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Domenico Serino,1 Marta Elena Santarone,2 Davide Caputo,3 Lucia Fusco21Department of Child Neurology, Royal Aberdeen Children’s Hospital, Aberdeen, UK; 2Department of Neuroscience, Bambino Gesù Children’s Hospital, Rome, Italy; 3Neurology Unit, Neuroscience Department, San Paolo Hospital, Milan, ItalyAbstract: Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy with a yet undefined etiology, affecting healthy children. It is characterized by acute manifestation of recurrent seizures or refractory status epilepticus preceded by febrile illness, but without evidence of infectious encephalitis. To date, the absence of specific biomarkers poses a significant diagnostic challenge; nonetheless, early diagnosis is very important for optimal management. FIRES is mostly irreversible and its sequelae include drug-resistant epilepsy and neuropsychological impairments. The treatment of FIRES represents a significant challenge for clinicians and is associated with low success rates. Early introduction of ketogenic diet seems to represent the most effective and promising treatment. This review aims to highlight the most recent insights on clinical features, terminology, epidemiology, pathogenesis, diagnostic challenges and therapeutic options.Keywords: FIRES, NORSE, epilepsy syndromes, inflammatory epilepsies, status epilepticus, drug-resistance

Abstract: Background: The phenotypical consequence of the heterozygous chromosome 7q11.23 interstitial microdeletion is the Williams–Beuren syndrome, a very well‐known genetic multi‐systemic disorder. Much less is known about the reverse condition, the heterozygous interstitial microduplication of 7q11.23 region. The first molecular cytogenetic description was published in 2005, and only after several years were the reported patients numerous enough to attempt a description of a common phenotype. Method: By using a broad multidisciplinary approach, we investigated 12 patients with this rare genetic anomaly. Ten of them harboured the duplication of the classical Williams–Beuren syndrome region and two a slightly larger duplication. Upon a detailed description of the clinical and psychological features, we used electroencephalography and magnetic resonance imaging to explore neurophysiological function and brain structures. Results: We analysed the clinical, psychological, neuroradiological and neurophysiological features of 12 yet‐unpublished individuals affected by this rare genetic anomaly, focusing specifically on the last two aspects. Several structural abnormalities of the central nervous system were detected, like ventriculomegaly, hypotrophic cerebellum, hypotrophic corpus callosum and hypoplastic temporal lobes. Although only one of 12 individuals suffered from seizures during childhood, three others had abnormal electroencephalography findings prominent in the anterior brain regions, without any visible seizures to date. Conclusion: Taken together, we enlarged the yet‐underrepresented cohort in the literature of patients affected by 7q11.23 microduplication syndrome and shed further light on neuroradiological and neurophysiological aspects of this rare genetic syndrome. [ABSTRACT FROM AUTHOR]

Objective: We studied the electrographic features of tonic seizures (TS) with bilateral contraction and tonic-clonic seizures (TCS) without focal signs occurring during the first year of life to evaluate if there is a correlation with outcome., Methods: We retrospectively reviewed patients aged 1 to 12 months with at least one TS or TCS recorded with video-EEG between 2011 and 2021 in our Epilepsy Monitoring Unit. We analyzed the following electrographic features: seizure duration, presence and duration of focal ictal EEG onset, and post-ictal generalized EEG suppression (PGES). Among clinical variables, we collected age at epilepsy onset, age at TS and TCS recording, response to anti-seizure medications, genetic and neuroimaging findings, epileptic syndrome classification., Results: Overall, we recorded 2577 seizures in 1769 patients. One-hundred-twenty-eight seizures (5%) were clinically labeled either as TS or TCS in 41 patients (2%). Out of 41 patients, 17 (41%) presented with TS, and 24 (59%) with TCS. Thirteen patients (32%) had a Self-limited Epilepsy, and 28 (68%) a Developmental and Epileptic Encephalopathy (DEE). Seventy-two percent of genetically tested patients had pathogenic gene variants. None had structural epilepsy. Mean age at epilepsy onset was 4.48 months (range 3 days-12 months). Age at seizure onset was earlier in patients presenting with TS versus patients presenting with TCS (2.31 months vs. 6.01 months; p = 0.001) and in DEEs versus Self-limited Epilepsies (3.23 months vs. 7.16 months; p = 0.001). TS were exclusively present in DEEs (p = 0.001), and TCS were recorded in both DEEs and Self-limited Epilepsies. Focal ictal EEG onset was evident in 92 % of TCS, and in none of TS. Generalized ictal EEG onset was documented in 100 % of TS, and in 8 % of TCS. Focal ictal EEG onset occurred more frequently (100 % vs. 32 %; p = 0.000) and was significantly longer (30.61 s vs. 16.22 s; p = 0.020) in Self-limited Epilepsies versus DEEs. PGES was observed in 18 out of 41 (44 %) and was more frequent in Self-limited Epilepsies (p = 0.026)., Significance: This study provides insights into the electroclinical features of TS and TCS in infants that may help distinguish Self-limited Epilepsies from DEEs soon after epilepsy onset., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: In recent years, adjunctive therapies for epilepsy management are being explored due to considerable side effects carried by antiepileptic drugs (AEDs) and widespread reports of drug-resistant epilepsy. One such approach is non-invasive musical neurostimulation. Within this context, Mozart's sonata K448 has received particular attention following reports of reduced seizure frequency and a decrease in epileptiform discharges during and after music exposure; often described as the 'Mozart effect'. However, controversy exists around the effectiveness of K448 in epilepsy and the strength and quality of the evidence supporting it. Therefore, this study aims to systematically review the available literature around the Mozart effect, in both adult and paediatric cases of epilepsy., Methods: We carried out a literature search on PubMed, Science Direct, Scopus and Web of Science using the query string ALL= (Mozart AND epileps*). Selected clinical studies were classified based on the age of the population studied, as paediatric (0-18 years), adult (19 years or older) or a combination of the two. All the studies were evaluated using the Johns Hopkins Nursing Evidence-Based Practice (JHNEBP) rating scale to determine the strength of the evidence (level) and the quality of the research evidence., Results: Out of 538 records, 25 studies were selected, grouped based on the age of the population studied and evaluated using the JHNEBP rating scale. Ten level 1 studies, which represent the strongest evidence, were identified, including six RCTs and three meta-analyses. Nine of these ten studies show a decrease in epileptiform discharges and in seizure frequency following exposure to Mozart's K448. One multiverse analysis reported lack of statistically significant evidence to support the use of K448 in epilepsy or any other medical condition., Conclusions: A growing body of evidence supports the Mozart effect on epilepsy, with notable studies including RCTs and comprehensive meta-analyses. This review identified nine level 1 studies, conducted by research groups worldwide, which endorse the use of Mozart's music to reduce seizures and epileptiform discharges in adult and paediatric epilepsy patients. However, existing research exhibits limitations like varying protocols, small sample sizes and diverse treatment regimens. Additionally, studies that combine adult and paediatric patients fail to take account of developmental differences between these two groups - particularly with regards to brain maturation and neurophysiology - which could negatively impact upon the accuracy of findings by obscuring important age-related differences in response to intervention. Adequately addressing these limitations will be crucial to demonstrating proof of concept; otherwise, a potentially valuable, non-invasive, accessible, and affordable therapeutic option for drug-resistant epilepsy will remain on the medical fringe. Further research with larger samples and stricter protocols, particularly considering patient age and drug regimens, is required., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Super-refractory Status Epilepticus (SRSE) is a rare condition in which SE persists or recurs ≥24 h after the onset of anesthesia. Although its characteristics are well defined in adulthood, only few studies on children are available., Methods: we retrospectively analyzed the population of patients with SRSE aged <18 years treated in the Pediatric Intensive Care Unit of the Bambino Gesù Pediatric Hospital. We assessed clinical history, etiology, neuroimaging, electro-clinical features of SRSE, treatments and neurological status after SRSE cessation., Results: We identified 22 children with median age at SRSE onset of 3.1 years (IQR 1.3-7.3) and SRSE duration of 22.0 days (IQR 11.2-30.5) Before SRSE, 17 patients (77.3%) had an abnormal neurological examination, 18 (81.8%) had a diagnosis of epilepsy, 8 of which already presented an episode of SE. Only 4 patients (18.2%) had New Onset SRSE. Eleven patients had a progressive etiology (PE), 9 had a remote etiology (RE) and 2 patients had an acute etiology (AE). Amongst PE the most frequent etiologies were mitochondrial diseases, while among RE they were Developmental Epileptic Encephalopathies of genetic origin. Time to SRSE cessation was significantly longer in PE (p = 0.04). After SRSE, 8 patients, (7 with PE) showed a significant worsening of neurological status. In this group, mean time at SE cessation was significantly longer (p = 0.05)., Conclusions: pediatric SRSE is mostly associated with progressive diseases and remote etiologies. Underlying etiology seems to impact both on SRSE duration and subsequent neurological evolution, however more studies are needed to confirm these findings., (Copyright © 2022 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Epileptic Spasms (ES) is a type of seizure usually occurring in the context of a severe childhood epileptic syndrome associated to significant Electroencephalogram (EEG) abnormalities. There are three scenarios in which ES may occur. The first one is represented by West Syndrome (WS): ES occur in a previously non encephalopathic infant in association with the development of a hypsarrhythmic EEG pattern. In most cases, standard treatment with Adrenocorticotropic Hormone (ACTH), steroids or vigabatrin leads to a reversal of the electroclinical picture. The second scenario is represented by Developmental and Epileptic Encephalopathies (DEEs): ES are documented, often along other seizures types, in an infant who often shows developmental delay since birth; the EEG pattern is pathological both in wakefulness and in sleep, without typical features of hypsarrhythmia; therapies (with the exception of few potentially treatable syndromes) are poorly effective. The last scenario is represented by ES in the context of Focal Epilepsies (FEs): ES, sometimes showing focal signs or closely related to focal seizures, are associated with focal brain lesions. Treatment with ACTH, steroids or vigabatrin may not be effective as well as antiepileptic drugs for focal epilepsies. In drug-resistant patients, surgery should be considered. Although there are some gaps in our current scientific knowledge concerning the peculiar electroclinical and physiopathological features of ES, we nowadays possess the necessary tools to correctly frame this unique seizure type into one of these scenarios and therefore properly manage the diagnostic and therapeutic workup., Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: Increasing rates of illicit drug use during pregnancy may be associated with risk for long-term health problems in prenatally exposed children., Objective: To identify the associations of prenatal exposure to illicit drugs with organization of the newborn brain., Design, Setting, and Participants: For this cohort study, a volunteer sample of 210 illicit drug-using and nonusing mothers and their newborns was enrolled from prenatal clinics and drug abuse treatment programs in New York, New York. Enrollment, scanning, and long-term follow-up occurred from September 2004 through February 2012, and image processing and statistical analyses continued through fall 2018. In addition to 26 participants with incomplete data, a total of 64 mothers were lost to follow-up during pregnancy, and 13 newborns were lost to follow-up at birth because of perinatal complications., Exposures: Newborns were assigned to 1 of 4 primary exposure groups based on the history of most frequent maternal drug use: marijuana, cocaine, methadone maintenance, and/or heroin. Unexposed newborns were controls., Main Outcomes and Measures: Unsedated magnetic resonance imaging (MRI) of newborn brains was performed shortly after birth. Infant neurodevelopmental outcomes were assessed at age 12 months. MRI modalities included anatomical imaging, diffusion tensor imaging, T2 relaxometry, and magnetic resonance spectroscopic imaging. Infant neurodevelopmental outcomes included Bayley scales of infant development-III and Vineland Adaptive Behavior Scales. Statistical analyses were performed with results represented on the brain images., Results: Of 118 mothers, 42 (35%) were in the control group (mean [SD] age, 25.9 [6.1] years), 29 (25%) were in the cocaine group (mean [SD] age, 29.0 [6.1] years), 29 (25%) were in the marijuana group (mean [SD] age, 24.3 [5.5] years), and 18 (15%) were in the methadone and/or heroin group (mean [SD] age, 30.9 [5.7] years). Not all newborns could be scanned successfully; therefore, usable MRIs were acquired for 118 newborns from predominantly minority groups and with economically disadvantaged mothers. Anatomic abnormalities were detected in similar locations across all 3 drug exposures and included smaller volumes in the dorsal, medial, and ventral surfaces of the frontal lobe and dose-related increases in volumes in the lateral temporal lobe, dorsal parietal lobe, and superior frontal gyrus. Dose-related increases in diffusion tensor measures of tissue organization, decreases in T2 relaxometry times, and increases in spectroscopy metabolite concentrations were similar across exposures. These associations of exposures with brain measures were similar to the associations of newborn age with brain measures. The anatomic and diffusion tensor imaging measures suppressively mediated the associations of prenatal exposure with poorer 12-month infant outcomes., Conclusions and Relevance: The findings suggest that prenatal drug exposure is associated with measures of newborn brain tissue in patterns that may indicate that exposures accelerated normal fetal brain maturation, which in turn mediated the associations with poorer 12-month infant outcomes.

Background: Childhood epilepsies are a heterogeneous group of conditions differing in diagnostic criteria, management, and outcome. Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a neurodegenerative condition caused by biallelic TPP1 variants. This disorder presents with subtle and relatively non-specific symptoms, mimicking those observed in more common paediatric epilepsies and followed by rapid psychomotor deterioration and drug-resistant epilepsy. A prompt diagnosis is essential to adopt appropriate treatment and disease management strategies., Methods: This is a prospective, multicentre study on the efficiency of targeted re-sequencing in the early identification of the genetic causes of childhood epilepsy, with particular regard to CLN2. After phenotypic characterization, a 283-gene Next Generation Sequencing panel was performed in 21 Italian children with neurodevelopmental abnormalities, aged between 24 and 60 months, experiencing first unprovoked seizure after 2 years of age., Results: The average age at enrolment was 39.9 months, with a mean age at seizure onset of 30.9 months and a mean time interval between seizure onset and targeted resequencing of 9 months. Genetic confirmation was achieved in 4 out of 21 patients, with a diagnostic yield of 19%. In one case, the homozygous splice acceptor variant c.509-1G > C in TPP1 was identified, leading to a CLN2 diagnosis. Three pathogenic variants in MECP2 were also detected in three patients, including the frameshift variant c.1157&#95;1186delinsA (p.Leu386Hisfs*9) in a girl with negative single gene sequencing. Variants of unknown significance (VUS) were found in 11 out of 21 (52.4%) individuals, whereas no clinically significant variants were observed in the remaining 6 subjects., Conclusions: Our findings support the efficacy of target re-sequencing in the identification of the genetic causes of childhood epilepsy and suggest that this technique might prove successful in the early detection of CLN2 as well as other neurodevelopmental conditions.

Background: Thyroid fine-needle aspiration (FNA) is a reliable and cost-effective diagnostic tool for establishing the nature of thyroid nodules, although up to 30% of FNAs are still classified as "indeterminate." Molecular testing of FNAs could improve preoperative diagnosis, thereby reducing unnecessary surgery. In this multicenter prospective study the authors investigated, using a 7-gene assay, the distribution and diagnostic impact of BRAF, RAS, RET/PTC, and PAX8/PPARg, the most frequent genomic alterations occurring during thyroid oncogenesis., Methods: In total, of 1172 routine FNAs from 7 centers in southern Italy were classified according to the Bethesda System for Reporting Thyroid Cytopathology. Each specimen was tested, and molecular data were compared with available histology or cytologic follow-up., Results: In particular, for atypia of undetermined significance/follicular lesion of undetermined significance cases, the 7-gene test confirmed the high positive predictive value of BRAFV600E and BRAF-like mutations (80%) and the moderate positive predictive value of RAS-like alterations (32.4%), suggesting different surgical management, depending on the type of mutation. The rate of mutation-positive FNAs was strictly related to the risk of malignancy of each diagnostic class, supporting the identification of prognostically relevant diagnostic categories., Conclusions: The 7-gene panel test improves the preoperative risk stratification of indeterminate thyroid FNAs, especially when considering the biologic significance of the different types of mutations. Moreover, the rate of mutation-positive FNAs is related to the risk of malignancy of each diagnostic class., (© 2019 American Cancer Society.)

Berardinelli-Seip syndrome, or congenital generalized lipodystrophy type 2 (CGL2), is characterized by a lack of subcutaneous adipose tissue and precocious metabolic syndrome with insulin resistance, resulting in diabetes, dyslipidaemia, hepatic steatosis, cardiomyopathy, and acanthosis nigricans. Most reported mutations are associated with mild, non-progressive neurological impairment. We describe the clinical and EEG data of a patient with progressive myoclonus epilepsy (PME), CGL2, and progressive neurological impairment, carrying a homozygous BSCL2 nonsense mutation. The patient had epilepsy onset at the age of two, characterized by monthly generalized tonic-clonic seizures. By the age of three, he presented with drug-resistant ongoing myoclonic absence seizures, photosensitivity, progressive neurological degeneration, and moderate cognitive delay. Molecular analysis of the BSCL2 gene yielded a homozygous c.(1076dupC) p.(Glu360*) mutation. Application of a vagus nerve stimulator led to temporary improvement in seizure frequency, general neurological condition, and EEG background activity. Specific BSCL2 mutations may lead to a peculiar CGL2 phenotype characterized by PME and progressive neurodegeneration. Application of a vagus nerve stimulator, rarely used for PMEs, may prove beneficial, if only temporarily, for both seizure frequency and general neurological condition.

Acute compression on the brainstem or acute increase in intracranial pressure may induce non-epileptic events varying from tonic seizures to axial rigidity with motor automatism, sometimes clearly characterized by decerebrate or decorticate paroxysmal posturing. The EEG correlate is characterized by diffuse asynchronous slow waves of variable amplitude. The mechanism behind such events, known as "cerebellar seizures or fits", is linked to cerebellar herniation and brainstem compression and is not of cortical origin. Misrecognition of such entity may entail an incongruous therapeutic intervention in a life-threatening situation. We describe two emblematic paediatric cases of cerebellar fits caused by diffuse oedema and brainstem compression: a 10-year-old girl with acute disseminated encephalomyelitis (ADEM) and a 2-year-old girl with severe respiratory distress symptomatic of Fallot tetralogy. We also describe the EEG correlate recorded during the events., (Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: To describe the clinical, neuropsychological, and psychopathologic features of a cohort of children with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy at time of recruitment and through the first month. The selected population will be followed for 2-5 years after enrollment to investigate the epilepsy course and identify early predictors of drug resistance., Methods: In this observational, multicenter, nationwide study, children (age 1 month-12.9 years) with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy were consecutively enrolled in 15 Italian tertiary childhood epilepsy centers. Inclusion criteria were as follows: (1) diagnosis of symptomatic focal epilepsy due to acquired and developmental etiologies, and presumed symptomatic focal epilepsy; (2) age at diagnosis older than 1 month and <13 years; and (3) written informed consent. Children were subdivided into three groups: ≤3 years, >3 to 6 years, and >6 years. Clinical, electroencephalography (EEG), neuroimaging, and neuropsychological variables were identified for statistical analyses., Results: Two hundred fifty-nine children were enrolled (116 female and 143 male). Median age: 4.4 years (range 1 month-12.9 years); 46.0% (n = 119) of children were younger than 3 years, 24% (61) from 3 to 6 years of age, and 30% (79) older than 6 years. Neurologic examination findings were normal in 71.8%. Brain magnetic resonance imaging (MRI) was abnormal in 59.9%. Children age ≤3 years experienced the highest seizure frequency in the first month after recruitment (p < 0.0001). Monotherapy in the first month was used in 67.2%. Cognitive tests at baseline revealed abnormal scores in 30%; behavioral problems were present in 21%. At multivariate analysis, higher chances to exhibit more than five seizures in the first month after epilepsy onset was confirmed for younger children and those with temporal lobe epilepsy., Significance: In this prospective cohort study, an extensive characterization of epilepsy onset in children with symptomatic or presumed symptomatic focal epilepsies is reported in relation to the age group and the localization of the epileptogenic zone., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Peri-ictal water drinking (PIWD) has been reported as the action of drinking during or within two minutes of an electroclinical seizure. It is considered a peri-ictal vegetative symptom, evident both during childhood and adulthood epilepsy. The aim of this paper was to describe the clinical and electroencephalographic features of two new adult subjects suffering from symptomatic temporal lobe epilepsy with episodes of PIWD recorded by VIDEO-EEG and to review literature data in order to better define this peculiar event during seizures, a rare and probably underestimated semiological sign. To date, 51 cases with focal epilepsy and seizures associated with PIWD have been reported. All patients presented with temporal lobe epilepsy. All cases but one had symptomatic epilepsy. Most of the patients had an involvement of the right hemisphere. Water drinking was reported as an ictal sign in the majority of patients, and less frequently was reported as postictal. We believe that PIWD might be considered a rare automatic behaviour, like other automatisms. Automatisms are more frequently described in patients with temporal lobe epilepsy. PIWD was reported also to have lateralizing significance in the non-dominant temporal lobe, however, because of its rarity, this finding remains unclear.

Background: Given the rarity of this condition, especially in children, there is a paucity of large reported paediatric case series of anti-N-methyl-d-aspartate receptor encephalitis., Methods: To contribute to define the features of this condition, we describe retrospectively a new nationwide case series of 20 children (50% females), referred by 13 Italian centres., Results: Mean age at onset was 8 years (range 3-17). Prodromal symptoms were reported in 31.6%; onset was with neurological symptoms in 70%, and with behavioural/psychiatric disturbances in 30%. Most patients developed a severe clinical picture (90%), and 41% experienced medical complications; children 12-18 years old seemed to be more severe and symptomatic than younger patients. All children received first-line immune therapy; second-line treatment was administered to 45%. Relapses occurred in 15%. At last follow-up (mean 23.9 months, range 5-82), 85% patients had mRS 0-1; this rate was higher among older patients, and in those receiving first immune therapy within 1 month., Conclusions: Our case series confirms a symptomatologic core of paediatric anti-N-methyl-d-aspartate receptor encephalitis, even though displaying some distinctive features that may be explained by a specific genetic background or by the limited number of patients. The growing incidence of this condition, the relative age-dependent variability of its manifestations, the availability of immunotherapy and the possible better outcome with early treatment impose a high index of clinical suspicion be maintained. In the absence of data suggesting other specific etiologies, paediatricians should consider this diagnosis for children presenting with neurological and/or behavioural or psychiatric disturbances, regardless of age and gender., (Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Introduction: Recent animal and human epidemiological studies suggest that early childhood exposure to anesthesia may have adverse effects on brain development. As more than 50% of pregnant women in the United States and one-third in the United Kingdom receive regional anesthesia during labor and delivery, understanding the effects of perinatal anesthesia on postnatal brain development has important public health relevance., Methods: We used high-resolution magnetic resonance imaging (MRI) to assess the effects of regional anesthesia during labor and delivery as part of a larger study of perinatal exposures on the morphological features of the neonatal brain. We mapped morphological features of the cortical surface in 37 healthy infants, 24 exposed and 13 unexposed to regional anesthesia at delivery, who were scanned within the first 6 weeks of life., Results: Infants exposed to maternal anesthesia compared with unexposed infants had greater local volumes in portions of the frontal and occipital lobes bilaterally and right posterior portion of the cingulate gyrus. Longer durations of exposure to anesthesia correlated positively with local volumes in the occipital lobe., Conclusions: Anesthesia exposure during labor and delivery was associated with larger volumes in portions of the frontal and occipital lobes and cingulate gyrus in neonates. Longitudinal MRI studies are needed to determine whether these morphological effects of anesthesia persist and what their consequences on cognition and behavior may be., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Focal cortical dysplasia (FCD) has been recognized as one of the most frequent causes of drug resistant epilepsy, especially in children. In infancy, onset of FCD-related epilepsy is substantially characterized by epileptic spasms (ES) or focal seizures. Which elements pertaining to the FCD are responsible for the onset of one type of seizure over the other is still unclear. Purpose of our study was to compare the characteristics of FCDs in terms of lateralization and site in patients with epileptic spasms versus patients with focal seizures., Methods: We retrospectively reviewed data from 41 patients with FCD related epilepsy with onset during the first 14 months of life. Seizure semeiology and drug resistance were analyzed, as were age at onset and FCD site and lateralization., Results: Twenty-one children had focal seizures, 11 had ES and nine had focal seizures followed by ES. Mean age at onset was respectively 8.2, 5.1 and 1.8 months. Drug resistance was present in respectively 38.5%, 34.6% and 26.9% of children. Among patients with only ES, 90.9% had an exclusively frontal FCD localization, versus 42.9% of patients with focal seizures and 11.1% of patients with focal seizures followed by ES. FCD lateralization was right sided respectively in 47.6%, 81.8% and 66.7% of patients., Conclusions: Frontal lobe localization of FCDs was closely associated with ES (p=0.001). Moreover we also found that patients with focal seizures followed by ES had a significantly earlier age at onset compared to patients with focal seizures only (p<0.001). The association between ES and right-sided FCD lateralization, even if numerically suggestive, did not reach statistical significance (p=0.16). There was no significant association between seizure type and drug resistance (p=0.08)., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Gilles de la Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor and vocal tics, frequently associated with psychiatric co-morbidities. Despite the significant level of heritability, the genetic architecture of TS still remains elusive. Herein, we investigated an Italian family where an 8-year-old boy, his father, and paternal uncle have a diagnosis of TS. Array-CGH and high resolution SNP-array analyses revealed a heterozygous microdeletion of ∼135 kb at the 7q36.2 locus in the proband and his father. Fluorescent in situ hybridization and quantitative PCR (qPCR) analyses confirmed the presence of the alteration also in the paternal uncle. The deletion selectively involves the first exon of the DPP6 gene, leading to a down-regulation of its expression, as demonstrated by the reduced messenger RNA (mRNA) levels assessed by RT-qPCR. The DPP6 gene encodes for a type II membrane glycoprotein expressed predominantly in the central nervous system. To date, a de novo DPP6 exonic duplication, of uncertain significance, was reported in one patient with TS. Moreover, the DPP6 gene has been implicated in the pathogenesis of autism spectrum disorder (ASD) and, notably, in haloperidol-induced dyskinesia. This first familial case provides evidence for association between DPP6 haploinsufficiency and TS, further suggesting a plausible molecular link between TS and ASD, and might shed some light on the efficacy and tolerability profiles of antidopaminergic agents used for tic management, thus prompting further studies on a larger cohort of patients.

The duplication of the Williams-Beuren syndrome (WBS) region (7q11.23) is a copy number variant associated with autism spectrum disorder (ASD). One of the most intriguing aspects is that the reciprocal microdeletion causes WBS, characterized by hypersociability, marked empathy, and a relative capacity in verbal short-term memory and language. Herein, we studied, by using functional morphological and volumetric magnetic resonance, a 17-year-old male patient who displays a de novo 7q11.23 duplication and ASD. The limbic system of the patient appeared hypo-functional, while the total brain volume was increased, thus contrasting, in an opposite and intriguing manner, with the global brain volume reduction reported in WBS. Even if these findings come from the analysis of a single patient and, therefore, have to be considered preliminary results, they encourage carrying on further functional and volumetric studies in patients with 7q11.23 duplication, to fully elucidate the role of this gene-dosage alteration on brain development and limbic system function.

Background: Dup(14q12) harboring FOXG1 has been recently reported in individuals with developmental delay of variable severity, delayed/absent speech, and epilepsy/infantile spasms. FOXG1 was described as a dosage-sensitive gene encoding G1, a forkhead protein that is a brain-specific transcription factor with a role in brain development., Patients: We extensively reviewed all published cases with dup(14) harboring FOXG1 and highlighted those epileptological features that are more commonly found among such cases. We also describe one new patient, detailing his peculiar clinical and neurophysiological findings., Results: To date, 15 patients with dup(14) including FOXG1 have been reported; within those patients, nine also presented with epilepsy. At onset, the more frequent seizure type in the report and also in our patient is the epileptic spasm. Focal seizures might also be present. Outcomes in patients with epilepsy associated with dup(14) should be considered separately regarding seizures and cognitive and motor development. In the majority of patients (seven of 10, including ours), seizures tend to disappear and motor skills improve; however, instead stagnation of cognitive development is evident in all of them, associated with severe speech difficulties., Conclusions: There are some common features that should be considered: seizures with onset during the first year of life, particularly clusters of spasms and focal seizures with hypsarrhythmic electroencephalograph pattern; different degrees of cognitive impairment possibly associated with behavior disturbances and severe speech disabilities; and dysmorphic features in the absence of significant microcephaly., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Hemiconvulsion-Hemiplegia (HH) syndrome represents an uncommon consequence of prolonged unilateral clonic or hemiconvulsive status epilepticus in childhood, usually occurring during a febrile illness, followed by ipsilateral hemiplegia. The subsequent appearance of focal seizures configures the so called Hemiconvulsion-Hemiplegia-Epilepsy (HHE) syndrome. The pathogenesis of HH/HHE syndrome is still unclear. We describe the case of a 4 year-old girl with congenital adrenal hyperplasia (CAH) whom developed HH/HHE syndrome with drug resistant seizures at the age of 21 months and underwent left cerebral hemispherotomy at the age of 3 years and 6 months. Histopathological findings showed the presence of an underlying inflammatory-degenerative process. Disregulation of the inflammatory cascade has been proposed as one of the possible pathogenetic mechanisms underlying HH/HHE syndrome. To our knowledge however, this is the first report of an association with a histologically documented inflammatory process. The clinical and histopathological findings of our reported case lend support to the possible role of inflammation in the pathogenesis of HH/HHE syndrome., (Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Purpose: Dravet syndrome (DS) is a rare disorder with seizure onset in the first year of life, typically beginning with prolonged febrile hemiclonic seizures or generalized tonic-clonic seizures. Photosensitivity is reported in more than 40% of patients. We present two cases of DS in which we had the chance to record occipital seizures induced by Intermittent Photic Stimulation (IPS)., Method: We retrospectively reviewed the medical records of 32 children affected by DS. All clinical notes were reviewed in order to evaluate the occurrence of seizures induced by IPS., Results: Among the 32 reviewed clinical records, two patients with IPS-induced seizures were found. In both patients seizures originated from the occipital-temporal region. Clinical history was characterized by generalized tonic-clonic seizures, and myoclonia. At the age respectively of 11 months and 20 months they presented a prolonged focal seizure induced by IPS at a frequency of 10 Hz. During the follow-up they additionally presented with hypomotor seizures, also induced by IPS during laboratory EEG examinations. The semiology of hypomotor seizures resembled what is described as "complex partial status", a type of non-convulsive status with ictal discharges arising unilaterally from the occipito-temporal region., Conclusion: Based on available literature, IPS induced occipital seizures have not been reported during the first year of life. Although pathophysiological features are not yet completely understood, both photosensitivity and occipital seizures should be considered in the diagnostic evaluation in DS. The documentation of IPS induced occipital seizures might contribute to widen the clinical and neurophysiological spectra of DS., (Copyright © 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

We describe the EEG findings of an infant with early-onset epileptic encephalopathy with mutation of the KCNQ2 gene and a family history of neonatal seizures. The infant presented with multifocal drug-resistant seizures with onset during the third day of life. Family history was positive for early-onset neonatal seizures. Metabolic screening and neuroimaging were negative. Direct sequencing of KCQN2 from both the mother and child revealed a heterozygous cytosine-to-guanine mutation (Dedek et al., 2003). Interictal EEG showed a very discontinuous pattern which evolved towards a defined burst-suppression pattern during sleep and a multifocal, random, attenuation pattern during wakefulness. Focal, tonic seizures with head deviation, sometimes followed by asynchronous and asymmetrical clonic jerks, eyelid myoclonias, and polypnoea, were recorded. Ictal EEG was characterised by focal, low-voltage, fast activity, followed by recruiting theta rhythms and bilateral, focal, spike-wave complexes, alternatively localised to one hemisphere and subsequently diffusing to the other. ACTH therapy was introduced, resulting in a significant improvement in EEG activity and gradual reduction in seizure frequency, with cessation at age 13 weeks. [Published with video sequences].

Ring chromosome 14 [r(14)] is a rare disorder. The aim of this study was to describe two new cases of r(14) drug-resistant epilepsy, and, through an extensive review of literature, highlight those epileptological features which are more commonly found and which may help in early diagnosis, genetic counseling, and treatment. Epilepsy onset in r(14) syndrome takes place during the first year of life; seizures are generalized or focal and less frequently myoclonic. Seizures might be induced by fever. Focal seizures are characterized by staring, eye or head deviation, respiratory arrest, swallowing, and hypertonia/hypotonia or clonic movements. Ictal EEG might show both focal and diffuse discharges. Interictal EEG reveals mainly focal abnormalities. Mental retardation represents a constant feature. Neurological assessment yields a delay in motor skill acquisition and less frequently both pyramidal and cerebellar signs. Dysmorphic features are evident in the majority of cases. Epilepsy associated with r(14) has many features that entail a challenging diagnostic process. The reported cases of r(14)-related epilepsy seem to highlight a series of common elements which may be helpful in pointing the clinician towards a correct diagnosis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Many references and communications regarding neurosurgical topics in elderly patients underline the interest of our Unit for this subject. We already presented in 1978 a series of 75 patients over 60 years of age operated on for intracranial aneurysms; we reported a 90% of success in all the cases operated with clinical grade 1 or 2 according to Botterel grading system on admission. In 1986, during the XXXV Congress of the Italian Neurosurgical Society, we presented other 15 cases operated for intracranial aneurysm over 70 years of age. We present an upgrading of our casistic.