Perampanel as adjuvant treatment in epileptic encephalopathies: A multicenter study in routine clinical practice.

OBJECTIVE: Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of syndromes, including Lennox-Gastaut syndrome (LGS), which are refractory to multiple therapies. Perampanel efficacy has been reported in LGS but further real-world evidence is needed in DEEs. METHODS: A multicenter, retrospective, 1-year observational study in patients with DEEs on adjuvant perampanel treatment was conducted to assess perampanel safety and effectiveness in this type of patients in a real-world setting. Seizure types [focal onset seizures (FOS), generalized tonic-clonic seizures (GTCS), tonic seizures (TS), atonic seizures (AtS), atypical absences (AA), and myoclonic seizures (MS)] and seizure clusters were divided in different frequency groups: daily, weekly, and monthly seizures, and absent or seizure freedom. Patients could have more than one seizure type. For each frequency group, group change and seizure freedom were analyzed. RESULTS: Eighty-seven patients diagnosed with DEEs (45 males) of median age 22 [1-70] years were included. The most frequent DEEs were LGS (35.6%) and Lennox-like syndrome (37.9%). At baseline 20 patients had three to five types of seizures, 36 patients had two types of seizures and 31 patients had one predominant type of seizure. The mean number of seizure types per patient at baseline was 2.12 ± 0.97 which was reduced to 1.62 ± 0.91 at 12 months (p < 0.001). Overall, 51.7% of patients had a significant improvement in at least one seizure type. At baseline, 45 patients had GTCS, 42 FOS, 41 TS, 18 AA, 16 AtS, 11 MS, and 30 seizures clusters. Seizure freedom for each specific type at 12 months was significantly achieved by 35% of patients with GTCS (p < 0.001), 17% (p = 0.016) with TS and 37% with seizure clusters (p < 0.001). Patients achieved seizure freedom from other seizure types but with no statistical significance: 7% FOS-free, 28% AA-free, 6% Ats-free, and 18% MS-free. Regarding changes of group at 12 months, 22% of TS and 19% of FOS improved significantly to a group with lower seizure frequency (p = 0.004 and p = 0.02, respectively). In remaining groups (4% of GTCS, 11% of AA, 18% of Ats, 18% of MS, and 13% of seizure clusters), the improvement was not statistically significant. Twenty-nine patients discontinued perampanel: 18 (21%) due to AEs, 8 (9%) due to lack of efficacy, and 3 (3%) due to seizure worsening. Adverse events, mostly mild or moderate, were reported in 53% of patients, and irritability/mood changes (22%) and somnolence (17%) were the most frequent. CONCLUSION: This is the first large-scale real-world study with perampanel across different seizure types in patients with DEEs. Perampanel was effective, especially in GTCS, TS, and FOS, as well as in seizure clusters. Perampanel was generally well-tolerated without unexpected AEs.

Evolución neurológica y resultados de la cirugía pediátrica del arco aórtico mediante perfusión cerebral selectiva / Neurological changes and outcomes of paediatric surgery of the aortic arch using selective cerebral perfusion

INTRODUCCIÓN: Los objetivos son analizar las alteraciones neuropsicológicas a medio plazo de los niños intervenidos del arco aórtico mediante perfusión cerebral selectiva (PCS) y detectar posibles factores modificables en la técnica quirúrgica que pueden ayudar a minimizar la afectación neurológica posterior. MATERIAL Y MÉTODOS: Se establecieron como criterios de inclusión: patología del arco aórtico intervenida mediante PCS durante el primer año de vida, entre el 10 de agosto del 2004 y el 24 de mayo del 2016, fisiología biventricular y edad gestacional mayor de 31 semanas. En ausencia de cromosomopatía, se clasificaron desde el punto de vista neurológico siguiendo el modified Rankin score. En mayores de 4 años se realizaron estudios de inteligencia, nivel de atención, maduración y aptitudes psicolingüísticas. RESULTADOS: Se incluyeron ochenta y dos pacientes, cuya edad media en el momento de la cirugía fue de 1,8 meses. El flujo medio en PCS fue de 32 ml/kg/min. El tiempo medio de PCS fue de 31 min. La mortalidad global de la serie fue del 14,8%. Con disfunción neurológica se observaron un 35,9% y se detectaron como factores de riesgo: cirugía en menores de 10 días de edad, duración de PCS mayor de 40 min y la duración del enfriamiento o calentamiento. Un 35,2% de los pacientes mayor de 5 años fueron diagnosticados de déficit de atención. CONCLUSIONES: Los pacientes intervenidos en el primer año de vida con PCS precisan un seguimiento neuropsicológico y hay factores modificables quirúrgicos que pueden influir en el desarrollo neurológico

INTRODUCTION: The aims of this article are to analyse the neuropsychological changes in the medium-term in children subjected to aortic arch surgery using selective cerebral perfusion (SCP), as well as to detect any modifiable factors in the surgical technique that may contribute to minimising the subsequent neurological involvement. MATERIAL AND METHODS: Inclusion criteria were established as: aortic arch disease operated on using SCP during the first year of life, between 10 August 2004 and 24 May 2016, biventricular physiology, and gestational age greater than 31 weeks. In the absence of a chromosomal disease, they were classified, from a neurological point of view, using the Rankin score. Children over 4-years of age were subjected to intelligence studies, including attention level, development, and psycho-lingual skills. RESULTS: The study included a total of 82 patients with a mean age of 1.8 months. The mean SCP flow was 32 ml/kg/min. The mean time of SCP was 31 minutes. The overall mortality of the series was 14.8%. Neurological dysfunction was observed in 35.9% of patients, and the following were detected as risk factors: surgery in patients less than 10-days-old, duration of SCP greater than 40minutes, and the time required for the cooling down and/or warming-up. Attention deficit was diagnosed in 35.2% of patients greater than 5-years-old. CONCLUSIONS: Patients operated on using SCP in in the first year of life required a neuropsychological follow-up, and there are modifiable surgical factors that may have an influence on neurological development

[Neurological changes and outcomes of paediatric surgery of the aortic arch using selective cerebral perfusion]. / Evolución neurológica y resultados de la cirugía pediátrica del arco aórtico mediante perfusión cerebral selectiva.

INTRODUCTION: The aims of this article are to analyse the neuropsychological changes in the medium-term in children subjected to aortic arch surgery using selective cerebral perfusion (SCP), as well as to detect any modifiable factors in the surgical technique that may contribute to minimising the subsequent neurological involvement. MATERIAL AND METHODS: Inclusion criteria were established as: aortic arch disease operated on using SCP during the first year of life, between 10 August 2004 and 24 May 2016, biventricular physiology, and gestational age greater than 31 weeks. In the absence of a chromosomal disease, they were classified, from a neurological point of view, using the Rankin score. Children over 4-years of age were subjected to intelligence studies, including attention level, development, and psycho-lingual skills. RESULTS: The study included a total of 82 patients with a mean age of 1.8 months. The mean SCP flow was 32ml/kg/min. The mean time of SCP was 31minutes. The overall mortality of the series was 14.8%. Neurological dysfunction was observed in 35.9% of patients, and the following were detected as risk factors: surgery in patients less than 10-days-old, duration of SCP greater than 40minutes, and the time required for the cooling down and/or warming-up. Attention deficit was diagnosed in 35.2% of patients greater than 5-years-old. CONCLUSIONS: Patients operated on using SCP in in the first year of life required a neuropsychological follow-up, and there are modifiable surgical factors that may have an influence on neurological development.

Rendimiento neuropsicológico en la neurofibromatosis tipo 1 / Neuropsychological performance in neurofibromatosis type 1

Introducción: La neurofibromatosis tipo 1 (NF1) es un trastorno genético con manifestaciones clínicas muy variables que pueden expresarse en el sistema nervioso central y periférico, así como en piel, hueso, sistema endocrinológico y vascular. Los aspectos neuropsicológicos de la NF1 en la infancia continúan sin ser suficientemente conocidos, existiendo controversia acerca de los posibles déficits que definen el perfil cognitivo de estos niños. Objetivo: Estudiar el rendimiento neuropsicológico de un grupo de pacientes con NF1 en comparación con un grupo de control de niños sanos. Sujetos y método: Se estudia el rendimiento neuropsicológico de un grupo de 23 niños y niñas con diagnóstico de NF1, con una edad media de 8,7 años ± 1,39 comparado con otro grupo formado por 21 niños sanos con una edad media de 8,9 años ± 1,41 con características sociodemográficas similares. A todos los sujetos se les aplicó la Escala de Inteligencia de Wechsler infantil (WISC-IV). Resultados: Se observa en el grupo con NF1 un rendimiento menor que el grupo control en los índices globales del WISC-IV: comprensión verbal, razonamiento perceptivo, memoria de trabajo, velocidad de procesamiento y cociente intelectual global. Únicamente en los subtest de claves y semejanzas no se han apreciado diferencias estadísticamente significativas entre ambos grupos. Conclusión: Los resultados reflejan la existencia de alteraciones neurocognitivas sutiles y generalizadas en la muestra de niños con NF1, que afectan a la mayoría de los dominios cognitivos evaluados. Se subraya la necesidad de que reciban una atención neuropsicológica específica precoz para prevenir el mayor riesgo de presentar dificultades de aprendizaje y fracaso escolar (AU)

Introduction: Neurofibromatosis type 1 (NF1) is a genetic disorder with various clinical manifestations that affect the peripheral and central nervous system, as well as the skin, bones and endocrine and vascular system. There is still insufficient knowledge of neuropsychological effects of NF1 on children, and there is some controversy about the cognitive deficits that defines the cognitive profile of patients affected by this disorder. Aims: In this study an analysis is made of the neuropsychological performance of a group of patients affected by NF1, compared with a control group of healthy children. Subjects and method: A comparison was made between the neuropsychological performance of a group of 23 boys and girls with a mean age of 8.7 years (+/-1.39) and diagnosed with NF1, and a control group consisting of 21 healthy children, with mean age of 8.9 years (+/- 1.41) and with similar socio-demographic characteristics. The Wechsler Intelligence Scale for Children (WISC) was applied to evaluate the subjects of both groups. Results: The group of patients affected with NF1 showed a lower performance in every primary index of WISC IV: Verbal Comprehension Index, Fluid Reasoning Index, Working Memory Index, Processing Speed Index, and full Scale IQ. Only in two subscales were no statistically significant differences observed: similarities and coding. Conclusion: The results show subtle and generalised neuropsychological alterations in the sample of children affected with NF1, which affect most of cognitive domains that have been evaluated. Proper specific and early neuropsychological treatment should be provided in order to prevent the high risk for these children of presenting learning difficulties and school failure (AU)

[Neuropsychological performance in neurofibromatosis type 1]. / Rendimiento neuropsicológico en la neurofibromatosis tipo 1.

INTRODUCTION: Neurofibromatosis type 1 (NF1) is a genetic disorder with various clinical manifestations that affect the peripheral and central nervous system, as well as the skin, bones and endocrine and vascular system. There is still insufficient knowledge of neuropsychological effects of NF1 on children, and there is some controversy about the cognitive deficits that defines the cognitive profile of patients affected by this disorder. AIMS: In this study an analysis is made of the neuropsychological performance of a group of patients affected by NF1, compared with a control group of healthy children. SUBJECTS AND METHOD: A comparison was made between the neuropsychological performance of a group of 23 boys and girls with a mean age of 8.7 years (+/-1.39) and diagnosed with NF1, and a control group consisting of 21 healthy children, with mean age of 8.9 years (+/- 1.41) and with similar socio-demographic characteristics. The Wechsler Intelligence Scale for Children (WISC) was applied to evaluate the subjects of both groups. RESULTS: The group of patients affected with NF1 showed a lower performance in every primary index of WISC IV: Verbal Comprehension Index, Fluid Reasoning Index, Working Memory Index, Processing Speed Index, and full Scale IQ. Only in two subscales were no statistically significant differences observed: similarities and coding. CONCLUSION: The results show subtle and generalised neuropsychological alterations in the sample of children affected with NF1, which affect most of cognitive domains that have been evaluated. Proper specific and early neuropsychological treatment should be provided in order to prevent the high risk for these children of presenting learning difficulties and school failure.

Attention deficit hyperactivity disorder: genetic association study in a cohort of Spanish children.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) has a strong genetic component. The study is aimed to test the association of 34 polymorphisms with ADHD symptomatology considering the role of clinical subtypes and sex in a Spanish population. METHODS: A cohort of ADHD 290 patients and 340 controls aged 6-18 years were included in a case-control study, stratified by sex and ADHD subtype. Multivariate logistic regression was used to detect the combined effects of multiple variants. RESULTS: After correcting for multiple testing, we found several significant associations between the polymorphisms and ADHD (p value corrected ≤0.05): (1) SLC6A4 and LPHN3 were associated in the total population; (2) SLC6A2, SLC6A3, SLC6A4 and LPHN3 were associated in the combined subtype; and (3) LPHN3 was associated in the male sample. Multivariable logistic regression was used to estimate the influence of these variables for the total sample, combined and inattentive subtype, female and male sample, revealing that these factors contributed to 8.5, 14.6, 2.6, 16.5 and 8.5 % of the variance respectively. CONCLUSIONS: We report evidence of the genetic contribution of common variants to the ADHD phenotype in four genes, with the LPHN3 gene playing a particularly important role. Future studies should investigate the contribution of genetic variants to the risk of ADHD considering their role in specific sex or subtype, as doing so may produce more predictable and robust models.