Intersecting kinematic encoding and readout of intention in autism.

Observers with autism spectrum disorders (ASDs) find it difficult to read intentions from movements. However, the computational bases of these difficulties are unknown. Do these difficulties reflect an intention readout deficit, or are they more likely rooted in kinematic (dis-)similarities between typical and ASD kinematics? We combined motion tracking, psychophysics, and computational analyses to uncover single-trial intention readout computations in typically developing (TD) children (n = 35) and children with ASD (n = 35) who observed actions performed by TD children and children with ASD. Average intention discrimination performance was above chance for TD observers but not for ASD observers. However, single-trial analysis showed that both TD and ASD observers read single-trial variations in movement kinematics. TD readers were better able to identify intention-informative kinematic features during observation of TD actions; conversely, ASD readers were better able to identify intention-informative features during observation of ASD actions. Crucially, while TD observers were generally able to extract the intention information encoded in movement kinematics, those with autism were unable to do so. These results extend existing conceptions of mind reading in ASD by suggesting that intention reading difficulties reflect both an interaction failure, rooted in kinematic dissimilarity between TD and ASD kinematics (at the level of feature identification), and an individual readout deficit (at the level of information extraction), accompanied by an overall reduced sensitivity of intention readout to single-trial variations in movement kinematics.

Critical-like Brain Dynamics in a Continuum from Second- to First-Order Phase Transition.

The classic brain criticality hypothesis postulates that the brain benefits from operating near a continuous second-order phase transition. Slow feedback regulation of neuronal activity could, however, lead to a discontinuous first-order transition and thereby bistable activity. Observations of bistability in awake brain activity have nonetheless remained scarce and its functional significance unclear. Moreover, there is no empirical evidence to support the hypothesis that the human brain could flexibly operate near either a first- or second-order phase transition despite such a continuum being common in models. Here, using computational modeling, we found bistable synchronization dynamics to emerge through elevated positive feedback and occur exclusively in a regimen of critical-like dynamics. We then assessed bistability in vivo with resting-state MEG in healthy adults (7 females, 11 males) and stereo-electroencephalography in epilepsy patients (28 females, 36 males). This analysis revealed that a large fraction of the neocortices exhibited varying degrees of bistability in neuronal oscillations from 3 to 200 Hz. In line with our modeling results, the neuronal bistability was positively correlated with classic assessment of brain criticality across narrow-band frequencies. Excessive bistability was predictive of epileptic pathophysiology in the patients, whereas moderate bistability was positively correlated with task performance in the healthy subjects. These empirical findings thus reveal the human brain as a one-of-a-kind complex system that exhibits critical-like dynamics in a continuum between continuous and discontinuous phase transitions.SIGNIFICANCE STATEMENT In the model, while synchrony per se was controlled by connectivity, increasing positive local feedback led to gradually emerging bistable synchrony with scale-free dynamics, suggesting a continuum between second- and first-order phase transitions in synchrony dynamics inside a critical-like regimen. In resting-state MEG and SEEG, bistability of ongoing neuronal oscillations was pervasive across brain areas and frequency bands and was observed only with concurring critical-like dynamics as the modeling predicted. As evidence for functional relevance, moderate bistability was positively correlated with executive functioning in the healthy subjects, and excessive bistability was associated with epileptic pathophysiology. These findings show that critical-like neuronal dynamics in vivo involves both continuous and discontinuous phase transitions in a frequency-, neuroanatomy-, and state-dependent manner.

Biallelic loss-of-function variants in CACHD1 cause a novel neurodevelopmental syndrome with facial dysmorphism and multisystem congenital abnormalities.

PURPOSE: We established the genetic etiology of a syndromic neurodevelopmental condition characterized by variable cognitive impairment, recognizable facial dysmorphism, and a constellation of extra-neurological manifestations. METHODS: We performed phenotypic characterization of 6 participants from 4 unrelated families presenting with a neurodevelopmental syndrome and used exome sequencing to investigate the underlying genetic cause. To probe relevance to the neurodevelopmental phenotype and craniofacial dysmorphism, we established two- and three-dimensional human stem cell-derived neural models and generated a stable cachd1 zebrafish mutant on a transgenic cartilage reporter line. RESULTS: Affected individuals showed mild cognitive impairment, dysmorphism featuring oculo-auriculo abnormalities, and developmental defects involving genitourinary and digestive tracts. Exome sequencing revealed biallelic putative loss-of-function variants in CACHD1 segregating with disease in all pedigrees. RNA sequencing in CACHD1-depleted neural progenitors revealed abnormal expression of genes with key roles in Wnt signaling, neurodevelopment, and organ morphogenesis. CACHD1 depletion in neural progenitors resulted in reduced percentages of post-mitotic neurons and enlargement of 3D neurospheres. Homozygous cachd1 mutant larvae showed mandibular patterning defects mimicking human facial dysmorphism. CONCLUSION: Our findings support the role of loss-of-function variants in CACHD1 as the cause of a rare neurodevelopmental syndrome with facial dysmorphism and multisystem abnormalities.

Neuronal synchrony and critical bistability: Mechanistic biomarkers for localizing the epileptogenic network.

OBJECTIVE: Postsurgical seizure freedom in drug-resistant epilepsy (DRE) patients varies from 30% to 80%, implying that in many cases the current approaches fail to fully map the epileptogenic zone (EZ). We aimed to advance a novel approach to better characterize epileptogenicity and investigate whether the EZ encompasses a broader epileptogenic network (EpiNet) beyond the seizure zone (SZ) that exhibits seizure activity. METHODS: We first used computational modeling to test putative complex systems-driven and systems neuroscience-driven mechanistic biomarkers for epileptogenicity. We then used these biomarkers to extract features from resting-state stereoelectroencephalograms recorded from DRE patients and trained supervised classifiers to localize the SZ against gold standard clinical localization. To further explore the prevalence of pathological features in an extended brain network outside of the clinically identified SZ, we also used unsupervised classification. RESULTS: Supervised SZ classification trained on individual features achieved accuracies of .6-.7 area under the receiver operating characteristic curve (AUC). Combining all criticality and synchrony features further improved the AUC to .85. Unsupervised classification discovered an EpiNet-like cluster of brain regions, in which 51% of brain regions were outside of the SZ. Brain regions in the EpiNet-like cluster engaged in interareal hypersynchrony and locally exhibited high-amplitude bistability and excessive inhibition, which was strikingly similar to the high seizure risk regime revealed by our computational modeling. SIGNIFICANCE: The finding that combining biomarkers improves SZ localization accuracy indicates that the novel mechanistic biomarkers for epileptogenicity employed here yield synergistic information. On the other hand, the discovery of SZ-like brain dynamics outside of the clinically defined SZ provides empirical evidence of an extended pathophysiological EpiNet.

Rapid eye movement sleep and epilepsy: exploring interactions and therapeutic prospects.

While research interest in the relationship between sleep and epilepsy is growing, it primarily centres on the effects of non-rapid eye movement (NREM) sleep in favouring seizures. Nonetheless, a noteworthy aspect is the observation that, in the lives of patients with epilepsy, REM sleep represents the moment with the least epileptic activity and the lowest probability of having a seizure. Studies demonstrate a suppressive effect of phasic REM sleep on interictal epileptiform discharges, potentially offering insights into epilepsy localisation and management. Furthermore, epilepsy impacts REM sleep, with successful treatment correlating with improved REM sleep quality. Novel therapeutic strategies aim to harness REM's anti-epileptic effects, including pharmacological approaches targeting orexinergic systems and neuromodulation techniques promoting cortical desynchronisation. These findings underscore the intricate relationship between REM sleep and epilepsy, highlighting avenues for further research and therapeutic innovation in epilepsy management.

Brain and spine malformations and neurodevelopmental disorders in a cohort of children with CAKUT.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) represent 20-30% of all birth defects and are often associated with extra-renal malformations. We investigated the frequency of brain/spine malformations and neurological features in children with CAKUT. METHODS: We reviewed the clinico-radiological and genetic data of 199 out of 1,165 children with CAKUT evaluated from 2006 to 2023 (99 males, mean age at MRI 6.4 years) who underwent brain and/or spine MRI. Patients were grouped according to the type of CAKUT (CAKUT-K involving the kidney and CAKUT-H involving the inferior urinary tract). Group comparisons were performed using χ2 and Fisher exact tests. RESULTS: Brain/spine malformations were observed in 101/199 subjects (50.7%), 8.6% (101/1165) of our CAKUT population, including midbrain-hindbrain anomalies (40/158, 25.3%), commissural malformations (36/158, 22.7%), malformation of cortical development (23/158, 14.5%), Chiari I anomaly (12/199, 6%), cranio-cervical junction malformations (12/199, 6%), vertebral defects (46/94, 48.9%), caudal regression syndrome (29/94, 30.8%), and other spinal dysraphisms (13/94, 13.8%). Brain/spine malformations were more frequent in the CAKUT-K group (62.4%, p < 0.001). Sixty-two subjects (62/199, 31.2%) had developmental delay/intellectual disability. Neurological examination was abnormal in 40/199 (20.1%). Seizures and/or electroencephalographic anomalies were reported in 28/199 (14%) and behavior problems in 19/199 subjects (9%). Developmental delay/intellectual disability was more frequent in kidney dysplasia (65.2%) and agenesis (40.7%) (p = 0.001). CONCLUSIONS: We report a relative high frequency of brain/spine malformations and neurodevelopmental disorders in children with CAKUT who underwent MRI examinations in a tertiary referral center, widening the spectrum of anomalies associated with this condition.

Local neurodynamics as a signature of cortical areas: new insights from sleep.

Sleep crucial for the animal survival is accompanied by huge changes in neuronal electrical activity over time, the neurodynamics. Here, drawing on intracranial stereo-electroencephalographic (sEEG) recordings from the Montreal Neurological Institute (MNI), we analyzed local neurodynamics in the waking state at rest and during the N2, N3, and rapid eye movement (REM) sleep phases. Higuchi fractal dimension (HFD)-a measure of signal complexity-was studied as a feature of the local neurodynamics of the primary motor (M1), somatosensory (S1), and auditory (A1) cortices. The key working hypothesis, that the relationships between local neurodynamics preserve in all sleep phases despite the neurodynamics complexity reduces in sleep compared with wakefulness, was supported by the results. In fact, while HFD awake > REM > N2 > N3 (P < 0.001 consistently), HFD in M1 > S1 > A1 in awake and all sleep stages (P < 0.05 consistently). Also power spectral density was studied for consistency with previous investigations. Meaningfully, we found a local specificity of neurodynamics, well quantified by the fractal dimension, expressed in wakefulness and during sleep. We reinforce the idea that neurodynamic may become a new criterion for cortical parcellation, prospectively improving the understanding and ability of compensatory interventions for behavioral disorders.

European expert guidance on management of sleep onset insomnia and melatonin use in typically developing children.

Sleeping problems are prevalent among children and adolescents, often leading to frequent consultations with pediatricians. While cognitive-behavioral therapy has shown effectiveness, especially in the short term, there is a lack of globally endorsed guidelines for the use of pharmaceuticals or over-the-counter remedies in managing sleep onset insomnia. An expert panel of pediatric sleep specialists and chronobiologists met in October 2023 to develop practical recommendations for pediatricians on the management of sleep onset insomnia in typically developing children. When sleep onset insomnia is present in otherwise healthy children, the management should follow a stepwise approach. Practical sleep hygiene indications and adaptive bedtime routine, followed by behavioral therapies, must be the first step. When these measures are not effective, low-dose melatonin, administered 30-60 min before bedtime, might be helpful in children over 2 years old. Melatonin use should be monitored by pediatricians to evaluate the efficacy as well as the presence of adverse effects.    Conclusion: Low-dose melatonin is a useful strategy for managing sleep onset insomnia in healthy children who have not improved or have responded insufficiently to sleep hygiene and behavioral interventions.

Surgical treatment of cavernous malformation-related epilepsy in children: case series, systematic review, and meta-analysis.

OBJECTIVE: Cerebral cavernous malformations (CCMs) are cerebral vascular lesions that occasionally occur with seizures. We present a retrospective case series from IRCCS Gaslini Children's Hospital, a systematic review, and meta-analysis of the literature with the goal of elucidating the post-surgery seizure outcome in children with CCMs. METHODS: a retrospective review of children with cavernous malformation related epilepsy who underwent surgery at Gaslini Children's Hospital from 2005 to 2022 was conducted. We also conducted a comprehensive search on PubMed/MEDLINE and Scopus databases from January 1989 to August 2022. Inclusion criteria were: presence of CCMs-related epilepsy, in under 18 years old subjects with a clear lesion site. Presence of post-surgery seizure outcome and follow-up ≥ 12 months. RESULTS: we identified 30 manuscripts and 223 patients with CCMs-related epilepsy, including 17 patients reported in our series. We identified 85.7% Engel class I subjects. The risk of expected neurological deficits was 3.7%; that of unexpected neurological deficits 2.8%. We found no statistically significant correlations between Engel class and the following factors: site of lesion, type of seizure, drug resistance, duration of disease, type of surgery, presence of multiple CCMs. However, we found some interesting trends: longer disease duration and drug resistance seem to be more frequent in subjects in Engel class II, III and IV; multiple cavernomas would not seem to influence seizure outcome. CONCLUSIONS: epilepsy surgery in children with CCMs is a safe and successful treatment option. Further studies are necessary to define the impact of clinical features on seizure prognosis.

An in-vivo validation of ESI methods with focal sources.

Electrophysiological source imaging (ESI) aims at reconstructing the precise origin of brain activity from measurements of the electric field on the scalp. Across laboratories/research centers/hospitals, ESI is performed with different methods, partly due to the ill-posedness of the underlying mathematical problem. However, it is difficult to find systematic comparisons involving a wide variety of methods. Further, existing comparisons rarely take into account the variability of the results with respect to the input parameters. Finally, comparisons are typically performed using either synthetic data, or in-vivo data where the ground-truth is only roughly known. We use an in-vivo high-density EEG dataset recorded during intracranial single pulse electrical stimulation, in which the true sources are substantially dipolar and their locations are precisely known. We compare ten different ESI methods, using their implementation in the MNE-Python package: MNE, dSPM, LORETA, sLORETA, eLORETA, LCMV beamformers, irMxNE, Gamma Map, SESAME and dipole fitting. We perform comparisons under multiple choices of input parameters, to assess the accuracy of the best reconstruction, as well as the impact of such parameters on the localization performance. Best reconstructions often fall within 1 cm from the true source, with most accurate methods hitting an average localization error of 1.2 cm and outperforming least accurate ones erring by 2.5 cm. As expected, dipolar and sparsity-promoting methods tend to outperform distributed methods. For several distributed methods, the best regularization parameter turned out to be the one in principle associated with low SNR, despite the high SNR of the available dataset. Depth weighting played no role for two out of the six methods implementing it. Sensitivity to input parameters varied widely between methods. While one would expect high variability being associated with low localization error at the best solution, this is not always the case, with some methods producing highly variable results and high localization error, and other methods producing stable results with low localization error. In particular, recent dipolar and sparsity-promoting methods provide significantly better results than older distributed methods. As we repeated the tests with "conventional" (32 channels) and dense (64, 128, 256 channels) EEG recordings, we observed little impact of the number of channels on localization accuracy; however, for distributed methods denser montages provide smaller spatial dispersion. Overall findings confirm that EEG is a reliable technique for localization of point sources and therefore reinforce the importance that ESI may have in the clinical context, especially when applied to identify the surgical target in potential candidates for epilepsy surgery.

Ketamine as advanced second-line treatment in benzodiazepine-refractory convulsive status epilepticus in children.

Status epilepticus (SE) is one of the most common neurological emergencies in children. To date, there is no definitive evidence to guide treatment of SE refractory to benzodiazepines. The main objectives of treatment protocols are to expedite therapeutic decisions and to use fast- and short-acting medications without significant adverse effects. Protocols differ among institutions, and most frequently valproate, phenytoin, and levetiracetam are used as second-line treatment. After failure of first- and second-line medications, admission to the intensive care unit and continuous infusion of anesthetics are usually indicated. Ketamine is a noncompetitive N-methyl-D-aspartate receptor antagonist that has been safely used for the treatment of refractory SE in adults and children. In animal models of SE, ketamine demonstrated antiepileptic and neuroprotective properties and synergistic effects with other antiseizure medications. We reviewed the literature to demonstrate the potential role of ketamine as an advanced second-line agent in the treatment of SE. Pharmacological targets, pathophysiology of SE, and the receptor trafficking hypothesis are reviewed and presented. The pharmacology of ketamine is outlined with related properties, advantages, and side effects. We summarize the most recent and relevant publications on experimental and clinical studies on ketamine in SE. Key expert opinion is also reported. Considering the current knowledge on SE pathophysiology, early sequential polytherapy should include ketamine for its wide range of positive assets. Future research and clinical trials on SE pharmacotherapy should focus on the role of ketamine as second-line medication.

Automatic video analysis and classification of sleep-related hypermotor seizures and disorders of arousal.

OBJECTIVE: Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy with seizures occurring mostly during sleep. SHE seizures present different motor characteristics ranging from dystonic posturing to hyperkinetic motor patterns, sometimes associated with affective symptoms and complex behaviors. Disorders of arousal (DOA) are sleep disorders with paroxysmal episodes that may present analogies with SHE seizures. Accurate interpretation of the different SHE patterns and their differentiation from DOA manifestations can be difficult and expensive, and can require highly skilled personnel not always available. Furthermore, it is operator dependent. METHODS: Common techniques for human motion analysis, such as wearable sensors (e.g., accelerometers) and motion capture systems, have been considered to overcome these problems. Unfortunately, these systems are cumbersome and they require trained personnel for marker and sensor positioning, limiting their use in the epilepsy domain. To overcome these problems, recently significant effort has been spent in studying automatic methods based on video analysis for the characterization of human motion. Systems based on computer vision and deep learning have been exploited in many fields, but epilepsy has received limited attention. RESULTS: In this paper, we present a pipeline composed of a set of three-dimensional convolutional neural networks that, starting from video recordings, reached an overall accuracy of 80% in the classification of different SHE semiology patterns and DOA. SIGNIFICANCE: The preliminary results obtained in this study highlight that our deep learning pipeline could be used by physicians as a tool to support them in the differential diagnosis of the different patterns of SHE and DOA, and encourage further investigation.

Genuine cross-frequency coupling networks in human resting-state electrophysiological recordings.

Phase synchronization of neuronal oscillations in specific frequency bands coordinates anatomically distributed neuronal processing and communication. Typically, oscillations and synchronization take place concurrently in many distinct frequencies, which serve separate computational roles in cognitive functions. While within-frequency phase synchronization has been studied extensively, less is known about the mechanisms that govern neuronal processing distributed across frequencies and brain regions. Such integration of processing between frequencies could be achieved via cross-frequency coupling (CFC), either by phase-amplitude coupling (PAC) or by n:m-cross-frequency phase synchrony (CFS). So far, studies have mostly focused on local CFC in individual brain regions, whereas the presence and functional organization of CFC between brain areas have remained largely unknown. We posit that interareal CFC may be essential for large-scale coordination of neuronal activity and investigate here whether genuine CFC networks are present in human resting-state (RS) brain activity. To assess the functional organization of CFC networks, we identified brain-wide CFC networks at mesoscale resolution from stereoelectroencephalography (SEEG) and at macroscale resolution from source-reconstructed magnetoencephalography (MEG) data. We developed a novel, to our knowledge, graph-theoretical method to distinguish genuine CFC from spurious CFC that may arise from nonsinusoidal signals ubiquitous in neuronal activity. We show that genuine interareal CFC is present in human RS activity in both SEEG and MEG data. Both CFS and PAC networks coupled theta and alpha oscillations with higher frequencies in large-scale networks connecting anterior and posterior brain regions. CFS and PAC networks had distinct spectral patterns and opposing distribution of low- and high-frequency network hubs, implying that they constitute distinct CFC mechanisms. The strength of CFS networks was also predictive of cognitive performance in a separate neuropsychological assessment. In conclusion, these results provide evidence for interareal CFS and PAC being 2 distinct mechanisms for coupling oscillations across frequencies in large-scale brain networks.

Current models of insomnia disorder: a theoretical review on the potential role of the orexinergic pathway with implications for insomnia treatment.

Insomnia disorder is considered as a stress-related disorder associated with hyperarousal, stress and emotion dysregulation and the instability of the 'flip-flop' switch system. The orexinergic system is well known for its key role in sleep and arousal processes but also in the allostatic system regulating stress and emotions and may thus be of major interest for insomnia and its treatment. Accordingly, we discuss the potential role of orexins on sleep processes, brain systems modulating stress and emotions with potential implications for insomnia pathophysiology. We reviewed available data on the effect of dual orexin receptor antagonists (DORAs) on sleep and brain systems modulating stress/emotions with implications for insomnia treatment. We present our findings as a narrative review. Few data in animals and humans have reported that disrupted sleep and insomnia may be related to the overactivation of orexinergic system, while some more consistent data in humans and animals reported the overactivation of orexins in response to acute stress and in stress-related disorders. Taken together these findings may let us hypothesise that an orexins overactivation may be associated with stress-related hyperarousal and the hyperactivation of arousal-promoting systems in insomnia. On the other hand, it is possible that by rebalancing orexins with DORAs we may regulate both sleep and allostatic systems, in turn, contributing to a 'switch off' of hyperarousal in insomnia. Nevertheless, more studies are needed to clarify the role of the orexin system in insomnia and to evaluate the effects of DORAs on sleep, stress and emotions regulating systems.

The effects of ketogenic dietary therapies on sleep: A scoping review.

Sleep problems are common in neurological conditions for which ketogenic dietary therapies (KDTs) are recognised as an effective intervention (drug-resistant epilepsy, autism spectrum disorder, and migraine). Given the composite framework of action of ketogenic dietary therapies, the prevalence of sleep disturbance, and the importance of sleep regulation, the present scoping review aimed at identifying and mapping available evidence of the effects of ketogenic dietary therapies on sleep. A comprehensive web-based literature search was performed retrieving publications published to June 2023 using PubMed and Scopus, yielding to 277 records. Twenty papers were finally selected and included in the review. Data were abstracted by independent coders. High variability was identified in study design and sleep outcome evaluation among the selected studies. Several changes in sleep quality and sleep structure under ketogenic dietary therapies were found, namely an improvement of overall sleep quality, improvement in the difficulty falling asleep and nighttime awakenings, improvement in daytime sleepiness and an increase of REM sleep. The relevance and possible physiological explanations of these changes, clinical recommendations, and future directions in the field are discussed.

Supratentorial Demyelinating Lesions Following Severe Acute Respiratory Syndrome Coronavirus-2 Infection: A Pediatric Case Report.

INTRODUCTION: Most coronavirus disease 2019 (COVID-19) pediatric patients are asymptomatic; however, several neurological manifestations associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have been reported. Demyelinating events such as acute disseminated encephalomyelitis have been recently included among potential complications of COVID-19. CASE REPORT: We describe the case of a 12-year-old boy who developed central nervous system demyelinating lesions following SARS-CoV-2 infection. Two months prior he had been diagnosed with panuveitis but was otherwise healthy. Three weeks after testing positive for SARS-CoV-2, he started to complain of right temporal headache associated with right orbital pain without vision impairment. Brain magnetic resonance imaging showed large leukodystrophy-like demyelinating lesions. Standard electroencephalogram revealed a slow activity on the right hemisphere. His clinical and electroencephalographic course was favorable, with a good response to corticosteroid therapy and infusions of intravenous immunoglobulins. Delayed but complete resolution of brain lesions was noted on imaging. CONCLUSION: Our case contributes to broaden the knowledge regarding the spectrum of possible complications of SARS-CoV-2 infection. The relative lack of clinical manifestations in our patient can be seen as a warning not to underestimate even mild neurological symptoms correlated with COVID-19.

Electroclinical Features of Epilepsy in Kleefstra Syndrome.

BACKGROUND: Kleefstra syndrome (KS) or 9q34.3 microdeletion syndrome (OMIM #610253) is a rare genetic condition featuring intellectual disability, hypotonia, and dysmorphic facial features. Autism spectrum disorder, severe language impairment, and sleep disorders have also been described. The syndrome can be either caused by a microdeletion in 9q34.3 or by pathogenic variants in the euchromatin histone methyltransferase 1 gene (EHMT1, *607001). Although epilepsy has been reported in 20 to 30% of subjects, a detailed description of epileptic features and underlying etiology is still lacking. The purpose of this study is to investigate epilepsy features in a cohort of epileptic patients with KS. METHODS: This multicenter study investigated eight patients with KS and epilepsy. Our findings were compared with literature data. RESULTS: We included five patients with 9q or 9q34.33 deletions, a subject with a complex translocation involving EHMT1, and two with pathogenic EHMT1 variants. All patients presented with moderate to severe developmental delay, language impairment, microcephaly, and infantile hypotonia. Although the epileptic manifestations were heterogeneous, most patients experienced focal seizures. The seizure frequency differs according to the age of epilepsy onset, with patients with early-onset epilepsy (before 36 months of age) presenting more frequent seizures. An overtime reduction in seizure frequency, as well as in antiseizure drug number, was observed in all patients. Developmental delay degree did not correlate with seizure onset and frequency or drug resistance. CONCLUSION: Epilepsy is a frequent finding in KS, but the underlying pathogenetic mechanism and specific features remain elusive.

Influence of isolated low-grade intracranial haemorrhages on the neurodevelopmental outcome of infants born very low birthweight.

AIM: To determine whether isolated low-grade germinal matrix-intraventricular haemorrhages (LG-GMH-IVH) and low-grade punctate cerebellar haemorrhages (LG-CBH) contribute to the neurodevelopment of infants born preterm with very low birthweight (VLBW). METHOD: A prospective observational cohort study was conducted on infants born with VLBW hospitalized from January 2012 to July 2017 who had undergone serial cranial ultrasounds since birth and magnetic resonance susceptibility-weighted imaging of the brain at term-corrected age. Only those with VLBW carrying isolated LG-GMH-IVH (grades 1 or 2) or isolated LG-CBH (punctate cerebellar haemorrhages ≤4 mm in diameter) or absence of lesions (no-lesion) were enrolled and followed up to 3 years. The Griffiths Mental Development Scales, Extended and Revised version (GMDS-ER), were used to assess neurodevelopment, considering unsatisfactory scores less than 85. Behaviour, according to the criteria of the International Classification of Diseases, 10th Revision, and rehabilitation data were noted. RESULTS: Two-hundred and forty infants with VLBW were enrolled: 34 with LG-GMH-IVH, 17 with LG-CBH, and 189 as no-lesion. The LG-GMH-IVH and LG-CBH groups scored worse than the no-lesion group on all GMDS-ER scores for 1 year, 2 years, and 3 years. The LG-CBH group scored lower than the LG-GMH-IVH group for total GMDS-ER scores at 1 year and 2 years but not at 3 years. At 3 years, compared with the LG-CBH group, those with LG-GMH-IVH received less and later physical therapy, with more frequent attention problems. The odds ratio for unsatisfactory GMDS-ER scores corrected for gestational age was 5.75 for LG-CBH (95% confidence interval 1.92-17.25; p = 0.002) and 2.67 for LG-GMH-IVH (95% confidence interval 1.16-6.13; p = 0.02). INTERPRETATION: Low-grade haemorrhages affect the neurodevelopment of very-low-birthweight infants. Early rehabilitation might have contributed to their development.

Sleep and epilepsy: A snapshot of knowledge and future research lines.

Sleep and epilepsy have a reciprocal relationship, and have been recognized as bedfellows since antiquity. However, research on this topic has made a big step forward only in recent years. In this narrative review we summarize the most stimulating discoveries and insights reached by the "European school." In particular, different aspects concerning the sleep-epilepsy interactions are analysed: (a) the effects of sleep on epilepsy; (b) the effects of epilepsy on sleep structure; (c) the relationship between epilepsy, sleep and epileptogenesis; (d) the impact of epileptic activity during sleep on cognition; (e) the relationship between epilepsy and the circadian rhythm; (f) the history and features of sleep hypermotor epilepsy and its differential diagnosis; (g) the relationship between epilepsy and sleep disorders.

Alternating Hemiplegia of Childhood in a Child Harboring a Novel TBC1D24 Mutation: Case Report and Literature Review.

Alternating Hemiplegia of Childhood (AHC) is a rare neurological disease characterized by early-onset recurrent paroxysmal events and persistent neurological deficits. TBC1D24 gene variants have been associated with a phenotypic spectrum having epilepsy as the main clinical manifestation. Herein, we report the case of a child affected by developmental delay, polymorphic seizures, and nonepileptic episodes characterized by hemiplegia or bilateral plegia, pallor, hypotonia, and dystonic postures without loss of consciousness that resolved with sleep. Noteworthy, the patient fulfills all the diagnostic criteria for AHC. An epilepsy gene panel revealed a novel TBC1D24 mutation. This variant may be considered a PM5, according to the American College of Medical Genetics and Genomics guidelines. TBC1D24 gene variants are associated with various clinical features, and increasing data confirms the association with permanent and paroxysmal movement disorders. Our report suggests that the TBC1D24 molecular analysis could be considered in the diagnostic workup of AHC patients.