Sleep in children with refractory epilepsy and epileptic encephalopathies: A systematic review of literature.

Children with epilepsy have more sleep disorders compared to healthy children. The bidirectional interaction between epilepsy and sleep is not completely understood. However, disruption of sleep architecture during childhood may have consequences for cognitive development. As children with drug-refractory epilepsy often have intellectual disability, sleep disruption could be an important contributing factor in severity of their cognitive impairment. To better understand these interactions, sleep architecture in children with drug-refractory epilepsy and epileptic encephalopathies should be investigated. In this review, we conducted a systematic literature search on this topic. Articles that investigated sleep macro- and/or microstructure by means of electroencephalogram/polysomnography were included, as well as articles that used validated questionnaires. Sixteen articles were reviewed, eight of which used polysomnography. Only 2 articles examined sleep in children with epileptic encephalopathies. Consistent findings on measures of sleep architecture were a reduction in REM percentage and an increase in sleep fragmentation when comparing drug-refractory patients with non-refractory and healthy subjects. The findings on slow wave sleep were less clear. Studies with questionnaires unambiguously confirmed subjectively more sleep problems in children with drug-refractory epilepsy. This is the first review of literature in this patient population. More good quality sleep studies in children with drug-refractory epilepsy are warranted. The use of wearables in the home setting together with automatic sleep staging could provide more insights.

Worldwide policies on epilepsy and blood donation: a survey among blood services.

BACKGROUND AND OBJECTIVES: Epilepsy is a common neurological disorder characterized by the appearance of seizures. Often, epilepsy patients are temporarily or permanently excluded from blood donation. To gain a better understanding of the policies that are currently applied, we performed a survey among blood services. METHODS: A cross-sectional, Web-based questionnaire using the online Questback tool was developed and distributed to 46 representatives of blood services worldwide. The questionnaire was composed of nine questions. RESULTS: A total of 27 respondents, representing blood services in 26 countries on five continents, participated in the survey. Current policies range from permanent acceptance over temporary exclusion to permanent exclusion. Rationales for these different policies are diverse. The majority of blood services (59·3%) apply temporary exclusion as their policy, though no consensus exists on the length of time that epilepsy patients have to be medication-free or seizure-free. None of the respondents could provide data about adverse events in epilepsy patients during the blood donation process. CONCLUSIONS: The results of this survey indicate a large discrepancy in policies applied worldwide. A lack of scientific evidence could be one of the underlying reasons. Therefore, it is of paramount importance to further research the potential risks for donors and recipients regarding blood donation by people with epilepsy. This can then serve as a base for evidence-based policymaking and lead to safer and more effective blood transfusion programmes.

Evaluation of the language profile in children with rolandic epilepsy and developmental dysphasia: Evidence for distinct strengths and weaknesses.

Although benign, rolandic epilepsy (RE) or benign childhood epilepsy with centro-temporal spikes is often associated with language impairment. Recently, fronto-rolandic EEG abnormalities have been described in children with developmental dysphasia (DD), suggesting an interaction between language impairment and interictal epileptiform discharges. To investigate if a behavioral-linguistic continuum between RE and DD exists, a clinical prospective study was carried out to evaluate the language profile of 15 children with RE and 22 children with DD. Language skills were assessed using an extensive, standardized test battery. Language was found to be impaired in both study groups, however RE and DD were associated with distinct language impairment profiles. Children with RE had difficulties with sentence comprehension, semantic verbal fluency and auditory short-term memory, which are unrelated to age of epilepsy onset and laterality of epileptic focus. In children with DD, sentence comprehension and verbal fluency were among their relative strengths, whereas sentence and lexical production constituted relative weaknesses.

Low-dose fenfluramine significantly reduces seizure frequency in Dravet syndrome: a prospective study of a new cohort of patients.

BACKGROUND AND PURPOSE: Dravet syndrome (DS) is a severe, drug-resistant epilepsy. Fenfluramine has been reported to have a long-term clinically meaningful anticonvulsive effect in patients with DS. METHODS: This prospective, open-label study assessed the safety and effectiveness of low-dose fenfluramine in a new cohort of patients with DS. Following a 3-month baseline period, fenfluramine was added to each patient's current antiepileptic drug regimen at a dose of 0.25-1.0 mg/kg/day (max. 20 mg/day). The incidence of major motor seizures (tonic, clonic, tonic-clonic, atonic and myoclonic seizures lasting >30 s) in both the baseline and treatment periods was assessed via a seizure diary. Periodic echocardiographic examinations during the treatment period were used to assess cardiovascular safety. RESULTS: Nine patients (aged 1.2-29.8 years) enrolled in the study and were treated with fenfluramine for a median duration of 1.5 (range, 0.3-5.1) years. Median frequency of major motor seizures was 15.0/month in the baseline period. All patients demonstrated a reduction in seizure frequency during the treatment period with a median reduction of 75% (range, 28-100%). Seven patients (78%) experienced a ≥50% reduction in major motor seizure frequency. The most common adverse events were somnolence (n = 5) and anorexia (n = 4). No evidence of cardiac valvulopathy or pulmonary hypertension was observed. CONCLUSIONS: The effectiveness and safety of low-dose fenfluramine as an add-on therapy for DS in this new prospective cohort supports previous findings.

Effects of adjunctive zonisamide treatment on weight and body mass index in children with partial epilepsy.

BACKGROUND: Zonisamide has been associated with weight loss in children and adults. AIMS OF THE STUDY: To assess the effects of adjunctive zonisamide on weight and body mass index (BMI) in children with partial epilepsy. METHODS: A subanalysis was conducted of a Phase III trial and extension study, in which children with partial epilepsy received adjunctive zonisamide (target dose 8 mg/kg/day; maximum 500 mg/day). Changes in weight were correlated with skeletal development and sexual maturation. RESULTS: Overall, 179 children (93 male, 86 female; age 6-18 years) received zonisamide (mean duration 370.6 days). Weight loss ≥ 5% was reported for 64 of 179 (35.8%) zonisamide-treated children. Of these, 46.9% were overweight/obese at study entry, compared with 23.4% at study end (P = 0.0007); 48.4% had normal weight at study entry, compared with 65.6% at study end (P = 0.03). Three patients were underweight at study entry, and four more became underweight by study end. No consistent correlations between weight loss and skeletal development or sexual maturation were observed. CONCLUSIONS: Approximately one-third of children treated with zonisamide experienced ≥ 5% weight loss. Weight loss was most apparent in children with high baseline BMI values and did not appear to be associated with any consistent effects on growth and development.

Propagation of magnetic vortices using nanocontacts as tunable attractors.

Magnetic vortices in thin films are in-plane spiral spin configurations with a core in which the magnetization twists out of the film plane. Vortices result from the competition between atomic-scale exchange forces and long-range dipolar interactions. They are often the ground state of magnetic dots, and have applications in medicine, microwave generation and information storage. The compact nature of the vortex core, which is 10-20 nm wide, makes it a suitable probe of magnetism at the nanoscale. However, thus far the positioning of a vortex has been possible only in confined structures, which prevents its transport over large distances. Here we show that vortices can be propagated in an unconstrained system that comprises electrical nanocontacts (NCs). The NCs are used as tunable vortex attractors in a manner that resembles the propelling of space craft with gravitational slingshots. By passing current from the NCs to a ferromagnetic film, circulating magnetic fields are generated, which nucleate the vortex and create a potential well for it. The current becomes spin polarized in the film, and thereby drives the vortex into gyration through spin-transfer torques. The vortex can be guided from one NC to another by tuning attractive strengths of the NCs. We anticipate that NC networks may be used as multiterminal sources of vortices and spin waves (as well as heat, spin and charge flows) to sense the fundamental interactions between physical objects and fluxes of the next-generation spintronic devices.

Spinal dermal sinuses and dermal sinus-like stalks analysis of 14 cases with suggestions for embryologic mechanisms resulting in dermal sinus-like stalks.

BACKGROUND: Spinal dermal sinuses consist of an epithelium-lined tract extending from the skin towards the spinal cord, often resulting in infections or tethered cord syndrome. Recently, a variant called dermal sinus-like stalk was described as an analogous tract but not containing an epithelium-lined lumen. AIMS: We aimed to describe the findings in our patients, subdivide our specimens into both conditions, compare the characteristics of both groups and search for possible embryologic mechanisms of dermal sinus-like stalks. METHODS: We performed a retrospective analysis of all patients operated in our hospital for both conditions between 1996 and 2012. RESULTS: 14 patients were operated upon for spinal dermal sinuses (n = 5) and spinal dermal sinus like-stalks (n = 9). Patients were mainly referred from other hospitals due to skin abnormalities and were evaluated at mean age of 7 weeks and operated upon at mean age of 1 year and 2 months. Primary reason for referral was skin abnormalities in both groups, though there were two cases of meningitis in dermal sinus patients and 2 of recurrent urinary tract infections in dermal sinus-like stalk patients. Consistent with previous findings, dermal sinus-like stalk patients do not have a history of meningitis, lack dermoid or epidermoid tumours along their tract, and are histologically of pure mesodermal origin. Dermal sinus-like stalks might result from interposition of mesenchyme during primary or secondary neurulation. CONCLUSIONS: We consider dermal sinus-like stalks as a rare but currently under diagnosed condition with different clinical, pathological and probably also embryologic characteristics compared to spinal dermal sinuses.

Early respiratory dysfunction as a biomarker for epileptic encephalopathy.

OBJECTIVES: West syndrome is an epileptic encephalopathy starting in infancy with almost continuous interictal epileptic activity, so-called hypsarrhythmia pattern, and therefore is an interesting model for investigating the effect of interictal epileptic activity on autonomic function. It is known that autonomic dysfunction contributes to morbidity and mortality in epilepsy. Our aim is to investigate the effect of interictal epileptic activity in West syndrome on respiratory control. MATERIALS AND METHODS: Interictal single-lead ECG signals were extracted from 24-h video-EEG recordings in 10 children suffering from West syndrome and 14 control subjects. RR interval time series were calculated, and respiration was derived from the ECG signal. ECG-derived respiration (EDR) signals were computed and time and frequency domain parameters were extracted to characterize the respiration pattern. RESULTS: In time domain, the standard deviation of the EDR signal is significantly lower in patients with West syndrome compared to control subjects. This finding is an indication of a less variable respiratory rate. In frequency domain, we analyzed the mean power spectrum for the EDR. In patients with West syndrome, there is more activity at the lower frequencies considered to be a risk factor for apneas. Second, there is an attenuated peak at the higher frequency band where normal respiratory rate is to be found, indicating an abnormal breathing pattern. CONCLUSIONS: Our results show that there is a clear dysfunction in autonomic respiratory control in patients with West syndrome, in between the typical ictal epileptic spasms, compared to control subjects. Respiration is more fixed and contains a higher risk of apneas.

Underlying neurological dysfunction in children with language, speech or learning difficulties and a verbal IQ--performance IQ discrepancy.

INTRODUCTION AND AIM: We investigated the relationship between possible underlying neurological dysfunction and a significant discrepancy between verbal IQ/performance IQ (VIQ-PIQ) in children with language, speech or learning difficulties. METHODS: In a retrospective study, we analysed data obtained from intelligence testing and neurological evaluation in 49 children with a significant VIQ-PIQ discrepancy (> or = 25 points) who were referred because of language, speech or learning difficulties to the Multidisciplinary University Centre for Logopedics and Audiology (MUCLA) of the University Hospitals of Leuven, Belgium. RESULTS: The group of children broke down into a group of 35 children with PIQ > VIQ and a group of 14 children with VIQ > PIQ. In the first group, neurological data were present for 24 children. The neurological history and clinical neurological examination were normal in all cases. Brain MRI was performed in 15 cases and proved to be normal in all children. Brain activity was assessed with long-term video EEG monitoring in ten children. In two children, the EEG results were abnormal: there was an epileptic focus in one child and a manifest alteration in the EEG typical of Landau-Kleffner syndrome in the other. In the second group of 14 children whose VIQ was higher than the PIQ, neurological data were available for ten children. Neurological history and clinical neurological examination were normal in all cases. Brain MRI was performed in five cases and was normal in all children. EEG monitoring was performed in one child. This revealed benign childhood epilepsy with centrotemporal spikes. CONCLUSIONS: In a small number of children (9%) with speech, language and learning difficulties and a discrepancy between VIQ and PIQ, an underlying neurological abnormality is present. We recommend referring children with a significant VIQ-PIQ mismatch to a paediatric neurologist. As an epileptic disorder seems to be the most common underlying neurological pathology in this specific group of children, EEG monitoring should be recommended in these children. Neuro-imaging should only be used in selected patients.

Plasmon filters and resonators in metal-insulator-metal waveguides.

We present the numerical and experimental demonstration of plasmonic Bragg filters and resonators inside metal-insulator-metal (MIM) waveguides. The presented filters and resonators are fabricated using standard top down lithography methods. The optical bandgap of the integrated Bragg filters is experimentally observed and its optical properties are investigated as a function of the grating pitch and the number of grating periods. Transmission filters based on a nanocavity resonance were measured, obtaining Q-factors above 30. Tuning of the cavity wavelength was experimentally achieved by varying the cavity length.

Within-subject variability during spatial working memory in children with ADHD: an event-related potentials study.

Working memory (WM) dysfunction and increased within-subject variability are known issues in attention deficit/hyperactivity disorder (ADHD) patients. Little is known about the electrophysiological characteristics of this variability. We evaluated behavioral and electrophysiological within-subject variability taking developmental aspects into account in a group of ADHD patients. Multichannel (n = 31) event-related potentials (ERP) were measured during a visuo-spatial backmatching task; 44 children (8-16 years old) were tested: 22 children with ADHD, combined (n = 17) and inattentive (n = 5) type, and 22 age- and intelligence-matched control children. One-backmatching (BM1) and two-backmatching (BM2) tasks were performed. Classical behavioral parameters and target and nontarget ERP were compared between groups. In addition, motor response variability and ERP amplitude variability were studied. Age-related changes in both motor response and ERP amplitude variability were analyzed in each group. Attention deficit/hyperactivity disorder children made more commission errors, which was more pronounced in the difficult (BM2) task. No difference between groups was found in ERP amplitude and in motor response variability. However, ADHD patients had higher ERP amplitude variability, which was again more pronounced in the difficult WM task. A delayed maturation of amplitude variability was seen in ADHD patients with a slower than in controls decrease in variability with age. This amplitude variability was correlated with the number of commissions, but in an opposite way for ADHD and control children. Our findings indicate an impaired visuo-spatial WM processing in ADHD children with greater ERP amplitude variability compared to controls. Our results also support the view of a delayed cortical development of visuo-spatial WM circuits in this disorder.

Specific magnetic isolation for direct detection of HPV16.

Finding a suitable DNA purification system is vital for the success of many PCR based diagnostic tests. This report demonstrates the value of magnetic beads in combination with real-time PCR for the sequence-specific isolation and detection of episomal HPV16 DNA. In order to maximize the isolation, two purification procedures were evaluated. Compared to the indirect method, in which the target was magnetically labeled after being hybridized to the capture probes, much higher efficiencies were obtained by directly capturing the target using DNA functionalized beads. These higher efficiencies were obtained by carefully tuning the capture probe density on the beads. When modifying the beads with dual-biotinylated capture probes or introducing beads modified with different capture probes, the amount of HPV16 isolated from spiked clinical swab samples even increased further. This not only resulted in the use of dual-biotinylated capture probes in higher purification efficiencies, but also the thermostability of the DNA-bead linkage was found to improve. In summary, this study shows that DNA functionalized magnetic beads are very promising diagnostic tools as they allow for a specific, simple, and fast isolation and concentration of minute quantities of DNA from complex clinical samples.

Understanding nanoscale temperature gradients in magnetic nanocontacts.

We have determined the temperature profile in magnetic nanocontacts under applied current densities typical of spin-torque oscillators (∼10(8) A/cm2). The study combines experimental measurements of the electrical and magnetic properties of the nanocontacts and full three-dimensional simulations of the heat and current flow in these systems. It is found that the quadratic current-induced increase of the resistance due to Joule heating is independent of the applied temperature from 6 to 300 K. In terms of magnetization dynamics, the measured current-induced vortex nucleation, a thermally activated process, is found to be consistent with local temperatures increases of between 147 and 225 K. Simulations reproduce the experimental findings and show that significant thermal gradients exist out to 450 nm from the nanocontact.

Screening for cerebral visual impairment: value of a CVI questionnaire.

The objective of the study was to investigate the screening utility of a questionnaire for cerebral visual impairment (CVI) by correlating the questionnaire with diagnostic tools such as the L94, the Test of Visual Perceptual Skills - Revised and the Visual Perception subtask of the Beery test of VisuoMotor Integration.The questionnaire consisted of 46 items, exploring different characteristics of CVI. We consecutively recruited 91 children. Parents filled out the questionnaire after which all children were seen for a diagnostic evaluation of CVI.There were 58 boys. Subjects' mean age was 6.10 years. A median of 12 items was ticked in the 45 children with CVI and 7 in the children without impairment. The domain 'visual attitude' scored positive most frequently. A logistic regression model using individual items, yielded Receiver Operating Curves for the questionnaire with good areas under the curve of 0.81 against the L94, 0.78 against the TVPS-R and 0.84 against the VP subtask. The sum score of the 6 domains was found to be an easy-obtainable score with a good sensitivity and specificity profile.This CVI questionnaire is a viable tool that has the potential of being implemented as part of a routine screening procedure for CVI.

The BOLD correlates of the visual P1 and N1 in single-trial analysis of simultaneous EEG-fMRI recordings during a spatial detection task.

Simultaneous EEG-fMRI measurements can combine the high spatial resolution of fMRI with the high temporal resolution of EEG. Therefore, we applied this approach to the study of peripheral vision. More specifically, we presented visual field quadrant fragments of checkerboards and a full central checkerboard in a simple detection task. A technique called "integration-by-prediction" was used to integrate EEG and fMRI data. In particular, we used vectors of single-trial ERP amplitude differences between left and right occipital electrodes as regressors in an ERP-informed fMRI analysis. The amplitude differences for the regressors were measured at the latencies of the visual P1 and N1 components. Our results indicated that the traditional event-related fMRI analysis revealed mostly activations in the vicinity of the primary visual cortex and in the ventral visual stream, while both P1 and N1 regressors revealed activation of areas in the temporo-parietal junction. We conclude that simultaneous EEG-fMRI in a spatial detection task can separate visual processing at 100-200 ms from stimulus onset from the rest of the information processing in the brain.

Impaired spatial working memory in children with well-controlled epilepsy: an event-related potentials study.

PURPOSE: To find out whether children with epilepsy did show different event-related potentials (ERP) compared to healthy children during performance in a visuo-spatial working memory (WM) task. METHODS: Multichannel ERPs were measured during a visuo-spatial backmatching task. A quantitative analysis technique, based on Statistical Parametric Mapping, was used to analyze the ERP data. 62 children were tested (6-16 years old): 31 children with well-controlled epilepsy and 31 age- and intelligence-matched healthy children. One-backmatching (BM1) and two-backmatching (BM2) tasks were performed. Behavioral performance and target and nontarget ERPs were compared across groups in both tasks. RESULTS: No behavioral differences were found between groups in the easy BM1 task. In the difficult BM2 task, children with epilepsy made significantly more omission errors. ERP analysis showed significantly higher amplitudes over frontal and central regions between 300 and 500 ms poststimulus in the epilepsy group compared to the control group. This effect was most pronounced in BM2. DISCUSSION: This study shows that children with well-controlled epilepsy and normal intelligence demonstrate compensatory recruitment of their WM network during a visuo-spatial working memory task. Increasing the difficulty of the task (BM2) enhances this general neurophysiological finding and parallels the behavioral performance. SIGNIFICANCE: Our results illustrate that epilepsy induces different cortical activity during working memory tasks, even when behavioral performance is normal.

Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations.

OBJECTIVES: Heterozygous mutations in STXBP1, encoding the syntaxin binding protein 1, have recently been identified in Ohtahara syndrome, an epileptic encephalopathy with very early onset. In order to explore the phenotypic spectrum associated with STXBP1 mutations, we analyzed a cohort of patients with unexplained early-onset epileptic encephalopathies. METHODS: We collected and clinically characterized 106 patients with early-onset epileptic encephalopathies. Mutation analysis of the STXBP1 gene was done using sequence analysis of the exon and intron-exon boundaries and multiplex amplification quantification to detect copy number variations. RESULTS: We identified 4 truncating mutations and 2 microdeletions partially affecting STXBP1 in 6 of the 106 patients. All mutations are predicted to abolish STXBP1 function and 5 mutations were proven to occur de novo. None of the mutation-carrying patients had Ohtahara syndrome. One patient was diagnosed with West syndrome at disease onset, while the initial phenotype of 5 further patients did not fit into a specific recognized epilepsy syndrome. Three of these patients later evolved to West syndrome. All patients had severe to profound mental retardation, and ataxia or dyskinetic movements were present in 5 patients. CONCLUSION: This study shows that mutations in STXBP1 are not limited to patients with Ohtahara syndrome, but are also present in 10% (5/49) of patients with an early-onset epileptic encephalopathy that does not fit into either Ohtahara or West syndrome and rarely in typical West syndrome. STXBP1 mutational analysis should be considered in the diagnostic evaluation of this challenging group of patients.

Cardiac changes in epilepsy.

Epilepsy and seizures can have a dramatic effect on the autonomic nervous system by involvement of the central autonomic control centers. The peri-ictal changes can lead to short-term alteration of cardiac functions in patients with seizures, and are partially hemispheric specific. Changes in heart rhythm, conduction and even subtle signs of ischemia have been reported. Ictal asystole and the lock-step phenomenon during seizures play an important role in the pathophysiology of SUDEP. In patients with longlasting epilepsy and multiple seizures, there are now convincing arguments for a chronic dysfunction of the autonomic nervous system. In this sense, heart rate variability can be considered as a biomarker of autonomic dysfunction in epilepsy. Early recognition of these short- and long-term cardiac effects will become useful in predicting seizures and in guiding more individualized treatment in the near future.

Impact of pre-concentration to covalently biofunctionalize suspended nanoparticles.

The effective biofunctionalization of nanoparticles is crucial for biomedical applications. In this study we investigated the covalent biofunctionalization of magnetic nanoparticles based on carbodiimide activation. An important aspect in the covalent biofunctionalization of nanoparticles has been neglected, namely pre-concentration. Exploiting the electrostatic attraction forces between a protein and the nanoparticle surface will favor the covalent immobilization. We showed that low ionic strength buffers with a pH slightly lower than the pI of the selected biomolecules is needed to increase the yield of covalent immobilization. Additionally, it is demonstrated that the covalently immobilized proteins are bioactive, relying on a sandwich assay using gold nanoparticles as reporter labels.

Increased stability of mercapto alkane functionalized Au nanoparticles towards DNA sensing.

The use of gold nanoparticles (GNPs) in bioassays is often hampered by their colloidal stability. In this study, gold nanoparticles coated with different mercapto alkanes were investigated towards their stability. Hereto, the effects of the alkane chain length (5-11 methylene groups), the type of functional end-group (-OH or -COOH) and the amount of incorporated poly-ethylene oxide units (none, 3 or 6) on the GNP stabilization was evaluated. Based on these results, an optimal mercapto alkane (HS(CH(2))(11)PEO(6)COOH) was selected to increase the colloidal stability up to 2 M NaCl. Furthermore, it was proved that this mercapto alkane is ideally suited to enhance the stability of DNA functionalized GNPs in high electrolytic hybridization buffers. The effectiveness of these DNA functionalized GNPs was demonstrated in a sandwich assay using a surface plasmon resonance biosensor. The superior stability of these nanoparticles during hybridization may lead to enhanced biosensor technologies.