[Effectiveness and safety of levetiracetam in 133 children with medication resistant epileptic seizures]. / Eficacia y tolerabilidad del levetiracetam en 133 niños con crisis epilépticas farmacorresistentes.

INTRODUCTION: Levetiracetam (LEV) is the latest drug approved in the European Union for use in polytherapy in children over 4 years of age with partial epileptic seizures that are resistant to other antiepileptic drugs. AIM. To report our experience of associating LEV in children with medication resistant epileptic seizures. PATIENTS AND METHODS: We conducted an open, observational, respective study involving 133 children with refractory epilepsies: 106 with focal seizures and 27 with other types of seizures. LEV was associated over a period of more than 6 months and we evaluated its repercussion on the frequency of the seizures and the side effects related to the drug. RESULTS: With average doses of LEV of 1,192 +/- 749 mg/day the frequency of the seizures was reduced by over 50% in 58.6% of cases and seizures were quelled in 15.8% of patients. Side effects were produced in 27.8% of cases, and were usually transient or tolerable; these effects led to withdrawal of LEV in only eight cases (6.02%). In 37 children (27.8%), their relatives noted an improvement in their social behaviour and cognitive abilities. CONCLUSIONS: a) LEV is an effective drug that is well tolerated in children with refractory epilepsy; b) Its effectiveness in different types of seizures indicates a broad therapeutic spectrum; and c) LEV can even condition favourable secondary effects, a circumstance that has been reported only exceptionally in the case of other antiepileptic drugs.

[Angelman syndrome: physical characteristics and behavioural phenotype in 37 patients with confirmed genetic diagnosis]. / Síndrome de Angelman: características físicas y fenotipo conductual en 37 pacientes con diagnóstico genético confirmado.

INTRODUCTION: Angelman syndrome (AS) is characterised by mental retardation, ataxic gait, epilepsy, absence of language and a special series of physical traits behavioural phenotype. Its incidence is estimated as one in every 20,000 individuals. On the basis of discoveries made in molecular biology, patients can be classified as belonging to five types: deletion, paternal uniparental disomy (UPD), imprinting defects, mutation of the UBE3A ubiquitin protein ligase gene and unidentified mechanism (15% 20% of patients). Some studies report significant correlations between the phenotype and the genetic cause. PATIENTS AND METHODS: We reviewed, retrospectively, 37 patients suffering from AS with a positive genetic study and who had been controlled for at least two years in the Neurological Service at the Hospital Sant Joan de D u. Data was collected on physical characteristics, behavioural phenotype, type of communication, sleep disorders and the medication they needed, as well as epilepsy, start age, types of seizures, medication, schooling and social integration. RESULTS: 87% of cases were due to de novo deletion, 8% were caused by UPD, and 5% had their origins in imprinting defects. The average age of diagnosis was 6.5 years. The sleep disorders present in 48% of the patients required medication in 67% of cases, and 95% presented epilepsy. The most frequent seizures were myoclonic, tonic clonic and atonic. The electroencephalogram (EEG) was the characteristic found in the AS in 68%. The most effective treatment was afforded by valproate and clonazepam. CONCLUSIONS: As regards the phenotype, no differences were found according to the genetic alteration. The most effective treatment for the sleep disorders was melatonin. Epilepsy was an almost constant finding in our series, as was cognitive affectation. Lastly, it must be pointed out that educational and socio occupational integration is difficult for patients suffering from AS.

Síndrome de Angelman: características físicas y fenotipo conductual en 37 pacientes con diagnóstico genético confirmado / Angelman syndrome: physical characteristics and behavioural phenotype in 37 patients with confirmed genetic diagnosis

Introducción. El síndrome de Angelman (SA) se caracteriza por un retraso mental, marcha atáxica, epilepsia, ausencia de lenguaje y una serie de rasgos físicos y un fenotipo conductual especiales. Su incidencia estimada es de uno por cada 20.000 individuos. Basándose en los hallazgos de biología molecular, los pacientes pueden ser clasificados en cinco formas: deleción, disomía uniparental paterna (DUP), defecto de impronta, mutación en el gen de la proteína ligasa de ubiquitina E3 (UBE3A) y mecanismo no identificado (15 por ciento-20 por ciento de los pacientes). Algunos estudios refieren correlaciones significativas entre el fenotipo y la causa genética. Pacientes y métodos. Revisamos retrospectivamente 37 pacientes afectos de SA con un estudio genético positivo y que han sido controlados durante un mínimo de dos años en el Servicio de Neurología del Hospital Sant Joan de Déu. Se recogen datos de las características físicas, fenotipo conductual, tipo de comunicación, trastorno de sueño y la medicación que precisaron; epilepsia, edad de inicio, tipo de crisis, medicación, la escolaridad e integración social. Resultados. El 87 por ciento se debe a deleción de novo; 8 por ciento de DUP; 5 por ciento de alteración de impronta. La edad media del diagnóstico fue de 6,5 años. Los trastornos del sueño presentes en el 48 por ciento de los pacientes precisaron medicación en el 67 por ciento de los casos, y presentaron epilepsia el 95 por ciento; las crisis más frecuentes son las mioclonías, tonicoclónicas y atónicas. El electroencefalograma (EEG) fue el característico encontrado en el SA en el 68 por ciento. Los tratamientos más eficaces fueron el valproato y el clonacepam. Conclusiones. En cuanto al fenotipo, no encontramos diferencias según la alteración genética. El tratamiento más efectivo para los trastornos del sueño fue la melatonina. La epilepsia fue un hallazgo casi constante en nuestra serie, así como la afectación cognitiva. Por último, es preciso señalar las dificultades de integración escolar y sociolaboral en los pacientes con SA (AU)

Creación de un modelo de mielomeningocele en el feto de conejo / Creation of a model for myelomeningocele in fetal rabbits

Las disrafias espinales comportan paraplejia; incontinencia fecal, vejiga neurogénica, disfunción sexual, hidrocefalia y malformaciones esqueléticas en los recién nacidos. Su etiología y patogénesis todavía son desconocidas y probablemente multifactoriales. Objetivo. Determinar si la exposición de la médula al espacio amniótico produce una lesión funcional e histológicamente similar al mielomeningocele del adulto. Material y métodos. Se han utilizado 48 fetos de conejo, a los que se les ha realizado una espina bífida quirúrgica en el día 23 de gestación (normal: 31 días) mediante resección de un fragmento de piel de la región lumbosacra y laminectomía posterior. El feto con dicha lesión es reintroducido en el útero, dejándose continuar la gestación. En el día 30 se extraen los fetos operados y un grupo de fetos no operados como controles. Se les realiza una valoración clínico-neurológica, estudio de potenciales evocados somatosensoriales de extremidades superiores e inferiores y estudio histológico del segmento vertebral y medular afectado. Resultados. Ha habido 26 supervivientes, todos ellos con deformidad y falta de movilidad en las extremidades inferiores. Los potenciales evocados han mostrado que no hay respuesta al estímulo recibido desde las extremidades inferiores en los animales afectos de espina bífida y sí en las extremidades superiores y en los controles. El análisis anatomopatológico objetiva una médula espinal aplanada y descubierta. Conclusión. Este modelo de mielomeningocele en feto de conejo reproduce varias características de las disrafias espinales humanas, por lo que puede utilizarse para estudiar la fisiopatología de la espina bífida. (AU)

[Creation of a model for myelomeningocele in rabbit embryos]. / Creación de un modelo de mielomeningocele en el feto de conejo.

UNLABELLED: Spinal dysraphism causes paraplegia, fecal incontinence, neurogenic bladder, sexual dysfunction, hydrocephalus and skeletal abnormalities in newborns. Its ethiology and pathogenesis are still not known, and probably multifactorial. AIM: To determine whether spinal cord exposition to the amniotic space causes a functional (impairment) and anatomic lesion similar to that of human myelomeningocele. MATERIAL AND METHODS: Forty-eight fetal rabbits underwent to create spina bifida on the 23rd gestational day (term is 31 days). The procedure consisted of lumbosacral skin excision and posterior laminectomy. The fetuses are allowed to continue their gestation. On the 30th gestational by the operated fetuses were harvested, together with a group of nonoperated littermates for control. A clinical and neurologic evaluation was done, as well a study of somato-sensorial evoked potentials in the upper and lower limb and histologic study of the affected vertebral and cordial segment. RESULTS: The 26 surviving animals had deformity and lack of movement of the lower limbs. Evoked potentials showed absent response to stimuli in the lower limbs of animals with spina bifida, whereas upper limbs and control animals did respond. Histologically the spinal cord of the operated rabbits was uncovered and flattened. CONCLUSION: This model of myelomeningocele in fetal rabbit reproduces a variety of features similar to human spinal dysraphism, and hence can be used to study the pathophysiology of spina bifida.

[Mitochondrial encephalomyelitis, lactic acidosis and cerebrovascular accidents (MELAS) in pediatric age with the A3243G mutation in the tRNALeu(UUR) gene of mitochondrial DNA]. / Encefalomiopatía mitocondrial, acidosis láctica y accidentes cerebrovasculares (MELAS) en edad pediátrica con la mutación A3243G en el gen del ARNtLeu(UUR) del ADN mitocondrial.

OBJECTIVES: To evaluate three patients with the mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome (MELAS) diagnosed in childhood, with particular reference to the initial symptoms and clinical evolution during the first stage at a pediatric age, and to compare them with other studies on the subject. PATIENTS AND METHODS: Two boys and a girl of 10, 11 and 13 years had tests on lactate, pyruvate and aminoacids in biological fluids under basal conditions and also functional tests and enzyme activity assay of the mitochondrial respiratory chain of a muscle biopsy. We also analysed the particular DNA mutations related to MELAS in different tissues from these patients and in lymphocytes from members of the mothers' families who could be tested. RESULTS: The patients fulfilled the clinical criteria for the MELAS syndrome. Neuroimaging showed cerebrovascular accidents. Neurophysiological studies showed myopathy in one patient and neuroaxonal neuropathy in another. In two cases ophthalmological study showed retinitis pigmentaria and during cerebrovascular accidents transient phenomena of homonymous hemianopsia and cortical blindness were seen. In all patients muscle biopsy showed ragged red fibres and the biochemical study showed an enzyme deficit in the respiratory mitochondrial chain. On molecular genetic study of the mitochondrial DNA (mtDNA) there was a particular mutation A3243G on the tRNA(Leu) in all patients and some members of the mothers' families. CONCLUSIONS: In children with frequent episodes of migraine headaches, vomiting, refractory epilepsy and fatigue the presence of a mitochondrial disease should be suspected. On detection of mtDNA mutations MELAS may be diagnosed even without all the clinical criteria which characterise this syndrome.

Encefalomiopatía mitocondrial, acidosis lácticay accidentes cerebrovasculares (MELAS) en edad pediátricacon la mutación A3243G en el gen del ARNtLeu(UUR)del ADN mitocondrial / Mitochondrial encephalomyopathy, lactic acidosis and cerebrovascular accidents (MELAS) in children with the A3243G mutation of the tRNA(Leu)(UUR) gene of DNA mitochondria

Objetivos. Evaluar tres pacientes afectos de síndrome de encefalopatía mitocondrial, acidosis láctica y accidentes cerebrovasculares (MELAS) con diagnóstico en la infancia; en especial, los síntomas iniciales y la evolución clínica durante los primeros estadios en edad pediátrica, y compararlos con los descritos en otros estudios publicados sobre el tema. Pacientes y métodos. Dos varones y una mujer de 10, 11 y 13 años, a quienes se realizaron determinaciones de lactato, piruvato y aminoácidos en fluidos biológicos en condiciones basales, así como, tras pruebas funcionales y de las actividades enzimáticas de la cadena respiratoria mitocondrial, en biopsia muscular. Se analizaron también las mutaciones puntuales del ADN relacionadas con MELAS en diferentes tejidos de los pacientes y en linfocitos de sus familiares de línea materna disponibles. Resultados. Los enfermos cumplían los criterios clínicos de síndrome de MELAS. La neuroimagen demostró los accidentes cerebrovasculares. Los estudios neurofisiológicos mostraron en un paciente una miopatía y en otro una neuropatía neuroaxonal. En dos casos, el estudio oftalmológico reveló una retinitis pigmentaria y, en el transcurso de los accidentes cerebrovasculares, se observaron fenómenos transitorios de hemianopsia homónima y ceguera cortical. La biopsia muscular mostró en todos los enfermos fibras rojo rasgadas y el estudio bioquímico, un déficit enzimático de la cadena respiratoria mitocondrial. El estudio genético molecular del ADN mitocondrial (ADNmt) detectó la presencia de la mutación puntual A3243G del gen del ARNtLeu en todos los pacientes y en algunos familiares de línea materna. Conclusiones. En niños con episodios frecuentes de cefalea migrañosa, vómitos, epilepsia rebelde y fatiga debemos sospechar una enfermedad mitocondrial. Con la detección de mutaciones de ADNmt, el diagnóstico de MELAS puede realizarse sin que hayan aparecido aún todos los criterios clínicos que caracterizan este síndrome (AU)

[The bereitschaftspotential. The concept and methodology for acquiring it]. / El Bereitschaftspotential. Concepto y metodología de adquisición.

INTRODUCTION: The movement of extension of the index finger in a stereotyped manner, not as a reaction to any external or internal stimulus, is preceded by EEG activity representing activity of the supplementary motor area of the motor cortex. DEVELOPMENT: By averaging retrograde EEG activity prior to movement, the Bereitschaftspotential (BP) may be obtained, using the German nomenclature of the earliest investigators who first described it and its components NS1 and NS2. We include a table with normal values obtained from a group of healthy persons. CONCLUSION: In our study we show the usefulness of off-line methodology with manual adjustment of the start of EMG activity to obtain better morphological definition and greater voltage of the BP. At the same time, continual acquisition with the trigger adjusted to a prefixed threshold (on-line methodology) means that a smaller BP is obtained, especially in persons with difficulty in the organization of this movement.

El bereitschaftspotential. Concepto y metodología de adquisición / The bereitschaftspotential. Concept and methodology for acquiring it

Introducción. El movimiento de extensión del dedo índice de forma esterotipada, sin reaccionar a ningún estímulo externo o interno, está precedida de una actividad EEG que representa la activación del área motora suplementaria y del córtex motor. Desarrollo. Mediante un procedimiento de promediación retrógrada de la actividad EEG previa al movimiento se obtiene el Bereitschaftspotential (BP), según la nomenclatura alemana de los primeros investigadores que la describieron, y sus componentes NS1 y NS2. Se adjunta una tabla con los valores normales conseguidos en un grupo de sujetos sanos. Conclusión. En nuestro trabajo mostramos la conveniencia de utilizar una metodología off-line y ajustar de forma manual el inicio de la actividad EMG para obtener un BP de mejor definición morfológica y voltajes más amplios; mientras que la adquisición continua con ajuste del trigger a un umbral prefijado (metodología on-line) determina la obtención de un BP menos amplio, sobre todo en los sujetos que manifiestan alguna dificultad en la organización del movimiento (AU)

Diagnosis and follow-up of a case of peroxisomal disorder with peroxisomal mosaicism.

Peroxisomal disorder phenotypes are the result of mutations that cause defective peroxisomal assembly or alterations in the import mechanism of peroxisomal proteins that lead to multiple peroxisomal dysfunctions, or the result of a peroxisomal enzymatic deficiency with a single peroxisomal dysfunction. With complementation analysis, 16 groups have been found. Assignment of the genetic defect has been described for some of the complementation groups. We describe the clinical evolution and follow-up over 10 years of a patient who belongs to complementation group 4, although he showed a milder clinical course. It has been found in fibroblasts different peroxisome populations, normal processing and expression of beta-oxidation PTS1 and PTS2 proteins, abnormal ALD protein distribution and normal plasmalogen biosynthesis; abnormal beta-oxidation metabolites have also been detected in serum. Ultrastructural studies in liver showed peroxisomal mosaicism as in fibroblasts. It has been taken into account that peroxisomal mosaicism may lead to variability in peroxisomal diagnostic parameters, making difficult the final diagnosis in these patients.

[P300 potentials evoked by visual stimulation]. / Potencial P300 provocado por estímulos visuales.

INTRODUCTION: The P300 potential is a long-latency endogenous component of the event-related potentials to low-probability target stimuli. The same stimulus delivered without cognitive process does not provoke endogenous components; moreover event-related potentials are not dependent of the sensory pathways used for stimulating the subjects. P300 potential is a biological parameter used in scientific investigations in Clinical Neurophysiology, Neurology, Psychophysiology and Psychiatry. The most frequent methodology for obtaining P300 event-related potential is based on the 'odd-ball' paradigm using auditory stimulation. In this revision we analyzed the difficulties of this methodology and we propose to use the visual stimulation in order to obtain well defined P300 potential, based on a better signal to noise ratio and minor overlapping of exogenous and endogenous components of the evoked potentials. The improvement in the quality of the results obtained when comparing with auditory stimulation, it is supposed to facilitate that the use of P300 potential overflows the field of the investigation and permits their extensive use in the clinical practice.

[The Ohtahara's syndrome: a special form of age-dependent epilepsy]. / Síndrome de Ohtahara: una forma de epilepsia edad-dependiente.

The aim of this report is to review the clinical and the outcome data in four patients with Ohtahara syndrome at Sant Joan de Déu Hospital, Barcelona, following the same clinical and electroencephalografic criteria reported by the author. The etiology of this syndrome is unknown and plurifactorial. Investigation studies were negative except for the EEG and neuroimaging. MRI was performed in two children, and pachigyria was observed in one and mycropoligyria in the other. There were no response to cofactors, phenobarbital, vigabatrine and valproate. Therefore two patients underwent treatment with ACTH with no response in one and good response in the other. Two patients died at 2 and 6 months; other one was transferred to another center at 6 months-old and was lost at follow-up. The fourth patient, fourteen-month-old, is free of seizures with improvement of EEG register with important development retardation. We conclude that Ohtahara syndrome is a severe neonatal epilepsy with poor neurologic outcome; MRI detects often brain malformations as cortical dysplasia and a therapeutic trial of ACTH is indicated because the possibility of control of the seizures.

Abnormalities of the Bereitschaftspotential and MRI pallidal signal in non-encephalopathic cirrhotic patients.

In cirrhotic patients, even in the non-encephalopathic state, MRI may show an increased signal in globus pallidus in T1-weighted sequences, the clinical significance of which is still poorly characterized. A dysfunction of the motor circuit of the basal ganglia might be predicted if the increased MRI signal expressed alterations in the globus pallidus activity. We compared the Bereitschaftspotential (BP) in 15 non-encephalopathic cirrhotic patients and 15 age-matched controls and found that the amplitude of the early component and the peak negativity of the BP before the electromyogram onset were significantly reduced in the patient group. The intensity of the pallidal signal was related to the plasma ammonia level but the amplitudes of the BP were not related to the pallidal signal or to ammonia. These findings indicate that a defective activity of the cortical areas implicated in the preparation of movement, not specifically related to the pallidal signal, can be present in cirrhotic patients, even in the non-encephalopathic state.

Docosahexaenoic acid--a new therapeutic approach to peroxisomal-disorder patients: experience with two cases.

Docosahexaenoic acid (DHA, 22:6 omega 3) is a major constituent of brain membrane phospholipids and photoreceptor cells. Patients with generalized peroxisomal disorders have extremely low levels of DHA in the brain and other tissues. Since a DHA deficiency could explain some basic symptoms in peroxisomal-disorder patients, we tested the possible beneficial effects of DHA in two patients with neonatal adrenoleukodystrophy (NALD). Before the treatment, both patients had very low DHA levels in plasma and erythrocytes. We first gave DHA in the form of fish oil and, in both patients, the rapid increase in red-cell DHA levels indicated that this fatty acid was being absorbed and incorporated into membrane phospholipids very fast. However, a low ratio 22:6 omega 3/22:5 omega 3 was still present in erythrocyte membranes, and the content of 20:5 omega 3 (eicosapentaenoic acid) was too high with the fish oil diet. We then began treatment with pure DHA ethyl ester and, after a few weeks, erythrocyte omega 3 polyunsaturated fatty acids were normal. There was an increase in the 18:0 molecular species of plasmalogens in both patients, most significantly in the child with affected plasmalogen biosynthesis in cultured fibroblasts. In the less severely affected NALD patient, treatment with DHA produced a very significant decrease in the ratios 24:1/22:0 and 26:1/22:0, and this child improved neurologically. The present data suggest that DHA deficiency may be the cause for some of the most characteristic abnormalities in peroxisomal-disorder patients and open new therapeutic possibilities for these patients.

Higher incidence of carpal tunnel syndrome in oophorectomized women.

To determine whether the hormonal changes of the menopause are related to the onset of carpal tunnel syndrome (CTS), 53 healthy women, younger than 44 years, and subjected to bilateral oophorectomy between 1 and 4 years before the study, were evaluated. Seventy healthy menstruating women matched for age were used as controls. In those complaining of symptoms and presenting signs suggestive of CTS, sensory and motor nerve conduction studies were done. In the oophorectomized group, 17 of 53 (32%) had clinical CTS, while only seven of 70 of the control group (10%) did so (relative risk for the oophorectomized group = 4.25; 95% confidence intervals 1.47 and 12.61). The nerve conduction studies were abnormal in 14 of 16 oophorectomized women (87.5%), and in only one of seven of the control group (14.2%; P less than 0.002). Symptoms tended to be milder in the controls. Symptoms developed in the first year after oophorectomy in 14 of the 17 women with CTS. This suggests that women develop CTS after oophorectomy more frequently than controls.