Cerebral Venous Thrombosis in Pediatric Age: Risk Factors and Prognosis.

INTRODUCTION: Cerebral venous thrombosis (CVT) is a rare but potentially fatal disease in pediatric age with an important morbimortality. In adults several factors have been associated with worse outcomes, however there are still few studies in children. This study aims to identify risk factors associated with clinical manifestations and long-term sequelae in pediatric CVT. METHODS: Retrospective analysis of pediatric inpatients admitted to a tertiary-care hospital due to CVT between 2008 and 2020. RESULTS: Fifty-four children were included, 56% male, median age of 6.5 years (9 months-17.3 years). Permanent risk factors were identified in 13 patients (malignancy, 8; hematologic condition, 5) and transient risk factors in 47, including head and neck infections (57%) and head trauma (15%). Multiple venous sinuses involvement was present in 65% and the deep venous system was affected in four patients. Seventeen percent had intracranial hemorrhage and 9% cerebral infarction. Sixty-four percent of patients with multiple venous sinuses involvement presented with severe clinical manifestations: impaired consciousness, intracranial hypertension, acute symptomatic seizures or focal deficits. Regarding long-term prognosis, six patients had major sequelae: epilepsy (n = 3), sensory motor deficits (n = 2), and cognitive impairment (n = 3). Permanent risk factors were associated with severe clinical manifestations (p = 0.043). Cerebral infarction and intracranial hemorrhage were associated with major sequelae (p = 0.006 and p = 0.03, respectively, adjusted for age and sex). CONCLUSION: Permanent risk factors, involvement of multiple venous sinuses, intracranial hemorrhage, and cerebral infarction, were related to worse prognosis. Detection and early management of risk factors may limit CVT extension and reduce its morbimortality.

Child Neurology: Anti-Hu Encephalitis in an Adolescent With a Mediastinal Seminoma.

Anti-Hu antibodies are associated with autoimmune syndromes, mainly limbic encephalitis, encephalomyelitis, and painful sensory polyneuropathy (Denny-Brown). We report the case of a 15-year-old boy presenting with epilepsia partialis continua (EPC) found to have a right middle frontal gyrus brain lesion without atrophy or contralateral involvement. After partial resection, neuropathology revealed neuronal loss, reactive gliosis and astrocytosis, and perivascular mononuclear inflammatory infiltrate and features of neuronophagia resembling Rasmussen encephalitis. Suboptimal response to antiseizure drugs and surgery prompted further workup with identification of positive serum anti-Hu antibodies and a mediastinal seminoma. The patient was treated with immunotherapy including steroids, IV immunoglobulin, azathioprine, rituximab, plasmapheresis, and mediastinal lesion resection. However, he continued to experience EPC and psychomotor impairment along with left hemiparesis and dysarthria. Given clinical progression with failure to respond to immunotherapy and antiseizure polytherapy, hemispherotomy was attempted and seizure freedom achieved. A review of the literature found only 16 cases of neurologic presentations associated with anti-Hu antibodies in children, confirming the rarity of EPC in these cases. Thus, this report provides a new observation of germ cell mediastinal tumor associated with anti-Hu antibodies in children, broadening the spectrum of anti-Hu-associated neurologic disorders in children and highlighting the importance of considering antineuronal antibody testing in children presenting with EPC and brain lesions suggestive of Rasmussen encephalitis.

RHOBTB2 p.Arg511Trp Mutation in Early Infantile Epileptic Encephalopathy-64: Review and Case Report.

Early infantile epileptic encephalopathy-64 (EIEE 64), also called RHOBTB2-related developmental and epileptic encephalopathy (DEE), is caused by heterozygous pathogenic variants (EIEE 64; MIM#618004) in the Rho-related BTB domain-containing protein 2 ( RHOBTB2 ) gene. To date, only 13 cases with RHOBTB2-related DEE have been reported. We add to the literature the 14th case of EIEE 64, identified by whole exome sequencing, caused by a heterozygous pathogenic variant in RHOBTB2 (c.1531C > T), p.Arg511Trp. This additional case supports the main features of RHOBTB2-related DEE: infantile-onset seizures, severe intellectual disability, impaired motor functions, postnatal microcephaly, recurrent status epilepticus, and hemiparesis after seizures.

Successful Treatment of a Child With Epileptic Encephalopathy With Spike-Wave Activation in Sleep and GRIN2A Variant Using Sulthiame.

Epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS) and developmental EE-SWAS (DEE-SWAS) are characterized by variable combinations of cognitive, language, behavioral, and/or motor regression associated with continuous or near-continuous diffuse spike-and-wave complexes during sleep. Glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) variants have been associated with EE-SWAS. It encodes the most relevant GluN2 subunit of the N-methyl-D-aspartate receptor (NMDAR). Sulthiame reduces NMDAR-mediated neuronal excitability and has been progressively used as monotherapy in self-limited epilepsy with centrotemporal spikes (SeLECTS) or as add-ontherapy in EE-SWAS/DEE-SWAS. A five-year-old female, with family history of epilepsy, was initially diagnosed with SeLECTS and medicated with valproic acid (VPA). One year later, she presented a focal to bilateral tonic-clonic seizure during sleep and learning difficulty. The electroencephalogram revealed continuous spike-and-wave during sleep leading to the diagnosis of EE-SWAS. Prednisolone was effective, but there was repeated recurrence after its discontinuation and associated adverse effects. As an alternative, sulthiame was added to VPA. Four years later, she remains clinically stable. Genetic testing revealed a GRIN2A missense variant, C.3228C>A (p.Asn1076Lys). Sulthiame appeared effective in this recurrent EE-SWAS child, who presented a GRIN2A missense variant with possible NMDAR gain-of-function and adverse effects of corticosteroids. Functional studies​​​​​​​ of GRIN2A variants might become a future tool for individualized therapies.

Cerebral venous thrombosis in adolescence: Looking beyond the obvious.

Behçet's disease (BD) is a rare systemic vasculitis with multisystemic involvement. Neurological involvement, called neuro-Behçet's disease (NBD), mostly involves the central nervous system and cerebral venous thrombosis (CVT) is the predominant neurological manifestation in the pediatric age. A 12-year-old female with a past medical history of a CVT, without an identifiable etiology, was admitted with a five-day right fronto-orbital headache. Neuroimage showed a subacute thrombosis of a right superficial sylvian vein, with indirect signs of intracranial hypertension and no imaging signs of vasculitis. Prothrombotic screening and immunologic study were normal. She was started on acetazolamide and hypocoagulation with progressively improving. She had a history of frequent oral aphthae and an episode of a genital ulcer three months before admission. Pathergy test was negative. HLA-B51 was positive. She was diagnosed with NBD and started therapy with colchicine and infliximab. After discharge, the patient remains without symptoms, hypocoagulated, and on infliximab regimen, without complications to report. This case, only diagnosed in the second episode of CVT, is paradigmatic of the difficulty in establishing the diagnosis of BD.

Classical fragile-X phenotype in a female infant disclosed by comprehensive genomic studies.

BACKGROUND: We describe a female infant with Fragile-X syndrome, with a fully expanded FMR1 allele and preferential inactivation of the homologous X-chromosome carrying a de novo deletion. This unusual and rare case demonstrates the importance of a detailed genomic approach, the absence of which could be misguiding, and calls for reflection on the current clinical and diagnostic workup for developmental disabilities. CASE PRESENTATION: We present a female infant, referred for genetic testing due to psychomotor developmental delay without specific dysmorphic features or relevant family history. FMR1 mutation screening revealed a methylated full mutation and a normal but inactive FMR1 allele, which led to further investigation. Complete skewing of X-chromosome inactivation towards the paternally-inherited normal-sized FMR1 allele was found. No pathogenic variants were identified in the XIST promoter. Microarray analysis revealed a 439 kb deletion at Xq28, in a region known to be associated with extreme skewing of X-chromosome inactivation. CONCLUSIONS: Overall results enable us to conclude that the developmental delay is the cumulative result of a methylated FMR1 full mutation on the active X-chromosome and the inactivation of the other homologue carrying the de novo 439 kb deletion. Our findings should be taken into consideration in future guidelines for the diagnostic workup on the diagnosis of intellectual disabilities, particularly in female infant cases.

[Clinical and Epidemiological Study of Complicated Infection by Varicella-Zoster Virus in the Pediatric Age]. / Estudo Clínico-Epidemiológico da Infeção Complicada por Vírus Varicela-Zoster na Idade Pediátrica.

INTRODUCTION: In Portugal, the incidence of complicated infection by varicella-zoster virus is unknown. The purpose of this study was to describe the epidemiological and clinical features of complicated infection by varicella-zoster virus in children. MATERIAL AND METHODS: Retrospective review of the clinical files of patients admitted between January 1999 and July 2013, with a diagnosis of complicated varicella-zoster virus infection. RESULTS: Ninety-four patients were hospitalized with complicated varicella-zoster virus infection, two of them by reactivation of latent infection. The median age was 38 (IQR 18 - 65) months. The most frequent types of complications were bacterial overinfection of the skin and subcutaneous cellular tissue (37.2%) and respiratory complications (24.5%). Other complications were neurologic complications (19.1%), gastrointestinal (9.6%), hematologic (5.3%) and osteoarticular (4.3%). In 38 patients invasive bacterial infections were diagnosed, with bacteremia in 6 patients. The median age was highest in the immunological complications compared with infectious complications. Neurological complications occurred mainly in healthy children, while infectious complications, including the invasive bacterial infections were more frequent in patients treated with ibuprofen and/or corticosteroids. The evolution was favorable in most cases. DISCUSSION: The complications of varicella-zoster virus infection occurred mainly in pre-school age and in healthy children. Infectious complications, particularly respiratory complications and bacterial overinfection of the skin and subcutaneous cellular tissue, were the most frequent. There was association between infectious complications and previous therapy with ibuprofen and / or corticosteroids. CONCLUSION: Multicenter studies should be planned in order to optimize and adjust the vaccine strategies to our reality.

Introdução: Em Portugal, a incidência da infeção complicada por vírus varicela-zoster e respetivos custos é desconhecida. O objetivo deste estudo foi descrever as características clinico-epidemiológicas dos doentes em idade pediátrica internados com o diagnóstico de infeção complicada por vírus varicela-zoster. Material e Métodos: Estudo descritivo, baseado na análise dos processos clínicos dos doentes internados entre janeiro de 1999 e julho de 2013, com diagnóstico de infeção complicada por vírus varicela-zoster. Resultados: Foram internados 94 doentes por infeção complicada a vírus varicela-zoster, dois por reativação de infeção latente. A mediana da idade foi 38 (IQR 18 - 65) meses. As complicações mais frequentes foram as infeciosas (70,2%), destacando-se a sobreinfeção bacteriana da pele/tecido celular subcut'neo (37,2%) e as complicações respiratórias (24,5%). Seguiram-se as complicações neurológicas (19,1%), gastrointestinais (9,6%), hematológicas (5,3%) e osteoarticulares (4,3%). Diagnosticaram-se 38 (40,4%) infeções bacterianas invasivas, seis com bacteriemia. A mediana da idade na admissão foi mais elevada nas complicações imunológicas relativamente às complicações infeciosas. As complicações neurológicas ocorreram preferencialmente em crianças saudáveis, enquanto as complicações infeciosas, nomeadamente as infeções bacterianas invasivas foram mais frequentes nos doentes medicados com ibuprofeno e/ou corticoide. A evolução foi favorável na maioria dos casos. Discussão: As complicações da infeção pelo vírus varicela-zoster ocorreram preferencialmente em idade pré-escolar e doentes saudáveis. As complicações infeciosas, nomeadamente as dermatológicas e respiratórias, foram as mais frequentes, tendo sido verificada associação com a terapêutica prévia com ibuprofeno e /ou corticoide.Conclusão: Estudos multicêntricos deverão ser planeados com o intuito de otimizar e ajustar as estratégias vacinais à nossa realidade.