GLUT-1DS resistant to ketogenic diet: from clinical feature to in silico analysis. An exemplificative case report with a literature review.

Glucose transporter type 1 deficiency syndrome (GLUT-1DS) is characterized by alterations in glucose translocation through the blood-brain barrier (BBB) due to mutation involving the GLUT-1 transporter. The fundamental therapy is ketogenic diet (KD) that provide an alternative energetic substrate - ketone bodies that across the BBB via MCT-1 - for the brain. Symptoms are various and include intractable seizure, acquired microcephalia, abnormal ocular movement, movement disorder, and neurodevelopment delay secondary to an energetic crisis for persistent neuroglycopenia. KD is extremely effective in controlling epileptic seizures and has a positive impact on movement disorders and cognitive impairment. Cases of KD resistance are rare, and only a few of them are reported in the literature, all regarding seizure. Our study describes a peculiar case of GLUT-1DS due to a new deletion involving the first codon of SLC2A1 gene determining a loss of function with a resistance to KD admitted to hospital due to intractable episodes of dystonia. This patient presented a worsening of symptomatology at higher ketonemia values but without hyperketosis and showed a complete resolution of symptomatology while maintaining low ketonemia values. Our study proposes an in-silico genomic and proteomic analysis aimed at explaining the atypical response to KD exhibited by our patient. In this way, we propose a new clinical and research approach based on precision medicine and molecular modelling to be applied to patients with GLUT-1DS resistant to first-line treatment with ketogenic diet by in silico study of genetic and altered protein product.

Obesity as a Confounding Factor in the Diagnosis of Wilson's Disease: Case Report of Two Siblings with the Same Genotype but Different Clinical Courses.

Wilson's disease (WD) is a biallelic disease-causing variant in the ATP7B gene on chromosome 13q14.3 that results in copper accumulation in many organs, particularly the liver and brain. The phenotypic spectrum is wide and symptoms at onset can be heterogeneous. We describe two Sicilian siblings, a young man and his elder sister, both compound heterozygous for the variants c.1286-2A>G and c.2668G>A (p.Val890Met) in the ATB7B gene. The male patient presented with liver cirrhosis, which quickly progressed to end-stage liver disease (Child-Pugh score = C10), while his sister had moderate steatotic liver disease (SLD). Our findings highlight that SLD may not always be related to obesity in overweight patients, especially when there are other potential risk factors such as a family history of chronic liver disease, or the persistence of high transaminase despite the adoption of adequate dietary and pharmacological intervention. Screening for conditions such as WD could identify patients at risk of developing SLD and avoid delays in diagnosis. Phenotypic variability in WD is considerable; therefore, further studies are needed to identify which WD patients have a greater risk of developing SLD and determine factors that can predict the severity of the disease.

Clinical, prognostic and pathophysiological implications of MOG-IgG detection in the CSF: the importance of intrathecal MOG-IgG synthesis.

BACKGROUND: Cerebrospinal fluid myelin oligodendrocyte glycoprotein IgG (CSF MOG-IgG) are found in a proportion of patients with MOG antibody-associated disorder (MOGAD) and have been associated with severe disease presentations. However, most studies did not systematically investigate the role of MOG-IgG intrathecal synthesis (ITS). METHODS: We retrospectively studied 960 consecutive patients with paired serum and CSF samples screened for MOG-IgG using a live cell-based assays. MOG-IgG-specific antibody index (AIMOG) was systematically calculated using serum and CSF titres to assess MOG-IgG ITS, and clinical features were compared between MOG-IgG CSF+/CSF- and ITS+/ITS- patients. RESULTS: MOG-IgG were found in 55/960 patients (5.7%; serum+/CSF-: 58.2%, serum+/CSF+: 34.5%; serum-/CSF+: 7.3%). Serum/CSF MOG-IgG titres showed a moderate correlation in patients without ITS (ρ=0.47 (CI 0.18 to 0.68), p<0.001), but not in those with ITS (ρ=0.14 (CI -0.46 to -0.65), p=0.65). There were no clinical-paraclinical differences between MOG-IgG CSF+ vs CSF- patients. Conversely, patients with MOG-IgG ITS showed pyramidal symptoms (73% vs 32%, p=0.03), spinal cord involvement (82% vs 39%, p=0.02) and severe outcome at follow-up (36% vs 5%, p=0.02) more frequently than those without MOG-IgG ITS. A multivariate logistic regression model indicated that MOG-IgG ITS was an independent predictor of a poor outcome (OR: 14.93 (CI 1.40 to 19.1); p=0.03). AIMOG correlated with Expanded Disability Status Scale (EDSS) scores at disease nadir and at last follow-up (p=0.02 and p=0.01). CONCLUSIONS: Consistently with physiopathology, MOG-IgG ITS is a promising prognostic factor in MOGAD, and its calculation could enhance the clinical relevance of CSF MOG-IgG testing, making a case for its introduction in clinical practice.

Prognostic relevance of quantitative and longitudinal MOG antibody testing in patients with MOGAD: a multicentre retrospective study.

BACKGROUND: IgG antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) define a subset of associated disorders (myelin oligodendrocyte glycoprotein associated disorders (MOGAD)) that can have a relapsing course. However, information on relapse predictors is scarce. The utility of retesting MOG-IgG over time and measuring their titres is uncertain. We aimed to evaluate the clinical relevance of longitudinal MOG-IgG titre measurement to predict relapses in patients with MOGAD. METHODS: In this retrospective multicentre Italian cohort study, we recruited patients with MOGAD and available longitudinal samples (at least one >3 months after disease onset) and tested them with a live cell-based assay with endpoint titration (1:160 cut-off). Samples were classified as 'attack' (within 30 days since a disease attack (n=59, 17%)) and 'remission' (≥31 days after attack (n=295, 83%)). RESULTS: We included 102 patients with MOGAD (57% adult and 43% paediatric) with a total of 354 samples (83% from remission and 17% from attack). Median titres were higher during attacks (1:1280 vs 1:640, p=0.001). Median onset titres did not correlate with attack-related disability, age or relapses. Remission titres were higher in relapsing patients (p=0.02). When considering the first remission sample available for each patient, titres >1:2560 were predictors of relapsing course in survival (log rank, p<0.001) and multivariate analysis (p<0.001, HR: 10.9, 95% CI 3.4 to 35.2). MOG-IgG seroconversion to negative was associated with a 95% relapse incidence rate reduction (incidence rate ratio: 0.05, p<0.001). CONCLUSIONS: Persistent MOG-IgG positivity and high remission titres are associated with an increased relapse risk. Longitudinal MOG-IgG titres could be useful to stratify patients to be treated with long term immunosuppression.

KCNQ2-Related Epilepsy: Genotype-Phenotype Relationship with Tailored Antiseizure Medication (ASM)-A Systematic Review.

BACKGROUND: Autosomal dominant mutations of the KCNQ2 gene can cause two epileptic disorders: benign familial neonatal seizures (BFNS) and developmental epileptic encephalopathy (DEE). This systematic review aims to identify the best reported therapy for these patients, relating to phenotype, neurodevelopmental outcome, and an eventual correlation between phenotype and genotype. METHODS: We searched on PubMed using the search terms "KCNQ2" AND "therapy" and "KCNQ2" AND "treatment"; we found 304 articles. Of these, 29 met our criteria. We collected the data from 194 patients. All 29 articles were retrospective studies. RESULTS: In all, 104 patients were classified as DEE and 90 as BFNS. After treatment began, 95% of BFNS patients became seizure free, whereas the seizures stopped only in 73% of those with DEE. Phenobarbital and sodium channel blockers were the most used treatment in BFNS. Most of the DEE patients (95%) needed polytherapy for seizure control and even that did not prevent subsequent developmental impairment (77%).Missense mutations were discovered in 96% of DEE patients; these were less common in BFNS (50%), followed by large deletion (16%), truncation (16%), splice donor site (10%), and frameshift (7%). CONCLUSION: Phenobarbital or carbamazepine appears to be the most effective antiseizure medication for children with a "benign" variant. On the contrary, polytherapy is often needed for DEE patients, even if it does not seem to improve neurological outcomes. In DEE patients, most mutations were located in S4 and S6 helix, which could serve as a potential target for the development of more specific treatment in the future.

Ketogenic Diet in Neonates with Drug-Resistant Epilepsy: Efficacy and Side Effects-A Single Center's Initial Experience.

BACKGROUND: For patients with pharmacoresistant epilepsy, a therapeutic option is ketogenic diet. Currently, data on young infants are scarce, particularly during hospitalization in the neonatal intensive care unit (NICU). OBJECTIVE: The aim of the present study was to evaluate the short-term (3-month) efficacy and side effects of ketogenic diet in infants with "drugs-resistant" epilepsy treated during NICU stay. METHODS: This retrospective study included infants aged under 2 months started on ketogenic diet during NICU hospitalization to treat drug-resistant epilepsy from April 2018 to November 2022. RESULTS: Thirteen term-born infants were included, three (23.1%) of whom were excluded because they did not respond to the ketogenic diet. Finally, we included 10 infants. Six (60%) patients took three antiepileptics before starting the ketogenic diet, while four (40%) took more drugs. Diet had a good response in four (40%) patients. In four patients, the ketogenic diet was suspended because of the onset of serious side effects. The emetic levels of sodium, potassium, and chlorine, pH, and onset of diarrhea, constipation, and gastroesophageal reflux showed significant differences. Ketonuria was higher and blood pH lower in the group that took more than three drugs than in the group taking fewer than three drugs. CONCLUSION: The ketogenic diet is efficacious and safe in infants, but the early and aggressive management of adverse reactions is important to improve the safety and effectiveness of the ketogenic treatment.

Mild Hypoxic-Ischemic Encephalopathy: Can Neurophysiological Monitoring Predict Unfavorable Neurological Outcome? A Systematic Review and Meta-analysis.

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. KEY POINTS: · HIE is responsible for long-term neurological outcome, even in newborns with mild HIE.. · No correlation was found between EEG/aEEG trace in infants with mild HIE and neurological sequelae.. · Neurophysiological monitoring, in mild HIE, cannot predic neurodevelopmental outcome..

Mosaic RASopathies: A review of disorders caused by somatic pathogenic variants in the genes of the RAS/MAPK pathway.

Mosaic RASopathies are a heterogeneous group of diseases characterized by the presence at birth or early onset of congenital anomalies, cutaneous and vascular anomalies, segmental overgrowth, and increased cancer risk. They are caused by somatic pathogenic variants of the genes belonging the RAt Sarcoma Mitogen-activated protein kinase (RAS/MAPK) pathway causing its hyperactivation. Here, we review the clinical and molecular characteristics of this heterogeneous group of diseases, including the possibilities of molecular diagnosis and new therapeutic perspectives.

A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease.

PURPOSE: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. METHODS: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. RESULTS: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. CONCLUSION: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration.

Multiple primary malignances managed with surgical excision: a case report with next generation sequencing analysis.

BACKGROUND: Multiple primary malignancies (MPM) are defined as tumors originating in the same individual without any correlation between them. In addition to morphological and immunohistochemical analyses, sensitive DNA sequencing methods such as next generation sequencing (NGS) may help to discriminate the common or different genetic alterations driving each malignancy, to better diagnose these uncommon cases. METHODS AND RESULTS: Here we report the case of a man who developed a poorly differentiated gastric adenocarcinoma invading the pancreas followed, two years later, by a colorectal cancer involving also the kidney and the diaphragm. Despite the advanced stage of both diseases, adjuvant chemotherapy was successful. While the second tumor was initially interpreted as a relapse of his stomach cancer, NGS-based mutation profiling of the two carcinomas revealed two distinct malignances, independently developing in different times and indicative of metachronous MPM. Indeed, sequencing of cancer-associated genes identified somatic mutations only in the first gastric cancer, besides germline variants on three different genes (PDGFRA, APC and TP53). However, analysis of both somatic and germline mutations with bio-informatics prediction tools failed to find a correlation between these variants and the unexpectedly good prognosis of both cancers. CONCLUSIONS: In summary, NGS analysis contributed to defined different molecular profiles for two tumors developed in the span of two years, thus allowing diagnosing the case as MPN. However, NGS was unable to establish a direct correlation between the identified alterations and cancer development.

Neonatal ischemic limb lesions: From etiology to topical nitroglycerine. A case series analysis.

Although rare, ischemic lesions in neonates may occur in Neonatal Intensive Care Units (NICUs) secondary to routine procedures and/or medicaments. We present double-center case series, reporting three preterm neonates with ischemic lesions following cardiac arrest and radial blood sampling. The overall outcome after treatment with 2% nitroglycerine (NTG) ointment showed optimal results with no adverse events. The most frequent causes responsible for the onset of such lesions are peripheral arterial catheterization procedures and dopamine extravasation. Our series describe the cardiac arrest as an underestimated cause of onset. Despite the optimal results emerging from the treatment of such lesions with NTG ointment, both in our experience and in the scientific literature, a defined protocol for its use in NICUs is not currently available, hence the need for further studies.

Evidences of emerging pain consciousness during prenatal development: a narrative review.

BACKGROUND: The study of consciousness has always been considered a challenge for neonatologists, even more when considering the uterine period. Our review aimed to individuate at what gestational age the fetus, which later became a premature infant, can feel the perception of external stimuli. Therefore, the aim of our review was to study the onset of consciousness during the fetal life. MATERIALS AND METHODS: A literature search was performed in Medline-PubMed database. We included all papers found with the following MeSH words: "consciousness or cognition or awareness or comprehension or cognitive or consciousness of pain" in combination with "embryo or fetus or fetal life or newborn." Studies were selected if titles and/or abstracts suggested an association between formation of consciousness (the basics of neurodevelopment) and preterm infant or fetus. Titles and abstracts were first screened by three independent reviewers according to Cochrane Collaboration's recommendations. RESULTS: From the literature review, we found only 8 papers describing the onset of consciousness in the transition period from fetus to premature newborn. Therefore, according to these papers, we temporally analyzed the formation of the thalamocortical connections that are the basis of consciousness. CONCLUSIONS: We can conclude that from a neuroanatomical point of view, it is rather unlikely that the infant can be seen as a conscious human before 24 weeks of gestational age, thus before all the thalamocortical connections are established. Further literature data have to confirm this hypothesis.

Pathogenic correlation between mosaic variegated aneuploidy 1 (MVA1) and a novel BUB1B variant: a reappraisal of a severe syndrome.

BACKGROUND: The BUB 1 mitotic checkpoint serine/threonine kinase B (BUB1B) gene encodes a key protein in the mitotic spindle checkpoint, which acts as a surveillance mechanism, crucial for the maintenance of the correct chromosome number during cell deviation. Mutations of BUB1B gene are linked to mosaic variegated aneuploidy 1 (MVA1) syndrome, a rare autosomal recessive disorder characterized by widespread mosaic aneuploidies, involving different chromosomes and tissues. MVA1 is clinically characterized by intrauterine growth restriction, post-natal growth retardation, and severe neurologic impairment including microcephaly, developmental delay/intellectual disability, epileptic seizures, and generalized hypotonia. Malignancies are also serious sequelae associated with the disorder. We reported on a case of two-year-old Italian girl with MVA1 who shows severe neurologic impairment, microcephaly and epileptic seizures. MATERIALS AND METHODS: Clinical data collection and genetic diagnosis of the patient were assessed. Mutational analysis covers the chromosomal microarray analysis, the gene methylation pattern studied using the methylation-specific multiplex ligation-dependent probe amplification, and the family-based Whole Exome Sequencing (WES). A literature research based on reported cases of MVA and premature chromatid separation was also included. RESULTS: Karyotyping has revealed 12% of mosaics in the patient who carries a novel variant in BUB1B gene (c.2679A > T, p.Arg893Ser) detected by WES. Thirty-one cases of MVA1 including the present report, and four prenatally diagnosed cases with MVA1 were selected and inspected. CONCLUSION: Clinical and genetic findings reported in the girl strongly suggest a new MVA1 genotype-phenotype correlation and lead to a reappraisal of a severe syndrome. Diagnosis and in-depth follow-up provided worthwhile data.

Autoimmune encephalitis and CSF anti-AMPA GluR3 antibodies in childhood: a case report and literature review.

Acute autoimmune encephalitis is a severe neurological disorder presenting with altered level of consciousness, confusion, irritability, headache, vomiting, and in some cases seizures. An infective event precedes by 1-2 weeks the onset of the symptoms. Cognitive impairment is considered the cardinal symptom. The autoimmune encephalitis comprises an increasingly group of inflammatory brain disorder caused by an underlying abnormal immune response to the CNS to the infective agent. In children, several antibodies have been recorded as causative agent. Among these, GAD65, MOG, and NMDAR antibodies are more commonly reported and with less frequency, the Dopamine-2 receptor, GABA A receptor, GABA B receptor, and Glycinereceptorandm-GluR5. We report here a 10-year-old male with acute autoimmune encephalitis with altered status of consciousness and severe cerebral involvement at the brain-MRI. Serum and cerebrospinal fluid disclosed the presence of anti-AMPA-GluR3 antibodies suggesting a possible pathogenetic correlation with the disorder presented by the proband. Precocious treatment with intravenous methylprednisolone and immunoglobulin resulted in progressive but constant improvement. At 3-month follow-up, the clinical condition of the child and the neuro-radiological brain anomalies returned to the normal. At the 2-year follow-up, no recurrence or other disturbances were reported.

aEEG vs cEEG's sensivity for seizure detection in the setting of neonatal intensive care units: A systematic review and meta-analysis.

AIM: Amplitude-integrated electroencephalography (aEEG)'s accuracy compared to conventional electroencephalography (cEEG) has not been fully established. The aim of our study was to conduct a systematic review on the sensitivity of the aEEG for neonatal seizure detection. METHODS: Studies from PubMed and Google Scholar databases comparing recordings of cEEG and aEEG in newborns were included according to the PRISMA method. A quality assessment using the QUADAS-2 tool was provided. A random-effect model was used to account for different sources of variations among studies. Publication biases were represented by a funnel plot, and funnel plot symmetry was assessed. RESULTS: Fourteen studies were reported; sensitivity of each diagnostic tool used (single-channel aEEG, two-channel aEEG, two-channel aEEG plus raw trace EEG) was compared to that of the gold-standard cEEG and to those of the other methods used. Overall sensitivity of the aEEG ranged from 31.25% to 90%. CONCLUSION: Our study provides evidence that sensitivity of aEEG varies significantly and that seizure detection rate is lower than that of cEEG. The two-channel aEEG with raw trace EEG shows a high sensitivity and might represent a valid alternative to the cEEG in the setting of neonatal intensive care units (NICUs).

Pulse Oximetry Saturation (Spo2) Monitoring in the Neonatal Intensive Care Unit (NICU): The Challenge for Providers: A Systematic Review.

BACKGROUND: In the neonatal intensive care unit (NICU), maintaining an oxygenation level that avoids both hypoxemia and hyperoxemia is challenging. Pulse oximetry has become fundamental for noninvasive monitoring of saturation of peripheral oxygen (Spo2) in preterm newborns. PURPOSE: The aim of this systematic review is to determine Spo2 target values in order to avoid hypoxemia or hyperoxemia and complications arising from these. METHOD AND SEARCH STRATEGY: For this systematic review, articles were audited from 2010 to 2020 using the PRISMA guidelines. PubMed, MEDLINE, Google Scholar, and Scopus databases were used, and search terms were related to use of pulse oximetry in the NICU. RESULTS: The result showed that 12 of 20 (60%) studies focused on target values but without a unanimous agreement on values, although 5 of 12 studies (41.66%) suggested a lower value target of 85% and 4 of 12 studies (33.33%) recommended 95% as the higher target value. Other authors showed no difference in the incidence of adverse events comparing different target values and focused the importance more on the fluctuation of the value than on the target value itself. IMPLICATION FOR PRACTICE: Reaching a balance in the oxygen administration so as to avoid potential complications associated with hypoxemia or hyperoxemia is a challenge for the clinicians. IMPLICATION FOR RESEARCH: Further studies on fluctuation of Spo2 comparing different starting targets could better clarify the role of fluctuations and the absolute target values.Video Abstract available at:https://journals.na.lww.com/advancesinneonatalcare/Pages/videogallery.aspx?autoPlay=false&videoId=49.

Neurocutaneous syndromes in art and antiquities.

Neurocutaneous syndromes are a group of genetic disorders affecting the skin, the central and peripheral nervous system, and the eye with congenital abnormalities and/or tumors. Manifestations may also involve the heart, vessels, lungs, kidneys, endocrine glands and bones. When people with these disorders are portrayed in works of art, physicians have speculated on possible diagnoses. In particular, many figures have been labeled as possibly having a neurocutaneous disorder, sometimes distorting the popular conception of these diseases. We review numerous documents, drawings, prints, lithographs, xylographs, and portraits which span the ages from antiquity to the era of the pioneers behind the eponyms, depicting a large spectrum of neurocutaneous disorders.

Neurodevelopmental outcomes of neonatal non-epileptic paroxysmal events: a prospective study.

AIM: To report on psychomotor development and outcomes in term born neonates with non-epileptic paroxysmal events (NEPEs). METHOD: From October 2017 to March 2019 we enrolled 38 consecutive term born neonates (22 males, 16 females; aged between 0-28d), born at the University Hospital San Marco in Catania, Italy, with NEPEs. We performed the Hammersmith Neonatal Neurological Examination scale (at enrolment), the Hammersmith Infant Neurological Examination (HINE) scale (at age 3, 6, 9, and 12mo), and the Griffiths scale (at age 12mo). RESULTS: The age at onset of first paroxysmal manifestations ranged from birth to 4 days. We recorded a suboptimal global score in 18 out of 38 patients at enrolment and in 10 out of 38 patients at age 3 months (>70% of these infants were male); all events disappeared within 6 months of life. At age 6, 9, and 12 months, all infants scored within normal values on the HINE and Griffiths scale. INTERPRETATION: Patients with NEPEs achieve neurodevelopment optimal scores within their first year of life. WHAT THIS PAPER ADDS: Neonates experiencing non-epileptic paroxysmal events (NEPEs) can be examined with the Hammersmith Neonatal Neurological Examination, Hammersmith Infant Neurological Examination, and Griffiths scale at follow-up. Newborn infants with NEPEs achieve optimal scores within the first year of life.

Neonatal seizures as onset of Inborn Errors of Metabolism (IEMs): from diagnosis to treatment. A systematic review.

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.

Sutures ultrasound: useful diagnostic screening for posterior plagiocephaly.

PURPOSE: Posterior plagiocephaly (PP) is a common clinical condition in pediatric age. There are two main causes of PP: postural plagiocephaly and craniosynostosis. Early diagnosis is important, as it prevents neurological complications and emergencies. Diagnosis in the past was often made late and with imaging tests that subjected the infant to a high radiation load. Suture ultrasound does not use ionizing radiation; it is easy to perform, allows an early diagnosis, and directs toward the execution of the cranial 3D-CT scan, neurosurgical consultation, and possible intervention. The aim of the study is to describe the high sensitivity and specificity of suture ultrasound for the differential diagnosis between plagiocephaly and craniosynostosis. METHODS: We reported our prospective experience and compared it with the data in the literature through a systematic review. The systematic review was conducted on electronic medical databases (PubMed, Embase, Cochrane Library, Scopus, and Web of Science) evaluating the published literature up to November 2020. According to Preferred Reporting Items for Systematic Reviews and Meta-ANALYSES (PRISMA statement), we identified 2 eligible studies. Additionally, according to AMSTAR 2, all included reviews have been critically rated as high quality. A total of 120 infants with abnormal skull shape were examined in NICU. All underwent clinical and ultrasound examination. RESULTS: Of the total, 105 (87.5%) had plagiocephaly and 15 dolichocephaly/scaphocephaly (12.5%). None of these had associated other types of malformations and/or neurological disorders. The synostotic suture was identified ultrasonographically in 1 infant and subsequently confirmed by 3D CT scan (100%). CONCLUSION: Cranial sutures ultrasonography can be considered in infants a selective, excellent screening method for the evaluation of skull shape deformities as first technique before the 3D CT scan exam and subsequent neurosurgical evaluation. Cranial suture ultrasonography should be considered part of clinical practice especially for pediatricians.