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Anticonvulsivantes , Hipercinese , Vigabatrina , Humanos , Vigabatrina/efeitos adversos , Hipercinese/induzido quimicamente , Anticonvulsivantes/efeitos adversos , Masculino , Feminino , Espasmos Infantis/tratamento farmacológico , Eletroencefalografia , Gravação em Vídeo , Pré-Escolar , CriançaRESUMO
OBJECTIVES: About 10 million individuals in USA presented annually in the emergency department (ED) with chest pain or with signs and symptoms of acute coronary syndrome (ACS). The advent of point of care (POC) devices, able to measure high sensitivity troponin, are a very interesting tool in the ED setting for its rapid turnaround time (<10â¯min). METHODS: The present study evaluates the diagnostic performance of the Atellica VTLi (Siemens) in real life setting using the clinical data derived from integrated diagnoses of emergency room staff and cardiologist and in comparison with standard laboratory hs-cTnT assay (Cobas 8000, Elecsys, Roche). 966 patients admitted to the emergency department of "G. Mazzini Hospital" in Teramo, Italy, from July 27, 2022, through June 09, 2023, were enrolled. RESULTS: The diagnostic performance of POC hs-cTnI was evaluated. An appropriate POC hs-cTnI threshold values <4â¯ng/L supplied a sensitivity and an NPV of 100â¯% (95â¯% CI: 99.5-100) in order to achieve rapid rule out for MI through a single measurement at patient presentation in the ED. Furthermore, a derivation POC hs-cTnI concentration >54â¯ng/L provided a specificity of 97.2â¯% (95â¯% CI: 95.9-98.1) and a PPV of 43.5â¯% (95â¯% CI: 40.3-46.7) for ruling in MI. CONCLUSIONS: This platform showed comparable diagnostic performance for myocardial infarction to the central laboratory. Our data suggest the possible use of the Atellica VTLi hs-cTnI POC assay either in emergency department of urban medical centre, either in rural hospital for triage and patient management.
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BACKGROUND: Pallister-Killian syndrome (PKS) is a rare genetic disorder caused by mosaic tetrasomy of 12p with wide neurological involvement. Intellectual disability, developmental delay, behavioral problems, epilepsy, sleep disturbances, and brain malformations have been described in most individuals, with a broad phenotypic spectrum. This observational study, conducted through brain MRI scan analysis on a cohort of patients with genetically confirmed PKS, aims to systematically investigate the neuroradiological features of this syndrome and identify the possible existence of a typical pattern. Moreover, a literature review differentiating the different types of neuroimaging data was conducted for comparison with our population. RESULTS: Thirty-one individuals were enrolled (17 females/14 males; age range 0.1-17.5 years old at first MRI). An experienced pediatric neuroradiologist reviewed brain MRIs, blindly to clinical data. Brain abnormalities were observed in all but one individual (compared to the 34% frequency found in the literature review). Corpus callosum abnormalities were found in 20/30 (67%) patients: 6 had callosal hypoplasia; 8 had global hypoplasia with hypoplastic splenium; 4 had only hypoplastic splenium; and 2 had a thin corpus callosum. Cerebral hypoplasia/atrophy was found in 23/31 (74%) and ventriculomegaly in 20/31 (65%). Other frequent features were the enlargement of the cisterna magna in 15/30 (50%) and polymicrogyria in 14/29 (48%). Conversely, the frequency of the latter was found to be 4% from the literature review. Notably, in our population, polymicrogyria was in the perisylvian area in all 14 cases, and it was bilateral in 10/14. CONCLUSIONS: Brain abnormalities are very common in PKS and occur much more frequently than previously reported. Bilateral perisylvian polymicrogyria was a main aspect of our population. Our findings provide an additional tool for early diagnosis.Further studies to investigate the possible correlations with both genotype and phenotype may help to define the etiopathogenesis of the neurologic phenotype of this syndrome.
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Encefalopatias , Transtornos Cromossômicos , Polimicrogiria , Masculino , Feminino , Humanos , Criança , Lactente , Pré-Escolar , Adolescente , Transtornos Cromossômicos/diagnóstico por imagem , Transtornos Cromossômicos/genética , Neuroimagem , Encéfalo/diagnóstico por imagem , Cromossomos Humanos Par 12 , Estudos Observacionais como AssuntoRESUMO
[This corrects the article DOI: 10.3389/fped.2023.1094246.].
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PURPOSE: This retrospective chart review study (GWEP20052) evaluated plant-derived highly purified cannabidiol (CBD; Epidyolex®; 100 mg/mL oral solution) use without clobazam as add-on therapy in patients aged ≥2 years with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) enrolled in a European Early Access Program. METHODS: Data were extracted from patient charts covering a period starting 3 months before CBD treatment and concluding after 12 months of CBD treatment, or sooner if a patient discontinued CBD or started clobazam. RESULTS: Of 114 enrolled patients, data were available for 107 (92 LGS, 15 DS) who received CBD without clobazam for ≥3 months. Mean age: 14.5 (LGS) and 10.5 (DS) years; female: 44% (LGS) and 67% (DS). Mean time-averaged CBD dose: 13.54 (LGS) and 11.56 (DS) mg/kg/day. Median change from baseline in seizure frequency per 28 days over 3-month intervals varied from -6.2% to -20.9% for LGS and 0% to -16.7% for DS. Achievement of ≥50% reduction in drop (LGS) or convulsive (DS) seizures at 3 and 12 months: LGS, 19% (n = 69) and 30% (n = 53); DS, 21% (n = 14) and 13% (n = 8). Retention on CBD without clobazam (enrolled set): 94%, 80%, 69%, and 63% at 3, 6, 9, and 12 months. Adverse event (AE) incidence was 31%, most commonly somnolence, seizure, diarrhea, and decreased appetite. Two patients discontinued CBD owing to AEs, and four patients with LGS experienced elevated liver enzymes. CONCLUSION: Results support favorable effectiveness and retention of CBD without concomitant clobazam for up to 12 months in clinical practice.
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Canabidiol , Epilepsias Mioclônicas , Síndrome de Lennox-Gastaut , Humanos , Adolescente , Canabidiol/uso terapêutico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Clobazam/uso terapêutico , Estudos Retrospectivos , Anticonvulsivantes/uso terapêutico , Epilepsias Mioclônicas/tratamento farmacológico , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Resultado do TratamentoRESUMO
Introduction: Thrombotic events in neonates and children represent a rare although severe occurrence in view of the associated risk of mortality and sequelae. Quality evidence is limited in this field, and registry studies provide an essential base for research. The aim of this paper is to present the new Italian Registry of Infantile Thrombosis (RITI), set it into the scene of international thrombosis and stroke registries, and provide some insight on the challenges associated with registry management. Methods: We present the detailed structure and content of the new RITI registry, a brief overview of its main data, and a reflection on its features, pitfalls and the main challenges related to its management. Results: The RITI, initially started in 2007 and officially re-launched in 2017 after structural modifications, is a non-interventional retrospective and prospective registry study collecting data on neonatal and pediatric patients (0-18 years) who experienced a systemic or cerebral thrombotic event in Italy. The RITI is managed by a multidisciplinary team with expertise in pediatric thrombosis, and participation is open to all Italian physicians, on a voluntary basis. The overall aim of the registry is to acquire new evidence to better characterize the population of children with thrombotic events and improve their management and outcome. 48 Italian pediatric and intensive care units are actively involved in the RITI, including 85 medical doctors from 16 Italian regions. A total of 1,001 neonates and children affected by cerebral or systemic thrombosis have been enrolled. Discussion: The RITI is one of the largest available European registries of neonatal and pediatric thrombosis. National registries like the RITI represent a model for the study of rare conditions based on multidisciplinary and multicenter collaboration, aimed at overcoming the limitations due to small populations of patients, and creating a network of experts for patient referral and continuous education. Moreover, registry studies have a pivotal role in the research on pediatric thrombosis, due to the limited feasibility of high-quality studies. In our experience, the main critical stages, pitfalls and challenges in registry management include adequate registry designing, diffusion, data completeness and quality control.
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This study aimed to evaluate the type and severity of neurological involvement in children with SARS-CoV-2 infection or multisystem inflammatory syndrome in children (MIS-C) and compare these findings between the two groups. Children hospitalized with the diagnosis of COVID-19 or MIS-C at Meyer Children's Hospital between February 2020 and June 2022 were retrospectively studied. One hundred twenty-two patients were enrolled, 95 in the COVID-19 group and 27 in the MIS-C group. In the COVID-19 group, impairment of consciousness was found in 67.4% of patients, headache in 18.9% and about 16.8% of patients experienced seizures. In this group, three patients were diagnosed with arterial ischemic stroke and one patient was diagnosed with Guillain-Barré syndrome (GBS). In the MIS-C group, about 70% of patients experienced consciousness impairment, about 20% behavioral changes, and another 20% mood deflection. Neurological symptoms and signs were highly heterogeneous and could be differentiated in COVID-19 and MIS-C. Consciousness impairment remained the most frequent manifestation in both groups, potentially underlying an encephalopathy. We also highlight the importance of considering psychiatric symptoms in children with COVID-19 and/or MIS-C. Most neurological manifestations were mild in our series; however, severe complications such as ischemic stroke and GBS are worthy of note.
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OBJECTIVE: To discuss the results of the KETASER01 trial and the reasons for its failure, particularly in view of future studies. METHODS: KETASER01 is a multicenter, randomized, controlled, open-label, sequentially designed, non-profit Italian study that aimed to assess the efficacy of ketamine compared with conventional anesthetics in the treatment of refractory convulsive status epilepticus (RCSE) in children. RESULTS: During the 5-year recruitment phase, a total of 76 RCSEs treated with third-line therapy were observed in five of the 10 participating Centers; only 10 individuals (five for each study arm; five females, mean age 6.5 ± 6.3 years) were enrolled in the KETASER01 study. Two of the five patients (40%) in the experimental arm were successfully treated with ketamine and two of the five (40%) children in the control arm, where successfully treated with thiopental. In the remaining six (60%) enrolled patients, RCSE was not controlled by the randomized anesthetic(s). SIGNIFICANCE: The KETASER01 study was prematurely halted due to low eligibility of patients and no successful recruitment. No conclusions can be drawn regarding the objectives of the study. Here, we discuss the KETASER01 results and critically analyze the reasons for its failure in view of future trials.
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Anestésicos , Ketamina , Estado Epiléptico , Criança , Pré-Escolar , Protocolos Clínicos , Feminino , Humanos , Lactente , Ketamina/uso terapêutico , Masculino , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Estado Epiléptico/tratamento farmacológico , TiopentalRESUMO
Background: Moyamoya is a rare progressive cerebral arteriopathy, occurring as an isolated phenomenon (moyamoya disease, MMD) or associated with other conditions (moyamoya syndrome, MMS), responsible for 6-10% of all childhood strokes and transient ischemic attacks (TIAs). Methods: We conducted a retrospective multicenter study on pediatric-onset MMD/MMS in Italy in order to characterize disease presentation, course, management, neuroradiology, and outcome in a European country. Results: A total of 65 patients (34/65 women) with MMD (27/65) or MMS (38/65) were included. About 18% (12/65) of patients were asymptomatic and diagnosed incidentally during investigations performed for an underlying condition (incMMS), whereas 82% (53/65) of patients with MMD or MMS were diagnosed due to the presence of neurological symptoms (symptMMD/MMS). Of these latter, before diagnosis, 66% (43/65) of patients suffered from cerebrovascular events with or without other manifestations (ischemic stroke 42%, 27/65; TIA 32%, 21/65; and no hemorrhagic strokes), 18% (12/65) of them reported headache (in 4/12 headache was not associated with any other manifestation), and 26% (17/65) of them experienced multiple phenotypes (≥2 among: stroke/TIA/seizures/headache/others). Neuroradiology disclosed ≥1 ischemic lesion in 67% (39/58) of patients and posterior circulation involvement in 51% (30/58) of them. About 73% (47/64) of patients underwent surgery, and 69% (45/65) of them received aspirin, but after diagnosis, further stroke events occurred in 20% (12/61) of them, including operated patients (11%, 5/47). Between symptom onset and last follow-up, the overall patient/year incidence of stroke was 10.26% (IC 95% 7.58-13.88%). At last follow-up (median 4 years after diagnosis, range 0.5-15), 43% (26/61) of patients had motor deficits, 31% (19/61) of them had intellectual disability, 13% (8/61) of them had epilepsy, 11% (7/61) of them had behavioral problems, and 25% (13/52) of them had mRS > 2. The proportion of final mRS > 2 was significantly higher in patients with symptMMD/MMS than in patients with incMMS (p = 0.021). Onset age <4 years and stroke before diagnosis were significantly associated with increased risk of intellectual disability (p = 0.0010 and p = 0.0071, respectively) and mRS > 2 at follow-up (p = 0.0106 and p = 0.0009, respectively). Conclusions: Moyamoya is a severe condition that may affect young children and frequently cause cerebrovascular events throughout the disease course, but may also manifest with multiple and non-cerebrovascular clinical phenotypes including headache (isolated or associated with other manifestations), seizures, and movement disorder. Younger onset age and stroke before diagnosis may associate with increased risk of worse outcome (final mRS > 2).
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CHD2 encodes the chromodomain helicase DNA-binding protein 2, an ATP-dependent enzyme that acts as a chromatin remodeler. CHD2 pathogenic variants have been associated with various early onset phenotypes including developmental and epileptic encephalopathy, self-limiting or pharmacoresponsive epilepsies and neurodevelopmental disorders without epilepsy. We reviewed 84 previously reported patients carrying 76 different CHD2 pathogenic or likely pathogenic variants and describe 18 unreported patients carrying 12 novel pathogenic or likely pathogenic variants, two recurrent likely pathogenic variants (in two patients each), three previously reported pathogenic variants, one gross deletion. We also describe a novel phenotype of adult-onset pharmacoresistant epilepsy, associated with a novel CHD2 missense likely pathogenic variant, located in an interdomain region. A combined review of previously published and our own observations indicates that although most patients (72.5%) carry truncating CHD2 pathogenic variants, CHD2-related phenotypes encompass a wide spectrum of conditions with developmental delay/intellectual disability (ID), including prominent language impairment, attention deficit hyperactivity disorder and autistic spectrum disorder. Epilepsy is present in 92% of patients with a median age at seizure onset of 2 years and 6 months. Generalized epilepsy types are prevalent and account for 75.5% of all epilepsies, with photosensitivity being a common feature and adult-onset nonsyndromic epilepsy a rare presentation. No clear genotype-phenotype correlation has emerged.
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Epilepsia , Transtornos do Neurodesenvolvimento , Proteínas de Ligação a DNA/genética , Eletroencefalografia , Epilepsia/genética , Humanos , Mutação , Transtornos do Neurodesenvolvimento/genética , FenótipoRESUMO
Febrile infection-related epilepsy syndrome (FIRES) is a devastating immune inflammatory-mediated epileptic encephalopathy. Herein, we discuss a previously healthy 8-year-old boy with FIRES in whom high dosages of conventional and nonconventional anesthetics were ineffective in treating SE, as were ketogenic diet, intravenous corticosteroids, and immunoglobulins. After 29 days of prolonged SRSE, the patient was successfully treated with sevoflurane paired with plasma exchange, for a total of five days, thus obtaining a stable EEG suppression burst pattern with no adverse events. Anakinra at the dosage of 100 mg b.i.d. was started seven days after sevoflurane and plasma exchange had been discontinued and was effective in ensuring non-recurrence of SE. Sevoflurane as bridge therapy for immunosuppressive treatment could be considered an early, safe, and effective option in treating convulsive SE in which an autoimmune-inflammatory etiology can reasonably be hypothesized.
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Síndromes Epilépticas , Estado Epiléptico , Criança , Síndromes Epilépticas/complicações , Síndromes Epilépticas/terapia , Humanos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Troca Plasmática/efeitos adversos , Sevoflurano , Estado Epiléptico/etiologiaRESUMO
This study aimed to measure the interoceptive accuracy (IA) of individuals with high (highs), medium (mediums), and low hypnotizability (lows) through the heartbeat-counting task during 3 relaxation trials. Participants completed the Multidimensional Assessment of Interoceptive Awareness (MAIA), ECG and skin conductance (SC) were monitored, and the experienced difficulty in counting was reported. Results showed similar counting difficulty and number of actual heartbeats in highs, mediums, and lows. SC decreased in highs during all trials, in mediums and lows only in the third trial. IA measured as [1 - (Çrecorded heartbeats-counted heartbeatsÇ)/recorded heartbeats] was negatively correlated with hypnotizability and not correlated with interoceptive sensitivity (IS) measured by MAIA scales. Among mediums, IA was higher in males than in females.
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Hipnose , Feminino , Frequência Cardíaca , Humanos , Masculino , RelaxamentoRESUMO
Background: Purified cannabidiol (CBD) was administered to highly refractory patients with Dravet (DS) or Lennox-Gastaut (LGS) syndromes in an ongoing expanded access program (EAP). Herein, we report interim results on CBD safety and seizure outcomes in patients treated for a 12-month period. Material and Methods: Thirty centers were enrolled from December 2018 to December 2019 within the open-label prospective EAP up to a maximum of 25 mg/kg per day. Adverse effects and liver function tests were assessed after 2 weeks; 1, 3, and 6 months of treatment; and periodically thereafter. Seizure endpoints were the percentage of patients with ≥50 and 100% reduction in seizures compared to baseline. Results: A total of 93 patients were enrolled and included in the safety analysis. Eighty-two patients [27 (32.9%) DS, 55 (67.1%) LGS] with at least 3 months of treatment have been included in the effectiveness analysis; median previously failed antiseizure medications was eight. Pediatric and adult patients were uniformly represented in the cohort. At 3-month follow-up, compared to the 28-day baseline period, the percentage of patients with at least a 50% reduction in seizure frequency was 40.2% (plus 1.2% seizure-free). Retention rate was similar according to diagnosis, while we found an increased number of patients remaining under treatment in the adult group. CBD was mostly coadministered with valproic acid (62.2%) and clobazam (41.5%). In the safety dataset, 29 (31.2%) dropped out: reasons were lack of efficacy [16 (17.2%)] and adverse events (AEs) [12 (12.9%)], and one met withdrawal criteria (1.1%). Most reported AEs were somnolence (22.6%) and diarrhea (11.9%), followed by transaminase elevation and loss of appetite. Conclusions: CBD is associated with improved seizure control also in a considerable proportion of highly refractory patients with DS and LGS independently from clobazam use. Overall, CBD safety and effectiveness are not dose-related in this cohort.
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OBJECTIVE: To describe the phenotypic spectrum in patients with MBD5-associated neurodevelopmental disorder (MAND) and seizures; features of MAND include intellectual disability, epilepsy, psychiatric features of aggression and hyperactivity, and dysmorphic features including short stature and microcephaly, sleep disturbance, and ataxia. METHODS: We performed phenotyping on patients with MBD5 deletions, duplications, or point mutations and a history of seizures. RESULTS: Twenty-three patients with MAND and seizures were included. Median seizure onset age was 2.9 years (range 3 days-13 years). The most common seizure type was generalized tonic-clonic; focal, atypical absence, tonic, drop attacks, and myoclonic seizures occurred frequently. Seven children had convulsive status epilepticus and 3 nonconvulsive status epilepticus. Fever, viral illnesses, and hot weather provoked seizures. EEG studies in 17/21 patients were abnormal, typically showing slow generalized spike-wave and background slowing. Nine had drug-resistant epilepsy, although 3 eventually became seizure-free. All but one had moderate-to-severe developmental impairment. Epilepsy syndromes included Lennox-Gastaut syndrome, myoclonic-atonic epilepsy, and infantile spasms syndrome. Behavioral problems in 20/23 included aggression, self-injurious behavior, and sleep disturbance. CONCLUSIONS: MBD5 disruption may be associated with severe early childhood-onset developmental and epileptic encephalopathy. Because neuropsychiatric dysfunction is common and severe, it should be an important focus of clinical management.
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OBJECTIVE: The term 'precision medicine' describes a rational treatment strategy tailored to one person that reverses or modifies the disease pathophysiology. In epilepsy, single case and small cohort reports document nascent precision medicine strategies in specific genetic epilepsies. The aim of this multicentre observational study was to investigate the deeper complexity of precision medicine in epilepsy. METHODS: A systematic survey of patients with epilepsy with a molecular genetic diagnosis was conducted in six tertiary epilepsy centres including children and adults. A standardised questionnaire was used for data collection, including genetic findings and impact on clinical and therapeutic management. RESULTS: We included 293 patients with genetic epilepsies, 137 children and 156 adults, 162 females and 131 males. Treatment changes were undertaken because of the genetic findings in 94 patients (32%), including rational precision medicine treatment and/or a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms. There was a rational precision medicine treatment for 56 patients (19%), and this was tried in 33/56 (59%) and was successful (ie, >50% seizure reduction) in 10/33 (30%) patients. In 73/293 (25%) patients there was a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms, and this was successful in 24/73 (33%). SIGNIFICANCE: Our survey of clinical practice in specialised epilepsy centres shows high variability of clinical outcomes following the identification of a genetic cause for an epilepsy. Meaningful change in the treatment paradigm after genetic testing is not yet possible for many people with epilepsy. This systematic survey provides an overview of the current application of precision medicine in the epilepsies, and suggests the adoption of a more considered approach.
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Epilepsia/genética , Medicina de Precisão , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: To alert about the wide margin of unpredictability that distribution of somatic MTOR mosaicism may have in the brain and the risk for independent epileptogenesis arising from the seemingly healthy contralateral hemisphere after complete removal of epileptogenic focal cortical dysplasia (FCD). METHODS: Clinical, EEG, MRI, histopathology, and molecular genetics in 2 patients (1 and 2) treated with focal resections and subsequent complete hemispherectomy for epileptogenic FCD due to somatic MTOR mutations. Autoptic brain study of bilateral asymmetric hemispheric dysplasia and identification of alternative allele fraction (AAF) rates for AKT1 (patient 3). RESULTS: The strongly hyperactivating p.Ser2215Phe (patient 1) and p.Leu1460Pro (patient 2) MTOR mutations were at low-level AAF in the dysplastic tissue. After repeated resections and eventual complete hemispherectomy, both patients manifested intractable seizures arising from the contralateral, seemingly healthy hemisphere. In patient 3, the p.Glu17Lys AKT1 mutation exhibited random distribution and AAF rates in different tissues with double levels in the more severely dysplastic cerebral hemisphere. CONCLUSIONS: Our understanding of the distribution of somatic mutations in the brain in relation to the type of malformation and its hypothesized time of origin may be faulty. Large studies may reveal that the risk of a first surgery being disappointing might be related more to the specific somatic mammalian target of rapamycin mutation identified than to completeness of resection and that the advantages of repeated resections after a first unsuccessful operation should be weighed against the risk of the contralateral hemisphere becoming in turn epileptogenic.
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INTRODUCTION: The aim of the work was to update the "Guidelines for the Management of Severe Traumatic Brain Injury" published in 2012, to reflect the new available evidence, and develop the Italian national guideline for the management of severe pediatric head injuries to reduce variation in practice and ensure optimal care to patients. EVIDENCE ACQUISITION: MEDLINE and EMBASE were searched from January 2009 to October 2017. Inclusion criteria were English language, pediatric populations (0-18 years) or mixed populations (pediatric/adult) with available age subgroup analyses. The guideline development process was started by the Promoting Group that composed a multidisciplinary panel of experts, with the representatives of the Scientific Societies, the independent expert specialists and a representative of the Patient Associations. The panel selected the clinical questions, discussed the evidence and formulated the text of the recommendations. The documentarists of the University of Florence oversaw the bibliographic research strategy. A group of literature reviewers evaluated the selected literature and compiled the table of evidence for each clinical question. EVIDENCE SYNTHESIS: The search strategies identified 4254 articles. We selected 3227 abstract (first screening) and, finally included 67 articles (second screening) to update the guideline. This Italian update includes 25 evidence-based recommendations and 5 research recommendations. CONCLUSIONS: In recent years, progress has been made on the understanding of severe pediatric brain injury, as well as on that concerning all major traumatic pathology. This has led to a progressive improvement in the clinical outcome, although the quantity and quality of evidence remains particularly low.