Perioperative Brain Injury in Relation to Early Neurodevelopment Among Children with Severe Congenital Heart Disease: Results from a European Collaboration.

OBJECTIVE: To examine the relationship between perioperative brain injury and neurodevelopment during early childhood in patients with severe congenital heart disease (CHD). STUDY DESIGN: One hundred and seventy children with CHD and born at term who required cardiopulmonary bypass surgery in the first 6 weeks after birth were recruited from 3 European centers and underwent preoperative and postoperative brain MRIs. Uniform description of imaging findings was performed and an overall brain injury score was created, based on the sum of the worst preoperative or postoperative brain injury subscores. Motor and cognitive outcomes were assessed with the Bayley Scales of Infant and Toddler Development Third Edition at 12 to 30 months of age. The relationship between brain injury score and clinical outcome was assessed using multiple linear regression analysis, adjusting for CHD severity, length of hospital stay (LOS), socioeconomic status (SES), and age at follow-up. RESULTS: Neither the overall brain injury score nor any of the brain injury subscores correlated with motor or cognitive outcome. The number of preoperative white matter lesions was significantly associated with gross motor outcome after correction for multiple testing (P = .013, ß = -0.50). SES was independently associated with cognitive outcome (P < .001, ß = 0.26), and LOS with motor outcome (P < .001, ß = -0.35). CONCLUSION: Preoperative white matter lesions appear to be the most predictive MRI marker for adverse early childhood gross motor outcome in this large European cohort of infants with severe CHD. LOS as a marker of disease severity, and SES influence outcome and future intervention trials need to address these risk factors.

Determinants of Functional Outcome after Pediatric Hemispherotomy.

OBJECTIVE: We aimed to evaluate determinants of functional outcome after pediatric hemispherotomy in a large and recent multicenter cohort. METHODS: We retrospectively investigated the functional outcomes of 455 children who underwent hemispherotomy at 5 epilepsy centers in 2000-2016. We identified determinants of unaided walking, voluntary grasping with the hemiplegic hand, and speaking through Bayesian multivariable regression modeling using missing data imputation. RESULTS: Seventy-five percent of children were seizure-free, and 44% stopped antiseizure medication at a 5.1-year mean follow-up (range = 1-17.1). Seventy-seven percent of children could walk unaided, 8% could grasp voluntarily, and 68% could speak at the last follow-up. Children were unlikely to walk when they had contralateral magnetic resonance imaging (MRI) abnormalities (40/73, p = 0.04), recurrent seizures following hemispherotomy (62/109, p = 0.04), and moderately (50/61, p = 0.03) or severely impaired (127/199, p = 0.001) postsurgical intellectual functioning, but were likely to walk when they were older at outcome determination (p = 0.01). Children were unlikely to grasp voluntarily with the hand contralateral to surgery when they had Rasmussen encephalitis (0/61, p = 0.001) or Sturge-Weber syndrome (0/32, p = 0.007). Children were unlikely to speak when they had contralateral MRI abnormalities (30/69, p = 0.002) and longer epilepsy duration (p = 0.01), but likely to speak when they had Sturge-Weber syndrome (29/35, p = 0.01), were older at surgery (p = 0.04), and were older at outcome determination (p < 0.001). INTERPRETATION: Etiology and bilaterality of structural brain abnormalities were key determinants of functional outcome after hemispherotomy. Longer epilepsy duration affected language outcomes. Not surprisingly, walking and talking ability increased with older age at outcome evaluation. ANN NEUROL 2024;95:377-387.

Efficient organisation of the contralateral hemisphere connectome is associated with improvement in intelligence quotient after paediatric epilepsy surgery.

OBJECTIVE: Aims of epilepsy surgery in childhood include optimising seizure control and facilitating cognitive development. Predicting which children will improve cognitively is challenging. We investigated the association of the pre-operative structural connectome of the contralateral non-operated hemisphere with improvement in intelligence quotient (IQ) post-operatively. METHODS: Consecutive children who had undergone unilateral resective procedures for epilepsy at a single centre were retrospectively identified. We included those with pre-operative volume T1-weighted non-contrast brain magnetic resonance imaging (MRI), no visible contralateral MRI abnormalities, and both pre-operative and two years post-operative IQ assessment. The MRI of the hemisphere contralateral to the side of resection was anatomically parcellated into 34 cortical regions and the covariance of cortical thickness between regions was used to create binary and weighted group connectomes. RESULTS: Eleven patients with a post-operative IQ increase of at least 10 points at two years were compared with twenty-four patients with no change in IQ score. Children who gained at least 10 IQ points post-operatively had a more efficiently structured contralateral hemisphere connectome with higher global efficiency (0.74) compared to those whose IQ did not change at two years (0.58, p = 0.014). This was consistent across thresholds and both binary and weighted networks. There were no statistically significant group differences in age, sex, age at onset of epilepsy, pre-operative IQ, mean cortical thickness, side or site of procedure, two year post-operative Engel scores or use of anti-seizure medications between the two groups. CONCLUSIONS: Surgical procedures to reduce or stop seizures may allow children with an efficiently structured contralateral hemisphere to achieve their cognitive potential.

The association of structural connectome efficiency with cognition in children with epilepsy.

OBJECTIVE: Cognitive impairment is common in children with epilepsy (CWE), but understanding the underlying pathological processes is challenging. We aimed to investigate the association of structural brain network organisation with cognition. METHODS: This was a retrospective cohort study of CWE without structural brain abnormalities, comparing whole brain network characteristics between those with cognitive impairment and those with intact cognition. We created structural whole-brain connectomes from anatomical and diffusion tensor magnetic resonance imaging using the number of streamlines and tract-averaged fractional anisotropy. We assessed the differences in average path length and global network efficiency between children with cognitive impairment and those without,using multivariable analyses to account for possible clinical group differences. RESULTS: Twenty-eight CWE and cognitive impairment had lower whole brain network global efficiency compared with 34 children with intact cognition (0.54, standard deviation (SD):0.003 vs. 0.56, SD:0.002, p < 0.001), which is equivalent to longer normalized network average path lengths (1.14, SD:0.05 vs. 1.10, SD:0.02, p = 0.003). In multivariable logistic regression cognitive impairment was not significantly associated with age of onset, duration of epilepsy, or number of antiseizure medications, but was independently associated with daily seizures (p = 0.04) and normalized average path length (p = 0.007). CONCLUSIONS: Higher structural network average path length and lower global network efficiency may be imaging biomarkers of cognitive impairment in epilepsy. Understanding what leads to changes in structural connectivity could aid identification of modifiable risk factors for cognitive impairment. These findings are only applicable to the specific cohort studied, and further confirmation in other cohorts is required.

Neurocognitive, Psychosocial, and Quality of Life Outcomes After Multisystem Inflammatory Syndrome in Children Admitted to the PICU.

OBJECTIVES: To investigate neurocognitive, psychosocial, and quality of life (QoL) outcomes in children with Multisystem Inflammatory Syndrome in Children (MIS-C) seen 3-6 months after PICU admission. DESIGN: National prospective cohort study March 2020 to November 2021. SETTING: Seven PICUs in the Netherlands. PATIENTS: Children with MIS-C (0-17 yr) admitted to a PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children and/or parents were seen median (interquartile range [IQR] 4 mo [3-5 mo]) after PICU admission. Testing included assessment of neurocognitive, psychosocial, and QoL outcomes with reference to Dutch pre-COVID-19 general population norms. Effect sizes (Hedges' g ) were used to indicate the strengths and clinical relevance of differences: 0.2 small, 0.5 medium, and 0.8 and above large. Of 69 children with MIS-C, 49 (median age 11.6 yr [IQR 9.3-15.6 yr]) attended follow-up. General intelligence and verbal memory scores were normal compared with population norms. Twenty-nine of the 49 followed-up (59%) underwent extensive testing with worse function in domains such as visual memory, g = 1.0 (95% CI, 0.6-1.4), sustained attention, g = 2.0 (95% CI 1.4-2.4), and planning, g = 0.5 (95% CI, 0.1-0.9). The children also had more emotional and behavioral problems, g = 0.4 (95% CI 0.1-0.7), and had lower QoL scores in domains such as physical functioning g = 1.3 (95% CI 0.9-1.6), school functioning g = 1.1 (95% CI 0.7-1.4), and increased fatigue g = 0.5 (95% CI 0.1-0.9) compared with population norms. Elevated risk for posttraumatic stress disorder (PTSD) was seen in 10 of 30 children (33%) with MIS-C. Last, in the 32 parents, no elevated risk for PTSD was found. CONCLUSIONS: Children with MIS-C requiring PICU admission had normal overall intelligence 4 months after PICU discharge. Nevertheless, these children reported more emotional and behavioral problems, more PTSD, and worse QoL compared with general population norms. In a subset undergoing more extensive testing, we also identified irregularities in neurocognitive functions. Whether these impairments are caused by the viral or inflammatory response, the PICU admission, or COVID-19 restrictions remains to be investigated.

The profile of cognitive impairment and hemodynamic compromise in moyamoya: a single-center prospective cohort study.

OBJECTIVE: Patients with moyamoya vasculopathy often experience cognitive impairments. In this prospective single-center study, the authors investigated the profile of neurocognitive impairment and its relation with the severity of ischemic brain lesions and hemodynamic compromise. METHODS: Patients treated in a Dutch tertiary referral center were prospectively included. All patients underwent standardized neuropsychological evaluation, MRI, digital subtraction angiography, and [15O]H2O-PET (to measure cerebrovascular reactivity [CVR]). The authors determined z-scores for 7 cognitive domains and the proportion of patients with cognitive impairment (z-score < -1.5 SD in at least one domain). The authors explored associations between patient characteristics, imaging and CVR findings, and cognitive scores per domain by using multivariable linear regression and Bayesian regression analysis. RESULTS: A total of 40 patients (22 children; 75% females) were included. The median age for children was 9 years (range 1-16 years); for adults it was 39 years (range 19-53 years). Thirty patients (75%) had an infarction, and 31 patients (78%) had impaired CVR (steal phenomenon). Six of 7 cognitive domains scored below the population norm. Twenty-nine patients (73%) had cognitive impairment. Adults performed better than children in the cognitive domain visuospatial functioning (p = 0.033, Bayes factor = 4.0), and children performed better in processing speed (p = 0.041, Bayes factor = 3.5). The authors did not find an association between infarction, white matter disease, or CVR and cognitive domains. CONCLUSIONS: In this Western cohort, cognitive functioning in patients with moyamoya vasculopathy was below the population norm, and 73% had cognitive impairment in at least one domain. The cognitive profile differed between adults and children. The authors could not find an association with imaging findings.

Clinical Outcome, Cognition, and Cerebrovascular Reactivity after Surgical Treatment for Moyamoya Vasculopathy: A Dutch Prospective, Single-Center Cohort Study.

Background: It remains unclear whether revascularization of moyamoya vasculopathy (MMV) has a positive effect on cognitive function. In this prospective, single-center study, we investigated the effect of revascularization on cognitive function in patients with MMV. We report clinical and radiological outcome parameters and the associations between clinical determinants and change in neurocognitive functioning. Methods: We consecutively included all MMV patients at a Dutch tertiary referral hospital who underwent pre- and postoperative standardized neuropsychological evaluation, [15O]H2O-PET (including cerebrovascular reactivity (CVR)), MRI, cerebral angiography, and completed standardized questionnaires on clinical outcome and quality of life (QOL). To explore the association between patient characteristics, imaging findings, and change in the z-scores of the cognitive domains, we used multivariable linear- and Bayesian regression analysis. Results: We included 40 patients of whom 35 (27 females, 21 children) were treated surgically. One patient died after surgery, and two withdrew from the study. TIA- and headache frequency and modified Rankin scale (mRS) improved (resp. p = 0.001, 0.019, 0.039). Eleven patients (seven children) developed a new infarct during follow-up (31%), five of which were symptomatic. CVR-scores improved significantly (p < 0.0005). The language domain improved (p = 0.029); other domains remained stable. In adults, there was an improvement in QOL. We could not find an association between change in imaging and cognitive scores. Conclusion: In this cohort of Western MMV patients, TIA frequency, headache, CVR, and mRS improved significantly after revascularization. The language domain significantly improved, while others remained stable. We could not find an association between changes in CVR and cognitive scores.

Intraoperative electrocorticography using high-frequency oscillations or spikes to tailor epilepsy surgery in the Netherlands (the HFO trial): a randomised, single-blind, adaptive non-inferiority trial.

BACKGROUND: Intraoperative electrocorticography is used to tailor epilepsy surgery by analysing interictal spikes or spike patterns that can delineate epileptogenic tissue. High-frequency oscillations (HFOs) on intraoperative electrocorticography have been proposed as a new biomarker of epileptogenic tissue, with higher specificity than spikes. We prospectively tested the non-inferiority of HFO-guided tailoring of epilepsy surgery to spike-guided tailoring on seizure freedom at 1 year. METHODS: The HFO trial was a randomised, single-blind, adaptive non-inferiority trial at an epilepsy surgery centre (UMC Utrecht) in the Netherlands. We recruited children and adults (no age limits) who had been referred for intraoperative electrocorticography-tailored epilepsy surgery. Participants were randomly allocated (1:1) to either HFO-guided or spike-guided tailoring, using an online randomisation scheme with permuted blocks generated by an independent data manager, stratified by epilepsy type. Treatment allocation was masked to participants and clinicians who documented seizure outcome, but not to the study team or neurosurgeon. Ictiform spike patterns were always considered in surgical decision making. The primary endpoint was seizure outcome after 1 year (dichotomised as seizure freedom [defined as Engel 1A-B] vs seizure recurrence [Engel 1C-4]). We predefined a non-inferiority margin of 10% risk difference. Analysis was by intention to treat, with prespecified subgroup analyses by epilepsy type and for confounders. This completed trial is registered with the Dutch Trial Register, Toetsingonline ABR.NL44527.041.13, and ClinicalTrials.gov, NCT02207673. FINDINGS: Between Oct 10, 2014, and Jan 31, 2020, 78 individuals were enrolled to the study and randomly assigned (39 to HFO-guided tailoring and 39 to spike-guided tailoring). There was no loss to follow-up. Seizure freedom at 1 year occurred in 26 (67%) of 39 participants in the HFO-guided group and 35 (90%) of 39 in the spike-guided group (risk difference -23·5%, 90% CI -39·1 to -7·9; for the 48 patients with temporal lobe epilepsy, the risk difference was -25·5%, -45·1 to -6·0, and for the 30 patients with extratemporal lobe epilepsy it was -20·3%, -46·0 to 5·4). Pathology associated with poor prognosis was identified as a confounding factor, with an adjusted risk difference of -7·9% (90% CI -20·7 to 4·9; adjusted risk difference -12·5%, -31·0 to 5·9, for temporal lobe epilepsy and 5·8%, -7·7 to 19·5, for extratemporal lobe epilepsy). We recorded eight serious adverse events (five in the HFO-guided group and three in the spike-guided group) requiring hospitalisation. No patients died. INTERPRETATION: HFO-guided tailoring of epilepsy surgery was not non-inferior to spike-guided tailoring on intraoperative electrocorticography. After adjustment for confounders, HFOs show non-inferiority in extratemporal lobe epilepsy. This trial challenges the clinical value of HFOs as an epilepsy biomarker, especially in temporal lobe epilepsy. Further research is needed to establish whether HFO-guided intraoperative electrocorticography holds promise in extratemporal lobe epilepsy. FUNDING: UMCU Alexandre Suerman, EpilepsieNL, RMI Talent Fellowship, European Research Council, and MING Fund.

Cumulative effects of antiseizure medication on intelligence in children with focal epilepsy

Objective: Antiseizure medication may have long-term effects on the neurodevelopment of children. We aimed to investigate the association between cumulative antiseizure medication load and intelligence quotient (IQ) in relation to brain volume and cortical thickness. Methods: A retrospective analysis of children with focal epilepsy who underwent neuropsychological assessment and MRI between the ages of 5-12 years in a tertiary epilepsy centre was performed. Cumulative medication load was presented in medication years. We studied the association between total medication load and IQ with multivariable linear regression, corrected for epilepsy-related confounders: age at first treatment, aetiology, maximum seizure frequency, duration of active epilepsy, history of secondary generalized seizures, history of status epilepticus, and the number of antiseizure medications used at time of neuropsychological assessment. Results: We included 59 children. Median medication load was 5.3 medication-years (interquartile range: 2.0 ­ 11.1) and mean total IQ (± standard deviation) was 77.4±18.9. A significant negative relation between medication load and total IQ was found with a decrease of 1.2 IQ-points per medication-year (95% confidence interval: -2.0 to -0.3) after correcting for confounders. Medication load and IQ were both not significantly associated with brain volume or cortical thickness. Significance: Higher cumulative medication load is associated with lower total IQ after adjusting for epilepsy-related confounders. We found no evidence to support the hypothesis that the medication-related IQ decrease was mediated by volumetric brain changes. However, these results should be interpreted with caution, and prospective, longitudinal confirmation of these findings is required. Lastly, it should be stressed that effective seizure prevention often outweighs the potential negative effects of antiseizure medication.

Bimanual performance in children with unilateral perinatal arterial ischaemic stroke or periventricular haemorrhagic infarction.

BACKGROUND: Long term outcome data on bimanual performance in children with perinatal arterial ischaemic stroke (PAIS) and periventricular haemorrhagic infarction (PVHI) with and without unilateral spastic cerebral palsy (USCP) is sparse. AIMS: To assess bimanual performance in children with PAIS or PVHI with and without USCP and to explore the relationship with unilateral hand function and full-scale IQ (FSIQ) in a cross-sectional study. METHODS: Fifty-two children with PAIS (n = 27) or PVHI (n = 25) participated at a median age of 12 years and 1 month (range 6-20 years). The Bruininks Oseretsky Test of Motor Proficiency-2 (bimanual precision and dexterity subtest), Assisting Hand Assessment, Purdue Pegboard Test and Wechsler Intelligence scale were administered. RESULTS: Bimanual dexterity was worse in children with USCP (p < 0.02) without a difference for the pathology groups. In children without USCP (n = 21), those with PAIS showed a better bimanual precision compared to children with PVHI (p < 0.04). The AHA score and the Purdue Pegboard score of the dominant hand explained 51% of the variance in bimanual precision and dexterity in children with USCP. In absence of USCP, FSIQ together with AHA scores explained 66% of the variance in bimanual precision and FSIQ together with the Purdue Pegboard Test score of the dominant hand, 71% of the variance in bimanual dexterity. CONCLUSIONS: Children with PAIS without USCP have a more favourable bimanual hand function compared to children with PVHI. This difference appears to be associated with a preserved FSIQ.

Development and Validation of Prediction Models for Developmental and Intellectual Outcome Following Pediatric Epilepsy Surgery.

BACKGROUND AND OBJECTIVES: To identify predictors of postoperative intelligence and developmental quotients (IQ/DQ) and develop and validate clinically applicable IQ/DQ prediction models. METHODS: We retrospectively analyzed neuropsychological outcomes and their possible determinants for children treated in Bethel and Utrecht since 1990. We performed separate analyses for patients with IQ and those with only DQ available. We developed prediction models based on presurgical determinants to predict dichotomized levels of performance (IQ ≥85, IQ ≥70, DQ ≥50). RESULTS: IQ/DQ data before and 2 years after surgery were available for 492 patients (IQ n = 365, DQ n = 127). At a cutoff level ±10 points, the chance of improvement was considerably higher than the chance of deterioration (IQ 37.3% vs 6.6% and DQ 31.5% vs 15.0%, respectively). Presurgical IQ/DQ was the strongest predictor of postoperative cognition (IQ r = 0.85, p <0.001; DQ r = 0.57, p <0.001). Two IQ models were developed in the Bethel cohort (n = 258) and externally validated in the Utrecht cohort (n = 102). For DQ, we developed the model in the Bethel cohort and used 10-fold cross-validation. Models allowed good prediction at all 3 cutoff levels (correct classification for IQ ≥85 = 86%, IQ ≥70 = 91%, DQ ≥50 = 76%). External validation of the IQ models showed high accuracy (IQ ≥85: 0.82, confidence interval [CI] 0.75-0.91; IQ ≥70: 0.84, CI 0.77-0.92) and excellent discrimination (receiver operating characteristic curves: IQ ≥85: area under the curve [AUC] 0.90, CI 0.84-0.96; IQ ≥70: AUC 0.92, CI 0.87-0.97). DISCUSSION: After epilepsy surgery in children, the risk of cognitive deterioration is very low. Presurgical development has a strong effect on the postoperative trajectory. The presented models can improve presurgical counseling of patients and parents by reliably predicting cognitive outcomes. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for children undergoing epilepsy surgery presurgical IQ/DQ was the strongest predictor of postoperative cognition.

Mammillary body atrophy and other MRI correlates of school-age outcome following neonatal hypoxic-ischemic encephalopathy.

The mammillary bodies (MB) and hippocampi are important for memory function and are often affected following neonatal hypoxic ischemic encephalopathy (HIE). The aim of this study was to assess neurodevelopmental outcome in 10-year-old children with HIE with and without therapeutic hypothermia. Additional aims were to assess the associations between MB atrophy, brain volumes (including the hippocampi), white matter microstructure and neurodevelopmental outcome at school-age. Ten-year-old children with HIE were included, who were treated with therapeutic hypothermia (n = 22) or would have qualified but were born before this became standard of care (n = 28). Children completed a neuropsychological and motor assessment and MRI. Mammillary bodies were scored as normal or atrophic at 10 years. Brain volumes were segmented on childhood MRI and DTI scans were analysed using tract-based spatial statistics. Children with HIE suffered from neurocognitive and memory problems at school-age, irrespective of hypothermia. Hippocampal volumes and MB atrophy were associated with total and performance IQ, processing speed and episodic memory in both groups. Normal MB and larger hippocampi were positively associated with global fractional anisotropy. In conclusion, injury to the MB and hippocampi was associated with neurocognition and memory at school-age in HIE and might be an early biomarker for neurocognitive and memory problems.

Is autism driven by epilepsy in infants with Tuberous Sclerosis Complex?

OBJECTIVE: To evaluate the relationship between age at seizure onset and neurodevelopmental outcome at age 24 months in infants with TSC, as well as the effect on neurodevelopmental outcome of early versus conventional treatment of epileptic seizures with vigabatrin (80-150 mg/kg/day). METHODS: Infants with TSC, aged ≤4 months and without previous seizures were enrolled in a prospective study and closely followed with monthly video EEG and serial standardized neurodevelopmental testing (Bayley Scales of Infant Development and Autism Diagnostic Observation Schedule). RESULTS: Eighty infants were enrolled. At the age of 24 months testing identified risk of Autism Spectrum Disorder (ASD) in 24/80 children (30.0%), and developmental delay (DD) in 26/80 (32.5%). Children with epilepsy (51/80; 63.8%) had a higher risk of ASD (P = 0.02) and DD (P = 0.001). Overall, no child presented with moderate or severe DD at 24 months (developmental quotient < 55). In 20% of children abnormal developmental trajectories were detected before the onset of seizures. Furthermore, 21% of all children with risk of ASD at 24 months had not developed seizures at that timepoint. There was no significant difference between early and conventional treatment with respect to rate of risk of ASD (P = 0.8) or DD (P = 0.9) at 24 months. INTERPRETATION: This study confirms a relationship between epilepsy and risk of ASD/DD. However, in this combined randomized/open label study, early treatment with vigabatrin did not alter the risk of ASD or DD at age 2 years.

High frequency oscillations relate to cognitive improvement after epilepsy surgery in children.

OBJECTIVE: To investigate how high frequency oscillations (HFOs; ripples 80-250 Hz, fast ripples (FRs) 250-500 Hz) and spikes in intra-operative electrocorticography (ioECoG) relate to cognitive outcome after epilepsy surgery in children. METHODS: We retrospectively included 20 children who were seizure free after epilepsy surgery using ioECoG and determined their intelligence quotients (IQ) pre- and two years postoperatively. We analyzed whether the number of HFOs and spikes in pre- and postresection ioECoGs, and their change in the non-resected areas relate to cognitive improvement (with ≥ 5 IQ points increase considered to be clinically relevant (=IQ+ group) and < 5 IQ points as irrelevant (=IQ- group)). RESULTS: The IQ+ group showed significantly more FRs in the resected tissue (p = 0.01) and less FRs in the postresection ioECoG (p = 0.045) compared to the IQ- group. Postresection decrease of ripples on spikes was correlated with postoperative cognitive improvement (correlation coefficient = -0.62 with p = 0.01). CONCLUSIONS: Postoperative cognitive improvement was related to reduction of pathological HFOs signified by removing FR generating areas with subsequently less residual FRs, and decrease of ripples on spikes in the resection edge of the non-resected area. SIGNIFICANCE: HFOs recorded in ioECoG could play a role as biomarkers in the prediction and understanding of cognitive outcome after epilepsy surgery.

Social functioning of children after epilepsy surgery: A literature review.

This literature review on social functioning of children after epilepsy surgery is based on 24 papers addressing two categories of social functioning: social cognition (n = 4) and general social functioning (n = 20). Overall, studies that compared with healthy peers revealed children who had undergone epilepsy surgery to have more problems in both social cognition and general social functioning. Half of the studies found some improvement in social functioning in the first year(s) after epilepsy surgery, but this pertained to general social functioning, not to social cognition. The persistence of the problems in social cognition after surgery may be related to the critical period of brain maturation, lacking improvement of impairments in related cognitive domains or to a defective underlying brain condition - rather than to the epilepsy. Problems in general social functioning may be explained by the adjustments the children and their families had to make because of the child's drug-resistant epilepsy and difficulties to adjust to the new situation after surgery. The neurological and behavioral explanations are likely to be interrelated in light of the multifaceted and complex nature of social functioning. Epilepsy surgery does not appear to solve the problems in social functioning associated with having had drug-resistant epilepsy. As social functioning is an important aspect of healthy development, it should be assessed comprehensively in order to obtain a knowledge base that allows 1) proper treatment of children with epilepsy (CwE) and 2) counseling patients and families prior to and after epilepsy surgery.

Cognitive functioning after epilepsy surgery in children with mild malformation of cortical development and focal cortical dysplasia.

Mild malformation of cortical development (mMCD) and focal cortical dysplasia (FCD) subtypes combined are by far the most common histological diagnoses in children who undergo surgery as treatment for refractory epilepsy. In patients with refractory epilepsy, a substantial burden of disease is due to cognitive impairment. We studied intelligence quotient (IQ) or developmental quotient (DQ) values and their change after epilepsy surgery in a consecutive series of 42 children (median age at surgery: 4.5, range: 0-17.0 years) with refractory epilepsy due to mMCD/FCD. Cognitive impairment, defined as IQ/DQ below 70, was present in 51% prior to surgery. Cognitive impairment was associated with earlier onset of epilepsy, longer epilepsy duration, and FCD type I histology. Clinically relevant improvement of ≥10 IQ/DQ points was found in 24% of children and was related to the presence of presurgical epileptic encephalopathy (EE). At time of postsurgical cognitive testing, 59% of children were completely seizure-free (Engel 1A). We found no association between cognitive outcome and seizure or medication status at two years of follow-up. Epilepsy surgery in children with mMCD or FCD not only is likely to result in complete and continuous seizure freedom, but also improves cognitive function in many.

Cognitive Functions in Children and Adults with Moyamoya Vasculopathy: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Patients with moyamoya vasculopathy (MMV) may experience cognitive impairment, but its reported frequency, severity, and nature vary. In a systematic review and metaanalysis, we aimed to assess the presence, severity, and nature of cognitive impairments in children and adults with MMV. METHODS: We followed the MOOSE guidelines for meta-analysis and systematic reviews of observational studies. We searched Ovid Medline and Embase for studies published between January 1, 1969 and October 4, 2016. Independent reviewers extracted data for mean intelligence quotient (IQ) and standardized z-scores for cognitive tests, and determined percentages of children and adults with cognitive deficits, before and after conservative or surgical treatment. We explored associations between summary measures of study characteristics and cognitive impairments by linear regression analysis. RESULTS: We included 17 studies (11 studies reporting on 281 children, six on 153 adults). In children, the median percentage with impaired cognition was 30% (range, 13% to 67%); median IQ was 98 (range, 71 to 107). Median z-score was -0.39 for memory, and -0.43 for processing speed. In adults, the median percentage with impaired cognition was 31% (range, 0% to 69%); median IQ was 95 (range, 94 to 99). Median z-scores of cognitive domains were between -0.9 and -0.4, with multiple domains being affected. We could not identify determinants of cognitive impairment. CONCLUSION: s A large proportion of children and adults with MMV have cognitive impairment, with modest to large deficits across various cognitive domains. Further studies should investigate determinants of cognitive deficits and deterioration, and the influence of revascularization treatment on cognitive functioning.

Current standards of neuropsychological assessment in epilepsy surgery centers across Europe.

We explored the current practice with respect to the neuropsychological assessment of surgical epilepsy patients in European epilepsy centers, with the aim of harmonizing and establishing common standards. Twenty-six epilepsy centers and members of "E-PILEPSY" (a European pilot network of reference centers in refractory epilepsy and epilepsy surgery), were asked to report the status of neuropsychological assessment in adults and children via two different surveys. There was a consensus among these centers regarding the role of neuropsychology in the presurgical workup. Strong agreement was found on indications (localization, epileptic dysfunctions, adverse drugs effects, and postoperative monitoring) and the domains to be evaluated (memory, attention, executive functions, language, visuospatial skills, intelligence, depression, anxiety, and quality of life). Although 186 different tests are in use throughout these European centers, a core group of tests reflecting a moderate level of agreement could be discerned. Variability exists with regard to indications, protocols, and paradigms for the assessment of hemispheric language dominance. For the tests in use, little published evidence of clinical validity in epilepsy was provided. Participants in the survey reported a need for improvement concerning the validity of the tests, tools for the assessment of everyday functioning and accelerated forgetting, national norms, and test co-normalization. Based on the present survey, we documented a consensus regarding the indications and principles of neuropsychological testing. Despite the variety of tests in use, the survey indicated that there may be a core set of tests chosen based on experience, as well as on published evidence. By combining these findings with the results of an ongoing systematic literature review, we aim for a battery that can be recommended for the use across epilepsy surgical centers in Europe.

The spectrum of long-term cognitive and functional outcome after hemispherectomy in childhood.

PURPOSE: To evaluate cognition, behavior, daily functioning and health-related quality of life (HrQoL) five years to more than a decade after hemispherectomy (HE) in childhood. METHODS: This countrywide Dutch cohort study of 31 patients, who underwent HE between 1994 and 2009, included a semi-structured interview with parents, an assessment of cognition, and screening of behavioral problems and HrQoL. RESULTS: Twenty-two school-age children and young adults [median age 13.8 years (0.5 at epilepsy onset, 5.3 at HE)] were assessed with age-appropriate cognitive tests. IQ ranged from 45 to 82 (median 61). Despite performing below mean norm scores, these participants could learn and remember, sustain attention, inhibit irrelevant responses, read and write. Nine more children [median age 9.7 years (0.25 at epilepsy onset, 1.4 at HE)] were so mentally retarded that age-appropriate testing was impossible. This group was almost totally dependent on others in daily activities, had the highest proportion of pre-existing contralateral MRI-abnormalities and after HE the highest rates of seizure recurrence and behavioral problems. Parents in both groups rated HrQoL surprisingly positively (mean VAS-score 72.5), with a scarce low rating (40). All parents reported problems with respect to their children's self-care, daily activities and mobility. CONCLUSION: At least five years after HE, cognitive, behavioral and daily functioning encompasses a broad spectrum that varies from profound retardation and almost total dependence to low normal cognition and a reasonably independent existence. Pre-existing contralateral MRI abnormalities reflect a more generally affected brain with a limited ability to mediate development after HE.

Cognitive consequences of early versus late antiepileptic drug withdrawal after pediatric epilepsy surgery, the TimeToStop (TTS) trial: study protocol for a randomized controlled trial.

BACKGROUND: The goals of intentional curative pediatric epilepsy surgery are to achieve seizure-freedom and antiepileptic drug (AED) freedom. Retrospective cohort studies have indicated that early postoperative AED withdrawal unmasks incomplete surgical success and AED dependency sooner, but not at the cost of long-term seizure outcome. Moreover, AED withdrawal seemed to improve cognitive outcome. A randomized trial is needed to confirm these findings. We hypothesized that early AED withdrawal in children is not only safe, but also beneficial with respect to cognitive functioning. DESIGN: This is a multi-center pragmatic randomized clinical trial to investigate whether early AED withdrawal improves cognitive function, in terms of attention, executive function and intelligence, quality of life and behavior, and to confirm safety in terms of eventual seizure freedom, seizure recurrences and "seizure and AED freedom." Patients will be randomly allocated in parallel groups (1:1) to either early or late AED withdrawal. Randomization will be concealed and stratified for preoperative IQ and medical center. In the early withdrawal arm reduction of AEDs will start 4 months after surgery, while in the late withdrawal arm reduction starts 12 months after surgery, with intended complete cessation of drugs after 12 and 20 months respectively. Cognitive outcome measurements will be performed preoperatively, and at 1 and 2 years following surgery, and consist of assessment of attention and executive functioning using the EpiTrack Junior test and intelligence expressed as IQ (Wechsler Intelligence Scales). Seizure outcomes will be assessed at 24 months after surgery, and at 20 months following start of AED reduction. We aim to randomize 180 patients who underwent anticipated curative epilepsy surgery below 16 years of age, were able to perform the EpiTrack Junior test preoperatively, and have no predictors of poor postoperative seizure prognosis (multifocal magnetic resonance imaging (MRI) abnormalities, incomplete resection of the lesion, epileptic postoperative electroencephalogram (EEG) abnormalities, or more than three AEDs at the time of surgery). DISCUSSION: Growing experience with epilepsy surgery has changed the view towards postoperative medication policy. In a European collaboration, we designed a multi-center pragmatic randomized clinical trial comparing early with late AED withdrawal to investigate benefits and safety of early AED withdrawal. The TTS trial is supported by the Dutch Epilepsy Fund (NL 08-10) ISRCTN88423240/ 08/05/2013.