RESUMEN
AIMS: Glioneuronal tumours (GNTs) are poorly distinguished by their histology and lack robust diagnostic indicators. Previously, we showed that common GNTs comprise two molecularly distinct groups, correlating poorly with histology. To refine diagnosis, we constructed a methylation-based model for GNT classification, subsequently evaluating standards for molecular stratification by methylation, histology and radiology. METHODS: We comprehensively analysed methylation, radiology and histology for 83 GNT samples: a training cohort of 49, previously classified into molecularly defined groups by genomic profiles, plus a validation cohort of 34. We identified histological and radiological correlates to molecular classification and constructed a methylation-based support vector machine (SVM) model for prediction. Subsequently, we contrasted methylation, radiological and histological classifications in validation GNTs. RESULTS: By methylation clustering, all training and 23/34 validation GNTs segregated into two groups, the remaining 11 clustering alongside control cortex. Histological review identified prominent astrocytic/oligodendrocyte-like components, dysplastic neurons and a specific glioneuronal element as discriminators between groups. However, these were present in only a subset of tumours. Radiological review identified location, margin definition, enhancement and T2 FLAIR-rim sign as discriminators. When validation GNTs were classified by SVM, 22/23 classified correctly, comparing favourably against histology and radiology that resolved 17/22 and 15/21, respectively, where data were available for comparison. CONCLUSIONS: Diagnostic criteria inadequately reflect glioneuronal tumour biology, leaving a proportion unresolvable. In the largest cohort of molecularly defined glioneuronal tumours, we develop molecular, histological and radiological approaches for biologically meaningful classification and demonstrate almost all cases are resolvable, emphasising the importance of an integrated diagnostic approach.
Asunto(s)
Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Neoplasias Neuroepiteliales , Radiología , Humanos , Neoplasias Encefálicas/patología , Metilación de ADN , Neoplasias Neuroepiteliales/genética , Neoplasias del Sistema Nervioso Central/genéticaRESUMEN
AIM: To investigate the rate of successful withdrawal of antiseizure medication (ASM) after starting the ketogenic diet in children and identify predictive factors. METHOD: We retrospectively reviewed data of children with epilepsy, who were treated with the ketogenic diet for 6 months or longer at our institution, over a 5-year period. We defined successful withdrawal of one or more medications as a time period of 3 months or more off this medication without restarting it or starting a new agent. Predictive clinical factors were investigated using binary multivariable logistic regression. RESULTS: Seventy-one children were included (28 females, 43 males; median age at seizure onset 5 months, median age at diet initiation 58.5 months, median duration of ketogenic diet 27.7 months). Reduction of one or more ASMs was attempted in 54 out of 71 (76%) children and was successful in 34 out of 54 (63%), including discontinuation of all ASMs in 13. Younger age at the start of the ketogenic diet was associated with higher odds of successful ASM withdrawal. ASM withdrawal was successful in 11 out of 19 children with less than 50% seizure reduction at 3 months. INTERPRETATION: Reduction of ASM was achieved in two-thirds of patients after the start of the ketogenic diet, where attempted, and can be successful even with little or unchanged seizure frequency while on the diet.
Asunto(s)
Dieta Cetogénica , Epilepsia Refractaria , Epilepsia , Masculino , Femenino , Niño , Humanos , Lactante , Preescolar , Estudios Retrospectivos , Epilepsia Refractaria/tratamiento farmacológico , Convulsiones/tratamiento farmacológico , Epilepsia/tratamiento farmacológico , Resultado del TratamientoRESUMEN
OBJECTIVE: The term 'precision medicine' describes a rational treatment strategy tailored to one person that reverses or modifies the disease pathophysiology. In epilepsy, single case and small cohort reports document nascent precision medicine strategies in specific genetic epilepsies. The aim of this multicentre observational study was to investigate the deeper complexity of precision medicine in epilepsy. METHODS: A systematic survey of patients with epilepsy with a molecular genetic diagnosis was conducted in six tertiary epilepsy centres including children and adults. A standardised questionnaire was used for data collection, including genetic findings and impact on clinical and therapeutic management. RESULTS: We included 293 patients with genetic epilepsies, 137 children and 156 adults, 162 females and 131 males. Treatment changes were undertaken because of the genetic findings in 94 patients (32%), including rational precision medicine treatment and/or a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms. There was a rational precision medicine treatment for 56 patients (19%), and this was tried in 33/56 (59%) and was successful (ie, >50% seizure reduction) in 10/33 (30%) patients. In 73/293 (25%) patients there was a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms, and this was successful in 24/73 (33%). SIGNIFICANCE: Our survey of clinical practice in specialised epilepsy centres shows high variability of clinical outcomes following the identification of a genetic cause for an epilepsy. Meaningful change in the treatment paradigm after genetic testing is not yet possible for many people with epilepsy. This systematic survey provides an overview of the current application of precision medicine in the epilepsies, and suggests the adoption of a more considered approach.
Asunto(s)
Epilepsia/genética , Medicina de Precisión , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVE: In epilepsy surgery, which aims to treat seizures and thereby to improve the lives of persons with drug-resistant epilepsy, the chances of attaining seizure relief must be carefully weighed against the risks of complications and expected adverse events. The interpretation of data regarding complications of epilepsy surgery and invasive diagnostic procedures is hampered by a lack of uniform definitions and method of data collection. METHODS: Based on a review of previous definitions and classifications of complications, we developed a proposal for a new classification. This proposal was then subject to revisions after expert opinion within E-pilepsy, an EU-funded European pilot network of reference centers in refractory epilepsy and epilepsy surgery, later incorporated into the ERN (European Reference Network) EpiCARE. This version was discussed with recognized experts, and a final protocol was agreed to after further revision. The final protocol was evaluated in practical use over 1 year in three of the participating centers. One hundred seventy-four consecutive procedures were included with 35 reported complications. RESULTS: This report presents a multidimensional classification of complications in epilepsy surgery and invasive diagnostic procedures, where complications are characterized in terms of their immediate effects, resulting permanent symptoms, and consequences on activities of daily living. SIGNIFICANCE: We propose that the protocol will be helpful in the work to promote safety in epilepsy surgery and for future studies designed to identify risk factors for complications. Further work is needed to address the reporting of outcomes as regards neuropsychological function, activities of daily living, and quality of life.
Asunto(s)
Epilepsia Refractaria , Epilepsia , Actividades Cotidianas , Epilepsia Refractaria/diagnóstico , Epilepsia Refractaria/cirugía , Epilepsia/diagnóstico , Epilepsia/cirugía , Estudios de Factibilidad , Humanos , Calidad de Vida , Literatura de Revisión como Asunto , Factores de Riesgo , ConvulsionesRESUMEN
Fenfluramine hydrochloride has classically been described as acting pharmacologically through a serotonergic mechanism. Therefore, it was initially used as an anorectic drug, given that impaired serotonin homeostasis may be associated with increased food intake. Although positive results were documented, cardiovascular concerns resulted in its temporary withdrawal. Nevertheless, a novel role in patients with epilepsy was later suggested by isolated clinical observations. The wide application of genetic testing allowed the classification (predominantly as Dravet syndrome) of patients in whom benefit was seen, while with the development of zebrafish models, its antiepileptic properties were confirmed at a molecular level. Data from randomized clinical trials have shown a beneficial effect of fenfluramine, as an adjunct therapy, on seizure control for children with Dravet syndrome, though there is still uncertainty about the impact on neurodevelopment in these patients. No signs of heart valve disease have been documented to date. Long-term and appropriately designed clinical studies will verify whether fenfluramine is a therapeutic agent of high importance, living up to the promise shown so far. What this paper adds Fenfluramine is a very promising repurposed therapy specifically for seizures in Dravet syndrome. The long-term effect of fenfluramine on neurodevelopmental prognosis requires further investigation.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Fenfluramina/uso terapéutico , Convulsiones/tratamiento farmacológico , HumanosRESUMEN
ABSTRACT: The differential diagnosis of scrotal pain in childhood is a challenge for every primary care physician. We report the case of a 5-year-old boy presenting to the emergency department owing to acute left scrotal pain. Ultrasound screening revealed a Morgagni hydatid in the left testis, which was surgically removed. X-rays revealed microcalcifications of the cyst wall and stroma, signs indicative of chronic inflammation. Results of histological examination confirmed radiographic evaluation. No similar use of x-rays has been described in literature before, to the best of our knowledge. A brief discussion also follows about Morgagni hydatid in childhood.
Asunto(s)
Dolor Agudo , Enfermedades de los Genitales Masculinos , Preescolar , Humanos , Masculino , Escroto/diagnóstico por imagen , Testículo , UltrasonografíaRESUMEN
Nutritional interventions are gaining remarkable attention as complementary management options for autism. Our aim is to provide literature data about the impact of the administration of dietary supplements during pregnancy on the risk of autism spectrum disorder in the offspring. A comprehensive search was undertaken by 2 reviewers independently using PubMed as the medical database source. Prospective clinical and experimental studies were considered and no year-of-publication restriction was placed. We were able to identify 4 basic (conducted in rodents) and 3 clinical research papers fulfilling our selection criteria. Supplements studied included folic acid, iron, multivitamins, choline, vitamin D, and docosahexaenoic acid. Choline and folic acid had a significant impact on the expression of autism-related genes. However, from a clinical point of view, prenatal folate administration did not reduce the risk of autism. Similarly, iron had no significant impact, while the use of multivitamins in moderate frequency had a protective effect. The use of vitamin D and docosahexaenoic acid during gestation decreased the incidence of autism in animal models. In conclusion, available data are controversial and cannot change current routine practice. More large-scale prospective studies are needed to identify the real effect of nutritional supplements and also optimize their administration.Key teaching pointsMultivitamins use during pregnancy can exert a protective effect on the risk of autism, although depending on the frequency of use. Nevertheless, prenatal iron and folate were not shown to have any significant impact.Research based on animal models showed that choline and folic acid can have a significant impact on the expression of autism-related genes in a sex-specific manner.Furthermore, the use of vitamin D and docosahexaenoic acid during gestation seem to decrease the incidence of autism in animal offspring.In the future, more clinical, large-scale prospective and methodologically homogenous clinical studies are needed to further investigate the effect of the periconceptional use of nutritional supplements on autism risk.
Asunto(s)
Trastorno del Espectro Autista/epidemiología , Suplementos Dietéticos , Atención Prenatal/métodos , Animales , Colina/administración & dosificación , Ácidos Docosahexaenoicos/administración & dosificación , Femenino , Ácido Fólico/administración & dosificación , Humanos , Fenómenos Fisiologicos Nutricionales Maternos , Estado Nutricional , Embarazo , Vitamina D/administración & dosificación , Vitaminas/administración & dosificaciónRESUMEN
Human respiratory syncytial virus (RSV) is the leading cause of acute bronchiolitis in infants and young children. Children under the age of 2 years, hospitalized for bronchiolitis in the pediatric clinic of a tertiary hospital in northern Greece, were tested for RSV infection during two RSV seasons (2016-2017 and 2017-2018). RSV was detected in 37 of 71 (52.1%) patients, most of them younger than 6 months. Both RSV subtypes were detected - RSV-A (54.1%) and RSV-B (45.9%) - with predominance of RSV-A during the 2016-2017 and RSV-B during the 2017-2018 season. RSV-A and RSV-B sequences clustered within the ON1 and BA genotypes, respectively. Compared to the prototype strains, several amino acid substitutions were observed in the duplication region of the G gene. The study provides a first insight into the molecular epidemiology of RSV in Greece.
Asunto(s)
Neurología , Política Pública , Humanos , Neurología/educación , Encéfalo/crecimiento & desarrolloRESUMEN
Background The aim of this study is to investigate through polysomnography sleep quality in children with rolandic epilepsy and compare sleep variables between these children and healthy controls. Methods Our study population included 15 children with rolandic epilepsy and 27 healthy children who underwent overnight polysomnography. Parameters about sleep architecture and sleep respiratory events were recorded and analyzed. The level of statistical significance was set at 0.05. Results Patients and controls did not differ in basic epidemiological traits. The percentage of sleep stage rapid eye movement was significantly lower in the epilepsy group. Moreover, the mean value of the obstructive apnea index and the obstructive apnea-hypopnea index was significantly higher in children with rolandic epilepsy compared with healthy children. Longest apnea duration and basal Spo 2 during sleep had also the trend to be higher and lower, respectively, in children with epilepsy. Conclusions Children with rolandic epilepsy exhibit alterations in sleep architecture, as well as in sleep respiratory patterns. Therefore, sleep quality should be routinely considered in the long-term follow-up of these children.
Asunto(s)
Epilepsia Rolándica/complicaciones , Trastornos del Sueño-Vigilia/etiología , Adolescente , Niño , Estudios Transversales , Femenino , Hemoglobinas/metabolismo , Humanos , Masculino , PolisomnografíaRESUMEN
PURPOSE: Our aim is to review studies which assess the prevalence of sleep apneas in children with epilepsy and discuss possible mechanisms linking these two conditions, as well as the impact of sleep apneas on the prognosis of these children. METHODS: PubMed was used as the medical database source, and articles were selected and classified according to their originality, level of evidence, and relevance to the broad scope of the review. RESULTS: Children with epilepsy have a higher prevalence of sleep breathing disorders in comparison to healthy children, but this prevalence varies widely depending on the methodology of each study. Major risk factors for sleep apneas in childhood epilepsy include mainly poor seizure control and antiepileptic drug polytherapy. Indeed, epilepsy can trigger sleep apneas, as abnormal electrical discharge amplifies sleep-induced breathing instability, antiepileptic drugs disturb muscle tone, and vagus nerve stimulation modulates neurotransmission to airway muscles. On the other hand, sleep apneas enhance sleep fragmentation, thus reducing the threshold for the appearance of seizures. Moreover, they have a negative effect on the neurocognitive profile of these children, as they disturb neuroplasticity mechanisms and also have a probable association with sudden unexpected death in epilepsy. The surgical treatment of sleep apneas has been found to reduce seizure frequency, and this can offer new therapeutic choices. CONCLUSIONS: Between sleep apneas and childhood epilepsy, there is a complex relationship with reciprocal interactions. The presence of sleep apneas should be taken into account when designing the management of these children, as it creates therapeutic opportunities and limitations.
Asunto(s)
Epilepsia/diagnóstico , Epilepsia/epidemiología , Apnea Obstructiva del Sueño/diagnóstico , Apnea Obstructiva del Sueño/epidemiología , Niño , Comorbilidad , Estudios Transversales , Humanos , PronósticoRESUMEN
A 9-year-old boy, with a history of repair of severe coarctation of the aorta through balloon angioplasty 2 weeks ago, presented in the emergency paediatric department with symptoms consistent with transient cerebral ischaemia. MRI revealed an area of cerebral infarction in the right frontal lobe. Causes of cerebral ischaemia after aortic coarctation repair are briefly discussed.
Asunto(s)
Angioplastia Coronaria con Balón/efectos adversos , Coartación Aórtica/complicaciones , Isquemia Encefálica/etiología , Coartación Aórtica/terapia , Niño , Humanos , Imagen por Resonancia Magnética , Masculino , Complicaciones PosoperatoriasRESUMEN
Repurposing is one of the key opportunities to address the unmet rare diseases therapeutic need. Based on cases of drug repurposing in small population conditions, and previous work in drug repurposing, we analyzed the most important lessons learned, such as the sharing of clinical observations, reaching out to regulatory scientific advice at an early stage, and public-private collaboration. In addition, current upcoming trends in the field of drug repurposing in rare diseases were analyzed, including the role these trends could play in the rare diseases' ecosystem. Specifically, we cover the opportunities of innovation platforms, the use of real-world data, the use of artificial intelligence, regulatory initiatives in repurposing, and patient engagement throughout the repurposing project. The outcomes from these emerging activities will help progress the field of drug repurposing for the benefit of patients, public health and medicines development.
RESUMEN
PURPOSE OF REVIEW: This article highlights basic concepts of seizures and epilepsy in pediatric patients, as well as basic treatment principles for this age group. RECENT FINDINGS: Epilepsy is the most common neurologic disorder in childhood. Accurate diagnosis is key; in older children, epileptic seizures need to be differentiated from various paroxysmal nonepileptic events, whereas in neonates, the majority of seizures are subclinical (electroencephalographic). Antiseizure medications remain the first-line treatment, but ketogenic diet and epilepsy surgery have also shown positive outcomes and can decrease drug burden. Genetic causes account for approximately 30% of cases, and the recognition of electroclinical syndromes is being replaced by the concept of genetic spectrums. Precision medicine therapies are promising, but wide application in daily practice still has a long way to go. Early access to specialist centers and optimal treatments positively affects prognosis and future neurodevelopment. SUMMARY: Although novel findings from all fields of research are being incorporated into everyday clinical practice, a better quality of life for children with seizures and epilepsy and their families is the ultimate priority.
Asunto(s)
Epilepsia , Calidad de Vida , Niño , Electroencefalografía , Epilepsia/tratamiento farmacológico , Epilepsia/terapia , Humanos , Recién Nacido , Pronóstico , Convulsiones/tratamiento farmacológico , Convulsiones/terapiaRESUMEN
Charcot-Marie-Tooth 4C is characterized by early-onset, rapid progression, and mainly associated with SH3TC2 gene mutations. We reported a male patient carrying a novel heterozygous nonsense mutation in SH3TC2 gene along with a heterozygous known pathogenic mutation. Symptoms began at 15 months and by 14 years, he presented significant motor impairment. Both parents exhibited one of the mutations in the heterozygous state, while his 8-year-old brother carried the same compound heterozygosity, showing only a mild phenotype. In our case, we discussed the contribution of compound heterozygosity to intrafamilial variability in Charcot-Marie-Tooth and the role of modifying genes.
RESUMEN
BACKGROUND: Respiratory failure is the principal source of morbidity and mortality among patients with Duchenne muscular dystrophy exerting a negative influence on their total quality of life. The aim of this review is to provide systematically current literature evidence about the effects of different treatment options (available or under development) for Duchenne muscular dystrophy on the pulmonary function of these patients. METHODS: A comprehensive search was undertaken using multiple health-related databases, while two independent reviewers assessed the eligibility of studies. A third person addressed any disagreements between reviewers. The quality of the methodology of the included studies was also assessed. RESULTS: A total of 19 original research papers (nine evaluating the role of steroids, six idebenone, three eteplirsen, one stem-cell therapy, and one ataluren) were found to fulfill our selection criteria with the majority of them (14 of 19) being prospective studies, not always including a control group. Endpoints mainly used in these studies were values of pulmonary function tests. Current and under development treatments proved to be safe and no significant adverse events were reported. A beneficial impact on pulmonary function was described by authors in the majority of these studies. The principal effect was slowing of lung disease progress, as expressed by spirometric values. However, the risk of bias was introduced in many of the above studies, while high heterogeneity in terms of treatment protocols and outcome measures limits the comparability of the results. CONCLUSION: Glucocorticoids remain the best-studied pharmacologic therapy for Duchenne muscular dystrophy and very likely delay the expected decline in lung function. With regard to new therapeutic agents, initial study results are encouraging. However, larger clinical trials are needed that minimize the risk of study bias, optimize the comparability of treatment groups, examine clinically meaningful pulmonary outcome measures, and include long-term follow up.
Asunto(s)
Distrofia Muscular de Duchenne/terapia , Glucocorticoides/uso terapéutico , Humanos , Pulmón/fisiopatología , Masculino , Morfolinos , Estudios Prospectivos , Calidad de Vida , Pruebas de Función Respiratoria , Ubiquinona/análogos & derivadosRESUMEN
BACKGROUND: In recent years advances in the field of pharmacogenomics have expanded the concept for more individualized treatments. Our aim is to provide literature data about the relationship between genetic polymorphisms and efficacy of antiepileptic drugs in children. METHODS: Pubmed was used as the main medical database source. Only original research papers were considered. No year-of-publication restriction was placed. Quality of evidence was assessed according to American Academy of Neurology guidelines. RESULTS: A total of 12 cross-sectional and case-control studies fulfilled our selection criteria. ABCB1 gene was associated with drug responsiveness in 2 out of 6 studies and ABCC2 gene in 1 out of 1 studies. SCN1A gene was also associated with seizure control in 4 out of 5 studies. Cytochrome P450 genes were found to significantly affect drug responsiveness in 2 out of 4 studies, while polymorphisms of uridinediphosphateglucuronosyltransferaseUGT2B7 gene predisposed to drug-resistance in 1 out of 2 studies. CONCLUSION: Variability in genes coding for sodium channels, drug transporters and cytochrome P450 enzymes can have a significant impact on response to antiepileptic drugs. Larger prospective studies with better stratification of samples are needed to shed light on these associations.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Resistencia a Medicamentos/genética , Epilepsia/tratamiento farmacológico , Farmacogenética , Variantes Farmacogenómicas/genética , Estudios de Casos y Controles , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Estudios ProspectivosRESUMEN
BACKGROUND: Sleep undergoes changes from birth to adulthood, while sleep disorders are associated with various cognitive deficiencies in childhood. In parallel, prematurity is known to predispose to poor neurodevelopmental outcomes. Our aim is to provide literature data about factors influencing sleep in the premature infants and sleep outcomes in this population. METHODS: A systematic review was conducted using a variety of health-related databases. Original research papers were considered and no year-of-publication restriction was placed. RESULTS: In total, 22 articles fulfilled our selection criteria. Available studies present remarkable heterogeneity in terms of methodological design. Compared to full term, premature infants exhibit significant differences in sleep structure, which mainly include differences in electroencephalographic spectral values, in total sleep time and in arousal threshold. Furthermore, prematurity seems to be a risk factor of sleep breathing disorders in childhood and adolescence. Data about the effect of methylxanthines and the environment of neonatal intensive care unit is controversial. With regard to the impact of prematurity-related sleep disorders on future neurodevelopment, available research papers are generally few. CONCLUSIONS: The alterations in sleep patterns are an outcome of prematurity (immaturity of nervous system) as well as of postnatal factors and comorbidities. Sleep problems in this population of infants seems to be a missing piece of the puzzle of impaired neurodevelopment. Future studies should focus on interventions to improve sleep hygiene and limit neurodevelopmental problems.
Asunto(s)
Enfermedades del Prematuro/etiología , Recien Nacido Prematuro , Enfermedades del Sistema Nervioso/etiología , Trastornos del Sueño-Vigilia/etiología , Electroencefalografía , Humanos , Recién Nacido , Factores de RiesgoRESUMEN
We describe the case of a 5-year-old girl with severe congenital neutropenia presenting with recurrent skin and respiratory infections. Sequence analysis of ELANE and HAX1 genes identified a mutation in heterozygous state in exon 2 of the ELANE gene: c.157C > G (p.His53Asp), not previously described in the literature at the exon coding level. Given the autosomal dominant inheritance and the location of the mutation within a "hotspot," this mutation was considered as clinically relevant. ELANE should be screened in patients with congenital neutropenia of no obvious etiology. A detailed medical history and clinical evaluation can prevent unnecessary investigations allowing for a targeted diagnostic strategy.