Subcortical nuclei volumes are associated with cognition in children post-convulsive status epilepticus: Results at nine years follow-up.

PURPOSE: The purpose of the present study was to investigate the relationship between subcortical nuclei volume and cognition in children with post-convulsive status epilepticus (CSE). METHODS: Structural T1-weighted magnetic resonance imaging (MRI) scans (Siemens Avanto, 1.5 T) and neuropsychological assessments (full-scale intelligence quotient (FSIQ) and Global Memory Scores (GMS)) were collected from subjects at a mean 8.5 years post-CSE (prolonged febrile seizures (PFS), n = 30; symptomatic/known, n = 28; and other, n = 12) and from age- and sex-matched healthy controls (HC). Subjects with CSE were stratified into those with lower cognitive ability (LCA) (CSE+, n = 22) and those without (CSE-, n = 48). Quantitative volumetric analysis using Functional MRI of the Brain Software Library (FSL) (Analysis Group, FMRIB, Oxford) provided segmented MRI brain volumes. Univariate analysis of covariance (ANCOVA) was performed to compare subcortical nuclei volumes across subgroups. Multivariable linear regression was performed for each subcortical structure and for total subcortical volume (SCV) to identify significant predictors of LCA (FSIQ <85) while adjusting for etiology, age, socioeconomic status, sex, CSE duration, and intracranial volume (ICV); Bonferroni correction was applied for the analysis of individual subcortical nuclei. RESULTS: Seventy subjects (11.8 ±â€¯3.4 standard deviation (SD) years; 34 males) and 72 controls (12.1 ±â€¯3.0SD years; 29 males) underwent analysis. Significantly smaller volumes of the left thalamus, left caudate, right caudate, and SCV were found in subjects with CSE+ compared with HC, after adjustment for intracranial, gray matter (GM), or cortical/cerebellar volume. When compared with subjects with CSE-, subjects with CSE+ also had smaller volumes of the left thalamus, left pallidum, right pallidum, and SCV. Individual subcortical nuclei were not associated, but SCV was associated with FSIQ (p = 0.005) and GMS (p = 0.014). Intracranial volume and etiology were similarly predictive. CONCLUSIONS: Nine years post-CSE, SCV is significantly lower in children who have LCA compared with those that do not. However, in this cohort, we are unable to determine whether the relationship is independent of ICV or etiology. Future, larger scale studies may help tease this out.

Intelligence and memory outcomes within 10 years of childhood convulsive status epilepticus.

Long-term intelligence and memory outcomes of children post convulsive status epilepticus (CSE) have not been systematically investigated despite evidence of short-term impairments in CSE. The present study aimed to describe intelligence and memory outcomes in children within 10 years of CSE and identify potential risk factors for adverse outcomes. In this cohort study, children originally identified by the population-based North London Convulsive Status Epilepticus in Childhood Surveillance Study (NLSTEPSS) were prospectively recruited between July 2009 and February 2013 and invited for neuropsychological assessments and magnetic resonance imaging (MRI) scans. Full-scale intelligence quotients (FSIQs) were measured using the Wechsler Abbreviated Scales of Intelligence (WASI), and global memory scores (GMS) was assessed using the Children's Memory Scale (CMS). The cohort was analyzed as a whole and stratified into a prolonged febrile seizures (PFS) and non-PFS group. Their performance was compared with population norms and controls. Regression models were fitted to identify predictors of outcomes. With a mean of 8.9 years post-CSE, 28.5% of eligible participants were unable to undertake testing because of their severe neurodevelopmental deficits. Children with CSE who undertook formal testing (N = 94) were shown to have significantly lower FSIQ (p = 0.001) and GMS (p = 0.025) from controls; the PFS group (N = 34) had lower FSIQs (p = 0.022) but similar memory quotients (p = 0.88) with controls. Intracranial volume (ICV), developmental delay at baseline, and active epilepsy at follow-up were predictive of long-term outcomes in the non-PFS group. The relationship between ICV and outcomes was absent in the PFS group despite its presence in the control and non-PFS groups. Post-CSE, survivors reveal significant intelligence and memory impairments, but prognosis differs by CSE type; memory scores are uncompromised in the PFS group despite evidence of their lower FSIQ whereas both are compromised in the non-PFS group. Correlations between brain volumes and outcomes differ in the PFS, non-PFS, and control groups and require further investigation.

Long-term prognosis after childhood convulsive status epilepticus: a prospective cohort study.

BACKGROUND: The prognosis of convulsive status epilepticus (CSE), a common childhood medical neurological emergency, is not well characterised. We aimed to investigate the long-term outcomes in a cohort of participants who previously had CSE. METHODS: In this prospective study, we followed up a population-based childhood CSE cohort from north London, UK (the north London convulsive status epilepticus surveillance study cohort; NLSTEPSS). We collected data from structured clinical neurological assessment, neurocognitive assessment (Wechsler Abbreviated Scale of Intelligence), brain MRI, medical records, and structured interviews with participants and their parents to determine neurological outcomes, with adverse outcome defined as presence of one or more of epilepsy (active or in remission), motor disability, intellectual disability, or statement of special educational needs. We applied multiple imputation to address missing data and performed binary logistic regression analyses on complete-case and imputed datasets to investigate sociodemographic and CSE factors associated with adverse outcomes. FINDINGS: Of 203 survivors (90% of inception cohort), 134 (66%) were assessed at a median follow-up of 8·9 years (IQR 8·2-9·5). The cumulative incidence of epilepsy was 24·7% (95% CI 16·2-35·6), with most (89%) emerging within 18 months after CSE. The cumulative incidence of epilepsy was lower in patients with prolonged febrile seizures (14·3%, 6·3-29·4) and survivors of acute symptomatic CSE (13·3%, 3·7-37·9) than in those of remote symptomatic CSE (45·5%, 21·3-72·0) and unclassified CSE (50·0%, 25·4-74·6). One participant (2·9%, 0·5-14·5) in the prolonged febrile seizures group developed temporal lobe epilepsy with mesial temporal sclerosis. The absence of fever at CSE was the only predictor of incident epilepsy (odds ratio [OR] 7·5, 95% CI 2·25-25·1). Motor and intellectual disability was seen predominantly in participants who had idiopathic and cryptogenic CSE (seven [36·8%, 95% CI 19·1-59·0] and 16 [84·2%, 62·4-94·5] of 19, respectively) and remote symptomatic CSE (33 [62·3%, 48·8-74·1] and 40 [75·5%, 62·4-85·1] of 53), and most of these participants had pre-existing disabilities. Pre-existing epilepsy was the only predictor of intellectual disability (OR 8·0, 95% CI 1·1-59·6). 51·5% (95% CI 43·1-59·8) of those followed up had a statement of special educational needs. INTERPRETATION: Childhood CSE is associated with substantial long-term neurological morbidity, but primarily in those who have epilepsy, neurological abnormalities, or both before the episode of CSE. Survivors without neurological abnormalities before CSE have favourable outcomes. FUNDING: BUPA Foundation, The Academy of Medical Sciences, Wellcome Trust, National Institute for Health Research, and Young Epilepsy.

Long-term behavioural outcomes after paediatric convulsive status epilepticus: a population-based cohort study.

AIM: To describe behavioural and psychiatric outcomes of children within 10 years of convulsive status epilepticus (CSE). METHOD: Children originally identified by the population-based North London Convulsive Status Epilepticus in Childhood Surveillance Study were followed-up between July 2009 and February 2013. They were grouped into epilepsy- and non-epilepsy-related CSE, and compared with population norms and healthy controls using the Strengths and Difficulties Questionnaire; the Autism Spectrum Screening Questionnaire; and the Swanson, Nolan, and Pelham questionnaire. Children who scored above recommended clinical cut-offs on any scale were invited for a neuropsychiatric assessment. Regression models were fitted to identify clinically relevant covariates associated with behavioural outcomes. RESULTS: At a mean follow-up of 8.1 years post-CSE, 28% of enrolled children were found to have a psychiatric disorder. Children with epilepsy-related CSE scored higher than norms on all scales and children with non-epilepsy-related CSE scored higher than norms on the Strengths and Difficulties Questionnaire and the Autism Spectrum Screening Questionnaire. Presence of seizures at baseline and recurrence of CSE was associated with worse outcomes in the group with epilepsy. Intellectual abilities were associated with behavioural outcomes in all participants. INTERPRETATION: A large proportion of children manifest behavioural issues 8 years after CSE. The present data highlight the need for behavioural screening in children with neurodevelopmental impairments post-CSE. WHAT THIS PAPER ADDS: Eight years post convulsive status epilepticus (CSE), 37% of parents report behavioural issues. Of enrolled children, 28% were found to have a Diagnostic and Statistical Manual mental disorder. Intellectual abilities are strongly associated with behavioural outcomes in children post-CSE.

Long-term white matter tract reorganization following prolonged febrile seizures.

OBJECTIVE: Diffusion magnetic resonance imaging (MRI) studies have demonstrated acute white matter changes following prolonged febrile seizures (PFS), but their longer-term evolution is unknown. We investigated a population-based cohort to determine white matter diffusion properties 8 years after PFS. METHODS: We used diffusion tensor imaging (DTI) and applied Tract-Based Spatial Statistics for voxel-wise comparison of white matter microstructure between 26 children with PFS and 27 age-matched healthy controls. Age, gender, handedness, and hippocampal volumes were entered as covariates for voxel-wise analysis. RESULTS: Mean duration between the episode of PFS and follow-up was 8.2 years (range 6.7-9.6). All children were neurologically normal, and had normal conventional neuroimaging. On voxel-wise analysis, compared to controls, the PFS group had (1) increased fractional anisotropy in early maturing central white matter tracts, (2) increased mean and axial diffusivity in several peripheral white matter tracts and late-maturing central white matter tracts, and (3) increased radial diffusivity in peripheral white matter tracts. None of the tracts had reduced fractional anisotropy or diffusivity indices in the PFS group. SIGNIFICANCE: In this homogeneous, population-based sample, we found increased fractional anisotropy in early maturing central white matter tracts and increased mean and axial diffusivity with/without increased radial diffusivity in several late-maturing peripheral white matter tracts 8 years post-PFS. We propose disruption in white matter maturation secondary to seizure-induced axonal injury, with subsequent neuroplasticity and microstructural reorganization as a plausible explanation.

Hippocampal volume loss following childhood convulsive status epilepticus is not limited to prolonged febrile seizures.

PURPOSE: Childhood convulsive status epilepticus (CSE), in particular prolonged febrile seizures (PFS), has been linked with mesial temporal sclerosis (MTS). Previous studies have shown that hippocampal injury occurs in the acute phase immediately following CSE, but little is known about the longer term evolution of such injury. This study aimed to investigate the longer term outcome of childhood CSE with sequential magnetic resonance imaging (MRI) looking for progressive hippocampal injury during the first year post-CSE. METHODS: Eighty children (0.18-15.5 years) underwent brain MRI 1 month post-CSE, 50 with a repeat MRI at 6 months and 46 with repeat MRI at 12 months post-CSE. Thirty-one control subjects without neurologic problems had a single brain MRI for comparison. Hippocampal volumes were measured from each MRI scan by two independent observers, and hippocampal growth rates were estimated in each patient with suitable imaging. KEY FINDINGS: Hippocampal volume loss was found in 20-30% of patients and was not associated with the etiology or clinical features of CSE, including seizure duration or focality. A borderline association was found between a history of previous seizures (p = 0.063) and the number of previous febrile seizures (p = 0.051), suggesting that multiple insults may be important in the pathogenesis of progressive hippocampal injury. SIGNIFICANCE: It is apparent that progressive hippocampal damage can occur after CSE of any etiology and is not limited to PFS. Repeated seizures may play an important role, but further follow-up is needed to determine any other risk factors and proportion of children showing initial volume loss progress to clinical MTS and temporal lobe epilepsy.

Early developmental outcomes in children following convulsive status epilepticus: a longitudinal study.

PURPOSE: Convulsive status epilepticus (CSE) is the most common pediatric neurologic emergency and is often associated with unfavorable neurodevelopmental outcomes. The early developmental trajectory of children following CSE has not been previously investigated, leaving a gap in our understanding of how these adverse long-term outcomes emerge. METHODS: We prospectively recruited children aged between 1 and 42 months from a predefined geographic region of North London who had at least one episode of CSE and classified them as prolonged febrile seizures (PFS) or nonfebrile CSE. Neuropsychological and imaging investigations were conducted within 6 weeks of CSE (baseline) and were repeated a year later (follow-up). Neurodevelopment was assessed using the Bayley Scales of Infant Development III and compared to normally developing children. Predictors of neurodevelopmental scores at baseline and follow-up were investigated using regression analyses. KEY FINDINGS: Of the 54 children that underwent investigations a mean of 38 days following CSE, 27 had PFS (mean age 18.4 months) and 27 had nonfebrile CSE (mean age 15.5 months). In addition, 17 healthy controls were assessed (mean age 20.49 months). Children with nonfebrile CSE had a worse developmental outcome than children with PFS (p < 0.002), despite there being no differences in seizure characteristics. In contrast to expectations, the PFS group had a worse developmental outcome than controls (p = 0.002). There were no significant differences in performance from baseline to 1-year follow-up for the 70.4% of children who provided data. Seizure characteristics were not shown to be significant predictors of performance. SIGNIFICANCE: CSE is associated with developmental impairments within 6 weeks of the acute event that continue to be present a year onward. This is also true of PFS cases that under-perform relative to controls despite mean scores within the clinically normal range. The absence of a change in performance from baseline to follow-up as well as the lack of a relationship between seizure characteristics and developmental outcomes supports the notion that premorbid abilities may be overshadowing any direct effects of CSE itself on outcome.

Recognition memory is impaired in children after prolonged febrile seizures.

Children with a history of a prolonged febrile seizure show signs of acute hippocampal injury on magnetic resonance imaging. In addition, animal studies have shown that adult rats who suffered febrile seizures during development reveal memory impairments. Together, these lines of evidence suggest that memory impairments related to hippocampal injury may be evident in human children after prolonged febrile seizures. The current study addressed this question by investigating memory abilities in 26 children soon after a prolonged febrile seizure (median: 37.5 days) and compared their results to those of 37 normally developing children. Fifteen patients were reassessed at a mean of 12.5 months after their first assessment to determine the transiency of any observed effects. We used the visual paired comparison task to test memory abilities in our group, as this task does not depend on verbal abilities and also because successful performance on the task has been proven to depend on the presence of functional hippocampi. Our findings show that patients perform as well as controls in the absence of a delay between the learning phase and the memory test, suggesting that both groups are able to form representations of the presented stimulus. However, after a 5-min delay, patients' recognition memory is not different from chance, and comparison of patients and controls points to an accelerated forgetting rate in the prolonged febrile seizure group. The patients' performance was not related to the time elapsed from the acute event or the duration of the prolonged febrile seizure, suggesting that the observed effect is not a by-product of the seizure itself or a delayed effect of medication administered to terminate the seizure. By contrast, performance was related to hippocampal size; participants with the smallest mean hippocampal volumes revealed the biggest drop in performance from the immediate to the delayed paradigm. At follow-up, children were still showing deficiencies in recognizing a face after a 5-min delay. Similarly, this suggests that the observed memory impairments are not a transient effect of the prolonged febrile seizures. This is the first report of such impairments in humans, and it is clinically significant given the links between mesial temporal sclerosis and prolonged febrile seizures. The persistence of these impairments a year onwards signals the potential benefits of intervention in these children who run the risk of developing episodic memory deficits in later childhood.

Links between infant temperament and neurophysiological measures of attention to happy and fearful faces.

BACKGROUND: Developing control of attention helps infants to regulate their emotions, and individual differences in attention skills may shape how infants perceive and respond to their socio-emotional environments. This study examined whether the temperamental dimensions of self-regulation and negative emotionality relate to infants' attention skills and whether the emotional content of the attended stimulus affects this relation. METHODS: Event-related potentials provided a neurophysiological index of attention (Nc) while 3 to 13-month-old infants viewed images of happy and fearful facial expressions. Temperament was measured via parent report using the Infant Behavior Questionnaire-Revised. RESULTS: The peak latency of the Nc was slower for infants with lower regulatory capacity, independent of facial expression. The amplitude of the Nc over right fronto-central electrodes was related to both self-regulation and negative emotionality, but the effects differed by emotion: infants with better self-regulation had larger Nc responses to fearful faces, and infants scoring higher on negative emotionality had larger Nc responses to happy faces. These results are discussed in relation to the development of executive attention networks and their modulation by the amygdala.

The role of magnetic resonance imaging in the follow-up of children with convulsive status epilepticus.

AIM: The aim of this study was to determine the yield of magnetic resonance imaging (MRI) after an episode of childhood convulsive status epilepticus (CSE) and to identify the clinical predictors of an abnormal brain scan. METHOD: Children were recruited following an episode of CSE from an established clinical network in north London. Eighty children (age range 1mo-16y; 39 males; 41 females) were enrolled and seen for clinical assessment and brain MRI within 13 weeks of suffering from an episode of CSE. Scans were reviewed by two neuroradiologists and classified as normal (normal/normal-variant) or abnormal (minor/major abnormality). Factors predictive of an abnormal scan were investigated using logistic regression. RESULTS: Eighty children were recruited at a mean of 31.8 days (5-90d) after suffering from CSE. Structural abnormalities were found in 31%. Abnormal neurological examination at assessment (odds ratio [OR] 190.46), CSE that was not a prolonged febrile seizure (OR 77.12), and a continuous rather than an intermittent seizure (OR 29.98) were all predictive of an abnormal scan. No children with previous neuroimaging had new findings that altered their clinical management. INTERPRETATION: Brain MRI should be considered for all children with a history of CSE who have not previously undergone MRI, especially those with non-prolonged febrile seizure CSE, those with persisting neurological abnormalities 2 to 13 weeks after CSE, and those with continuous CSE.

Tourette's syndrome (TS): inhibitory performance in adults with uncomplicated TS.

Tourette's syndrome (TS) is a neurodevelopmental disorder linked with frontostriatal dysfunction. Previous work has shown some evidence of mild performance deficits on a range of different tasks that involve inhibitory processes. The present study evaluated this in adult participants with uncomplicated TS. Interference control was measured using the Stroop and flanker tasks and a Stroop-flanker task that combined the inhibitory demands of both. Motor inhibition was measured using a letter continuous performance test (CPT) task and word CPT tasks that manipulated the inhibitory demands using compatible and incompatible words. The TS group was found to be slower than the control group on most measures, but showed differential slowing under conditions with enhanced inhibitory demands on the combined Stroop-flanker and the incompatible CPT tasks. The findings suggest that TS-alone is linked to mild impairments in aspects of inhibitory function, and that these can be detected by relatively powerful inhibitory manipulations. A range of different types of inhibitory tasks may be sensitive to TS-alone, and this may depend on both the type of inhibition and the strength of the inhibitory manipulation.

Repeat and Point: differentiating semantic dementia from progressive non-fluent aphasia.

To determine whether a new, simple, quick measure, the Repeat and Point test, reliably differentiates between semantic dementia (SD) and progressive non-fluent aphasia (PNFA). Fifteen patients with SD, six patients with PNFA and 18 healthy controls were administered the Repeat and Point test. Participants were required to repeat 10 multi-syllabic concrete nouns and, following each repetition, to point to the word's pictorial referent amongst an array of six semantically and perceptually similar foils. Patients with SD were consistently impaired relative to PNFA patients and controls on the comprehension (pointing) component of the task, whereas patients with PNFA showed no significant deficit on pointing but were impaired at the production (repeating) component. Discriminant function analysis confirmed perfect classification of the individual patients into their respective groups: criteria involving a ratio of the two scores are provided. The Repeat and Point test is particularly appropriate for routine use in a clinical context: it is quick and easy to administer and score; it reliably discriminated between the two patient groups, SD and PNFA; and it offers a simple rule of thumb, i.e., the Repeat-to-Point ratio, to aid in the diagnosis of these two language variants of frontotemporal dementia (FTD).

Interpretation of mentalistic actions and sarcastic remarks: effects of frontal and posterior lesions on mentalising.

Recent work has linked mentalising ability to ventromedial frontal brain regions, the temporal poles and the temporo-parietal junction. The present study set out to examine the performance of participants with focal frontal and posterior lesions and a matched healthy control group on mentalising tasks with different types of pragmatic materials. Four types of materials were used: control physical events, human actions, and direct and indirect sarcastic remarks. Ability to interpret these was tested by asking participants both to explain the events, actions or remarks, and then to choose the best solution from four alternatives presented. Those with frontal lesions were impaired in comprehension of each of the sets of mentalistic materials, but were intact in comprehension of the control non-mentalistic items. There was some evidence linking the generation of free responses for the mentalistic materials to lateral frontal regions; this may be mediated by executive skills. There was also evidence linking selection amongst alternative solutions to right frontal regions, particularly ventromedial areas. There was little evidence that posterior regions played any significant part, at least for the present mentalistic materials. Errors in sarcasm comprehension made by participants with frontal lesions revealed that these were not always literal in nature, suggesting two separable components in comprehension: appreciating that a meaning is not intended literally, and understanding the specific meaning in the social context.