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OBJECTIVE: Arterial ischemic stroke (AIS) is an important cause of acquired brain injury in children. Few prospective population-based studies of childhood AIS have been completed. We aimed to investigate the outcome of childhood AIS 12 months after the event in a population-based cohort. METHODS: Children aged 29 days to < 16 years with radiologically confirmed AIS occurring over a 1-year period residing in southern England (population = 5.99 million children) were eligible for inclusion. Outcome was assessed during a home visit using the Pediatric Stroke Outcome Measure (PSOM). Parental impressions of recovery were assessed using the Pediatric Stroke Recurrence and Recovery Questionnaire. PSOM score was estimated via telephone interview or clinician interview whenever home visit was not possible. RESULTS: Ninety-six children with AIS were identified. Two children were lost to follow-up. Nine of 94 (10%) children died before the 12-month follow-up. One child had an AIS recurrence. PSOM scores were available for 78 of 85 living children at follow-up. Thirty-nine of 78 (50%) had a good outcome (total PSOM score < 1), and 39 of 78 (50%) had a poor outcome. Seizures at onset of AIS were associated with a poor outcome (odds ratio = 3.5, 95% confidence interval = 1.16-10.6). Twenty-eight of 73 (38%) children were judged by their carers to have fully recovered. Ten of 84 (12%) children had recurrent seizures, and 17 of 84 (20%) reported recurrent headaches. INTERPRETATION: AIS carries a significant risk of mortality and long-term neurological deficit. However, the rates of mortality, recurrence, and neurological impairment were markedly lower in this study than previously published figures in the United Kingdom. Ann Neurol 2016;79:784-793.
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In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders.
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Epilepsia/genética , Epilepsia/patología , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Canales de Potasio/genética , Niño , Preescolar , Cromosomas Humanos Par 9 , Epilepsia/diagnóstico , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Canal de Potasio KCNQ2/genética , Masculino , Mutación , Canal de Sodio Activado por Voltaje NAV1.2/genética , Patología Molecular , Canales de potasio activados por Sodio , Proteínas Proto-Oncogénicas c-cbl/genética , Disomía Uniparental , Adulto JovenRESUMEN
BACKGROUND: Stroke is a major cause of mortality in children. Conditions that mimic stroke also cause severe morbidity and require prompt diagnosis and treatment. We have investigated the time to diagnosis in a cohort of children with stroke. METHODS: A population-based cohort of children with stroke was prospectively identified in the south of England. Case notes, electronic hospital admission databases and radiology records were reviewed. Timing of symptom onset, presentation to hospital, first neuroimaging, first diagnostic neuroimaging and presenting clinical features were recorded. RESULTS: Ninety-six children with an arterial ischaemic stroke (AIS) and 43 with a haemorrhagic stroke (HS) were identified. The median time from symptom onset to diagnostic neuroimaging was 24.3â h in AIS and 2.9â h in HS. The initial imaging modality was CT in 68% of cases of AIS. CT was diagnostic of AIS in 66% of cases. MRI was diagnostic in 100%. If initial neuroimaging was non-diagnostic in AIS, then median time to diagnosis was 44â h. CT was diagnostic in 95% of HS cases. Presentation outside normal working hours resulted in delayed neuroimaging in AIS (13 vs 3â h, p=0.032). Diffuse neurological signs or a Glasgow Coma Scale <9 resulted in more expeditious neuroimaging in both HS and AIS. CONCLUSIONS: The diagnosis of AIS in children is delayed at every stage of the pathway but most profoundly when the first neuroimaging is CT scanning, which is non-diagnostic. MRI should be the initial imaging modality of choice in any suspected case of childhood AIS.
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Diagnóstico Tardío/estadística & datos numéricos , Accidente Cerebrovascular/diagnóstico , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Neuroimagen/estadística & datos numéricos , Estudios Prospectivos , Factores de Tiempo , Tomografía Computarizada por Rayos XRESUMEN
Brown-Vialetto-Van Laere syndrome (BVVLS) is a genetic condition caused by a mutation in the C20orf54 gene, which also codes for an intestinal riboflavin transporter. We report the case of a female who presented at 22 months with acute-onset stridor and generalized muscle weakness, in whom a genetic diagnosis of BVVLS was made, and whose symptoms improved on therapy with high-dose riboflavin. She had previously been developing normally and was able to walk at 11 months, then developed progressive muscle weakness at 22 months, and within 2 weeks was unable to sit without support. She also demonstrated stridor and paradoxical breathing indicating diaphragmatic weakness, and required continuous non-invasive ventilation (NIV) through a tracheostomy. After treatment with riboflavin she was able to walk unaided, and her Gross Motor Functional Classification level improved from level IV to level I, having fully regained the motor function she showed before symptom onset. There were no longer signs of diaphragmatic paralysis while on NIV, and she was able to tolerate 10-minute periods off NIV before paradoxical breathing again became apparent. We therefore recommend that in all cases suspected to be in the BVVLS or Fazio-Londe spectrum, early treatment with high-dose riboflavin must be considered.
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Parálisis Bulbar Progresiva/tratamiento farmacológico , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Riboflavina/administración & dosificación , Complejo Vitamínico B/administración & dosificación , Administración Oral , Relación Dosis-Respuesta a Droga , Femenino , Humanos , LactanteRESUMEN
Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a treatable condition resulting from impaired glucose transport into the brain. The classical presentation is with infantile-onset epilepsy and severe developmental delay. Non-classical phenotypes with movement disorders and early-onset absence epilepsy are increasingly recognized and the clinical spectrum is expanding. The hallmark is hypoglycorrhachia (cerebrospinal fluid [CSF] glucose<2.2 mmol/l) in the presence of normoglycaemia with a CSF/blood glucose ratio of less than 0.4. GLUT1DS is due to a mutation in the solute carrier family 2, member 1 gene (SLC2A1). We present five individuals (four males, one female), all of whom had a mild phenotype, highlighting the importance of considering this diagnosis in unexplained neurological disorders associated with mild learning difficulties, subtle motor delay, early-onset absence epilepsy, fluctuating gait disorders, and/or dystonia. The mean age at diagnosis was 8 years 8 months. This paper also shows phenotypical parallels between GLUT1DS and paroxysmal exertion-induced dyskinesia.
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Transportador de Glucosa de Tipo 1/genética , Glucosa/líquido cefalorraquídeo , Adolescente , Errores Innatos del Metabolismo de los Carbohidratos/líquido cefalorraquídeo , Errores Innatos del Metabolismo de los Carbohidratos/diagnóstico , Errores Innatos del Metabolismo de los Carbohidratos/genética , Errores Innatos del Metabolismo de los Carbohidratos/fisiopatología , Niño , Preescolar , Diagnóstico Diferencial , Distonía/genética , Epilepsia Tipo Ausencia/genética , Femenino , Marcha , Humanos , Masculino , Proteínas de Transporte de Monosacáridos/líquido cefalorraquídeo , Proteínas de Transporte de Monosacáridos/deficiencia , Proteínas de Transporte de Monosacáridos/genética , Actividad Motora , Mutación , Fenotipo , Índice de Severidad de la EnfermedadAsunto(s)
Corea/diagnóstico , Epilepsia Tipo Ausencia/diagnóstico , Medicina General/métodos , Transportador de Glucosa de Tipo 1/deficiencia , Anamnesis/métodos , Pediatría/métodos , Anticonvulsivantes/uso terapéutico , Preescolar , Corea/genética , Diagnóstico Diferencial , Electroencefalografía , Epilepsia Tipo Ausencia/tratamiento farmacológico , Epilepsia Tipo Ausencia/genética , Femenino , Transportador de Glucosa de Tipo 1/genética , HumanosRESUMEN
OBJECTIVE: To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease. METHODS: We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques. RESULTS: Patients first presented in early childhood (median age of presentation 10 months, range 0-48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16. CONCLUSIONS: Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia.
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BACKGROUND: Arterial ischaemic stroke is an important cause of acquired brain injury in children. Few prospective population-based studies of childhood arterial ischaemic stroke have been undertaken. We aimed to investigate the epidemiology and clinical features of childhood arterial ischaemic stroke in a population-based cohort. METHODS: Children aged 29 days to less than 16 years with radiologically confirmed arterial ischaemic stroke occurring over a 1-year period (July 1, 2008, to June 30, 2009) residing in southern England (population denominator 5·99 million children) were eligible for inclusion. Cases were identified using several sources (paediatric neurologists and trainees, the British Paediatric Neurology Surveillance Unit, paediatricians, radiologists, physiotherapists, neurosurgeons, parents, and the Paediatric Intensive Care Audit Network). Cases were confirmed by personal examination of cases and case notes. Details of presenting features, risk factors, and investigations for risk factors were recorded by analysis of case notes. Capture-recapture analysis was used to estimate completeness of ascertainment. FINDINGS: We identified 96 cases of arterial ischaemic stroke. The crude incidence of childhood arterial ischaemic stroke was 1·60 per 100â000 per year (95% CI 1·30-1·96). Capture-recapture analysis suggested that case ascertainment was 89% (95% CI 77-97) complete. The incidence of arterial ischaemic stroke was highest in children aged under 1 year (4·14 per 100â000 per year, 95% CI 2·36-6·72). There was no difference in the risk of arterial ischaemic stroke between sexes (crude incidence 1·60 per 100â000 per year [95% CI 1·18-2·12] for boys and 1·61 per 100â000 per year [1·18-2·14] for girls). Asian (relative risk 2·14, 95% CI 1·11-3·85; p=0·017) and black (2·28, 1·00-4·60; p=0·034) children were at higher risk of arterial ischaemic stroke than were white children. 82 (85%) children had focal features (most commonly hemiparesis) at presentation. Seizures were more common in younger children (≤1 year) and headache was more common in older children (>5 years; p<0·0001). At least one risk factor for childhood arterial ischaemic stroke was identified in 80 (83%) cases. INTERPRETATION: Age and racial group, but not sex, affected the risk of arterial ischaemic stroke in children. Investigation of such differences might provide causative insights. FUNDING: The Stroke Association, UK.
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Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiología , Vigilancia de la Población/métodos , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Adolescente , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Estudios Prospectivos , Factores de RiesgoRESUMEN
Isolated paediatric neurosarcoidosis (IPN) is exceptionally rare and only seven cases have been reported so far in the literature. We report the clinical and radiological profile of a 7 year-old boy with epilepsia partialis continua (EPC) who was initially thought to have Acute Disseminated Encephalomyelitis (ADEM), but was subsequently found to have isolated neurosarcoidosis. Additionally, we performed a literature search on Medline and Embase and secondary sources of data such as reference list of articles reviewed. Whilst cranial neuropathy is the commonest presenting feature in adults with neurosarcoidosis, paediatric patients are more likely to present with seizures. Diagnosis presents a clinical challenge as a result of its protean manifestations. Due to its rarity, there remains a lack of evidence base to inform the best choice of treatment for these children. Our patient was successfully treated with a combination of various immunomodulants.
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Enfermedades del Sistema Nervioso Central/diagnóstico , Enfermedades del Sistema Nervioso Central/terapia , Encefalomielitis Aguda Diseminada/diagnóstico , Epilepsia Parcial Continua/diagnóstico , Sarcoidosis/diagnóstico , Sarcoidosis/terapia , Convulsiones/diagnóstico , Enfermedades del Sistema Nervioso Central/complicaciones , Niño , Diagnóstico Diferencial , Encefalomielitis Aguda Diseminada/complicaciones , Epilepsia Parcial Continua/fisiopatología , Humanos , Inmunomodulación/inmunología , Masculino , Sarcoidosis/complicaciones , Convulsiones/complicaciones , Resultado del TratamientoRESUMEN
Mutations in the recently described RARS2 gene encoding for mitochondrial arginyl-transfer RNA synthetase give rise to a disorder characterised by early onset seizures, progressive microcephaly and developmental delay. The disorder was named pontocerebellar hypoplasia type 6 (PCH6) based on the corresponding radiological findings observed in the original cases. We report two siblings with the RARS2 mutation who displayed typical clinical features of PCH6, but who had distinct neuroimaging features. Early scans showed marked supratentorial, rather than infratentorial, atrophy, and the pons remained preserved throughout. One sibling also had bilateral subdural effusions at presentation. The deceleration in head growth pointed to an evolving genetic/metabolic process giving rise to cerebral atrophy and secondary subdural effusions. RARS2 mutations should be considered in infants presenting with seizures, subdural effusions, decelerating head growth and evidence of cerebral atrophy even in the absence of pontocerebellar hypoplasia on imaging.
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Arginino-ARNt Ligasa/genética , Cerebelo/anomalías , Atrofias Olivopontocerebelosas/genética , Puente/anomalías , Efusión Subdural/genética , Cerebelo/patología , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Masculino , Mutación , Atrofias Olivopontocerebelosas/diagnóstico , Puente/patología , Hermanos , Efusión Subdural/diagnóstico , Efusión Subdural/patologíaRESUMEN
PATIENTS AND METHODS: In this retrospective study, 36 children referred to paediatric neurology and neurosurgery during April 1995-June 1998 with a diagnosis of subdural haematoma (SDH) were studied. Nine were accidental secondary to witnessed trauma and 4 were iatrogenic. Non-accidental head injury (NAHI) was suspected in the remaining 23 children. RESULTS: After a full clinical, radiological and social assessment, NAHI was diagnosed in 14, lateral sinus thrombosis in 1, 2 were accepted as accidental and 6 remained unexplained. In the NAHI group (n=14), 12 were between 4 and 16 weeks of age, 12 (85%) had retinal haemorrhages and skeletal surveys showed evidence of additional injury in 8. Computerised tomography (CT) brain scans showed bilateral SDH in 11, and 6 had inter-hemispheric bleeding along with loss of grey-white differentiation. Eleven had magnetic resonance imaging (MRI), which yielded additional information in 7. Seven required intensive care, and 2 died. Twelve had surgical aspiration. In the group with no satisfactory explanation for SDH ( n=6); 5 had neonatal problems, all except 1 were older than 5 months of age and not as ill with bilateral, old SDH. All but 1 had skeletal surveys, which were normal, and eye examination showed no retinal haemorrhages. A social services enquiry was non-contributory. CONCLUSIONS: SDH is frequently traumatic whether accidental or non-accidental. SDH due to NAHI tends to present before 4 months of age with an inconsistent history; the patients are more seriously ill and have other findings, such as fractures and retinal haemorrhages. A small subgroup of patients was identified who had isolated, old SDH and in whom full investigation remained inconclusive. A consistent, comprehensive approach needs to be maintained in all cases with the essential backup of detailed neuro-imaging including MRI.