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Aim: To evaluate clinicians' and patients' perceptions of pharmacogenetic testing in a clinical setting. Materials & methods: This is a pragmatic mixed-method prospective observational study. Hospital pharmacists and neurologists participated in focus groups regarding pharmacogenetic testing; patients who received pharmacogenetic testing and their community pharmacists completed surveys to assess their perception of these tests. Results: Most study participants had a positive view of pharmacogenetic testing. Three major themes were identified from the focus groups: receptiveness to pharmacogenetic testing, pharmacogenetic test characteristics and integrating pharmacogenetic tests into practice. Conclusion: The views reported are encouraging for the eventual implementation of pharmacogenetics in practice. Local integration of these tests is an essential step to improve patient care through personalized medicine.

Objective Altered sensory processing is common in intellectual disability (ID). Here, we study electroencephalographic responses to auditory stimulation in human subjects presenting a rare condition (mutations in SYNGAP1) which causes ID, epilepsy and autism. Methods Auditory evoked potentials, time-frequency and inter-trial coherence analyses were used to compare subjects with SYNGAP1 mutations with Down syndrome (DS) and neurotypical (NT) participants (N = 61 ranging from three to 19 years of age). Results Altered synchronization in the brain responses to sound were found in both ID groups. The SYNGAP1 mutations group showed less phase-locking in early time windows and lower frequency bands compared to NT, and in later time windows compared to NT and DS. Time-frequency analysis showed more power in beta-gamma in the SYNGAP1 group compared to NT participants. Conclusions This study indicated reduced synchronization as well as more high frequencies power in SYNGAP1 mutations, while maintained synchronization was found in the DS group. These results might reflect dysfunctional sensory information processing caused by excitation/inhibition imbalance, or an imperfect compensatory mechanism in SYNGAP1 mutations individuals. Significance Our study is the first to reveal brain response abnormalities in auditory sensory processing in SYNGAP1 mutations individuals, that are distinct from DS, another ID condition.

Confucianism is an important Chinese tradition from which many philosophers have drawn inspiration, right up to the present day. We spoke to Dr Philippe Major and Professor Ralph Weber about their work investigating modern Confucianism, and its importance to understanding contemporary China.

ImportanceHealth-related quality of life (HRQOL) is regarded as a key outcome for evaluating treatment efficacy. However, it is uncertain how HRQOL evolves after epilepsy surgery compared with medical therapy, such as whether it continues to improve over time, improves and then remains stable, or deteriorates after a period of time.ObjectiveTo assess trajectory of HRQOL over 2 years in children with drug-resistant epilepsy (DRE) treated with surgery compared with medical therapy.Design, Setting, and ParticipantsProspective cohort study assessing HRQOL longitudinally over 2 years. Participants were children recruited from 8 epilepsy centers in Canada from 2014 to 2019 with suspected DRE aged 4 to 18 years who were evaluated for surgery. Data were analyzed from May 2014 to December 2021.ExposuresEpilepsy surgery or medical therapy.Main Outcomes and MeasuresHRQOL was measured using the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE)-55. HRQOL and seizure frequency were assessed at baseline, 6-month, 1-year, and 2-year follow-ups. Clinical, parent, and family characteristics were assessed at baseline. A linear mixed model was used to evaluate HRQOL over time, adjusting for baseline clinical, parent, and family characteristics.ResultsThere were 111 surgical and 154 medical patients (mean [SD] age at baseline was 11.0 [4.1] years; 118 [45%] were female). At baseline, HRQOL was similar among surgical and medical patients. HRQOL of surgical patients was 3.0 (95% CI, −0.7 to 6.8) points higher at 6-month, 4.9 (95% CI, 0.7 to 9.1) points higher at 1-year, and 5.1 (95% CI, 0.7 to 9.5) points higher at 2-year follow-ups compared with medical patients. Surgical patients experienced greater improvements in social functioning relative to medical patients, but not for cognitive, emotional, and physical functioning. At 2-year follow-up, 72% of surgical patients were seizure-free, compared with 33% of medical patients. Seizure-free patients reported higher HRQOL than those who were not.Conclusions and RelevanceThis study provided evidence on the association between epilepsy surgery and children’s HRQOL, with improvement in HRQOL occurring within the first year and remaining stable 2 years after surgery. By demonstrating that surgery improved seizure freedom and HRQOL, which has downstream effects such as better educational attainment, reduced health care resource utilization, and health care cost, these findings suggest that the high costs of surgery are justified, and that improved access to epilepsy surgery is necessary.

This article adopts Ernesto Laclau’s notion of empty signifier to discuss Tang Junyi’s uses of the concept of lixing (‘reason’ or ‘rationality’) in his seminal work Cultural Consciousness and Moral Reason (文化意識與道德理性; 1958). My dual goal, in doing so, is to bring to light the relations of power constitutive of the text’s discourse on lixing and relate them to the problematic of writing philosophy from the periphery. I argue that in this work, lixing’s dual referents—as a translation of ‘reason’ and as denoting a Neo-Confucian faculty to intuit moral truths—allow Tang to inscribe himself in a philosophical field designed to exclude non-Western philosophies, while at the same time enabling him to symbolically relegate Euro-American philosophy to a peripheral position by filling in the notion of lixing with a content that legitimizes his own agenda. Tang could thus authorize his Confucian metaphysics by presenting it as the true content of lixing, understood not only as a universal faculty enabling humanity’s access to all that is universal, but also as a condition sine qua non of for one’s inclusion in the philosophical game. By attempting to co-opt the empty signifier (lixing/reason) for his own purposes, I argue Tang employs one of two possible strategies that can be adopted by those situated at the periphery in order to oppose the hegemon; one that leaves the structure of power relations intact but working in favor of the periphery.

Genetically determined leukoencephalopathies comprise a group of rare inherited white matter disorders. The majority are progressive diseases resulting in early death. We performed a cross-sectional pilot study including 55 parents from 36 families to assess the level of stress experienced by parents of patients with genetically determined leukoencephalopathies, aged 1 month to 12 years. Thirty-four mothers and 21 fathers completed the Parenting Stress Index–4th Edition. One demographic questionnaire was completed per family. Detailed clinical data was gathered on all patients. Statistical analysis was performed with total stress percentile score as the primary outcome. Mothers and fathers had significantly higher stress levels compared with the normative sample; 20% of parents had high levels of stress whereas 11% had clinically significant levels of stress. Mothers and fathers had comparable total stress percentile scores. We identified pediatric behavioral difficulties and gross motor function to be factors influencing stress in mothers. Our study is the first to examine parental stress in this population and highlights the need for parental support early in the disease course. In this pilot study, we demonstrated that using the Parenting Stress Index–4th Edition to assess stress levels in parents of patients with genetically determined leukoencephalopathies is feasible, leads to valuable and actionable results, and should be used in larger, prospective studies.

This study investigated which specific behavioural issues is best associated with adaptive functioning in three specific genetic syndromes. Behavioural issues were assessed in neurotypical (NT) (n = 43), Tuberous sclerosis complex (TSC) (n = 19), Down syndrome (DS) (n = 24) and Fragile X syndrome (FXS) (n = 23) participants ranging from 3 to 30 years of age. First, we compared the behaviours characteristics between these genetic conditions and also according to age within these clinical groups. Multiple regressions included five behavioural scales (CBCL/BSI) and IQ as factors associated with adaptive functioning (ABAS-II’s composite scores). These regressions were carried out in order to observe which behavioural characteristics are associated with adaptive functioning in each syndrome. Results showed specific behavioural profiles between syndromes but no differences between ages within syndromes. Results also showed that IQ and inattention/ hyperactivity accounted for a large amount of variance of adaptive functioning in TSC and FXS groups in almost all adaptive domains. A lower IQ and more issues in attention and hyperactivity were associated with a lower adaptive functioning. These results are consistent with existing literature on adaptive functioning through neurodevelopmental disorders (Chromik et al. 2019; Stein et al. 1995; Sikora et al. 2012; Liss et al. 2001; Kanne et al. 2011). Results linking social issues and anxiety to adaptive functioning remained inconsistent.

We present five cases of pediatric drug-resistant epilepsy (DRE) that failed management using high cannabidiol (CBD) doses, but had significant reduction in seizure frequency with reintroduction or increasing doses of tetrahydrocannabinol (THC). There is growing evidence supporting the use of whole-plant CBD-rich extracts (containing THC and other cannabinoids) in the treatment of pediatric DRE. Based on our experiences and reports in the literature, we propose that, in patients who fail management with an initial trial of high-dose CBD-focused therapy, there may be a role for add-on THC-focused formulations.

This article situates Xiong Shili’s 熊十力 classic work New Treatise on the Uniqueness of Consciousness (Xin Weishi Lun 新唯識論, 1932) within the central dilemma of post-May Fourth China surrounding the concerns with so-called modern universalism and Chinese particularism. I look at the way the text portrays its author as situated both within particular traditions and outside of them (in a realm of universality) in order to show how the figure of the author is presented as a site wherein Chinese/Asian particularism and universalism can be fused. My central aim, in doing so, is to argue that within the text’s discourse on the positioning of its author resides an implicit argument for the universality of Chinese or Asian philosophy—as interpreted and subsumed by the text—and against the hegemonic intentions of Western philosophy. Yet I also suggest that the text reiterates a conception of universality and an intention to monopolize the universal which are characteristic of hegemonic discourses.

Objective To examine longitudinal changes and predictors of depression and anxiety 2 years following resective epilepsy surgery, compared to no surgery, in children with drug-resistant epilepsy (DRE). Method This multicenter cohort study involved 128 children and adolescents with DRE (48 surgical, 80 nonsurgical; 8–18 years) who completed self-report measures of depression and anxiety at baseline and follow-up (6-month, 1-year, 2-year). Child demographic (age, sex, IQ) and seizure (age at onset, duration, frequency, site and side) variables were collected. Results Linear mixed-effects models controlling for age at enrolment found a time by treatment by seizure outcome interaction for depression. A negative linear trend across time (reduction in symptoms) was found for surgical patients, irrespective of seizure outcome. In contrast, the linear trend differed depending on seizure outcome in nonsurgical patients; a negative trend was found for those with continued seizures, whereas a positive trend (increase in symptoms) was found for those who achieved seizure freedom. Only a main effect of time was found for anxiety indicating a reduction in symptoms across patient groups. Multivariate regressions failed to find baseline predictors of depression or anxiety at 2-year follow-up in surgical patients. Older age, not baseline anxiety or depression, predicted greater symptoms of anxiety and depression at 2-year follow-up in nonsurgical patients. Conclusion Children with DRE reported improvement in anxiety and depression, irrespective of whether they achieve seizure control, across the 2 years following surgery. In contrast, children with DRE who did not undergo surgery, but achieved seizure freedom, reported worsening of depressive symptoms, which may indicate difficulty adjusting to life without seizures and highlight the potential need for ongoing medical and psychosocial follow-up and support.

Background Disease severity is tremendously variable in tuberous sclerosis complex (TSC). In contrast with the detailed guidelines available for TSC diagnosis and management, clinical practice lacks adequate tools to evaluate the prognosis, especially in the case of in utero diagnosis. In addition, the correlation between genotypes and phenotypes remains a challenge, in part due to the large number of mutations linked to TSC. In this report, we describe a case of severe TSC diagnosed in utero and associated with a specific mutation in the gene tuberous sclerosis complex 2 (TSC2). Case presentation A mother was referred for a thorough investigation following the observation by ultrasound of cardiac abnormalities in her fetus. The mother was healthy and reported frequent, intense and long-lasting hiccups/spasms in the fetus. The fetus of gestational age 33 weeks and 4 days was found to have multiple cardiac tumors with cardiac ultrasound. Brain magnetic resonance imaging (MRI) performed in utero revealed the presence of sub-ependymal nodules and of abnormal signals disseminated in the white matter, in the cerebral cortex and in the cerebellum. Following diagnosis of definite TSC, pregnancy interruption was chosen by the parents. Genetic testing of the fetus exposed a duplication in exon 41 of TSC2 (c.5169dupA), which was absent in the parents. The autopsy ascertained the high severity of brain damage characterized by an extensive disorganisation of white and grey matter in most cerebral lobes. Conclusions This case presentation is the first to depict the association between a de novo TSC2 c.5169dupA and multi-organ manifestation together with indications of a particularly high disease severity. This report can help physicians to perform early clinical diagnosis of TSC and to evaluate the prognosis.

A 2-year-old Caucasian boy with tuberous sclerosis complex presented to the emergency department with lethargy and new onset myoclonias. Pancreatitis, thrombocytopenia, and coagulopathy associated to a decreased level of consciousness were diagnosed. Valproic acid had been initiated 13 months before and had been slowly increased to a dose of approximately 38 mg/kg/day. All the symptoms resolved after discontinuation of the medication. The clinical presentation of this child highlights that valproic acid-related pancreatitis can present with decreased level of consciousness without associated gastrointestinal symptoms. Adverse drug reactions associated with valproic acid can lead to damage of multiple organs and may prove fatal if not promptly recognized and managed.

This article argues that Eastern and Western Cultures and Their Philosophies adopts an ambiguous attitude vis-a-vis the relation between tradition and modernity, incorporating both traditionalist and anti-traditionalist attitudes with an at-times reconciliatory approach to tradition and modernity. This ambiguity, it is argued, can be seen as representative of historical tensions the text set out to resolve.

Background Fragile X syndrome (FXS) is a neurodevelopmental genetic disorder causing cognitive and behavioural deficits. Repetition suppression (RS), a learning phenomenon in which stimulus repetitions result in diminished brain activity, has been found to be impaired in FXS. Alterations in RS have been associated with behavioural problems in FXS; however, relations between RS and intellectual functioning have not yet been elucidated. Methods EEG was recorded in 14 FXS participants and 25 neurotypical controls during an auditory habituation paradigm using repeatedly presented pseudowords. Non-phased locked signal energy was compared across presentations and between groups using linear mixed models (LMMs) in order to investigate RS effects across repetitions and brain areas and a possible relation to non-verbal IQ (NVIQ) in FXS. In addition, we explored group differences according to NVIQ and we probed the feasibility of training a support vector machine to predict cognitive functioning levels across FXS participants based on single-trial RS features. Results LMM analyses showed that repetition effects differ between groups (FXS vs. controls) as well as with respect to NVIQ in FXS. When exploring group differences in RS patterns, we found that neurotypical controls revealed the expected pattern of RS between the first and second presentations of a pseudoword. More importantly, while FXS participants in the ≤ 42 NVIQ group showed no RS, the > 42 NVIQ group showed a delayed RS response after several presentations. Concordantly, single-trial estimates of repetition effects over the first four repetitions provided the highest decoding accuracies in the classification between the FXS participant groups. Conclusion Electrophysiological measures of repetition effects provide a non-invasive and unbiased measure of brain responses sensitive to cognitive functioning levels, which may be useful for clinical trials in FXS. Electronic supplementary material The online version of this article (10.1186/s11689-018-9223-3) contains supplementary material, which is available to authorized users.

This article discusses how Liang Shuming's Dong–Xi wenhua ji qi zhexue (Eastern and Western Cultures and Their Philosophies) adopted a genealogical mode of textual authorization which took shape in its depiction of Chinese history as a failure to live up to an ideal way of life imagined by Confucius. Implied in this discourse was the idea that Liang himself had been the first Confucian to understand what Confucius had truly meant. This genealogical discourse authorizing Liang and his text by linking them directly to Confucius was further strengthened by a rhetoric which naturalized the discourse passed down from Confucius to Liang, distinguishing it from other forms of discourse seen as artificial. Finally, the text's genealogical discourse also managed to incorporate the May Fourth critique of Confucianism by rejecting the historical manifestations of Confucianism before salvaging an ideal imagined by Confucius which was presented as uncontaminated by history and Confucianism's enmeshment in state power.

This article discusses the temporalization of space central to the mainstream discourse of European modernity: a discourse which hierarchized all cultural spaces into a temporal narrative enabling Europe’s self-portrayal as the emancipatory future of humanity. This discourse created a gap between the perceived particularism of non-European cultures (seen as traditional) and the universalism of a modernity associated with the contemporary cultures of Europe and North America, while portraying modernization as a passage from the former to the latter. Chinese intellectuals who adopted this metanarrative therefore faced the following challenge: how can Chinese particularism be adapted to a culture of modernity regarded as universal? While May Fourth iconoclasts answered this question by simply rejecting the idea that an accommodation between Chinese particularism and modern universalism was possible, other intellectuals attempted to argue that at least some aspects of Chinese culture could still be of value within the context of modern universalism. This article discusses an interesting instance of such an attempt at negotiating the perceived tension between the modern discourse of universalism and the particularism of Chinese culture, as provided by Liang Shuming in Eastern and Western Cultures and Their Philosophies. This work attempted to show that Chinese culture could still be of value within the context of modernity by providing a new metanarrative which peripherized the role of Western culture in the process of modernization. This article suggests, however, that by adopting a portrayal of modernization as a passage from particularism to universalism, Chinese culture could be reauthorized, within Liang’s metanarrative, only at the cost of being de-complexified, homogenized, and de-historicized; only at the cost of being no longer Chinese.

BACKGROUND: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine.METHODS: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care.RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated.CONCLUSIONS: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.

Seizures are common in critically ill neonates. Both seizures and antiepileptic treatments may lead to short term complications and worsen the outcomes. Predicting the risks of seizure reoccurrence could enable individual treatment regimens and better outcomes. We aimed to identify EEG signatures of seizure reoccurrence by investigating periictal electrographic features and spectral power characteristics in hypothermic neonates with hypoxic-ischemic encephalopathy (HIE) with or without reoccurrence of seizures on rewarming.We recruited five consecutive HIE neonates, submitted to continuous EEG monitoring, with high seizure burden (20% per hour) while undergoing therapeutic hypothermia. Two of them had reoccurrence of seizures on rewarming. We performed quantitative analysis of fifteen artifact-free consecutive seizures to appreciate spectral power changes between the interictal, preictal and ictal periods, separately for each patient. Visual analysis allowed description of electrographic features associated with ictal events.Every patient demonstrated a significant increase in overall spectral power from the interictal to preictal and ictal periods (p0.01). Alpha power increase was more pronounced in the two patients with reoccurrence of seizures on rewarming and significant when comparing both interictal-to-preictal and interictal-to-ictal periods. This alpha activity increase could be also appreciated using visual analysis and distinguished neonates with and without seizure reoccurrence.This distinct alpha activity preceding ictal onset could represent a biomarker of propensity for seizure reoccurrence in neonates. Future studies should be performed to confirm whether quantitative periictal characteristics and electrographic features allow predicting the risks of seizure reoccurrence in HIE neonates and other critically ill patients.

Background Sturge–Weber syndrome is characterized by a facial port-wine stain associated with either or both a retinal angioma and a cerebral pial angioma. Because a pial angioma may not be evident on the initial imaging studies, individuals at risk for epilepsy are often not identified before their first seizure. The aim of this study is to identify predictive factors predisposing Sturge–Weber patients to epilepsy. Methods The medical archives and photography database of our institution were reviewed to identify Sturge–Weber Syndrome patients followed up between 1990 and 2015. Patients without epilepsy were compared with patients with epilepsy based on the location of the port-wine stain, its extent and cerebral imaging. Results Twenty-four patients were included in the study. Thirteen did not develop epilepsy. Patients with bilateral port-wine stain were at higher risk of epilepsy ( P = 0.03). Unilateral port-wine stain did not increase the risk of epilepsy ( P = 0.29) regardless of its extent. The presence of developmental venous anomalies on brain imaging was also associated with a higher risk of epilepsy ( P = 0.03). Conclusions Bilateral facial port-wine stain and cerebral developmental venous anomalies increase the risk of epilepsy in Sturge–Weber syndrome patients. Because they can be detected at birth, they might guide preventive management and follow-up.

Sensory processing is the gateway to information processing and more complex processes such as learning. Alterations in sensory processing is a common phenotype of many genetic syndromes associated with intellectual disability (ID). It is currently unknown whether sensory processing alterations converge or diverge on brain responses between syndromes. Here, we compare for the first time four genetic conditions with ID using the same basic sensory learning paradigm. One hundred and five participants, aged between 3 and 30 years old, composing four clinical ID groups and one control group, were recruited: Fragile X syndrome (FXS; n = 14), tuberous sclerosis complex (TSC; n = 9), Down syndrome (DS; n = 19), SYNGAP1 mutations (n = 8) and Neurotypical controls (NT; n = 55)). All groups included female and male participants. Brain responses were recorded using electroencephalography (EEG) during an audio-visual task that involved three repetitions of the pronunciation of the phoneme /a/. Event Related Potentials (ERP) were used to: 1) compare peak-to-peak amplitudes between groups, 2) evaluate the presence of repetition suppression within each group and 3) compare the relative repetition suppression between groups. Our results revealed larger overall amplitudes in FXS. A repetition suppression (RS) pattern was found in the NT group, FXS and DS, suggesting spared repetition suppression in a multimodal task in these two ID syndromes. Interestingly, FXS presented a stronger RS on one peak-to-peak value in comparison with the NT. The results of our study reveal the distinctiveness of ERP and RS brain responses in ID syndromes. Further studies should be conducted to understand the molecular mechanisms involved in these patterns of responses.

Background:Little knowledge exists on the availability of academic and community paediatric neurology positions. This knowledge is crucial for making workforce decisions. Our study aimed to: 1) obtain information regarding the availability of positions for paediatric neurologists in academic centres; 2) survey paediatric neurology trainees regarding their perceptions of employment issues and career plans; 3) survey practicing community paediatric neurologists 4) convene a group of paediatric neurologists to develop consensus regarding how to address these workforce issues.Methods:Surveys addressing workforce issues regarding paediatric neurology in Canada were sent to: 1) all paediatric neurology program directors in Canada (n=9) who then solicited information from division heads and from paediatric neurologists in surrounding areas; 2) paediatric neurology trainees in Canada (n=57) and; 3) community paediatric neurologists (n=27). A meeting was held with relevant stakeholders to develop a consensus on how to approach employment issues.Results:The response rate was 100% from program directors, 57.9% from residents and 44% from community paediatric neurologists. We found that the number of projected positions in academic paediatric neurology is fewer than the number of paediatric neurologists that are being trained over the next five to ten years, despite a clinical need for paediatric neurologists. Paediatric neurology residents are concerned about job availability and desire more career counselling.Conclusions:There is a current and projected clinical demand for paediatric neurologists despite a lack of academic positions. Training programs should focus on community neurology as a viable career option.

Fatty acid oxidation disorders and lipin-1 deficiency are the commonest genetic causes of rhabdomyolysis in children. We describe a lipin-1-deficient boy with recurrent, severe rhabdomyolytic episodes from the age of 4 years. Analysis of the LPIN1 gene that encodes lipin-1 revealed a novel homozygous frameshift mutation in exon 9, c.1381delC (p.Leu461SerfsX47), and complete uniparental isodisomy of maternal chromosome 2. This mutation is predicted to cause complete lipin-1 deficiency. The patient had six rhabdomyolytic crises, with creatine kinase (CK) levels up to 300,000 U/L (normal, 30 to 200). Plasma CK remained elevated between crises. A treatment protocol was instituted, with early aggressive monitoring, hydration, electrolyte replacement and high caloric, high carbohydrate intake. The patient received dexamethasone during two crises, which was well-tolerated and in these episodes, peak CK values were lower than in preceding episodes. Studies of anti-inflammatory therapy may be indicated in lipin-1 deficiency.

Summary Introduction Children with benign epilepsy with centro-temporal spikes (BECTS) often have language problems. Abnormal epileptic activity is found in central and temporal brain regions, which are involved in reading and semantic and syntactic comprehension. Using functional magnetic resonance imaging (fMRI), we examined reading networks in BECTS children with a new sentence reading comprehension task involving semantic and syntactic processing. Method Fifteen children with BECTS (age=11y 1m±16 m; 12 boys) and 18 healthy controls (age=11 y 8m±20 m; 11 boys) performed an fMRI reading comprehension task in which they read a pair of syntactically complex sentences and decided whether the target sentence (the second sentence in the pair) was true or false with respect to the first sentence. All children also underwent an exhaustive neuropsychological assessment. Results We demonstrated weaknesses in several cognitive domains in BECTS children. During the sentence reading fMRI task, left inferior frontal regions and bilateral temporal areas were activated in BECTS children and healthy controls. However, additional brain regions such as the left hippocampus and precuneus were activated in BECTS children. Moreover, specific activation was found in the left caudate and putamen in BECTS children but not in healthy controls. Cognitive results and accuracy during the fMRI task were associated with specific brain activation patterns. Conclusion BECTS children recruited a wider network to perform the fMRI sentence reading comprehension task, with specific activation in the left dorsal striatum. BECTS cognitive performance differently predicted functional activation in frontal and temporal regions compared to controls, suggesting differences in brain network organisation that contribute to reading comprehension.

BACKGROUND Lymphangioleiomyomatosis (LAM) is a manifestation of tuberous sclerosis complex (TSC) that causes destruction of the lung and chronic respiratory failure. Population-based estimates of demographics, clinical outcomes, and health-care utilization are lacking for TSC and LAM. METHODS Data on demographics, clinical outcomes, and health-care utilization in the Quebec ministerial provincial health-care database were analyzed for their association with TSC and LAM. RESULTS A total of 1,004 subjects with TSC were identified using International Classification of Diseases, Ninth and 10th Revisions, codes for a prevalence of one in 7,872 people. There were 38 subjects with LAM, nine of whom also had TSC. Mean ages as well as the mean age at death were lower in the LAM and TSC group than in the control group. Mortality rates were higher in subjects with LAM than in those with TSC or in control subjects. Subjects with LAM experienced more medical visits and hospitalizations than did those with TSC and control subjects; these were associated with higher health-care costs. Frequently prescribed drugs in TSC or LAM included anticonvulsants, antidepressants, and sedatives; the use of mammalian target of rapamycin inhibitors was uncommon. CONCLUSIONS The prevalence of TSC in Quebec, Canada, is similar to estimates from previously published surveys. LAM is likely underreported, perhaps due to suboptimal case identification or referral. Health-care utilization and mortality for LAM are high, suggesting that timely diagnosis and therapy could be beneficial. Mental health disorders may be an unrecognized clinical feature of LAM. These results provide a population-based background for policymakers and researchers to better address the needs of patients with TSC and LAM.

Unilateral hippocampal atrophy (HA) is considered as a precursor of mesial temporal sclerosis (MTS) in some patients with temporal lobe epilepsy. However, in other cases, it has been suggested that HA without MTS may constitute a distinct epileptic entity. Hippocampal atrophy without MTS was defined as HA without T2-weighted hyperintensity, loss of internal architecture, or associated lesion seen on the MRI data. To date, no study has focused on the cognitive pattern of children with epilepsy with HA without MTS. The objectives of the present study were to characterize the cognitive profile of these children and to investigate the presence (or the absence) of material-specific memory deficits in these young patients, as found in patients with MTS. Toward this end, 16 young patients with epilepsy with either left or right HA without MTS completed a set of neuropsychological tests, assessing overall intelligence, verbal memory and nonverbal memory, and some aspects of attention and executive functions. Results showed normal intellectual functioning without specific memory deficits in these patients. Furthermore, comparison between patients with left HA and patients with right HA failed to reveal a material-specific lateralized memory pattern. Instead, attention and executive functions were found to be impaired in most patients. These results suggest that HA may constitute a distinct epileptic entity, and this information may help health-care providers initiate appropriate and timely interventions.

Item does not contain fulltext Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.

Rolandic epilepsy (RE), also called benign epilepsy with centrotemporal spikes (BECTS) is the most common childhood epilepsy syndrome. RE is associated with cognitive difficulties, which can affect children's quality of life. The underlying causes of these cognitive impairments are unclear. The objective of this prospective study is to investigate sub-cortical morphological alterations in RE children with left, right, or bilateral hemispheric focus and its association with cognition.Participants include 41 children with rolandic epilepsy and 38 healthy controls (age 8-14 years), recruited from CHU Sainte-Justine Montreal Children Hospital (N=40) and Basel's Children Hospital (N=39). Quantitative volumetric assessment of putamen and caudate structures was performed on T1-weighted MR scans along with the morphological analysis to test for differences between patients and controls. These analyses were performed considering the side of epilepsy focus in all participants. Correlations were investigated between the sub-cortical morphometry and cognitive indices such as intelligence quotient (IQ), verbal comprehension index (VCI), perceptual reasoning index (PRI), working memory index (WMI), and processing speed index (PSI).Children with bilateral BECTS showed statistically significant volume reduction in right caudate (p.05), while no statistically significant putamen volumetric changes were detected in BECTS participants compared to normal controls. According to a spectral-based groupwise shape analysis, regional alterations were found in both putamen and caudate structures of children with BECTS. In particular, children with left BECTS showed significant outward local deformity in left putamen and individuals with bilateral BECTS showed inward local group differences in both right putamen and right caudate. The correlation assessment showed positive association between the volume of the left caudate and cognitive indices in the group containing all BECTS participants. Negative correlation was found between putamen sub-regional shape alterations and cognition in individuals with right BECTS and in all BECTS participants. Negative associations between caudate sub-regional morphologies and cognitive indices were detected in left cohort.We have confirmed putamen and caudate shape alterations in children with BECTS. However, our results further suggest that variations in sub-cortical shape affect cognitive functions. Importantly, we have demonstrated that shape alterations and their relation with cognition depend on the side of epilepsy focus. Our results point to different syndromic entities in the BECTS population.

Fragile X Syndrome (FXS) is a neurodevelopmental genetic disorder associated with cognitive and behavioural deficits. In particular, neuronal habituation processes have been shown to be altered in FXS patients. Yet, while such deficits have been primarily explored using auditory stimuli, less is known in the visual modality. Here, we investigated the putative alteration of repetition suppression using faces in FXS patients compared to controls that had the same age distribution. Electroencephalographic (EEG) signals were acquired while participants were presented with 18 different faces, each repeated ten times successively. The repetition suppression effect was probed by comparing the brain responses to the first and second presentation, based on task-evoked event-related potentials (ERP) as well as on task-induced oscillatory activity. We found different patterns of habituation for controls and patients both in ERP and oscillatory power. While the N170 was not affected by face repetition in controls, it was altered in FXS patients. Conversely, while a repetition suppression effect was observed in the theta band (4–8 Hz) over frontal and parieto-occipital areas in controls, it was not seen in FXS patients. These results provide the first evidence for diminished ERP and oscillatory habituation effects in response to face repetitions in FXS. These findings extend previous observations of impairments in learning mechanisms and may be linked to deficits in the maturation processes of synapses caused by the mutation. The present study contributes to bridging the gap between animal models of synaptic plasticity dysfunctions and human research in FXS.

BACKGROUND Infants with childhood-onset epilepsies, including epileptic encephalopathies, are at high risk of developmental challenges such as motor and language delays. There has been a growing focus on developmental screening instruments due to the association between delayed development and long-term adverse outcomes, including negative impacts on health-related quality of life, school achievement and social participation. Therefore, children with developmental delays should be referred as early as possible to rehabilitation services such as occupational, physical, or speech therapy. Developmental screening using standardized tools is recommended in order to identify the high-risk children that require additional developmental assessments. The Ages and Stages Questionnaires (ASQ), a parent-completed developmental screening tool, is one of the more cited and recommended developmental screening tools. However, its utility in children with early-onset epilepsy has yet to be validated. OBJECTIVES This study aimed to determine the validity of the ASQ for identifying children with new-onset epilepsy who require further professional developmental rehabilitation. DESIGN/METHODS Fifty infants (25 males) with seizure onset under 3 years of age were prospectively recruited. Parents completed the ASQ-3 before the first clinic appointment. The ASQ-3 evaluates 5 domains of development. An ASQ score below 2 standard deviations (SD) on any one of the domains was considered abnormal. Once completed, all infants were evaluated by a multidisciplinary team including neurologists, occupational therapists, and physical therapists to determine if they should be referred for further rehabilitation interventions. Accuracy of the ASQ was calculated in terms of sensibility, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS Mean age at the initial evaluation was 13.1 months (SD=8.22). Among the 50 infants, 36 (72%) received a score CONCLUSION The ASQ, a well-known parent-completed developmental screening tool, when abnormal shows adequate validity for the identification of children with early-onset epilepsy who require developmental assessments and interventions by rehabilitation professionals. Our results also provide further evidence that development delay is the rule rather than the exception in infants with new onset epilepsy.

Infantile spasms (IS) is a catastrophic epilepsy where treatment precocity improves outcome. Previous studies demonstrated an association between asymmetric hypsarrhythmia on EEG and ipsilateral hemispheric lesions on MRI, suggesting a possible role of cortical lesions in the initiation of IS. Epileptiform abnormalities appearing during early infancy have also been linked to IS emergence. We hypothesized that focal lateralized EEG abnormalities during the prehyspasrrhythmic period will be associated with asymmetric hypsarrhythmia at IS onset. We recruited a retrospective cohort of 80 infants, 7.4 ± 3.6 months old at the onset of hypsarrhythmia and IS, admitted to Sainte-Justine Hospital between 2007 and 2016. Seven infants showed an asymmetric hypsarrhythmia pattern and, as expected, all of them had lateralized lesions on MRI. Of the remaining 73, 42 had abnormal MRI, but only 3 infants had lateralized lesions (100% vs 7.1%, p Six had focal lateralized, while 23 multifocal abnormalities. The proportion of patients with focal abnormalities was higher in those who developed asymmetric compared to symmetric hypsarrhythmia (50% vs 13.3%, p Our data confirm the link between asymmetric hypsarrhythmia and lateralized MRI lesions. Moreover, we show that focal lateralized EEG abnormalities precede asymmetric hypsarrythmia, which supports the involvement of cerebral cortex in the IS genesis. More sensitive EEG biomarkers of high IS risk may help developing preventative treatments that will improve outcomes in IS.

Tuberous sclerosis complex is associated with benign tumors such as cardiac rhabdomyomas (RHM) caused by the disinhibition of the mammalian target of rapamycin (mTOR) protein. Recent reports on everolimus, an mTOR inhibitor, have shown size reduction of RHM. We compared cases recently treated with everolimus to historic controls whose first echocardiography was within first month of life. The largest dimension of the largest RHM was reported as a percentage compared to the earliest echocardiography study. Treatment of the four cases was started at a median age of 6.5 days (range 2–20) with an initial enteral dose of 0.1 mg daily, aiming at a therapeutic serum trough level of 5–15 ng/mL. Median duration of everolimus treatment was 73 days (range 34–138). Compared to 10 historic controls, everolimus-treated patients had 11.8 times faster RHM size regression rate (slope −0.0285 vs. −0.0024; p

Background We assessed central and peripheral visual field processing in children with epilepsy who were exposed to vigabatrin during infancy. Methods Steady-state visual evoked potentials and pattern electroretinograms to field-specific radial checkerboards flickering at two cycle frequencies (7.5 and 6 Hz for central and peripheral stimulations, respectively) were recorded from Oz and at the eye in seven school-age children (10.1 ± 3.5 years) exposed to vigabatrin early in life, compared with children early exposed to other antiepileptic drugs (n = 9) and healthy children (n = 8). The stimulation was made of two concentric circles (0 to 5 and 30 to 60 degrees of angle) and presented at four contrast levels (96%, 64%, 32%, and 16%). Results Ocular responses were similar in all groups for central but not for the peripheral stimulations, which were significantly lower in the vigabatrin-exposed group at high contrast level. This peripheral retinal response was negatively correlated to vigabatrin exposure duration. Cortical responses to central stimulations, including contrast response functions in the children with epilepsy in both groups, were lower than those in normally developing children. Conclusions Alteration of ocular processing was found only in the vigabatrin-exposed children. Central cortical processing, however, was impaired in both epileptic groups, with more pronounced effects in vigabatrin-exposed children. Our study suggests that asymptomatic long-term visual toxicity may still be present at school age, even several years after discontinuation of drug therapy.

Lacosamide is an antiepileptic drug approved for the treatment of focal epilepsy in adult patients. The aim of this observational study was to review our centre's experience with lacosamide and to characterize its effectiveness and tolerability as an adjunctive antiepileptic drug in a retrospective cohort of children with refractory focal epilepsy.We retrospectively reviewed the medical records of 22 patients who received lacosamide from November 2009 to April 2014 at the CHU Ste-Justine, University of Montreal. Treatment responders were defined as children with a ≥50% reduction in seizure frequency compared to baseline, and this was determined three months after the initiation of treatment and at the last follow-up visit.We included 14 boys and eight girls with a mean age of 12.9 years (SD: 5.2; range: 5.2-20.7 years) at the initiation of treatment. The average length of follow-up was 11.9 months. Patients had previously received an average of 7.5 antiepileptic drugs. The mean number of concomitant antiepileptic drugs was 2.3. The mean initial and maintenance doses were 2.9 and 8.4 mg/kg/d, respectively. Thirteen (59%) and ten (45%) patients were responders after three months of treatment and at the last follow-up visit, respectively. One became seizure-free. Adverse effects were reported in 11 patients and none were severe. Responders and non-responders were identical with respect to all studied parameters except gender, with the proportion of responders being greater in girls than in boys (75% vs 29%; p=0.035).Our study adds evidence that lacosamide appears to be a safe and effective adjunctive therapy for children with refractory focal epilepsy.

Summary Purpose: The phenotypic and etiologic spectrum in adults with nodular heterotopias (NHs) has been well characterized. However, there are no large pediatric case series. We, therefore, wanted to review the clinical features of NHs in our population. Methods: Hospital records of 31 patients with pathology or imaging-confirmed NHs were reviewed. Two-sided Fisher's exact t-test was used to assess associations between distribution of NHs and specific clinical features. Key Findings: NHs were distributed as follows: 8 (26%) unilateral focal subependymal, 3 (10%) unilateral diffuse subependymal, 5 (16%) bilateral focal subependymal, 12 (39%) bilateral diffuse subependymal, and 3 (10%) isolated subcortical. The phenotypic spectrum in our population differs from that described in adults. Significant morbidity and mortality are associated with presentation in childhood. Twenty-two of 31 patients (71%) died in the neonatal period or in childhood. Additional cerebral malformations were found in 80% and systemic malformations in 74%. The majority of patients had developmental delay, intellectual deficit, and intractable epilepsy. Patients with unilateral focal NHs were more likely to have ventriculomegaly (p = 0.027), and those with bilateral diffuse NHs more likely to have cerebellar abnormalities (p = 0.007). Isolated subcortical NHs were associated with multiple malformations (p = 0.049) and cardiac abnormalities (p = 0.027). Underlying etiology was heterogeneous and determined in only six cases (19%): del chr 1p36, del chr 15q11, pyruvate dehydrogenase deficiency, sialic acidosis type 1, Aicardi syndrome, and FLNA mutation. Significance: NHs are present in childhood as part of multiple cerebral and systemic malformations; developmental delay and refractory seizures are the rule rather than the exception. Milder forms go unrecognized until seizure onset in adulthood.