Evolution of source EEG synchronization in early Alzheimer's disease.

Alzheimer's disease (AD) disrupts functional connectivity in distributed cortical networks. We analyzed changes in the S-estimator, a measure of multivariate intraregional synchronization, in electroencephalogram (EEG) source space in 15 mild AD patients versus 15 age-matched controls to evaluate its potential as a marker of AD progression. All participants underwent 2 clinical evaluations and 2 EEG recording sessions on diagnosis and after a year. The main effect of AD was hyposynchronization in the medial temporal and frontal regions and relative hypersynchronization in posterior cingulate, precuneus, cuneus, and parietotemporal cortices. However, the S-estimator did not change over time in either group. This result motivated an analysis of rapidly progressing AD versus slow-progressing patients. Rapidly progressing AD patients showed a significant reduction in synchronization with time, manifest in left frontotemporal cortex. Thus, the evolution of source EEG synchronization over time is correlated with the rate of disease progression and should be considered as a cost-effective AD biomarker.

Pédiatrie [Perinatal asphyxia and neonatal hydronephrosis]

Perinatal asphyxia. Perinatal asphyxia remains one of the most important causes for high mortality and morbidity in the neonatal population. Despite intensive animal and clinical research in this field, no pharmocological strategy has been shown neuroprotective in humans. Moderate hypothermia for severely and moderately asphyctic babies has been aknowledged since a few years as therapeutical approach to improve the outcome of these infants, specifically the long-term follow up (18 months). Neonatal hydronephrosis. Neonatal hydronephrosis is a pathology that requires regular and efficient follow up by a multidisciplinary team. One of the causes of neonatal hydronephrosis is obstructive pathologies which may endanger the kidney. We have developed a strategy that allows a rapid diagnosis of obstructive pathologies with minimal radiological exams. Moreover, this strategy assures the coordination between obstetricians, neonatologists, pediatric urologists, and pediatric nephrologists.

A homozygous missense mutation in SCNN1A is responsible for a transient neonatal form of pseudohypoaldosteronism type 1.

Pseudohypoaldosteronism type 1 (PHA1) is a monogenic disorder of mineralocorticoid resistance characterized by salt wasting, hyperkalemia, high aldosterone levels, and failure to thrive. An autosomal recessive form (AR-PHA1) is caused by mutations in the epithelial sodium channel ENaC with usually severe and persisting multiorgan symptoms. The autosomal dominant form of PHA1 (AD-PHA1) is due to mutations in the mineralocorticoid receptor causing milder and transient symptoms restricted to the kidney. We identified a homozygous missense mutation in the SCNN1A gene (c.727T>C/p.Ser(243)Pro), encoding α-subunit of ENaC (α-ENaC) in a prematurely born boy with a severe salt-losing syndrome. The patient improved rapidly under treatment, and dietary salt supplementation could be stopped after 6 mo. Interestingly, the patient's sibling born at term and harboring the same homozygous Ser(243)Pro mutation showed no symptom of salt-losing nephropathy. In vitro expression of the αSer(243)Pro ENaC mutant revealed a slight but significant decrease in ENaC activity that is exacerbated in the presence of high Na(+) load. Our study provides the first evidence that ENaC activity is critical for the maintenance of salt balance in the immature kidney of preterm babies. Together with previous studies, it shows that, when the kidney is fully mature, the severity of the symptoms of AR-PHA1 is related to the degree of the ENaC loss of function. Finally, this study identifies a novel functional domain in the extracellular loop of ENaC.

Asymmetric POSTS associated with unilateral EEG abnormalities.

OBJECTIVE: Positive occipital sharp transient of the sleep (POSTS) are considered a normal variant of non-REM sleep EEG. We describe a small series of patients with asymmetric POSTS and ipsilateral abnormal EEG findings. METHODS: Over a period of 30 weeks, we prospectively observed five consecutive subjects with strictly unilateral POSTS associated with ispilateral electrographic abnormalities. They represent 0.4% of all EEG performed over the same time lapse (5/1130), including inpatients, outpatients and long-term monitoring. RESULTS: Four women and one boy suffering from epileptic seizures (aged 7-76 years old) had unilateral POSTS, occurring only on the right side, during light sleep. They also presented ipsilateral epileptiform abnormalities. CONCLUSION: The fact that POSTS were asymmetric and found only on the same side as the abnormalities raises the question whether these transients should still be considered physiological or could be interpreted at times as markers of underlying electrical abnormalities, pointing to an increased cortical excitability on the more active side. Although larger samples are needed to confirm our preliminary results, this case study questions the interpretation of POSTS as a uniformly normal variant.

Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial.

Glutathione (GSH) dysregulation at the gene, protein, and functional levels has been observed in schizophrenia patients. Together with disease-like anomalies in GSH deficit experimental models, it suggests that such redox dysregulation can play a critical role in altering neural connectivity and synchronization, and thus possibly causing schizophrenia symptoms. To determine whether increased GSH levels would modulate EEG synchronization, N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients in a randomized, double-blind, crossover protocol for 60 days, followed by placebo for another 60 days (or vice versa). We analyzed whole-head topography of the multivariate phase synchronization (MPS) for 128-channel resting-state EEGs that were recorded at the onset, at the point of crossover, and at the end of the protocol. In this proof of concept study, the treatment with NAC significantly increased MPS compared to placebo over the left parieto-temporal, the right temporal, and the bilateral prefrontal regions. These changes were robust both at the group and at the individual level. Although MPS increase was observed in the absence of clinical improvement at a group level, it correlated with individual change estimated by Liddle's disorganization scale. Therefore, significant changes in EEG synchronization induced by NAC administration may precede clinically detectable improvement, highlighting its possible utility as a biomarker of treatment efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01506765.

Adaptive tracking of EEG oscillations.

Neuronal oscillations are an important aspect of EEG recordings. These oscillations are supposed to be involved in several cognitive mechanisms. For instance, oscillatory activity is considered a key component for the top-down control of perception. However, measuring this activity and its influence requires precise extraction of frequency components. This processing is not straightforward. Particularly, difficulties with extracting oscillations arise due to their time-varying characteristics. Moreover, when phase information is needed, it is of the utmost importance to extract narrow-band signals. This paper presents a novel method using adaptive filters for tracking and extracting these time-varying oscillations. This scheme is designed to maximize the oscillatory behavior at the output of the adaptive filter. It is then capable of tracking an oscillation and describing its temporal evolution even during low amplitude time segments. Moreover, this method can be extended in order to track several oscillations simultaneously and to use multiple signals. These two extensions are particularly relevant in the framework of EEG data processing, where oscillations are active at the same time in different frequency bands and signals are recorded with multiple sensors. The presented tracking scheme is first tested with synthetic signals in order to highlight its capabilities. Then it is applied to data recorded during a visual shape discrimination experiment for assessing its usefulness during EEG processing and in detecting functionally relevant changes. This method is an interesting additional processing step for providing alternative information compared to classical time-frequency analyses and for improving the detection and analysis of cross-frequency couplings.

The neonatal progeroid syndrome (Wiedemann-Rautenstrauch) and its relationship to Pelizaeus-Merzbacher's disease.

The neuropathology of a clinically well-documented case of the neonatal progeroid syndrome Wiedemann-Rautenstrauch is described. The most striking feature was a nearly complete absence of mature myelin in the brain. When immunohistochemistry for myelin basic protein was applied, some subcortical nerve fibres were accompanied by immature myelin sheaths. The neuropathology corresponds exactly to that of Pelizaeus-Merzbacher disease (Seitelberger type). Furthermore, this morphology, with the presence of myelin basic protein in the absence of mature myelin sheaths is reminiscent of the early stages of myelination in the newborn. From a brief review of the literature on Wiedemann-Rautenstrauch syndrome, we conclude, that the neuropathology of the syndrome is heterogeneous, and that there is relationship between the progeroid aspect and pathological myelination.

Prognostic value of continuous EEG monitoring during therapeutic hypothermia after cardiac arrest.

Introduction: Continuous EEG (cEEG) is increasingly used to monitor brain function in neuro-ICU patients. However, its value in patients with coma after cardiac arrest (CA), particularly in the setting of therapeutic hypothermia (TH), is only beginning to be elucidated. The aim of this study was to examine whether cEEG performed during TH may predict outcome. Methods: From April 2009 to April 2010, we prospectively studied 34 consecutive comatose patients treated with TH after CA who were monitored with cEEG, initiated during hypothermia and maintained after rewarming. EEG background reactivity to painful stimulation was tested. We analyzed the association between cEEG findings and neurologic outcome, assessed at 2 months with the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). Results: Continuous EEG recording was started 12 ± 6 hours after CA and lasted 30 ± 11 hours. Nonreactive cEEG background (12 of 15 (75%) among nonsurvivors versus none of 19 (0) survivors; P < 0.001) and prolonged discontinuous "burst-suppression" activity (11 of 15 (73%) versus none of 19; P < 0.001) were significantly associated with mortality. EEG seizures with absent background reactivity also differed significantly (seven of 15 (47%) versus none of 12 (0); P = 0.001). In patients with nonreactive background or seizures/epileptiform discharges on cEEG, no improvement was seen after TH. Nonreactive cEEG background during TH had a positive predictive value of 100% (95% confidence interval (CI), 74 to 100%) and a false-positive rate of 0 (95% CI, 0 to 18%) for mortality. All survivors had cEEG background reactivity, and the majority of them (14 (74%) of 19) had a favorable outcome (CPC 1 or 2). Conclusions: Continuous EEG monitoring showing a nonreactive or discontinuous background during TH is strongly associated with unfavorable outcome in patients with coma after CA. These data warrant larger studies to confirm the value of continuous EEG monitoring in predicting prognosis after CA and TH.

Endocytosis, autophagy and JNK inhibition in neuroprotection against excitotoxicity and neonatal cerebral ischemia

Abstract : Neonatal stroke occurs in 1 out of 4000 live births and usually leads to serious motor and cognitive disabilities. Ischemic brain injury results from a complex of pathophysiological events that evolve over space and time making it difficult to devise successful therapy. To date, there are no effective treatments for perinatal brain damage. Most clinical trials of neuroprotectaot drugs have failed because of their side-effects. For this reason it is important to find ways to target drugs specifically into the stressed cells. In this study we plan to contribute to the development of an efficient neuroprotective strategy against excitotoxic cell death in the neonate. In order to achieve this goal, several strategies were followed. A recently described phenomenon of induced endocytosis associated with excitotoxicity was more deeply investigated. As a simplified model we used dissociated cortical neurons exposed to an excitotoxic dose of NMDA, and we showed that this phenomenon depends on clathrin and dynamin. Using a model of neonatal focal cerebral ischemia, we demonstrated that the excitotoxicity-related endocytosis targets molecules such as TAT peptides into stressed neurons. These appear to be viable, raising the possibility of using this phenomenon as a doorway for neuroprotection. One part of the project was devoted to the study of the TAT-conjugated JNK inhibitory peptide, D-JNKI1. Adose-response study showed strong neuroprotection over a wide dose-range in the case of delayed administration (either intravenous or intraperitoneal). Since D-JNKI1 is aTAT-linked peptide, we investigated the role of its own NMDA-induced endocytosis in its neuroprotective efficacy. Furthermore, we showed that this endocytosis is JNK dependent, and that D-JNKI1 regulates its own uptake. We additionally studied the different types of cell death involved in a model of neonatal focal cerebral ischemia. Necrosis occurred rapidly in the center of the lesion whereas apoptosis and autophagic cell death occurred late at the lesion border. Inhibiting apoptosis was not protective, but use of autophagy inhibitor 3methyladenine provided a strong neuroprotection. Finally, combining two neuroprotectants that target different intracellular pathways was neuroprotective in a severe model of cerebral ischemia where neither of the drugs was efficient when administered individually. Résumé : L'ischémie néonatale connaît une incidence de 1 naissance sur 4000, entraînant généralement de sérieux dysfonctionnements moteurs et cognitifs. L'ischémie cérébrale résulte d'évènements physiopathologiques complexes qui évoluent dans l'espace et le temps rendant difficile la conception de thérapies efficaces. A l'heure actuelle, aucun traitement n'existe pour lutter contre les accidents vasculaires cérébraux qui se produisent autour de la naissance. La plupart des essais cliniques concernant des molécules neuroprotectrices ont échoué du fait de leurs effets secondaires néfastes. Pour cette raison, il est important de trouver des moyens de cibler les drogues dans les cellules stressées spécifiquement. Dans cette étude nous visons à participer au développement d'une stratégie neuroprotectrice efficace contre l'ischémie cérébrale chez le nouveau-né. Dans ce but, plusieurs stratégies ont été poursuivies. Un nouveau phénomène d'endocytose induite par un stimulus excitotoxique a été récemment décrit. Une partie de cette étude va consister à mieux comprendre ce phénomène. Pour céla, nous avons utilisé comme modèle d'étude simplifié des cultures dissociées de neurones corticaux exposées à une dose excitotoxique de NMDA. Nous avons ainsi montré que cette endocytose associée à l'excitotoxicité dépend de la clathrine et de la dynamine. A l'aide d'un modèle d'ischémie cérébrale focale chez le raton de 12 jours, nous avons démontré que cette endocytose induite par l'excitotoxicité permet de cibler des molécules diverses et en particulier les peptides TAT dans les neurones stressés. Ces neurones fortement endocytiques apparaissent comme étant encore viables, ouvrant la possibilité d'utiliser cette endocytose comme moyen d'entrée pour des molécules thérapeutiques. Une partie du projet a été consacrée à l'étude d'un inhibiteur de la voie JNK, couplé au TAT, appelé D-JNKI1. Des études de dose réponse du D-JNKI1 ont été réalisées chez l'animal, testant les effets d'une administration retardée en injection intraveineuse ou intra péritonéale. Ces études démontrent qu'une large gamme de dose permet d'obCenir une réduction de la taille de la lésion. Comme D-JNK11 est couplé au peptide TAT, nous avons étudié la contribution que sa propre endocytose lors de l'excitotoxicité apporte à ses effets protecteurs. Par ailleurs, nous avons montré que cette endocytose induite par l'excitotoxicité dépend de la voie de signalisation JNK et que D-JNK11 est donc capable de réguler sa propre entrée. Nous avons en parallèle étudié les différents types de mort cellulaires impliqués dans le développement de la lésion dans un modèle sévère d'ischémie cérébrale chez le raton nouveau-né. La mort cellulaire par nécrose se développe rapidement dans le centre de la lésion alors que les morts cellulaires par apoptose et autophagique vont apparaître plus tard et au bord de la lésion. Inhiber l'apoptose n'a pas permis de réduire la taille de la lésion alors que l'utilisation d'un inhibiteur d'autophagie, la 3-méthyladénine, procure une forte neuroprotection. Finalement, la combinaison de deux peptides qui ciblent différentes voies de signalisation intracellulaire permet d'obtenir une bonne protection dans le modèle d'ischémie sévère dans lequel aucun des deux peptides administré séparément n'a donné d'effets bénéfiques.

Seizure detection with automated EEG analysis: a validation study focusing on periodic patterns.

OBJECTIVE: To evaluate an automated seizure detection (ASD) algorithm in EEGs with periodic and other challenging patterns. METHODS: Selected EEGs recorded in patients over 1year old were classified into four groups: A. Periodic lateralized epileptiform discharges (PLEDs) with intermixed electrical seizures. B. PLEDs without seizures. C. Electrical seizures and no PLEDs. D. No PLEDs or seizures. Recordings were analyzed by the Persyst P12 software, and compared to the raw EEG, interpreted by two experienced neurophysiologists; Positive percent agreement (PPA) and false-positive rates/hour (FPR) were calculated. RESULTS: We assessed 98 recordings (Group A=21 patients; B=29, C=17, D=31). Total duration was 82.7h (median: 1h); containing 268 seizures. The software detected 204 (=76.1%) seizures; all ictal events were captured in 29/38 (76.3%) patients; in only in 3 (7.7%) no seizures were detected. Median PPA was 100% (range 0-100; interquartile range 50-100), and the median FPR 0/h (range 0-75.8; interquartile range 0-4.5); however, lower performances were seen in the groups containing periodic discharges. CONCLUSION: This analysis provides data regarding the yield of the ASD in a particularly difficult subset of EEG recordings, showing that periodic discharges may bias the results. SIGNIFICANCE: Ongoing refinements in this technique might enhance its utility and lead to a more extensive application.

Multiple sulfatase deficiency with neonatal manifestation.

Multiple Sulfatase Deficiency (MSD; OMIM 272200) is a rare autosomal recessive inborn error of metabolism caused by mutations in the sulfatase modifying factor 1 gene, encoding the formyglycine-generating enzyme (FGE), and resulting in tissue accumulation of sulfatides, sulphated glycosaminoglycans, sphingolipids and steroid sulfates. Less than 50 cases have been published so far. We report a new case of MSD presenting in the newborn period with hypotonia, apnoea, cyanosis and rolling eyes, hepato-splenomegaly and deafness. This patient was compound heterozygous for two so far undescribed SUMF1 mutations (c.191C¿>¿A; p.S64X and c.818A¿>¿G; p.D273G).

Paralyzed neonatal larynx in adduction. Case series, systematic review and analysis.

OBJECTIVE: Bilateral vocal cord abductor paralysis (BVCAbP) is considered a rare cause of stridor in the newborn. The goal of this work is to present a case series and to review systematically the literature on bilateral vocal cord abductor paralysis in the newborn to better characterize the current knowledge on this entity. METHODS: We performed a systematic literature review with Medline (1950-2011). The authors screened all cases of BVCAbP reported and selected those affecting newborns. RESULTS: Out of the 129 articles screened, 16 were included. A total of 69 cases could be retrieved and analyzed. Associated co-morbidities were found in 54% of the patients, most notably malformative conditions (intracranial or other), or a positive perinatal history (trauma/asphyxia, prematurity). Tracheostomy placement was required in 59% of children, and of these 44% were successfully decannulated. In terms of functional outcome full recovery or improvement were seen in 61% of patients. Major underlying co-morbidities affected negatively the functional outcome (p=.004), but not the need for tracheostomy (p=.604) or the decannulation success rate (p=.063). CONCLUSION: BVCAbP in the newborn is a serious cause of airway obstruction. It can be seen either in a context of multisystem anomalies or as an isolated finding. Newborns with major co-morbidities affecting their normal development are more likely to have poor functional outcomes and to remain tracheostomy-dependant.

Differential effects of sodium oxybate and baclofen on EEG, sleep, neurobehavioral performance, and memory.

STUDY OBJECTIVES: Sodium oxybate (SO) is a GABA(B) agonist used to treat the sleep disorder narcolepsy. SO was shown to increase slow wave sleep (SWS) and EEG delta power (0.75-4.5 Hz), both indexes of NREM sleep (NREMS) intensity and depth, suggesting that SO enhances recuperative function of NREM. We investigated whether SO induces physiological deep sleep. DESIGN: SO was administered before an afternoon nap or before the subsequent experimental night in 13 healthy volunteers. The effects of SO were compared to baclofen (BAC), another GABA(B) receptor agonist, to assess the role of GABA(B) receptors in the SO response. MEASUREMENTS AND RESULTS: As expected, a nap significantly decreased sleep need and intensity the subsequent night. Both drugs reversed this nap effect on the subsequent night by decreasing sleep latency and increasing total sleep time, SWS during the first NREMS episode, and EEG delta and theta (0.75-7.25 Hz) power during NREMS. The SO-induced increase in EEG delta and theta power was, however, not specific to NREMS and was also observed during REM sleep (REMS) and wakefulness. Moreover, the high levels of delta power during a nap following SO administration did not affect delta power the following night. SO and BAC taken before the nap did not improve subsequent psychomotor performance and subjective alertness, or memory consolidation. Finally, SO and BAC strongly promoted the appearance of sleep onset REM periods. CONCLUSIONS: The SO-induced EEG slow waves seem not to be functionally similar to physiological slow waves. Our findings also suggest a role for GABA(B) receptors in REMS generation. CITATION: Vienne J; Lecciso G; Constantinescu I; Schwartz S; Franken P; Heinzer R; Tafti M. Differential effects of sodium oxybate and baclofen on EEG, sleep, neurobehavioral performance, and memory. SLEEP 2012;35(8):1071-1084.

Severe transient neonatal lactic acidosis during prophylactic zidovudine treatment.

Zidovudine (ZDV) treatment during pregnancy, delivery and the postnatal period is effective in reducing the maternal-infant transmission of the human immunodeficiency virus. Reported adverse effects in the neonate during this longterm treatment are bone marrow suppression and elevation in aspartate aminotransferase activity. We report a case of severe ZDV-associated lactic acidosis in a neonate, which resolved rapidly following discontinuation of ZDV. The mechanisms leading to this side effect are poorly understood.