AbstractDisheveled EGL-10 and pleckstrin domain-containing protein 5 (DEPDC5) is a key member of the GAP activity toward rags complex 1 complex, which inhibits the mammalian target of rapamycin complex 1 (mTORC1) pathway. DEPDC5 loss-of-function mutations lead to an aberrant activation of the mTOR signaling. At neuronal level, the increased mTOR cascade causes the generation of epileptogenic dysplastic neuronal circuits and it is often associated with malformation of cortical development. The DEPDC5 phenotypic spectrum ranges from sporadic early-onset epilepsies with poor neurodevelopmental outcomes to familial focal epilepsies and sudden unexpected death in epilepsy; a high rate of inter- and intrafamilial variability has been reported. To date, clear genotype–phenotype correlations have not been proven. More studies are required to elucidate the significance of likely pathogenic/variants of uncertain significance. The pursuit of a molecular targeted antiepileptic therapy is a future challenge.

Objective Hypoxic-ischemic encephalopathy (HIE) is the second cause of neonatal deaths and one of the main conditions responsible for long-term neurological disability. Contrary to past belief, children with mild HIE can also experience long-term neurological sequelae. The aim of this systematic review is to determine the predictive value of long-term neurological outcome of (electroencephalogram) EEG/amplitude-integrated electroencephalogram (aEEG) in children who complained mild HIE. Study Design From a first search on PubMed, Google Scholar, and clinicalTrials.gov databases, only five articles were considered suitable for this study review. A statistical meta-analysis with the evaluation of odds ratio was performed on three of these studies. Results No correlation was found between the characteristics of the electrical activity of the brain obtained through EEG/aEEG in infants with mild HIE and subsequent neurological involvement. Conclusion EEG/aEEG monitoring in infants with mild HIE cannot be considered a useful tool in predicting their neurodevelopmental outcome, and its use for this purpose is reported as barely reliable.

Objective:Epileptic spasms are a type of seizure defined as a sudden flexion or extension predominantly of axial and/or truncal limb muscles that occur with a noticeable periodicity. Routine electroencephalogram supports the diagnosis of epileptic spasms, which can occur due to different causes. The present study aimed to evaluate a possible association between the electro-clinical pattern and the underlying etiology of epileptic spasms in infants.Materials and methods:We retrospectively reviewed the clinical and video-EEG data on 104 patients (aged from 1 to 22  months), admitted to our tertiary hospital in Catania and the tertiary hospital in Buenos Aires, from January 2013 to December 2020, with a confirmed diagnosis of epileptic spasms. We divided the patient sample into structural, genetic, infectious, metabolic, immune, and unknown, based on etiology. Fleiss' kappa (К) was used to assess agreement among raters in the electroencephalographic interpretation of hypsarrhythmia. A multivariate and bivariate analysis was conducted to understand the role of the different video-EEG variables on the etiology of epileptic spasms. Furthermore, decision trees were constructed for the classification of variables.Results:The results showed a statistically significant correlation between epileptic spasms semiology and etiology: flexor spasms were associated with spasms due to genetic cause (87.5%; OR < 1); whereas mixed spasms were associated with spasms from a structural cause (40%; OR < 1). The results showed a relationship between ictal and interictal EEG and epileptic spasms etiology: 73% of patients with slow waves and sharp waves or slow waves on the ictal EEG, and asymmetric hypsarrhythmia or hemi hypsarrhythmia on the interictal EEG, had spasms with structural etiology, whereas 69% of patients with genetic etiology presented typical interictal hypsarrhythmia with high-amplitude polymorphic delta with multifocal spike or modified hypsarrhythmia on interictal EEG and slow waves on the ictal EEG.Conclusion:This study confirms that video-EEG is a key element for the diagnosis of epileptic spasms, also playing an important role in the clinical practice to determine the etiology.

Treatment of childhood seizures is a pressing challenge within neuropediatrics because of its severe impact to the children and families affected by these debilitating disorders. It is of upmost importance to make an early diagnosis, to start a promptly treatment, to use therapy and dosage of the drug appropriately, based on the specific epileptic type and epileptic syndrome. Single therapy with appropriate dosage is the main approach to treatment. When the drug is the cause of an idiosyncratic reaction it is advisable to replace the suboptimal seizure response with another antiepileptic drug, combined therapy with two antiepileptic drugs is also a viable option. In childhood, polytherapy using more than two antiepileptic drugs remains controversial because the harm of interaction with deleterious drugs could potentially replace the damage caused by the seizures themselves. The use of three or more antiepileptic drugs should be limited to epileptic seizures that are particularly resistant to drugs and when non-drug antiepileptic therapies have failed. An approach to the difficult topic of epileptic treatment in childhood is reported. Key point: mono vs polytherapy in epileptic children; single and alternative therapy in epileptic children; use or three or more AEDs in children.

Neonatal seizures (NS) occur in the first 28 days of life; they represent an important emergency that requires a rapid diagnostic work-up to start a prompt therapy. The most common causes of NS include: intraventricular haemorrhage, hypoxic-ischemic encephalopathy, hypoglycemia, electrolyte imbalance, neonatal stroke or central nervous system infection. Nevertheless, an Inborn Error of Metabolism (IEM) should be suspected in case of NS especially if these are resistant to common antiseizure drugs (ASDs) and with metabolic decompensation. Nowadays, Expanded Newborn Screening (ENS) has changed the natural history of some IEMs allowing a rapid diagnosis and a prompt onset of specific therapy; nevertheless, not all IEMs are detected by such screening (e.g. Molybdenum-Cofactor Deficiency, Hypophosphatasia, GLUT1-Deficiency Syndrome) and for this reason neonatologists have to screen for these diseases in the diagnostic work-up of NS. For IEMs, there are not specific semiology of seizures and EEG patterns. Herein, we report a systematic review on those IEMs that lead to NS and epilepsy in the neonatal period, studying only those IEMs not included in the ENS with tandem mass, suggesting clinical, biochemical features, and diagnostic work-up. Remarkably, we have observed a worse neurological outcome in infants undergoing only a treatment with common AED for their seizures, in comparison to those primarily treated with specific anti-convulsant treatment for the underlying metabolic disease (e.g.Ketogenic Diet, B6 vitamin). For this reason, we underline the importance of an early diagnosis in order to promptly intervene with a targeted treatment without waiting for drug resistance to arise.

A short review on the clinical presentation of pediatrics cases of Bickerstaff brain encephalitis emphasizing the broad clinical spectrum of the disease. Cases of pediatric Bickerstaff's brainstem encephalitis collected on three electronic medical databases (PubMed, Cochrane Library and Scopus Web of Science) are reviewed. The inclusion criteria of the cases were based on the clinical characteristics of the disorder in the pediatric age. We reviewed 20 articles on Bickerstaff's brainstem encephalitis, identifying 40 pediatric cases focused on the clinical symptoms. We saw that the prevalence was higher in male subjects, and the median age at diagnosis was 8 years. The phenotype of pediatrics patients was similar to previously published literature. We identify three cases of overlapping forms between Bickerstaff brain encephalitis and Guillain-Barré Syndrome in patients with lower limbs weakness and typical signs of Bickerstaff brain encephalitis, suggesting a combined involvement of the central and peripheral nervous system. Although there is no defined data on incidence and prevalence in the literature, Bickerstaff's brainstem encephalitis appears to be a rare disorder, especially in children. The incidence of Bickerstaff brain encephalitis and Guillain-Barré Syndrome, and Miller Fisher Syndrome has been underrated in the past, primarily due to an underestimation of the forms with a Peripheral Nervous System involvement. Bickerstaff brain encephalitis usually has a rapid and acute onset within 2-4 weeks, characterized by a typical picture of ophthalmoplegia, hyperreflexia, cerebellar symptoms as ataxia. The subsequent manifestations of hyperreflexia or consciousness disturbances as drowsiness, sleepiness, or coma, indicative of central involvement, suggest a Bickerstaff brain encephalitis clinical diagnosis.

Background : PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder associated with Streptococcal Infection) are heterogeneous syndromes identified as post-infectious complications regarding Central Nervous System with specific involvement of neuropsychiatric and behavioral skills. The various treatment strategies employed focus on elimination of inciting infectious agents (antibiotics), support of the immune system (intravenous immunoglobulin, IVIG), suppression of the autoimmune mechanism (IVIG, plasmapheresis, steroids), and/or direct treatment of psychiatric symptoms (antidepressants, anxiolytics, mood stabilizers). However, especially in the last 20 years, the surgical role of tonsillectomy / adenoidectomy has assumed greater importance in the scientific literature, although presenting conflicting results it has however been included in the list of treatments available for PANDAS. Material and methods : A structured search of the MEDLINE online database (time interval from 2000 to 2020) was undertaken. Keywords “PANDAS” were combined with “tonsillectomy”. The criteria for inclusion of citations were English language case reports and case series with confirmed and definitive cases of PANDAS according to the Institute of Mental Health Clinical Diagnostic Criteria for PANDAS. Discussion: We performed a mini review of the literature to evaluate the published evidence regarding surgical treatment (tonsillectomy) of PANDAS . We compared the main selected studies of the last twenty years on the subject, noting a progressive loss of importance of the use of the wide-ranging surgical method. Conclusions : Over the years, surgical treatment seems to have assumed a second level position in the main treatments of the disease. But in a multidisciplinary approach to the disease some patients can still benefit from this method. In the next future a multidisciplinary program must be tailored to a child’s specific needs.

Pediatric acute-onset neuropsychiatric syndrome (PANS) is a condition characterized by the abrupt, dramatic onset of obsessive–compulsive disorder (OCD) or eating restriction accompanied by equally abrupt and severe comorbid neuropsychiatric symptoms. PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection) is a heterogeneous syndrome identified as post-Streptococcus pyogenes infection (β-hemolytic Streptococcus group A) complications regarding the central nervous system with specific involvement of neuropsychiatric and behavioral skills. In the first part of our study, we share our experience in the treatment of a group of extreme-grade (according to CY-BOCS severity scale) symptomatic patients with intravenous immunoglobulin (IVIG), following the most recent studies regarding the dosage of the drug. Our contribution is to share our experience made on a sample of 55 patients all in the highest level of a severity grade. In the second part of our study, we also analyze the literature on PANS/PANDAS rehabilitation therapy, since in the literature there is no discussion of union and comparison on this method. Objective: This study aims to evaluate the clinical features of the patients observed from different Italian cohorts, with the attempt at evaluating clinical response to IVIG treatment in children with an extreme severity grade of PANS/PANDAS disease. Furthermore, after having analyzed the literature, we propose rehabilitation therapy as an added value to the pharmacological treatment. Materials and Methods: A total of 55 patients with a diagnosis of PANS/PANDAS, who belonged to an extreme grade of disease, were enrolled. All patients were administered with IVIG treatment at 2 g/kg per day for two consecutive days. Results: From our study, a noticeable improvement (until complete remission) of symptoms was evident for at least one year in 47 out of 55 (85%) observed children, while 11 out of these 43 (25%) showed an evident symptoms remission in a single attempt and the remaining 32 (75%) required a second administration to notice a lasting symptomatic improvement.

The 8p inverted duplication/deletion is a rare chromosomal rearrangement clinically featuring neurodevelopmental delay, mild to severe cognitive impairment, heart congenital defects and brain abnormalities. Patients affected also present typical facial dysmorphisms and skeletal malformations, and it is thought that the composite clinical picture may fall into the chromosomal rearrangement architecture. With the major aim of better framing its related clinical and diagnostic paths, we describe a patient carrying a de novo invdupde[8p] whose clinical features have not been described so far. Hence, through an extensive genotype–phenotype correlation analysis and by reviewing the dedicated scientific literature, we compared our patient’s features with those reported in other patients, which allows us to place our proband’s expressiveness in an intermediate area, widening the scope of the already known invdupde[8p] genotype–phenotype relationship.