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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Duplication of the VHL and IRAK2 genes in a patient with mental retardation/multiple congenital anomalies, epilepsy and ectomorphic habitus.

Partial 3p duplications are very rare. Often they are reported in translocations involving other chromosomes, whereas deletions encompassing the VHL gene in 3p25.3 predispose to Van-Hippel Lindau syndrome. We report here a paternally-inherited microduplication of 3p25.3 detected by array comparative genomic hybridisation (aCGH) in a 17 year-old male patient presenting with mental retardation and multiple congenital anomalies (MR/MCA), epilepsy and ectomorphic habitus. He has no tumour and there is no history of familial cancer. We refined the duplication by Multiplex Ligation-dependent Probe Amplification (MLPA) to a 251 kb region encompassing the VHL and IRAK2 genes. The duplication is likely to be causal. Interestingly, duplication of IRAK2 can cause epilepsy. Disruption of the GHRL gene can explain the ectomorphic habitus. To our knowledge, this is the smallest 3p duplication encompassing the VHL region. Its prognosis is unknown and a long-term follow-up is essential for an early diagnosis of malignancy.

Direct current control of three magnon scattering processes in spin-valve nanocontacts.

We have investigated the generation of spin waves in the free layer of an extended spin-valve structure with a nanoscaled point contact driven by both microwave and direct electric current using Brillouin light scattering microscopy. Simultaneously with the directly excited spin waves, strong nonlinear effects are observed, namely, the generation of eigenmodes with integer multiple frequencies (2f, 3f, 4f) and modes with noninteger factors (0.5f, 1.5f) with respect to the excitation frequency f. The origin of these nonlinear modes is traced back to three-magnon-scattering processes. The direct current influence on the generation of the fundamental mode at frequency f is related to the spin-transfer torque, while the efficiency of three-magnon-scattering processes is controlled by the Oersted field as an additional effect of the direct current.

Assessment of cerebral visual impairment with the L94 visual perceptual battery: clinical value and correlation with MRI findings.

In this article we describe visual perceptual abilities of a clinical population, referred for visual problems to our multidisciplinary team and assessed with the five computer tasks from the L94 visual perceptual battery. Clinical and neuroimaging findings were correlated with the findings on this task battery. Seventy children (35 males, 35 females) constituted our cohort. Age ranged from 4 to 20 years (mean 7y [SD 3y]). Forty children were born before 37 weeks gestational age. Thirty-six children had cerebral palsy (CP), of whom 24 had spastic diplegia, five had spastic hemiplegia, and four had spastic quadriplegia. Three children had ataxic CP. Perceptual visual impairment (PVI) was established in comparison to the performance age obtained on non-verbal intelligence subtests, instead of chronological age. Our results suggest that children with a history of preterm birth and a clinical CP picture are most at risk for a specific PVI. Correlations among other clinical variables did not define a clinical subgroup more at risk. Children with periventricular leucomalacia were almost equally represented in both PVI and non-PVI groups. Normal magnetic resonance imaging did not exclude the presence of PVI. In these children, however, we found another impairment profile, more in favour of dorsal stream impairment.

Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations.

OBJECTIVE: We have recently shown that de novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders. To better define the range of these abnormalities, we searched for additional mutations in a cohort of 100 patients with lissencephaly spectrum for whom no mutation was identified in DCX, LIS1 and ARX genes and compared these data to five previously described patients with TUBA1A mutations. RESULTS: We detected de novo TUBA1A mutations in six patients and highlight the existence of a prominent form of TUBA1A related lissencephaly. In four patients, the mutations identified, c.1190T>C (p.L397P), c.1265G>A (p.R422H), c.1264C>T (p.R422C), c.1306G>T (p.G436R), have not been reported before and in two others, the mutation corresponds to a recurrent missense mutation, c.790C>T (p.R264C), likely to be a hot spot of mutation. All together, it emerges that the TUBA1A related lissencephaly spectrum ranges from perisylvian pachygyria, in the less severe form, to posteriorly predominant pachygyria in the most severe, associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. When compared with a large series of lissencephaly of other origins (ILS17, ILSX or unknown origin), these features appear to be specific to TUBA1A related lissencephaly. In addition, TUBA1A mutated patients share a common clinical phenotype that consists of congenital microcephaly, mental retardation and diplegia/tetraplegia. CONCLUSIONS: Our data highlight the presence of consistent and specific abnormalities that should allow the differentiation of TUBA1A related lissencephalies from those related to LIS1, DCX and ARX genes.

Stroke diagnosis with lab-on-a-chip.

A magnetic-based sensing platform with increased sensitivity has been developed for integration into lab-on-a-chip systems. The methodology consists of moving the magnetic particles to the most sensitive spot of the sensor. To demonstrate its effectiveness, the protein S100betabeta, a diagnostic marker for stroke, was used as target protein.

A second locus for Aicardi-Goutieres syndrome at chromosome 13q14-21.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is an autosomal recessive, early onset encephalopathy characterised by calcification of the basal ganglia, chronic cerebrospinal fluid lymphocytosis, and negative serological investigations for common prenatal infections. AGS may result from a perturbation of interferon alpha metabolism. The disorder is genetically heterogeneous with approximately 50% of families mapping to the first known locus at 3p21 (AGS1). METHODS: A genome-wide scan was performed in 10 families with a clinical diagnosis of AGS in whom linkage to AGS1 had been excluded. Higher density genotyping in regions of interest was also undertaken using the 10 mapping pedigrees and seven additional AGS families. RESULTS: Our results demonstrate significant linkage to a second AGS locus (AGS2) at chromosome 13q14-21 with a maximum multipoint heterogeneity logarithm of the odds (LOD) score of 5.75 at D13S768. The AGS2 locus lies within a 4.7 cM region as defined by a 1 LOD-unit support interval. CONCLUSIONS: We have identified a second AGS disease locus and at least one further locus. As in a number of other conditions, genetic heterogeneity represents a significant obstacle to gene identification in AGS. The localisation of AGS2 represents an important step in this process.