IntroductionStudy 512 aimed to assess the efficacy and safety of perampanel (PER) as the first add-on therapy.MethodsIn this 12-month, prospective, observational, multicenter study, people with epilepsy (PWE) aged ≥12 years with focal-onset seizures or generalized tonic–clonic seizures (GTCS) associated with idiopathic generalized epilepsy received PER as the first add-on therapy to antiseizure medication (ASM) monotherapy. The primary efficacy endpoint was the retention rate at 12 months. Other endpoints included change in seizure frequency from baseline; pragmatic seizure freedom rate (proportion of PWE in the full analysis set achieving freedom from all seizures); responder rate (≥50% seizure frequency reduction from baseline), changes from baseline in the 10-item Quality of Life in Epilepsy questionnaire (QOLIE-10) total score, the Epworth Sleepiness Scale (ESS), and the age-corrected EpiTrack and EpiTrack Junior total score; safety/tolerability (treatment-emergent adverse events [TEAEs]); and PER dose.ResultsOf 184 PWE (Safety Set, n = 182; Full Analysis Set, n = 174), 135 (73.4%) completed the 12-month study. The mean PER dose was 4.7 mg/day. Retention rate at 12 months was 74.2% in the overall population, 81.8% in the 12 to <18 years age group, 74.3% in the 18 to <65 years age group, and 66.7% in the ≥65 years age group. Retention rates were similar between PWE with focal-onset seizures (74.5%) and GTCS (75.0%). The median reduction in monthly seizure frequency per 28 days from baseline to 12 months was 78.6% in the overall population, 92.3% in the 12 to <18 age group, 75.0% in the 18 to <65 years age group, and 87.5% in the ≥65 years age group. In the overall population, pragmatic seizure freedom rates at 12 months were 36.2% (all seizures), 34.1% (all focal seizures), and 45.5% (GTCS); the responder rate at 12 months was 64.4% in the overall population. In total, 52.7% of PWE experienced TEAEs, and 12.1% discontinued due to TEAEs. No significant changes were identified from baseline to 12 months in QOLIE-10, ESS, and the age-corrected EpiTrack and EpiTrack Junior scores.ConclusionPER was efficacious for focal and generalized seizures across all age groups and was generally well-tolerated, as demonstrated by the high retention rates at 12 months.

Sturge-Weber syndrome (SWS) is a sporadic congenital vascular disorder which typically presents with a facial port-wine stain and capillary malformations affecting the brain and eye.We present the case of a 15-month-old boy admitted to the paediatric emergency department with right arm palsy and focal clonic seizure on the right side of the body, without a facial nevus.Brain MRI revealed leptomeningeal angiomatosis suggestive of SWS.Despite the absence of the characteristic facial port-wine stain, diagnosis of SWS remains clinical and must be suspected whenever there are focal seizures associated with focal neurological deficits.In this case report we describe the clinical presentation, imaging findings and management of this rare presentation of SWS.We are reporting this case as few patients have been described in the literature.

Defects in the mitochondrial DNA (mtDNA) cause mtDNA depletion syndrome (MTDPS), a subclass of mitochondrial disorders that are genetically and phenotypically heterogeneous. MTDPS is a rare autosomal recessive disease caused by a mutation of a nuclear gene named FBXL4 (F -box and leucine-rich repeat protein 4), located on chromosome 6. This nuclear -encoded mitochondrial protein plays a vital role in mitochondrial bioenergetics, mtDNA maintenance, and mitochondrial dynamics. Pathogenic variants in the FBXL4 gene reduce mtDNA synthesis, resulting in a large decrease in the mtDNA content in cells, which is essential for normal energy production. These pathogenic variants in the FBXL4 gene are associated with an encephalomyopathy MTDPS type 13 (MTDPS13), a rare and severe multisystemic disorder mainly characterized by infant -onset encephalomyopathy and lactic acidosis, developmental delay, hypotonia with feeding difficulties and failure to thrive. Other features may include the central nervous system and the ophthalmologic, cardiac, gastrointestinal, genitourinary, and immunological systems. Herein, we report the case of an infant born to consanguineous Pakistani parents with an early onset of severe lactic acidosis, hypotonia, feeding difficulties, hypertro phic cardiomyopathy, supraventricular tachycardia, and transient neutropenia harboring a homozygous variant in the FBXL4 (c.370C>T [p.Q124*]) gene. This variant was identified in the patient's parents in heterozygosity. He started medical treatment (with coenzyme Q10, propranolol, and sodium bicarbonate) and multidisciplinary support. As a result, a progressive improvement in postural tone and feeding autonomy was observed during the first months of life. Therefore, encephalomyopathy MTDPS13 should be suspected when dealing with patients with severe congenital lactic acidosis and developmental impairment.

We present the case of a boy in his middle childhood with gait ataxia and loss of reflexes with a 1-year onset. He had a background of an autism spectrum disorder but was otherwise healthy. A paediatric cardiology assessment was requested to investigate possible cardiac involvement associated to his neurological symptoms. Even though he had no cardiac symptoms and a normal electrocardiography, the echocardiogram revealed severe asymmetric left ventricle hypertrophy consistent with hypertrophic cardiomyopathy. This prompted genetic testing and the diagnosis of Friedreich's ataxia was confirmed.

Pediatric cerebral sinus venous thrombosis (CSVT) is a rare entity. Risk factors differ from the adults, and treatment is not consensual. With this work, we aimed to characterize a pediatric cohort from two Portuguese tertiary centers. All patients under 18 years old with confirmed CSVT admitted between 2006 and 2019 were retrospectively included. Demographics, clinical presentation, workup, and follow-up were evaluated. Fifty-three patients were included, 29 were male (54.7%). Median age was 5 years (IQR 11.08, range 0–17 years old). Headache, seizures and impairment of consciousness were the most frequent manifestations. A risk factor was identified in 90.6% (n = 48), mostly infections (43.8%; n = 21). CNS complications were comprised of hemorrhage, venous infarction, hydrocephalus and edema. Treatment included anticoagulation in 36 patients (67.9%), and there were no recurrences on follow-up. Prognosis was favorable, with most patients presenting no or only slight disability comparing to same age and sex children, on the follow-up. In this cohort, impairment of consciousness was the most frequent clinical presentation and infections were the most frequent risk factors. The outcome was mainly favorable, with most patients presenting none or mild disability and without recurrences on follow-up. Studies are needed to define the criteria for anticoagulation and its recommended duration in children.

Objective:Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies.Methods:Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease.Results:Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers.Significance:The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.

Posterior reversible leukoencephalopathy syndrome (PRES) is a rare entity among children, characterised by acute neurological symptoms and radiological findings. The role of clinical symptoms and neuroimaging in predicting the prognosis of PRES have not been well-characterised. A retrospective descriptive study of children with PRES, admitted to a Paediatric Intensive Care Unit during a 10-year period, was performed to describe its characteristics, compare the accuracy of computed tomography (CT) scan and MRI on diagnosis and identify prognostic factors on paediatric population. Sixteen cases were identified. Most patients (13; 81%) presented underlying disorders, including malignancies (5; 31%), chronic kidney disease (3; 19%) and post-transplant status (3; 19%). Hypertension (15; 94%) was the most common trigger. All patients had seizures, 9 patients (56%) altered state of consciousness, 8 (50%) headache. CT scan was performed in 15 patients (94%) and MRI in 13 (81%); 1 patient underwent only MRI. MRI allows the identification of new areas of vasogenic oedema and a correct diagnosis of PRES when CT scan was inconclusive. Two patients (13%) remained with neurological sequelae and one died. In two patients (13%) cognitive disorders (specific learning disorder, intellectual disability, motor tic disorder) were diagnosed during follow-up period. Clinical presentation was not statistically associated with outcome. Also, atypical neuroimaging (haemorrhagic and unilateral lesions) were not statistically related with poor neurological or cognitive outcome. However, prospective studies with a larger cohort are needed to establish prognostic factors of PRES in the paediatric population.

Pathogenic variants in the NGLY1 gene are associated with a Congenital Disorder of Deglycosylation (CDDG) characterized by delays in reaching developmental milestones, complex hyperkinetic movement disorder, transient elevation of transaminases, and alacrima or hypolacrima. To date, only few cases of NGLY1 deficiency have been identified and reported in the literature. This report highlights a first child of non-consanguineous parents with no relevant family history who presented with hypotonia and poor weight gain since birth. At 2 months, the child developed paroxysmal cervical dystonia, posteriorly resolving spontaneously by age of 3. Subsequently, delays in reaching developmental milestones, ataxia, dyskinesia, visual impairment due to cone rod retinal dystrophy, low triglycerides, and persistently elevated liver transaminases were observed. Extensive etiological investigation was performed, including array-CGH and metabolic evaluation with no abnormalities to note. Trio whole exome analysis identified a homozygous pathogenic variant of the NGLY1 gene, c.1891del (p.Gln631Serfs*7), consistent with CDDG. Both parents were confirmed to be heterozygous carriers. The authors discuss in this case, the clinical presentation, the diagnostic challenges, and review other relevant NGLY1 deficiency cases previously reported in the literature. This case, along with the previous reported in the literature, indicates that pathogenic variants in NGLY1 cause a recognizable phenotype and should be considered in patients with a typical presentation. It also suggests that decreased sweating is not present universally in these patients.

Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering.TRAPPC4was recently implicated in a recessive neurodevelopmental condition in four unrelated families due to a shared c.454+3A>G splice variant. Here, we report 23 patients from 17 independent families with an early-infantile-onset neurodegenerative presentation, where we also identified the homozygous variant hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G) inTRAPPC4through exome or genome sequencing. No other clinically relevantTRAPPC4variants were identified among any of over 10,000 patients with neurodevelopmental conditions. We found the carrier frequency ofTRAPPC4c.454+3A>G was 2.4-5.4 per 10,000 healthy individuals. Affected individuals with the homozygousTRAPPC4c.454+3A>G variant showed profound psychomotor delay, developmental regression, early-onset epilepsy, microcephaly and progressive spastic tetraplegia. Based upon RNA sequencing, the variant resulted in partial exon 3 skipping and generation of an aberrant transcript owing to use of a downstream cryptic splice donor site, predicting a premature stop codon and nonsense mediated decay. These data confirm the pathogenicity of theTRAPPC4c.454+3A>G variant, and refine the clinical presentation ofTRAPPC4-related encephalopathy.

INTRODUCTION:Epileptic encephalopathies of childhood are characterized by early seizure-onset and adverse neurological outcomes. The development of new genetic techniques has allowed an exponential identification of the genes that are involved. Over the last years, we have observed a revolution in the diagnostic paradigm. However, there are no international guidelines regarding the diagnosis of genetic epileptic encephalopathies. We aim to discuss the current knowledge about the genetic architecture of epileptic encephalopathies of childhood.MATERIAL AND METHODS:review of the literature about infantile epileptic encephalopathies and the genetic tests currently available. A systematic approach and a diagnostic algorithm to use in clinical practice were proposed.RESULTS:Initially the patient's phenotype should be determined based on the seizure type, electroencephalogram pattern and neuroimaging. Patients with unclear etiology after brain magnetic resonance imaging should undergo an appropriate metabolic investigation to promptly exclude treatable conditions. Further studies should also include other genetic causes, mainly if associated with particular phenotypic features. Chromosomal microarray analysis should be firstly considered, particularly if dysmorphic or polymalformative abnormalities are present. If this is negative and/or there are no physical features, the next step should be next-generation sequencing multigene panels or whole-exome sequencing. Single gene study should only be considered when the patient's phenotype is highly suggestive of a specific syndrome.CONCLUSION:The revolution of the genetic knowledge about epileptic encephalopathies of childhood has led to a complex diagnostic approach. This new paradigm poses significant implications in genetic counselling, treatment and prognosis.

Gilles de la Tourette syndrome (GTS) is a neurobehavioral disorder comprising motor and vocal tics. In most cases it is associated with other disorders such as obsessive-compulsive disorder (OCD). In refractory cases deep brain stimulation (DBS) is a valid treatment option. This paper describes the case of a 15-year-old adolescent with an extremely refractory GTS with associated OCD. The patient developed catatonia associated with OCD, which partially remitted after electroconvulsive therapy. At the peak of the disease the Yale Global Tic Severity Scale (YGTSS) was 100 and the patient required sedation and intubation. All medical treatment options were unsuccessful. Bilateral DBS of the anterior limb of internal capsule (ALIC)/bed nucleus of stria terminalis (BST) region was performed, using a target below the BST and a trajectory through the ALIC, with stimulation of contacts 0 and 3. Two weeks after surgery sedatives were suspended and the patient was successfully extubated. One year after surgery the patient reached a YGTSS of 19, representing an 81% improvement. OCD completely resolved. Adverse events were a superficial infection and weight gain. In conclusion, this ALIC/BST stimulation appears to have been an effective and safe treatment for GTS with OCD in this case. Young age should not be an exclusion criterion for DBS in severe GTS and OCD. Further studies should be pursued for this target.

Introduction.The concrete burden of neonatal seizures in neurodevelopmental outcome of term newborns is still unknown in literature.The aim of this study was to describe prognostic predictors in neonatal seizures. Subjects and methods.Observational prospective study of term neonates with clinical seizures from a tertiary center (2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018).Adverse outcome was determined as death, global developmental delay, cerebral palsy or epilepsy.Perinatal characteristics, etiology, electrographic features, neuroimaging and antiepileptic treatment were analyzed in a logistic regression model. Results.A total of 102 newborns were included (52 infants with normal outcome).Twelve fatalities were registered.In the survival group, 38 children had an adverse outcome (28 global developmental delay, 27 cerebral palsy, 21 epilepsy).From the prognostic variables identified in univariate analysis, perinatal complications, seizure onset in the first day of life, moderate to severe abnormal background activity, abnormal amplitude-integrated EEG pattern, and treatment response remained independently associated with adverse outcome after a logistic regression model. Conclusions.There is conflicting data about surrogate markers in neonatal seizures.Aside from confirming the predictive value of previously described variables, we observed that amplitude-integrated EEG monitoring is a forthcoming prognostic tool.Future approaches may include a wider use of amplitude-integrated EEG monitoring, being crucial for timely seizure identification and prompt treatment.

We report the case of a 9-year-old girl with linear scleroderma en coup de sabre (LSCS) who developed progressive white matter involvement, presenting as intractable hemiplegic migraine-like attacks induced by exercise. After a period of severely aggressive course, clinical and radiological stabilization was achieved under immunosuppressant treatment. Intrathecal synthesis of IgG and lymphocytic pleocytosis provided indirect evidence of a chronic inflammatory process of the central nervous system. We discuss the possible immunopathogenic mechanisms responsible for the neurocutaneous involvement in LSCS, favouring the hypothesis of an autoimmune and inflammatory vasculopathy. The singular occurrence of hemiplegic migraine triggered by exertion add further insight to the currently unknown pathogenesis of scleroderma disorder. In addition, we highlight the importance of intensive immunosuppression approaches in selected cases, contrasting with the classic benign course of LCSC.

INTRODUCTION:The concrete burden of neonatal seizures in neurodevelopmental outcome of term newborns is still unknown in literature. The aim of this study was to describe prognostic predictors in neonatal seizures.SUBJECTS AND METHODS:Observational prospective study of term neonates with clinical seizures from a tertiary center (2009-2018). Adverse outcome was determined as death, global developmental delay, cerebral palsy or epilepsy. Perinatal characteristics, etiology, electrographic features, neuroimaging and antiepileptic treatment were analyzed in a logistic regression model.RESULTS:A total of 102 newborns were included (52 infants with normal outcome). Twelve fatalities were registered. In the survival group, 38 children had an adverse outcome (28 global developmental delay, 27 cerebral palsy, 21 epilepsy). From the prognostic variables identified in univariate analysis, perinatal complications, seizure onset in the first day of life, moderate to severe abnormal background activity, abnormal amplitude-integrated EEG pattern, and treatment response remained independently associated with adverse outcome after a logistic regression model.CONCLUSIONS:There is conflicting data about surrogate markers in neonatal seizures. Aside from confirming the predictive value of previously described variables, we observed that amplitude-integrated EEG monitoring is a forthcoming prognostic tool. Future approaches may include a wider use of amplitude-integrated EEG monitoring, being crucial for timely seizure identification and prompt treatment.

In order to characterize the genetic architecture of epilepsy in a pediatric population from the Iberian Peninsula (including the Canary Islands), we conducted targeted exome sequencing of 246 patients with infantile-onset seizures with or without neurodevelopmental delay. We detected 107 variants in 48 different genes, which were implicated in neuronal excitability, neurodevelopment, synaptic transmission, and metabolic pathways. In 104 cases (42%) we detected variant(s) that we classified as pathogenic or likely pathogenic. Of the 48 mutated genes, 32 were dominant, 8 recessive and 8 X-linked. Of the patients for whom family studies could be performed and in whom pathogenic variants were identified in dominant or X-linked genes, 82% carried de novo mutations. The involvement of small copy number variations (CNVs) is 9%. The use of progressively updated custom panels with high mean vertical coverage enabled establishment of a definitive diagnosis in a large proportion of cases (42%) and detection of CNVs (even duplications) with high fidelity. In 10.5% of patients we detected associations that are pending confirmation via functional and/or familial studies. Our findings had important consequences for the clinical management of the probands, since a large proportion of the cohort had been clinically misdiagnosed, and their families were subsequently able to avail of genetic counseling. In some cases, a more appropriate treatment was selected for the patient in question, or an inappropriate treatment discontinued. Our findings suggest the existence of modifier genes that may explain the incomplete penetrance of some epilepsy-related genes. We discuss possible reasons for non-diagnosis and future research directions. Further studies will be required to uncover the roles of structural variants, epimutations, and oligogenic inheritance in epilepsy, thereby providing a more complete molecular picture of this disease. In summary, given the broad phenotypic spectrum of most epilepsy-related genes, efficient genomic tools like the targeted exome sequencing panel described here are essential for early diagnosis and treatment, and should be implemented as first-tier diagnostic tools for children with epilepsy without a clear etiologic basis.

Introduction: Whole-exome sequencing (WES) has emerged as a successful diagnostic tool in the study of genetic disease and has proven to be particularly effective in identifying disease-associated genes that reveal the etiology of disorders affecting patients with previously unresolved genetic conditions. Clinical case: 11 years old boy, son of non-consanguineous healthy parents. He was born at term, following an uneventful pregnancy and delivery. Axial hypotonia was noticed during the first 6 months of life, followed by psychomotor delay (preferentially in motor over cognitive skills) and dystonia with choreo-athetosis.

Introdução: As lesões vasculares do sistema nervoso central, nomeadamente o acidente vascular cerebral hemorrágico, o acidente vascular cerebral isquémico e trombose venosa cerebral, são causa importante de morbilidade e mortalidade. Existem poucos estudos sobre a melhor abordagem terapêutica em pediatria. O objetivo deste estudo foi descrever a abordagem e outcome neurológico dos doentes admitidos numa unidade de cuidados intensivos pediátricos com lesões vasculares cerebrais não traumáticas. Métodos: Estudo retrospetivo baseado nos processos clínicos de doentes internados numa unidade de cuidados intensivos pediátricos entre janeiro de 2007 e dezembro de 2013 com lesão vascular cerebral não traumática. Resultados: Incluíram-se 45 doentes, mediana da idade 8,2 anos, 70% do sexo masculino. Ocorreram 22 casos (49%) de acidente vascular cerebral hemorrágico, 15 de acidente vascular cerebral isquémico (33%) e oito de trombose venosa cerebral (18%). Necessitaram de intervenção neurocirúrgica 18 doentes e neurorradiológica cinco doentes. Um doente fez trombólise sistémica utilizando alteplase, 76% necessitaram de controlo médico da hipertensão intracraniana, 57% de ventilação mecânica, 30% de suporte cardiovascular e 28% de terapêutica antiepilética. Ocorreram cinco óbitos (11%), quatro em doentes com acidente vascular cerebral hemorrágico. Utilizando a escala KOSCHI (King’s Outcome Scale for Childhood Head Injury), atualmente 23 (51%) doentes são independentes, incluindo 17 que não apresentam qualquer sequela. Discussão: Registaram-se, em média, seis internamentos por ano por acidente vascular cerebral não traumático, sendo mais frequente o hemorrágico. A precocidade do diagnóstico e a referenciação atempada para centros especializados são cruciais para a melhoria do prognóstico. A abordagem multidisciplinar num centro com disponibilidade permanente de recursos humanos e materiais terá contribuído para a sobrevida e boa recuperação funcional verificada na maioria dos casos.

Aims: To report a case of pharyngeal-cervical-brachial variant of Guillain-Barre syndrome, which is characterized by rapidly progressive bulbar palsy with upper limb, neck and oropharyngeal involvement. It is a rare disorder in childhood and most cases have been described in adolescents. CaseDescription: A seven year-old-boy presented with dysarthria, hoarseness, dysphagia, facial diplegia and bilateral progressive upper limb weakness. These symptoms started two weeks after a gastrointestinal infection. Nerve conduction studies were compatible with an acute demyelinating polyneuropathy in the upper extremities. Anti-ganglioside antibodies in the serum (anti-GT1a, GD1a, GQ1b) were positive and Campylobacter jejuni was isolated from stools. The patient was treated with intravenous immunoglobulin and needed ventilatory support during the first 12 days of admission. He was discharged at day 15 showing improvement of his neurological deficits. He fully recovered after eleven months of follow-up.Conclusions: Although pharyngeal-cervical-brachial variant of Guillain-Barre syndrome is uncommon in children, it should be considered in a child with acute bulbar dysfunction because a timely diagnosis allows the early institution of therapeutic measures that can be lifesaving.

O Síndrome Nefrótico Congénito (SNC), nomeadamente primário, tem-se caracterizado históricamente por um prognóstico muito reservado, com morte em geral nos primeiros 6 meses de vida.Contudo, os avanços registados na terapêutica de suporte, diálise peritoneal crónica e transplantação renal na infância permitiram modificar este quadro.Os autores apresentam uma revisão das mais recentes estratégias terapêuticas utilizadas no SNC, propondo um protocolo de tratamento actualizado para esta patologia.