Exploring the core network of the structural covariance network in childhood absence epilepsy.

Childhood absence epilepsy (CAE) is a generalized pediatric epilepsy, which is generally considered to be a benign condition since most children become seizure-free before reaching adulthood. However, cognitive deficits and changes of brain morphological have been previously reported in CAE. These morphological changes, even if they might be very subtle, are not independent due to the underlying network structure and can be captured by the structural covariance network (SCN). In this study, SCNs were used to quantify the structural brain network for children with CAE as well as controls. Seventeen children with CAE (6-12y) and fifteen controls (6-12y) were included. To estimate the SCN, T1-weighted images were acquired and parcellated into 68 cortical regions. Graph measures characterizing the core network architecture, i.e. the assortativity and rich-club coefficient, were calculated for all individuals. Multivariable linear regression models, including age and sex as covariates, were used to assess differences between children with CAE and controls. Additionally, potential relations between the core network and cognitive performance was investigated. A lower assortativity (i.e. less efficiently organized core network organization) was found for children with CAE compared to controls. Moreover, better cognitive performance was found to relate to stronger assortative mixing pattern (i.e. more efficient core network structure). Rich-club coefficients did not differ between groups, nor relate to cognitions. The core network organization of the SCN in children with CAE tend to be less efficient organized compared to controls, and relates to cognitive performance, and therefore this study provides novel insights into the SCN organization in relation to CAE and cognition.

Neurophysiological signatures reflect differences in visual attention during absence seizures.

OBJECTIVE: Absences affect visual attention and eye movements variably. Here, we explore whether the dissimilarity of these symptoms during absences is reflected in differences in electroencephalographic (EEG) features, functional connectivity, and activation of the frontal eye field. METHODS: Pediatric patients with absences performed a computerized choice reaction time task, with simultaneous recording of EEG and eye-tracking. We quantified visual attention and eye movements with reaction times, response correctness, and EEG features. Finally, we studied brain networks involved in the generation and propagation of seizures. RESULTS: Ten pediatric patients had absences during the measurement. Five patients had preserved eye movements (preserved group) and five patients showed disrupted eye movements (unpreserved group) during seizures. Source reconstruction showed a stronger involvement of the right frontal eye field during absences in the unpreserved group than in the preserved group (dipole fraction 1.02% and 0.34%, respectively, p < 0.05). Graph analysis revealed different connection fractions of specific channels. CONCLUSIONS: The impairment of visual attention varies among patients with absences and is associated with differences in EEG features, network activation, and involvement of the right frontal eye field. SIGNIFICANCE: Assessing the visual attention of patients with absences can be usefully employed in clinical practice for tailored advice to the individual patient.

A Potential Multimodal Test for Clinical Assessment of Visual Attention in Neurological Disorders.

Attention is an important aspect of human brain function and often affected in neurological disorders. Objective assessment of attention may assist in patient care, both for diagnostics and prognostication. We present a compact test using a combination of a choice reaction time task, eye-tracking and EEG for assessment of visual attention in the clinic. The system quantifies reaction time, parameters of eye movements (i.e. saccade metrics and fixations) and event related potentials (ERPs) in a single and fast (15 min) experimental design. We present pilot data from controls, patients with mild traumatic brain injury and epilepsy, to illustrate its potential use in assessing attention in neurological patients. Reaction times and eye metrics such as fixation duration, saccade duration and latency show significant differences (p < .05) between neurological patients and controls. Late ERP components (200-800 ms) can be detected in the central line channels for all subjects, but no significant group differences could be found in the peak latencies and mean amplitudes. Our system has potential to assess key features of visual attention in the clinic. Pilot data show significant differences in reaction times and eye metrics between controls and patients, illustrating its promising use for diagnostics and prognostication.

Neurocognitive and behavioural profile in Panayiotopoulos syndrome.

AIM: To determine neurocognitive performance and behavioural problems in children with Panayiotopoulos syndrome. METHOD: All 18 children (10 females, 8 males; mean age 4y 7mo; SD 1y 10mo) diagnosed with Panayiotopoulos syndrome at the Kempenhaeghe Epilepsy Center in the Netherlands between 2010 and 2017 were analysed retrospectively. All underwent a neuropsychological/behavioural assessment, an academic assessment, and a 24-hour electroencephalogram. RESULTS: Mean full-scale IQ (93.5; range 76-123; p=0.04) and performance IQ (93.2; range 76-126; p=0.04) were within the normal range, although significantly lower compared to the normative mean. Verbal IQ (96.3; range 76-118) and processing speed (96.1; range 74-114) were not significantly lower. Simple auditory/visual reaction times, visual attention, visual-motor integration, and verbal memory were significantly lower compared to normative values. On average, patients with Panayiotopoulos syndrome were 8 months behind in arithmetic speed and 11 months behind in reading speed for the number of months in school. Behavioural questionnaires revealed significantly higher scores on reported internalizing behavioural problems. INTERPRETATION: Children with Panayiotopoulos syndrome demonstrated diffuse cognitive dysfunction in full-scale IQ, performance IQ, visual attention, visual-motor integration, and verbal memory. A high incidence of internalizing behavioural problems was reported. This strongly suggests neuropsychological and behavioural comorbidity in children with Panayiotopoulos syndrome. WHAT THIS PAPER ADDS: Children with Panayiotopoulos syndrome are at risk for cognitive deficits in various cognitive domains. Children with Panayiotopoulos syndrome are also prone to internalizing behavioural problems. Mild-to-severe academic underachievement was present in more than half of the children with Panayiotopoulos syndrome.

Constructing an Axonal-Specific Myelin Developmental Graph and its Application to Childhood Absence Epilepsy.

BACKGROUND AND PURPOSE: The process of myelination starts in utero around 20 weeks of gestation and continues through adulthood. We first set out to characterize the maturation of the tract-specific myelin content in healthy subjects from childhood (7-12 years) into adulthood (18-32 years). Second, we apply the resulting development graph to children with childhood absence epilepsy (CAE), a pediatric epilepsy that was previously characterized by changes in myelin content. METHODS: In a prospective cross-sectional study, 15 healthy children (7-12 years), 14 healthy adult participants (18-32 years) and 17 children with a clinical diagnosis of CAE (6-12 years) were included. For each participant, diffusion weighted images were acquired to reconstruct bundles of white matter tracts and multi-echo multi-slice GRASE images were acquired for myelin-water estimation. Subsequently, a tract-specific myelin development graph was constructed using the percentual difference in myelin-water content from childhood (12 year) to adulthood (25 year). RESULTS: The graph revealed myelination patterns, where tracts in the central regions myelinate prior to peripheral tracts and intra-hemispheric tracts as well as tracts in the left hemisphere myelinate prior to inter-hemispheric tracts and tracts in the right hemisphere, respectively. No significant differences were found in myelin-water content between children with CAE and healthy children for neither the early developing tracts, nor the tracts that develop in a later stage. However, the difference between the myelin-water of late and early developing tracts is significantly smaller in the children with CAE. CONCLUSION: These results indicate that CAE is associated with widespread neurodevelopmental myelin differences.

Correction to: Towards a Better Understanding of Cognitive Deficits in Absence Epilepsy: a Systematic Review and Meta-Analysis.

Due to an error during the editorial phase, a correction regarding Fig. 2 is added to the original article: "Towards a Better Understanding of Cognitive Deficits in Absence Epilepsy: a Systematic Review and Meta-Analysis". Please see below correct Fig. 2.

Towards a Better Understanding of Cognitive Deficits in Absence Epilepsy: a Systematic Review and Meta-Analysis.

Cognition in absence epilepsy (AE) is generally considered undisturbed. However, reports on cognitive deficits in AE in recent years have suggested otherwise. This review systematically assesses current literature on cognitive performance in children with AE. A systematic literature search was performed in Pubmed, Embase, Cochrane and Web of Science. All studies reporting on cognitive performance in children with AE were considered. In total 33 studies were eligible for inclusion. Neuropsychological tests were classified into the following domains: intelligence; executive function; attention; language; motor & sensory-perceptual examinations; visuoperceptual/visuospatial/visuoconstructional function; memory and learning; achievement. Random-effect meta-analyses were conducted by estimating the pooled mean and/or pooling the mean difference in case-control studies. Full-scale IQ in children with AE was estimated at 96.78 (95%CI:94.46-99.10) across all available studies and in case-control studies IQ was on average 8.03 (95%CI:-10.45- -5.61) lower. Verbal IQ was estimated at 97.98 (95%CI:95.80-100.16) for all studies and 9.01 (95%CI:12.11- -5.90) points lower in case-control studies. Performance IQ was estimated at 97.23 (93.24-101.22) for all available studies and 5.32 (95%CI:-8.27-2.36) points lower in case-control studies. Lower performance was most often reported in executive function (cognitive flexibility, planning, and verbal fluency) and attention (sustained, selective and divided attention). Reports on school difficulties, neurodevelopmental problems, and attentional problems were high. In conclusion, in contrast to common beliefs, lower than average neurocognitive performance was noted in multiple cognitive domains, which may influence academic and psychosocial development.

Lower myelin-water content of the frontal lobe in childhood absence epilepsy.

OBJECTIVE: The frontal lobe in childhood absence epilepsy (CAE) might be affected due to the suggested involvement of the frontal lobe during absence seizures and reports on attentional deficits. Previously, subtle white matter abnormalities have been reported in CAE. However, the impact of one of the most characteristic components of the white matter, the myelin content, remains underdetermined. Therefore, this study investigated whether the myelin content in frontal areas is adversely affected in CAE compared to controls. METHODS: Seventeen children with childhood absence epilepsy (mean age ± standard deviation [SD], 9.2 ± 2.1 years) and 15 age- and sex-matched controls (mean age ± SD, 9.8 ± 1.8 years) underwent neuropsychological assessment and a magnetic resonance imaging (MRI) examination. T2 relaxometry scans were used to distinguish myelin-water from tissue water and to determine the myelin-water fraction (MWF) in the frontal, temporal, parietal, occipital, and insular lobes. A linear regression model including age and sex as covariates was used to investigate group differences. Furthermore, the relationship of MWF with cognitive performance and epilepsy characteristics was determined. RESULTS: The frontal lobe revealed a significantly lower myelin-water content in children with CAE compared to controls over the developmental age range of 6-12 years (5.7 ± 1.0% vs 6.6 ± 1.1%, P = 0.02). This association was not found for any of the other four lobes (P > 0.10). No significant relation was found between myelin-water content and cognitive performance or epilepsy characteristics. SIGNIFICANCE: The lower frontal myelin-water content of children with CAE in comparison with healthy controls probably reflects an altered neurodevelopmental aspect in CAE, of which the underlying mechanisms still need to be unraveled.

Cognitive development in absence epilepsy during long-term follow-up.

Absence epilepsy (AE) has been associated with lower than average cognitive functioning, which are clinically relevant in some and may predispose to problems later in life. This study aimed to assess cognitive development during long-term follow-up in children with AE. Thirty-one children with AE, who had undergone two neuropsychological assessments between 2010 and 2017 were analyzed retrospectively. Cognitive measurements were 1.7 ± 0.95 years apart. The difference in neurocognitive test scores was assessed on a group level and on an individual level using reliable change methodology. Results show that sustained attention was lower at the first measurement compared to the normative mean. Sustained attention improved during follow-up and 7 out of 14 children showed improvement after correction for practice effects. Receptive vocabulary showed a decline over time, but did not differ from the normative mean. Significant lower mean group scores were present for performance IQ, perceptual organization, processing speed, simple reaction times, and visual motor integration, while being stable over time in the majority of children. Cognitive development was not associated with seizure freedom. Mild-to-severe academic underachievement was present in 65% and comorbidities that might affect learning in 38%. This study in children with AE showed improvement in sustained attention during long-term follow-up while other cognitive weaknesses persisted over time, regardless of seizure freedom.

Frontal lobe connectivity and cognitive impairment in pediatric frontal lobe epilepsy.

PURPOSE: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its etiology is unknown. With functional magnetic resonance imaging (fMRI), we have explored the relationship between brain activation, functional connectivity, and cognitive functioning in a cohort of pediatric patients with FLE and healthy controls. METHODS: Thirty-two children aged 8-13 years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural and functional brain MRI. We investigated to which extent brain regions activated in response to a working memory task and assessed functional connectivity between distant brain regions. Data of patients were compared to controls, and patients were grouped as cognitively impaired or unimpaired. KEY FINDINGS: Children with FLE showed a global decrease in functional brain connectivity compared to healthy controls, whereas brain activation patterns in children with FLE remained relatively intact. Children with FLE complicated by cognitive impairment typically showed a decrease in frontal lobe connectivity. This decreased frontal lobe connectivity comprised both connections within the frontal lobe as well as connections from the frontal lobe to the parietal lobe, temporal lobe, cerebellum, and basal ganglia. SIGNIFICANCE: Decreased functional frontal lobe connectivity is associated with cognitive impairment in pediatric FLE. The importance of impairment of functional integrity within the frontal lobe network, as well as its connections to distant areas, provides new insights in the etiology of the broad-range cognitive impairments in children with FLE.

Microstructural and functional MRI studies of cognitive impairment in epilepsy.

Cognitive impairment is the most common comorbidity in children with epilepsy, but its pathophysiology and predisposing conditions remain unknown. Clinical epilepsy characteristics are not conclusive in determining cognitive outcome. Because many children with epilepsy do not have macrostructural magnetic resonance imaging (MRI) abnormalities, the underlying substrate for cognitive impairment may be found at the microstructural or functional level. In the last two decades, new MRI techniques have been developed that have the potential to visualize microstructural or functional abnormalities associated with cognitive impairment. These include volumetric MRI, voxel-based morphometry (VBM), diffusion tensor imaging (DTI), MR spectroscopy (MRS), and functional MRI (fMRI). All of these techniques have shed new light on various aspects associated with, or underlying, cognitive impairment, although their use in epilepsy has been limited and focused mostly on adults. Therefore, in this review, the use of all these different MRI techniques to unravel cognitive impairment in epilepsy is discussed both in adults and children with epilepsy. Volumetric MRI and VBM have revealed significant volume losses in the area of the seizure focus as well as in distant areas. DTI adds evidence of loss of integrity of connections from the seizure focus to distant areas as well as between distant areas. MRS and fMRI have shown impaired function both in the area of the seizure focus as well as in distant structures. For this review we have compiled and compared findings from the various techniques to conclude that cognitive impairment in epilepsy results from a network disorder in which the (micro)structures as well as the functionality can be disturbed.

Cognitive and behavioural findings in children with frontal lobe epilepsy.

BACKGROUND: Frontal Lobe Epilepsy (FLE) is the second most frequent type of partial epilepsy and its onset is generally in childhood. Though cognitive and behavioural impairments have been described as co-morbid disorders in epilepsy, their extent in FLE, particularly in children, remains unknown. AIMS: In this study, we assess cognitive skills and behaviour in a cohort of paediatric FLE patients. METHODS: We measured the performance of 71 children with cryptogenic FLE on intelligence tests, neuropsychological tests, and behavioural questionnaires. Age-dependent normative values were used for reference. Results were related to epilepsy-factors including age at epilepsy onset, duration of epilepsy, seizure frequency, localisation of the epileptic focus and drug load. RESULTS: Paediatric FLE patients performed worse on intellectual and neuropsychological tests compared to reference values, and had a delay in school achievement. The performance of patients was typically worse on tasks measuring visual-spatial functions, memory, psychomotor speed and alertness. High seizure frequency was associated with lower scores on the arithmetic subtest of the intelligence scale; the other epilepsy-factors had no statistically significant influence on intelligence test or neuropsychological test outcome. Behavioural problems included attention problems, anxiety and internalising behaviour. These were not significantly related to epilepsy-factors. CONCLUSIONS: Children with cryptogenic FLE show a broad range of cognitive and behavioural impairments, compared to reference values. While high seizure frequency may affect performance on selected cognitive measures, other epilepsy-factors do not seem to influence cognition and behaviour. Study of micro-structural or functional brain abnormalities that underlie these cognitive and behavioural impairments are warranted.

Cognitive and behavioral complications of frontal lobe epilepsy in children: a review of the literature.

Frontal lobe epilepsy (FLE) is considered the second most common type of the localization-related epilepsies of childhood. Still, the etiology of FLE in children, its impact on cognitive functioning and behavior, as well as the response to antiepileptic drug treatment in children has not been sufficiently studied. This review focuses on these aspects of FLE in childhood, and reveals that FLE in childhood is most often cryptogenic, and impacts on a broad range of cognitive functions. The nature and severity of cognitive deficits are highly variable, although impaired attention and executive functions are most frequent. Young age at seizure onset is the only potential risk factor for poor cognitive outcome that has been consistently reported. The behavioral disturbances associated with FLE are also highly variable, although attention deficit/hyperactivity disorder seems most frequent. In 40% of children with FLE satisfactory seizure control could not be achieved. This is a higher percentage than reported for the general population of children with epilepsy. Therefore, pediatric FLE, even if cryptogenic in nature, is frequently complicated by impairment of cognitive function, behavioral disturbances, and therapy-resistance. Given the impact of these complications, there is a need for studies of the etiology of frontal lobe epilepsy-associated cognitive and behavioral disturbances, as well as pharmacotherapy-resistance.