Neurodevelopmental outcome of neonatal seizures: A longitudinal study.

INTRODUCTION: Neonatal seizures (NS) are the most common neurological emergency in the neonatal period. The International League Against Epilepsy (ILAE) proposed a new classification of NS based on semiology and highlighted the correlation between semiology and aetiology. However, neurodevelopmental outcomes have not been comprehensively evaluated based on this new classification. AIMS: To evaluate neurodevelopmental outcomes and potential risk factors for severe outcomes in NS. METHODS: Patients with video electroencephalogram confirmed NS were evaluated. Seizure aetiology, cerebral magnetic resonance imaging (MRI) data, background electroencephalograms data, general movements, and neurodevelopmental outcomes were analysed. Severe outcomes were one of the following: death, cerebral palsy, Griffiths developmental quotient <70, epilepsy, deafness, or blindness. RESULTS: A total of 74 neonates were evaluated: 62 (83.8 %) with acute provoked NS (primarily hypoxic-ischaemic encephalopathy), and 12 (16.2 %) with neonatal-onset epilepsies (self-limited neonatal epilepsy, developmental and epileptic encephalopathy, cerebral malformations). Of these, 32 (43.2 %) had electrographic seizures, while 42 (56.7 %) had electroclinical seizures - 38 (90.5 %) were motor (42.1 % clonic) and 4 (9.5 %) were non-motor phenomena. Severe outcomes occurred in 33 of the 74 (44.6 %) participants. In multivariate analysis, neonatal-onset epilepsies (odds ratio [OR]: 1.3; 95 % confidence interval [CI]: 1.1-1.6), status epilepticus (OR: 5.4; 95 % CI: 1.5-19.9), and abnormal general movements (OR: 3.4; 95 % CI: 1.9-7.6) were associated with severe outcomes. CONCLUSIONS: At present, hypoxic-ischaemic encephalopathy remains the most frequent aetiology of NS. The prognosis of neonatal-onset epilepsies was worse than that of acute provoked NS, and status epilepticus was the most predictive factor for adverse outcomes.

Aromatic L-Amino-Acid Decarboxylase Deficiency Screening by Analysis of 3-O-Methyldopa in Dried Blood Spots: Results of a Multicentric Study in Neurodevelopmental Disorders.

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare recessive metabolic disorder caused by pathogenic homozygous or compound heterozygous variants in the dopa decarboxylase (DDC) gene. Adeno-associated viral vector-mediated gene transfer of the human DDC gene injected into the putamen is available. The typical presentation is characterized by early-onset hypotonia, severe developmental delay, movement disorders, and dysautonomia. Recently, mild and even atypical phenotypes have been reported, increasing the diagnostic challenge. The aim of this multicentric study is to identify the prevalence of AADCd in a population of patients with phenotypic clusters characterized by neurodevelopmental disorders (developmental delay/intellectual disability, and/or autism) by 3-O-methyldopa (3-OMD) detection in dried blood spots (DBS). It is essential to identify AADCd promptly, especially within non-typical phenotypic clusters, because better results are obtained when therapy is quickly started in mild-moderate phenotypes. Between 2021 and 2023, 390 patients with non-specific phenotypes possibly associated with AADCd were tested; none resulted in a positive result. This result highlights that the population to be investigated for AADCd should have more defined clinical characteristics: association with common signs (hypotonia) and/or pathognomonic symptoms (oculogyric crisis and dysautonomia). It is necessary to continue to screen selected clusters for reaching diagnosis and improving long-term outcomes through treatment initiation. This underscores the role of newborn screening in identifying AADCd.

Malarial retinopathy in a preschool child: A case report with long-term paediatric and ophthamological follow-up.

AIM: To report a paediatric case of retinopathy-positive cerebral malaria, emphasizing the clinical significance of long-term neurological and ophthalmological follow-up (5,5 years). CASE REPORT: After a recent journey in Ghana, a 17-month-old African female child was admitted at the Paediatric Emergency Room with fever and vomiting. Blood smear confirmed a Plasmodium Falciparum parasitaemia. Iv quinine was promptly administered, but after a few hours, the child developed generalized seizures, requiring benzodiazepine therapy and assisted ventilation for severe desaturation. Brain imaging (CT and MRI), lumbar puncture and several electroencephalograms showed data compatible with cerebral involvement of malaria. Schepens ophthalmoscopy and Ret-Cam pictures acquisition revealed macular haemorrhages in the left eye with central whitening and bilateral capillary abnormalities, typical signs of malarial retinopathy. Antimalarial therapy and iv Levetiracetam allowed neurological improvement. Eleven days after the admission, the child was discharged, showing no neurological symptoms and with an improved EEG signal, a normalized fundus oculi and brain imaging. Neurological and ophthalmological long-term follow-up were conducted: EEG controls didn't reveal abnormalities and the complete ophthalmological assessment showed a regular visual acuity and fundus oculi, as well as a normal SD-OCT and electrophysiologic testing. CONCLUSION: Cerebral malaria is a severe complication, characterized by a high fatality rate and challenging diagnosis. A helpful instrument for diagnostic and prognostic evaluation is the ophthalmological detection of malarial retinopathy and its monitoring over time. In our patient the long term visual follow-up didn't reveal any adverse outcome.

EIF2B2 gene mutation causing early onset vanishing white matter disease: a case report.

BACKGROUND: Leukoencephalopathy with vanishing white matter (VWM) is an autosomal recessive neurological disease. The physiopathology of disease is still little understood, but it seems to involve impairment in maturation of astrocytes; as a consequence white matter is more prone to cellular stress. Disease is caused by mutations in five genes encoding subunits of the translation initiation factor eIF2B. We know five different types of VWM syndrome classified based different ages of onset (prenatal, infantile, childhood, juvenile and adult onset). CASE PRESENTATION: We report the case of a 4-month-old boy with early seizure onset, recurrent hypoglycemia and post mortem diagnosis of vanishing white matter disease (VMD). At the admission he presented suspected critical episodes, resolved after intravenous administration of benzodiazepines. The brain MRI showed total absence of myelination that suggested hypomyelination leukoencephalopathy. The whole exome sequencing (WES) revealed a variant of EIF2B2 gene (p. Val308Met) present in homozygosity. In this case report we also describe the clinical evolution of seizures, in fact the epileptic seizures had a polymorphic aspect, from several complex partial seizures secondarily generalized to status epilepticus. CONCLUSION: Infantile and early childhood onset forms are associated with chronic progressive neurological signs, with episodes of rapid neurological worsening, and poor prognosis, with death in few months or years. Clinical presentation of epilepsy is poorly documented and do not include detailed information about the type, time of onset and severity of seizures. No therapeutic strategies for VWM disease have been reported.

Prospective Evaluation of Ghrelin and Des-Acyl Ghrelin Plasma Levels in Children with Newly Diagnosed Epilepsy: Evidence for Reduced Ghrelin-to-Des-Acyl Ghrelin Ratio in Generalized Epilepsies.

Children with epilepsy and identified as responders to antiseizure medications (ASMs) were found to present markedly higher ghrelin plasma levels when compared to drug-resistant patients. However, it was undetermined if this phenotype could be influenced by the ASMs. Here, we prospectively investigated total ghrelin and des-acyl ghrelin (DAG) plasma levels by enzyme-linked immunosorbent assay before and after ASM administration. Inclusion criteria were: (i) subject with a suspicion of epilepsy; (ii) age ranging from 0 to 16 years; and (iii) informed consent signed by parents or caregivers. Exclusion criteria were acute or chronic metabolic disorders with occasional convulsions but without epilepsy. Fifty patients were followed over a period of one year in Italian neuropediatric centers. Apart from a few exceptions, the majority of children were responsive to ASMs. No differences were found in total ghrelin and DAG levels before and after the treatment, but total ghrelin levels were significantly lower in children with generalized epilepsy compared to those with combined focal and generalized epilepsy. Moreover, the ghrelin-to-DAG ratio was also markedly lower in generalized epilepsies compared to all the other types of epilepsy. Finally, ghrelin was unchanged by ASMs, including the first (e.g., carbamazepine), second (levetiracetam), and third (lacosamide) generation of anticonvulsants.

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.

A nationwide study on Sydenham's chorea: Clinical features, treatment and prognostic factors.

OBJECTIVES: Sydenham's Chorea (SC) is a neuropsychiatric disorder and a major manifestation of acute rheumatic fever. The erroneous assumption that SC is a benign and self-limiting disease, has led to a lack of high-quality scientific evidence of the therapeutical and prognostic features of SC. STUDY DESIGN: We retrospectively analyzed the medical records of patients <18-years old with SC in 17 Italian pediatric centers. Recorded data included clinical, instrumental and laboratory parameters. Prognostic risk factors including treatment regimens were assessed with univariate and multivariate sub-analysis. RESULTS: We included 171 patients with SC. 66% had generalized chorea, and 34% hemichorea. 81% had carditis (subclinical in 65%). Additional neurological symptoms were reported in 60% of the patients, mainly dysarthria and dysgraphia. 51% had neuropsychiatric symptoms at onset, which persisted after 12 months in 10%. Among psychiatric manifestations, the most common was anxiety disorder/depression (77%). Neurological remission was reached by 93% of the patients at 6 months; 9% relapsed. Patients were treated as follows: 11% penicillin alone, 37% immunomodulatory therapy, 16% symptomatic drugs (i.e. anti-seizure medication, dopamine antagonists) and 37% both symptomatic and immunomodulatory treatment. Neurological outcome did not differ between groups. Patients receiving symptomatic drugs had a higher risk of relapse on multivariate analysis (p = 0.045). CONCLUSIONS: Treatment of SC was largely heterogeneous. Based on our results, immunomodulatory therapy did not show higher efficacy at medium term, although it was associated to a slightly lower risk of relapse compared to symptomatic therapy. Longitudinal studies are needed to assess specific risk factors and best treatment options.

Further delineation of PIGB-related early infantile epileptic encephalopathy.

Pathogenic variants in phosphatidylinositol glycan anchor biosynthesis class B (PIGB) gene have been first described as the cause of early infantile epileptic encephalopathy 80 (EIEE-80) in 2019. This disorder, an inherited glycosylphosphatidylinositol deficiency, is associated with a complex neurologic phenotype, including developmental delay, early-onset epilepsy and peripheral neuropathy. We report on a 5 year-old girl born from consanguineous parents, manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus. Hypomyelination was documented on brain MRI. Whole-exome sequencing (WES) disclosed the likely pathogenic biallelic PIGB NM_004855.4: c.463G > C, p.(Asp155His) missense variant. In our patient, while other characteristic clinical, neuroimaging and laboratory findings (as described in the first research paper) were present, seizures were not a major clinical issue, thus contributing to our knowledge on this ultra-rare disorder.

Electroclinical features of MEF2C haploinsufficiency-related epilepsy: A multicenter European study.

PURPOSE: Epilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency. METHODS: We thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype. Clinical features (seizure types, onset, evolution, and response to therapy), EEG recordings during waking/sleep, and neuroimaging findings were analyzed. We also performed a detailed literature review using the terms "MEF2C", "seizures", and "epilepsy". RESULTS: Epilepsy was diagnosed in 19 out of 25 (~80%) subjects, with age at onset <30 months. Ten individuals (40%) presented with febrile seizures and myoclonic seizures occurred in ~50% of patients. Epileptiform abnormalities were observed in 20/25 patients (80%) and hypoplasia/partial agenesis of the corpus callosum was detected in 12/25 patients (~50%). Nine patients harbored a 5q14.3 deletion encompassing MEF2C and at least one other gene. In 7 out of 10 patients with myoclonic seizures, MIR9-2 and LINC00461 were also deleted, whereas ADGRV1 was involved in 3/4 patients with spasms. CONCLUSION: The epileptic phenotype of MEF2C-syndrome is variable. Febrile and myoclonic seizures are the most frequent, usually associated with a slowing of the background activity and irregular diffuse discharges of frontally dominant, symmetric or asymmetric, slow theta waves with interposed spike-and-waves complexes. The haploinsufficiency of ADGRV1, MIR9-2, and LINC00461 likely contributes to myoclonic seizures and spasms in patients with MEF2C syndrome.

Heart failure caused by VGAM: a lesson for diagnosis and treatment from a case and literature review.

We describe the case of a neonate with signs of heart failure. Echocardiography showed a structural normal heart shape with left ventricular dysfunction. At 2 months of age, a vein of Galen arteriovenous malformation was diagnosed through a brain magnetic resonance imaging. Embolization therapy was accomplished and a clinical and neurological follow-up was started. This clinical case highlights how important it is considering an intracranial cause in the differential diagnosis of neonatal congestive heart failure (CHF). We performed a narrative minireview of the literature about treatments and outcome of this malformation in association to CHF, to point out how complex the diagnosis of vein of Galen aneurysmal malformation (VGAM) may be and how an early diagnosis is important for its management.

Grisel's Syndrome in Children: Two Case Reports and Systematic Review of the Literature.

Background and Objective. Grisel's syndrome is a rare syndrome characterized by nontraumatic rotatory subluxation of the atlantoaxial joint. It usually affects children and typically presents with torticollis after ear, nose, and throat (ENT) surgery or head and neck infections. In the pediatric literature, there is only a small amount of available data; moreover, no systematic review has been previously done with focus on the pediatric population. We report our experience of two cases, and we provide a systematic review on Grisel's syndrome in children in order to offer a deeper insight about its clinical presentation, its current diagnosis, and principles of treatment. Case Reports and Review. We describe two boys of 9 and 8 years old, who developed atlantoaxial subluxation after adenoidectomy. Considering the early diagnosis, a conservative treatment was chosen, with no recurrence and no sequelae at follow-up. We identified 114 case reports, of which 90 describe children, for a total of 171 pediatric patients. Of the 154 cases in which cause was reported, 59.7% presented a head and neck infection and 35.7% had previous head and neck surgery. There is no sex prevalence (49.7% males versus 50.2% females). Mean delay in diagnosis is 33 days. Eight % of the patients had neurological impairment of the 165 cases which mentioned treatment, 96% underwent a conservative treatment, of whom the 8.8% recurred with the need of surgery. As a whole, 12% underwent surgery as a first- or second-line treatment. 3 6% of the patients whose follow-up was reported developed a sequela, minor limitation of neck movement being the most frequent. Conclusion. Grisel's syndrome should be suspected in children with painful unresponsive torticollis following ENT procedures or head and neck inflammation. CT scan with 3D reconstruction is the gold standard for diagnosis, allowing the identification of the subluxation and the classification according to the Fielding-Hawkins grading system. Surgical treatment is indicated in case of high-grade instability or failure of conservative treatment. Review of the literature shows how early diagnosis based on clinical and radiological evaluation is crucial in order to avoid surgical treatment and neurologic sequelae.

Mapping the Effect of Interictal Epileptic Activity Density During Wakefulness on Brain Functioning in Focal Childhood Epilepsies With Centrotemporal Spikes.

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common type of "self-limited focal epilepsies." In its typical presentation, CECTS is a condition reflecting non-lesional cortical hyperexcitability of rolandic regions. The benign evolution of this disorder is challenged by the frequent observation of associated neuropsychological deficits and behavioral impairment. The abundance (or frequency) of interictal centrotemporal spikes (CTS) in CECTS is considered a risk factor for deficits in cognition. Herein, we captured the hemodynamic changes triggered by the CTS density measure (i.e., the number of CTS for time bin) obtained in a cohort of CECTS, studied by means of video electroencephalophy/functional MRI during quite wakefulness. We aim to demonstrate a direct influence of the diurnal CTS frequency on epileptogenic and cognitive networks of children with CECTS. A total number of 8,950 CTS (range between 27 and 801) were recorded in 23 CECTS (21 male), with a mean number of 255 CTS/patient and a mean density of CTS/30 s equal to 10,866 ± 11.46. Two independent general linear model models were created for each patient based on the effect of interest: "individual CTS" in model 1 and "CTS density" in model 2. Hemodynamic correlates of CTS density revealed the involvement of a widespread cortical-subcortical network encompassing the sensory-motor cortex, the Broca's area, the premotor cortex, the thalamus, the putamen, and red nucleus, while in the CTS event-related model, changes were limited to blood-oxygen-level-dependent (BOLD) signal increases in the sensory-motor cortices. A linear relationship was observed between the CTS density hemodynamic changes and both disease duration (positive correlation) and age (negative correlation) within the language network and the bilateral insular cortices. Our results strongly support the critical role of the CTS frequency, even during wakefulness, to interfere with the normal functioning of language brain networks.

Infantile neuroaxonal dystrophy and PLA2G6-associated neurodegeneration: An update for the diagnosis.

Infantile neuroaxonal dystrophy is a rare neurodegenerative disorder characterized by infantile onset of rapid motor and cognitive regression and hypotonia evolving into spasticity. Recessively inherited mutations of the PLA2G6 gene are causative of infantile neuroaxonal dystrophy and other PLA2G6-associated neurodegeneration, which includes conditions known as atypical neuroaxonal dystrophy, Karak syndrome and early-onset dystonia-parkinsonism with cognitive impairment. Phenotypic spectrum continues to evolve and genotype-phenotype correlations are currently limited. Due to the overlapping phenotypes and heterogeneity of clinical findings characterization of the syndrome is not always achievable. We reviewed the most recent clinical and neuroradiological information in the way to make easier differential diagnosis with other degenerative disorders in the paediatric age. Recognizing subtle signs and symptoms is a fascinating challenge to drive towards better diagnostic and genetic investigations.

Interdural cavernous sinus dermoid cyst in a child: case report.

Interdural dermoid cysts (DCs) of the cavernous sinus (CS), located between the outer (dural) and inner layer (membranous) of the CS lateral wall, are rare lesions in children. The authors report on a 5-year-old boy with third cranial nerve palsy and exophthalmos who underwent gross-total removal of an interdural DC of the right CS via a frontotemporal approach. The patient had a good outcome and no recurrence at the 12-month follow-up. To the best of the authors' knowledge this is the second pediatric case of interdural DC described in the literature.

Extrastriate visual cortex in idiopathic occipital epilepsies: The contribution of retinotopic areas to spike generation.

OBJECTIVES: To provide insight into the pathophysiology of idiopathic childhood occipital epilepsies (ICOEs), by mapping the contribution of retinotopic visual areas to the generation and sustainment of epileptic activity. METHODS: Thirteen patients affected by ICOEs (mean age = 10.9 years) underwent a video electroencephalography-functional magnetic resonance imaging (EEG-fMRI) study. A flexible-related fMRI analysis was applied to estimate the shape of the blood oxygen level-dependent (BOLD) response in each patient. Second-level analysis was performed using the interictal EEG discharge (IED)-specific response shape for the ICOE group. The resulting fMRI t-maps were warped to the Population-Average, Landmark- and Surface-based (PALS)-B12 atlas in Caret. For localization purposes, functional results were plotted and compared against 19 retinotopic areas for each hemisphere. A correlation analysis was performed between the hemodynamic maps and electroclinical variables. RESULTS: The shape of the group-averaged hemodynamic response in ICOE patients showed an earlier time-to-peak and a more pronounced undershoot than the canonical hemodynamic response function (HRF). The random-effect analysis showed positive hemodynamic changes in the bilateral temporooccipital network. With regard to the retinotopic subdivision of the visual cortex, the primary visual area was consistently spared. Conversely, an extensive involvement of the occipitotemporal cortex, including the fusiform gyrus, and the occipitoparietal areas was observed. Moreover, a linear relationship was detected between the occipital spike-density and BOLD increases at the postcentral gyrus and temporooccipital cortex. SIGNIFICANCE: Our data indicate that both the ventral and dorsal visual pathways are involved in spike generation in ICOEs, to extents that vary between patients, and reinforce the concept of benign childhood seizure susceptibility syndrome as a substrate for ICOEs. Finally, these results underscore the need for appropriate neuropsychological testing in these children, aimed at revealing selective impairments in functions subserved by both visual pathways.

Paraplegia by spinal cord compression as the initial manifestation of Hodgkin's disease: a case report.

The 90% of Hodgkin's disease (HD) cases are originated by lymphnodes whereas 10% by extranodal regions as epidural space. Neurologic complications of HD can be classified as directly resulting from the disease or indirectly originated from the disease or from its treatment. Patients very rarely present with spinal cord compression (SCC)  due to epidural HD. Few cases of HD with such presentation have been reported in the literature. Primary spinal extradural HD with no further organ involvement is extremely rare. We report a case of a child with SCC as initial and unique presentation of HD.

Predictive diagnostic value for the clinical features accompanying intellectual disability in children with pathogenic copy number variations: a multivariate analysis.

BACKGROUND: Array comparative genomic hybridization (a-CGH) has become the first-tier investigation in patients with unexplained developmental delay/intellectual disability (DD/ID). Although the costs are progressively decreasing, a-CGH is still an expensive and labour-intensive technique: for this reason a definition of the categories of patients that can benefit the most of the analysis is needed. Aim of the study was to retrospectively analyze the clinical features of children with DD/ID attending the outpatient clinic of the Mother & Child Department of the University Hospital of Modena subjected to a-CGH, to verify by uni- and multivariate analysis the independent predictors of pathogenic CNVs. METHODS: 116 patients were included in the study. Data relative to the CNVs and to the patients' clinical features were analyzed for genotype/phenotype correlations. RESULTS AND CONCLUSIONS: 27 patients (23.3%) presented pathogenic CNVs (21 deletions, 3 duplications and 3 cases with both duplications and deletions). Univariate analysis showed a significant association of the pathogenic CNVs with the early onset of symptoms (before 1 yr of age) and the presence of malformations and dysmorphisms. Logistic regression analysis showed a significant independent predictive value for diagnosing a pathogenic CNV for malformations (P = 0.002) and dysmorphisms (P = 0.023), suggesting that those features should address a-CGH analysis as a high-priority test for diagnosis.

Case of stroke in a 7-year-old male after parvovirus B19 infection.

A 7-year-old male presented sudden-onset left hemiparesis, left-sided paresthesia, central paralysis of the left VII cranial nerve, and subsequent headache. Magnetic resonance scans were obtained 24 hours after admission. T(2)-weighted images disclosed hyperintensities located mainly in the posterior portion of the lenticular nucleus and in the head and body of the right caudate nucleus. A diagnosis of ischaemic stroke was made on the basis of neuroradiologic findings. Laboratory tests undertaken to establish the cause of stroke revealed parvovirus B19 infection preceding the neurologic abnormalities. In the absence of other known risk factors for stroke the possibility of parvovirus B19's being correlated with stroke onset is discussed.