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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.

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.

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.

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.

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.

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.

Purpose: There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy. We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study. Methods: The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 Δ9-tetrahydrocannabinol (THC): CBD up to 10-12 mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms, and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (Css, Min) of selected cannabinoids were quantified. Results: All seven participants tolerated the CHE up to 10-12 mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. CSS, Min plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. CSS, Min CBD levels associated with a >50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, CSS, Min levels of THC remained lower than what would be expected to cause intoxication. Conclusion: The preliminary data suggest an initial CBD target dose of 5-6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible non-linear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day.

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 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.

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.

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.

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.

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.

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.

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.

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.

Summary Purpose: We present two methods of implantation for the investigation of suspected insular and perisylvian epilepsy that combine depth and subdural electrodes to capitalize on the advantages of each technique. Methods: Retrospective study of all intracranial EEG studies that included insular electrodes from 2004–2010. Patients were divided according to the implantation scheme. The first method (type 1) consisted of a craniotomy, insertion of insular electrodes after microdissection of the sylvian fissure, orthogonal implantation of mesiotemporal structures with neuronavigation, and coverage of the adjacent lobes with subdural electrodes. The second method (type 2) consisted of magnetic resonance imaging (MRI)–stereotactic frame-guided depth electrode implantation into insula and hippocampus using sagittal axes, and insertion of subdural electrodes through burr holes to cover the adjacent lobes. The combined implantations were developed and performed by one neurosurgeon (AB). Key Findings: Nineteen patients had an intracranial study that sampled the insula, among other regions. Sixteen patients were implanted using the first method, which allowed a mean of 4, 5, 20, 15, and 42 contacts per patient to be positioned into/over the insular, mesial temporal, neocortical temporal, parietal, and frontal areas, respectively. The second method (three patients) allowed a mean of 8, 7, 16, 6, and 9 contacts per patient to sample the same areas, respectively. The four patients in whom transient neurologic deficits occurred were investigated with use of type 1 implantation. Significance: Combined depth and subdural electrodes can be used safely to investigate complex insular/perisylvian refractory epilepsy. Choice of implantation scheme should be individualized according to presurgical data and the need for functional localization.

Background Although epilepsy affects most patients with tuberous sclerosis complex (TSC), little is known about the natural history of epilepsy in this genetic disease.

Summary Nearly 90% of patients with tuberous sclerosis complex (TSC) develop epilepsy; however the mechanisms of epileptogenesis remain unclear. Some cortical tubers are thought to be epileptogenic while others are not. This study aimed to evaluate whether tuber burden, size or type seen on magnetic resonance imaging (MRI) co-registers with interictal epileptiform discharges on electroencephalogram (EEG). EEG and MRI data from 69 patients with TSC were reviewed by dividing the cerebrum into four quadrants. Quadrants containing greatest tuber burden, largest tuber, calcified tubers, cyst-like tubers, and no tubers were identified on MRI. For EEG analysis, spikes and sharp waves were counted and averaged to a value per minute, and each quadrant was assigned a score. MRI and EEG findings were compared in each patient. The presence of a cyst-like tuber in a quadrant correlated with a higher incidence of epileptiform activity in the same quadrant ( p =0.002). This finding supports the notion that cyst-like cortical tubers may contribute to the more severe epilepsy profile seen in TSC patients with these lesions. Quadrants containing greatest tuber burden, largest tubers, and calcified tubers were not predictive of regional interictal epileptiform activity. Furthermore, quadrants without any apparent tuber co-registered with interictal epileptiform discharges in two patients, suggesting a multifactorial component of epileptogenicity in TSC.

Background: Tuberous sclerosis complex (TSC) is a genetic condition characterized by the presence of hamartomatous lesions in multiple organs, including tubers in the brain. The majority of patients with TSC have epilepsy. Some cortical tubers are epileptic foci, while others appear to be physiologically quiescent. It is unknown whether variations in tuber morphology may account for this difference. The objectives of this study were to determine the frequency of cyst-like tubers in patients with TSC, whether cyst-like tubers correlate with TSC genotype, and whether cyst-like cortical tubers are associated with a history of infantile spasms, epilepsy, or refractory epilepsy. Methods: A retrospective chart review was performed of 173 patients with TSC. MRI images were evaluated for the presence of at least one cyst-like cortical tuber. Patient charts were then reviewed for genetic mutation, a history of infantile spasms, epilepsy, and epilepsy refractory to more than three medications. Results: A total of 46% of patients had at least one cyst-like cortical tuber present on neuroimaging. Patients with a TSC2 mutation were more likely to have a cyst-like tuber than patients with TSC1 mutation (p = 0.002) or patients with no mutation identified (p = 0.039). Patients with at least one cyst-like cortical tuber were more likely to have a history of infantile spasms (p = 0.00005), epilepsy (p = 0.0038), and refractory epilepsy (p = 0.0007) than patients without a cyst-like cortical tuber. Conclusion: Cyst-like cortical tubers are strongly associated with TSC2 gene mutation and a more aggressive seizure phenotype in patients with tuberous sclerosis complex.

Self-injurious behavior (SIB) has been observed in people with tuberous sclerosis complex (TSC), although the frequency of SIB in TSC is largely unknown. SIB is associated with intellectual and developmental disabilities, but there is no single cause of SIB. We retrospectively examined the frequency of SIB in a population of 257 patients with TSC and determined possible associations with SIB. We found a 10% frequency of SIB in our TSC population. When compared with patients without psychiatric symptoms, we identified a significantly higher rate of electroencephalographic interictal spikes in the left frontal lobe and a significantly lower number of tubers in the left occipital, parietal, and posterior temporal lobes. We also found that frequency of TSC2 mutation, history of infantile spasms, history of seizures, mental retardation, and autism are significantly associated with SIB.

The aim of the study described here was to characterize the efficacy and safety of vagus nerve stimulation in a population of patients with tuberous sclerosis complex (TSC) and intractable epilepsy.This retrospective study comprised 16 patients with TSC who underwent implantation of a vagus nerve stimulator for treatment of intractable epilepsy.The average age at vagus nerve stimulator implantation was 15 years (range: 2-44, SD: 12.5) and the average duration of follow-up on VNS was 4 years (range: 0.5-8.6, SD: 2.3). Outcome was rated class I (80% seizure frequency reduction) in 3 (19%), class II (50-79% reduction) in 5 (31%), class III (50% reduction) in 2 (13%), class IV (magnet benefit only) in 1 (6%), and class V (no improvement) in 5 (31%) patients. Intermittent magnet use was effective in aborting seizures in 8 (50%). Five (31%) patients reported an improved level of functioning.The findings suggest that the vagus nerve stimulation can be an effective and safe therapy for patients with TSC with intractable epilepsy.

To review the efficacy, cognitive outcome and safety profile in children treated with vigabatrin (VGB) for infantile spasms (IS) and partial epilepsies related to tuberous sclerosis complex (TSC) and other etiologies.Retrospective review of children followed in the Pediatric Epilepsy Program of Massachusetts General Hospital for Children between May 2001 and March 2006 who were treated with VGB.Eighty-four children were treated with VGB, 68 of them were treated for IS, and 59 were treated for partial seizures (PS). Etiology (TSC or other) was the only predictive factor for IS control with VGB (p0.0003). IS control was achieved in 73% of children with TSC and 27% of children with other etiologies (combined 56%). Partial onset seizures were controlled in 34% of all children, (17% seizure free,17%reduction in seizure frequency50%) and no predictive factor was found. Shorter time from seizure onset to VGB treatment (p0.027) and longer total time on VGB (p0.045) was associated with better IQ-developmental quotient (DQ) outcome in children treated for IS, but not with IS control. Adverse events were seen in 13%. Electroretinogram and/or behavioral visual field (VF) testing was done in 52%. VGB was discontinued in one case due to abnormal electroretinogram (ERG) findings.We confirm the efficacy of VGB in the treatment of IS and PS in an American population. VGB may improve cognitive outcome in the absence of complete IS control, but this finding is of uncertain clinical significance. VGB was well tolerated, and ophthalmologic side effects were uncommon.

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.

Background There are no established variables that predict the success of curative resective epilepsy surgery in children with tuberous sclerosis complex (TSC). Objective We performed a multicenter observational study to identify preoperative factors associated with seizure outcome in children with TSC undergoing resective epilepsy surgery. Methods A retrospective chart review was performed in eligible children at New York Medical Center, Miami Children's Hospital, Cleveland Clinic Foundation, BC Children's Hospital, Hospital for Sick Children, and Sainte-Justine Hospital between January 2005 and December 2013. A time-to-event analysis was performed. The "event" was defined as seizures after resective epilepsy surgery. Results Seventy-four patients (41 male) were included. The median age of the patients at the time of surgery was 120 months (range, 3-216 months). The median time to seizure recurrence was 24.0 ± 12.7 months. Engel Class I outcome was achieved in 48 (65%) and 37 (50%) patients at 1- and 2-year follow-up, respectively. On univariate analyses, younger age at seizure onset (hazard ratio [HR]: 2.03, 95% confidence interval [CI]: 1.03-4.00, P = .04), larger size of predominant tuber (HR: 1.03, 95% CI: 0.99-1.06, P = .12), and resection larger than a tuberectomy (HR: 1.86, 95% CI: 0.92-3.74, P = .084) were associated with a longer duration of seizure freedom. In multivariate analyses, resection larger than a tuberectomy (HR: 2.90, 95% CI: 1.17-7.18, P = .022) was independently associated with a longer duration of seizure freedom. Conclusion In this large consecutive cohort of children with TSC and medically intractable epilepsy, a greater extent of resection (more than just the tuber) is associated with a greater probability of seizure freedom. This suggests that the epileptogenic zone may include the cortex surrounding the presumed offending tuber.

Background: Planning for neurology training necessitated a reflection on the experience of graduates. We explored practice characteristics, and training experience of recent graduates. Methods: Graduates from 2010-2014 completed a survey. Results: Response rate was 37% of 211. 56% were female. 91% were adult neurologists. 65% practiced in an outpatient setting. 63% worked in academics. 85% completed subspecialty training (median 1 year). 36% work 3 days a week or less. 82% took general call (median 1 night weekly). Role preparation was considered very good or excellent for most; however poor or fair ratings were 17% in advocacy and 8% in leadership. Training feedback was at least “good” for 87%. Burnout a few times a week or more was noted by 5% (6% during residency, particularly PGY1 and 5). 64% felt overly burdened by paperwork. Although most felt training was adequate, it was poor or fair at preparing for practice management (85%) and personal balance (55%). Most conditions were under-observed in training environment. Many noted a need for more independent practice development and community neurology. Conclusions: Although our training was found to be very good, some identified needs included advocacy training, and more training in general neurology in the longitudinal outpatient/community settings.

Background Tuberous sclerosis complex is characterized by the growth of benign tumors in multiple organs, caused by the disinhibition of the mammalian target of rapamycin (mTOR) protein. mTOR inhibitors, such as everolimus, are used in patients with tuberous sclerosis complex, mainly to reduce the size of renal angiomyolipomas and subependymal giant cell astrocytomas. There are minimal data available regarding its use during the neonatal period. Methods We report clinical and pharmacological data of three neonates treated with the mTOR inhibitor everolimus (two hemodynamically significant cardiac rhabdomyomas and one voluminous subependymal giant cell astrocytoma). Results Beneficial clinical responses were observed in all three patients and the medication was generally well-tolerated. Optimal dose was 0.1 mg orally once daily and was confirmed with therapeutic drug monitoring. Conclusion Everolimus is a promising pharmacological approach to treat clinically significant inoperable cardiac rhabdomyomas or subependymal giant cell astrocytoma associated with tuberous sclerosis complex during the neonatal period.

Behavioral side effects related to the use of levetiracetam (LEV) in epilepsy are increasingly being recognized. Patients followed in our center have reported improvement of these side effects after starting pyridoxine (vitamin B(6)) supplements. Using mailed questionnaires, retrospective chart reviews, and phone call follow-ups, we analyzed 42 pediatric patients who had been treated with LEV and pyridoxine. Twenty-two patients started pyridoxine after being on LEV, and significant behavioral improvement was observed in nine (41%), no effect in eight (36%), deterioration in four (18%), and an uncertain effect in one. The effects of pyridoxine supplementation were observed during the first week. The remaining patients (20) were already on pyridoxine before LEV was started, started pyridoxine and LEV at the same time, or took pyridoxine intermittently. Pyridoxine is an easily available, inexpensive, and safe therapeutic option. Given these preliminary results, we plan to conduct a placebo-controlled cross-over study to better characterize these observations.

Seizures are common and worsen the outcome in critically ill neonates. Predicting seizure recurrence could allow individualizing antiepileptic treatment and improving the outcome. To identify EEG signatures of seizure recurrence, we investigated periictal spectral power and electrographic characteristics of seizures in five consecutive asphyxiated neonates under continuous EEG monitoring. All patients had high seizure burden while undergoing hypothermic neuroprotection. Two neonates had recurrence of seizures on rewarming. Spectral power analysis of fifteen artifact-free consecutive ictal events demonstrated, in all neonates, a significant increase in overall spectral power from the interictal to preictal and ictal periods ( p

Background: Sturge Weber Syndrome (SWS) patients at risk of epilepsy are often not identified before their first seizure which leads to unnecessary follow up of many patients with facial angioma. Methods: The medical photography database of our institution has been reviewed to identify SWS patients followed between 1993 and 2013. Patients with isolated glaucoma were compared to patients with epilepsy regarding the location of the facial angioma, the presence of asymmetrical background activity on EEG done prior epilepsy onset and cerebral imaging. Logistical regression tests and a p-value of 0.05 were used. Results: 21 patients with SWS have been identified. No significant difference was noted when patients were compared based on the laterality of the lesion (p=0.169), or the location of the facial angioma (p = 0.314 to 0.999). Only 2 epileptic patients had digital EEG done prior the onset of epilepsy and only 2 patients with glaucoma had digital EEG done during their follow up. No significant difference was noted between EEG background activities in the two groups (p= 0.514). The presence of venous drainage anomalies (VDA) predicted (p = 0.004) the onset of epilepsy. Conclusions: Cerebral VDA increases the risk of epilepsy in SWS patients. Since they can be detected at birth, they might guide the management.

Background Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome that can present with many disabling neurological disorders, the most common being epilepsy. Although it is a chronic multi-system disease, healthcare utilization and long-term outcome of subjects with TSC are not yet well defined. The goal of this study was to evaluate the direct cost and long-term outcome of TSC in the province of Quebec, compared to other forms of epilepsy and healthy controls. Methods Our provincial health care database was interrogated to determine use of medical services by patients with TSC, epilepsy and healthy controls from 1996 to 2011. Data on demographics, outcomes and health care utilization were analyzed. Results 1004 TSC, 41,934 with epilepsy and 41,934 controls were identified. The prevalence of TSC was 1/7872 compared to 1/189 for epilepsy. TSC experienced more hospitalizations, medical visits and prescription drug use. Their most common admission diagnosis was seizures and age at death was significantly lower: 61.3 years old for TSC vs 69.6 and 76.6 years old for epilepsy and controls ( p 0.001 ). Conclusions TSC subjects have a significantly higher burden of disease than other subjects with epilepsy. These results stress the need for specialized services in this population through the lifespan.

The purpose of this study was to characterize the epileptogenicity of tubers and surrounding cortex in patients with tuberous sclerosis complex (TSC). Three pediatric patients with TSC and intractable epilepsy underwent surgical resection of tubers associated with epileptogenic foci. In all patients, presurgical imaging revealed a prominent tuber that correlated on electroencephalography (EEG) with frequent interictal epileptiform discharges and electrographic seizures. Intracranial electrocorticography (ECoG) was performed using subdural grids placed over the tuber and surrounding cortex and depth electrodes positioned directly within the tuber. In all three patients, the depth electrode within the tuber was electrographically silent, whereas the surrounding cortical tissue showed significant epileptiform activity. The tuber and the electrically active adjacent cortex were resected. The patients experienced a drastic reduction in seizure frequency postsurgery. Epileptogenicity of cortical tubers may derive not from the lesion itself, but rather from the perturbation or abnormal development of the surrounding cortex.

Background: Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome that can present with many disabling neurological symptoms, the most common being seizures. Although it is a chronic systemic syndrome, healthcare utilization and long-term outcome of subjects with TSC are not well defined. The goal of this study was to evaluate the direct cost and long-term outcome of TSC compared to other forms of epilepsy and healthy controls. Methods: Our provincial health care database was interrogated to determine use of medical services by patients with TSC, epilepsy and healthy controls from 1996-2011. Data on demographics, outcomes and health care utilization were analyzed. Results: 1004 TSC, 41,934 with epilepsy and 41,934 controls were identified. The prevalence of TSC was 1/7,872 compared to 1/189 for epilepsy. TSC experienced more hospitalizations, medical visits and prescription drug use, resulting in higher total health care costs. Their most common admission diagnosis was seizures and age at death was significantly lower: 61,3 years old for TSC vs 69,6 and 76,6 years old for epilepsy and controls, (pConclusions: TSC subjects have a significantly higher burden of disease than other subjects with epilepsy. These results stress the need for specialized services in this population through the lifespan.

Background: Debate persists in Canada about the cost and benefit of vagal nerve stimulation in patients with refractory epilepsy. The aim of our study was to evaluate the impact of a vagal nerve stimulator on the seizure frequency and the admission rate of children with refractory epilepsies over five years of follow-up. Methods: 52 patients were implanted between 2000-2013. Of these, 37 were followed at CHU Sainte-Justine and 21 kept seizure diaries. Seizure frequency was compared to the baseline at 6 months, 12 months, 24 months and 60 months of follow up using a multivariate ANOVA analysis. The hospitalization rate was calculated as the mean difference between the number of hospitalizations prior to and after the implantation. Results: Seizure frequency decreased by 58% at 6 months, by 61% at 12 months, by 53% at 24 months and by 63% at 60 months of follow up respectively compared to the baseline (pConclusion: In our population, vagal nerve stimulation has a sustained impact on seizure frequency and hospitalization rates. This supports previous data from our group and others on cost-effectiveness of the technique in children with refractory epilepsy.

This study defines the clinical characteristics and evolution of 16 epileptic children with hippocampal asymmetry (HA) without sclerosis on MRI. The association of a positive family history of epilepsy (11/16), low incidence of febrile seizures (2/16), and benign prognosis (seizure control in monotherapy in 11/16, mean follow-up = 4.3 years, range 1 to 10) suggest a different clinical presentation than patients with mesial temporal sclerosis. Genetic studies of these mostly French Canadian families should help confirm the existence of a distinct syndrome.