Developmental outcome of electroencephalographic findings in SYNGAP1 encephalopathy.

SYNGAP1 haploinsufficiency results in a developmental and epileptic encephalopathy (DEE) causing generalized epilepsies accompanied by a spectrum of neurodevelopmental symptoms. Concerning interictal epileptiform discharges (IEDs) in electroencephalograms (EEG), potential biomarkers have been postulated, including changes in background activity, fixation-off sensitivity (FOS) or eye closure sensitivity (ECS). In this study we clinically evaluate a new cohort of 36 SYNGAP1-DEE individuals. Standardized questionnaires were employed to collect clinical, electroencephalographic and genetic data. We investigated electroencephalographic findings, focusing on the cortical distribution of interictal abnormalities and their changes with age. Among the 36 SYNGAP1-DEE cases 18 presented variants in the SYNGAP1 gene that had never been previously reported. The mean age of diagnosis was 8 years and 8 months, ranging from 2 to 17 years, with 55.9% being male. All subjects had global neurodevelopmental/language delay and behavioral abnormalities; 83.3% had moderate to profound intellectual disability (ID), 91.7% displayed autistic traits, 73% experienced sleep disorders and 86.1% suffered from epileptic seizures, mainly eyelid myoclonia with absences (55.3%). A total of 63 VEEGs were revised, observing a worsening of certain EEG findings with increasing age. A disorganized background was observed in all age ranges, yet this was more common among older cases. The main IEDs were bilateral synchronous and asynchronous posterior discharges, accounting for ≥50% in all age ranges. Generalized alterations with maximum amplitude in the anterior region showed as the second most frequent IED (≥15% in all age ranges) and were also more common with increasing age. Finally, diffuse fast activity was much more prevalent in cases with 6 years or older. To the best of our knowledge, this is the first study to analyze EEG features across different age groups, revealing an increase in interictal abnormalities over infancy and adolescence. Our findings suggest that SYNGAP1 haploinsufficiency has complex effects in human brain development, some of which might unravel at different developmental stages. Furthermore, they highlight the potential of baseline EEG to identify candidate biomarkers and the importance of natural history studies to develop specialized therapies and clinical trials.

Síndrome de Sweet mielodisplásico corticodependiente. A propósito de un caso / Corticosteroid-dependent myelodysplastic Sweet's syndrome. Presentation of a case

Fundamento y objetivo: El síndrome de Sweet o dermatosis neutrofílica febril aguda es una enfermedad inflamatoria infrecuente de fisiopatología desconocida, aunque las evidencias clínicas y bioquímicas sugieren que las citocinas tienen un papel importante en su etiopatogenia. Se distinguen 5 grupos etiológicos: idiopático, parainflamatorio, secundario a fármacos, asociado a embarazo y paraneoplásico. Este último grupo representa el 20% de los casos, asociados el 85% de ellos a neoplasias hematológicas y el 15% a tumores sólidos. Paciente: Se presenta el caso de un paciente afecto de síndrome de Sweet con afectación dermatológica atípica, asociado a un síndrome mielodisplásico y también a un síndrome de Cushing iatrogénico secundario a altas dosis de corticoides cuya evolución fue desfavorable. Resultados: Positividad de los reactantes de fase aguda (RFA) durante los brotes, destacando la elevación precoz de la interleucina 6 (IL-6) seguida del seroamiloide A (SAA) y proteína C reactiva (PCR), encontrándose diferencias estadísticamente significativas (p<0,05) entre la PCR y el SAA. Conclusiones: Un síndrome de Sweet en un varón con múltiples recaídas y localización dermatológica no clásica, cuando se asocia a alteraciones hematológicas, con un incremento de los RFA y elevación precoz de la IL-6 debe orientar el diagnóstico clínico hacia un origen paraneoplásico y hematológico

Background and objective: Sweet's syndrome or acute febrile neutrophilic dermatosis is a rare inflammatory disease of unknown pathophysiology, although clinical and biochemical evidence suggests that cytokines play an important role in its aetiopathogenesis. It is classified into five groups: idiopathic, para-inflammatory, secondary to drugs, associated with pregnancy, and para-neoplastic in 20% of cases, with 85% of these linked to haematological disorders, and 15% to solid tumours. Patient: A report is presented on a patient with Sweet's Syndrome with atypical dermatological involvement, associated with myelodysplastic syndrome, and iatrogenic Cushing's syndrome secondary to high-doses of corticosteroids, with an unfavorable outcome. Results: Acute phase reactants (APR) were increased during the outbreaks, with the early elevation of interleukin 6 (IL6) being highlighted, followed by serum amyloid A (SAA) and C-reactive protein (CRP), with statistically significant differences (P<.05) between CRP and SAA. Conclusions: A Sweet's syndrome in a male with multiple relapses and a non-classical dermatological location, associated haematological abnormalities, and an increase in APR with early elevation of IL6, should lead to a clinical diagnosis of paraneoplastic and haematological origin

PLA2G6-associated neurodegeneration: New insights into brain abnormalities and disease progression.

INTRODUCTION: PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features. METHODS: Observational clinical study in a cohort of infantile and childhood onset PLAN patients and genetic analysis of the PLA2G6 gene. We analysed chronological evolution in terms of age at onset and disease course through a 66-item questionnaire. We performed qualitative and quantitative assessment of MRI abnormalities and searched for clinical and radiological phenotype and genotype correlations. RESULTS: Sixteen PLAN patients (mean age: 10.2 years, range 3-33) were evaluated, with a median onset (years) of signs/symptoms as follows: neurological regression (1.5), oculomotor abnormalities (1.5), hypotonia (1.8), gait loss (2.2), pyramidal signs (3.0), axonal neuropathy (3.0), dysphagia (4.0), optic atrophy (4.0), psychiatric symptoms (4.0), seizures (5.9), joint contractures (6.0), dystonia (8.0), bladder dysfunction (13.0) and parkinsonism (15.0). MRI assessment identified cerebellar atrophy (19/19), brain iron deposition (10/19), clava hypertrophy (8/19) and T2/FLAIR hyperintensity of the cerebellar cortex (6/19). The mid-sagittal vermis relative diameter (MVRD) correlated with age at onset of clinical variants, meaning that the earlier the onset, the more severe the cerebellar atrophy. All patients harboured missense, nonsense and frameshift mutations in PLA2G6, including four novel variants. CONCLUSIONS: Cerebellar atrophy was a universal radiological sign in infantile and childhood onset PLAN, and correlated with the severity of the phenotype. Iron accumulation within the globus pallidum and substantia nigra was also a common and strikingly uniform feature regardless of the phenotype.

Microcefalia primaria hereditaria de tipo 5. No todo es virus del Zika / Hereditary primary microcephaly type 5. Not everything is Zika virus

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Crisis epilépticas y pseudocrisis: la importancia del diagnóstico diferencial / Epileptic and non-epileptic psychogenic seizures: the importance of differential diagnosis

Las crisis no epilépticas psicógenas (CNEP) son episodios paroxísticos de alteración conductual sin los cambios esperables en el electroencefalograma ni la asociación a una disfunción del sistema nervioso central. Constituyen un desafío diagnóstico para neurólogos, psiquiatras y/o psicólogos, así como también puede suponer un reto terapéutico dada la complejidad contextual de muchos de los casos. La exploración psicopatológica y clínica y el estudio con video EEG son las pruebas complementarias que aportan la información más relevante para el diagnóstico. El objetivo de presentar este Caso Clínico es plantear las dificultades que suele tener el diagnóstico diferencial entre epilepsia y CNEP, destacando la importancia del abordaje multidisciplinar y la detección precoz, para diseñar un plan de tratamiento específico que posibilite una mejoría clínica y pronóstica

Psychogenic Non-Epileptic Seizures (PNES) are paroxysmal episodes of altered behavior without the expected changes in the electroencephalogram neither the association with a dysfunction of the central nervous system. PNES constitute a diagnostic challenge for neurologists, psychiatrists and/or psychologists, as well as also therapeutic challenge can suppose given the contextual complexity of many cases. Psychopathologic and clinical examination and the study with EEG video are the complementary tests that provide the most relevant information for the diagnosis. The aim of presenting this Case Report is to highlight the difficulty of differential diagnosis between epilepsy and PNES, emphasizing the importance of the multidisciplinary approach and the early detection, to design a specific treatment that allow a clinical and prognostic improvement

Experiencia en el diagnóstico molecular de neuropatías hereditarias en un hospital pediátrico de tercer nivel / Experience in molecular diagnostic in hereditary neuropathies in a pediatric tertiary hospital

Introducción. La enfermedad de Charcot-Marie-Tooth (CMT) es la neuropatía hereditaria sensitivomotora más frecuente. Avances en el diagnóstico molecular han incrementado las posibilidades diagnósticas de estos pacientes. Pacientes y métodos. Estudio retrospectivo de 36 casos pediátricos diagnosticados de CMT en un centro terciario en el período 2003-2015. Resultados. Se identificaron 16 pacientes con CMT1A por una duplicación en PMP22; dos casos se diagnosticaron de neuropatía hereditaria con predisposición a parálisis por presión, uno de ellos con una mutación puntual en PMP22; un varón con un fenotipo leve desmielinizante se diagnosticó de CMTX1 por mutación en GJB1; un paciente con una hipotonía paralítica en el nacimiento y un patrón axonal por mutación en MFN2; un paciente de origen rumano se diagnosticó de CMT4D por una mutación en el gen NDRG1; una paciente con una atrofia muscular espinal congénita distal con neuropatía axonal leve asociada por mutación en el gen TRPV4; tres niñas de una familia consanguínea de etnia gitana se diagnosticaron de CMT axonal con descargas neuromiotónicas por una mutación en el gen HINT1; 12 pacientes no tienen diagnóstico molecular actualmente, cuatro de ellos de etnia gitana. Conclusiones. CMT1A predominó en nuestra serie (44%), como corresponde a la bibliografía. Destacamos la descripción de una paciente con una mutación en TRPV4 recientemente descrita como causa de CMT2C y tres casos de una misma familia consanguínea gitana con la misma mutación en el gen HINT1 recientemente publicada como causa de neuropatía axonal con neuromiotonía autosómica recesiva (AR-CMT2). El porcentaje de casos sin diagnóstico molecular es similar al de grandes series europeas (AU)

Introduction. Charcot-Marie-Tooth (CMT) is the most common hereditary sensory motor neuropathy. Advances in molecular diagnosis have increased the diagnostic possibilities of these patients. Patients and methods. Retrospective study of 36 pediatric patients diagnosed with CMT in a tertiary center in 2003-2015. Results. We found 16 patients were diagnosed by a duplication in PMP22; two cases were diagnosed of hereditary neuropathy with liability to pressure palsies, one with a point mutation in PMP22; a male with a mild demyelinating phenotype, without family history, was diagnosed with GJB1 mutation; in a patient with a peripheral hypotonia at birth and axonal pattern in EMG by mutation in MFN2; a gypsy patient, with consanguineous family, CMT4D, was identified by a mutation in the gene NDRG1; a patient with multiplex congenital arthrogryposis and vocal cord paralysis, whose mother had a scapular-peroneal syndrome, had a congenital spinal muscular atrophy with mild distal axonal neuropathy by mutation in gene TRPV4; three girls, from a gypsy consanguineous family, with axonal CMT with neuromyotonic discharges were diagnosed by a mutation in the gene HINT1; twelve patients haven’t molecular diagnosis currently. Conclusions. CMT1A predominated in our series (44%), as previous studies. We emphasize the description of a patient with a mutation in TRPV4 recently described as a cause of CMT2C and three cases, of gypsy consanguineous family, with the same mutation in HINT1 gene, recently described as a cause of axonal neuropathy with neuromyotonia, autosomal recessive (AR-CMT2). The proportion of patients without molecular diagnosis is similar to main European series (AU)

[Experience in molecular diagnostic in hereditary neuropathies in a pediatric tertiary hospital]. / Experiencia en el diagnóstico molecular de neuropatías hereditarias en un hospital pediátrico de tercer nivel.

INTRODUCTION: Charcot-Marie-Tooth (CMT) is the most common hereditary sensory motor neuropathy. Advances in molecular diagnosis have increased the diagnostic possibilities of these patients. PATIENTS AND METHODS: Retrospective study of 36 pediatric patients diagnosed with CMT in a tertiary center in 2003-2015. RESULTS: We found 16 patients were diagnosed by a duplication in PMP22; two cases were diagnosed of hereditary neuropathy with liability to pressure palsies, one with a point mutation in PMP22; a male with a mild demyelinating phenotype, without family history, was diagnosed with GJB1 mutation; in a patient with a peripheral hypotonia at birth and axonal pattern in EMG by mutation in MFN2; a gypsy patient, with consanguineous family, CMT4D, was identified by a mutation in the gene NDRG1; a patient with multiplex congenital arthrogryposis and vocal cord paralysis, whose mother had a scapular-peroneal syndrome, had a congenital spinal muscular atrophy with mild distal axonal neuropathy by mutation in gene TRPV4; three girls, from a gypsy consanguineous family, with axonal CMT with neuromyotonic discharges were diagnosed by a mutation in the gene HINT1; twelve patients haven't molecular diagnosis currently. CONCLUSIONS: CMT1A predominated in our series (44%), as previous studies. We emphasize the description of a patient with a mutation in TRPV4 recently described as a cause of CMT2C and three cases, of gypsy consanguineous family, with the same mutation in HINT1 gene, recently described as a cause of axonal neuropathy with neuromyotonia, autosomal recessive (AR-CMT2). The proportion of patients without molecular diagnosis is similar to main European series.

TITLE: Experiencia en el diagnostico molecular de neuropatias hereditarias en un hospital pediatrico de tercer nivel.Introduccion. La enfermedad de Charcot-Marie-Tooth (CMT) es la neuropatia hereditaria sensitivomotora mas frecuente. Avances en el diagnostico molecular han incrementado las posibilidades diagnosticas de estos pacientes. Pacientes y metodos. Estudio retrospectivo de 36 casos pediatricos diagnosticados de CMT en un centro terciario en el periodo 2003-2015. Resultados. Se identificaron 16 pacientes con CMT1A por una duplicacion en PMP22; dos casos se diagnosticaron de neuropatia hereditaria con predisposicion a paralisis por presion, uno de ellos con una mutacion puntual en PMP22; un varon con un fenotipo leve desmielinizante se diagnostico de CMTX1 por mutacion en GJB1; un paciente con una hipotonia paralitica en el nacimiento y un patron axonal por mutacion en MFN2; un paciente de origen rumano se diagnostico de CMT4D por una mutacion en el gen NDRG1; una paciente con una atrofia muscular espinal congenita distal con neuropatia axonal leve asociada por mutacion en el gen TRPV4; tres niñas de una familia consanguinea de etnia gitana se diagnosticaron de CMT axonal con descargas neuromiotonicas por una mutacion en el gen HINT1; 12 pacientes no tienen diagnostico molecular actualmente, cuatro de ellos de etnia gitana. Conclusiones. CMT1A predomino en nuestra serie (44%), como corresponde a la bibliografia. Destacamos la descripcion de una paciente con una mutacion en TRPV4 recientemente descrita como causa de CMT2C y tres casos de una misma familia consanguinea gitana con la misma mutacion en el gen HINT1 recientemente publicada como causa de neuropatia axonal con neuromiotonia autosomica recesiva (AR-CMT2). El porcentaje de casos sin diagnostico molecular es similar al de grandes series europeas.

Respuesta a everolimús en pacientes con astrocitoma de células gigantes asociado al complejo esclerosis tuberosa / Response to everolimus in patients with giant cell astrocytoma associated to tuberous sclerosis complex

Introducción. Los astrocitomas subependimarios de células gigantes (SEGA) se presentan en el 5-20% de los pacientes con complejo esclerosis tuberosa (CET) y son los tumores cerebrales más comunes en el CET. Son tumores benignos, de estirpe glioneural, que se desarrollan fundamentalmente en las primeras dos décadas de la vida, en general cercanos al foramen de Monro, y pueden ocasionar hidrocefalia e hipertensión intracraneal. Constituyen la principal causa de muerte en el CET. Recientemente, los inhibidores mTOR han demostrado ser una alternativa terapéutica a la resección quirúrgica. Objetivo. Describir nuestra experiencia con everolimús para el tratamiento de pacientes con SEGA y CET. Pacientes y métodos. Estudio prospectivo de la respuesta de los pacientes con CET y al menos un SEGA en crecimiento. Resultados. Recibieron tratamiento tres mujeres y tres varones con una edad media de 12,3 años. Un paciente había sido previamente intervenido quirúrgicamente por SEGA con hidrocefalia. El diámetro máximo medio del SEGA al inicio del tratamiento era de 15,3 mm (rango: 11,3-24,8 mm). Se inició tratamiento con everolimús, 2,5 mg/día por vía oral en pacientes con superficie corporal < 1,2 m2 y 5 mg/día en pacientes con superficie corporal > 1,2 m2. Dos pacientes presentaron hipertrigliceridemia; uno, anorexia; otro, un afta; y una paciente, amenorrea. La reducción media del volumen del SEGA a los tres meses de tratamiento fue del 46%, y la reducción se mantuvo estable en controles posteriores (6-25 meses). Conclusiones. El tratamiento con everolimús disminuye el tamaño de los SEGA asociados a CET con un perfil de seguridad adecuado, y constituye una alternativa a la cirugía en casos seleccionados (AU)

Introduction. Subependymal giant cell astrocytomas (SEGA) appear in 5-20% of patients with tuberous sclerosis complex (TSC) and are the most common brain tumours in TSC. They are benign tumours, of a glioneural stock, that develop mainly in the first two decades of life, generally close to the foramen of Monro, and can trigger hydrocephalus and intracranial hypertension. It is one of the leading causes of death in TSC. Recently mTOR inhibitors have proved to be a therapeutic alternative to surgical excision. Aim. To describe our experience of using everolimus to treat patients with SEGA and TSC. Patients and methods. We conducted a prospective study of the responses of patients with TSC and at least one SEGA undergoing growth. Results. Three females and three males with a mean age of 12.3 years received treatment. One patient had previously undergone surgery due to SEGA with hydrocephalus. The maximum mean diameter of the SEGA on beginning treatment was 15.3 mm (range: 11.3-24.8 mm). Treatment was established with everolimus, 2.5 mg/day administered orally in patients with a body surface area < 1.2 m2, and 5 mg/day in patients with a body surface area > 1.2 m2. Two patients presented hypertriglyceridemia; one, anorexia; another, a mouth ulcer; and one, amenorrhoea. The mean reduction in the volume of the SEGA at three months of treatment was 46%, and the reduction remained steady in later control examinations (6-25 months). Conclusions. Treatment with everolimus reduces the size of SEGA associated with TSC with an adequate safety profile, and constitutes an alternative to surgery in certain cases (AU)

[Response to everolimus in patients with giant cell astrocytoma associated to tuberous sclerosis complex]. / Respuesta a everolimus en pacientes con astrocitoma de celulas gigantes asociado al complejo esclerosis tuberosa.

INTRODUCTION: Subependymal giant cell astrocytomas (SEGA) appear in 5-20% of patients with tuberous sclerosis complex (TSC) and are the most common brain tumours in TSC. They are benign tumours, of a glioneural stock, that develop mainly in the first two decades of life, generally close to the foramen of Monro, and can trigger hydrocephalus and intracranial hypertension. It is one of the leading causes of death in TSC. Recently mTOR inhibitors have proved to be a therapeutic alternative to surgical excision. AIM. To describe our experience of using everolimus to treat patients with SEGA and TSC. PATIENTS AND METHODS: We conducted a prospective study of the responses of patients with TSC and at least one SEGA undergoing growth. RESULTS: Three females and three males with a mean age of 12.3 years received treatment. One patient had previously undergone surgery due to SEGA with hydrocephalus. The maximum mean diameter of the SEGA on beginning treatment was 15.3 mm (range: 11.3-24.8 mm). Treatment was established with everolimus, 2.5 mg/day administered orally in patients with a body surface area < 1.2 m2, and 5 mg/day in patients with a body surface area > 1.2 m2. Two patients presented hypertriglyceridemia; one, anorexia; another, a mouth ulcer; and one, amenorrhoea. The mean reduction in the volume of the SEGA at three months of treatment was 46%, and the reduction remained steady in later control examinations (6-25 months). CONCLUSIONS: Treatment with everolimus reduces the size of SEGA associated with TSC with an adequate safety profile, and constitutes an alternative to surgery in certain cases.

TITLE: Respuesta a everolimus en pacientes con astrocitoma de celulas gigantes asociado al complejo esclerosis tuberosa.Introduccion. Los astrocitomas subependimarios de celulas gigantes (SEGA) se presentan en el 5-20% de los pacientes con complejo esclerosis tuberosa (CET) y son los tumores cerebrales mas comunes en el CET. Son tumores benignos, de estirpe glioneural, que se desarrollan fundamentalmente en las primeras dos decadas de la vida, en general cercanos al foramen de Monro, y pueden ocasionar hidrocefalia e hipertension intracraneal. Constituyen la principal causa de muerte en el CET. Recientemente, los inhibidores mTOR han demostrado ser una alternativa terapeutica a la reseccion quirurgica. Objetivo. Describir nuestra experiencia con everolimus para el tratamiento de pacientes con SEGA y CET. Pacientes y metodos. Estudio prospectivo de la respuesta de los pacientes con CET y al menos un SEGA en crecimiento. Resultados. Recibieron tratamiento tres mujeres y tres varones con una edad media de 12,3 años. Un paciente habia sido previamente intervenido quirurgicamente por SEGA con hidrocefalia. El diametro maximo medio del SEGA al inicio del tratamiento era de 15,3 mm (rango: 11,3-24,8 mm). Se inicio tratamiento con everolimus, 2,5 mg/dia por via oral en pacientes con superficie corporal < 1,2 m2 y 5 mg/dia en pacientes con superficie corporal > 1,2 m2. Dos pacientes presentaron hipertrigliceridemia; uno, anorexia; otro, un afta; y una paciente, amenorrea. La reduccion media del volumen del SEGA a los tres meses de tratamiento fue del 46%, y la reduccion se mantuvo estable en controles posteriores (6-25 meses). Conclusiones. El tratamiento con everolimus disminuye el tamaño de los SEGA asociados a CET con un perfil de seguridad adecuado, y constituye una alternativa a la cirugia en casos seleccionados.

Coste-efectividad de una solución bucal de midazolam en el tratamiento de las crisis convulsivas prolongadas en el entorno ambulatorio en España / Cost-effectiveness of buccal midazolam in the treatment of prolonged convulsive seizures in the outpatient setting in Spain

Introducción. El tratamiento de las crisis epilépticas prolongadas requiere disponer de una medicación de rescate cómoda, segura y efectiva. Actualmente, el tratamiento estándar en la comunidad es el diacepam rectal. La introducción de una solución bucal de midazolam abre una perspectiva nueva en el tratamiento. Objetivo. Evaluar el coste-efectividad del midazolam bucal respecto al diacepam rectal para los niños con un diagnóstico de epilepsia que presentan crisis convulsivas prolongadas en la comunidad en España. Materiales y métodos. Modelo coste-efectividad desde la perspectiva del Sistema Nacional de Salud (SNS) español, con resultados presentados en términos de costes y años de vida ajustados por calidad. Los datos se obtuvieron de varias fuentes, incluidas las estimaciones de efectividad clínica de un ensayo clínico, de un panel Delphi en España y de una encuesta nacional a padres de niños con epilepsia para determinar las prácticas actuales. Resultados. El tratamiento con midazolam bucal produce un ahorro de costes en comparación con el diacepam rectal. El ahorro para el SNS español es de 5.484 euros por paciente al año. El tratamiento con midazolam bucal ofrece una mejora en la calidad de vida relacionada con la salud. Esto, unido al ahorro de costes, hace que el midazolam bucal sea dominante frente al diacepam rectal en todos los escenarios examinados. Conclusión. Los resultados del modelo muestran que el midazolam bucal es más coste-efectivo que el diacepam rectal debido a una reducción en la necesidad de llamadas a la ambulancia y estancias en el hospital, así como a una mejora en la calidad de vida relacionada con la salud (AU)

Introduction. To be able to treat prolonged epileptic crises practical, safe and effective rescue medication is needed. Today, the standard treatment in community healthcare is rectal diazepam. The introduction of a buccal solution of midazolam opens up a new perspective in their treatment. Aims. To evaluate the cost-effectiveness of buccal midazolam with respect to rectal diazepam for children diagnosed with epilepsy who present prolonged convulsive seizures in the community setting in Spain. Materials and methods. The study produces a model of its cost-effectiveness from the perspective of the Spanish National Health System (SNS), with the outcomes presented in terms of cost-quality adjusted life years. Data were collected from different sources, including estimations regarding the clinical effectiveness from a clinical trial, from a Delphi panel in Spain and from a national survey carried out on parents of children with epilepsy in order to determine the current practices. Results. Treatment with buccal midazolam produces a saving in costs in comparison to rectal diazepam. The amount saved by the Spanish SNS comes to 5,484 euros per patient per year. Treatment with buccal midazolam offers an improved health-related quality of life. This, together with the savings in costs, means that there is a dominance of buccal midazolam over rectal diazepam in all the settings that have been examined. Conclusions. The results obtained with the model show that buccal midazolam is more cost-effective than rectal diazepam due to a reduction in the need to call out ambulances and for stays in hospital, as well as an improved health-related quality of life (AU)

[Cost-effectiveness of buccal midazolam in the treatment of prolonged convulsive seizures in the outpatient setting in Spain]. / Coste-efectividad de una solucion bucal de midazolam en el tratamiento de las crisis convulsivas prolongadas en el entorno ambulatorio en España.

INTRODUCTION: To be able to treat prolonged epileptic crises practical, safe and effective rescue medication is needed. Today, the standard treatment in community healthcare is rectal diazepam. The introduction of a buccal solution of midazolam opens up a new perspective in their treatment. AIMS: To evaluate the cost-effectiveness of buccal midazolam with respect to rectal diazepam for children diagnosed with epilepsy who present prolonged convulsive seizures in the community setting in Spain. MATERIALS AND METHODS: The study produces a model of its cost-effectiveness from the perspective of the Spanish National Health System (SNS), with the outcomes presented in terms of cost-quality adjusted life years. Data were collected from different sources, including estimations regarding the clinical effectiveness from a clinical trial, from a Delphi panel in Spain and from a national survey carried out on parents of children with epilepsy in order to determine the current practices. RESULTS: Treatment with buccal midazolam produces a saving in costs in comparison to rectal diazepam. The amount saved by the Spanish SNS comes to 5,484 euros per patient per year. Treatment with buccal midazolam offers an improved health-related quality of life. This, together with the savings in costs, means that there is a dominance of buccal midazolam over rectal diazepam in all the settings that have been examined. CONCLUSIONS: The results obtained with the model show that buccal midazolam is more cost-effective than rectal diazepam due to a reduction in the need to call out ambulances and for stays in hospital, as well as an improved health-related quality of life.

TITLE: Coste-efectividad de una solucion bucal de midazolam en el tratamiento de las crisis convulsivas prolongadas en el entorno ambulatorio en España.Introduccion. El tratamiento de las crisis epilepticas prolongadas requiere disponer de una medicacion de rescate comoda, segura y efectiva. Actualmente, el tratamiento estandar en la comunidad es el diacepam rectal. La introduccion de una solucion bucal de midazolam abre una perspectiva nueva en el tratamiento. Objetivo. Evaluar el coste-efectividad del midazolam bucal respecto al diacepam rectal para los niños con un diagnostico de epilepsia que presentan crisis convulsivas prolongadas en la comunidad en España. Materiales y metodos. Modelo coste-efectividad desde la perspectiva del Sistema Nacional de Salud (SNS) español, con resultados presentados en terminos de costes y años de vida ajustados por calidad. Los datos se obtuvieron de varias fuentes, incluidas las estimaciones de efectividad clinica de un ensayo clinico, de un panel Delphi en España y de una encuesta nacional a padres de niños con epilepsia para determinar las practicas actuales. Resultados. El tratamiento con midazolam bucal produce un ahorro de costes en comparacion con el diacepam rectal. El ahorro para el SNS español es de 5.484 euros por paciente al año. El tratamiento con midazolam bucal ofrece una mejora en la calidad de vida relacionada con la salud. Esto, unido al ahorro de costes, hace que el midazolam bucal sea dominante frente al diacepam rectal en todos los escenarios examinados. Conclusion. Los resultados del modelo muestran que el midazolam bucal es mas coste-efectivo que el diacepam rectal debido a una reduccion en la necesidad de llamadas a la ambulancia y estancias en el hospital, asi como a una mejora en la calidad de vida relacionada con la salud.

Infant botulism in Andalusia (Southern Spain).

BACKGROUND: Infant botulism (IB) is caused by the intestinal colonization by Clostridium botulinum in the first year of life and its subsequent production of neurotoxins. Traditionally, IB has been associated to honey consumption. IB cases tend to cluster in geographic regions. In Europe, IB is a rare disorder. From 1976 through 2006, 65 cases were identified in 13 European countries. In Spain, in the last 15 years, most of the cases have been reported in one region, Andalusia (Southern Spain). A specific treatment for IB type A and type B (BabyBIG) is available outside of the United States since 2005. METHODS: and aims: We performed a retrospective review of IB cases detected in Andalusia since 1997 and compare them with the cases of IB reported in Europe. RESULTS: We identified 11 confirmed cases of IB in Andalusia since 1997, and 14 cases in Spain. Nine out of 11 cases were detected since 2007; none of these infants had been exposed to honey consumption. One case in 1997 and another in 2000 were associated to honey. Two cases were treated with BabyBIG in 2007. In the period 2006-2012 the cases of IB reported in Europe were 54. CONCLUSIONS: We identified a considerable increase in the incidence of IB since 2006. A tendency to a reduction in the number of cases of IB linked to honey consumption has also been identified. An increase in the exposure to these bacteria from the environment could be presumed. Clinicians should maintain a high index of suspicion for this treatable disorder.

Síndrome de Aicardi: estudio retrospectivo de una serie de siete casos / Aicardi syndrome: retrospective study of a series of seven case reports

Introducción. El síndrome de Aicardi es un trastorno presumiblemente dominante ligado al cromosoma X, que afecta en exclusiva a mujeres, clásicamente definido por la tríada de agenesia del cuerpo calloso, lagunas coriorretinianas y espasmos infantiles, letal en varones en la vida intrauterina. Pacientes y métodos. Estudio descriptivo retrospectivo de pacientes diagnosticadas y seguidas hasta el final de la edad pediátrica de síndrome de Aicardi en dos hospitales universitarios durante un período de 29 años. Resultados. Encontramos siete niñas, todas desarrollaron espasmos infantiles antes de los 6 meses de edad. La evolución fue a espasmos más allá de la infancia (n = 2), a epilepsia parcial farmacorresistente (n = 3) y a epilepsia parcial bien controlada (n = 1). Seis casos presentaron retraso mental grave-profundo, y uno, moderado-grave. Fallecieron dos niñas a los 2 y 6 años. En todas, los estudios de neuroimagen mostraron agenesia del cuerpo calloso, quistes intracraneales y malformaciones del desarrollo cortical cerebral, además de lesiones oftalmológicas: lagunas coriorretinianas (n = 7), anoftalmia/microftalmia (n = 4) y coloboma del nervio óptico (n = 3). Otros hallazgos fueron cardiopatía ongénita, anomalías costovertebrales, linfangioma cervical e hipertricosis focal. Conclusiones. El síndrome de Aicardi debe sospecharse en niñas con espasmos infantiles y agenesia del cuerpo calloso. Deben descartarse en estas pacientes las alteraciones oftalmológicas, las anomalías de la migración y organización neuronal y los quistes intracraneales. El pronóstico es grave por su elevada morbimortalidad y por la frecuente evolución a epilepsia refractaria y retraso mental grave (AU)

Introduction. The Aicardi syndrome is a disorder presumably X-linked dominant, classically defined by the triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile spasms, with lethality in males. Patients and methods. Retrospective descriptive study of patients diagnosed with Aicardi syndrome over a period of 29 years in two tertiary pediatric hospitals. Results. We found seven women that developed infantile spasms before 6 months of age, epileptic spasms persisting beyond infancy in two cases, a refractory symptomatic partial epilepsy in three patients, and well-controlled partial epilepsy in one girl. Six cases presented severe-profound mental retardation and moderate-severe in a girl. Two girls died at 2 and 6 years-old. In all patients neuroimaging studies showed agenesis of the corpus callosum, intracranial cysts and malformations of cortical development. Ophthalmological lesions were chorioretinal lacunae in seven cases, anophthalmia/microphthalmia in four girls and optic nerve coloboma in three patients. Other findings were congenital heart disease, costovertebral abnormalities, cervical lymphangioma and focal hypertrichosis. Conclusions. The Aicardi syndrome should be suspected in girls with infantile spasms and agenesis of the corpus callosum. It is necessary to rule out these ophthalmologic abnormalities, malformations of cortical development and intracranial cysts. The prognosis is poor due to its high mortality and its evolution to refractory epilepsy and profound mental retardation (AU)

[Aicardi syndrome: retrospective study of a series of seven case reports]. / Sindrome de Aicardi: estudio retrospectivo de una serie de siete casos.

INTRODUCTION: The Aicardi syndrome is a disorder presumably X-linked dominant, classically defined by the triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile spasms, with lethality in males. PATIENTS AND METHODS: Retrospective descriptive study of patients diagnosed with Aicardi syndrome over a period of 29 years in two tertiary pediatric hospitals. RESULTS: We found seven women that developed infantile spasms before 6 months of age, epileptic spasms persisting beyond infancy in two cases, a refractory symptomatic partial epilepsy in three patients, and well-controlled partial epilepsy in one girl. Six cases presented severe-profound mental retardation and moderate-severe in a girl. Two girls died at 2 and 6 years-old. In all patients neuroimaging studies showed agenesis of the corpus callosum, intracranial cysts and malformations of cortical development. Ophthalmological lesions were chorioretinal lacunae in seven cases, anophthalmia/microphthalmia in four girls and optic nerve coloboma in three patients. Other findings were congenital heart disease, costovertebral abnormalities, cervical lymphangioma and focal hypertrichosis. CONCLUSIONS: The Aicardi syndrome should be suspected in girls with infantile spasms and agenesis of the corpus callosum. It is necessary to rule out these ophthalmologic abnormalities, malformations of cortical development and intracranial cysts. The prognosis is poor due to its high mortality and its evolution to refractory epilepsy and profound mental retardation.

TITLE: Sindrome de Aicardi: estudio retrospectivo de una serie de siete casos.Introduccion. El sindrome de Aicardi es un trastorno presumiblemente dominante ligado al cromosoma X, que afecta en exclusiva a mujeres, clasicamente definido por la triada de agenesia del cuerpo calloso, lagunas coriorretinianas y espasmos infantiles, letal en varones en la vida intrauterina. Pacientes y metodos. Estudio descriptivo retrospectivo de pacientes diagnosticadas y seguidas hasta el final de la edad pediatrica de sindrome de Aicardi en dos hospitales universitarios durante un periodo de 29 años. Resultados. Encontramos siete niñas, todas desarrollaron espasmos infantiles antes de los 6 meses de edad. La evolucion fue a espasmos mas alla de la infancia (n = 2), a epilepsia parcial farmacorresistente (n = 3) y a epilepsia parcial bien controlada (n = 1). Seis casos presentaron retraso mental grave-profundo, y uno, moderado-grave. Fallecieron dos niñas a los 2 y 6 años. En todas, los estudios de neuroimagen mostraron agenesia del cuerpo calloso, quistes intracraneales y malformaciones del desarrollo cortical cerebral, ademas de lesiones oftalmologicas: lagunas coriorretinianas (n = 7), anoftalmia/microftalmia (n = 4) y coloboma del nervio optico (n = 3). Otros hallazgos fueron cardiopatia congenita, anomalias costovertebrales, linfangioma cervical e hipertricosis focal. Conclusiones. El sindrome de Aicardi debe sospecharse en niñas con espasmos infantiles y agenesia del cuerpo calloso. Deben descartarse en estas pacientes las alteraciones oftalmologicas, las anomalias de la migracion y organizacion neuronal y los quistes intracraneales. El pronostico es grave por su elevada morbimortalidad y por la frecuente evolucion a epilepsia refractaria y retraso mental grave.

Lipofuscinosis neuronal ceroidea: algoritmo diagnóstico y descripción clínica de las variantes infantil tardía finlandesa (CLN5) y turca (CLN7) / Neuronal ceroid lipofuscinosis: diagnostic algorithm and clinical description of the variants late infantile Finnish (CLN5) and Turkish (CLN7) Introduction. The neuronal ceroid lipofuscinosis

Introducción. Las lipofuscinosis neuronales ceroideas (LNC) se clasifican, según la edad de inicio de la sintomatología, en cuatro formas clínicas principales en la infancia: infantil, infantil tardía, juvenil y congénita (CLN1, CLN2, CLN3 y CLN10).Las formas variantes infantiles tardías (CLN5, CLN6, CLN7 y CLN8) se caracterizan por una gran variabilidad fenotípica y la mayoría de los pacientes proceden de Finlandia y Turquía (variante finlandesa, CLN5, y turca, CLN7). Casos clínicos. Se describen tres pacientes con la variante finlandesa y un cuarto paciente con la variante turca, procedentes de diferentes familias. Se propone un algoritmo que facilite el diagnóstico de este grupo de enfermedades poco prevalentes. Las pacientes con la variante finlandesa iniciaron un trastorno de conducta entre los 2,6 y 4,6 años seguido de dificultades de aprendizaje y déficit visual a los 6 años de edad. Las crisis epilépticas generalizadas y mioclonoatónicas aparecieron a los 7 años con sacudidas mioclónicas posteriormente. Las pacientes desarrollaron ataxia y ceguera a los 9años, y manifestaron una importante discapacidad a los 11 años de edad. El paciente con la variante turca presentó epilepsia refractaria desde los 2 años de edad seguido de un rápido deterioro con ataxia, pérdida de la deambulación en los dos a tres años siguientes y estado vegetativo a los 11 años.Conclusiones. El espectro de las formas variantes de LNC presenta una distribución geográfica cada vez más amplia. Nuestro estudio aporta tres nuevas mutaciones en el gen CLN5 y propone un protocolo de diagnóstico que facilite los estudios de correlación genotipo-fenotipo (AU)

Introduction. The neuronal ceroid lipofuscinosis are classified based on age at onset into four main clinical forms in childhood: infantile, late infantile, juvenile and congenital (CLN1, CLN2, CLN3 and CLN10). The variant late infantile forms (CLN5, CLN6, CLN7 and CLN8) are characterized by a wide variability of the clinical phenotypes and the most patients are originated from Finland and Turkey (Finnish, CLN5, and Turkish, CLN7 variants). Case reports. We describe three unrelated patients with Finnish variant and another patient with Turkish variant. We describe an algorithm to facility the diagnosis of these low prevalence diseases. Patients with Finnish variant started withbehaviour disorder between 2.6 and 4.6 years of age followed by learning difficulties and visual failure at an age of 6 years. Generalised tonic-clonic and myoclonic seizures were observed at 7 years of age with myoclonic jerks later on. Patients developed ataxia and blindness within 9 years and increasingly disability at 11 years of age. The patient with Turkish variant started with refractory epilepsy at age of 2, followed by a severe neurodegeneration manifested by ataxia,loss of walking ability within 2-3 years and vegetative state at 11 years of age.Conclusions. The clinical spectrum of the variant late infantile forms shows a wide geographical distribution. We report three novel mutations in the CLN5 gene and a diagnostic algorithm to facility the correlation genotype-phenotype studies (AU)

[Neuronal ceroid lipofuscinosis: diagnostic algorithm and clinical description of the Finnish (CLN5) and Turkish (CLN7) variants late infantile]. / Lipofuscinosis neuronal ceroidea: algoritmo diagnóstico y descripción clínica de las variantes infantil tardía finlandesa (CLN5) y turca (CLN7).

INTRODUCTION: The neuronal ceroid lipofuscinosis are classified based on age at onset into four main clinical forms in child-hood: infantile, late infantile, juvenile and congenital (CLN1, CLN2, CLN3 and CLN10). The variant late infantile forms (CLN5, CLN6, CLN7 and CLN8) are characterized by a wide variability of the clinical phenotypes and the most patients are originated from Finland and Turkey (Finnish, CLN5, and Turkish, CLN7 variants). CASE REPORTS: We describe three unrelated patients with Finnish variant and another patient with Turkish variant. We describe an algorithm to facility the diagnosis of these low prevalence diseases. Patients with Finnish variant started with behaviour disorder between 2.6 and 4.6 years of age followed by learning difficulties and visual failure at an age of 6 years. Generalised tonic-clonic and myoclonic seizures were observed at 7 years of age with myoclonic jerks later on. Patients developed ataxia and blindness within 9 years and increasingly disability at 11 years of age. The patient with Turkish variant started with refractory epilepsy at age of 2, followed by a severe neurodegeneration manifested by ataxia, loss of walking ability within 2-3 years and vegetative state at 11 years of age. CONCLUSIONS: The clinical spectrum of the variant late infantile forms shows a wide geographical distribution. We report three novel mutations in the CLN5 gene and a diagnostic algorithm to facility the correlation genotype-phenotype studies.

Neuropsychiatric symptoms and intelligence quotient in autosomal dominant Segawa disease.

Segawa disease is a rare dystonia due to autosomal dominant guanosine triphosphate cyclohydrolase I (adGTPCH) deficiency, affecting dopamine and serotonin biosynthesis. Recently, the clinical phenotype was expanded to include psychiatric manifestations, such as depression, anxiety, obsessive-compulsive disorder, and sleep disturbances. Although cognitive and neuropsychiatric symptoms may be attributable to dopamine deficiency in the prefrontal cortex and frontostriatal circuitry, intelligence is considered normal in Segawa disease. Our aim was to investigate neuropsychiatric symptoms and intelligence quotients (IQ) in a series of individuals with adGTPCH deficiency. The assessment included a structured clinical interview following the DSM-IV-TR's guidelines, Beck's Depression Inventory, the State-Trait Anxiety Inventory, the Maudsley Obsessive-Compulsive Questionnaire, the Barratt Impulsiveness Scale-11 (BIS-11), the Oviedo Sleep Questionnaire, the Pittsburgh Sleep Quality Index, and the Wechsler Adult Intelligence Scale-Third Edition. Equivalent tests were applied to pediatric patients as appropriate for their age group. Fourteen patients with adGTPCH deficiency were evaluated (seven adult and seven pediatric patients). Depression, anxiety, and obsessive-compulsive symptoms were not more common than expected in the general population. However, the seven adults showed impulsivity in the BIS-11; nine individuals had an IQ in the range of borderline intellectual functioning to mild mental retardation, and sleep disturbances were found in four individuals. We found no differences between these results and the motor impairment. In conclusion, our findings would suggest that cognitive impairment, and impulsivity in adults, may be associated with Segawa disease.

[The use of bibliographic information resources and Web 2.0 by neuropaediatricians]. / Uso de recursos de información bibliográfica y Web 2.0 por neuropediatras.

AIM: To determine the state of knowledge and use of the main sources of bibliographic information and Web 2.0 resources in a sample of pediatricians linked professionally to child neurology. SUBJECTS AND METHODS: Anonymous opinion survey to 44 pediatricians (36 neuropediatric staffs and 8 residents) with two sections: sources of bibliographic information: (25 questions) and Web 2.0 resources (14 questions). RESULTS: The most consulted journals are Revista de Neurología and Anales de Pediatría. All use PubMed database and less frequently Índice Médico Español (40%) and Embase (27%); less than 20% use of other international and national databases. 81% of respondents used the Cochrane Library, and less frequently other sources of evidence-based medicine: Tripdatabase (39%), National Guideline Clearinghouse (37%), Excelencia Clínica (12%) and Sumsearch (3%). 45% regularly receive some e-TOC (electronic table of contents) of biomedical journals, but only 7% reported having used the RSS (really system syndication). The places to start searching for information are PubMed (55%) and Google (23%). The four resources most used of Web 2.0 are YouTube (73%), Facebook (43%), Picasa (27%) and blogs (25%). We don't found differences in response between the group of minus or equal to 34 and major or equal to 35 years. CONCLUSIONS: Knowledge of the patterns of use of information databases and Web 2.0 resources can identify the limitations and opportunities for improvement in the field of pediatric neurology training and information.

Juvenile neuronal ceroid lipofuscinosis: clinical course and genetic studies in Spanish patients.

BACKGROUND: Juvenile neuronal ceroid lipofuscinosis (JNCL, NCL3, Batten disease) is usually caused by a 1.02-kb deletion in the CLN3 gene. Mutations in the CLN1 gene may be associated with a variant form of JNCL (vJNCL). We report the clinical course and molecular studies in 24 patients with JNCL collected from 1975 to 2010 with the aim of assessing the natural history of the disorder and phenotype/genotype correlations. PATIENTS AND METHODS: Patients were classified into the groups of vJNCL with mutations in the CLN1 gene and/or granular osmiophilic deposit (GROD) inclusion bodies (n = 11) and classic JNCL (cJNCL) with mutations in the CLN3 gene and/or fingerprint (FP) profiles (n = 13). Psychomotor impairment included regression of acquired skills, cognitive decline, and clinical manifestations of the disease. We used Kaplan-Meier analyses to estimate the age of onset of psychomotor impairment. RESULTS: Patients with vJNCL showed learning delay at an earlier age (median 4 years, 95% confidence interval [CI] 3.1-4.8) than those in the cJNCL group (median 8 years, 95% CI 6.2-9.7) (P = 0.001) and regression of acquired skills at a younger age. Patients with vJNCL showed a more severe and progressive clinical course than those with cJNCL. There may be a Gypsy ancestry for V181L missense mutation in the CLN1 gene. CONCLUSIONS: The rate of disease progression may be useful to diagnose vJNCL or cJNCL, which should be confirmed by molecular studies in CLN1/CLN3 genes. Further studies of genotype/phenotype correlation will be helpful for understanding the pathogenesis of this disease.

Segawa syndrome due to mutation Q89X in the GCH1 gene: a possible founder effect in Córdoba (southern Spain).

Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency is an inborn error of neurotransmitter metabolism, with a prevalence of 0.5 per million, caused by mutations/deletions in the GCH1 gene. The finding of the mutation Q89X in the GCH1 gene in 23 patients from two pedigrees in an area inhabited by a population of 800,000 prompted us to consider that our cohort may have descended from a single founder. Twelve Q89X mutation-positive cases belonging to two families and 100 unrelated control subjects from the same geographical region were studied. Six microsatellite markers located near GCH1 were analyzed to validate a possible mutation-related founder haplotype. Haplotype analysis revealed two different haplotypes for six microsatellite markers that segregated with the Q89X mutation. A common haplotype in 10 out of 12 mutation carriers studied was identified. Two subjects carried a second haplotype, most probably because of a recombination event. However, at least 186 different haplotypes were established in the control subjects. In contrast with the frequencies of 83.3% and 16.7%, respectively, found for both mutation-segregating haplotypes, the frequency of none of the control haplotypes exceeded 1.5%. Dystonia was the most frequent symptom in our series, and parkinsonism was present in five patients. The large number of Q89X mutation carriers in our community is because of a founder effect. The same mutation in GCH1 causes a wide phenotypic spectrum of clinical variability occurring in this population of affected patients.