The effect of executive function on health related quality of life in children with self-limited epilepsy with centrotemporal spikes.

AIM: The current study aims to investigate the effect of Executive Functions (EFs) on Health Related Quality of Life (HRQoL) in a cohort of children with self-limited epilepsy with centrotemporal spikes (SeLECTS) and to identify possible factors that impact HRQoL specifically related to epilepsy-related variables and EFs skills. MATERIAL AND METHOD: The Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL) and The Behavior Rating Inventory of Executive Function (BRIEF-2 and BRIEF-P) were completed by the parents of 129 patients with SeLECTS. Demographic variables and epilepsy-related variables were collected. RESULTS: Our sample performed in the average range across all the subscales and summary scores of the PedsQL and performed in the normal range of the BRIEF questionnaire. We observed that a lower functioning in EFs was associated with lower overall HRQoL scores. We explored the relationship between epilepsy characteristics and scores on the PedsQL. We found that the use of antiseizure medications (ASMs), longer duration of the treatment, and a higher seizure frequency were associated with a lower HRQoL. Moreover, we observed that executive dysfunction was a significant predictor of reduced HRQoL. CONCLUSION: Our results suggest the importance of the identification of patients with SeLECTS with a high level of risk for a poor HRQoL. We may now add executive dysfunction to the list of known risk factors for poor HRQoL in children with SeLECTS, along with such factors as seizure frequency, recent seizures, use of ASMs and longer duration of therapy. The early identification of children with SeLECTS at risk of a poor HRQoL could allow the activation of adequate interventions.

WISC-IV intellectual profiles in Italian children with self-limited epilepsy with centrotemporal spikes.

OBJECTIVE: This study aimed to describe the intellectual profile based on the Wechsler Intelligence Scale for Children 4th edition (WISC-IV) in children with self-limited epilepsy with centrotemporal spikes (SeLECTS), with an attempt to define possible predictive epilepsy-related variables of cognitive performance. METHODS: The WISC-IV was assessed in 161 children with SeLECTS and their cognitive profiles were compared to a matched sample of healthy control children. RESULTS: Children with SeLECTS performed within normal range across all indices, demonstrating particular strength based on the Perceptual Reasoning Index. Compared to healthy control children, we observed a significant difference in performance based on the Full Scale Intelligence Quotient, Verbal Comprehension Index and Processing Speed Index. Regarding epilepsy-related variables, earlier onset of epilepsy, use of anti-seizure medications, the presence of neurodevelopmental disorders, a higher frequency of seizures, and a longer treatment duration were associated with an overall lower level of performance. SIGNIFICANCE: Children with SeLECTS performed within the average range for cognitive assessment based on the WISC-IV, demonstrating that children had normal levels of global intelligence. However, compared to healthy control children, children with SeLECTS showed a slightly lower level of performance. Reasoning skills represented the relative strengths in children with SeLECTS. Predictors of intellectual performance in patients with SeLECTS include epilepsy-related variables and neurodevelopmental comorbidities.

Overall cognitive profiles in patients with GLUT1 Deficiency Syndrome.

INTRODUCTION: Glucose Transporter Type I Deficiency Syndrome (GLUT1DS) classical symptoms are seizures, involuntary movements, and cognitive impairment but so far the literature has not devoted much attention to the last. METHODS: In our retrospective study involving 25 patients with established GLUT1DS diagnosis, we describe the cognitive impairment of these patients in detail and their response to the ketogenic diet in terms of cognitive improvement. RESULTS: We outlined a specific cognitive profile where performance skills were more affected than verbal ones, with prominent deficiencies in visuospatial and visuomotor abilities. We demonstrated the efficacy of ketogenic diet (KD) on cognitive outcome, with particular improvement tin total and verbal IQ; we found that timing of KD introduction was inversely related to IQ outcome: the later the starting of KD, the lower the IQ, more notable nonverbal scale (verbal IQ correlation coefficient -0.634, p-value = 0.015). We found a significant direct correlation between cognition and CSF/blood glucose ratio values: the higher the ratio, the better the cognitive improvement in response to diet (from T0-baseline evaluation to T1 on average 18 months after introduction of KD-: TIQ correlation coefficient 0.592, p-value = 0.26; VIQ correlation coefficient 0.555, p-value = 0.039). Finally, we demonstrated that a longer duration of treatment is necessary to find an improvement in patients with "severely low ratio." CONCLUSION: Our results were consistent with the hypothesis that timing of the diet introduction is a predictive factor of cognitive outcome in these patients, confirming that earlier initiation of the diet may prevent the onset of all GLUT1DS symptoms: epilepsy, movement disorders, and cognitive impairment.

Mapping the Effect of Interictal Epileptic Activity Density During Wakefulness on Brain Functioning in Focal Childhood Epilepsies With Centrotemporal Spikes.

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common type of "self-limited focal epilepsies." In its typical presentation, CECTS is a condition reflecting non-lesional cortical hyperexcitability of rolandic regions. The benign evolution of this disorder is challenged by the frequent observation of associated neuropsychological deficits and behavioral impairment. The abundance (or frequency) of interictal centrotemporal spikes (CTS) in CECTS is considered a risk factor for deficits in cognition. Herein, we captured the hemodynamic changes triggered by the CTS density measure (i.e., the number of CTS for time bin) obtained in a cohort of CECTS, studied by means of video electroencephalophy/functional MRI during quite wakefulness. We aim to demonstrate a direct influence of the diurnal CTS frequency on epileptogenic and cognitive networks of children with CECTS. A total number of 8,950 CTS (range between 27 and 801) were recorded in 23 CECTS (21 male), with a mean number of 255 CTS/patient and a mean density of CTS/30 s equal to 10,866 ± 11.46. Two independent general linear model models were created for each patient based on the effect of interest: "individual CTS" in model 1 and "CTS density" in model 2. Hemodynamic correlates of CTS density revealed the involvement of a widespread cortical-subcortical network encompassing the sensory-motor cortex, the Broca's area, the premotor cortex, the thalamus, the putamen, and red nucleus, while in the CTS event-related model, changes were limited to blood-oxygen-level-dependent (BOLD) signal increases in the sensory-motor cortices. A linear relationship was observed between the CTS density hemodynamic changes and both disease duration (positive correlation) and age (negative correlation) within the language network and the bilateral insular cortices. Our results strongly support the critical role of the CTS frequency, even during wakefulness, to interfere with the normal functioning of language brain networks.

West syndrome in three patients with brain injury and a benign course.

Infants with West Syndrome and underlying structural pathology typically experience persistent symptomatic focal seizures and intellectual disability. We performed a retrospective case review of 84 patients with West Syndrome evaluated at one institution between 1990 and 2013. From this group we identified three patients with West syndrome and congenital hemiplegia who later developed genetic epilepsy features and had normal intellectual development. This outcome is highly unusual and raises important questions about the relationship and possible influence of genetic epilepsy in patients with pre-existent West Syndrome and brain injury.

Neurobehavioral consequences of continuous spike and waves during slow sleep (CSWS) in a pediatric population: A pattern of developmental hindrance.

INTRODUCTION: Continuous spike and waves during slow sleep (CSWS) is a typical EEG pattern defined as diffuse, bilateral and recently also unilateral or focal localization spike-wave occurring in slow sleep or non-rapid eye movement sleep. Literature results so far point out a progressive deterioration and decline of intellectual functioning in CSWS patients, i.e. a loss of previously normally acquired skills, as well as persistent neurobehavioral disorders, beyond seizure and EEG control. The objective of this study was to shed light on the neurobehavioral impact of CSWS and to identify the potential clinical risk factors for development. METHODS: We conducted a retrospective study involving a series of 16 CSWS idiopathic patients age 3-16years, considering the entire duration of epilepsy from the onset to the outcome, i.e. remission of CSWS pattern. All patients were longitudinally assessed taking into account clinical (sex, age at onset, lateralization and localization of epileptiform abnormalities, spike wave index, number of antiepileptic drugs) and behavioral features. Intelligent Quotient (IQ) was measured in the whole sample, whereas visuo-spatial attention, visuo-motor skills, short term memory and academic abilities (reading and writing) were tested in 6 out of 16 patients. RESULTS: Our results showed that the most vulnerable from an intellectual point of view were those children who had an early-onset of CSWS whereas those with later onset resulted less affected (p=0.004). Neuropsychological outcome was better than the behavioral one and the lexical-semantic route in reading and writing resulted more severely affected compared to the phonological route. CONCLUSIONS: Cognitive deterioration is one but not the only consequence of CSWS. Especially with respect to verbal skills, CSWS is responsible of a pattern of consequences in terms of developmental hindrance, including slowing of development and stagnation, whereas deterioration is rare. Behavioral and academic problems tend to persist beyond epilepsy resolution.

Mismatch Negativity Recording in Children With Duchenne Muscular Dystrophy: A Preliminary Study Integrating Neurophysiological and Neuropsychological Results.

Many studies on Duchenne muscular dystrophy children support the hypothesis of a specific neuropsychological phenotype affecting mostly phonological skills. This prospective study aimed to shed light on the role of phonological abilities. Fourteen Duchenne muscular dystrophy children and 7 healthy children underwent mismatch negativity. Moreover, verbal intelligence, visuospatial attention, immediate verbal memory, working memory, grammar, vocabulary, visuomotor skills, reading, text comprehension, writing, and arithmetic were tested in Duchenne muscular dystrophy children. No significant difference between control and Duchenne muscular dystrophy children was found neither for mismatch negativity amplitude (P = .191 and .116, respectively) nor for latency (P = .135). Eight (57.14%) patients showed an impairment of immediate verbal memory and of visuomotor skills, 7 (63.64%) patients had a deficit in writing and arithmetic skills, even with a mean normal intelligence quotient. Taken together, the results put in evidence a heterogeneous neuropsychological profile not explainable on the basis of a phonological deficit.

Extrastriate visual cortex in idiopathic occipital epilepsies: The contribution of retinotopic areas to spike generation.

OBJECTIVES: To provide insight into the pathophysiology of idiopathic childhood occipital epilepsies (ICOEs), by mapping the contribution of retinotopic visual areas to the generation and sustainment of epileptic activity. METHODS: Thirteen patients affected by ICOEs (mean age = 10.9 years) underwent a video electroencephalography-functional magnetic resonance imaging (EEG-fMRI) study. A flexible-related fMRI analysis was applied to estimate the shape of the blood oxygen level-dependent (BOLD) response in each patient. Second-level analysis was performed using the interictal EEG discharge (IED)-specific response shape for the ICOE group. The resulting fMRI t-maps were warped to the Population-Average, Landmark- and Surface-based (PALS)-B12 atlas in Caret. For localization purposes, functional results were plotted and compared against 19 retinotopic areas for each hemisphere. A correlation analysis was performed between the hemodynamic maps and electroclinical variables. RESULTS: The shape of the group-averaged hemodynamic response in ICOE patients showed an earlier time-to-peak and a more pronounced undershoot than the canonical hemodynamic response function (HRF). The random-effect analysis showed positive hemodynamic changes in the bilateral temporooccipital network. With regard to the retinotopic subdivision of the visual cortex, the primary visual area was consistently spared. Conversely, an extensive involvement of the occipitotemporal cortex, including the fusiform gyrus, and the occipitoparietal areas was observed. Moreover, a linear relationship was detected between the occipital spike-density and BOLD increases at the postcentral gyrus and temporooccipital cortex. SIGNIFICANCE: Our data indicate that both the ventral and dorsal visual pathways are involved in spike generation in ICOEs, to extents that vary between patients, and reinforce the concept of benign childhood seizure susceptibility syndrome as a substrate for ICOEs. Finally, these results underscore the need for appropriate neuropsychological testing in these children, aimed at revealing selective impairments in functions subserved by both visual pathways.

Neuropsychological profile in new-onset benign epilepsy with centrotemporal spikes (BECTS): Focusing on executive functions.

PURPOSE: Increased evidence of subnormal neuropsychological functioning in new-onset childhood epilepsy has been obtained, although results are still rare and controversial. With a prospective study, we aimed to define the very early neuropsychological profile of children with benign epilepsy with centrotemporal spikes (BECTS), including executive functions (EF) because of their key role in learning. Additionally, we enrolled drug-naïve children, with a NREM sleep frequency of discharges <85% and with a Performance Intelligence Quotient equal or superior to 85, in order to exclude additional effects on the neuropsychological functioning. METHODS: Fifteen school-aged children with BECTS (mean age: 8.8years, standard deviation [SD]: 2.4years) and fifteen healthy children (mean age: 9.2years, [SD]: 2.5years) were enrolled and assessed with a comprehensive neuropsychological battery. The assessment included domain-specific standardized tests of language, EF, academic skills, visuomotor and visuospatial skills, and short-term memory. A p-value<0.05 was considered significant. RESULTS: Significant differences between patients and controls emerged with respect to 3 domains. Language was affected in color naming (p=.026), spoonerism (p=.003), and phonemic synthesis (p=.009). Executive functions appeared inadequate in the five point test with respect to the number of correct figures (p=.003) and errors (p=.008). In the domain of academic skills, significant differences between groups emerged regarding the number of mistakes in nonword writing (p=.001), nonword reading speed (p=.027), nonword reading number of mistakes (p=.019), and word reading errors (p=.023). DISCUSSION: Results showed that children with new-onset BECTS may demonstrate a range of neuropsychological dysfunctions, particularly affecting executive attention, despite a normal IQ, a low frequency of NREM sleep discharges, and the absence of drugs. These difficulties indicate a frontal dysfunction with cascading effects on language and academic skills. The inclusion of EF in the assessment battery and in the intervention since the very onset is warranted in order to avoid further and persistent academic difficulties.

Comparing cortical auditory processing in children with typical and atypical benign epilepsy with centrotemporal spikes: Electrophysiologic evidence of the role of non-rapid eye movement sleep abnormalities.

OBJECTIVE: The mismatch negativity (MMN) is an objective measure of central auditory discrimination. MMN alterations have been shown in children with language and/or developmental disorders. In benign focal epilepsies, neuropsychological disorders are often reported and linked to interictal epileptic discharges (IEDs) during non-rapid eye movement (NREM) sleep. There are few studies reporting MMN in children with benign epilepsy with centrotemporal spikes (BECTS) and sleep IEDs. Moreover, no MMN recording has yet been reported in atypical BECTS children with continuous spike-and-wave during sleep (CSWS). We retrospectively compared MMN in typical and atypical BECTS children, particularly addressing the impact of NREM sleep IEDs on auditory discrimination. Moreover, we attempted a neuropsychological characterization of patients. METHODS: The MMN was recorded in 9 normal controls and 23 patients (14 typical BECTS and 9 atypical BECTS) in an oddball paradigm with syllable stimuli. MMN, sleep electroencephalography (EEG) and neuropsychological evaluation were realized in the same testing session. RESULTS: Measurable MMN responses to speech stimuli were identified in both the control and patient groups. A significant difference between control and atypical BECTS children was found with respect to amplitude (p = 0.0061). Atypical BECTS also showed a lower MMN amplitude with respect to typical BECTS, but this difference did not reach statistical significance (p = 0.0545). Statistical comparisons between groups revealed no differences in latency. Among the neuropsychological variables, academic difficulties were significantly more prominent in the patients with atypical BECTS (p = 0.04). SIGNIFICANCE: CSWS EEG pattern affects auditory discrimination and may have a long-lasting impact on academic skills acquisition, whereas in typical BECTS children with a lower degree of IED NREM sleep, plastic brain reorganization or the preservation of participating networks may prevent such difficulty. Early electrophysiologic identification of auditory discrimination deficits in epileptic children could be used in early rehabilitation, thereby reducing the risk of developing neuropsychological disorders.

Memory impairment and Benign Epilepsy with centrotemporal spike (BECTS): a growing suspicion.

Benign Epilepsy with centrotemporal spikes (BECTS) is considered a benign type of epilepsy; nevertheless a significant number of children present clear and heterogeneous cognitive deficits such as memory disturbances. Thus far, evidence about memory impairment has been less than conclusive. To clarify the quality of memory functioning in BECTS children, an analysis of existing findings has been conducted trying to identify the type of memory deficits and their underlying factors. Short- and long-term declarative memory are impaired in BECTS children, with both verbal and non-verbal material; co-occurrence of attentional, linguistic and behavioral disturbances is reported. In children with continuous spikes and waves during the slow-wave sleep pattern the normal downscaling of slow-wave activity is absent, disrupting plastic brain processes of sleep-related memory consolidation. In BECTS children, NREM sleep interictal epileptiform discharges (IED) may interfere in the dialogue between temporal and frontal cortex, causing declarative memory deficits: the role of NREM sleep IED acquires a special importance, leading to methodological guidance and suggesting aims for future researches in the field of childhood neuroscience.

Neuropsychological development in children belonging to BECTS spectrum: long-term effect of epileptiform activity.

Benign epilepsy with centrotemporal spikes (BECTS) is an idiopathic focal epileptic syndrome in childhood. It is called "benign" because the seizure and cognitive outcomes are usually favorable, but a significant number of children with BECTS present heterogeneous cognitive deficits correlated to NREM sleep epileptiform discharges. The atypical evolutions of BECTS form a spectrum of conditions suggesting that slow sleep nocturnal interictal epileptiform discharges (IEDs) specifically determine the neuropsychological deficit. Few follow-up studies of neuropsychological outcome in BECTS are available, and very often, slow sleep has not been recorded throughout night sleep. The present study analyzed the long-term effects of IEDs during NREM sleep on neuropsychological development in children with rolandic spikes. Thirty-three children with a diagnosis of BECTS were monitored for at least two years. Results show that these children are at higher risk for residual verbal difficulties, and the abnormal neuropsychological development is significantly correlated with a greater frequency of NREM sleep discharges, school-age epilepsy onset, and a higher number of antiepileptic drugs (AEDs). The findings are discussed in terms of how slow sleep IEDs affect the consolidation of verbal skills during critical epochs of neuropsychological development.

Neuropsychological approaches to epileptic encephalopathies.

The International League Against Epilepsy (ILAE) Commission report on classification and terminology indicates that "diagnosing an individual as having an encephalopathic course requires demonstration of a failure to develop as expected relative to the same-aged peers or to regress in abilities." In this chapter, basing our discussion on the theoretical framework of neuroconstructivism, on the latest results deriving from functional neuroimaging and on the concept of system epilepsy, we use continuous spike-waves during slow-wave sleep (CSWS) as an example of how non-rapid eye movement (NREM) sleep spikes interfere with the organization and consolidation of neuropsychological networks in the sensitive phase of development, affecting also interconnected systems. Indeed, recent discoveries show that the normal overnight downscaling of slow wave activity (SWA) from the first to the last hours of sleep is absent in electrical status epilepticus during sleep (ESES) patients, thus impairing the neural process and possibly the local plastic changes associated with learning and other cognitive functions. Moreover, specific patterns of spike-induced activation (especially in perisylvian and/or prefrontal areas) and deactivation of default mode network (DMN) have been shown in patients with CSWS. Consequently, to date, we may conceive that the possible mechanisms underlying neuropsychological disorders in encephalopathic epilepsy (EE) may be double, since NREM sleep interictal epileptic discharges (IEDs) induce both a pathologic activation in epileptogenic areas and a pathologic deactivation of DMN beyond the epileptogenic zone. The growing body of literature on the effects of ESES in CSWS provides us with increasing knowledge on the complexity of brain development and a better understanding of plasticity, enlightening the pathogenesis of damage on developing neuropsychological functions. Finally, the need for an individually tailored interpretation of the neuropsychological testing results, expected to integrate neurophysiology and functional neuroimaging data, is suggested.

Neuropsychological findings: myoclonic astatic epilepsy (MAE) and Lennox-Gastaut syndrome (LGS).

PURPOSE: To identify a specific neuropsychological profile associated with myoclonic astatic epilepsy (MAE) and Lennox-Gastaut syndrome (LGS). METHODS: Seven patients diagnosed with MAE and four patients diagnosed with LGS were selected from patients referred to our Child Neurology Unit. The patients were assessed both clinically (awake, sleep, Holter EEG, seizures frequency, and semiology) and neuropsychologically (IQ, language, attention, visuospatial and visuomotor abilities, and behavior). One representative case of each syndrome is presented here. RESULTS: The clinical picture of the MAE patient resembled that of an MAE condition associated with transitory epileptic encephalopathy. The neuropsychological findings suggest that electroclinical anomalies can temporarily affect cognitive and behavioral functioning. Early effective antiepileptic drug (AED) treatment was found to improve cognitive outcome. In contrast, LGS was associated with mental retardation, which persisted after seizure control. CONCLUSIONS: At present, it remains difficult to delineate a precise neuropsychological profile associated with MAE and LGS. The cognitive outcome of MAE is variable and depends on the clinical pattern. With regard to LGS, the hypothesis of a genetic predisposition underlying both the epilepsy and the mental retardation is still valid. Alternatively, exposure to subclinical electrophysiological anomalies during a critical period of cerebral development may be responsible for the mental retardation. At the time the clinical manifestations appear, drug treatment, even if effective, would have only limited impact on cognitive outcome. However, early multidisciplinary intervention may help to improve behavior and communicative abilities, enhancing the quality of life of these children and their families.

The spectrum of idiopathic Rolandic epilepsy syndromes and idiopathic occipital epilepsies: from the benign to the disabling.

Benign childhood epilepsy with centrotemporal spikes (BCECTS) is an idiopathic focal epilepsy syndrome, the benign characteristics of which are debated; in fact, stable or intermittent specific neuropsychological deficits are frequent and may affect scholastic or adaptive abilities. Cognitive dysfunction may be related to a marked increment of the interictal epileptic discharges in NREM sleep: different degrees of neuropsychological deficits depend on the extent of awake and sleep activity and the predominant discharge localization. The age of onset and duration of atypical sleep EEG patterns may correlate with permanent cognitive impairments. These atypical clinical and EEG evolutions have been reported in the literature as different syndromes that constitute the spectrum of idiopathic rolandic epilepsy. Moreover, a clinical link between BCECTS and early-onset benign childhood occipital epilepsy has been demonstrated. According to the neurobiological approach, the spectrum of Idiopathic Rolandic Epilepsy is based on an age-dependent, idiopathic predisposition to focal seizures and sharp-wave discharges, as an expression of nonlesional cortical excitability. The involvement of a given area of the cerebral cortex may depend on the brain maturational stage.

Neuropsychological findings in Rolandic epilepsy and Landau-Kleffner syndrome.

In an attempt to correlate neuropsychological deficits and various neurophysiological aspects of focal epileptic activity in benign childhood epilepsy, we have reviewed the findings of a longitudinal group study of benign childhood epilepsy with centrotemporal spikes (BCECTS) and several case studies of continuous spike-waves during slow sleep syndrome (CSWS). We first distinguish the temporary neuropsychological impairments often observed in the natural history of BCECTS from the more long-lasting and more specific neuropsychological deficits associated with CSWS, of which the Landau-Kleffner syndrome (LKS) is the most studied clinical form. A series of metabolic findings from (18)FDG-PET studies in BCECTS and CSWS children have shown that specific cognitive impairment is related to increased glucose uptake in cortical areas restricted to the associative cortex coincident with the focus of spike-wave discharges. From recent functional neuroimaging data of three patients recovered from LKS, we address the issue of the pathophysiology of cognitive impairment persisting after complete recovery of epilepsy. Finally, we discuss the reliability of the study of mismatch negativity to address the issue of the early effect of interictal discharges in typical and atypical BCECTS on the auditory cortex and the development of speech processing essential to verbal learning.