The latest advances in the pharmacological management of focal epilepsies in children: a narrative review.

INTRODUCTION: Focal epilepsy constitutes the most common epilepsy in children, and medical treatment represents the first-line therapy in this condition. The main goal of medical treatment for children and adolescents with epilepsy is the achievement of seizure freedom or, in drug-resistant epilepsies, a significant seizure reduction, both minimizing antiseizure medications (ASM)-related adverse events, thus improving the patient's quality of life. However, up to 20-40% of pediatric epilepsies are refractory to drug treatments. New ASMs came to light in the pediatric landscape, improving the drug profile compared to that of the preexisting ones. Clinicians should consider several factors during the drug choice process, including patient and medication-specific characteristics. AREAS COVERED: This narrative review aims to summarize the latest evidence on the effectiveness and tolerability of the newest ASMs administered as monotherapy or adjunctive therapy in pediatric epilepsies with focal onset seizures, providing a practical appraisal based on the existing evidence. EXPERT OPINION: The latest ASMs have the potential to be effective in the pharmacological management of focal onset seizures in children, and treatment choice should consider several drug- and epilepsy-related factors. Future treatments should be increasingly personalized and targeted on patient-specific pathways. Future research should focus on discovering new chemical compounds and repurposing medications used for other indications.

Potential Predictors of Long COVID in Italian Children: A Cross-Sectional Survey.

BACKGROUND: Identifying predictive factors of long COVID syndrome (LCS) is essential to preventing and managing this condition. We investigated the prevalence, symptoms, and risk factors of LCS in a cohort of Italian children and adolescents. METHODS: We carried out a cross-sectional survey on demographic characteristics and clinical data related to COVID-19 phase and LCS in a cohort of children and adolescents, sending a questionnaire by using the PEDIATOTEM platform. RESULTS: The prevalence of LCS was 25% (99/396). The most frequent symptoms of LCS included nasal congestion, diarrhea, headache, and fatigue. We found no association between demographic data (gender, age, and ethnicity) and LCS. Additionally, we showed that patients with concurrent allergic rhinitis, atopic dermatitis, respiratory disease, gastrointestinal disease, and rheumatologic disease had a higher risk of LCS than patients without those comorbidities. Patients experiencing fatigue, muscle, and abdominal pain in COVID-19 showed a higher risk of LCS than patients complaining of other symptoms. We found no association between vaccination and LCS. CONCLUSIONS: Specific comorbidities or symptoms during acute illness were identified as being risk factors for LCS. Understanding which are the risk factors for LCS could yield a clearer picture of its pathogenesis.

Efficacy and safety of vigabatrin in patients with tuberous sclerosis complex and infantile epileptic spasm syndrome: a systematic review.

INTRODUCTION: Tuberous sclerosis complex (TSC) is a common genetic cause of epilepsy. Infantile epileptic spasm syndrome (IESS) is often the presenting neurologic feature, progressively evolving into refractory epilepsy. Vigabatrin (VGB) is often used in clinical practice as a first-line therapy in TSC with IESS. This systematic review aims to collect and analyze the efficacy data about VGB in TSC cases with IESS, in order to evaluate the strength of evidence in the literature. METHODS: A systematic search of trials, observational studies, and case series involving patients with TSC and IESS treated with VGB was performed using MEDLINE, CENTRAL, and the US NIH Clinical Trials Registry. Single case studies, animal and non-English language studies were excluded. Seventeen studies were selected, of which 3 were RCTs and 14 were observational studies. RESULTS: An overall response rate of 67% (231/343 responders) resulted from the analysis, with a spasm-free rate restricted to RCTs of 88% (29/33 subjects). CONCLUSIONS: Although all the studies analyzed reported beneficial effects of VGB in TSC patients with IESS, with higher response rates in comparison to non-TSC subjects with IESS, a low level of evidence and high heterogeneity do not guarantee sufficient strength for therapeutic recommendations.

Pediatric Headache in Primary Care and Emergency Departments: Consensus with RAND/UCLA Method.

Headache is the most frequent neurological symptom in childhood and the main reason for admission to pediatric emergency departments. The aim of this consensus document is to define a shared clinical pathway between primary care pediatricians (PCP) and hospitals for the management of children presenting with headache. For the purposes of the study, a group of hospital pediatricians and a group of PCP from the Emilia Romagna's health districts were selected to achieve consensus using the RAND/UCLA appropriateness method. Thirty-nine clinical scenarios were developed: for each scenario, participants were asked to rank the appropriateness of each option from 1 to 9. Agreement was reached if ≥75% of participants ranked within the same range of appropriateness. The answers, results, and discussion helped to define the appropriateness of procedures with a low level of evidence regarding different steps of the diagnostic-therapeutic process: primary care evaluation, emergency department evaluation, hospital admission, acute therapy, prophylaxis, and follow-up. The RAND proved to be a valid method to value appropriateness of procedures and define a diagnostic-therapeutic pathway suitable to the local reality in the management of pediatric headache. From our results, some useful recommendations were developed for optimizing the healthcare professionals' network among primary care services and hospitals.

Beyond neonatal seizures - epileptic evolution in preterm newborns: a systematic review and meta-analysis.

OBJECTIVE: To assess the potential risk of developing epilepsy in preterm newborns with neonatal seizures (NS). Two electronic databases (PubMed and Web of Sciences) were searched from inception to December 2020. Studies that investigated the outcome of epilepsy in neonates with NS were included. METHODS: Case-control, cross-sectional and cohort studies were included. Data synthesis was undertaken via systematic review and meta-analysis of available evidence. All review stages were conducted by three independent reviewers. We analysed data on neonates with NS who developed post-neonatal epilepsy (PNE) based on the data reported in the selected articles. We then investigated the development of PNE in term and preterm neonates. RESULTS: The initial search led to 568 citations, of which 12 were selected for the review and six were eligible for meta-analysis. Results of the meta-analysis showed no significant difference in the risk of developing PNE between full-term infants with NS (pooled OR [pOR]=0.92: 95% CI: 0.58-1.44) and preterm neonates. SIGNIFICANCE: Gestational age does not seem to be an independent predictor for the development of PNE in neonates with NS. More data are needed to explore the relationship between seizures in the neonatal period and epilepsy later in life.

Duplication of the Pituitary Gland (DPG)-Plus Syndrome Associated With Midline Anomalies and Precocious Puberty: A Case Report and Review of the Literature.

Duplication of the pituitary gland (DPG)-plus syndrome is a very rare developmental disorder with few cases described in the literature and characterized by multiple midline and central nervous system malformations. The hypothalamus and hypophysis involvement may be clinically associated with endocrine abnormalities. A 5.9-year-old female child was admitted to our Clinic for premature thelarche and acceleration of growth. DPG-plus syndrome with paired infundibula and pituitary glands was diagnosed after birth, when she appeared small for gestational age and she presented with lingual hypoplasia, cleft palate, right choanal stenosis, nasopharyngeal teratoma, and facial dysmorphisms. Neuroimaging revealed a duplication of the infundibula, the pituitary gland, and the dens of the epistropheus despite surgical removal of a rhino-pharyngeal mass performed at the age of two months. An array-CGH revealed a 2p12 deletion. At our evaluation, bone age assessment resulted advanced and initial pubertal activation was confirmed by Gonadotropin-Releasing Hormone stimulation test. Hormonal suppression treatment was started with satisfactory results. This case shows that DPG-plus syndrome must be considered in presence of midline and craniofacial malformations and endocrinological evaluations should be performed for the prompt and appropriate management of pubertal anomalies.

A Case of Atypical Bartonellosis in a 4-Year-Old Immunocompetent Child.

In most cases, infection due to Bartonella henselae causes a mild disease presenting with a regional lymphadenopathy frequently associated with a low-grade fever, headache, poor appetite and exhaustion that spontaneously resolves itself in a few weeks. As the infection is generally transmitted by cats through scratching or biting, the disease is named cat scratch disease (CSD). However, in 5-20% of cases, mainly in immunocompromised patients, systemic involvement can occur and CSD may result in major illness. This report describes a case of systemic CSD diagnosed in an immunocompetent 4-year-old child that can be used as an example of the problems that pediatricians must solve to reach a diagnosis of atypical CSD. Despite the child's lack of history suggesting any contact with cats and the absence of regional lymphadenopathy, the presence of a high fever, deterioration of their general condition, increased inflammatory biomarkers, hepatosplenic lesions (i.e., multiple abscesses), pericardial effusion with mild mitral valve regurgitation and a mild dilatation of the proximal and medial portion of the right coronary artery, seroconversion for B. henselae (IgG 1:256) supported the diagnosis of atypical CSD. Administration of oral azithromycin was initiated (10 mg/kg/die for 3 days) with a progressive normalization of clinical, laboratory and US hepatosplenic and cardiac findings. This case shows that the diagnosis of atypical CSD is challenging. The nonspecific, composite and variable clinical features of this disease require a careful evaluation in order to achieve a precise diagnosis and to avoid both a delayed diagnosis and therapy with a risk of negative evolution.

Sudden Infant Death Syndrome: Beyond Risk Factors.

Sudden infant death syndrome (SIDS) is defined as "the sudden death of an infant under 1 year of age which remains unexplained after thorough investigation including a complete autopsy, death scene investigation, and detailed clinical and pathological review". A significant decrease of SIDS deaths occurred in the last decades in most countries after the beginning of national campaigns, mainly as a consequence of the implementation of risk reduction action mostly concentrating on the improvement of sleep conditions. Nevertheless, infant mortality from SIDS still remains unacceptably high. There is an urgent need to get insight into previously unexplored aspects of the brain system with a special focus on high-risk groups. SIDS pathogenesis is associated with a multifactorial condition that comprehends genetic, environmental and sociocultural factors. Effective prevention of SIDS requires multiple interventions from different fields. Developing brain susceptibility, intrinsic vulnerability and early identification of infants with high risk of SIDS represents a challenge. Progress in SIDS research appears to be fundamental to the ultimate aim of eradicating SIDS deaths. A complex model that combines different risk factor data from biomarkers and omic analysis may represent a tool to identify a SIDS risk profile in newborn settings. If high risk is detected, the infant may be referred for further investigations and follow ups. This review aims to illustrate the most recent discoveries from different fields, analyzing the neuroanatomical, genetic, metabolic, proteomic, environmental and sociocultural aspects related to SIDS.

Management of Infants with Brief Resolved Unexplained Events (BRUE) and Apparent Life-Threatening Events (ALTE): A RAND/UCLA Appropriateness Approach.

Unexpected events of breath, tone, and skin color change in infants are a cause of considerable distress to the caregiver and there is still debate on their appropriate management. The aim of this study is to survey the trend in prevention, decision-making, and management of brief resolved unexplained events (BRUE)/apparent life-threatening events (ALTE) and to develop a shared protocol among hospitals and primary care pediatricians regarding hospital admission criteria, work-up and post-discharge monitoring of patients with BRUE/ALTE. For the study purpose, a panel of 54 experts was selected to achieve consensus using the RAND/UCLA appropriateness method. Twelve scenarios were developed: one addressed to primary prevention of ALTE and BRUE, and 11 focused on hospital management of BRUE and ALTE. For each scenario, participants were asked to rank each option from '1' (extremely inappropriate) to '9' (extremely appropriate). Results derived from panel meeting and discussion showed several points of agreement but also disagreement with different opinion emerged and the need of focused education on some areas. However, by combining previous recommendations with expert opinion, the application of the RAND/UCLA appropriateness permitted us to drive pediatricians to reasoned and informed decisions in term of evaluation, treatment and follow-up of infants with BRUE/ALTE, reducing inappropriate exams and hospitalisation and highlighting priorities for educational interventions.

Role of the KCNJ Gene Variants in the Clinical Outcome of Type 1 Diabetes.

Diabetes is considered as a disease with a wide and continuous clinical spectrum, ranging from Type 1 (T1D) and Type 2 Diabetes (T2D) with complex multifactorial causes. In the last years, particular attention has been focused on the predictive value and therapeutic potential of single nucleotide polymorphisms (SNPs). SNPs can alter the seed-sequence in miRNA's loci and miRNA target sites causing changes in the structure and influencing the binding function. Only few studies have investigated the clinical influence of SNPs, in particular potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ) gene variants in T1D population. The aim of the study is to investigate the occurrence and the possible metabolic significance of KCNJ polymorphism in a group of pediatric patients with T1D. The study was performed in a cohort of 90 Caucasian children and adolescents with T1D and 93 healthy subjects. Rs5210 polymorphism has been analyzed with a prevalence of the GG genotype in the patient group suggesting its association with T1D. Therefore, a relationship was found between GG genotype and body mass index (BMI) at diagnosis and insulin requirement (IR) after 6 months. The study suggested an action for rs5210 in determining the metabolic features of T1D pediatric patients, by showing some clues of insulin resistance in patients carrying that polymorphism.

Neonatal seizures in preterm infants: A systematic review of mortality risk and neurological outcomes from studies in the 2000's.

INTRODUCTION: Neonatal seizures (NS) are associated with increased mortality and risk of cerebral palsy, epilepsy and intellectual disability. We performed a systematic review with the primary objective to delineate the rate of these outcomes following NS in preterm infants from studies published in the 2000's and the secondary objective to identify risk factors. METHODS: Inclusion criteria: original articles published between 1/1/2000 and 12/31/2018, written in English, evaluating newborns ≤37 weeks of gestational age and suffering from NS, in which at least one of these was evaluated: epilepsy, cerebral palsy, intellectual disability/developmental delay, normal outcome, death. RESULTS: Twenty-two papers were selected and all were observational, with a retrospective design in 15. Three were population-based and twenty-one have a comparison. It has been found a 22-80 % of mortality, 11.3-38.9 % of epilepsy, 12-84.6 % of cerebral palsy, and 20-42.7 % of intellectual disability/developmental delay rate. An increased risk for all outcomes considered was reported. Risk factors for specific outcomes were provided by a minority of studies. However, inclusion criteria, definition of NS and measured outcomes, follow-up lengths differed considerably between studies. DISCUSSION: Results of the selected studies are only partially comparable or generalizable because of differences in study design. They have a risk for potential biases, although they provide (if analyzed) readily available prognostic factors, easy to apply in clinical practice. Prospective, population-based studies with EEG-defined NS are warranted in order to produce evidence-based guidance for management of preterm newborns with seizures.

Effect of Thyroid Hormones on Neurons and Neurodevelopment.

This review focuses on the current knowledge of the effects of thyroid hormones on central nervous system differentiation and development in animals and the human fetal brain. The outcomes of children with congenital hypothyroidism and of newborns with hypothyroid pregnant mothers are emphasized, focusing on how therapies could affect and especially improve the outcomes.

C1858T Polymorphism of Protein Tyrosine Phosphatase Non-receptor Type 22 (PTPN22): an eligible target for prevention of type 1 diabetes?

INTRODUCTION: In type 1 diabetes (T1D), several genetic factors are associated to ß-cell autoimmunity onset and clinical progression. HLA-genes play a major role in susceptibility and initiation of ß-cell autoimmunity, whereas non-HLA genes may influence the destruction rate. Areas covered: Our review focuses on the possible role of the PTPN22 C1858 T variant as a prognostic factor, given its influence on disease variability. Moreover, we present the potential role of C1858 T as a target for tertiary prevention trials and new therapeutic strategies, such as the LYP inhibitors. We used PubMed for literature research; key words were 'PTPN22', 'C1858 T polymorphism', 'lymphoid-specific tyrosine phosphatase' and 'type 1 diabetes'. We selected publications between 2000 and 2016. Expert commentary: Current data suggest that PTPN22 can be a promising target for therapeutic interventions and identification of at-risk subjects in autoimmune diseases such as T1D.

Pyomyositis is not only a tropical pathology: a case series.

BACKGROUND: Pyomyositis is an acute bacterial infection of skeletal muscle that results in localized abscess formation. This infection was thought to be endemic to tropical countries, and is also known as "tropical pyomyositis". However, pyomyositis is increasingly recognized in temperate climates and is frequently associated with an immunosuppressive condition, such as human immunodeficiency virus, malignancy, and diabetes mellitus. It is also found in healthy and athletic people after strenuous or vigorous exercise or following localized and possibly unnoticed trauma. It can be primary or secondary to neighboring or remote infection. Primary pyomyositis is a rare condition that can affect children and adolescents. Diagnosis can be delayed because the affected muscle is deeply situated and local signs are not apparent. This delay in diagnosis can result in increased morbidity and a significant mortality rate. The pediatric population, which comprises 35% of the reported pyomyositis cases, is an especially difficult subset of patients to diagnose. CASE PRESENTATION: In our series, we describe the cases of four previously healthy Caucasian children who were admitted to our Pediatric Department with different clinical presentations. Pyomyositis in our patients was related to factors affecting the muscle itself, including strenuous exercise and direct muscle trauma. Therapy was started with a cephalosporin antibiotic and teicoplanin was subsequently added. The minimum length of therapy was 3 weeks. CONCLUSIONS: The diagnosis of pyomyositis in our patients, none of whom were immune-compromised, is confirmation that this disease is not an exclusive pathology of tropical countries and demonstrates that there is an increasing prevalence of pyomyositis in temperate climates.

Pharmacological considerations in the use of stiripentol for the treatment of epilepsy.

INTRODUCTION: Despite the fact that more than 20 antiepileptic drugs (AEDs) are currently available, about one-third of patients still present drug resistance. Further efforts are required to develop novel and more efficacious therapeutic strategies, especially for refractory epileptic syndromes showing few and anecdotic therapeutic options. AREAS COVERED: Stiripentol (STP) is a second generation AED that shows GABAergic activity, with immature brain selectivity, and an indirect metabolic action on co-administered AEDs. Two pivotal studies demonstrated STP efficacy in patients with Dravet syndrome with refractory partial seizures, and marketing authorization in Europe, Canada and Japan was granted thereafter. Post-marketing surveys reported a good efficacy and tolerability profile. In addition, interesting data is currently emerging regarding off-label experimentation of STP in other forms of epilepsy. EXPERT OPINION: STP is an important addition to the limited treatment options available for patients resistant to common AEDs. The possibility to inhibit seizures through the metabolic pathway of lactate dehydrogenase and the inhibitory effects on the entry of Na(+) and Ca(2+) are the most recent findings to emerge about STP and could be proof of its neuroprotective action. Moreover, its positive effects on cognitive function, its good safety and tolerability profile and the increasing data about STP efficacy on other refractory epileptic syndromes may prove to be fertile grounds for further investigation.

Role of nutrition in preventing insulin resistance in children.

Nutrition during prenatal, early postnatal and pubertal period is crucial for the development of insulin resistance and its consequences. During prenatal period fetal environment and nutrition seems to interfere with metabolism programming later in life. The type of dietary carbohydrates, glycemic index, protein, fat and micronutrient content in maternal nutrition could influence insulin sensitivity in the newborn. The effects of lactation on metabolism and nutritional behavior later in life have been studied. Dietary habits and quality of diet during puberty could prevent the onset of a pathological insulin resistance through an adequate distribution of macro- and micronutrients, a diet rich in fibers and vegetables and poor in saturated fats, proteins and sugars. We want to overview the latest evidences on the risk of insulin resistance later in life due to both nutritional behaviors and components during the aforementioned periods of life, following a chronological outline from fetal development to adolescence.

The adverse event profile of levetiracetam: A meta-analysis on children and adults.

PURPOSE: To analyze the adverse events (AEs) significantly associated with levetiracetam (LEV) therapy through a meta-analysis of all available double-blind, randomized placebo-controlled trials (RCTs), performed in any age, gender, ethnic background and disease. General tolerability and study withdrawals due to AEs associated with LEV treatment were also investigated. In addition, a dose-effect responses relationship for all variables was assessed. METHODS: RCTs were identified searching Medline (PubMed), Embase and Cochrane CENTRAL for the words "Levetiracetam" and "randomized controlled trial", with different search strategies, setting the limits "humans" and "English". Very common and common AEs according to the summary of product characteristics were investigated. RevMan version 5.2 was used for the statistical analyses. Risk difference with 95% confidence intervals was used to investigate the association of any AEs and withdrawal with LEV. RESULTS: Twenty-six studies with 2832 patients were included in the RCTs analysis. Nasopharyngitis, somnolence, dizziness, nervousness/irritability and asthenia/fatigue were statistically significant associated with LEV. In addition, LEV was significantly associated with an increased risk of AEs-related withdrawals. No dose-response relationship was found for any of the assessed variables. CONCLUSIONS: This first large meta-analysis suggests that participants were more likely to discontinue LEV than placebo. The AE profile confirmed that LEV is associated with few unfavorable sedative, vestibulocerebellar and behavioral effects, such as nervousness and irritability. However, there does not seem to be a clear dose-response relationship.

Deletion 18p11.32p11.31 in a Child with Global Developmental Delay and Atypical, Drug-Resistant Absence Seizures.

We report the first case of an 18p11.32 deletion, detected by array CGH, associated with a drug-resistant form of atypical absence epilepsy, global developmental delay and no signs of holoprosencephaly (HPE). In particular, this region encompasses 19 genes, and none of these genes have been strictly associated with epilepsy. Among these, TGIF1 is expressed in the fetal and adult nervous system, and its deletion has been related to central nervous system diseases. TGIF1 deletions have previously been reported in patients with a comparable phenotype as seen in our case and in children whose neurological signs and symptoms were considerable, but not epileptiform. Mutations and deletions involving the TGIF1 gene have been described in patients with HPE in an autosomal dominant model of inheritance. However, TGIF1 mutations have also been reported in normal individuals and in patients with mental retardation or showing a very mild phenotype, suggesting the characteristic of incomplete penetrance and variable expressivity. Therefore, a TGIF1 deletion may not be always related to HPE, and it may have a link to the development of epilepsy.

Autonomic neuropathy in diabetes mellitus.

Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes, often overlooked and misdiagnosed. It is a systemic-wide disorder that may be asymptomatic in the early stages. The most studied and clinically important form of DAN is cardiovascular autonomic neuropathy defined as the impairment of autonomic control of the cardiovascular system in patients with diabetes after exclusion of other causes. The reported prevalence of DAN varies widely depending on inconsistent definition, different diagnostic method, different patient cohorts studied. The pathogenesis is still unclear and probably multifactorial. Once DAN becomes clinically evident, no form of therapy has been identified, which can effectively stop or reverse it. Prevention strategies are based on strict glycemic control with intensive insulin treatment, multifactorial intervention, and lifestyle modification including control of hypertension, dyslipidemia, stop smoking, weight loss, and adequate physical exercise. The present review summarizes the latest knowledge regarding clinical presentation, epidemiology, pathogenesis, and management of DAN, with some mention to childhood and adolescent population.