), the total seizure time (start of stimulus until the absence of seizure behavior), and the highest Racine stage. Interobserver variability and intraobserver variability were assessed in and between sessions #1 and #3 using a 2-way mixed intraclass correlation or Cohen's kappa depending on the variable. RESULTS: Interobserver agreement in session #1 was 0.664 for seizure occurrence, 0.861 for total seizure time, and 0.797 for the highest Racine stage. In session #3, interobserver agreement on seizure occurrence declined to 0.492, total seizure time declined to 0.625, and agreement for the highest Racine stage was 0.725. Interobserver agreement was scored insufficiently on focal R2 seizures in both sessions (0.287 and 0.182). Intraobserver agreement reached >0.80 agreement for seizure occurrence, highest seizure score, and total seizure time in 3 out of 4 observers. Racine's scale stage 2 seizure scores were only 0.135 in one observer but 0.650, 0.810, and 0.635 in the other observers. DISCUSSION AND CONCLUSION: Overall, interobserver agreement and intraobserver agreement in scoring with Racine's scale were adequate. However, because interobserver agreement declined after a period of individually scoring videos, we suggest periodic repetition of the standardized instruction in the course of evaluating videos in order to ensure reproducible results.

Transition to adult medical care for adolescents with epilepsy.

INTRODUCTION: During transition to adult medical care, the adolescent with epilepsy is especially prone to emotional, mental, physical, and social developmental difficulties, leading to stigma and poor psychosocial and socioeconomic outcome in the long term. OBJECTIVES: The aim of this review is twofold: to describe the psychosocial and medical transition from adolescence to adulthood and to evaluate the most effective model for transitional services in adolescents with epilepsy. METHODS: We searched PubMed for quantitative and qualitative data about transition from adolescence to adulthood in patients with epilepsy. RESULTS: A total of 49 articles were retrieved. We reviewed personal, psychosocial, and medical issues during transition and their long-term individual and societal consequences. Identifying risk factors for poor transition can lead to appropriate interventions for patients and their family. Although the concept of multidisciplinary transition care for adolescents with epilepsy is widely recognized, only a few transition clinics have been established. There is lack of evidence for their quality and cost-effectiveness. CONCLUSION: In addition to medical problems, more attention should be paid to the risk of psychosocial problems during transition from pediatric to adult care. The implementation of transition care for adolescents with epilepsy is considered beneficial; however, its effectiveness should be further investigated.

Developing from child to adult: Risk factors for poor psychosocial outcome in adolescents and young adults with epilepsy.

INTRODUCTION: Childhood-onset epilepsy during the years of transition to adulthood may affect normal social, physical, and mental development, frequently leading to psychosocial and health-related problems in the long term. OBJECTIVE: This study aimed to describe the main characteristics of patients in transition and to identify risk factors for poor psychosocial outcome in adolescents and young adults with epilepsy. METHODS: Patients with epilepsy, 15-25years of age, who visited the Kempenhaeghe Epilepsy Transition Clinic from March 2012 to December 2014 were included (n=138). Predefined risk scores for medical, educational/occupational status, and independence/separation/identity were obtained, along with individual risk profile scores for poor psychosocial outcome. Multivariate linear regression analysis and discriminant analysis were used to identify variables associated with an increased risk of poor long-term psychosocial outcome. RESULTS: Demographic, epilepsy-related, and psychosocial variables associated with a high risk of poor long-term outcome were lower intelligence, higher seizure frequency, ongoing seizures, and an unsupportive and unstable family environment. Using the aforementioned factors in combination, we were able to correctly classify the majority (55.1%) of the patients regarding their risk of poor psychosocial outcome. CONCLUSION: Our analysis may allow early identification of patients at high risk of prevention, preferably at pretransition age. The combination of a chronic refractory epilepsy and an unstable family environment constitutes a higher risk of transition problems and poor outcome in adulthood. As a consequence, early interventions should be put into place to protect youth at risk of poor transition outcome.

Autism and behavior in adult patients with Dravet syndrome (DS).

INTRODUCTION: Autism and behavioral characteristics in adults with Dravet syndrome (DS) have rarely been systematically studied. METHOD: Three scales were used to assess the outcomes of DS in adulthood in terms of autism and behavior. All the adult patients with DS, nine male and four female, aged between 18 and 60 years, living at the Epilepsy Center Kempenhaeghe in The Netherlands were included in the study. In addition, the past medical history of each patient was systematically screened for diagnoses like autism, Pervasive Development Disorder-Not Otherwise Specified (PDD-NOS), autism spectrum disorder (ASD), hyperactivity, Attention Deficit Hyperactivity Disorder (ADHD), and self-mutilation. Information concerning past and current use of psychoactive drugs was also evaluated. RESULTS: Eight patients (61.5%) were classified as having autism spectrum disorder (ASD) according to the AVZ-R or according to the medical record. Self-mutilation was seen in four patients (30.8%), hyperactivity in none. Three patients (23.1%) currently used psychoactive drugs. CONCLUSION: Autism spectrum disorders persist in adult patients with DS, while certain characteristics associated with behavioral problems, such as hyperactivity or use of psychoactive medication, seem to be less prominent than in childhood.

Changes in the frequency of benign focal spikes accompany changes in central information processing speed: a prospective 2-year follow-up study.

We prospectively examined whether changes in the frequency of benign focal spikes accompany changes in cognition. Twenty-six children with benign focal spikes (19 with Rolandic epilepsy) and learning difficulties were examined with repeated 24-hour EEG recordings, three cognitive tests on central information processing speed (CIPS), and questionnaires on cognition and behavior at baseline, 6months, and 2years. Antiepileptic drug changes were allowed when estimated necessary by the treating physician. At baseline, a lower CIPS was correlated with a higher frequency of diurnal interictal epileptiform discharges (IEDs) and with worse academic achievement. At follow-up, there was a significant correlation between changes in CIPS and EEG changes in wakefulness (in the same direction) when the EEG outcome was dichotomized in IED frequency "increased" or "not increased". Behavioral problems were more often observed in patients with higher frequency of IEDs in sleep at baseline and in those with ongoing IEDs compared with those with EEG remission (without or with sporadic IEDs in the recording) at the end of the study period. No changes were observed in the results of the questionnaires. A lower diurnal IED frequency at baseline, lack of serial IEDs, and occurrence of only unilateral IEDs were correlated with a higher chance of EEG remission at 2-year follow-up. Electroencephalography remission could not be predicted from other epilepsy variables except from seizure freedom in the last six months. Our results confirm the nonbenign character of 'benign' focal spikes. Whether an early and stable EEG remission can be achieved through antiepileptic treatment and whether this is of benefit for cognitive development should be examined in prospective placebo-controlled randomized trials.

Neurophysiological correlates of dissociative symptoms.

OBJECTIVE: Dissociation is a mental process with psychological and somatoform manifestations, which is closely related to hypnotic suggestibility and essentially shows the ability to obtain distance from reality. An increased tendency to dissociate is a frequently reported characteristic of patients with functional neurological symptoms and syndromes (FNSS), which account for a substantial part of all neurological admissions. This review aims to investigate what heart rate variability (HRV), EEG and neuroimaging data (MRI) reveal about the nature of dissociation and related conditions. METHODS: Studies reporting HRV, EEG and neuroimaging data related to hypnosis, dissociation and FNSS were identified by searching the electronic databases Pubmed and ScienceDirect. RESULTS: The majority of the identified studies concerned the physiological characteristics of hypnosis; relatively few investigations on dissociation related FNSS were identified. General findings were increased parasympathetic functioning during hypnosis (as measured by HRV), and lower HRV in patients with FNSS. The large variety of EEG and functional MRI investigations with diverse results challenges definite conclusions, but evidence suggests that subcortical as well as (pre)frontal regions serve emotion regulation in dissociative conditions. Functional connectivity analyses suggest the presence of altered brain networks in patients with FNSS, in which limbic areas have an increased influence on motor preparatory regions. CONCLUSIONS: HRV, EEG and (functional) MRI are sensitive methods to detect physiological changes related to dissociation and dissociative disorders such as FNSS, and can possibly provide more information about their aetiology. The use of such measures could eventually provide biomarkers for earlier identification of patients at risk and appropriate treatment of dissociative conditions.

Pediatric frontal lobe epilepsy: white matter abnormalities and cognitive impairment.

OBJECTIVES: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE). Its etiology remains unknown. With diffusion tensor imaging, we have studied cerebral white matter properties and associations with cognitive functioning in children with FLE and healthy controls. METHODS: Thirty children aged 8-13 years with FLE of unknown cause and 39 healthy age-matched controls underwent neuropsychological assessment, structural and diffusion-weighted brain MRI. Patients were grouped as cognitively impaired or unimpaired, and their white matter diffusion properties were compared with the controls. RESULTS: Children with FLE had reduced apparent diffusion coefficients in various posteriorly located tract bundles, a reduced fractional anisotropy (FA) of the white matter tract between the right frontal and right occipital lobe, and smaller volumes of several collections of interlobar bundle tracts, compared with controls. The cognitively impaired patient group demonstrated significant increases in FA of the white matter of both occipital lobes, a reduced FA of white matter tract bundles between the right frontal and both left occipital lobe and subcortical white matter area, and smaller volumes of two collections of tract bundles connecting the frontal lobe with the temporal and parietal lobes, compared with controls. CONCLUSIONS: Children with FLE had white matter abnormalities mainly in posterior brain regions, not confined to the area of the seizure focus. Cognitively impaired children with FLE showed the most pronounced white matter abnormalities. These possibly reflect disturbed maturation and might be part of the etiology of the cognitive impairment.

Disentangling the relationship between epilepsy and its behavioral comorbidities - the need for prospective studies in new-onset epilepsies.

It has been long recognized that there is more to epilepsy than seizures. The prevalence of such neurobehavioral abnormalities as cognitive and mood disorders, autism spectrum disorder, and attention deficit and hyperactivity disorder (ADHD) is significantly higher among patients with epilepsy than in the general population. A long-held view that comorbidities of epilepsy represent mere epiphenomena of seizures has undergone substantial transformation during the past decade, as emerging clinical evidence and experimental evidence suggest the involvement of specific neurobiological mechanisms in the evolution of neurobehavioral deficits in patients with epilepsy. Developmental aspects of both epilepsy and its comorbidities, as well as the frequently reported reciprocal connection between these disorders, both add other dimensions to the already complex problem. In light of progress in effective seizure management in many patients with epilepsy, the importance of neurobehavioral comorbidities has become acute, as the latter are frequently more detrimental to patients' quality of life compared with seizures. This calls for a serious increase in efforts to effectively predict, manage, and ideally cure these comorbidities. Coordinated multicenter clinical, translational, and basic research studies focusing on epidemiology, neuropsychology, neurophysiology, imaging, genetics, epigenetics, and pharmacology of neurobehavioral comorbidities of epilepsy are absolutely instrumental for ensuring tangible progress in the field. Clinical research should focus more on new-onset epilepsy and put particular emphasis on longitudinal studies in large cohorts of patients and groups at risk, while translational research should primarily focus on the development of valid preclinical systems which would allow investigating the fundamental mechanism of epilepsy comorbidities. The final goal of the described research efforts would lie in producing an armamentarium of evidence-based diagnostic tools and therapeutic interventions which would at minimum mitigate and at maximum prevent or abolish neurobehavioral comorbidities of epilepsy and, thus, improve the quality of life of those patients with epilepsy who suffer from the said comorbidities.

The effects of vagus nerve stimulation on tryptophan metabolites in children with intractable epilepsy.

BACKGROUND: The mechanism of action of vagus nerve stimulation (VNS) in intractable epilepsy is not entirely clarified. It is believed that VNS causes alterations in cytokines, which can lead to rebalancing the release of neurotoxic and neuroprotective tryptophan metabolites. We aimed to evaluate VNS effects on tryptophan metabolites and on epileptic seizures and investigated whether the antiepileptic effectiveness correlated with changes in tryptophan metabolism. METHODS: Forty-one children with intractable epilepsy were included in a randomized, active-controlled, double-blind study. After a baseline period of 12 weeks, all children underwent implantation of a vagus nerve stimulator and entered a blinded active-controlled phase of 20 weeks. Half of the children received high-output (therapeutic) stimulation (n=21), while the other half received low-output (active control) stimulation (n=20). Subsequently, all children received high-output stimulation for another 19 weeks (add-on phase). Tryptophan metabolites were assessed in plasma and cerebrospinal fluid (CSF) by use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and compared between high- and low-output groups and between the end of both study phases and baseline. Seizure frequency was recorded using seizure diaries. Mood was assessed using Profile of Mood States (POMS) questionnaires. RESULTS: Regarding tryptophan metabolites, anthranilic acid (AA) levels were significantly higher at the end of the add-on phase compared with baseline (p=0.002) and correlated significantly with improvement of mood (τ=-0.39, p=0.037) and seizure frequency reduction (τ=-0.33, p<0.01). No significant changes were found between high- and low-output groups regarding seizure frequency. CONCLUSION: Vagus nerve stimulation induces a consistent increase in AA, a neuroprotective and anticonvulsant tryptophan metabolite. Moreover, increased AA levels are associated with improvement in mood and reduction of seizure frequency.

Abnormal modular organization of functional networks in cognitively impaired children with frontal lobe epilepsy.

Many children with frontal lobe epilepsy (FLE) have significant cognitive comorbidity, for which the underlying mechanism has not yet been unraveled, but is likely related to disturbed cerebral network integrity. Using resting-state fMRI, we investigated whether cerebral network characteristics are associated with epilepsy and cognitive comorbidity. We included 37 children with FLE and 41 healthy age-matched controls. Cognitive performance was determined by means of a computerized visual searching task. A connectivity matrix for 82 cortical and subcortical brain regions was generated for each subject by calculating the inter-regional correlation of the fMRI time signals. From the connectivity matrix, graph metrics were calculated and the anatomical configuration of aberrant connections and modular organization was investigated. Both patients and controls displayed efficiently organized networks. However, FLE patients displayed a higher modularity, implying that subnetworks are less interconnected. Impaired cognition was associated with higher modularity scores and abnormal modular organization of the brain, which was mainly expressed as a decrease in long-range and an increase in interhemispheric connectivity in patients. We showed that network modularity analysis provides a sensitive marker for cognitive impairment in FLE and suggest that abnormally interconnected functional subnetworks of the brain might underlie the cognitive problems in children with FLE.