[Severe myoclonic epilepsy in infancy (Dravet's syndrome). Its nosological characteristics and therapeutic aspects]. / Epilepsia mioclónica grave de la infancia (síndrome de Dravet). Ubicación nosológica y aspectos terapéuticos.

AIMS: Severe myoclonic epilepsy in infancy (SMEI) is an epileptic syndrome recognised by the ICE of 1985 and 1989 and in the proposal put forward by the ILAE Task Force on Classification and Terminology in 2001. In this paper, its historical development, nosological characteristics and treatment are described. DEVELOPMENT: Although identified by Dravet in 1978, it has been called severe myoclonic epilepsy in infancy since 1981. As an alternative the name polymorphic epilepsy has also been put forward and in 2001 the ILAE recognised the eponym Dravet's syndrome. We describe how it may be mistaken for febrile convulsions in the early stages and later for Lennox Gastaut syndrome, Doose's myoclonic astatic epilepsy and certain progressive myoclonic epilepsies. We outline the risk factors, recognised in 1992, that facilitate an early diagnosis and the defining clinical criteria established in 1984. We point out the existence of atypical forms due to the absence of some of the defining criteria, which will never be above one, to formulate a diagnosis of SMEI. The frequency with which a family background of febrile convulsions and epilepsy appears seems to point to a genetic origin. Recently, de novo mutations have been found in the alpha subunit of the voltage dependent sodium channel as well as mutations in the gamma subunit of the GABAA receptor. Nosologically, it is located in group 3 of the 1989 ICE, which corresponds to epileptic syndromes without a focal determination, or which are generalised, and on the list of epilepsy/syndromes that was presented in 2001. SMEI is an epilepsy syndrome which is, in most cases, resistant to classical and new AED, and other more unusual treatment. The drugs that have proved to be more effective, although only relatively so, are topiramate, valproate and the benzodiazepines. At present another alternative that has appeared is stiripentol. Intravenous use of immunoglobulins can be useful. CONCLUSIONS: Dravet's syndrome, admitted as such by the ILAE in 2001 and probably caused by de novo mutations in the sodium channels or in the GABAA receptors, is one of the severest forms of epilepsy in infancy with very little or no response to current antiepileptic drugs. Those that have been seen to be most effective are topiramate, the benzodiazepines, valproate and, more recently, stiripentol.

Epilepsia mioclónica grave de la infancia (síndrome de Dravet). Ubicación nosológica y aspectos terapéuticos / Severe myoclonic epilepsy in infancy (dravet's syndrome). Its nosological characteristics and therapeutic aspects

Objetivo. La epilepsia mioclónica grave de la infancia (EMGI) es un síndrome epiléptico reconocido en las ICE de 1985 y 1989 y en la propuesta del Grupo de Trabajo de Clasificación y Terminología de la ILAE en 2001. Se describe su desarrollo histórico, ubicación nosológica y tratamiento. Desarrollo. Identificado por Dravet en 1978, se denomina epilepsia mioclónica grave de la infancia en 1981; se propone, como alternativa, la denominación de epilepsia polimorfa, y se reconoce con el epónimo de síndrome de Dravet por la ILAE en 2001. Se señala su posible confusión inicial con las convulsiones febriles y, posteriormente, con el síndrome de Lennox-Gastaut, la epilepsia mioclonicoastática de Doose y algunas epilepsias mioclónicas progresivas. Se exponen los factores de riesgo, que facilitan un diagnóstico precoz, reconocidos en 1992, y los criterios clínicos de definición establecidos en 1984. Se señala la existencia de formas atípicas por la ausencia de algunos de los criterios de definición, que nunca serán superiores a uno para formular el diagnóstico de EMGI. La frecuencia de antecedentes familiares de convulsiones febriles y epilepsia sugieren un origen genético; se han encontrado recientemente mutaciones de novo en la subunidad a del canal de sodio dependiente de voltaje, y también en la subunidad g del receptor GABAA. Nosológicamente, se ubica en el grupo 3 de la ICE de 1989, que corresponde a los síndromes epilépticos sin determinación focal o generalizada, y en la lista de epilepsia/síndromes que se presentó en 2001. La EMGI es un síndrome epiléptico refractario, en la mayoria de los casos, a los fármacos antiepilépticos clásicos, a los nuevos y a otras terapéuticas no habituales. Los fármacos que han mostrado una mayor eficacia, siempre relativa, han sido el topiramato, el valproato y las benzodiacepinas. Actualmente surge como alternativa el estiripentol. Las inmunoglobulinas por vía endovenosa pueden ser útiles. Conclusiones. El síndrome de Dravet, admitido como tal por la ILAE en el 2001, de muy probable origen genético por mutaciones de novo en los canales de sodio o en los receptores GABAA, es una de las epilepsias más graves de la infancia, con escasa o nula respuesta a los fármacos antiepilépticos actuales. Los que han mostrado una relativa mayor eficacia son el topiramato, las benzodiacepinas, el valproato y, recientemente, el estiripentol (AU)

Aims. Severe myoclonic epilepsy in infancy (SMEI) is an epileptic syndrome recognised by the ICE of 1985 and 1989 and in the proposal put forward by the ILAE Task Force on Classification and Terminology in 2001. In this paper, its historical development, nosological characteristics and treatment are described. Development. Although identified by Dravet in 1978, it has been called severe myoclonic epilepsy in infancy since 1981. As an alternative the name polymorphic epilepsy has also been put forward and in 2001 the ILAE recognised the eponym Dravet’s syndrome. We describe how it may be mistaken for febrile convulsions in the early stages and later for Lennox-Gastaut syndrome, Doose’s myoclonic-astatic epilepsy and certain progressive myoclonic epilepsies. We outline the risk factors, recognised in 1992, that facilitate an early diagnosis and the defining clinical criteria established in 1984. We point out the existence of atypical forms due to the absence of some of the defining criteria, which will never be above one, to formulate a diagnosis of SMEI. The frequency with which a family background of febrile convulsions and epilepsy appears seems to point to a genetic origin. Recently, de novo mutations have been found in the alpha subunit of the voltage-dependent sodium channel as well as mutations in the gamma subunit of the GABAA receptor. Nosologically, it is located in group 3 of the 1989 ICE, which corresponds to epileptic syndromes without a focal determination, or which are generalised, and on the list of epilepsy/syndromes that was presented in 2001. SMEI is an epilepsy syndrome which is, in most cases, resistant to classical and new AED, and other more unusual treatment. The drugs that have proved to be more effective, although only relatively so, are topiramate, valproate and the benzodiazepines. At present another alternative that has appeared is stiripentol. Intravenous use of immunoglobulins can be useful. Conclusions. Dravet’s syndrome, admitted as such by the ILAE in 2001 and probably caused by de novo mutations in the sodium channels or in the GABAA receptors, is one of the severest forms of epilepsy in infancy with very little or no response to current antiepileptic drugs. Those that have been seen to be most effective are topiramate, the benzodiazepines, valproate and, more recently, stiripentol (AU)

[Progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO syndrome). A case report]. / Encefalopatía progresiva con edema, hipsarritmia y atrofia óptica (síndrome PEHO). Aportacion de un caso.

INTRODUCTION: Progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO syndrome) is a pathological process that begins in the first months of life and quickly leads to a very serious encephalopathy. We report the case of an infant suffering from PEHO syndrome and discuss its pathogenesis. CASE REPORT: A 4 year old male, the son of parents who were not blood related, with no pre or perinatal background of interest, who, from the first month, was seen to have a moderate retardation in psychomotor development and generalised hypotonia. These clinical signs increased progressively over the next months. From the age of 6 months onwards infantile spasms were observed, together with an EEG displaying hypsarrhythmic characteristics, slight facial oedema as well as in the hands, abnormal ocular movements and loss of vision with optic atrophy. In the neuroimaging serial studies, MRI showed a progressive atrophy of the brain stem and the cerebellum associated with cortical atrophy, hypoplasia of the corpus callosum and retarded myelination. CONCLUSIONS: Diagnosis of PEHO syndrome is essentially clinical with the help of neuroimaging, since there is no biological or genetic marker. The case described fulfils the criteria required for diagnosis of PEHO syndrome. The existence of cases in the family suggests that PEHO syndrome is due to a genetically based neurodevelopmental disorder. To our knowledge this is the first case reported in Spain.

Encefalopatía progresiva con edema, hipsarritmia y atrofia óptica (síndrome PEHO). Aportación de un caso / Progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO syndrome). A case report

Introducción. La encefalopatía progresiva con edema, hipsarritmia y atrofia óptica (síndrome PEHO) es un proceso patológico que se inicia en los primeros meses de la vida y conduce rápidamente a una encefalopatía muy grave. Se aporta el caso de un niño afectado de un síndrome PEHO y se discute su patogenia. Caso clínico. Varón de 4 años de edad, hijo de padres no consanguíneos, sin antecedentes prenatales y perinatales de interés, en el que se aprecia desde el primer mes un leve retraso en el desarrollo psicomotor e hipotonía generalizada, signos clínicos que se incrementan progresivamente en los meses siguientes. A partir de los 6 meses se observan espasmos infantiles, EEG de características hipsarrítmicas, ligero edema facial y de manos, movimientos oculares anormales y pérdida de visión con atrofia óptica. En los estudios seriados de neuroimagen, la RM muestra una atrofia progresiva del tronco cerebral y el cerebelo asociada a atrofia cortical, hipoplasia del cuerpo calloso y retraso en la mielinización. Conclusiones. El diagnóstico del síndrome PEHO es esencialmente clínico y de neuroimagen, ya que no existe ningún marcador biológico o genético. El caso presentado reúne los criterios exigibles para diagnosticarse de síndrome PEHO. La existencia de casos familiares sugiere que el síndrome PEHO se debe a un trastorno del neurodesarrollo de base genética.Según nuestro conocimiento, es el primer caso aportado en España (AU)

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[Clinical phenotypes of classic Rett syndrome]. / Fenotipos clínicos del síndrome de Rett clásico.

INTRODUCTION: Rett syndrome (RS) is a progressive neurological disorder that is diagnosed by essential, supportive and exclusion clinical criteria, and development takes place in four stages. It has been shown to be caused by de novo mutations of a gene located in the long arm of the dominant X chromosome that codes for the methyl CpG binding protein (MECP2). It has been observed that girls with classic RS (CRS) present distinguishing nuances with respect to the age of onset of the different criteria and as regards the progression of the disorder. Taking the ability or failure to walk as a reference, we have established three phenotypes. METHOD: Phenotype I. Ambulant CRS, which corresponds to a permanent stage III, or a stage III that lasts a long time before going into stage IV. The loss of the ability to use the hands in a purposeful way takes place at the age of 25.6 months, social withdrawal at 25.4 months, language impairment at 20 months, stereotypic hand movements at 22.8 months and signs of spasticity appear around the age of 8-10 years. Phenotype II. Ambulant CRS. Transitory, which corresponds to an early stage IV-A. The first signs of abnormality appear around the age of 9-10 months. This is followed by the loss of the purposeful use of the hands towards the age of 23.4 months, social withdrawal around 21.4 months, language impairment at 20 months, stereotypic hand movements at 25.2 months and scoliosis, neuromotor disorders and trophic and vasomotor disorders at the age of 4-5 years. Phenotype III. Non ambulant CRS, which corresponds to stage IV-B. It begins with hypotonia towards the age of 5-6 months, loss of voluntary grasping at 17.8 months, social withdrawal at 18 months, language impairment at the age of 12 months, stereotypic hand movements at 13 months and early onset of motor, trophic and vasomotor disorders. Genetic studies were conducted in 12 girls and MECP2 gene mutations were found in 10 of them, belonging to the three different phenotypes. CONCLUSIONS: We have established three phenotypes in RS according to the ability to walk. If walking is not achieved or the ability is lost early on, speech loss, social withdrawal and the onset of stereotypic movements, motor, trophic and vasomotor disorders all progress more quickly. Mutations in the MECP2 gene have been found in the three phenotypes. In 16.6% the genotype was normal. Greater accuracy is required in the definition of cases of CRS in order to establish phenotype genotype correlations.

Fenotipos clínicos del síndrome de Rett clásico / Clinical phenotypes of classic rett syndrome

Introducción. El síndrome de Rett (SR) es un trastorno neurológico progresivo del desarrollo que se diagnostica por criterios clínicos necesarios, de apoyo y de exclusión, y cuya evolución se establece en cuatro estadios. Se ha comprobado que lo causan mutaciones de novo de un gen, localizado en el brazo largo del cromosoma X dominante, que codifica la proteína de fijación de la metil CPG (MECP2). Se ha observado que las niñas con SR clásico (SRC) presentan matices diferenciales en la edad de aparición de los diferentes criterios y en la evolución. Hemos establecido tres fenotipos tomando como referencia la adquisición o no de la marcha. Desarrollo. Fenotipo I. SRC ambulante, que corresponde a un estadio III permanente o de larga evolución antes de pasar al estadio IV. La pérdida del uso útil de las manos tiene lugar a los 25,6 meses, el retraimiento social a los 25,4 meses, el déficit del lenguaje a los 20 meses y las estereotipias manuales a los 22,8 meses; los signos de espasticidad aparecen hacia los 8-10 años. Fenotipo II. SRC ambulante transitoria, corresponde a un estadio IV-A precoz. Los primeros signos de anormalidad aparecen hacia los 9-10 meses. La pérdida del uso propositivo de las manos ocurre hacia los 23,4 meses, el retraimiento social hacia los 21,4 meses, el déficit del lenguaje a los 20 meses, las estereotipias manuales a los 25,2 meses y la escoliosis, trastornos neuromotores y trastornos tróficos y vasomotores a los 4-5 años. Fenotipo III. SRC no ambulante, que corresponde a un estadio IV-B. Se inicia con hipotonía hacia los 5-6 meses, pérdida de la prensión voluntaria a los 17,8 meses, retraimiento social a los 18, déficit del lenguaje a los 12 meses, estereotipias manuales a los 13 meses e inicio precoz de trastornos motores, tróficos y vasomotores. Se realizó un estudio genético a 12 niñas, en 10 de las cuales, perteneciente a los tres fenotipos, se encontró mutación en el gen de MECP2. Conclusiones. Se establecen tres fenotipos en el SR en función de la adquisición de la marcha.Si no adquieren la marcha o la pierden precozmente, la evolución es más rápida en la pérdida de la palabra, retraimiento social, aparición de estereotipias y trastornos motores, tróficos y vasomotores. En los tres fenotipos se han encontrado mutaciones en el gen MECP2. En el 16,6 por ciento, el genotipo ha sido normal. Se necesita una mayor precisión en la definición de los SRC para poder establecer correlaciones fenotipo-genotipo (AU)

Introduction. Rett syndrome (RS) is a progressive neurological disorder that is diagnosed by essential, supportive and exclusion clinical criteria, and development takes place in four stages. It has been shown to be caused by de novo mutations of a gene located in the long arm of the dominant X chromosome that codes for the methyl CpG binding protein (MECP2). It has been observed that girls with classic RS (CRS) present distinguishing nuances with respect to the age of onset of the different criteria and as regards the progression of the disorder. Taking the ability or failure to walk as a reference, we have established three phenotypes. Method. Phenotype I. Ambulant CRS, which corresponds to a permanent stage III, or a stage III that lasts a long time before going into stage IV. The loss of the ability to use the hands in a purposeful way takes place at the age of 25.6 months, social withdrawal at 25.4 months, language impairment at 20 months, stereotypic hand movements at 22.8 months and signs of spasticity appear around the age of 8-10 years. Phenotype II. Ambulant CRS. Transitory, which corresponds to an early stage IV-A. The first signs of abnormality appear around the age of 9-10 months. This is followed by the loss of the purposeful use of the hands towards the age of 23.4 months, social withdrawal around 21.4 months, language impairment at 20 months, stereotypic hand movements at 25.2 months and scoliosis, neuromotor disorders and trophic and vasomotor disorders at the age of 4-5 years. Phenotype III. Non-ambulant CRS, which corresponds to stage IV-B. It begins with hypotonia towards the age of 5-6 months, loss of voluntary grasping at 17.8 months, social withdrawal at 18 months, language impairment at the age of 12 months, stereotypic hand movements at 13 months and early onset of motor, trophic and vasomotor disorders. Genetic studies were conducted in 12 girls and MECP2 gene mutations were found in 10 of them, belonging to the three different phenotypes. Conclusions. We have established three phenotypes in RS according to the ability to walk. If walking is not achieved or the ability is lost early on, speech loss, social withdrawal and the onset of stereotypic movements, motor, trophic and vasomotor disorders all progress more quickly. Mutations in the MECP2 gene have been found in the three phenotypes. In 16.6% the genotype was normal. Greater accuracy is required in the definition of cases of CRS in order to establish phenotype-genotype correlations (AU)

[Anhidrosis and hyperthermia associated with treatment with topiramate]. / Anhidrosis e hipertermia asociadas al tratamiento con topiramato.

INTRODUCTION: It has been observed that if topiramate (TPM) is given together with other antiepileptic drugs when the temperature of the environment is high, a disorder involving sweating and thermo regulation may be seen as a side effect. PATIENTS AND METHODS: We describe ten patients, of an average age of 7 years and 8 months, with refractory epileptic seizures. All were treated with topiramate, associated with the antiepileptic drugs they had been taking previously. During the summer months, when the environmental temperature was over 37 C, they had slight hyperthermia, hypohydrosis or more usually anhydrosis, red faces and tiredness which was markedly worse on effort. In one case there was also retention of urine and four others had known side effects. In seven patients the symptoms disappeared when the dose of TPM was reduced or the environment became cooler. In the other three cases TPM was withdrawn, due to the severe adverse effects seen in two cases and for being ineffective as treatment in the other cases. CONCLUSIONS: It is considered that in predisposed children, TPM causes autonomic dysfunction, probably of central origin, which is seen as a disorder of sweating and thermoregulation. Although the mechanism of this disorder is not known, since it occurs when the temperature is over 37 C, it would seem that it is due to a reduction in carbonic anhydrase isoenzymes II and IV. We suggest that it would be useful to establish a method to predict the patients at risk in summer, in hot regions, at the first sign of fatigability.

Anhidrosis e hipertermia asociadas al tratamiento con topiramato / Anhydrosis and hyperthermia associated with treatment with topiramate

Introducción. Se ha observado que el tratamiento con topiramato (TPM) añadido a otros fármacos antiepilépticos, cuando la temperatura ambiental es alta, produce un trastorno de la sudación y termorregulación como efecto adverso. Pacientes y métodos. En 10 pacientes, con edad media de 7 años y 8 meses, afectos de crisis epilépticas refractarias y en tratamiento con TPM combinado con los fármacos que tomaba con anterioridad, durante los meses de verano, cuando la temperatura ambiental sobrepasa los 37 ºC, se ha presentado leve hipertermia, hipo o habitualmente anhidrosis, nrojecimiento facial y cansancio que se acentúa sensiblemente con el esfuerzo. En un caso se ha asociado a retención de orina y en otros cuatro a efectos adversos ya conocidos. En siete pacientes, los síntomas desaparecieron al disminuir la dosis de TPM o al bajar la temperatura ambiental. En otros tres casos se suspendió TPM, por la gravedad de los efectos adversos en dos, y en otro, por ineficacia terapéutica. Conclusiones. Se estima que el TPM produce en niños predispuestos una disfunción autonómica, de probable origen central, que se expresa por un trastorno de la sudación y termorregulación. Aunque el mecanismo de producción de este trastorno se desconoce, el hecho de que aparezca a partir de los 37 ºC sugiere que se deba a la disminución de las isoenzimas II y IV de la anhidrasa carbónica. Se sugiere la conveniencia de establecer un método para predecir los pacientes de riesgo en verano, en regiones calurosas, al menor signo de fatiga (AU)

Topiramate in the treatment of severe myoclonic epilepsy in infancy.

The aim of this study was to assess the effectiveness of topiramate (TPM) as an add-on regimen in reducing seizure rate in a population sample of patients diagnosed with severe myoclonic epilepsy in infancy (SME). Eighteen patients were evaluated. The mean observation time was 10.5 months (range, 6-18 months). Seizure frequency and type were recorded. Topiramate was administered as an add-on regimen at a starting dose of 1 mg kg(-1)and titrated to a maximum of 6-8 mg per kg per day. Different escalation rates were used, mainly weekly or fortnightly increments of dose. Three patients (16.6%) became seizure free, and 10 (55.6%) had a >50% reduction in seizure frequency: six of them (22.2%) achieved a reduction greater than 75%. Side-effects were observed in nine patients, eight with a weekly titration schedule and one with a fortnightly schedule. TPM is effective as adjunctive therapy for SME. Side-effects were mild and transient, generally related to rapid dosage titration.

[Clinical course of epileptic seizures in Rett's syndrome]. / Evolución de las crisis epilépticas en el síndrome de Rett.

INTRODUCTION: Seventeen girls diagnosed as Rett syndrome (RS) patients suffer or have suffered epileptic fits; we have analyzed the evolution of these seizures. The RS diagnosis is based on criteria established by the Rett Syndrome Diagnostic Criteria Working Group in 1988. PATIENTS AND METHODS: All girls have had clinical, biochemical, electroneurophysiological neuroimaging and cytogenetic studies done on them. Periodic EEG were carried out while the girls were awake; all had night-time EEGs done. The females are aged between 7 y 5 m, and 22 y 7 m (medium 14 years, 8 months). The age at first seizure was between 18 m and 7 y 8 m (median 4 years 5 months). RESULTS: The clinic semiology is in decreasing order: tonic, generalized clonic, partial, absence and myoclonic seizures; eight patients have had more than one type of seizures. The frequency is variable: one or more continuous seizures in 6 cases, sporadic seizures in 3 cases, series of seizures in 4 cases, and subnitrant seizures in 4 cases. The evolution is variable: 6 cases have presented only the first fit, and 11 cases recurrent seizures which in 5 have ceased between 8 and 9 years, and 1 case at 13 years. CONCLUSIONS: The study shows that the epileptic seizures in RS present three evolution profiles: 1. One or more non recurrent seizures (35.3%); 2. Recurrent seizures until 8-9 years (35.3%); 3. Recurrent seizures in subnitrant form which continued after puberty (29.4%).