Search

Purpose We aimed to identify prognostic factors for survival and long-term intellectual and developmental outcome in neonatal patients with early-onset urea cycle disorders (UCD) experiencing hyperammonaemic coma. Methods We retrospectively analysed ammonia (NH3) and glutamine levels, electroencephalogram and brain images obtained during neonatal coma of UCD patients born between 1995 and 2011 and managed at a single centre and correlated them to survival and intellectual and developmental outcome. Results We included 38 neonates suffering from deficiencies of argininosuccinate synthetase (ASSD, N = 12), ornithine transcarbamylase (OTCD, N = 10), carbamoylphosphate synthetase 1 (CPSD, N = 7), argininosuccinate lyase (ASLD, N = 7), N-acetylglutamate synthase (NAGS, N = 1) or arginase (ARGD, N = 1). Symptoms occurred earlier in mitochondrial than in cytosolic UCD. Sixty-eight percent of patients survived, with a mean (standard deviation-SD) follow-up of 10.4 (5.3) years. Mortality was mostly observed in OTCD (N = 7/10) and CPSD (N = 4/7) patients. Plasma NH3 level during the neonatal period, expressed as area under the curve, but not glutamine level was associated with mortality (p = .044 and p = .610). 62.1% of the patients had normal intellectual and developmental outcome. Intellectual and developmental outcome tended to correlate with UCD subtype (p = .052). No difference in plasma NH3 or glutamine level during the neonatal period among developmental outcomes was identified. EEG severity was linked to UCD subtypes (p = .004), ammonia levels (p = .037), duration of coma (p = .043), and mortality during the neonatal period (p = .020). Status epilepticus was recorded in 6 patients, 3 of whom died neonatally, 1 developed a severe intellectual disability while the 2 last patients had a normal development. Conclusion UCD subtypes differed by survival rate, intellectual and developmental outcome and EEG features in the neonatal period. Hyperammonaemia expressed as area under the curve was associated with survival but not with intellectual and developmental outcome whereas glutamine was not associated with one of these outcomes. Prognostic value of video-EEG monitoring and the association between status epilepticus and mortality should be assessed in neonatal hyperammonaemic coma in further studies.

Seizures caused by beta-lactam antibiotics are relatively rare. However, they represent a clinically significant phenomenon and have been widely reported in all age groups. Here we describe two infants presenting subtle multifocal seizures with a migrating aspect on EEG during beta-lactam antibiotic treatment with agents from the carbapenem group (meropenem) and the cephalosporin group (ceftazidime).

Claudin-5 is the most enriched tight junction protein at the blood–brain barrier. Perturbations in its levels of expression have been observed across numerous neurological and neuropsychiatric conditions; however, pathogenic variants in the coding sequence of the gene have never been reported previously. Here, we report the identification of a novel de novo mutation (c.178G>A) in the CLDN5 gene in two unrelated cases of alternating hemiplegia with microcephaly. This mutation (G60R) lies within the first extracellular loop of claudin-5 and based on protein modelling and sequence alignment, we predicted it would modify claudin-5 to become an anion-selective junctional component as opposed to a purely barrier-forming protein. Generation of stably transfected cell lines expressing wild-type or G60R claudin-5 showed that the tight junctions could still form in the presence of the G60R mutation but that the barrier against small molecules was clearly attenuated and displayed higher Cl− ion permeability and lower Na+ permeability. While this study strongly suggests that CLDN5 associated alternating hemiplegia is a channelopathy, it is also the first study to identify the conversion of the blood–brain barrier to an anion-selective channel mediated by a dominant acting variant in CLDN5.

Aim: Compare efficacies of deflazacort and prednisone/prednisolone in providing clinically meaningful delays in loss of physical milestones in patients with nonsense mutation Duchenne muscular dystrophy. Materials & methods: Placebo data from Phase IIb (ClinicalTrials.gov Identifier: NCT00592553) and ACT DMD (ClinicalTrials.gov Identifier: NCT01826487) ataluren nonsense mutation Duchenne muscular dystrophy clinical trials were retrospectively combined in meta-analyses (intent-to-treat population; for change from baseline to week 48 in 6-min walk distance [6MWD] and timed function tests). Results: Significant improvements in change in 6-min walk distance with deflazacort versus prednisone/prednisolone (least-squares mean difference 39.54 m [95% CI: 13.799, 65.286; p = 0.0026]). Significant and clinically meaningful improvements in 4-stair climb and 4-stair descend for deflazacort versus prednisone/prednisolone. Conclusion: Deflazacort provides clinically meaningful delays in loss of physical milestones over 48 weeks compared with prednisone/prednisolone for patients with nonsense mutation Duchenne muscular dystrophy.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss among the population above 85 worldwide. There are two main types of AMD: neovascular and dry AMD. Neovascular AMD leads to macular changes resulting from abnormal choroidal neovascularization. Untreated neovascular AMD leads to scar formation and irreversible sight deterioration. Dry AMD in consequence leads to atrophic changes of the macula. The last decades brought a breakthrough in the therapy of neovascular age-related macular degeneration by introduction of, firstly, photodynamic therapy and, later, anti-VEGF agents administered intravitreally in order to stop neoangiogenesis. However, the treatment of dry AMD is still challenging. Among the directions in dry AMD treatment, the most promising are complement cascade inhibitors and complement cascade targeted gene therapy. In the article we outline the main directions in up-to-date experimental and practical approaches to wet and dry AMD therapy with the emphasis on antiangiogenic factors and gene therapy focused on the inhibition of pathological angiogenesis.

BackgroundAutistic spectrum disorders (ASDs) with developmental delay and seizures are a genetically heterogeneous group of diseases caused by at least 700 different genes. Still, a number of cases remain genetically undiagnosed.ObjectiveThe objective of this study was to identify and characterise pathogenic variants in two individuals from unrelated families, both of whom presented a similar clinical phenotype that included an ASD, intellectual disability (ID) and seizures.MethodsWhole-exome sequencing was used to identify pathogenic variants in the two individuals. Functional studies performed in the Drosophila melanogaster model was used to assess the protein function in vivo.ResultsProbands shared a heterozygous de novo secretory carrier membrane protein (SCAMP5) variant (NM_001178111.1:c.538G>T) resulting in a p.Gly180Trp missense variant. SCAMP5 belongs to a family of tetraspanin membrane proteins found in secretory and endocytic compartments of neuronal synapses. In the fly SCAMP orthologue, the p.Gly302Trp genotype corresponds to human p.Gly180Trp. Western blot analysis of proteins overexpressed in the Drosophila fat body showed strongly reduced levels of the SCAMP p.Gly302Trp protein compared with the wild-type protein, indicating that the mutant either reduced expression or increased turnover of the protein. The expression of the fly homologue of the human SCAMP5 p.Gly180Trp mutation caused similar eye and neuronal phenotypes as the expression of SCAMP RNAi, suggesting a dominant-negative effect.ConclusionOur study identifies SCAMP5 deficiency as a cause for ASD and ID and underscores the importance of synaptic vesicular trafficking in neurodevelopmental disorders.

Culture has been identified as a factor influencing the way people communicate and behave. Though often imperceptible by its members, cross-cultural interactions can lead to misunderstandings and conflicts. Despite ex-military and civilian trained pilots frequently flying together, there has been a lack of research describing each professional sub-culture. The current study aims to bridge that gap by exploring how professional culture interacts in the cockpit and how it affects pilots’ safety behaviours. The study used in-depth semi-structured interviews with 15 participants (14 helicopter pilots) to collect data on effects of professional culture. The data were analysed using conventional content analysis. Content analysis indicated five separate categories relevant to perceptions of professional culture. The findings indicate that pilots acknowledge the cultural differences present between themselves and others, and that culture can have an effect on their and other’s safety behaviours. The participants suggested that various sub-culture types can have impact on flight safety through their effects on communication and the way people interact, but not through technical skills of flying the aircraft. The differences between military and civilian training and flying were discussed in depth. This research highlights the various ways in which culture affects pilots’ safety behaviours and interactions with one another. It also provides an in-depth look at the way pilots perceive and experience cross-cultural interactions in the cockpit.

Objective We aimed to describe epilepsy and EEG patterns related to vigilance states and age, in chromosome15-long-arm-duplication-syndrome (dup15q) children with epilepsy, in both duplication types: interstitial (intdup15) and isodicentric (idic15). Methods Clinical data and 70 EEGs of 12 patients (5 intdup15, 7 idic15), followed from 4.5 m.o to 17y4m (median follow-up 8y3m), were retrospectively reviewed. EEGs were analyzed visually and using power spectrum analysis. Results Seventy video-EEGs were analyzed (1–16 per patient, median 6), follow-up lasting up to 8y10m (median 4y2m): 25 EEGs in intdup15 (8 m.o to 12y.o, median 4y6m) and 45 EEGs in idic15 (7 m.o to 12 y.o, median 15 m). Epilepsy: 6 West syndrome (WS) (2intdup15, 4idic15); 4 Lennox-Gastaut syndromes (LGS) (1 intdup15, 3 idic15), 2 evolving from WS; focal epilepsy (3 intdup15). In idic15, WS displayed additional myoclonic seizures (3), atypical (4) or no hypsarrhythmia (2) and posterior predominant spike and polyspike bursts (4). Beta-band rapid-rhythms (RR): present in 11 patients, power decreased during non-REM-sleep, localization shifted from diffuse to anterior, peak frequency increased with age. Conclusion WS with peculiar electro-clinical features and LGS, along with beta-band RR decreasing in non-REM-sleep and shifting from diffuse to anterior localization with age are recognizable features pointing towards dup15q diagnosis in children with autism spectrum disorder and developmental delay. Significance This study describes electroclinical features in both interstitial and isodicentric duplications of chromosome 15q, in epileptic children, including some recent extensions regarding sleep features; and illustrates how the temporo-spatial organization of beta oscillations can be of significant help in directing towards dup15q diagnosis hypothesis.

Background Arthrogryposis multiplex congenita (AMC) is the direct consequence of reduced fetal movements. AMC includes a large spectrum of diseases which result from variants in genes encoding components required for the formation or the function of the neuromuscular system. AMC may also result from central nervous involvement. SCN1A encodes Nav1.1, a critical component of voltage-dependent sodium channels which underlie action potential generation and propagation. Variants of SCN1A are known to be responsible for Dravet syndrome, a severe early-onset epileptic encephalopathy. We report pathogenic heterozygous missense de novo variants in SCN1A in three unrelated individuals with AMC. Methods Whole-exome sequencing was performed from DNA of the index case of AMC families. Heterozygous missense variants in SCN1A (p.Leu893Phe, p.Ala989Thr, p.Ile236Thr) were identified in three patients. Sanger sequencing confirmed the variants and showed that they occurred de novo. Results AMC was diagnosed from the second trimester of pregnancy in the three patients. One of them developed drug-resistant epileptic seizures from birth. We showed that SCN1A is expressed in both brain and spinal cord but not in skeletal muscle during human development. The lack of motor denervation as established by electromyographic studies or pathological examination of the spinal cord or skeletal muscle in the affected individuals suggests that AMC is caused by brain involvement. Conclusion We show for the first time that SCN1A variants are responsible for early-onset motor defect leading to AMC indicating a critical role of SCN1A in prenatal motor development and broadening the phenotypic spectrum of variants in SCN1A.

International audience; Objective - We aimed to characterize epilepsy of infancy with migrating focal seizures (EIMFS), a rare, severe early onset developmental epilepsy related to KCNT1 mutation, and to define specific electroencephalography (EEG) markers using EEG quantitative analysis. The ultimate goal would be to improve early diagnosis and to better understand seizure onset and propagation of EIMFS as compared to other early onset developmental epilepsy. Methods - EEG of 7 EIMFS patients with KCNT1 mutations (115 seizures) and 17 patients with other early onset epilepsies (30 seizures) was included in this study. After detection of seizure onset and termination, spatiotemporal characteristics were quantified. Seizure propagation dynamics were analyzed using chronograms and phase coherence. Results - In patients with EIMFS, seizures started and were localized predominantly in temporal and occipital areas, and evolved with a stable frequency (4-10 Hz). Inter- and intrahemispheric migrations were present in 60% of EIMFS seizures with high intraindividual reproducibility of temporospatial dynamics. Interhemispheric migrating seizures spread in 71% from temporal or occipital channels to the homologous contralateral ones, whereas intrahemispheric seizures involved mainly frontotemporal, temporal, and occipital channels. Causality links were present between ictal activities detected under different channels during migrating seizures. Finally, time delay index (based on delays between the different ictal onsets) and phase correlation index (based on coherence of ictal activities) allowed discrimination of EIMFS and non-EIMFS seizures with a specificity of 91.2% and a sensitivity of 84.4%. Significance - We showed that the migrating pattern in EIMFS is not a random process, as suggested previously, and that it is a particular propagation pattern that follows the classical propagation pathways. It is notable that this study reveals specific EEG markers (time delay and phase correlation) accessible to visual evaluation, which will improve EIMFS diagnosis.

Protocadherin 19 (PCDH19) mutations have been identified in epilepsy in females with mental retardation as well as patients with a "Dravet-like" phenotype. We aimed to elucidate the electroclinical phenotype associated with PCDH19 mutation, which is currently difficult to identify at onset leading to a delay in diagnosis. We retrospectively reviewed clinical and EEG data for 13 consecutive patients with PCDH19 mutations or deletions diagnosed at our centers from 2009 to 2011, and followed these patients into adolescence and adulthood. We identified a specific temporal sequence of electroclinical manifestations, identified as three main stages. During the first two years of life, previously healthy girls presented with clusters of afebrile focal seizures. Early seizures were recorded on video-EEG in 10/13 patients, and were focal (n=8) with temporo-occipital and frontal onset. Three patients with strictly stereotyped focal seizures underwent a pre-surgical work-up. Two patients started with generalized seizures, one presenting with early-onset atypical absences and the other generalized tonic-clonic seizures. During the course of the disease, from two to 10 years, seizures became fever-sensitive and continued to recur in clusters, although these were less frequent. Seizures were mainly described by eyewitnesses as generalized tonic-clonic, even though three of five seizures, recorded on EEG, showed a focal onset with fast bilateral spread. Atypical absences and fever-induced tonic-clonic seizures remained frequent in only one patient until the age of 16 years. No specific treatment or combination appeared to be more effective over another. Various degrees of cognitive or behavioural impairment were reported for all patients, but it was in the second decade that behavioural disturbances prevailed with hetero-aggressiveness and behaviour associated with frontal lobe abnormalities leading to psychosis in two. Early recognition of the above features should improve early diagnosis and long-term management of patients with epilepsy and PCDH19 mutations.

Background and aims Phospholipase A2 associated neurodegeneration (PLAN) is a heterogeneous autosomal recessive disorder caused by mutations in the ubiquitously expressed PLA2G6 gene. It is responsible for delayed brain iron accumulation and induces progressive psychomotor regression. We report the concomitant clinical, radiological and neurophysiological findings in PLAN patients in an attempt to determine the contribution of each test to guide diagnosis. Methods Concomitant clinical, radiological, electroencephalographic (EEG) and electrodiagnostic testing (EDX) findings in a series of 8 consecutive genetically confirmed PLAN patients were collected. Results All patients presented marked motor axonal loss, with decreased or absent distal compound muscle action potentials, acute and chronic denervation at needle electromyography, in contrast with preservation of sensory conduction. EEG showed high-amplitude fast activity in all patients aged above 15 months. Two patients showing severe neonatal hypotonia displayed atypical hypsarhythmia and epileptic spasms. Iron deposition in globus pallidus was observed in only two patients aged above 6 years. Conclusions Peripheral involvement is an early feature in PLAN recognizable by EDX at an earlier stage than typical iron accumulation in the brain. Furthermore, the association of West syndrome and axonal motor neuropathy may represent positive clues in favor of PLAN. This results emphasize the interest of early and repeated EDX.

Objective To evaluate continuing stiripentol treatment in adulthood in Dravet syndrome (DS). Method Longitudinal data were collected from the last visit prior to age 15 years (V15 y ) to the last visit in adulthood (Vadult ) in the 40 DS patients (32 typical, eight atypical) of a French historical cohort (Paris) of subjects who continued stiripentol from childhood or adolescence to adulthood. Results At Vadult (18-40 years, median = 23 years), all the patients were still receiving stiripentol (exposure = 3-24 years, median = 18 years), associated with clobazam (40/40), valproate (39/40), and topiramate (21/40). Between V15 y and Vadult , stiripentol was interrupted in five patients (two for adverse events) but reintroduced following seizure aggravation. Loss of appetite affected 15 of 40 patients but resolved after reducing the dose of stiripentol or valproate; no other new stiripentol-related adverse events were reported. Mean stiripentol dose was progressively decreased from 39 to 25 mg/kg/d (P = 0.0002), whereas clobazam (0.27 mg/kg/d) and valproate (14 mg/kg/d) remained stable. At Vadult , 37 of 40 patients still had generalized tonic-clonic seizures, but none still had status epilepticus (vs three at V15 y ) and only one had myoclonia. During adulthood, generalized tonic-clonic seizure frequency and duration continued to decrease (P = 0.02, P = 0.008) and 10 patients experienced seizure-free periods ≥ 1 years (up to 5 years). All patients already had intellectual disability at V15 y , but retardation was more severe at Vadult (P = 0.03). Furthermore, neurological/gait condition had declined (two patients became bedridden) and behavior had worsened (P 15 years) and the DS patients treated from adult age or stiripentol-naive subjects reported in the literature. Significance The efficacy and safety of the stiripentol/valproate/clobazam combination started at pediatric age are maintained at very long term during adulthood. Such prolonged stiripentol therapy tends to positively impact the late prognosis of epilepsy, especially when initiated before adolescence.

Purpose Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by a facial port-wine stain, a glaucoma, and a leptomeningeal angioma. Epilepsy occurs in more than 75% of affected children, and seizures occurring in the first year of life are associated with a poor neurological prognosis. The aim of this study was to identify possible predictive markers of epilepsy on electroencephalogram (EEG) performed prior to seizure onset in children with SWS. Methods This study included children with a diagnosis of SWS who had an EEG performed prior to seizure onset. Patients who did not develop epilepsy had a minimum follow-up of 3-years. We compared EEG characteristics of patients who developed epilepsy with patients who did not develop epilepsy by the time of their follow-up. Results Eleven children were included in this study. EEG was performed at the median age of 2.1 months (range 1.0–22.1). Six children developed seizures with a time interval between EEG and seizure onset ranging from 2 days to 21 months. EEG background activity was asymmetric in 8 patients, 5 of whom later developed epilepsy. Focal interictal spikes or sharp waves were exclusively recorded in patients who developed later epilepsy (4 out of 6). One of these patients had a supposed false positive EEG as he did not developed epilepsy until 21 months later and one patient had a false negative EEG with seizures occurring 2 days after a normal EEG. Conclusion Spikes on EEG might be a useful marker to identify patients with SWS at risk of developing epilepsy. Their predictive value should be assessed in larger prospective studies.

Objectives Little is known about off-label use and manipulations to achieve the prescribed dose of antiepileptic drugs (AEDs) in outpatient prescriptions. This study aimed to evaluate this practice in a tertiary center for child epilepsy. Methods We reviewed off-label use and manipulations of AEDs delivered to the outpatient's epilepsy clinic. Multivariate logistic regressions were used to determine the factors associated with off-label and manipulated uses. Results Five hundred eleven consultations generated 897 AED deliveries (1.75/consultation). Off-label use involved 182 (20.3%) of prescribed AEDs. Factors associated with off-label use were polytherapy and new AEDs while increase of age and nondevelopmental and structural–metabolic etiologies have a protective effect. Among the 1725 doses of AEDs prescribed per day, 33.5% generated manipulations (n = 582): 40% inadequate (n = 237) and 60% adequate (203 syrups, 112 scored tablets, 30 drops medicine). Polytherapy (p Conclusion Off-label use and manipulations of AEDs remain an important problem in home care of children with epilepsy. This is mainly a concern for the most vulnerable groups, i.e., young patients, patients undergoing polytherapy, and patients with developmental and epileptic encephalopathy (DEE). International initiatives have been launched to improve the availability of labeled and adapted drugs in this population.

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals.

Purpose Benign neonatal sleep myoclonus is a common nonepileptic condition occurring in neurologically normal full-term newborns. During jerks, EEG has always been described as normal. The aim of this study was to describe EEG changes associated with the myoclonic jerks. Methods Polygraphic video-EEG recordings of four full-term neonates presenting benign neonatal sleep myoclonus were studied. Myoclonic jerks were analyzed regarding their topography, frequency, propagation pattern, and reflex component. EEG averaging time-locked to myoclonic jerks and to somatosensory stimuli (realized by tapping on palms and feet) was performed to study eventual EEG correlates of myoclonus and to asses somatosensory evoked responses-for the latter, two control newborns were added. Results Visual analysis of the EEG disclosed theta band slow waves on central and vertex electrodes concomitant to myoclonic jerks and jerk-locked back-averaging disclosed a sequence of deflections, not preceding, but following the myoclonus. This response predominated on the vertex electrode (CZ) and consisted of five components (N1, P1, N2, P2, and N3), with only the three later components being constantly present (at 110, 200, and 350-500 ms, respectively). Back-averaging locked to the tactile stimuli in four subjects and two control newborns showed similar components and were comparable to those described in the literature as late somatosensory evoked responses in full-term newborns. Conclusions Myoclonic jerks in benign neonatal sleep myoclonus can evoke visually identifiable EEG potentials on vertex electrodes corresponding to somatosensory responses. This EEG aspect may be misleading and could give rise to an anti-seizure treatment that mostly worsens the condition.

Objectives To describe the semiology and EEG characteristics of the age-related pattern of sleep/nocturnal (S/N) seizures in patients with Dravet Syndrome (DS). Methods We retrospectively analysed the clinical and EEG data of DS patients followed at our reference centre for Rare Epilepsies. We included patients aged two years and older who fulfilled clinical and EEG criteria of DS (ILAE 1989). Genetic testing for SCN1A was done in all, followed by PCDH19 if this was negative. Patients showing a genetic abnormality in PCDH19 were excluded. Of 73 DS patients followed at our centre, 26 (15 males and 11 females), called the S/N group, experienced a switch in the circadian rhythm of seizures, from mainly awake/diurnal to mainly S/N seizures. We retrospectively analysed their clinical, EEG and genetic data. We have compared them to a second group of 7 patients (4 males and 3 females), aged more than 11 years, the non-S/N group, who did not develop S/N seizures. Results We observed a pattern of S/N seizures concomitant with a decrease of awake seizures between 4 and 11 years (median 6 years 6 months). S/N seizures were brief but often occurred in clusters of 2–15 per night. Seizures were mostly focal (26) with frontal-central onset (25) and tonic or tonic-vibratory in semiology. S/N seizure clusters were difficult to control despite many AEDs trials. Benzodiazepines reduced seizure recurrence within a cluster in some patients. While no significant differences were found between groups regarding clinical features, the presence of frontal and central anomalies on wake and sleep EEG was significantly associated with the presence of the S/N pattern. Conclusions Patients with DS often develop a characteristic clinical and EEG pattern with S/N tonic and tonic clonic seizures that is often underdiagnosed. Seizure semiology and EEG pattern differ from LGS but may worsen the quality of sleep of such patients and their families. The possible role of this pattern in SUDEP occurring mainly during sleep and at the same age should be further explored. Current AEDs have limited efficacy and specific drug trials should be proposed.

Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, characterized by impaired glycosylation. Multisystemic involvement is common and neurological impairment is notably severe and disabling, concerning the central and peripheral nervous system. Epilepsy is frequent, but detailed electroclinical description is rare. We describe, retrospectively, the electroclinical features in five children with CDG and epileptic spasms. Epileptic spasms were observed in patients with ALG1-, ALG6, ALG11-CDG and CDG-Ix, and occurred at an early age, before 6 months in all cases, except one who had spasms that started at 18 months. In this patient, spasms had an unusual aspect; they did not occur in clusters and were immediately preceded by a myoclonus. All but one child also presented rare myoclonias. On EEG, background activity was poorly organized with abundant posterior spike and fast rhythm activity, but without hypsarrhythmia. At the last evaluation (age range: 6-12 years), two patients still presented epileptic spasms and subcortical myoclonias, one showed rare generalized tonic-clonic seizures, and two were seizure-free. CDG disorders can be associated with epileptic spasms showing particular features, such as absence of hypsarrhythmia, posterior EEG anomalies, and an unusual combination of epileptic spasms with myoclonus. These features, associated with pre-existing developmental delay and subcortical myoclonias, may shift toward CDG screening. [Published with video sequence and supplemental EEG plates on www.epilepticdisorders.com]. info:eu-repo/semantics/publishedVersion

Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences., SCOPUS: ar.j, info:eu-repo/semantics/published

The reason why some children and adolescent with epilepsy (CAWE) still challenge the "inclusive" educative policy needs to be explored.We conducted a transversal study in French medical, social, and educative rehab centers (MSERCs) dedicated to CAWE to describe the profile of 263 centers-involved (CI)-CAWE. Centers-involved CAWE were prospectively followed from September 2012 to August 2013. Medical, social, and educative rehab centers were dichotomized according to their care-provider agreement (i.e., CAWE of "moderate" (M) vs. "severe" (S) conditions). Clinical factors known to impact clinical outcome and quality of life (QoL) in epilepsy and four disabling conditions at risk to impact school life (i.e., cognitive and psychiatric/behavioral disorders, risk of physical hazards (i.e., refractory seizures with unpredictable loss of tone and/or awareness), and one or more seizure/week) were evaluated. The electronic chart of the French collaborative database (namely GRENAT) was used for data collection allowing comparison with the profile of 731 "normally integrated and schooled" (NIS)-CAWE extracted from GRENAT and matching for generation (i.e., born between 1988 and 2006).Centers-involved CAWE's profile was found, after adjustment, to be associated with clinical factors and disabling conditions reflecting the poorest clinical outcome and health-related quality of life (HR-QoL) (all p 0.001). A cutoff of two disabilities/child highly discriminated NIS-CAWE vs. CI-CAWE. Centers-involved CAWE of S-MSERCs were the most severe (all p 0.001), and the type of cognitive disability (i.e., intellectual disability (ID) vs. specific learning disorders (SLD)) highly paralleled the types of MSERCs (S vs. M). Using a parent-informant questionnaire, the number of disabilities/child was found to correlate with both the evaluation of the impact of epilepsy (r = 0.47, p 0.001) and the HR-QoL (r = 0.37, p 0.001). A satisfactory social life was reported (83.8%) even after S vs. M dichotomization (77.2% vs. 94.7%; p 0.001).Multiple disabilities rather than epilepsy per se challenge the inclusive educative policy. Evaluation of disabilities could be the missing bridge to optimize this policy and understand its limits.

International audience; Epilepsy of infancy with migrating focal seizures was first described in 1995. Fifteen years later, KCNT1 gene mutations were identified as the major disease-causing gene of this disease. Currently, the data on epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations are heterogeneous and many questions remain unanswered including the prognosis and the long-term outcome especially regarding epilepsy, neurological and developmental status and the presence of microcephaly. The aim of this study was to assess data from patients with epilepsy in infancy with migrating focal seizures with KCNT1 mutations to refine the phenotype spectrum and the outcome. We used mind maps based on medical reports of children followed in the network of the French reference centre for rare epilepsies and we developed family surveys to assess the long-term outcome. Seventeen patients were included [age median (25th-75th percentile) 4 (2-15) years, sex ratio 1.4, length of follow-up 4 (2-15) years]. Seventy-one per cent started at 6 (1-52) days with sporadic motor seizures (n = 12), increasing up to a stormy phase with long lasting migrating seizures at 57 (30-89) days. The others entered this stormy phase directly at 1 (1-23) day. Ten patients entered a consecutive phase at 1.3 (1-2.8) years where seizures persisted at least daily (n = 8), but presented different semiology brief and hypertonic with a nocturnal (n = 6) and clustered (n = 6) aspects. Suppression interictal patterns were identified on the EEG in 71% of patients (n = 12) sometimes from the first EEG (n = 6). Three patients received quinidine without reported efficacy. Long-term outcome was poor with neurological sequelae and active epilepsy except for one patient who had an early and long-lasting seizure-free period. Extracerebral symptoms probably linked with KCNT1 mutation were present, including arteriovenous fistula, dilated cardiomyopathy and precocious puberty. Eight patients (47%) had died at 3 (1.5-15.4) years including three from suspected sudden unexpected death in epilepsy. Refining the electro-clinical characteristics and the temporal sequence of epilepsy in infancy with migrating focal seizures should help diagnosis of this epilepsy. A better knowledge of the outcome allows one to advise families and to define the appropriate follow-up and therapies. Extracerebral involvement should be investigated, in particular the cardiac system, as it may be involved in the high prevalence of sudden unexpected death in epilepsy in these cases.

This Article was originally published under Nature Research’s License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

We report the cases of a brother and a sister of nonconsanguineous parents who developed progressive microcephaly and had tremor, irritability, spasticity, startle reflexes, and permanent erratic myoclonus since birth. Focal clonic seizures, status epilepticus, and infantile spasms appeared later, during the first months of life, while erratic myoclonic jerks persisted. Electroencephalogram initially showed multifocal spikes that evolved into modified hypsarrhythmia and then discontinuous activity, evoking the progressive nature of the condition. Magnetic resonance imaging showed brain atrophy and poor myelination. Plasma and cerebrospinal fluid asparagine levels were normal or moderately reduced on repeat testing. Both infants died at the age of 8 months in status epilepticus. Neuropathology of the brother revealed diffuse neuronal loss and astrocytic gliosis predominating in superficial layers of temporal and frontal lobes and in thalamus with almost absent myelin, as a consequence of the neuronal death. Whole exome sequencing of the siblings and parents revealed compound heterozygous c.1439C > T (p.Ser480Phe) and c.1648C > T (p.Arg550Cys) mutations in the ASNS gene, indicating asparagine synthetase (ASNS) deficiency. Electroclinical epileptic phenotype and neuropathological findings of ASNS deficiency are reminiscent of neonatal pyridoxine-dependent epilepsy, thus suggesting common pathophysiological mechanism possibly related to cytotoxic glutamate accumulation.

To test whether an integrated passive and active aeration system could be an effective solution for aerobic decomposition of municipal waste in technical conditions, a full-scale composting reactor was designed. The waste was actively aerated for 5d, passively aerated for 35 d, and then actively aerated for 5d, and the entire composting process was monitored. During the 45-day observation period, changes in the fractional, morphological and physico-chemical characteristics of the waste at the top of the reactor differed from those in the center of the reactor. The fractional and morphological analysis made during the entire process of stabilization, showed the total reduction of organic matter measured of 82 wt% and 86 wt% at the respective depths. The reduction of organic matter calculated using the results of Lost of Ignition (LOI) and Total Organic Carbon (TOC) showed, respectively, 40.51-46.62% organic matter loss at the top and 45.33-53.39% in the center of the reactor. At the end of the process, moisture content, LOI and TOC at the top were 3.29%, 6.10% and 4.13% higher, respectively, than in the center. The results showed that application of passive aeration in larger scale simultaneously allows the thermophilic levels to be maintained during municipal solid waste composting process while not inhibiting microbial activity in the reactor.

ObjectiveAlthough a number of modifiable and non-modifiable causes were implicated in arterial stiffness, its pathogenesis remains elusive, and very little is known about aortic elasticity in supraventricular arrhythmias. The potential role of disturbed kynurenine metabolism in the pathogenesis of cardiovascular disease has been recently suggested. Thus, we studied the correlations of aortic stiffness and echocardiographic parameters with biochemical markers and serum level of kynurenic acid (KYNA), an endothelial derivative of tryptophan, formed along the kynurenine pathway, among patients with atrial fibrillation (AF).MethodsStudy cohort comprised 100 patients with persistent AF (43 females/57 males). Arterial stiffness index (ASI), structural and functional indices of left atrium (LA) and left ventricle (LV) were evaluated electrocardiographically. Biochemical analyses included the measurements of serum KYNA (HPLC) and of the selected markers of lipids and glucose metabolism, thyroid status, kidney function, inflammation and coagulation.ResultsKYNA (β = 0.389, P = 0.029), homocysteine (β = 0.256, P = 0.40), total cholesterol (β = 0.814; P = 0.044), LDL (β = 0.663; P = 0.44), TSH (β = 0.262, P = 0.02), fT3 (β = -0.333, P = 0.009), fT4 (β = -0.275, P = 0.043) and creatinine (β = 0.374, P = 0.043) were independently correlated with ASI. ASI was also independently associated with LV end-systolic diameter (LVEDd; β = 1.751, P = 0.045), midwall fractional shortening (mFS; β = -1.266, P = 0.007), ratio mFS/end-systolic stress (mFS/ESS; β = -0.235, P = 0.026), LV shortening fraction (FS; β = -0.254, P = 0.017), and LA volume index (LAVI; β = 0.944, P = 0.022).ConclusionsIn patients with AF, aortic stiffness correlated positively with KYNA, biochemical risk factors of atherosclerosis and with the indices of diastolic dysfunction of LV and LA. Revealed relationship between ASI and KYNA is an original observation, suggesting a potential role of disturbed kynurenine metabolism in the pathogenesis of arterial stiffening. KYNA, synthesis of which is influenced by homocysteine, emerges as a novel, non-classical factor associated with ASI in patients with AF.

EEG changes during the perinatal period, infancy, childhood, and adolescence are concomitant with brain growth, myelination, expanding connectivity, and overall maturation, which are particularly fast during the first year of life. EEG aspects of early brain development are accessible in preterm during the third trimester of gestational age, and they evolve to full-term, infancy, and childhood EEG patterns. Each of these age periods shares specific EEG features that reach gross adult outlines in the first year. Interpreting EEG needs therefore a deep knowledge of pathological and normal EEG patterns with their variants belonging to each age range. Recording EEG during these periods also requires adapting the recording techniques to the specific age in order to obtain interpretable records. This chapter describes normal EEG features and variants, characteristic patterns of development, and some patterns that are unusual for age, from the neonatal period to adolescence.

Objective Heterozygous mutations in the ATP1A3 gene are responsible for various neurological disorders, ranging from early-onset alternating hemiplegia of childhood to adult-onset dystonia-parkinsonism. Next generation sequencing allowed the description of other phenotypes, including early-onset epileptic encephalopathy in two patients. We report on three more patients carrying ATP1A3 mutations with a close phenotype and discuss the relationship of this phenotype to alternating hemiplegia of childhood. Methods The patients’ DNA underwent next generation sequencing. A retrospective analysis of clinical case records is reported. Results Each of the three patients had an unreported heterozygous de novo sequence variant in ATP1A3. These patients shared a similar phenotype characterized by early-onset attacks of movement disorders, some of which proved to be epileptic, and severe developmental delay. (Hemi)plegic attacks had not been considered before genetic testing. Significance Together with the two previously reported cases, our patients confirm that ATP1A3 mutations are associated with a phenotype combining features of early-onset encephalopathy, epilepsy and dystonic fits, as in the most severe forms of alternating hemiplegia of childhood, but in which (hemi)plegic attacks are absent or only suspected retrospectively.

International audience; Characteristic preterm EEG patterns of "Delta-brushes" (DBs) have been reported in the temporal cortex following auditory stimuli, but their spatio-temporal dynamics remains elusive. Using 32-electrode EEG recordings and co-registration of electrodes' position to 3D-MRI of age-matched neonates, we explored the cortical auditory-evoked responses (AERs) after 'click' stimuli in 30 healthy neonates aged 30-38 post-menstrual weeks (PMW). (1) We visually identified auditory-evoked DBs within AERs in all the babies between 30 and 33 PMW and a decreasing response rate afterwards. (2) The AERs showed an increase in EEG power from delta to gamma frequency bands over the middle and posterior temporal regions with higher values in quiet sleep and on the right. (3) Time-frequency and averaging analyses showed that the delta component of DBs, which negatively peaked around 550 and 750 ms over the middle and posterior temporal regions, respectively, was superimposed with fast (alpha-gamma) oscillations and corresponded to the late part of the cortical auditory-evoked potential (CAEP), a feature missed when using classical CAEP processing. As evoked DBs rate and AERs delta to alpha frequency power decreased until full term, auditory-evoked DBs are thus associated with the prenatal development of auditory processing and may suggest an early emerging hemispheric specialization.

BACKGROUND: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses.METHODS: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181.FINDINGS: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred.INTERPRETATION: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components.FUNDING: Biogen.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, 10.1016/j.pjnns.2018.02.008. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Long-term video-EEG corresponds to a recording ranging from 1 to 24 h or even longer. It is indicated in the following situations: diagnosis of epileptic syndromes or unclassified epilepsy, pre-surgical evaluation for drug-resistant epilepsy, follow-up of epilepsy or in cases of paroxysmal symptoms whose etiology remains uncertain. There are some specificities related to paediatric care: a dedicated pediatric unit; continuous monitoring covering at least a full 24-hour period, especially in the context of pre-surgical evaluation; the requirement of presence by the parents, technician or nurse; and stronger attachment of electrodes (cup electrodes), the number of which is adapted to the age of the child. The chosen duration of the monitoring also depends on the frequency of seizures or paroxysmal events. The polygraphy must be adapted to the type and topography of movements. It is essential to have at least an electrocardiography (ECG) channel, respiratory sensor and electromyography (EMG) on both deltoids. There is no age limit for performing long-term video-EEG even in newborns and infants; nevertheless because of scalp fragility, strict surveillance of the baby's skin condition is required. In the specific context of pre-surgical evaluation, long-term video-EEG must record all types of seizures observed in the child. This monitoring is essential in order to develop hypotheses regarding the seizure onset zone, based on electroclinical correlations, which should be adapted to the child's age and the psychomotor development.

The concept of epilepsy syndromes, introduced in 1989, was defined as “clusters of signs and symptoms customarily occurring together”. Definition of epilepsy syndromes based on electro-clinical features facilitated clinical practice and, whenever possible, clinical research in homogeneous groups of patients with epilepsies. Progress in the fields of neuroimaging and genetics made it rapidly clear that, although crucial, the electro-clinical description of epilepsy syndromes was not sufficient to allow much needed development of targeted therapies and a better understanding of the underlying pathophysiological mechanisms of seizures. The 2017 ILAE position paper on Classification of the Epilepsies recognized that “as a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking”. The concept of “epilepsy syndromes” evolved, incorporating issues related to aetiologies and comorbidities. A comprehensive update (and revision where necessary) of the EEG diagnostic criteria in the light of the 2017 revised terminology and concepts was deemed necessary. Part 2 covers the neonatal and paediatric syndromes in accordance with the age of onset. [Published with educational EEG plates at www.epilepticdisorders.com].

Rational. The concept of epilepsy syndromes, introduced in 1989, was defined as “clusters of signs and symptoms customarily occurring together”. Definition of epilepsy syndromes based on electro-clinical features facilitated clinical practice and, whenever possible, clinical research in homogeneous groups of patients with epilepsies. Progress in the fields of neuroimaging and genetics made it rapidly clear that, although crucial, the electro-clinical description of epilepsy syndromes was not sufficient to allow much needed development of targeted therapies and a better understanding of the underlying pathophysiological mechanisms of seizures. The 2017 ILAE position paper on Classification of the Epilepsies recognized that “as a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking”. The concept of “epilepsy syndromes” evolved, incorporating issues related to aetiologies and comorbidities. A comprehensive update (and revision where necessary) of the EEG diagnostic criteria in the light of the 2017 revised terminology and concepts was deemed necessary. Methods. The work was commissioned by the Neurophysiology Task Force of the ILAE Committee on the Diagnostic Methods. Diagnostic criteria and recording procedures were developed by group consensus, reached through an “informal”, internal decision-making process. Each working group member was allocated a number of syndromes, and a standard structured template was used. International literature was extensively reviewed. Results. We developed a simple diagnostic system that is applicable to all epilepsy syndromes which allows the physician (i) to rate the strength of EEG diagnosis (degree of diagnostic certainty) by weighting EEG findings in relation to the available clinical information or the specific clinical question, and ii) to suggest further EEG diagnostics where conclusive diagnostic evidence is lacking. We also propose a system of syndrome-specific recording protocols that, used with the relevant clinical presentation or specific clinical question, may maximize activation of epileptic discharges and ultimately help with standardization of EEG recording across departments, worldwide. Because recording methodology also depends on available resources, a two-tier system was developed to embrace clinical EEG services in resource-limited and industrialized countries. A clinical practice statement for each of the epilepsy syndromes discussed underscores the crucial role of the clinical information with regards to both the optimization of the EEG recording and mainly its meaningful interpretation. Part I covers Genetic (Idiopathic) generalized epilepsies and syndromes, Reflex epilepsies, structural and genetic focal (lobar) syndromes and Progressive Myoclonus Epilepsies [Published with educational EEG plates on www.epilepticdisorders.com].

We present analytical formulae for the Sommerfeld corrections to the annihilation of massive colored particles into quarks and gluons through the strong interaction. These corrections are essential to accurately compute the dark matter relic density for coannihilation with colored partners. Our formulae allow to compute the Sommerfeld effect, not only for the lowest term in the angular momentum expansion of the amplitude, but for all orders in the partial wave expansion. In particular, we carefully account for the effects of the spin of the annihilating particle on the symmetry of the two-particle wave function. This work focuses on strongly interacting particles of arbitrary spin in the triplet, sextet and octet color representations. For typical velocities during freeze-out, we find that including Sommerfeld corrections on the next-to-leading order partial wave leads to modifications of up to ten to twenty percent on the total annihilation cross section. Complementary to QCD, we generalize our results to particles charged under an arbitrary unbroken SU(N) gauge group, as encountered in dark glueball models. In connection with this paper a Mathematica notebook is provided to compute the Sommerfeld corrections for colored particles up to arbitrary order in the angular momentum expansion., Comment: 41 pages, 5 figures, matches EPJC version

We perform a general study of the relic density and LHC constraints on simplified models where the dark matter coannihilates with a strongly interacting particle X. In these models, the dark matter depletion is driven by the self-annihilation of X to pairs of quarks and gluons through the strong interaction. The phenomenology of these scenarios therefore only depends on the dark matter mass and the mass splitting between dark matter and X as well as the quantum numbers of X. In this paper, we consider simplified models where X can be either a scalar, a fermion or a vector, as well as a color triplet, sextet or octet. We compute the dark matter relic density constraints taking into account Sommerfeld corrections and bound state formation. Furthermore, we examine the restrictions from thermal equilibrium, the lifetime of X and the current and future LHC bounds on X pair production. All constraints are comprehensively presented in the mass splitting versus dark matter mass plane. While the relic density constraints can lead to upper bounds on the dark matter mass ranging from 2 TeV to more than 10 TeV across our models, the prospective LHC bounds range from 800 to 1500 GeV. A full coverage of the strongly coannihilating dark matter parameter space would therefore require hadron colliders with significantly higher center of mass energies., 34 pages, 8 figures, matches JHEP version

The aim was to localize the interictal cerebral perfusion abnormalities of focal cortical dysplasia (FCD) in children with Arterial Spin Labeling MRI (ASL) in a retrospective study of nine consecutive children explored with multimodal investigation during interictal periods. We analyzed brain morphology with a 1.5T MRI and a dedicated protocol for epilepsy. Brain perfusion was quantified with pseudo continuous ASL. Brain metabolism was imaged with (18)FDG-PET in six patients. Microvessel histology was studied in five children who underwent epilepsy surgery with CD34 immunostaining on FCD and control samples. Localized decrease of cerebral blood flow (CBF) was found on visual analysis in all patients with ASL. It was co-localized with the structural MRI abnormalities in every case, with PET hypo-metabolism in 5/6 cases, and with histologically proven FCD type IIb in 5/5 cases (all seizure free after surgery). CBF was lower (Kruskal-Wallis test, p=0.001) in FCD than in normal cortex. The total count of CD34+ microvessels was similar in FCD and control cases, but microvasculature showed disorganized architecture. Interictal ASL is a non-invasive method that may help to localize the epileptogenic zone showing hypo-perfusion in FCD. Whether this finding could be generalized to MRI-negative FCD needs to be further studied.

Electroencephalography allows the functional analysis of electrical brain cortical activity and is the gold standard for analyzing electrophysiological processes involved in epilepsy but also in several other dysfunctions of the central nervous system. Morphological imaging yields complementary data, yet it cannot replace the essential functional analysis tool that is EEG. Furthermore, EEG has the great advantage of being non-invasive, easy to perform and allows control tests when follow-up is necessary, even at the patient's bedside. Faced with the advances in knowledge, techniques and indications, the Societe de Neurophysiologie Clinique de Langue Francaise (SNCLF) and the Ligue Francaise Contre l'Epilepsie (LFCE) found it necessary to provide an update on EEG recommendations. This article will review the methodology applied to this work, refine the various topics detailed in the following chapters. It will go over the summary of recommendations for each of these chapters and underline proposals for writing an EEG report. Some questions could not be answered by the review of the literature; in those cases, an expert advice was given by the working and reading groups in addition to the guidelines