The cognitive effects of interictal epileptiform EEG discharges and short nonconvulsive epileptic seizures.

PURPOSE: Educational difficulties or even severe cognitive deterioration is seen in many childhood epilepsy syndromes. Many of those cognitive deficits are related directly to the brain disorder underlying the epilepsy syndrome. However, in other types of epilepsy, the epileptic seizures and/or epileptiform activity can be the dominant factor. This is especially unknown for the more "subtle" short nonconvulsive seizure types. For this reason, we analyzed a new cohort of children. METHODS: A cross-sectional study of 188 children with epilepsy. Electroencephalography (EEG)-video recordings and cognitive testing were performed simultaneously. The results of children with short nonconvulsive seizures during a 2-h testing session were compared with all children with epilepsy without seizures during the 2-h cognitive testing session and with controls without epilepsy. In a second analysis the cognitive effects of frequency of epileptiform EEG discharges were analyzed. KEY FINDINGS: The cognitive effects of short nonconvulsive seizures were large, ranging from 0.5 to 1 standard deviation and concerned global cognitive function, speed of central information processing, and memory function. In children without seizures during cognitive testing, the occurrence of frequent epileptiform discharges showed more subtle effects. These effects were independent from the occurrence of short nonconvulsive seizures. SIGNIFICANCE: We concluded that although the effect is less pronounced in number of areas involved and magnitude, the type of association between frequent epileptiform activity (>1% of the time) and cognitive function in children with epilepsy is comparable to the association between short nonconvulsive seizures and cognitive function.

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.

Value of re-interpretation of controversial EEGs in a tertiary epilepsy clinic.

OBJECTIVE: Diagnostic value and efficacy of re-interpretation of previous EEGs in 100 patients admitted to a tertiary epilepsy center with EEG results conflicting with the clinical diagnosis after the first visit. METHODS: EEGs were reclassified. A matched control group was included to assess the efficiency of the re-interpretation process. Efficacy was assessed by questionnaires and costs as number of technician hours needed. RESULTS: In 85 patients the previous EEG conclusion was known. In 43 the conclusion was altered. In 23 the epileptic activity changed from positive to negative (17) or the reverse (6). In 15 the focus changed (7 originally classified as generalized epileptic activity). In 5 the syndrome changed. 57% of the re-interpretation group needed no extra EEG afterwards. 96% of the re-interpretations were considered useful by requesting and 72% by not involved neurologists. The average time per EEG technologist per patient was 8,81h in controls and 5,40 in the re-interpretation group. CONCLUSIONS: In 43 from the 85 patients (51%) re-interpretation of 'controversial' EEGs led to a different opinion. The re-interpretations were useful and less time consuming, compared to new EEGs in controls. SIGNIFICANCE: Re-interpretation of 'controversial' EEGs is useful and cost effective.

Can an early 24-hour EEG predict the response to the ketogenic diet? A prospective study in 34 children and adults with refractory epilepsy treated with the ketogenic diet.

PURPOSE: We examined whether early EEG changes in a 24-h EEG at 6 weeks of treatment were related to the later clinical response to the ketogenic diet (KD) in a 6-month period of treatment. METHODS: We examined 34 patients with heterogeneous epilepsy syndromes (21 children, 13 adults) and found 9 clinical responders (≥50% seizure reduction); this is a responder rate of 26%. We visually counted the interictal epileptic discharge index (IED index) in % during 2h of wakefulness and in the first hour of sleep (method 1), and also globally reviewed EEG changes (method 2), while blinded to the effect of the KD. RESULTS: At group level we saw a correlation between nocturnal reduction of IED-index at 6 weeks and seizure reduction in the follow-up period. A proportional reduction in IED index of 30% from baseline in the sleep EEG, was associated with being a responder to the diet (Pearson Chi-square p=0.04). EEG scoring method 2 observed a significantly larger proportion of patients with EEG-improvement in sleep in KD responders than in non-responders (p=0.03). At individual level, however, EEG changes did not correlate very strongly to the response to the diet, as IED reduction in sleep was also seen in 15% (method 1) to 26% (method 2) of the non-responders. CONCLUSION: Nocturnal reduction of IEDs is related to the response to the KD, however in daily clinical practice, an early EEG to predict seizure reduction should not be advised for individual patients.

Delayed convergence between brain network structure and function in rolandic epilepsy.

INTRODUCTION: Rolandic epilepsy (RE) manifests during a critical phase of brain development, and has been associated with language impairments. Concordant abnormalities in structural and functional connectivity (SC and FC) have been described before. As SC and FC are under mutual influence, the current study investigates abnormalities in the SC-FC synergy in RE. METHODS: Twenty-two children with RE (age, mean ± SD: 11.3 ± 2.0 y) and 22 healthy controls (age 10.5 ± 1.6 y) underwent structural, diffusion weighted, and resting-state functional magnetic resonance imaging (MRI) at 3T. The probabilistic anatomical landmarks atlas was used to parcellate the (sub)cortical gray matter. Constrained spherical deconvolution tractography and correlation of time series were used to assess SC and FC, respectively. The SC-FC correlation was assessed as a function of age for the non-zero structural connections over a range of sparsity values (0.01-0.75). A modularity analysis was performed on the mean SC network of the controls to localize potential global effects to subnetworks. SC and FC were also assessed separately using graph analysis. RESULTS: The SC-FC correlation was significantly reduced in children with RE compared to healthy controls, especially for the youngest participants. This effect was most pronounced in a left and a right centro-temporal network, as well as in a medial parietal network. Graph analysis revealed no prominent abnormalities in SC or FC network organization. CONCLUSION: Since SC and FC converge during normal maturation, our finding of reduced SC-FC correlation illustrates impaired synergy between brain structure and function. More specifically, since this effect was most pronounced in the youngest participants, RE may represent a developmental disorder of delayed brain network maturation. The observed effects seem especially attributable to medial parietal connections, which forms an intermediate between bilateral centro-temporal modules of epileptiform activity, and bear relevance for language function.

Clinical evaluation of language fundamentals in Rolandic epilepsy, an assessment with CELF-4.

BACKGROUND: In clinical practice, Rolandic epilepsy is in many cases associated with developmental language impairment. However, from the literature it is unclear exactly which domains are affected; A wide variety of investigations are reported that each provide a different representation of language performance in these patients. AIMS: The aim of this study is to compare performance on the language domains between children with Rolandic epilepsy and healthy controls. METHODS: Prospective study of children with Rolandic epilepsy compared to healthy controls. 25 children (mean age 136.6 months, SD 23.0) with Rolandic epilepsy and 25 age-matched healthy controls were tested on their language function using the CELF-4 (Clinical evaluation of Language Fundamentals, Dutch edition). The healthy control were not matched regard to other important factors, particularly educational attainment and co-morbidity. Expressive language, receptive language, language content, language structure and language working memory were tested. RESULTS: In children with Rolandic epilepsy, the core language score was significant lower compared with healthy controls. They scored specifically lower on the receptive language index and language content index (both p = 0.002). A trend towards decreased expressive language index was observed (p = 0.054). Language structure and language working memory were in the normal range. CONCLUSION: Language was found to be impaired in children with typical Rolandic epilepsy. Especially semantic language processing including receptive language and language content was significantly impaired. The common denominator of these functions is semantic language processing.

Aberrant functional connectivity between motor and language networks in rolandic epilepsy.

INTRODUCTION: Rolandic epilepsy (RE) is an idiopathic focal childhood epilepsy with a well-established neuropsychological profile of language impairment. The aim of this study is to provide a functional correlate that links rolandic (sensorimotor) pathology to language problems using functional MRI. MATERIALS AND METHODS: Twenty-three children with RE (8-14 years old) and 21 matched controls underwent extensive language assessment (Clinical Evaluation of Language Fundamentals). fMRI was performed at rest and using word generation, reading, and finger tapping paradigms. Since no activation group differences were found, regions of interest (ROIs) were defined at pooled (patients and controls combined) activation maxima and in contralateral homotopic cortex, and used to assess language lateralization as well as for a resting-state connectivity analysis. Furthermore, the association between connection strength and language performance was investigated. RESULTS: Reduced language performance was found in the children with RE. Bilateral activation was found for both language tasks with some predominance of the left hemisphere in both groups. Compared to controls, patient connectivity was decreased between the left sensorimotor area and right inferior frontal gyrus (p<0.01). For this connection, lower connectivity was associated with lower language scores in the patient group (r=0.49, p=0.02), but not in the controls. CONCLUSION: Language laterality analysis revealed bilateral language representation in the age range under study (8-14 years). As a consequence, the connection of reduced functional connectivity we found represents an impaired interplay between motor and language networks, and aberrant functional connectivity associated with poorer language performance. These findings provide a first neuronal correlate in terms of aberrant resting-state functional connectivity for language impairment in RE.

Reduced structural connectivity between sensorimotor and language areas in rolandic epilepsy.

INTRODUCTION: Rolandic epilepsy (RE) is a childhood epilepsy with centrotemporal (rolandic) spikes, that is increasingly associated with language impairment. In this study, we tested for a white matter (connectivity) correlate, employing diffusion weighted MRI and language testing. METHODS: Twenty-three children with RE and 23 matched controls (age: 8-14 years) underwent structural (T1-weighted) and diffusion-weighted MRI (b = 1200 s/mm(2), 66 gradient directions) at 3T, as well as neuropsychological language testing. Combining tractography and a cortical segmentation derived from the T1-scan, the rolandic tract were reconstructed (pre- and postcentral gyri), and tract fractional anisotropy (FA) values were compared between patients and controls. Aberrant tracts were tested for correlations with language performance. RESULTS: Several reductions of tract FA were found in patients compared to controls, mostly in the left hemisphere; the most significant effects involved the left inferior frontal (p = 0.005) and supramarginal (p = 0.004) gyrus. In the patient group, lower tract FA values were correlated with lower language performance, among others for the connection between the left postcentral and inferior frontal gyrus (p = 0.043, R = 0.43). CONCLUSION: In RE, structural connectivity is reduced for several connections involving the rolandic regions, from which the epileptiform activity originates. Most of these aberrant tracts involve the left (typically language mediating) hemisphere, notably the pars opercularis of the inferior frontal gyrus (Broca's area) and the supramarginal gyrus (Wernicke's area). For the former, reduced language performance for lower tract FA was found in the patients. These findings provide a first microstructural white matter correlate for language impairment in RE.

Reduced functional integration of the sensorimotor and language network in rolandic epilepsy.

INTRODUCTION: Over the last years, evidence has accumulated that rolandic epilepsy (RE) is associated with serious cognitive comorbidities, including language impairment. However, the cerebral mechanism through which epileptiform activity in the rolandic (sensorimotor) areas may affect the language system is unknown. To investigate this, the connectivity between rolandic areas and regions involved in language processing is studied using functional MRI (fMRI). MATERIALS AND METHODS: fMRI data was acquired from 22 children with rolandic epilepsy and 22 age-matched controls (age range: 8-14 years), both at rest and using word-generation and reading tasks. Activation map analysis revealed no group differences (FWE-corrected, p < 0.05) and was therefore used to define regions of interest for pooled (patients and controls combined) language activation. Independent component analysis with dual regression was used to identify the sensorimotor resting-state network in all subjects. The associated functional connectivity maps were compared between groups at the regions of interest for language activation identified from the task data. In addition, neuropsychological language testing (Clinical Evaluation of Language Fundamentals, 4th edition) was performed. RESULTS: Functional connectivity with the sensorimotor network was reduced in patients compared to controls (p = 0.011) in the left inferior frontal gyrus, i.e. Broca's area as identified by the word-generation task. No aberrant functional connectivity values were found in the other regions of interest, nor were any associations found between functional connectivity and language performance. Neuropsychological testing confirmed language impairment in patients relative to controls (reductions in core language score, p = 0.03; language content index, p = 0.01; receptive language index, p = 0.005). CONCLUSION: Reduced functional connectivity was demonstrated between the sensorimotor network and the left inferior frontal gyrus (Broca's area) in children with RE, which might link epileptiform activity/seizures originating from the sensorimotor cortex to language impairment, and is in line with the identified neuropsychological profile of anterior language dysfunction.

Early onset of cortical thinning in children with rolandic epilepsy.

INTRODUCTION: Rolandic epilepsy, a childhood epilepsy associated with language impairments, was investigated for language-related cortical abnormalities. METHODS: Twenty-four children with rolandic epilepsy and 24 controls (age 8-14 years) were recruited and underwent the Clinical Evaluation of Language Fundamentals test. Structural MRI was performed at 3 T (voxel size 1 × 1 × 1 mm(3)) for fully automated quantitative assessment of cortical thickness. Regression analysis was used to test for differences between patients and controls and to assess the effect of age and language indices on cortical thickness. RESULTS: For patients the core language score (mean ± SD: 92 ± 18) was lower than for controls (106 ± 11, p = 0.0026) and below the norm of 100 ± 15 (p = 0.047). Patients showed specific impairments in receptive language index (87 ± 19, p = 0.002) and language content index (87 ± 18, p = 0.0016). Cortical thickness was reduced in patients (p < 0.05, multiple-comparisons corrected) in left perisylvian regions. Furthermore, extensive cortical thinning with age was found in predominantly left-lateralized frontal, centro-parietal and temporal regions. No associations were found between cortical thickness and language indices in the regions of aberrant cortex. CONCLUSION: The cortical abnormalities described represent subtle but significant pathomorphology in this critical phase of brain development (8-14 years) and suggest that rolandic epilepsy should not be considered merely a benign condition. Future studies employing longitudinal designs are prompted for further investigations into cerebral abnormalities in RE and associations with cognitive impairment and development.