Inflammatory Type Focal Cerebral Arteriopathy of the Posterior Circulation in Children: A Comparative Cohort Study.

BACKGROUND: Inflammatory type focal cerebral arteriopathy (FCA-i) in the anterior circulation (AC) is well characterized, and the focal cerebral arteriopathy severity score (FCASS) reflects the severity of the disease. We identified cases of FCA-i in the posterior circulation (PC) and adapted the FCASS to describe these cases. METHODS: In this comparative cohort study, patients from the Swiss NeuroPaediatric Stroke Registry with ischemic stroke due to FCA-i between January 2000 and December 2018 were analyzed. A comparison between PC and AC cases regarding pediatric National Institutes of Health Stroke Scale score and pediatric stroke outcome measure and FCASS was performed. We estimated infarct size by the modified pediatric Alberta Stroke Program Early Computed Tomography Score in children with AC stroke and the adapted Bernese posterior diffusion-weighted imaging score in the PC. RESULTS: Thirty-five children with a median age of 6.3 (interquartile range, 2.7-8.2 [95% CI, 0.9-15.6]; 20 male; 57.1%) years with FCA-i were identified. The total incidence rate was 0.15/100 000/year (95% CI, 0.11-0.21). Six had PC-FCA-i. Time to final FCASS was longer in the PC compared with AC; the evolution of FCASS did not differ. Initial pediatric National Institutes of Health Stroke Scale score was higher in children with FCA-i in the PC with a median of 10.0 (interquartile range, 5.75-21.0) compared with 4.5 (interquartile range, 2.0-8.0) in those with AC-FCA-i. Different from the anterior cases, PC infarct volume did not correlate with higher discharge, maximum, or final FCASS scores (Pearson correlation coefficient [r], 0.25, 0.35, and 0.54). CONCLUSIONS: FCA-i also affects the PC. These cases should be included in future investigations into FCA-i. Although it did not correlate with clinical outcomes in our cohort, the modified FCASS may well serve as a marker for the evolution of the arteriopathy in posterior FCA-i.

Hyperarousal features in the sleep architecture of individuals with and without insomnia.

Sleep architecture encodes relevant information on the structure of sleep and has been used to assess hyperarousal in insomnia. This study investigated whether polysomnography-derived sleep architecture displays signs of hyperarousal in individuals with insomnia compared with individuals without insomnia. Data from Phase 3 clinical trials, private clinics and a cohort study were analysed. A comprehensive set of sleep architecture features previously associated with hyperarousal were retrospectively analysed focusing on sleep-wake transition probabilities, electroencephalographic spectra and sleep spindles, and enriched with a novel machine learning algorithm called the Wake Electroencephalographic Similarity Index. This analysis included 1710 individuals with insomnia and 1455 individuals without insomnia. Results indicate that individuals with insomnia had a higher likelihood of waking from all sleep stages, and showed increased relative alpha during Wake and N1 sleep and increased theta power during Wake when compared with individuals without insomnia. Relative delta power was decreased and Wake Electroencephalographic Similarity Index scores were elevated across all sleep stages except N3, suggesting more wake-like activity during these stages in individuals with insomnia. Additionally, sleep spindle density was decreased, and spindle dispersion was increased in individuals with insomnia. These findings suggest that insomnia is characterized by a dysfunction in sleep quality with a continuous hyperarousal, evidenced by changes in sleep-wake architecture.

UHPLC-MS/MS-Based Identity Confirmation of Amino Acids Involved in Response to and Side Effects from Antiseizure Medications.

Real-time breath analysis using secondary electrospray ionization coupled with high-resolution mass spectrometry is a fast and noninvasive method to access the metabolic state of a person. However, it lacks the ability to unequivocally assign mass spectral features to compounds due to the absence of chromatographic separation. This can be overcomed by using exhaled breath condensate and conventional liquid chromatography-mass spectrometry (LC-MS) systems. In this study, to the best of our knowledge, we confirm for the first time the presence of six amino acids (GABA, Oxo-Pro, Asp, Gln, Glu, and Tyr) previously reported to be involved in response to and side effects from antiseizure medications in exhaled breath condensate and by extension in exhaled human breath. Raw data are publicly available at MetaboLights with the accession number MTBLS6760.

The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental and epileptic encephalopathy.

OBJECTIVE: Asparagine-linked glycosylation 13 (ALG13) deficiencies have been repeatedly described in the literature with the clinical phenotype of a developmental and epileptic encephalopathy (DEE). Most cases were females carrying the recurrent ALG13 de novo variant, p.(Asn107Ser), with normal transferrin electrophoresis. METHODS: We delineate the phenotypic spectrum of 38 individuals, 37 girls and one boy, 16 of them novel and 22 published, with the most common pathogenic ALG13 variant p.(Asn107Ser) and additionally report the phenotype of three individuals carrying other likely pathogenic ALG13 variants. RESULTS: The phenotypic spectrum often comprised pharmacoresistant epilepsy with epileptic spasms, mostly with onset within the first 6 months of life and with spasm persistence in one-half of the cases. Tonic seizures were the most prevalent additional seizure type. Electroencephalography showed hypsarrhythmia and at a later stage of the disease in one-third of all cases paroxysms of fast activity with electrodecrement. ALG13-related DEE was usually associated with severe to profound developmental delay; ambulation was acquired by one-third of the cases, whereas purposeful hand use was sparse or completely absent. Hand stereotypies and dyskinetic movements including dystonia or choreoathetosis were relatively frequent. Verbal communication skills were absent or poor, and eye contact and pursuit were often impaired. SIGNIFICANCE: X-linked ALG13-related DEE usually manifests as West syndrome with severe to profound developmental delay. It is predominantly caused by the recurrent de novo missense variant p.(Asn107Ser). Comprehensive functional studies will be able to prove or disprove an association with congenital disorder of glycosylation.

Drug-drug and drug-food interactions in an infant with early-onset SCN2A epilepsy treated with carbamazepine, phenytoin and a ketogenic diet.

Sodium channel 2 subunit α (SCN2A) mutations cause difficult-to-treat early-onset epilepsy. Effective treatment includes high-dose phenytoin or carbamazepine ± ketogenic diet (KD). We describe an infant with early-onset SCN2A-epilepsy with subtherapeutic carbamazepine concentration during transition from phenytoin treatment to avoid long-term neurotoxicity. The transition from high-dose phenytoin (20 mg kg-1 d-1 , concentration: ≥20 mg/L) with KD, to carbamazepine (50-75 mg kg-1 d-1 , concentration: 9-12 mg/L) lasted 85 days, which we suspected was due to significant drug-drug and/or drug-food interactions. Model-based analysis of carbamazepine pharmacokinetics quantified significant time- and dose-dependent phenytoin-mediated CYP3A4 induction and carbamazepine concentration-dependent auto-induction (apparent clearance increased up to 2.5/3-fold). Lower carbamazepine concentrations under KD were modelled as decreased relative bioavailability (44%), potentially related to decreased fraction absorbed (unexpected for this lipophilic drug), increased intestinal/hepatic metabolism and/or decreased protein-binding with KD. This suggests importance of carbamazepine-concentration monitoring during KD-introduction/removal and necessity of high carbamazepine doses to achieve therapeutic concentrations, especially in infants treated with high-dose phenytoin.

Subgroup analysis of seizure and cognitive outcome after vagal nerve stimulator implantation in children.

OBJECTIVE: Vagal nerve stimulator (VNS) implantation at an early age seems to lead to improved quality of life and cognitive outcome. The aim of this analysis is to evaluate whether specific patient or seizure characteristics might lead to better seizure control, cognitive outcome, and higher quality of life in children undergoing VNS implantation. METHODS: Primary outcome measure was reduction in seizure frequency. Secondary outcome measures were epilepsy outcome assessed by McHugh and Engel classifications, reduction in antiepileptic drugs (AED), developmental and cognitive outcome, as well as quality of life assessed through the pediatric quality of life (PEDSQL™) questionnaire and care giver impression (CGI) scale. Forty-five consecutive children undergoing VNS implantation were analyzed for the following subgroups: age (categorized to 1-2 years old, 3-5 years old, 6-12 years old, and 13-18 years old), sex, underlying cause (categorized to idiopathic, encephalitis, stroke, syndromic), duration of preoperative seizures (dichotomized to under or above 89 months, corresponding to the median of the whole cohort), and preoperative seizure frequency (dichotomized to under and above 360 seizures per month). RESULTS: Encephalitis as the underlying cause for seizures was the only variable significantly associated with higher reduction rate of seizure frequency. Patients with VNS implantation at the age of ≤ 2 years showed a strong association with better developmental and cognitive outcome, as well as quality of life. Shorter duration of preoperative seizures and higher preoperative seizure frequency showed a strong association with better developmental outcome, as well as quality of life. Engel outcome scores were significantly better in patients with epilepsy due to encephalitis (100% Engel I-III). However, patients with epilepsy due to encephalitis showed significantly higher complication rates (71.4%, p = 0.045). CONCLUSIONS: Children suffering from epilepsy due to encephalitis show higher seizure reduction rates after VNS implantation when compared with children suffering from epilepsy due to other causes. Developmental and cognitive outcomes as well as quality of life of children undergoing VNS implantation is strongly associated with shorter duration of preoperative seizures and implantation at a young age.

The rhythm of a preterm neonate's life: ultradian oscillations of heart rate, body temperature and sleep cycles.

The objectives are to characterize oscillations of physiological functions such as heart rate and body temperature, as well as the sleep cycle from behavioral states in generally stable preterm neonates during the first 5 days of life. Heart rate, body temperature as well as behavioral states were collected during a daily 3-h observation interval in 65 preterm neonates within the first 5 days of life. Participants were born before 32 weeks of gestational age or had a birth weight below 1500 g; neonates with asphyxia, proven sepsis or malformation were excluded. In total 263 observation intervals were available. Heart rate and body temperature were analyzed with mathematical models in the context of non-linear mixed effects modeling, and the sleep cycles were characterized with signal processing methods. The average period length of an oscillation in this preterm neonate population was 159 min for heart rate, 290 min for body temperature, and the average sleep cycle duration was 19 min. Oscillation of physiological functions as well as sleep cycles can be characterized in very preterm neonates within the first few days of life. The observed parameters heart rate, body temperature and sleep are running in a seemingly uncorrelated pace at that stage of development. Knowledge about such oscillations may help to guide nursing and medical care in these neonates as they do not yet follow a circadian rhythm.

Risk Factors for Postprocedural Arterial Ischemic Stroke in Children With Cardiac Disease.

BACKGROUND AND PURPOSE: Cardiac pathologies are the second most frequent risk factor (RF) in children with arterial ischemic stroke (AIS). This study aimed to analyze RFs for AIS in children with cardiac disease and cardiac intervention. METHODS: Data were drawn from the Swiss Neuropediatric Stroke Registry. Patients with cardiac disease and postprocedural AIS registered from 2000 until 2015 were analyzed for the cause of cardiac disease and for potential RFs. RESULTS: Forty-seven out of 78 children with cardiac disease had a cardiac intervention. Of these, 36 presented a postprocedural AIS. Median time from cardiac intervention to symptom onset was 4 days (interquartile range, 2-8.5); time to diagnosis of AIS was 2 days (interquartile range, 0-5.8). Main RFs for postprocedural AIS were hypotension, prosthetic cardiac material, right-to-left shunt, arrhythmias, low cardiac output, and infections. CONCLUSIONS: In children with postprocedural AIS, time to diagnosis was delayed. Most patients presented multiple potentially modifiable RFs as hemodynamic alterations and infections.

Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.

PURPOSE: Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features. METHODS: Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay. RESULTS: We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance. CONCLUSION: In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.

Feasibility, safety, and outcome of recanalization treatment in childhood stroke.

OBJECTIVE: Intravenous thrombolysis and endovascular therapy (IVT/EVT) are evidence-based treatments for adults with arterial ischemic stroke (AIS). However, randomized controlled trials in pediatric patients are lacking. This study aimed to describe feasibility, safety, and outcome of IVT/EVT in children with AIS. METHODS: This retrospective study (01/2000-12/2015) included a multicenter, population-based consecutive cohort of patients aged 1 month to 16 years, diagnosed with AIS and presenting with pediatric National Institutes of Health Stroke Scale (pedNIHSS) ≥ 4. Clinical and radiological data of patients receiving IVT/EVT were compared to those receiving standard care (SC) using linear regression to adjust for potential confounders. EVT included intra-arterial thrombolysis and/or mechanical thrombectomy. Outcome was assessed 6 months after stroke using the pediatric stroke outcome measure (PSOM). RESULTS: Overall, 150 patients (age 7.1 ± 4.9 years, 55 [37%] females) presented with pedNIHSS ≥ 4. Recanalization treatment was performed in 16 (11%), of whom 5 (3%) were treated with IVT and 11 (7%) with EVT. Patients receiving recanalization treatment were older (mean age = 11.0 vs 6.9 years, p = 0.01) and more severely affected (median pedNIHSS = 13.5 vs 8.0, p < 0.001). Death and bleeding complications did not differ between the 2 groups. Median (interquartile range) PSOM 6 months after AIS was 2.5 (1-4.3) and 1 (0-2) in the IVT/EVT and SC groups, respectively (p = 0.014). However, after multiple linear regression analysis, only higher baseline pedNIHSS remained associated with an unfavorable outcome (p < 0.001). INTERPRETATION: Recanalization treatment is feasible and seems to be safe in severely affected pediatric AIS patients. The assessment of efficacy of IVT/EVT in pediatric stroke patients requires larger studies. Ann Neurol 2018;83:1125-1132.

Heart rate fluctuation after birth predicts subsequent cardiorespiratory stability in preterm infants.

BACKGROUND: Cardiorespiratory stability of preterm infants is a prerequisite for discharge from the neonatal intensive care unit (NICU) but very difficult to predict. We aimed to assess whether characterizing heart rate fluctuation (HRF) within the first days of life has prognostic utility. METHODS: We conducted a prospective cohort study in 90 preterm infants using a previously validated surface diaphragmatic electromyography (sEMG) method to derive interbeat intervals. We characterized HRF by time series parameters including sample entropy (SampEn) and scaling exponent alpha (ScalExp) obtained from daily 3-h measurements. Data were analyzed by multivariable, multilevel linear regression. RESULTS: We obtained acceptable raw data from 309/330 sEMG measurements in 76/90 infants born at a mean (range) of 30.2 (24.7-34.0) weeks gestation. We found a significant negative association of SampEn with duration of respiratory support (R2 = 0.53, p < 0.001) and corrected age at discontinuation of caffeine therapy (R2 = 0.35, p < 0.001) after adjusting for sex, gestational age, birth weight z-score, and sepsis. CONCLUSIONS: Baseline SampEn calculated over the first 5 days of life carries prognostic utility for an estimation of subsequent respiratory support and pre-discharge cardiorespiratory stability in preterm infants, both important for planning of treatment and utilization of health care resources.

The role of sleep-related cognitive functions in the spectrum of benign epilepsy with centro-temporal spikes.

Heterogeneous cognitive deficits have been described in the spectrum of benign epilepsy with centro-temporal spikes, which strongly correlate with the intensity of interictal epileptiform discharges and its spreading, in particular during sleep, mostly within the perisylvian cognitive network. The aim of this review is to discuss current findings regarding the connection between sleep alterations and cognitive function in the spectrum of benign epilepsy with centro-temporal spikes. A longer sleep onset latency is the only evident sleep macrostructure alteration reported in the spectrum of benign epilepsy with centro-temporal spikes. On a microstructural level, a higher spike count of descending compared to ascending slopes of sleep cycles, an impairment of slow wave downscaling, and amplitude and slope of slow waves were found in the spectrum of benign epilepsy with centro-temporal spikes. Moreover, children with benign epilepsy with centro-temporal spikes had a reduced non-rapid eye movement sleep instability, in terms of cyclic alternating pattern, similar to that found in children with attention-deficit hyperactivity disorders and in children with obstructive sleep apnea and centro-temporal spike during sleep. Children with benign epilepsy with centro-temporal spikes have a known comorbidity with attention-deficit hyperactivity disorders and obstructive sleep apnea.Conclusion: Considering the common sleep microstructure alterations, the presence of attention deficit and hyperactivity and/or sleep apnea may be a considered warning sign in the case of benign epilepsy with centro-temporal spikes. What is Known: • Sleep related-cognitive deficits have been described in the spectrum of benign epilepsy with centro-temporal spikes. The degree of sleep alterations may predict the neurocognitive outcome, and help clinicians to choose the right treatment. What is New: • Considering the common sleep microstructure alterations, attention deficit and sleep apnea, may be a considered warning signs.

De novo GABRG2 mutations associated with epileptic encephalopathies.

Epileptic encephalopathies are a devastating group of severe childhood onset epilepsies with medication-resistant seizures and poor developmental outcomes. Many epileptic encephalopathies have a genetic aetiology and are often associated with de novo mutations in genes mediating synaptic transmission, including GABAA receptor subunit genes. Recently, we performed next generation sequencing on patients with a spectrum of epileptic encephalopathy phenotypes, and we identified five novel (A106T, I107T, P282S, R323W and F343L) and one known (R323Q) de novo GABRG2 pathogenic variants (mutations) in eight patients. To gain insight into the molecular basis for how these mutations contribute to epileptic encephalopathies, we compared the effects of the mutations on the properties of recombinant α1ß2γ2L GABAA receptors transiently expressed in HEK293T cells. Using a combination of patch clamp recording, immunoblotting, confocal imaging and structural modelling, we characterized the effects of these GABRG2 mutations on GABAA receptor biogenesis and channel function. Compared with wild-type α1ß2γ2L receptors, GABAA receptors containing a mutant γ2 subunit had reduced cell surface expression with altered subunit stoichiometry or decreased GABA-evoked whole-cell current amplitudes, but with different levels of reduction. While a causal role of these mutations cannot be established directly from these results, the functional analysis together with the genetic information suggests that these GABRG2 variants may be major contributors to the epileptic encephalopathy phenotypes. Our study further expands the GABRG2 phenotypic spectrum and supports growing evidence that defects in GABAergic neurotransmission participate in the pathogenesis of genetic epilepsies including epileptic encephalopathies.

Improved quality of life and cognition after early vagal nerve stimulator implantation in children.

OBJECTIVE: In patients with drug-resistant epilepsy, reduction of seizure duration and frequency at an early age is beneficial. Vagal nerve stimulator (VNS) was shown to reduce seizure frequency and duration in children; however, data in children under the age of 12 years are sparse. The aim of this study was to compare seizure outcome and quality of life after early (≤5 years of age) and late (>5 years of age) implantation of VNS in children. METHODS: This study reviewed 45 consecutive children undergoing VNS implantation. Primary outcome measure was the reduction of seizure frequency. Secondary outcome measures were epilepsy outcome assessed by the McHugh and Engel classifications, reduction of antiepileptic drugs (AEDs), psychomotor development, and quality of life measured by the Pediatric Quality of Life (PEDSQL™) questionnaire and caregiver impression (CGI) scale. The mean follow-up time was 72.3 months (±39.8 months). RESULTS: Out of 45 patients included, in 14 (31.1%), VNS was implanted early and in 31, (68.9%) late. Reduction of seizure frequency, McHugh and Engel classifications, and reduction of AED were comparable in both groups. Quality of life measured by the CGI scale (2.1 ±â€¯1.7 in the early group vs. 3.6 ±â€¯1.6 in the late group; p = 0.004), as well as the difference of total PEDSQL™ Core scores (12.0 ±â€¯24.0 in the early group vs. -5.2 ±â€¯14.9 in the late group; p = 0.01) and cognitive PEDSQL™ Core (30.6 ±â€¯32.0 in the early group vs. 2.4 ±â€¯24.3 in the late group; p = 0.03) between preoperative and follow-up was significantly higher in the early implantation group. CONCLUSION: Early VNS implantation in children leads to a significantly better quality of life and cognitive outcome compared with late implantation while reduction of seizure frequency and epilepsy outcome seems comparable. Therefore, in children with drug-resistant epilepsy, VNS implantation should be considered as early as possible.

Early vagal nerve stimulator implantation in children: personal experience and review of the literature.

AIM: Data concerning the benefit of vagal nerve stimulation (VNS) in children under the age of 12 years is sparse. It was shown that reduction of seizure frequency and duration at an early age could lead to better psychomotor development. We therefore compare the outcome between early (≤ 5 years of age) and late (> 5 years of age) implantation of VNS in children. METHODS: This study is a prospective review of patients analyzing primarily the reduction of seizure frequency and secondarily epilepsy outcome assessed by the McHugh and Engel classification, reduction of antiepileptic drugs (AED), psychomotor development measured by the Vineland Adaptive Behavior Scale (VABS), and quality of life using the caregiver impression (CGI) scale. Mean follow-up time was 36 and 31 months in the early and late group, respectively. RESULTS: Out of 12 consecutive VNS implantations for therapy refractory epilepsy, 5 were early implantations and 7 late implantations. Reduction of seizure frequency, McHugh and Engel classification, quality of life, psychomotor development and reduction of AED were comparable in both groups. One patient in the late group suffered from a postoperative infection resulting in explanation of the VNS device and re-implantation on the opposite side, while mortality rate was 0%. CONCLUSIONS: VNS seems to be a safe and feasible therapy in children even under the age of 5 years. Responder rate, quality of life, and psychomotor development do not seem to be influenced by the child's age at implantation; however, larger studies analyzing the outcome of early VNS implantation are warranted.

MTO1 mediates tissue specificity of OXPHOS defects via tRNA modification and translation optimization, which can be bypassed by dietary intervention.

Mitochondrial diseases often exhibit tissue-specific pathologies, but this phenomenon is poorly understood. Here we present regulation of mitochondrial translation by the Mitochondrial Translation Optimization Factor 1, MTO1, as a novel player in this scenario. We demonstrate that MTO1 mediates tRNA modification and controls mitochondrial translation rate in a highly tissue-specific manner associated with tissue-specific OXPHOS defects. Activation of mitochondrial proteases, aberrant translation products, as well as defects in OXPHOS complex assembly observed in MTO1 deficient mice further imply that MTO1 impacts translation fidelity. In our mouse model, MTO1-related OXPHOS deficiency can be bypassed by feeding a ketogenic diet. This therapeutic intervention is independent of the MTO1-mediated tRNA modification and involves balancing of mitochondrial and cellular secondary stress responses. Our results thereby establish mammalian MTO1 as a novel factor in the tissue-specific regulation of OXPHOS and fine tuning of mitochondrial translation accuracy.

Caffeine Citrate Dosing Adjustments to Assure Stable Caffeine Concentrations in Preterm Neonates.

OBJECTIVE: To identify dosing strategies that will assure stable caffeine concentrations in preterm neonates despite changing caffeine clearance during the first 8 weeks of life. METHODS: A 3-step simulation approach was used to compute caffeine doses that would achieve stable caffeine concentrations in the first 8 weeks after birth: (1) a mathematical weight change model was developed based on published weight distribution data; (2) a pharmacokinetic model was developed based on published models that accounts for individual body weight, postnatal, and gestational age on caffeine clearance and volume of distribution; and (3) caffeine concentrations were simulated for different dosing regimens. RESULTS: A standard dosing regimen of caffeine citrate (using a 20 mg/kg loading dose and 5 mg/kg/day maintenance dose) is associated with a maximal trough caffeine concentration of 15 mg/L after 1 week of treatment. However, trough concentrations subsequently exhibit a clinically relevant decrease because of increasing clearance. Model-based simulations indicate that an adjusted maintenance dose of 6 mg/kg/day in the second week, 7 mg/kg/day in the third to fourth week and 8 mg/kg/day in the fifth to eighth week assures stable caffeine concentrations with a target trough concentration of 15 mg/L. CONCLUSIONS: To assure stable caffeine concentrations during the first 8 weeks of life, the caffeine citrate maintenance dose needs to be increased by 1 mg/kg every 1-2 weeks. These simple adjustments are expected to maintain exposure to stable caffeine concentrations throughout this important developmental period and might enhance both the short- and long-term beneficial effects of caffeine treatment.

Fidgety movements in infants born very preterm: predictive value for cerebral palsy in a clinical multicentre setting.

AIM: This study assessed predictive values of fidgety movement assessment (FMA) in a large sample of infants born very preterm for developmental abnormalities, in particular for cerebral palsy (CP) at 2 years in an everyday clinical setting. METHOD: This is a multicentre study of infants born preterm with gestational age lower than 32.0 weeks. FMA was performed at 3 months corrected age; neurodevelopment (Bayley Scales of Infant Development, 2nd edition) and neurological abnormalities were assessed at 2 years. Predictive values of FMA for the development of CP were calculated and combined with abnormalities at cerebral ultrasound. RESULTS: Five hundred and thirty-five infants (gestational age 28.2wks [standard deviation 1.3wks]) were included. Eighty-one percent showed normal fidgety movements and 19% atypical (82 absent, 21 abnormal) fidgety movements. Absent fidgety movements predicted CP at 2 years with an odds ratio (OR) of 8.9 (95% confidence interval [CI] 4.1-17.0), a combination of atypical fidgety movements and major brain lesion on cerebral ultrasound predicted it with an OR of 17.8 (95% CI 5.2-61.6). Mean mental developmental index of infants with absent fidgety movements was significantly lower (p=0.012) than with normal fidgety movements. INTERPRETATION: Detection of infants at risk for later CP through FMA was good, but less robust when performed in a routine clinical setting; prediction improved when combined with neonatal cerebral ultrasound.

Immediate effects of phototherapy on sleep in very preterm neonates: an observational study.

Process C (internal clock) and Process S (sleep-wake homeostasis) are the basis of sleep-wake regulation. In the last trimester of pregnancy, foetal heart rate is synchronized with the maternal circadian rhythm. At birth, this interaction fails and an ultradian rhythm appears. Light exposure is a strong factor influencing the synchronization of sleep-wake processes. However, little is known about the effects of phototherapy on the sleep rhythm of premature babies. It was hypothesized that sleep in preterm infants would not differ during phototherapy, but that a maturation effect would be seen. Sleep states were studied in 38 infants born < 32 weeks gestational age and/or < 1 500 g birth weight. Videos of 3 h were taken over the first 5 days of life. Based on breathing and movement patterns, behavioural states were defined as: awake; active sleep; or quiet sleep. Videos with and without phototherapy were compared for amounts of quiet sleep and active states (awake + active sleep). No significant association between phototherapy and amount of quiet sleep was found (P = 0.083). Analysis of videos in infants not under phototherapy revealed an increase in time spent awake with increasing gestational age. The current data suggest that the ultradian rhythm of preterm infants seems to be independent of phototherapy, supporting the notion that sleep rhythm in this population is mainly driven by their internal clock.

Default mode network alterations during language task performance in children with benign epilepsy with centrotemporal spikes (BECTS).

Benign epilepsy with centrotemporal spikes (BECTS) is the most common idiopathic epileptic disorder in children. Besides reported cognitive deficits, functional alterations mostly in the reorganization of language areas have also been described. In several publications, it has been reported that activation of the default mode network (DMN) can be reduced or altered in different neuropsychiatric and neurological disorders in adults. Whether this also holds true for children with epilepsy has so far not been clarified. To determine the functional activation of the DMN in children with BECTS, 20 patients and 16 healthy controls were examined using functional magnetic resonance imaging (fMRI), while a sentence generation task and a reading task were applied in a block design manner. To study the default mode network and the functional alterations between groups, an independent component analysis (ICA) was computed and further analyzed using SPM5. Compared with controls, children with BECTS showed not only significantly less activation of the DMN during the rest condition but also less deactivation during cognitive effort. This was most apparent in the precuneus, a key region of the DMN, while subjects were generating sentences. From these findings, we hypothesize that children with BECTS show a functional deficit that is reflected by alterations in the DMN.