Altered spread of waves of activities at large scale is influenced by cortical thickness organization in temporal lobe epilepsy: a magnetic resonance imaging-high-density electroencephalography study.

Temporal lobe epilepsy is a brain network disorder characterized by alterations at both the structural and the functional levels. It remains unclear how structure and function are related and whether this has any clinical relevance. In the present work, we adopted a novel methodological approach investigating how network structural features influence the large-scale dynamics. The functional network was defined by the spatio-temporal spreading of aperiodic bursts of activations (neuronal avalanches), as observed utilizing high-density electroencephalography in patients with temporal lobe epilepsy. The structural network was modelled as the region-based thickness covariance. Loosely speaking, we quantified the similarity of the cortical thickness of any two brain regions, both across groups and at the individual level, the latter utilizing a novel approach to define the subject-wise structural covariance network. In order to compare the structural and functional networks (at the nodal level), we studied the correlation between the probability that a wave of activity would propagate from a source to a target region and the similarity of the source region thickness as compared with other target brain regions. Building on the recent evidence that large-waves of activities pathologically spread through the epileptogenic network in temporal lobe epilepsy, also during resting state, we hypothesize that the structural cortical organization might influence such altered spatio-temporal dynamics. We observed a stable cluster of structure-function correlation in the bilateral limbic areas across subjects, highlighting group-specific features for left, right and bilateral temporal epilepsy. The involvement of contralateral areas was observed in unilateral temporal lobe epilepsy. We showed that in temporal lobe epilepsy, alterations of structural and functional networks pair in the regions where seizures propagate and are linked to disease severity. In this study, we leveraged on a well-defined model of neurological disease and pushed forward personalization approaches potentially useful in clinical practice. Finally, the methods developed here could be exploited to investigate the relationship between structure-function networks at subject level in other neurological conditions.

Electroencephalographic microstates as a potential neurophysiological marker differentiating bilateral from unilateral temporal lobe epilepsy.

OBJECTIVE: Electroencephalographic (EEG) microstate abnormalities have been documented in different neurological disorders. We aimed to assess whether EEG microstates are altered also in patients with temporal epilepsy (TLE) and whether they show different activations in patients with unilateral TLE (UTLE) and bilateral TLE (BTLE). METHODS: Nineteen patients with UTLE, 12 with BTLE, and 15 healthy controls were enrolled. Resting state high-density electroencephalography (128 channels) was recorded for 15 min with closed eyes. We obtained a set of stable scalp maps representing the EEG activity, named microstates, from which we acquired the following variables: global explained variance (GEV), mean duration (MD), time coverage (TC), and frequency of occurrence (FO). Two-way repeated measures analysis of variance was used to compare groups, and Spearman correlation was performed to study the maps in association with the clinical and neuropsychological data. RESULTS: Patients with BTLE and UTLE showed differences in most of the parameters (GEV, MD, TC, FO) of the four microstate maps (A-D) compared to controls. Patients with BTLE showed a significant increase in all parameters for the microstates in Map-A and a decrease in Map-D compared to UTLE and controls. We observed a correlation between Map-A, disease duration, and spatial short-term memory, whereas microstate Map-D was correlated with the global intelligence score and short-term memory performance. SIGNIFICANCE: A global alteration of the neural dynamics was observed in patients with TLE compared to controls. A different pattern of EEG microstate abnormalities was identified in BTLE compared to UTLE, which might represent a distinctive biomarker.

Sequestration of translation initiation factors in p62 condensates.

Selective autophagy mediates the removal of harmful material from the cytoplasm. This cargo material is selected by cargo receptors, which orchestrate its sequestration within double-membrane autophagosomes and subsequent lysosomal degradation. The cargo receptor p62/SQSTM1 is present in cytoplasmic condensates, and a fraction of them are constantly delivered into lysosomes. However, the molecular composition of the p62 condensates is incompletely understood. To obtain insights into their composition, we develop a method to isolate these condensates and find that p62 condensates are enriched in components of the translation machinery. Furthermore, p62 interacts with translation initiation factors, and eukaryotic initiation factor 2α (eIF2α) and eIF4E are degraded by autophagy in a p62-dependent manner. Thus, p62-mediated autophagy may in part be linked to down-regulation of translation initiation. The p62 condensate isolation protocol developed here may facilitate the study of their contribution to cellular quality control and their roles in health and disease.

Neuropsychological Functioning in Bilateral versus Unilateral Temporal Lobe Epilepsy.

Although relatively specific anatomo-electro-clinical features of temporal lobe epilepsy (TLE) with bilateral ictal involvement (bitemporal epilepsy-BTLE) have been described, differentiating between BTLE and unilateral TLE (UTLE) remains challenging. Surgery is often the treatment of choice for drug-resistant UTLE, whereas its use is more controversial in BTLE. It is currently unclear whether neuropsychological assessment can contribute to the differential diagnosis. We retrospectively reviewed the neuropsychological evaluation of 46 consecutive patients with refractory TLE. Eighteen patients were diagnosed with BTLE on the basis of ictal electro-clinical data, in particular a video EEG recording of at least one seizure simultaneously involving the two temporal lobes without the possibility of lateralizing its onset or at least two different seizures independently arising from the two temporal lobes. Twenty-eight patients were classified as UTLE. Presurgery evaluation data were used in this study. Compared with UTLE, BTLE was associated with a lower intelligence quotient (IQ) and more severe impairment in long-term memory, the latter remaining significant even after controlling for IQ. No significant differences were found between right and left UTLE. In conclusion, BTLE and UTLE are associated with relatively distinct neuropsychological profiles, further supporting their classification as different disorders within the TLE spectrum.

The VEGA Tool to Check the Applicability Domain Gives Greater Confidence in the Prediction of In Silico Models.

A sound assessment of in silico models and their applicability domain can support the use of new approach methodologies (NAMs) in chemical risk assessment and requires increasing the users' confidence in this approach. Several approaches have been proposed to evaluate the applicability domain of such models, but their prediction power still needs a thorough assessment. In this context, the VEGA tool capable of assessing the applicability domain of in silico models is examined for a range of toxicological endpoints. The VEGA tool evaluates chemical structures and other features related to the predicted endpoints and is efficient in measuring applicability domain, enabling the user to identify less accurate predictions. This is demonstrated with many models addressing different endpoints, towards toxicity of relevance to human health, ecotoxicological endpoints, environmental fate, physicochemical and toxicokinetic properties, for both regression models and classifiers.

Toxicology of 3-monochloropropane-1,2-diol and its esters: a narrative review.

3-Monochloropropane-1,2-diol (3-MCPD) is a chiral molecule naturally existing as a racemic mixture of (R)- and (S)-enantiomers. It was thoroughly investigated during the 1970s as a male antifertility drug until research was abandoned because of the side effects observed in toxicity studies. More than 20 years later, 3-MCPD, both in the free form and esterified to the fatty acids, was detected in vegetable oil and discovered to be a widespread contaminant in different processed foods. This review summarises the main toxicological studies on 3-MCPD and its esters. Current knowledge shows that the kidney and reproductive system are the primary targets of 3-MCPD toxicity, followed by neurological and immune systems. Despite uncertainties, in vivo studies suggest that renal and reproductive toxicity is mediated by toxic metabolites, leading to inhibition of glycolysis and energy depletion. Few acute, short-term, and subchronic toxicity studies have investigated the 3-MCPD esters. The pattern of toxicity was similar to that of free 3-MCPD. Some evidence suggests that the toxicity of 3-MCPD diesters may be milder than 3-MCPD, likely because of an incomplete enzymatic hydrolysis in the equivalent free form in the gastrointestinal tract. Further research to clarify absorption, metabolism, and long-term toxicity of 3-MCPD esters would be pivotal to improve the risk assessment of these compounds via food.

Altered spreading of neuronal avalanches in temporal lobe epilepsy relates to cognitive performance: A resting-state hdEEG study.

OBJECTIVE: Large aperiodic bursts of activations named neuronal avalanches have been used to characterize whole-brain activity, as their presence typically relates to optimal dynamics. Epilepsy is characterized by alterations in large-scale brain network dynamics. Here we exploited neuronal avalanches to characterize differences in electroencephalography (EEG) basal activity, free from seizures and/or interictal spikes, between patients with temporal lobe epilepsy (TLE) and matched controls. METHOD: We defined neuronal avalanches as starting when the z-scored source-reconstructed EEG signals crossed a specific threshold in any region and ending when all regions returned to baseline. This technique avoids data manipulation or assumptions of signal stationarity, focusing on the aperiodic, scale-free components of the signals. We computed individual avalanche transition matrices to track the probability of avalanche spreading across any two regions, compared them between patients and controls, and related them to memory performance in patients. RESULTS: We observed a robust topography of significant edges clustering in regions functionally and structurally relevant for the TLE, such as the entorhinal cortex, the inferior parietal and fusiform area, the inferior temporal gyrus, and the anterior cingulate cortex. We detected a significant correlation between the centrality of the entorhinal cortex in the transition matrix and the long-term memory performance (delay recall Rey-Osterrieth Complex Figure Test). SIGNIFICANCE: Our results show that the propagation patterns of large-scale neuronal avalanches are altered in TLE during the resting state, suggesting a potential diagnostic application in epilepsy. Furthermore, the relationship between specific patterns of propagation and memory performance support the neurophysiological relevance of neuronal avalanches.

Brivaracetam add-on treatment in pediatric patients with severe drug-resistant epilepsy: Italian real-world evidence.

PURPOSE: To report the efficacy and tolerability of brivaracetam (BRV) in add-on therapy in pediatric patients with severe drug-resistant epilepsy. Prognostic factors of clinical outcome were also analyzed. METHODS: This Italian multicenter retrospective observational study was conducted on 45 pediatric patients with severe drug-resistant epilepsy, treated with BRV for at least 1 month and with a follow-up >6 months. Demographic, clinical, and treatment variables were assessed at T0 (baseline, BRV introduction) and T1 (6 months after BRV introduction). The response was defined as ≥50% seizure frequency reduction; responders and non-responders were then compared to assess potential prognostic factors. RESULTS: Forty-five patients (M = 28, mean age 12.4+/-4.4 years) were enrolled (focal epilepsy=14; generalized epilepsy=2; epileptic encephalopathy=29). At T1, 19/45 patients (42.2%) were responders (≥50% seizure frequency reduction), with 4 patients (8.9%) achieving a ≥ 75% seizure reduction and 2 patients (4.4%) becoming seizure free. Epilepsy onset at >12 months of age (p = 0.001), disease duration ≤6 years (p = 0.036), and lower seizure frequency at baseline (p = 0.008) were the prognostic factors significantly associated with a better prognosis. No significant difference emerged for demographics, epilepsy types/etiology, intellectual disability, or therapy variables. At T1, 21 patients (46.6%) discontinued BRV, mainly due to lack of efficacy (13 subjects; 28.9%) and adverse events in 8 patients (17.8%). CONCLUSION: Brivaracetam was an effective and tolerated treatment in pediatric patients with severe drug-resistant epilepsy, especially when the seizure onset was at >12 months of age, the epilepsy duration ≤6 years, and the seizure frequency before BRV treatment was low. Further and controlled studies are needed.

Resting state network dynamic reconfiguration and neuropsychological functioning in temporal lobe epilepsy: An HD-EEG investigation.

Temporal lobe epilepsy (TLE) is nowadays considered a network disorder impacting several cognitive domains. In this work we investigated dynamic network reconfiguration differences in patients with unilateral TLE compared to a healthy control group, focusing on two connectivity indices: flexibility and integration. We apply these indices for the first time to high-density EEG source-based functional connectivity. We observed that patients with TLE exhibited significantly lower flexibility than healthy controls in the Control, Default Mode and Attentive Dorsal networks, expressed in the delta, theta and alpha bands. In addition, patients with TLE displayed greater integration values across the majority of the resting state networks, especially in the delta, theta and gamma bands. Relevantly, a higher integration index in the Control, Attentive Dorsal and Visual networks in the delta band was correlated with lower performance in visual attention and executive functions. Moreover, a greater integration index in the gamma band of the Control, Somatomotor and Temporoparietal networks was related to lower long-term memory performance. These results suggest that patients with TLE display dysregulated network reconfiguration, with lower flexibility in the brain areas related to cognitive control and attention, together with excessive inter-network communication (integration index). Finally, the correlation between network integration and the reduced cognitive performance suggests a potential mechanism underlying specific alterations in neuropsychological profile of patients with TLE.

Ictal Electroencephalographic Characteristics of Nodding Syndrome: A Comparative Case-Series from South Sudan, Tanzania, and Uganda.

Nodding syndrome (NS) is a poorly understood form of childhood-onset epilepsy that is characterized by the pathognomonic ictal phenomenon of repetitive vertical head drops. To evaluate the underlying ictal neurophysiology, ictal EEG features were evaluated in nine participants with confirmed NS from South Sudan, Tanzania, and Uganda and ictal presence of high frequency gamma oscillations on scalp EEG were assessed. Ictal EEG during the head nodding episode predominantly showed generalized slow waves or sharp-and-slow wave complexes followed by electrodecrement. Augmentation of gamma activity (30-70 Hz) was seen during the head nodding episode in all the participants. We confirm that head nodding episodes in persons with NS from the three geographically distinct regions in sub-Saharan Africa share the common features of slow waves with electrodecrement and superimposed gamma activity. ANN NEUROL 2022;92:75-80.

Deep Brain Stimulation in childhood-onset dystonia due to brain pathology. A long-term study.

BACKGROUND: Pallidal Deep Brain Stimulation (DBS) is an established treatment option for isolated, inherited or idiopathic dystonia, however data on its safety and efficacy in other forms of dystonia are more limited. OBJECTIVES: Retrospective analysis of motor and non-motor outcomes in pediatric onset refractory dystonia due to static or progressive brain disorders in a cohort of patients with a DBS treatment duration ≥12 months. METHODS: Multidisciplinary assessments including standardised scales/tests of motor function, pain, quality of life, cognition and language were carried out before implantation and longitudinally afterwards. RESULTS: 9 patients were included, 7 had cerebral palsy. Mean age at implantation was 209 months ± 156, mean treatment duration 84 ± 37 months. DBS was well tolerated and positively affected both motor and non-motor functions. In particular, statistically significant improvements were documented in Burke-Fahn-Marsden Scale scores (- 19.9% p 0.01031) at 12 months and in long-term quality of life (+28.6%, p 0.0292). CONCLUSIONS: DBS may be a useful treatment option in generalized dystonia associated with brain pathology. Even when the motor benefits are limited, improvements in quality of life and non-motor functions, or the possible prevention of serious dystonia-related complications, may have a significant impact on overall clinical status.

Neuropsychological and behavioral profiles of self-limited epileptic syndromes of childhood: a cross-syndrome comparison.

Childhood epilepsy with centro-temporal spikes (CECTS), Childhood absence epilepsy (CAE) and Panayiotopoulos syndrome (PS) are some of the most common pediatric epileptic syndromes. Despite the relatively benign (self-limited) course of epilepsy, current evidence suggests that these conditions are associated with an increased risk of neuropsychological and behavioral comorbidities. This study provides a cross-epileptic syndromes' comparison reporting on the cognitive and behavioral profile of a cohort of 32 children with CECTS (n = 14), CAE (n = 10) and PS (n = 8), aged 6 to 15 years old. Frequent, although often subclinical cognitive difficulties involving attention, executive functions and academic abilities were found in children with CECTS and CAE, and to a lesser extent in PS. Internalizing symptoms (particularly anxiety) were more common in the PS group compared to CECTS and CAE based on parental reports. Correlational analysis revealed a significant correlation between phonemic fluency and seizure-free interval at the time of evaluation, suggesting a beneficial effect of epilepsy remission on this executive function measure in all the three groups. These results add to existing literature providing further detail on neuropsychological and behavioral peculiarities of children with CECTS, CAE, and PS. Moreover, the need for neuropsychological assessment as part of the standard childhood epilepsy evaluation is stressed. The results are discussed in the context of the current literature, highlighting areas of consensus and controversies related to the clinical management of these epileptic syndromes as well as directions for future research.

Epilepsy, electroclinical features, and long-term outcomes in Pitt-Hopkins syndrome due to pathogenic variants in the TCF4 gene.

BACKGROUND AND PURPOSE: Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by deletions/variants in the TCF4 gene. Seizures may be present in up to half of the patients, leading to a more severe disease burden. This study aims to analyse the electroclinical phenotype, treatment options, and long-term outcomes of epilepsy in PTHS. METHODS: A multicentre observational cohort study was performed, and the electroclinical data of PTHS individuals affected by epileptic seizures were retrospectively reviewed and analysed. RESULTS: The series includes 21 patients (11 female) with a median age at seizure onset of 2 years (range = 0.5-8). The median time of follow-up was 7.9 years (range = 2-27). Both generalized and focal epilepsies were present at the same prevalence (42.8%), whereas a minority of patients presented developmental and epileptic encephalopathies (14.4%). At the long-term follow-up, 42.8% achieved seizure freedom, whereas 42.8% developed drug-resistant epilepsy (DRE). The age at seizure onset was found to be an independent predictor for seizure outcome; in this regard, patients having seizure onset after the age of 2 years were more prone to achieve seizure freedom (odds ratio = 0.04, 95% confidence interval = 0.003-0.53; p = 0.01). During evolution, seizures tended to settle down, and even in patients with DRE, seizures tended to persist at a lower frequency and appeared to be more easily manageable over time. CONCLUSIONS: This study provides new insight into the natural history of epilepsy in PTHS. Better characterization of epileptic phenotype and prompt tailored treatment improve overall management and quality of life.

Brivaracetam in treating epileptic encephalopathy and refractory focal epilepsies in patients under 14 years of age.

OBJECTIVES: To analyze the efficacy and safety of Brivaracetam in pediatric patients with epileptic encephalopathy or unresponsive focal epilepsy. MATERIALS & METHODS: This retrospective study included eight pediatric patients with EE or unresponsive focal epilepsy. Inclusion criteria: (1) ≤14 years, (2) history of refractory epilepsy, (3) at least one month of continuous therapy with BRV, and (4) at least six months of follow-up. Exclusion criteria: (1) variation of concomitant antiepileptic drugs during the previous and/or subsequent four weeks of the BRV introduction, (2) levetiracetam in therapy, (3) epilepsy secondary to the progressive cerebral disease, tumor, or any other progressive neurodegenerative diseases, and (4) a status epilepticus a month before screening or during the baseline period. The efficacy of BRV was defined as ≥50% of seizure frequency reduction at the end of the follow-up, compared to baseline. RESULTS: All patients showed ≥50% seizure frequency reduction, of whom 37.5% were seizure-free, 25% had a frequency reduction of ≥75%, and 37.5% had frequency reduction of ≥ 50%. All patients with an epilepsy onset >12 months and epilepsy duration of ≤6 years were seizure-free. The maximum effect was achieved at 2 mg/kg/day, and focal seizures revealed a better response than epileptic encephalopathy. A remarkably positive effect of the Brivaracetam was noticed in patients with encephalopathy regarding the status epilepticus during sleep; however, no relevant side-effects were noted. CONCLUSION: Brivaracetam was an effective and well-tolerated treatment in pediatric patients with epileptic encephalopathy or unresponsive focal epilepsy, especially for the epilepsy onset >12 months and the epilepsy duration ≤6 years. The total effect was not dose-dependent. Brivaracetam could represent an indication of encephalopathy regarding the status epilepticus during sleep.

Developmental and epilepsy spectrum of Poirier-Bienvenu neurodevelopmental syndrome: Description of a new case study and review of the available literature.

AIM: To better characterize the clinical phenotype of Poirier-Bienvenu neurodevelopmental syndrome (OMIM ID: 618,732) due to pathogenic variants of the CSNK2B gene. METHOD: We reviewed the electro-clinical and developmental data of all 14 patients with de novo mutations of the CSNK2B gene reported in the literature and describe a further individual with a novel CSNK2B pathogenic variant. RESULTS: Clustered generalized tonic-clonic or myoclonic seizures with onset before the age of 18 months and delayed neurodevelopment were present in more than 75% of patients. Epilepsy was pharmaco-resistant in 40%. All the individuals (27%) with normal neurological development had pharmaco-sensitive epilepsy. The severity of cognitive and motor impairments was higher in the group with pharmaco-resistant epilepsy, and a statistically significant correlation between seizure control and the severity of cognitive impairment was documented (χ2(3) = 9.44; p = .024) INTERPRETATION: Early seizure onset, clustered seizures and delayed development in both males and females were early clinical markers in most patients with CSNK2B mutations. The entity of neurodevelopmental abnormalities was related to epilepsy severity. Prospective studies are required to better assess the relationship between epilepsy and developmental outcomes in this condition.

Investigation of dynamic functional connectivity of the source reconstructed epileptiform discharges in focal epilepsy: A graph theory approach.

OBJECTIVE: The aim of the present study is to investigate with noninvasive methods the modulation of dynamic functional connectivity during interictal epileptiform discharge (IED). METHOD: We reconstructed the cortical source of the EEG recorded IED of 17 patients with focal epilepsy. We then computed dynamic connectivity using the time resolved phase locking value (PLV). We derived graph theory indices (i.e. degree, strength, local efficiency, clustering coefficient and global efficiency). Finally, we selected the atlas node with the maximum activation as the IED cortical source investigating the graph indices dynamics in theta, alpha, beta and gamma frequency bands. RESULTS: We observed IED-locked modulations of the graph indexes depending on the frequency bands. We detected a modulation of the strength, clustering coefficient, local and global efficiency both in theta and in alpha bands, which also displayed modulations of the degree index. In the beta band only the global efficiency was modulated by the IED, while no effects were detected in the gamma band. Finally, we found a correlation between alpha and theta local efficiency, as well as alpha global efficiency, and the epilepsy duration. SIGNIFICANCE: Our findings suggest that the neural synchronization is not limited to the IED cortical source, but implies a phase synchronization across multiple brain areas. We hypothesize that the aberrant electrical activity originating from the IED locus is spread amongst the other network nodes throughout the low frequency bands (i.e. theta and alpha). Moreover, IED-dependent increase in the global efficiency indicates that the IED interfere with the whole network functioning. We finally discussed possible application of this methodology for future investigation.

Implicit cognitive flexibility in self-limited focal epilepsy of childhood: An HD-EEG study.

Self-limited focal epilepsy of childhood (SFEC) is often related to mild impairments in several neuropsychological domains, including cognitive flexibility, which is generally considered a process requiring volition and attention. However, recent evidence showed that it can be implicitly adjusted exploiting simple 'stimulus-response' associations as for example, the probability of the stimulus occurrence. Here, we evaluated the capability to implicitly extract environmental patterns of regularities and use them to flexibly adjust proactive control motor control. We tested 21 children with epilepsy (total IQ > 80; 13 with Childhood epilepsy with centro-temporal spikes, 8 with Panayiotopoulos syndrome (PS); 5-13 years old) compared to a healthy age-matched control group (32 participants). We used the Dynamic Temporal Prediction (DTP) task to investigate how behavioral performance is implicitly shaped by the manipulation of the stimulus occurrence probability over time. We recorded EEG to identify neural markers to differentiate the two groups. SFEC group showed a reduction in accuracy (p = .0013) and response speed (p < .001) as well as an absence of response adjustment (p = .65) in relation to the implicit changes in stimulus probability occurrence, in comparison to the control group. The epilepsy group performance in the DTP showed a significant correlation with the phonemic fluency (r = -0.50) and the Perseverations index of the CPT test (r = 0.53). Finally, children with SFEC did not show the modulation of the contingent negative variation (CNV) evoked potential. Overall, children with SFEC showed poor implicit flexibility compared to a control group. This pattern is individually related to high-level executive function, suggesting to extend neuropsychological assessment to the implicit domain.

Basal Ganglia Dysmorphism in Patients With Aicardi Syndrome.

OBJECTIVE: Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed. METHODS: Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed. RESULTS: Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported). CONCLUSION: The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes.

Strabismus surgery in Angelman syndrome: More than ocular alignment.

PURPOSE: To report and evaluate strabismus surgery in children with Angelman syndrome, in order to optimize and standardize surgical approach. Other purposes are to understand the possible relation between ocular findings and motor ability, and between improvement in ocular alignment and changes in motor skills in this population. DESIGN: Observational cross-sectional study. METHODS: Medical records of pediatric patients with Angelman syndrome, who underwent strabismus surgery, were investigated. Collected data included: genotype, gender, age at the time of surgery, refractive error, pre-operative strabismus, surgical procedure, surgical outcome, gross and fine motor development assessment pre- and post-operatively. RESULTS: Seventeen subjects, aged 3-15 years, were investigated. Fourteen patients were exotropic, three esotropic. Most patients presented astigmatism. Considering the exaggerated response to standard amounts of surgery and the risk of consecutive strabismus on long term follow-up reported by previous studies in children with developmental delay, a reduction of the amount of strabismus surgery was applied. Post-operatively, all patients presented with a significative reduction of the baseline deviation angle, with all esotropic patients and 7 exotropic patients (59%) achieving orthotropia. The surgical outcomes were variable according to the type and the amount of baseline strabismus, but no case presented with exaggerated surgical response. At baseline, patients showed important delays in all motor abilities, and, post-operatively, presented a significant improvement in walking and fine motor tasks. Pre- and post-operative motor abilities were negatively correlated to astigmatism, anisometropia, and amount of deviation. CONCLUSIONS: According to our data, the standard nomograms for strabismus surgery may be successfully applied in subjects with Angelman syndrome and exotropia. Our data suggest that the reduction of the deviation angle improves motor skills in strabismic pediatric patients with Angelman syndrome.

Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome.

OBJECTIVE: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. METHODS: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature. RESULTS: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. SIGNIFICANCE: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.