[Show abstract][Hide abstract] ABSTRACT: Tonic GABAA receptors are a subpopulation of receptors that generate long-lasting inhibition and thereby control network excitability. In recent years, these receptors have been implicated in various neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, and epilepsy. Their distinct subunit composition and function, compared to phasic GABAA receptors, opens the possibility to specifically modulate network properties. In this review, the role of tonic GABAA receptors in epilepsy and as potential antiepileptic target will be discussed.
[Show abstract][Hide abstract] ABSTRACT: Rationale
. Chorioamnionitis has been associated with increased risk for fetal brain damage. Although, it is now accepted that synaptic dysfunction might be responsible for functional deficits, synaptic densities/numbers after a fetal inflammatory challenge have not been studied in different regions yet. Therefore, we tested in this study the hypothesis that LPS-induced chorioamnionitis caused profound changes in synaptic densities in different regions of the fetal sheep brain.
Material and Methods
. Chorioamnionitis was induced by a 10 mg intra-amniotic LPS injection at two different exposure intervals. The fetal brain was studied at 125 days of gestation (term = 150 days) either 2 (LPS2D group) or 14 days (LPS14D group) after LPS or saline injection (control group). Synaptophysin immunohistochemistry was used to quantify the presynaptic density in layers 2-3 and 5-6 of the motor cortex, somatosensory cortex, entorhinal cortex, and piriforme cortex, in the nucleus caudatus and putamen and in CA1/2, CA3, and dentate gyrus of the hippocampus.
. There was a significant reduction in presynaptic bouton densities in layers 2-3 and 5-6 of the motor cortex and in layers 2-3 of the entorhinal and the somatosensory cortex, in the nucleus caudate and putamen and the CA1/2 and CA3 of the hippocampus in the LPS2D compared to control animals. Only in the motor cortex and putamen, the presynaptic density was significantly decreased in the LPS14 D compared to the control group. No changes were found in the dentate gyrus of the hippocampus and the piriforme cortex.
. We demonstrated that LPS-induced chorioamnionitis caused a decreased density in presynaptic boutons in different areas in the fetal brain. These synaptic changes seemed to be region-specific, with some regions being more affected than others, and seemed to be transient in some regions.
[Show abstract][Hide abstract] ABSTRACT: Clinical and experimental evidence suggests a role for the cerebellum in seizure control, while no data are available on cerebellar activity between seizures. We hypothesized that interictal regional activity of the deep cerebellar nuclei is reduced in epilepsy and tested this in an animal model by using ΔFosB and cytochrome oxidase (COX) (immuno)histochemistry. The expression of these two markers of neuronal activity was analysed in the dentate nucleus (DN), interpositus nucleus (IN), and fastigial nucleus (FN) of the cerebellum of fully amygdala kindled rats that were sacrificed 48 hours after their last seizure. The DN and FN of kindled rats exhibited 25 to 29% less ΔFosB immunopositive cells than their respective counterpart in sham controls (
). COX expression in the DN and FN of kindled animals was reduced by 32 to 33% compared to respective control values (
). These results indicate that an epileptogenic state is characterized by decreased activity of deep cerebellar nuclei, especially the DN and FN. Possible consequences may include a decreased activation of the thalamus, contributing to further seizure spread. Restoration of FN activity by low frequency electrical stimulation is suggested as a possible treatment option in chronic epilepsy.
[Show abstract][Hide abstract] ABSTRACT: The effectiveness of working memory (WM) training programmes is still a subject of debate. Previous reviews were heterogeneous with regard to participant characteristics of the studies included. To examine whether these programmes are of added value for children with learning disabilities (LDs), a systematic meta-analytic review was undertaken focusing specifically on LDs. Thirteen randomised controlled studies were included, with a total of 307 participants (age range = 5.5-17, Mean age across studies = 10.61, SD = 1.77). Potential moderator variables were examined, i.e., age, type of LD, training programme, training dose, design type, and type of control group. The meta-analysis indicated reliable short-term improvements in verbal WM, visuo-spatial WM, and word decoding in children with LDs after training (effect sizes ranged between 0.36 and 0.63), when compared to the untrained control group. These improvements sustained over time for up to eight months. Furthermore, children > 10 years seemed to benefit more in terms of verbal WM than younger children, both immediately after training as well as in the long-term. Other moderator variables did not have an effect on treatment efficacy.
[Show abstract][Hide abstract] ABSTRACT: Objective: To better understand the inflammatory response in the central nervous system (CNS) after lipopolysaccharide (LPS)-induced chorioamnionitis. Study design: Fetal sheep were exposed to intra-amniotic LPS 2 or 14 days before preterm delivery at 125 days of gestation. mRNA levels of cytokines, TLRs and anti-oxidants were determined in different CNS regions. Results: Interleukin 1β expression increased in hippocampus, cortex and cerebellum 2 days after LPS exposure, while Interleukin 8 expression increased in the periventricular white matter as well. Expression returned back to control levels after 14 days. Tumor necrosis factor-α expression increased in hippocampus and cortex after 2 days. Toll like receptor 4 expression was upregulated in all grey matter regions 2 and 14 days after exposure. Glutathione s-transferase mRNA levels were lower after 2 and 14 days in all grey matter regions. Conclusion: Intra-amniotic LPS exposure causes acute and region-specific changes in inflammatory markers in the fetal brain, with grey matter being more affected than white matter.
Full-text · Article · Jan 2015 · CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders)
[Show abstract][Hide abstract] ABSTRACT: Introduction Therapeutic hypothermia has become a standard neuroprotective treatment in term newborn infants following perinatal asphyxia. Hypothermia-induced changes in the reactivity of the vessels supplying the brain might play a role in its therapeutic or side effects. We investigated the putative age-related changes and the effect of clinically relevant cooling (33°C) on the reactivity of the newborn rat carotid artery.
Methods Carotid artery rings from 2–3 d-old and 9–10 d-old rats were mounted in myographs and studied at 33 and 37°C.
Results Hypothermia did not significantly affect the contractions induced by KCl and U46619, nor the relaxations induced by acetylcholine (ACh), the nitric oxide (NO) donor sodium nitroprusside (SNP), the NO-independent stimulator of soluble guanylate cyclase (sGC) BAY 41–2272, the β-adrenoceptor agonist isoproterenol, the adenylate cyclase activator forskolin, and acute hypoxia (PO2 3 kPa). The relaxations induced by ACh, isoproterenol, the β2-adrenoceptor agonist salbutamol, the β3-adrenoceptor agonist CL-316243 and hypoxia increased with postnatal age and were impaired by endothelium removal or by inhibition of NO synthase (L-NAME) or sGC (ODQ). By contrast, the relaxations induced by SNP, BAY 41–2272 and forskolin were endothelium-independent and did not change with age.
Conclusions Mild hypothermia (33°C) does not affect the reactivity of neonatal rat carotid arteries. Our data suggest a reduced NO bioavailability in the carotid artery during the first days of life. This transient reduction in endothelium-dependent relaxation might play a role in the adaptation of the circulatory system to birth and in the neonatal vascular response to insults such as hypoxia.
Full-text · Article · Jan 2015 · CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders)
[Show abstract][Hide abstract] ABSTRACT: Objectives
Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its aetiology is unknown. MRI scans often reveal no structural brain abnormalities that could explain the cognitive impairment. This does not exclude more subtle morphological abnormalities that can only be detected by automated morphometric techniques. AimsWith these techniques, we investigate the relationship between cortical brain morphology and cognitive functioning in a cohort of children with FLE and healthy controls. Materials and Methods
Thirty-four children aged 8-13years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural brain MRI. Patients were grouped as cognitively impaired or unimpaired. Intracranial volume, white matter volume, lobular cortical volume, cortical thickness and volumes of cortex structures were compared between patients and controls, and potential correlations with cognitive status were determined. ResultsThe group of cognitively impaired children with FLE had significantly smaller left temporal cortex volumes, specifically middle temporal grey matter volume and entorhinal cortex thickness. In addition, cognitively impaired children with FLE had smaller volumes of structures in the left and right frontal cortex, right temporal cortex and the left subcortical area. Conclusion
Cognitively impaired children with FLE have smaller volumes of various cortex structures within the frontal lobes and in extra-frontal regions, most notably temporal cortex volumes. These findings might well explain the broad scale of cognitive domains affected in children with FLE complicated by cognitive impairment and highlight that FLE impacts on areas beyond the frontal lobe.
[Show abstract][Hide abstract] ABSTRACT: Background
The mechanism of action of vagus nerve stimulation (VNS) in intractable epilepsy is not entirely clarified. It is believed that VNS causes alterations in cytokines, which can lead to rebalancing the release of neurotoxic and neuroprotective tryptophan metabolites. We aimed to evaluate VNS effects on tryptophan metabolites and on epileptic seizures and investigated whether the antiepileptic effectiveness correlated with changes in tryptophan metabolism.
Forty-one children with intractable epilepsy were included in a randomized, active-controlled, double-blind study. After a baseline period of 12 weeks, all children underwent implantation of a vagus nerve stimulator and entered a blinded active-controlled phase of 20 weeks. Half of the children received high-output (therapeutic) stimulation (n = 21), while the other half received low-output (active control) stimulation (n = 20). Subsequently, all children received high-output stimulation for another 19 weeks (add-on phase). Tryptophan metabolites were assessed in plasma and cerebrospinal fluid (CSF) by use of liquid chromatography–tandem mass spectrometry (LC–MS/MS) and compared between high- and low-output groups and between the end of both study phases and baseline. Seizure frequency was recorded using seizure diaries. Mood was assessed using Profile of Mood States (POMS) questionnaires.
Regarding tryptophan metabolites, anthranilic acid (AA) levels were significantly higher at the end of the add-on phase compared with baseline (p = 0.002) and correlated significantly with improvement of mood (τ = − 0.39, p = 0.037) and seizure frequency reduction (τ = − 0.33, p < 0.01). No significant changes were found between high- and low-output groups regarding seizure frequency.
Vagus nerve stimulation induces a consistent increase in AA, a neuroprotective and anticonvulsant tryptophan metabolite. Moreover, increased AA levels are associated with improvement in mood and reduction of seizure frequency.
No preview · Article · Aug 2014 · Epilepsy & Behavior
[Show abstract][Hide abstract] ABSTRACT: It is unclear to what extent neuropathological changes contribute to brain inflammation observed in temporal lobe epilepsy (TLE). Here, we compared cytokine levels between histopathologically-confirmed sclerotic hippocampi and histopathologically-confirmed normal hippocampi from TLE patients. We analyzed a similar cytokine panel in hippocampi from amygdala-kindled rats and we evaluated neuropathological changes by immunohistochemistry. In TLE patients, cytokine levels were not significantly different between sclerotic and non-sclerotic hippocampi. Though kindling resulted in increased astrocyte activation, cytokine levels and
microglia activation were unchanged. These results suggest that the chronic epileptic state in TLE can also occur in the absence of intracerebral inflammation.
•HS in TLE patients is not associated with a sustained brain inflammatory response.•Amygdala kindled seizures are not associated with a sustained inflammatory response.•Brain inflammation is not necessarily present in temporal lobe epilepsy.
Full-text · Article · Jun 2014 · Journal of neuroimmunology
[Show abstract][Hide abstract] ABSTRACT: Despite efforts to reduce mortality caused by stroke and perinatal asphyxia, these are still the 2(nd) largest cause of death worldwide in the age groups they affect. Furthermore, survivors of cerebral hypoxia-ischemia often suffer neurological morbidities. A better understanding of pathophysiological mechanisms in focal and global brain ischemia will contribute to the development of tailored therapeutic strategies. Similarly, insight in molecular pathways involved in preconditioning-induced brain protection will provide possibilities for future treatment. Microarray technology is a great tool for investigating large scale gene expression, and has been used in many experimental studies of cerebral ischemia and preconditioning to unravel molecular (patho-) physiology. However, the amount of data across microarray studies can be daunting and hard to interpret which is why we aim to provide a clear overview of available data in experimental rodent models. Findings for both injurious ischemia and preconditioning are reviewed under separate subtopics such as cellular stress, inflammation, cytoskeleton and cell signaling. Finally, we investigated the transcriptome signature of brain protection across preconditioning studies in search of transcripts that were expressed similarly across studies. Strikingly, when comparing genes discovered by single-gene analysis we observed only 15 genes present in two studies or more. We subjected these 15 transcripts to DAVID Annotation Clustering analysis to derive their shared biological meaning. Interestingly, the MAPK signaling pathway and more specifically the ERK1/2 pathway geared toward cell survival/proliferation was significantly enriched. To conclude, we advocate incorporating pathway analysis into all microarray data analysis in order to improve the detection of similarities between independently derived datasets.
[Show abstract][Hide abstract] ABSTRACT: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE). Its etiology remains unknown. With diffusion tensor imaging, we have studied cerebral white matter properties and associations with cognitive functioning in children with FLE and healthy controls.
Thirty children aged 8-13 years with FLE of unknown cause and 39 healthy age-matched controls underwent neuropsychological assessment, structural and diffusion-weighted brain MRI. Patients were grouped as cognitively impaired or unimpaired, and their white matter diffusion properties were compared with the controls.
Children with FLE had reduced apparent diffusion coefficients in various posteriorly located tract bundles, a reduced fractional anisotropy (FA) of the white matter tract between the right frontal and right occipital lobe, and smaller volumes of several collections of interlobar bundle tracts, compared with controls. The cognitively impaired patient group demonstrated significant increases in FA of the white matter of both occipital lobes, a reduced FA of white matter tract bundles between the right frontal and both left occipital lobe and subcortical white matter area, and smaller volumes of two collections of tract bundles connecting the frontal lobe with the temporal and parietal lobes, compared with controls.
Children with FLE had white matter abnormalities mainly in posterior brain regions, not confined to the area of the seizure focus. Cognitively impaired children with FLE showed the most pronounced white matter abnormalities. These possibly reflect disturbed maturation and might be part of the etiology of the cognitive impairment.
[Show abstract][Hide abstract] ABSTRACT: Little is known about the long-term effects of Continuous intrathecal Baclofen (CITB) therapy in non-ambulant children with intractable spastic Cerebral Palsy (CP).
To determine whether short-term beneficial effects of CITB therapy are present at the long-term, and whether caregivers would choose CITB therapy for their child again considering the advantages and disadvantages encountered over the years.
Long-term follow-up data were obtained of the children whom had previously participated in a RCT on CITB by the Dutch Study Group on Spasticity. Quality of life (QoL) was assessed by the Child Health Questionnaire (CHQ), current satisfaction with CITB was measured by use of a Visual Analogue Scale regarding previously set treatment goals, functioning in daily living was determined by a questionnaire concerning functioning of the child, and possible detrimental effects of CITB therapy encountered over the years were noted. All data were acquired via interview of the caregivers.
All 17 children of the former trial participated in this study. Previously identified significant positive effects on pain (CHQ 46.8 vs. 74.38, p = 0.002; VAS 2.4 vs. 8.01, p = 0.02), ease of care (VAS 2.0 vs. 7.26, p = 0.00), and mental health (CHQ 67.2 vs. 75.94, p = 0.010) were still present at the end of the trial. Novel significant positive effects were noted at six to nine years follow-up, i.e. significantly improved scores on the Parent Impact - Emotional subscale (CHQ 66.0 vs. 78.2, p = 0.008), Parent Impact - Time subscale (CHQ 68.9 vs. 91.72, p = 0.002), and the Physical Summary (CHQ 17.6 vs. 27.4, p = 0.019) compared to baseline. Ninety-four percent of the caregivers would choose CITB treatment again for their child again.
The beneficial effects of CITB are present at the long term and caregiver satisfaction is high.
No preview · Article · Jul 2013 · European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society
[Show abstract][Hide abstract] ABSTRACT: Based on the assumption that children with spinal dysraphism are exposed to a large amount of ionising radiation for diagnostic purposes, our objective was to estimate this exposure, expressed in cumulative effective dose.
Retrospective cohort study.
135 patients with spinal dysraphism and under 18 years of age treated at our institution between 1991 and 2010.
A total of 5874 radiological procedures were assessed of which 2916 (49.6%) involved ionising radiation. Mean cumulative effective dose of a child with spinal dysraphism during childhood was 23 mSv, while the individual cumulative effective dose ranged from 0.1 to 103 mSv. Although direct radiography accounted for 81.7% of examinations, the largest contributors to the cumulative effective dose were fluoroscopic examinations (40.4% of total cumulative effective dose).
Exposure to ionising radiation and associated cancer risk were lower than expected. Nevertheless, the use of ionising radiation should always be justified and the medical benefits should outweigh the risk of health detriment, especially in children.
Full-text · Article · Jul 2013 · Archives of Disease in Childhood
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND PURPOSE: Sprengel's deformity, a rare congenital malformation of the scapula, may be observed in combination with spinal dysraphism. The co-occurrence of these malformations suggests an unknown shared etiology. Therefore, we reviewed the medical records of eight children presenting with both malformations and performed a review of the literature. PATIENTS AND METHODS: Databases from four university medical centers were searched for children presenting between 1992 and 2012 with spinal dysraphism and a Sprengel's deformity. CONCLUSION: The combination of spinal dysraphism and Sprengel's deformity is rare, and is associated with segmentation defects of the spine and ribs. Although the etiology of both spinal dysraphism and Sprengel's deformity remains unclear, all deformities of the spine, ribs, and shoulder might result from a common genetic defect affecting somitogenesis.
Full-text · Article · Feb 2013 · Child s Nervous System
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: In clinical practice, Rolandic epilepsy is in many cases associated with developmental language impairment. However, from the literature it is unclear exactly which domains are affected; A wide variety of investigations are reported that each provide a different representation of language performance in these patients. AIMS: The aim of this study is to compare performance on the language domains between children with Rolandic epilepsy and healthy controls. METHODS: Prospective study of children with Rolandic epilepsy compared to healthy controls. 25 children (mean age 136.6 months, SD 23.0) with Rolandic epilepsy and 25 age-matched healthy controls were tested on their language function using the CELF-4 (Clinical evaluation of Language Fundamentals, Dutch edition). The healthy control were not matched regard to other important factors, particularly educational attainment and co-morbidity. Expressive language, receptive language, language content, language structure and language working memory were tested. RESULTS: In children with Rolandic epilepsy, the core language score was significant lower compared with healthy controls. They scored specifically lower on the receptive language index and language content index (both p = 0.002). A trend towards decreased expressive language index was observed (p = 0.054). Language structure and language working memory were in the normal range. CONCLUSION: Language was found to be impaired in children with typical Rolandic epilepsy. Especially semantic language processing including receptive language and language content was significantly impaired. The common denominator of these functions is semantic language processing.
No preview · Article · Feb 2013 · European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its etiology is unknown. With functional magnetic resonance imaging (fMRI), we have explored the relationship between brain activation, functional connectivity, and cognitive functioning in a cohort of pediatric patients with FLE and healthy controls.
Thirty-two children aged 8-13 years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural and functional brain MRI. We investigated to which extent brain regions activated in response to a working memory task and assessed functional connectivity between distant brain regions. Data of patients were compared to controls, and patients were grouped as cognitively impaired or unimpaired.
Children with FLE showed a global decrease in functional brain connectivity compared to healthy controls, whereas brain activation patterns in children with FLE remained relatively intact. Children with FLE complicated by cognitive impairment typically showed a decrease in frontal lobe connectivity. This decreased frontal lobe connectivity comprised both connections within the frontal lobe as well as connections from the frontal lobe to the parietal lobe, temporal lobe, cerebellum, and basal ganglia.
Decreased functional frontal lobe connectivity is associated with cognitive impairment in pediatric FLE. The importance of impairment of functional integrity within the frontal lobe network, as well as its connections to distant areas, provides new insights in the etiology of the broad-range cognitive impairments in children with FLE.