Corrigendum: The new Italian registry of infantile thrombosis (RITI): a reflection on its journey, challenges and pitfalls.

[This corrects the article DOI: 10.3389/fped.2023.1094246.].

Children under 6 years with acute headache in Pediatric Emergency Departments. A 2-year retrospective exploratory multicenter Italian study.

BACKGROUND: Preschool age (i.e. children under six years of age) represents a red flag for requiring neuroimaging to exclude secondary potentially urgent intracranial conditions (PUIC) in patients with acute headache. We investigated the clinical characteristics of preschoolers with headache to identify the features associated with a greater risk of secondary "dangerous" headache. METHODS: We performed a multicenter exploratory retrospective study in Italy from January 2017 to December 2018. Preschoolers with new-onset non-traumatic headache admitted to emergency department were included and were subsequently divided into two groups: hospitalized and discharged. Among hospitalized patients, we investigated the characteristics linked to potentially urgent intracranial conditions. RESULTS: We included 1455 preschoolers with acute headache. Vomiting, ocular motility disorders, ataxia, presence of neurological symptoms and signs, torticollis and nocturnal awakening were significantly associated to hospitalization. Among the 95 hospitalized patients, 34 (2.3%) had potentially urgent intracranial conditions and more frequently they had neurological symptoms and signs, papilledema, ataxia, cranial nerves paralysis, nocturnal awakening and vomiting. Nevertheless, on multivariable logistic regression analysis, we found that only ataxia and vomiting were associated with potentially urgent intracranial conditions. CONCLUSION: Our study identified clinical features that should be carefully evaluated in the emergency department in order to obtain a prompt diagnosis and treatment of potentially urgent intracranial conditions. The prevalence of potentially urgent intracranial conditions was low in the emergency department, which may suggest that age under six should not be considered an important risk factor for malignant causes as previously thought.

Risk and Prognosis of Thyroid Cancer in Patients with Graves' Disease: An Umbrella Review.

Graves' disease (GD) is an autoimmune disease considered the most common cause of hyperthyroidism. Some studies have investigated its relationship with the risk and prognosis of developing thyroid cancer. Considering that there is no consensus on the relationship between GD and thyroid cancer risk, this umbrella review aimed to summarize the epidemiologic evidence and evaluate its strength and validity on the associations of GD with thyroid cancer risk and its prognosis. This umbrella review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched PubMed and Scopus from January 2012 to December 2022. The strength of the epidemiological evidence was graded as high, moderate, or weak by the Measurement Tool to Assess Systematic Reviews (AMSTAR-2). "Strong" evidence was found for the risk of thyroid cancer in GD patients with thyroid nodular disease (OR: 5.30; 95% CI 2.43-12) and for the risk of mortality from thyroid cancer in these patients (OR 2.93, 95% CI 1.17-7.37, p = 0.02), particularly in Europe (OR 4.89; 95% CI 1.52-16). The results of this umbrella review should be interpreted with caution; as the evidence comes mostly from retrospective studies, potential concerns are selection and recall bias, and whether the empirically observed association reflects a causal relationship remains an open question.

The new Italian registry of infantile thrombosis (RITI): A reflection on its journey, challenges and pitfalls.

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.

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

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

Working as a team in airway surgery: History, present and perspectives.

Teamwork is one of the most important trend in modern medicine. Airway team were created in many places to respond in a multidisciplinary and coordinated way to challenging clinical problems which were beyond the possibility of an individual management. In this chapter, we illustrate the historical steps leading to the development of an airway team in a pediatric referral hospital, describe the present teamwork activity defining the key points for the creation of a team and discussing different organization models; finally we delineate possible future directions for the airway teams in the globalized world.

A Common 3'UTR Variant of the PHOX2B Gene Is Associated With Infant Life-Threatening and Sudden Death Events in the Italian Population.

Heterozygous mutations in the Paired like homeobox 2b (PHOX2B) gene are causative of congenital central hypoventilation syndrome (CCHS), a rare monogenic disorder belonging to the family of neurocristopathies and due to a defective development of the autonomic nervous system. Most patients manifest sudden symptoms within 1 year of birth, mainly represented by central apnea and cyanosis episodes. The sudden appearance of hypoxic manifestations in CCHS and their occurrence during sleep resemble two other unexplained perinatal disorders, apparent life-threatening event (ALTE) and sudden and unexpected infant death (SUID), among which the vast majority is represented by sudden infant death syndrome (SIDS). Differently from CCHS, characterized by Mendelian autosomal dominant inheritance, ALTE and SIDS are complex traits, where common genetic variants, together with external factors, may exert an additive effect with symptoms likely manifesting only over a "threshold." Given the similarities observed among the three abovementioned perinatal disorders, in this work, we have analyzed the frequency of PHOX2B common variants in two groups of Italian idiopathic ALTE (IALTE) and SUIDs/SIDS patients. Here, we report that the c*161G>A (rs114290493) SNP of the 3'UTR PHOX2B (i) became overrepresented in the two sets of patients compared to population matched healthy controls, and (ii) associated with decreased PHOX2B gene expression, likely mediated by miR-204, a microRNA already known to bind the 3'UTR of the PHOX2B gene. Overall, these results suggest that, at least in the Italian population, the SNP c*161G>A (rs114290493) does contribute, presumably in association with others mutations or polymorphisms, to confer susceptibility to sudden unexplained perinatal life-threatening or fatal disorders by increasing the effect of miR-204 in inducing PHOX2B expression down-regulation. However, these are preliminary observations that need to be confirmed on larger cohorts to achieve a clinical relevance.

Multidisciplinary study of sudden unexpected infant death in Liguria (Italy): a nine-year report.

INTRODUCTION: We conducted a retrospective analysis of cases of sudden unexpected infant death (SUID) referred to the SIDS-ALTE Center of the Liguria Region (Italy) from 2010 to 2018. In all cases, the death scene was inspected, and a multidisciplinary post-mortem evaluation was conducted. Our aim was to analyze the epidemiological data and etiological distribution. EVIDENCE ACQUISITION: We examined 15 cases initially classified as sudden infant death. EVIDENCE SYNTHESIS: In all cases, the death was initially unexplained. Seven cases involved males and eight involved females. Their mean age was 67.47 days; the youngest victim was 2 days old, while the oldest was 8.5 months (253 days). In 7 cases, the post-mortem analysis showed an infection of lung. In 4 cases, the prone position of the infant during sleep was identified as a risk factor. Only in one case the cause of death remains unexplained, and it was classified as sudden infant death syndrome II according to San Diego Classification. CONCLUSIONS: In the forensic approach to cases of SUID, it is always important to conduct a thorough multidisciplinary investigation. In order to avoid procedural errors that might compromise the post-mortem investigation, it is necessary to consider the medical and social history of both mother and child, in addition to the circumstances of the death. Moreover, a complete pediatric post-mortem examination and multidisciplinary discussion are required in order to identify potentially important causative or contributory factors.

Listeria meningitis complicated by hydrocephalus in an immunocompetent child: case report and review of the literature.

BACKGROUND: Listeria monocytogenes is a Gram-positive bacteria transmitted to human by animal stools, contaminated water and food. In children, Listeria monocytogenes typically affects newborns and immunocompromised patients often leading to invasive syndromes including sepsis, brain abscesses, meningitis, meningoencephalitis and rhombencephalitis. In healthy and immunocompetent children, Listeria meningitis is rare, but can progress rapidly and may be associated with severe complications (hydrocephalus, ventriculitis, cranial nerves palsy and cerebrospinal abscesses) and high mortality rate. CASE PRESENTATION: We describe a very uncommon case of meningoencephalitis due to Listeria monocytogenes in a 11-month-old immunocompetent girl. Cerebrospinal fluid (CSF) culture was positive on the second day. Antibiotic therapy was promptly started but the disease was complicated by neurological deterioration and decompensated hydrocephalus. The child required a very demanding pediatric and neurosurgical management and was discharged after 40 days without major sequelae. CONCLUSION: Listeria is difficult to isolate and it is not susceptible to first-line treatment for bacterial meningitis with extended-spectrum cephalosporins. Early recognition is therefore crucial for a positive outcome. Pediatricians have to perform close clinical monitoring of these children and be aware of possible complications. A review of all cases of Listeria meningitis complicated by hydrocephalus in healthy children has been performed, to provide an overview on clinical features, treatment options and outcome.

Characteristics of Acute Nystagmus in the Pediatric Emergency Department.

OBJECTIVES: Acute nystagmus (AN) is an uncommon neurologic sign in children presenting to pediatric emergency departments. We described the epidemiology, clinical features, and underlying causes of AN in a large cohort of children, aiming at identifying features associated with higher risk of severe underlying urgent conditions (UCs). METHODS: Clinical records of all patients aged 0 to 18 years presenting for AN to the pediatric emergency departments of 9 Italian hospitals in an 8-year period were retrospectively reviewed. Clinical and demographic features and the underlying causes were analyzed. A logistic regression model was applied to detect predictive variables associated with a higher risk of UCs. RESULTS: A total of 206 patients with AN were included (male-to-female ratio: 1.01; mean age: 8 years 11 months). The most frequently associated symptoms were headache (43.2%) and vertigo (42.2%). Ataxia (17.5%) and strabismus (13.1%) were the most common neurologic signs. Migraine (25.7%) and vestibular disorders (14.1%) were the most common causes of AN. Idiopathic infantile nystagmus was the most common cause in infants <1 year of age. UCs accounted for 18.9% of all cases, mostly represented by brain tumors (8.3%). Accordant with the logistic model, cranial nerve deficits, ataxia, or strabismus were strongly associated with an underlying UC. Presence of vertigo or attribution of a nonurgent triage code was associated with a reduced risk of UCs. CONCLUSIONS: AN should be considered an alarming finding in children given the risk of severe UCs. Cranial nerve palsy, ataxia, and strabismus should be considered red flags during the assessment of a child with AN.

Unexpected and Sudden Death Due to Undiagnosed Moraxella catarrhalis Meningoencephalitis in a 40-day-old Infant: Case Report and Literature Review.

Acute bacterial meningitis in infants and newborns represents a medical emergency and a significant cause of mortality and morbidity worldwide. Moraxella catarrhalis has been considered a microorganism with low pathogenic potential, and only in exceptional cases has it been found to cause meningitis in infants and immunocompetent people. We will now document an unusual case of an unexpected and sudden death of a 40-day-old infant due to acute meningitis from M. catarrhalis, apparently asymptomatic and subsequently diagnosed by an autopsy. According to our knowledge this is the first case of unexpected infant death due to undiagnosed M. catarrhalis meningitis.The suggested case, as well as for the rarity of such a fatal event, should be considered a caution to pediatrics and neonatologists for M. catarrhalis can cause paucisymptomatic meningoencephalitis in infants which can be potentially fatal.From a forensic point of view, an autopsy accompanied by a multidisciplinary assessment is always necessary in cases of unexpected infant deaths to identify the causes.

Unexpected Infant Death Due to Undiagnosed Biliary Atresia: A Case of Fatal Neglect.

Biliary atresia (BA) is a fatal condition resulting in the lack of effective biliary drainage leading invariably to liver failure and cirrhosis within a year, and it is often lethal within a few months in the absence of corrective surgery or liver transplantation. In fact, BA is the most common indication for pediatric liver transplantation.Herein, we present a rare case of unexpected infant death due to BA diagnosed only postmortem in a context of child neglect and carelessness on the part of the parents. It emerged from the clinical history that after a few months, the parents no longer took their daughter to any medical checkups despite the indications and express recommendations for follow-up. The autopsy revealed agenesis of the gallbladder with BA and complete disruption of the hepatic architecture and parenchyma from biliary cirrhosis. Histological examinations documented severe biliary cirrhosis from hypoplasia of the biliary ducts.The child neglect in this case proved fatal inasmuch as an early diagnosis by a pediatrician would have likely allowed appropriate surgical treatment, thus avoiding the untimely death of the child. We highlight the importance of educating and informing parents (especially the disadvantaged) in matters of health. At the same time, primary care physicians should closely monitor the conditions and development of infants so as to recognize the early warning signs and symptoms of BA, bearing in mind that a timely diagnosis and proper surgical treatment can save the lives of most of these children.

Sudden infant death syndrome: the role of multidisciplinary teams. Experience of the SIDS-ALTE Center of Liguria Region.

The aim of this paper was to highlight the importance of a multidisciplinary and multiprofessional management of SIDS for a complete approach to this tragic event. Both biomedical and psychosocial aspects are evaluated, focusing on the impact of SIDS diagnosis on the family. The paper describes the organization of our team, composed of a network of specialists involved in both prevention and management of SIDS. A protocol is proposed to improve SIDS diagnosis and management. In our team, the clinical pediatrician is the coordinator of specialists and the mediator between the family and the other specialists, thanks to his direct relationship with parents.

Development of stratification criteria of green codes in a pediatric emergency department: a pilot study.

BACKGROUND: The aim of this study was to find stratification criteria in a group of children assigned to the green triage category at an emergency department (ED). METHODS: We analyzed a sample of patients admitted to the ED of Gaslini Children's Hospital in Genoa between February 2014 and January 2015 who had been given a green code on triage. We analyzed the following parameters: age, sex, nationality, reason for admission, number and type of the procedures performed, length of stay in the ED, destination on discharge, color code and diagnosis on discharge. RESULTS: Of the 2875 patients enrolled, 258 (8.97%) were hospitalized, 135 (4.70%) were placed in short intensive observation, 1609 (55.97%) were discharged from the ED without any intervention, 829 (28.83%) were discharged after undergoing procedures (blood tests, microbiology investigation, imaging, specialist evaluation) and 44 (1.5%) spontaneously left the ED. Among the patients who were hospitalized and those kept under short intensive observation, the most frequent discharge diagnosis was gastrointestinal disease; among those patients discharged with and without undergoing procedures, the most frequent diagnosis was respiratory disease. The mean age of patients admitted to hospital and of those discharged without undergoing procedures was 46 months, while the mean ages of patients kept under short intensive observation and of those discharged after undergoing procedures were 54 and 61 months, respectively. CONCLUSIONS: These preliminary results suggest that one of the main criteria of stratification of green codes on triage is the association between 2 variables: age and pathology.

Medico-legal investigation in an explicable case of congenital central hypoventilation syndrome due to a rare variant of the PHOX2B gene.

The heterozygous PHOX2B gene mutation is related to congenital central hypoventilation syndrome (CCHS). It is characterized by defective autonomous nervous system development leading to inadequate breathing response to hypoxia and hypercapnia, leading to hypoventilation especially during non-REM sleep, but also during waking in the more severe cases. Herein we report a case of sudden death in a 28-day-old child. The mother reported the infant was found lying on her own bed in the prone position. The infant was wearing a romper and lying in her crib without any blanket or other objects. At autopsy no significant pathological findings were detected. Histologically, sparse aspirated milk residues were present in some lung fields. Toxicological and microbiological examinations were within the norm. The initial postmortem investigation ruled out any readily identifiable cause of death. However, genetic analysis revealed a rare heterozygous 21bp in-frame deletion of the polyalanine coding sequences of the PHOX2B gene. In-frame contractions of the poly-Ala tract of the PHOX2B gene have already been reported in patients with symptoms suggestive of sporadic hypoventilation, apparent life-threatening events or neonatal respiratory distress.

Acute hyperkinetic movement disorders in Italian paediatric emergency departments.

INTRODUCTION: Limited data exist on epidemiology, clinical presentation and management of acute hyperkinetic movement disorders (AHMD) in paediatric emergency departments (pED). METHODS: We retrospectively analysed a case series of 256 children (aged 2 months to 17 years) presenting with AHMD to the pEDs of six Italian tertiary care hospitals over a 2-year period (January 2012 to December 2013). RESULTS: The most common type of AHMD was tics (44.5%), followed by tremors (21.1%), chorea (13.7%), dystonia (10.2%), myoclonus (6.3%) and stereotypies (4.3%). Neuropsychiatric disorders (including tic disorders, psychogenic movement disorders and idiopathic stereotypies) were the most represented cause (51.2%). Inflammatory conditions (infectious and immune-mediated neurological disorders) accounted for 17.6% of the cases whereas non-inflammatory disorders (including drug-induced AHMDs, genetic/metabolic diseases, paroxysmal non-epileptic movements and idiopathic AHMDs) accounted for 31.2%. Neuropsychiatric disorders prevailed among preschoolers and schoolers (51.9% and 25.2%, respectively), non-inflammatory disorders were more frequent in infants and toddlers (63.8%), whereas inflammatory conditions were more often encountered among schoolers (73.3%). In 5 out of 36 Sydenham's chorea (SC) cases, tics were the presentation symptom on admission to emergency department (ED), highlighting the difficulties in early diagnosis of SC. Inflammatory disorders were associated with a longer hospital stay and a greater need of neuroimaging test compared with other disorders. CONCLUSIONS: This study provides the first large sample of paediatric patients presenting to the ED for AHMDs, helping to elucidate the epidemiology, aetiology and clinical presentation of these disorders.

Apparent Life-Threatening Events (ALTE): Italian guidelines.

Five years after the first edition, we have revised and updated the guidelines, re-examining the queries and relative recommendations, expanding the issues addressed with the introduction of a new entity, recently proposed by the American Academy of Pediatrics: BRUE, an acronym for Brief Resolved Unexplained Events. In this manuscript we will use the term BRUE only to refer to mild, idiopathic cases rather than simply replace the acronym ALTE per se.In our guidelines the acronym ALTE is used for severe cases that are unexplainable after the first and second level examinations.Although the term ALTE can be used to describe the common symptoms at the onset, whenever the aetiology is ascertained, the final diagnosis may be better specified as seizures, gastroesophageal reflux, infection, arrhythmia, etc. Lastly, we have addressed the emerging problem of the so-called Sudden Unexpected Postnatal Collapse (SUPC), that might be considered as a severe ALTE occurring in the first week of life.

Acute diplopia in the pediatric Emergency Department. A cohort multicenter Italian study.

BACKGROUND: Acute diplopia (AD) is an uncommon and distressing symptom of numerous ocular and neurological conditions, with potentially serious sequelaes. No data are present in pediatrics on the presentation and management of AD. AIM: This study investigated characteristics, etiology and health care utilization of the pediatric population with AD accessed to pediatric Emergency Departments (ED), trying to identify "red flags" associated with potentially life-threatening (LT) conditions. METHODS: We conducted a cohort multicenter study on children with AD in ten Italian hospitals. Patients were classified into diagnostic categories, comparing children with and without LT disease. RESULTS: 621 children presented AD at a rate of 3.6 per 10.000. The most frequent diagnosis among no-LT conditions (81.2%) were headache, ocular disorders and minor post-traumatic disease, while LT conditions (18.8%) were represented by brain tumors, demyelinating conditions, idiopathic intracranial hypertension and major post-traumatic diseases. The LT group showed a significantly higher age, with the odds increased by 1% for each month of age. Monocular diplopia occurred in 16.1%, but unlike adult one-fifth presented LT conditions. Binocular diplopia, associated ocular manifestations or extraocular neurological signs were significantly more common in the LT group. At regression logistic analysis strabismus and ptosis were associated with LT conditions. CONCLUSION: The majority of children presented no-LT conditions and more than one-fourth of patients had headache. Monocular diplopia in the LT group was never isolated but associated with other signs or symptoms. Our study was able to identify some specific ocular disturbances or neurologic signs potentially useful for ED physician to recognize patients with serious pathologies.