Molecular Mechanism Involved in the Pathogenesis of Early-Onset Epileptic Encephalopathy

Recent studies have shown that neurologic inflammation may both precipitate and sustain seizures, suggesting that inflammation may be involved not only in epileptogenesis but also in determining the drug-resistant profile. Extensive literature data during these last years have identified a number of inflammatory markers involved in these processes of "neuroimmunoinflammation" in epilepsy, with key roles for pro-inflammatory cytokines such as: IL-6, IL-17 and IL-17 Receptor (IL-17R) axis, Tumor-Necrosis-Factor Alpha (TNF-α) and Transforming-Growth-Factor Beta (TGF-β), all responsible for the induction of processes of blood-brain barrier (BBB) disruption and inflammation of the Central Nervous System (CNS) itself. Nevertheless, many of these inflammatory biomarkers have also been implicated in the pathophysiologic process of other neurological diseases. Future studies will be needed to identify the disease-specific biomarkers in order to distinguish epilepsies from other neurological diseases, as well as recognize different epileptic semiology. In this context, biological markers of BBB disruption, as well as those reflecting its integrity, can be useful tools to determine the pathological process of a variety of neurological diseases. However; how these molecules may help in the diagnosis and prognostication of epileptic disorders remains yet to be determined. Herein, authors present an extensive literature review on the involvement of both, systemic and neuronal immune systems, in the early onset of epileptic encephalopathy

A clinical review on megalencephaly: A large brain as a possible sign of cerebral impairment.

Megalencephaly and macrocephaly present with a head circumference measurement 2 standard deviations above the age-related mean. However, even if pathologic events resulting in both megalencephaly and macrocephaly may coexist, a distinction between these two entities is appropriate, as they represent clinical expression of different disorders with a different approach in clinical work-up, overall prognosis, and treatment. Megalencephaly defines an increased growth of cerebral structures related to dysfunctional anomalies during the various steps of brain development in the neuronal proliferation and/or migration phases or as a consequence of postnatal abnormal events. The disorders associated with megalencephaly are classically defined into 3 groups: idiopathic or benign, metabolic, and anatomic. In this article, we seek to underline the clinical aspect of megalencephaly, emphasizing the main disorders that manifest with this anomaly in an attempt to properly categorize these disorders within the megalencephaly group

Congenital muscular dystrophy: from muscle to brain.

Congenital muscular dystrophies (CMDs) are a wide group of muscular disorders that manifest with very early onset of muscular weakness, sometime associated to severe brain involvement.The histologic pattern of muscle anomalies is typical of dystrophic lesions but quite variable depending on the different stages and on the severity of the disorder.Recent classification of CMDs have been reported most of which based on the combination of clinical, biochemical, molecular and genetic findings, but genotype/phenotype correlation are in constant progression due to more diffuse utilization of the molecular analysis.In this article, the Authors report on CMDs belonging to the group of dystroglycanopathies and in particular on the most severe forms represented by the Fukuyama CMD, Muscle-Eye-Brain disease and Walker Walburg syndrome.Clinical diagnosis of infantile hypotonia is particularly difficult considering the different etiologic factors causing the lesions, the difficulty in localizing the involved CNS area (central vs. peripheral) and the limited role of the diagnostic procedures at this early age.The diagnostic evaluation is not easy mainly in differentiating the various types of CMDs, and represents a challenge for the neonatologists and pediatricians. Suggestions are reported on the way to reach a correct diagnosis with the appropriate use of the diagnostic means

Short-Term Neurodevelopmental Outcome in Term Neonates Treated with Phenobarbital versus Levetiracetam: A Single-Center Experience

BACKGROUND: Phenobarbital (PB) has been traditionally used as the first-line treatment for neonatal seizures. More recently, levetiracetam (LEV) has been increasingly used as a promising newer antiepileptic medication for treatment of seizures in neonates. OBJECTIVES: The aim of our study was to compare the effect of PB vs. LEV on short-term neurodevelopmental outcome in infants treated for neonatal seizures. METHOD: This randomized, one-blind prospective study was conducted on term neonates admitted to the Neonatal Intensive Care Unit of S. Bambino Hospital, University Hospital "Policlinico-Vittorio Emanuele," Catania, Italy, from February 2016 to February 2018. Thirty term neonates with seizures were randomized to receive PB or LEV; the Hammersmith Neonatal Neurological Examination (HNNE) was used at baseline (T0) and again one month after the initial treatment (T1). RESULTS: We found a significantly positive HNNE score for the developmental outcomes, specifically tone and posture, in neonates treated with LEV. There was no significant improvement in the HNNE score at T1 in the neonates treated with PB. CONCLUSION: This study suggests a positive effect of levetiracetam on tone and posture in term newborns treated for neonatal seizures. If future randomized-controlled studies also show better efficacy of LEV in the treatment of neonatal seizures, LEV might potentially be considered as the first-line anticonvulsant in this age grou

PRRT2 gene variant in a child with dysmorphic features, congenital microcephaly, and severe epileptic seizures: genotype-phenotype correlation?

BACKGROUND: Mutations in Proline-rich Transmembrane Protein 2 (PRRT2) have been primarily associated with individuals presenting with infantile epilepsy, including benign familial infantile epilepsy, benign infantile epilepsy, and benign myoclonus of early infancy, and/or with dyskinetic paroxysms such as paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, and exercise-induced dyskinesia. However, the clinical manifestations of this disorder vary widely. PRRT2 encodes a protein expressed in the central nervous system that is mainly localized in the pre-synaptic neurons and is involved in the modulation of synaptic neurotransmitter release. The anomalous function of this gene has been proposed to cause dysregulation of neuronal excitability and cerebral disorders. CASE PRESENTATION: We hereby report on a young child followed-up for three years who presents with a spectrum of clinical manifestations such as congenital microcephaly, dysmorphic features, severe intellectual disability, and drug-resistant epileptic encephalopathy in association with a synonymous variant in PRRT2 gene (c.501C > T; p.Thr167Ile) of unknown clinical significance variant (VUS) revealed by diagnostic exome sequencing. CONCLUSION: Several hypotheses have been advanced on the specific role that PRRT2 gene mutations play to cause the clinical features of affected patients. To our knowledge, the severe phenotype seen in this case has never been reported in association with any clinically actionable variant, as the missense substitution detected in PRRT2 gene. Intriguingly, the same mutation was reported in the healthy father: the action of modifying factors in the affected child may be hypothesized. The report of similar observations could extend the spectrum of clinical manifestations linked to this mutation

Total Hemi-overgrowth in Pigmentary Mosaicism of the (Hypomelanosis of) Ito Type: Eight Case Reports.

Pigmentary mosaicism of the (hypomelanosis of) Ito type is an umbrella term, which includes phenotypes characterized by mosaic hypopigmentation in the form of streaks, whorls, patchy, or more bizarre skin configurations (running along the lines of Blaschko): these cutaneous patterns can manifest as an isolated skin disorder (pigmentary mosaicism of the Ito type) or as a complex malformation syndrome in association with extracutaneous anomalies (most often of the musculoskeletal and/or nervous systems) (hypomelanosis of Ito). Affected individuals are anecdotally reported to have also partial or total body hemi-overgrowth (HOG), which often causes moderate to severe complications.We studied the occurrence and features of HOG in the 114 children and adults with mosaic pigmentary disorders of the Ito type diagnosed and followed up (from 2 to 22 years; average follow-up 16 years) at our Institutions.Eight patients (5 M, 3 F; aged 4 to 25 years; median age 16 years) out of the 114 analyzed (7%) fulfilled the criteria for unilateral HOG, with differences in diameter ranging from 0.4 to 4.0 cm (upper limbs) and 1.0 to 9.0 cm (lower limbs). Moreover, among these 8 patients, 5/8 filled in the 75th to 90th percentile for height; 6/8 had associated kyphoscoliosis; and 5/8 showed cognitive delays. No tumour complications were recorded. Overall, 6/8 HOG patients presented with additional (extracutaneous) syndromic manifestations, apart from the HOG (ie, with a clinical phenotype of hypomelanosis of Ito).The present study, which includes children and adults with the longest follow-up so far recorded, confirms the association between pigmentary mosaicism of the Ito type and HOG lowering previous estimates (7% vs 16%) for HOG in the context of mosaic hypopigmentation. A careful examination, looking at subtle to moderate asymmetries and associated complications within the spectrum of these mosaic pigmentary disorders, is recommended

Current status of laboratory and imaging diagnosis of neonatal necrotizing enterocolitis

Necrotizing enterocolitis continues to be a devastating disease process for very low birth weight infants in Neonatal Intensive Care Units. The aetiology and pathogenesis of necrotizing enterocolitis are not definitively understood. It is known that necrotizing enterocolitis is secondary to a complex interaction of multiple factors that results in mucosal damage, which leads to intestinal ischemia and necrosis. Advances in neonatal care, including resuscitation and ventilation support technology, have seen increased survival rates among premature neonates and a concomitant detection in the incidence of this intestinal disease.Diagnosis can be difficult, and identifying infants at the onset of disease remains a challenge. Early diagnosis, which relies on imaging findings, and initiation of prompt therapy are essential to limit morbidity and mortality. Moreover, early management is critical and life-saving.This review summarizes what is known on the laboratory and instrumental diagnostic strategies needed to improve neonatal outcomes and, possibily, to prevent the onset of an overt necrotizing enterocolitis

Celiac disease and headache in children: A narrative state of the art

Celiac disease (CD) is one of the most important entity of the wide spectrum of gluten-related disorders (GRDs). It is well known that neurological manifestation can be present either at the onset of CD, or appear during the development of the pathology, and different can be the neurologic findings. Clinical features are very variable, ranging from typical manifestations of gastrointestinal involvement to neurologic symptom. The most frequent neurologic signs reported were headache, epileptic seizure, migraine, mental retardation, ataxia and attention deficit and hyperactive disorder. Headache either in form of migraine, or in non-specific form represents one of the main clinical presentation in CD. The aim of this work is to provide a narrative review of the pediatric literature focused on the cephalalgic features of children with CD evaluating the potential benefits of a gluten free diet (GFD). Papers were identified by searching for related literature in Medline (PubMed) and Embase using the words “Celiac Disease” and “Headache” or “Migraine” by specifying “children”/“paediatric age” for reports published since 1972 till 31th October 2018. According to our inclusion criteria, a total of 25 papers has been evaluated. Although it is still controversial if headache is prevalent in CD children a correct compliance to a GFD seems to improve the neurological symptoms even if the underlying pathogenic relationship between CD and neurologic system involvement is still not fully understood. (www.actabiomedica.it)

Congenital generalized hypertrichosis: The skin as a clue to complex malformation syndromes

Hypertrichosis is defined as an excessive growth in body hair beyond the normal variation compared with individuals of the same age, race and sex and affecting areas not predominantly androgen-dependent. The term hirsutism is usually referred to patients, mainly women, who show excessive hair growth with male pattern distribution. Hypertrichosis is classified according to age of onset (congenital or acquired), extent of distribution (generalized or circumscribed), site involved, and to whether the disorder is isolated or associated with other anomalies. Congenital hypertrichosis is rare and may be an isolated condition of the skin or a component feature of other disorders. Acquired hypertrichosis is more frequent and is secondary to a variety of causes including drug side effects, metabolic and endocrine disorders, cutaneous auto-inflammatory or infectious diseases, malnutrition and anorexia nervosa, and ovarian and adrenal neoplasms. In most cases, hypertrichosis is not an isolated symptom but is associated with other clinical signs including intellective delay, epilepsy or complex body malformations. A review of congenital generalized hypertrichosis is reported with particular attention given to the disorders where excessive diffuse body hair is a sign indicating the presence of complex malformation syndromes. The clinical course of a patient, previously described, with a 20-year follow-up is reported