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.

Risk of breakthrough seizures depends on type and etiology of epilepsy.

OBJECTIVE: This study was undertaken to analyze whether the rate of breakthrough seizures in patients taking antiseizure medication (ASM) who have been seizure-free for at least 12 months varies among different types and etiologies of epilepsy. Given the relative ease of achieving seizure freedom with ASM in patients with post-ischemic stroke epilepsy, we hypothesized that this etiology is associated with a reduced risk of breakthrough seizures. METHODS: We defined a breakthrough seizure as an unprovoked seizure occurring while the patient was taking ASM after a period of at least 12 months without seizures. Data were analyzed retrospectively from a tertiary epilepsy outpatient clinic. Patients were eligible for inclusion if they either had a breakthrough seizure at any time or a seizure-free interval of at least 2 years. Our primary endpoint was rate of breakthrough seizures. We conducted univariable and multivariable analyses to identify variables associated with breakthrough seizures. RESULTS: Of 521 patients (53% females, median age = 49 years) included, 29% had a breakthrough seizure, which occurred after a median seizure-free interval of 34 months (quartiles = 22, 62). When controlling for clinically relevant covariates, breakthrough seizures were associated with post-ischemic stroke epilepsy (odds ratio [OR] = .267, 95% confidence interval [CI] = .075-.946), genetic generalized epilepsy (OR = .559; 95% CI = .319-.978), intellectual disability (OR = 2.768, 95% CI = 1.271-6.031), and the number of ASMs previously and currently tried (OR = 1.203, 95% CI = 1.056-1.371). Of the 151 patients with breakthrough seizures, 34.3% did not reachieve terminal 12-month seizure freedom at the last visit. SIGNIFICANCE: This is the first study to show an association between type and etiology of epilepsy and risk of breakthrough seizures. Our data suggest that epilepsies in which seizure freedom can be obtained more easily also exhibit a lower risk of breakthrough seizures. These findings may help to better counsel seizure-free patients on their further seizure prognosis.

Effects of hemodynamic alterations and oxygen saturation on cerebral perfusion in congenital heart disease.

BACKGROUND: Patients with severe congenital heart disease (CHD) are at risk for neurodevelopmental impairment. An abnormal cerebral blood supply caused by the altered cardiac physiology may limit optimal brain development. The aim of this study was to evaluate the effect of a systemic-to-pulmonary shunt, aortic arch obstruction and arterial oxygen saturation on cerebral perfusion in patients with severe CHD. METHODS: Patients with severe CHD requiring cardiac surgery within the first six weeks of life, who underwent pre- and/or postoperative brain magnetic resonance imaging (MRI), and healthy controls with one postnatal scan were included. Cerebral perfusion in deep and cortical gray matter was assessed by pseudocontinuous arterial spin labeling MRI. RESULTS: We included 59 CHD and 23 healthy control scans. The presence of a systemic-to-pulmonary shunt was associated with decreased perfusion in cortical (p = 0.003), but not in deep gray matter (p = 0.031). No evidence for an effect of aortic arch obstruction and arterial oxygen saturation on cerebral perfusion was found. After adjusting for hemodynamic and oxygen saturation parameters, deep (p = 0.018) and cortical (p = 0.012) gray matter perfusion was increased in patients with CHD compared to controls. CONCLUSION: We detected regional differences in compensation to the cerebral steal effect in patients with severe CHD. IMPACT: Patients with severe congenital heart disease (CHD) have altered postnatal brain hemodynamics. A systemic-to-pulmonary shunt was associated with decreased perfusion in cortical gray matter but preserved perfusion in deep gray matter, pointing towards regional differences in compensation to the cerebral steal effect. No effects of aortic arch obstruction and arterial oxygenation on cerebral perfusion were seen. Cerebral perfusion was increased in patients with CHD compared to healthy controls after adjusting for hemodynamic alterations and oxygen saturation. To improve neuroprotection and neurodevelopmental outcomes, it is important to increase our understanding of the factors influencing cerebral perfusion in neonates with severe CHD.

Non-discontinuation of antiseizure medication in seizure-free epilepsy patients.

BACKGROUND AND PURPOSE: In patients with epilepsy and sustained seizure freedom, guidelines recommend considering discontinuation of antiseizure medication (ASM) based on shared decision-making. This study aims to identify factors associated with non-discontinuation of ASM in seizure-free patients. METHODS: Retrospective data from three sites of an academic outpatient clinic were analyzed. Adult patients with epilepsy who have been seizure-free for ≥24 months on ASM monotherapy were included. The primary end-point was non-discontinuation of ASM, defined as no discontinuation or no dose reduction of ≥25% at the last outpatient clinic visit in the ultimate seizure-free interval. Secondary end-points included frequency of discussion on discontinuation attempts between patients and physicians, adherence to ASM discontinuation decisions, and post-discontinuation seizure outcomes. RESULTS: Out of 338 included patients, 81.7% did not discontinue ASM and did not reduce its dose, 11.5% discontinued ASM and 6.8% had a significant dose reduction. Factors independently associated with non-discontinuation of ASM were history of focal to bilateral or generalized tonic-clonic seizures (odds ratio [OR] 2.33, 95% confidence interval [CI] 1.08-5.06), history of breakthrough seizures (OR 3.32, 95% CI 1.10-10.04), history of failed attempts to discontinue or reduce the ASM dose (OR 4.67, 95% CI 1.03-21.11) and higher ASM load at the index visit (OR 6.10, 95% CI 2.09-17.78). Discontinuation attempts were made during the entire period of seizure freedom and were most commonly undertaken ≥10 years after the last seizure. CONCLUSIONS: This study provides insights into factors associated with the shared decision-making process regarding ASM discontinuation in seizure-free patients and highlights the importance of considering individual patient characteristics and seizure history.

[Epilepsy and pregnancy]. / Epilepsie und Schwangerschaft.

BACKGROUND: Regarding treatment of women of childbearing potential with epilepsy, several aspects of family planning and desire to have children have to be taken into account. OBJECTIVE: Overview of current data on mutual implications of epileptic seizures, antiseizure medication (ASM), pregnancy and child development. METHOD: Review of the current literature, discussion and presentation of resulting treatment recommendations. RESULTS: Many ASMs bear the potential for clinically relevant interactions with both contraceptives and altered concentrations of sexual hormones and modified pharmacokinetics during pregnancy. All ASMs show an increased risk for congenital malformations; however, due to seizure-related risks for the mother and child effective ASM treatment during pregnancy is crucial. CONCLUSION: When considering the special aspects of consultation and treatment of women of childbearing potential with epilepsy most pregnancies are uncomplicated.

Automatic and manual segmentation of the piriform cortex: Method development and validation in patients with temporal lobe epilepsy and Alzheimer's disease.

The piriform cortex (PC) is located at the junction of the temporal and frontal lobes. It is involved physiologically in olfaction as well as memory and plays an important role in epilepsy. Its study at scale is held back by the absence of automatic segmentation methods on MRI. We devised a manual segmentation protocol for PC volumes, integrated those manually derived images into the Hammers Atlas Database (n = 30) and used an extensively validated method (multi-atlas propagation with enhanced registration, MAPER) for automatic PC segmentation. We applied automated PC volumetry to patients with unilateral temporal lobe epilepsy with hippocampal sclerosis (TLE; n = 174 including n = 58 controls) and to the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 151, of whom with mild cognitive impairment (MCI), n = 71; Alzheimer's disease (AD), n = 33; controls, n = 47). In controls, mean PC volume was 485 mm3 on the right and 461 mm3 on the left. Automatic and manual segmentations overlapped with a Jaccard coefficient (intersection/union) of ~0.5 and a mean absolute volume difference of ~22 mm3 in healthy controls, ~0.40/ ~28 mm3 in patients with TLE, and ~ 0.34/~29 mm3 in patients with AD. In patients with TLE, PC atrophy lateralised to the side of hippocampal sclerosis (p < .001). In patients with MCI and AD, PC volumes were lower than those of controls bilaterally (p < .001). Overall, we have validated automatic PC volumetry in healthy controls and two types of pathology. The novel finding of early atrophy of PC at the stage of MCI possibly adds a novel biomarker. PC volumetry can now be applied at scale.

Neurometabolic changes in neonates with congenital heart defects and their relation to neurodevelopmental outcome.

BACKGROUND: Altered neurometabolite ratios in neonates undergoing cardiac surgery for congenital heart defects (CHD) may serve as a biomarker for altered brain development and neurodevelopment (ND). METHODS: We analyzed single voxel 3T PRESS H1-MRS data, acquired unilaterally in the left basal ganglia and white matter of 88 CHD neonates before and/or after neonatal cardiac surgery and 30 healthy controls. Metabolite ratios to Creatine (Cr) included glutamate (Glu/Cr), myo-Inositol (mI/Cr), glutamate and glutamine (Glx/Cr), and lactate (Lac/Cr). In addition, the developmental marker N-acetylaspartate to choline (NAA/Cho) was evaluated. All children underwent ND outcome testing using the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III) at 1 year of age. RESULTS: White matter NAA/Cho ratios were lower in CHD neonates compared to healthy controls (group beta estimate: -0.26, std. error 0.07, 95% CI: -0.40 - 0.13, p value <0.001, FDR corrected p value = 0.010). We found no correlation between pre- or postoperative white matter NAA/Cho with ND outcome while controlling for socioeconomic status and CHD diagnosis. CONCLUSION: Reduced white matter NAA/Cho in CHD neonates undergoing cardiac surgery may reflect a delay in brain maturation. Further long-term MRS studies are needed to improve our understanding of the clinical impact of altered metabolites on brain development and outcome. IMPACT: NAA/Cho was reduced in the white matter, but not the gray matter of CHD neonates compared to healthy controls. No correlation to the 1-year neurodevelopmental outcome (Bayley-III) was found. While the rapid change of NAA/Cho with age might make it a sensitive marker for a delay in brain maturation, the relationship to neurodevelopmental outcome requires further investigation.

Neuromonitoring, neuroimaging, and neurodevelopmental follow-up practices in neonatal congenital heart disease: a European survey.

BACKGROUND: Brain injury and neurodevelopmental impairment remain a concern in children with complex congenital heart disease (CHD). A practice guideline on neuromonitoring, neuroimaging, and neurodevelopmental follow-up in CHD patients undergoing cardiopulmonary bypass surgery is lacking. The aim of this survey was to systematically evaluate the current practice in centers across Europe. METHODS: An online-based structured survey was sent to pediatric cardiac surgical centers across Europe between April 2019 and June 2020. Results were summarized by descriptive statistics. RESULTS: Valid responses were received by 25 European centers, of which 23 completed the questionnaire to the last page. Near-infrared spectroscopy was the most commonly used neuromonitoring modality used in 64, 80, and 72% preoperatively, intraoperatively, and postoperatively, respectively. Neuroimaging was most commonly performed by means of cranial ultrasound in 96 and 84% preoperatively and postoperatively, respectively. Magnetic resonance imaging was obtained in 72 and 44% preoperatively and postoperatively, respectively, but was predominantly reserved for clinically symptomatic patients (preoperatively 67%, postoperatively 64%). Neurodevelopmental follow-up was implemented in 40% of centers and planned in 24%. CONCLUSIONS: Heterogeneity in perioperative neuromonitoring and neuroimaging practice in CHD in centers across Europe is large. The need for neurodevelopmental follow-up has been recognized. A clear practice guideline is urgently needed. IMPACT: There is large heterogeneity in neuromonitoring, neuroimaging, and neurodevelopmental follow-up practices among European centers caring for neonates with complex congenital heart disease. This study provides a systematic evaluation of the current neuromonitoring, neuroimaging, and neurodevelopmental follow-up practice in Europe. The results of this survey may serve as the basis for developing a clear practice guideline that could help to early detect and prevent neurological and neurodevelopmental sequelae in neonates with complex congenital heart disease.

Risk Factors for Perioperative Brain Lesions in Infants With Congenital Heart Disease: A European Collaboration.

BACKGROUND: Infants with congenital heart disease are at risk of brain injury and impaired neurodevelopment. The aim was to investigate risk factors for perioperative brain lesions in infants with congenital heart disease. METHODS: Infants with transposition of the great arteries, single ventricle physiology, and left ventricular outflow tract and/or aortic arch obstruction undergoing cardiac surgery <6 weeks after birth from 3 European cohorts (Utrecht, Zurich, and London) were combined. Brain lesions were scored on preoperative (transposition of the great arteries N=104; single ventricle physiology N=35; and left ventricular outflow tract and/or aortic arch obstruction N=41) and postoperative (transposition of the great arteries N=88; single ventricle physiology N=28; and left ventricular outflow tract and/or aortic arch obstruction N=30) magnetic resonance imaging for risk factor analysis of arterial ischemic stroke, cerebral sinus venous thrombosis, and white matter injury. RESULTS: Preoperatively, induced vaginal delivery (odds ratio [OR], 2.23 [95% CI, 1.06-4.70]) was associated with white matter injury and balloon atrial septostomy increased the risk of white matter injury (OR, 2.51 [95% CI, 1.23-5.20]) and arterial ischemic stroke (OR, 4.49 [95% CI, 1.20-21.49]). Postoperatively, younger postnatal age at surgery (OR, 1.18 [95% CI, 1.05-1.33]) and selective cerebral perfusion, particularly at ≤20 °C (OR, 13.46 [95% CI, 3.58-67.10]), were associated with new arterial ischemic stroke. Single ventricle physiology was associated with new white matter injury (OR, 2.88 [95% CI, 1.20-6.95]) and transposition of the great arteries with new cerebral sinus venous thrombosis (OR, 13.47 [95% CI, 2.28-95.66]). Delayed sternal closure (OR, 3.47 [95% CI, 1.08-13.06]) and lower intraoperative temperatures (OR, 1.22 [95% CI, 1.07-1.36]) also increased the risk of new cerebral sinus venous thrombosis. CONCLUSIONS: Delivery planning and surgery timing may be modifiable risk factors that allow personalized treatment to minimize the risk of perioperative brain injury in severe congenital heart disease. Further research is needed to optimize cerebral perfusion techniques for neonatal surgery and to confirm the relationship between cerebral sinus venous thrombosis and perioperative risk factors.

Perioperative Course and Socioeconomic Status Predict Long-Term Neurodevelopment Better Than Perioperative Conventional Neuroimaging in Children with Congenital Heart Disease.

OBJECTIVE: The objective of the study was to compare the use of neonatal conventional brain magnetic resonance imaging (MRI) with that of clinical factors and socioeconomic status (SES) to predict long-term neurodevelopment in children with severe congenital heart disease (CHD). STUDY DESIGN: In this prospective cohort study, perioperative MRIs were acquired in 57 term-born infants with CHD undergoing cardiopulmonary bypass surgery during their first year of life. Total brain volume (TBV) was measured using an automated method. Brain injury severity (BIS) was assessed by an established scoring system. The neurodevelopmental outcome was assessed at 6 years using standardized test batteries. A multiple linear regression model was used for cognitive and motor outcomes with postoperative TBV, perioperative BIS, CHD complexity, length of hospital stay, and SES as covariates. RESULTS: CHD diagnoses included univentricular heart defect (n = 15), transposition of the great arteries (n = 33), and acyanotic CHD (n = 9). Perioperative moderate-to-severe brain injury was detected in 15 (26%) patients. The total IQ was similar to test norms (P = .11), whereas the total motor score (P < .001) was lower. Neither postoperative TBV nor perioperative BIS predicted the total IQ, but SES (P < .001) and longer hospital stay (P = .004) did. No factor predicted the motor outcome. CONCLUSION: Although the predictive value of neonatal conventional MRIs for long-term neurodevelopment is low, duration of hospital stay and SES better predict the outcome in this CHD sample. These findings should be considered in initiating early therapeutic support.

Utility of 18F-fluorodeoxyglucose positron emission tomography in presurgical evaluation of patients with epilepsy: A multicenter study.

OBJECTIVE: 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) is widely used in presurgical assessment in patients with drug-resistant focal epilepsy (DRE) if magnetic resonance imaging (MRI) and scalp electroencephalography (EEG) do not localize the seizure onset zone or are discordant. METHODS: In this multicenter, retrospective observational cohort study, we included consecutive patients with DRE who had undergone FDG-PET as part of their presurgical workup. We assessed the utility of FDG-PET, which was defined as contributing to the decision-making process to refer for resection or intracranial EEG (iEEG) or to conclude surgery was not feasible. RESULTS: We included 951 patients in this study; 479 had temporal lobe epilepsy (TLE), 219 extratemporal epilepsy (ETLE), and 253 epilepsy of uncertain lobar origin. FDG-PET showed a distinct hypometabolism in 62% and was concordant with ictal EEG in 74% in TLE and in 56% in ETLE (p < .001). FDG-PET was useful in presurgical decision-making in 396 patients (47%) and most beneficial in TLE compared to ETLE (58% vs. 44%, p = .001). Overall, FDG-PET contributed to recommending resection in 78 cases (20%) and iEEG in 187 cases (47%); in 131 patients (33%), FDG-PET resulted in a conclusion that resection was not feasible. In TLE, seizure-freedom 1 year after surgery did not differ significantly (p = .48) between patients with negative MRI and EEG-PET concordance (n = 30, 65%) and those with positive MRI and concordant EEG (n = 46, 68%). In ETLE, half of patients with negative MRI and EEG-PET concordance and three quarters with positive MRI and concordant EEG were seizure-free postsurgery (n = 5 vs. n = 6, p = .28). SIGNIFICANCE: This is the largest reported cohort of patients with DRE who received presurgical FDG-PET, showing that FDG-PET is a useful diagnostic tool. MRI-negative and MRI-positive cases with concordant FDG-PET results (with either EEG or MRI) had a comparable outcome after surgery. These findings confirm the significance of FDG-PET in presurgical epilepsy diagnostics.

Motor and visuomotor function in 10-year-old children with congenital heart disease: association with behaviour.

BACKGROUND: Children with CHD are at increased risk for neurodevelopmental impairments. There is little information on long-term motor function and its association with behaviour. AIMS: To assess motor function and behaviour in a cohort of 10-year-old children with CHD after cardiopulmonary bypass surgery. METHODS: Motor performance and movement quality were examined in 129 children with CHD using the Zurich Neuromotor Assessment providing four timed and one qualitative component, and a total timed motor score was created based on the four timed components. The Beery Test of Visual-Motor Integration and the Strengths and Difficulties Questionnaire were administered. RESULTS: All Zurich Neuromotor Assessment motor tasks were below normative values (all p ≤ 0.001), and the prevalence of poor motor performance (≤10th percentile) ranged from 22.2% to 61.3% in the different components. Visuomotor integration and motor coordination were poorer compared to norms (all p ≤ 0.001). 14% of all analysed children had motor therapy at the age of 10 years. Children with a total motor score ≤10th percentile showed more internalising (p = 0.002) and externalising (p = 0.028) behavioural problems. CONCLUSIONS: School-aged children with CHD show impairments in a variety of motor domains which are related to behavioural problems. Our findings emphasise that motor problems can persist into school-age and require detailed assessment and support.

Neurocognitive functioning in young adults with congenital heart disease: insights from a case-control study.

BACKGROUND: While there is evidence that cognitive impairment of children with congenital heart disease (CHD) may persist into adolescence, little is known about the spectrum of neurocognitive functioning of young adults with this disorder. The aim of this study was to assess neurocognitive functioning in a population of young adults with different types of CHD. METHODS: Cross-sectional cohort study in young adults with CHD and a group-matched healthy control group. We assessed neurocognitive and general intellectual functioning with a comprehensive battery of standardised neuropsychological tests. In addition to task-based assessments, questionnaire data of executive dysfunctions in everyday life were measured with the Behaviour Rating Inventory of Executive Function - Adult Version. RESULTS: A total of 67 patients (55% men) with CHD and 55 healthy controls (51% men) were included for analysis. Mean age at assessment was 26.9 (3.68) and 26.0 (3.32) years, respectively. The CHD group performed poorer in the domains of Executive Functions, Memory, Attention & Speed, and general intellectual functioning. Patients with a CHD of severe complexity were more affected than patients with simple or moderate complexity. Behaviour Rating Inventory of Executive Function - Adult Version scores indicated that patients' self-rated deficits in behaviour regulation in everyday life was higher compared with healthy controls. CONCLUSION: Our findings indicate lower neurocognitive functioning in young adults with a CHD, particularly in those with severe defect complexity. In view of the potentially enhanced risk for cerebrovascular and neurodegenerative disease in this patient group as reported in the literature, systematic longitudinal monitoring of cognitive functioning is recommended.

[Imaging in the presurgical evaluation of epilepsy]. / Bildgebung in der prächirurgischen Epilepsiediagnostik.

While two thirds of patients with epilepsy become seizure-free with antiseizure medications, 30% remain drug-resistant. In drug-resistant focal epilepsy, epilepsy surgery offers an approximately 65% chance of becoming seizure-free; however, for a successful outcome of surgery a seizure focus must be precisely located, for which imaging techniques are essential. In recent years, the proportion of patients with apparently inconspicuous findings in magnetic resonance imaging (MRI) in the presurgical evaluation has increased. The sensitivity of MRI can be increased using special MRI sequences and MRI postprocessing techniques. Ictal and interictal source localization based on electroencephalography (EEG) and magnetencephalography (MEG) aim at determining the onset of interictal discharges and seizures. Nuclear medicine imaging techniques such as interictal positron emission tomography (PET) and ictal single photon emission computed tomography (SPECT) can detect chronic or acute seizure-related changes in brain metabolism and can indicate an epileptogenic focus even if MRI is inconspicuous. The results of these techniques are used to plan invasive EEG recordings and subsequently surgery. Concordant findings are associated with better surgical outcomes and show significantly higher rates of seizure freedom in the long-term seizure outcome.

[Benign Tumors of the Eyelid]. / Benigne Lidtumoren.

Benign tumors of the eyelids are manifold. They can severely impair the anatomical unit of upper and lower eyelid, which basically serves to protect the eyeball. Furthermore, they can induce reduction of visual acuity or cause a subjectively more or less strong aesthetic disturbance of appearance. Patients may visit the ophthalmologist by themselves or referred by a dermatologist or a general practitioner. Therefore, knowledge of the clinical signs and symptoms of benign tumors are mandatory to discriminate against malign tumors or to identify possible associated disease. In this article, the incidence, clinic, risk factors, symptomatology, histopathologic features, and probabilities of malignant transformation and recurrence of the most common benign eyelid tumors are presented. Objective of this article is to illustrate when to do further work-up to rule out systemic disease and when to do biopsy to rule out malignancy. Finally, the publication is giving an outlook on the use of artificial intelligence to diagnose lid tumors in the future.

P-glycoprotein overactivity in epileptogenic developmental lesions measured in vivo using (R)-[11 C]verapamil PET.

OBJECTIVE: Overexpression of the drug transporter P-glycoprotein (P-gp) is thought to be involved in drug-resistance in epilepsy by extrusion of antiepileptic drugs (AEDs). We used positron emission tomography (PET) and the P-gp substrate radiotracer (R)-[11 C]verapamil (VPM) together with the third-generation P-gp inhibitor tariquidar (TQD) to evaluate P-gp function in individuals with drug-resistant epileptogenic developmental lesions. METHODS: Twelve healthy controls (7 male, median age 45, range 35-55 years), and two patients with epileptogenic developmental lesions (2 male, aged 24 and 62 years) underwent VPM-PET scans before and 60 minutes after a 30-minute infusion of 2 and 3 mg/kg TQD. The influx rate constant, VPM-K1 , was estimated from the first 10 minutes of dynamic data using a single-tissue compartment model with a VPM plasma input function. Statistical parametric mapping (SPM) analysis was used to compare individual patients with the healthy controls. RESULTS: At baseline, SPM voxel-based analysis revealed significantly lower uptake of VPM corresponding to the area of the epileptogenic developmental lesion compared to 12 healthy controls (P < .048). This was accentuated following P-gp inhibition with TQD. After TQD, the uptake of VPM was significantly lower in the area of the epileptogenic developmental lesion compared to controls (P < .002). SIGNIFICANCE: This study provides further evidence of P-gp overactivity in patients with drug-resistant epilepsy, irrespective of the type of lesion. Identifying P-gp overactivity as an underlying contributor to drug-resistance in individual patients will enable novel treatment strategies aimed at overcoming or reversing P-gp overactivity.

Left temporal plane growth predicts language development in newborns with congenital heart disease.

Congenital heart defects are the most common congenital anomalies, accounting for a third of all congenital anomaly cases. While surgical correction dramatically improved survival rates, the lag behind normal neurodevelopment appears to persist. Deficits in higher cognitive functions are particularly common, including developmental delay in communication and oral-motor apraxia. It remains unclear whether the varying degree of cognitive developmental delay is reflected in variability in brain growth patterns. To answer this question, we aimed to investigate whether the rate of regional brain growth is correlated with later life neurodevelopment. Forty-four newborns were included in our study, of whom 33 were diagnosed with dextro-transposition of the great arteries and 11 with other forms of severe congenital heart defects. During the first month of life, neonates underwent corrective or palliative cardiovascular bypass surgery, pre- and postoperative cerebral MRI were performed 18.7 ± 7.03 days apart. MRI was performed in natural sleep on a 3.0 T scanner using an 8-channel head coil, fast spin-echo T2-weighted anatomical sequences were acquired in three planes. Based on the principles of deformation-based morphometry, we calculated brain growth rate maps reflecting average daily growth occurring between pre- and postoperative brain images. An explorative, whole-brain, threshold-free cluster enhancement analysis revealed strong correlation between the growth rate of the Heschl's gyrus, anterior planum temporale and language score at 12 months of age, corrected for demographic variables (P = 0.018, t = 5.656). No significant correlation was found between brain growth rates and motor or cognitive scores. Post hoc analysis showed that the length of hospitalization interacted with this correlation, longer hospitalization resulted in faster enlargement of the internal CSF spaces. Our longitudinal cohort study provides evidence for the early importance of left-dominant perisylvian regions in auditory and language development before direct postnatal exposure to native language. In congenital heart disease patients, the perioperative period results in a critical variability of brain growth rate in this region, which is a reliable neural correlate of language development at 1 year of age.

Sleep-dependent memory consolidation in children with self-limited focal epilepsies.

OBJECTIVE: Children with self-limited focal epilepsies of childhood (SLFE) are known to show impaired memory functions, particularly in the verbal domain. Interictal epileptiform discharges (IED) in these epilepsies are more pronounced in nonrapid eye movement (NREM) sleep. Nonrapid eye movement sleep is crucial for consolidation of newly-encoded memories. Therefore, we hypothesize that sleep-dependent memory consolidation is altered in relation to IED in children with SLFE. METHODS: We conducted a prospective case-control study. We applied a verbal (word pair) and a visuospatial (two-dimensional [2D] object location) learning task, both previously shown to benefit from sleep in terms of memory consolidation. Learning took place in the evening, and retrieval was tested in the morning after a night of sleep. Electroencephalogram (EEG) was recorded across night. After sleep-stage scoring, the spike-wave index (SWI) was assessed at the beginning and the end of sleep. Fourteen patients with SLFE (age: 5.5 to 11.6 years) were compared with 15 healthy controls (age: 6.8 to 9.1 years) examined in a previous study. RESULTS: In contrast to healthy controls (mean: +12.9% recalled word pairs, p = .003, standard deviation (SD) = 12.4%), patients did not show overnight performance gains in the verbal memory task (mean: +6.4% recalled word pairs, p > .05, SD = 17.3) Neither patients nor controls showed significant overnight changes in visuospatial task performance. Spike-wave index was negatively correlated with recall performance in the verbal but not in the visuospatial task. SIGNIFICANCE: We found evidence for impaired overnight improvement of performance in children with SLFE in a verbal learning task, with high SWI rates predicting low recall performance. We speculate that spike-waves hamper long-term memory consolidation by interfering with NREM sleep.

Cognitive outcome of early school-aged children born very preterm is not predicted by early short-term amplitude-integrated electroencephalography.

AIM: We investigated the association between early amplitude-integrated electroencephalography (aEEG) and cognitive outcome in very preterm infants at early school-age. METHODS: This prospective cohort study, conducted in the Department of Neonatology, University Hospital Zurich, Switzerland, from 2009 to 2012, comprised of infants born at <32 weeks of gestation, who underwent continuous aEEG recording during the first 4 days of life. Cognitive outcome was assessed with the Kaufman-Assessment Battery for Children at 5 years. Univariate and multivariate logistic regressions were calculated between aEEG parameters and normal cognitive outcome, defined as an intelligence quotient (IQ) of at least 85. RESULTS: The 118 (52.5% male) infants were born at a mean gestational age of 29.9 weeks and a mean birth weight of 1235 ± 363 g. We followed up 89 children at the age of five, and they had a mean IQ of 97.8 ± 12.7 with 21.3% under 85-and 2.2% had cerebral palsy. Univariate analyses found associations between aEEG measures and normal cognitive outcome, but these were no longer significant after adjustment for confounders. Socioeconomic status and neonatal morbidity were independent predictors of cognitive outcome. CONCLUSION: Early short-term aEEG did not predict later cognitive outcome in our cohort of very preterm infants.

White matter injury in term neonates with congenital heart diseases: Topology & comparison with preterm newborns.

BACKGROUND: Neonates with congenital heart disease (CHD) are at high risk of punctate white matter injury (WMI) and impaired brain development. We hypothesized that WMI in CHD neonates occurs in a characteristic distribution that shares topology with preterm WMI and that lower birth gestational age (GA) is associated with larger WMI volume. OBJECTIVE: (1) To quantitatively assess the volume and location of WMI in CHD neonates across three centres. (2) To compare the volume and spatial distribution of WMI between term CHD neonates and preterm neonates using lesion mapping. METHODS: In 216 term born CHD neonates from three prospective cohorts (mean birth GA: 39 weeks), WMI was identified in 86 neonates (UBC: 29; UCSF: 43; UCZ: 14) on pre- and/or post-operative T1 weighted MRI. WMI was manually segmented and volumes were calculated. A standard brain template was generated. Probabilistic WMI maps (total, pre- and post-operative) were developed in this common space. Using these maps, WMI in the term CHD neonates was compared with that in preterm neonates: 58 at early-in-life (mean postmenstrual age at scan 32.2 weeks); 41 at term-equivalent age (mean postmenstrual age at scan 40.1 weeks). RESULTS: The total WMI volumes of CHD neonates across centres did not differ (p = 0.068): UBC (median = 84.6 mm3, IQR = 26-174.7 mm3); UCSF (median = 104 mm3, IQR = 44-243 mm3); UCZ (median = 121 mm3, IQR = 68-200.8 mm3). The spatial distribution of WMI in CHD neonates showed strong concordance across centres with predilection for anterior and posterior rather than central lesions. Predominance of anterior lesions was apparent on the post-operative WMI map relative to the pre-operative map. Lower GA at birth predicted an increasing volume of WMI across the full cohort (41.1 mm3 increase of WMI per week decrease in gestational age; 95% CI 11.5-70.8; p = 0.007), when accounting for centre and heart lesion. While WMI in term CHD and preterm neonates occurs most commonly in the intermediate zone/outer subventricular zone there is a paucity of central lesions in the CHD neonates relative to preterms. CONCLUSIONS: WMI in term neonates with CHD occurs in a characteristic topology. The spatial distribution of WMI in term neonates with CHD reflects the expected maturation of pre-oligodendrocytes such that the central regions are less vulnerable than in the preterm neonates.