Cerebral and cerebellar pseudoatrophy associated with valproic acid. Report of three pediatric cases. / Pseudoatrofia cerebral y cerebelosa asociada a ácido valproico. Descripción de tres casos pediátricos.

INTRODUCTION: Cerebral and cerebellar pseudoatrophy is a rare adverse effect of valproic acid (VPA) that we need to be aware of, due to its diagnostic and therapeutic implications. CASE REPORT: We report three cases of children between 5 and 9 years old, with epilepsy and previous normal brain magnetic resonance imaging, who were taking the drug at correct doses. Pseudoatrophy manifests subacutely with symptoms and images of cerebral and/or cerebellar atrophy, reversible after drug withdrawal. DISCUSSION AND CONCLUSIONS: This is a type of VPA-related encephalopathy, different from dose-dependent toxic encephalopathy, hyperammonaemic encephalopathy or encephalopathy related to liver failure. In children, it causes cognitive, motor, mood and behavioral deterioration, and may be accompanied by epileptic decompensation. Withdrawing the drug leads to complete clinical-radiological recovery, and reducing the dose leads to improvement.

TITLE: Pseudoatrofia cerebral y cerebelosa asociada a ácido valproico. Descripción de tres casos pediátricos.Introducción. La pseudoatrofia cerebral y cerebelosa es un efecto adverso infrecuente del ácido valproico (VPA) que debemos conocer por sus implicaciones diagnósticas y terapéuticas. Caso clínico. Presentamos tres casos de niños de entre 5 y 9 años, con epilepsia y resonancia magnética craneal previa normal, que llevaban el fármaco con dosis correctas. La pseudoatrofia se manifiesta de forma subaguda con síntomas e imagen de atrofia cerebral y/o cerebelosa, reversible tras la retirada del fármaco. Discusión y conclusiones. Se trata de un tipo de encefalopatía relacionada con VPA diferente a la encefalopatía tóxica dependiente de la dosis, la encefalopatía hiperamoniémica o la relacionada con fallo hepático. En niños, cursa con deterioro cognitivo, motor, anímico y conductual, y puede acompañarse de descompensación epiléptica. La retirada del fármaco conlleva una recuperación completa clinicorradiológica, y la disminución de dosis, una mejoría.

Pseudoatrofia cerebral y cerebelosa asociada a ácido valproico. Descripción de tres casos pediátricos / Cerebral and cerebellar pseudoatrophy associated with valproic acid. Report of three pediatric cases

Introducción La pseudoatrofia cerebral y cerebelosa es un efecto adverso infrecuente del ácido valproico (VPA) que debemos conocer por sus implicaciones diagnósticas y terapéuticas. Caso clínico Presentamos tres casos de niños de entre 5 y 9 años, con epilepsia y resonancia magnética craneal previa normal, que llevaban el fármaco con dosis correctas. La pseudoatrofia se manifiesta de forma subaguda con síntomas e imagen de atrofia cerebral y/o cerebelosa, reversible tras la retirada del fármaco. Discusión y conclusiones. Se trata de un tipo de encefalopatía relacionada con VPA diferente a la encefalopatía tóxica dependiente de la dosis, la encefalopatía hiperamoniémica o la relacionada con fallo hepático. En niños, cursa con deterioro cognitivo, motor, anímico y conductual, y puede acompañarse de descompensación epiléptica. La retirada del fármaco conlleva una recuperación completa clinicorradiológica, y la disminución de dosis, una mejoría. (AU)

INTRODUCTION Cerebral and cerebellar pseudoatrophy is a rare adverse effect of valproic acid (VPA) that we need to be aware of, due to its diagnostic and therapeutic implications. CASE REPORT We report three cases of children between 5 and 9 years old, with epilepsy and previous normal brain magnetic resonance imaging, who were taking the drug at correct doses. Pseudoatrophy manifests subacutely with symptoms and images of cerebral and/or cerebellar atrophy, reversible after drug withdrawal. Discussion and conclusions. This is a type of VPA-related encephalopathy, different from dose-dependent toxic encephalopathy, hyperammonaemic encephalopathy or encephalopathy related to liver failure. In children, it causes cognitive, motor, mood and behavioral deterioration, and may be accompanied by epileptic decompensation. Withdrawing the drug leads to complete clinical-radiological recovery, and reducing the dose leads to improvement. (AU)

Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation.

BACKGROUND: The Ehlers-Danlos syndrome (EDS) comprises a group of hereditary connective tissue disorders. Periventricular nodular heterotopia (PNH) is a human neuronal migration disorder characterised by seizures and conglomerates of neural cells around the lateral ventricles of the brain, caused by FLNA mutations. FLNA encodes filamin A, an actin binding protein involved in cytoskeletal organisation. The amino-terminal actin binding domain (ABD) of filamins contains two tandem calponin homology domains, CHD1 and CHD2. OBJECTIVE: To report clinical and genetic analyses in a Spanish family affected by a connective tissue disorder suggestive of EDS type III and PNH. METHODS: A clinical and molecular study was undertaken in the three affected women. Clinical histories, physical and neurological examinations, brain magnetic resonance imaging studies, and skin biopsies were done. Genetic analysis of the FLNA gene was undertaken by direct sequencing and restriction fragment length polymorphism analysis. RESULTS: Mutation analysis of the FLNA gene resulted in the identification of a novel mutation in exon 3 (c.383C-->T) segregating with the combination of both syndromes. This mutation results in a substitution of an alanine residue (A128V) in CHD1. CONCLUSIONS: The findings suggest that the Ala128Val mutation causes the dual EDS-PNH phenotype. This association constitutes a new variant within the EDS spectrum. This is the first description of a familial EDS-PNH association with a mutation in FLNA.

[Open-label, prospective and observational study of efficacy and tolerability with levetiracetam during one year of follow-up]. / Estudio abierto, prospectivo y observacional de eficacia y tolerabilidad con levetiracetam durante 1 año de seguimiento.

OBJECTIVE: Analyze efficacy and tolerability of levetiracetam under clinical practice conditions. METHODS: An open-label, observational and prospective study with a one-year follow-up period, was conducted. All the patients in whom treatment was initiated with levetiracetam between January 2002 and January 2004 in the site where the study was conducted were included. The patients were evaluated in the baseline visit and months 1, 3, 6 and 12. The following were collected in the baseline visit: age, gender, age at onset of the episode, types of episodes, type of epilepsy, etiology, monthly rate of episodes and number of anti-epileptic drugs (AED) used. During the follow-up visits, episodes, adverse effects and concomitant AED were counted. Analysis was conducted by intention-to-treat (ITT) and in the patients who completed one year of follow-up. RESULTS: One hundred eight patients were enrolled in the study. Most had partial complex seizures (63.1 %) and partial epilepsy (88 %). Eighty-one patients completed the one year of follow-up (75 %). In relationship to the ITT, the percentage of responders was 63 % and the percentage of seizure-free patients 35.2 %. These percentages remained stable during the study. Secondary effects were maintained in 21 patients (19.4 %), resulting in withdrawal in 9 patients (8.3 %). The most frequent adverse event was somnolence. Monotherapy was achieved with levetiracetam at the end of the one year of follow-up in 18 patients (16.7%) CONCLUSIONS: This study shows the efficacy and tolerability, which rarely led to withdrawal, of levetiracetam under conditions of clinical practice.

Hepatic disease as the first manifestation of progressive myoclonus epilepsy of Lafora.

BACKGROUND: Lafora disease (LD; progressive myoclonus epilepsy type 2; EPM2) is an autosomal recessive disorder caused by mutations in the EPM2A and EPM2B genes. LD is characterized by the presence of strongly PAS-positive intracellular inclusions (Lafora bodies) in several tissues. Glycogen storage disease type IV (GSD-IV; Andersen disease) is an autosomal recessive disorder characterized by cirrhosis leading to severe liver failure. GSD-IV has been associated with mutations in the glycogen branching enzyme gene (GBE). Histopathologic changes of the liver in both diseases show an identical appearance, although cirrhosis has never been described in patients with LD. We report a LD family in which the proband presented severe liver failure at onset of the disease. METHODS: Clinical histories, physical and neurologic examination, laboratory tests, EEGs, MRI of the brain, and liver or axillary skin biopsies were performed in the two affected siblings. The diagnosis was confirmed by molecular genetic analysis of the EPM2A, EPM2B, and GBE genes and loci. RESULTS: During the first decade of life, abnormalities in liver function tests were detected in the two affected siblings. The proband's liver dysfunction was severe enough to require liver transplantation. Subsequently, both sibs developed LD. Mutation analysis of EPM2A revealed a homozygous Arg241stop mutation in both patients. CONCLUSIONS: This is the first description of severe hepatic dysfunction as the initial clinical manifestation of LD. The phenotypic differences between the two affected siblings suggest that modifier genes must condition clinical expression of the disease outside the CNS.

Lafora disease due to EPM2B mutations: a clinical and genetic study.

OBJECTIVE: To study EPM2B gene mutations and genotype-phenotype correlations in patients with Lafora disease. METHODS: The authors performed a clinical and mutational analysis of 25 patients, from 23 families, diagnosed with Lafora disease who had not shown mutations in the EPM2A gene. RESULTS: The authors identified 18 mutations in EPM2B, including 12 novel mutations: 4 nonsense mutations (R265X, C26X, W219X, and E67X), a 6-base pair (bp) microdeletion resulting in a two amino acid deletion (V294_K295del), a 4-bp insertion resulting in a frameshift mutation (S339fs12), and 6 missense mutations (D308A, I198N, C68Y, E67Q, P264H, and D233A). In our data set of 77 families with Lafora disease, 54 (70.1%) tested probands have mutations in EPM2A, 21 (27.3%) in EPM2B, and 2 (2.6%) have no mutations in either gene. The course of the disease was longer in patients with EPM2B mutations vs patients with EPM2A mutations. CONCLUSIONS: Genetic allelic heterogeneity is present in Lafora disease associated with mutations in EPM2B. Patients with mutations in EPM2A and EPM2B express similar clinical manifestation, although patients with EPM2B-associated Lafora disease seem to have a slightly milder clinical course. The lack of mutations in EPM2A and EPM2B in two families could be because of the presence of mutations in noncoding, nontested regions or the existence of an additional gene associated with Lafora disease.

Estudio abierto, prospectivo y observacional de eficacia y tolerabilidad con levetiracetam durante 1 año de seguimiento / Open-label, prospective and observational study of efficacy and tolerability with levetiracetam during one year of follow-up

Objetivo. Analizar la eficacia y tolerabilidad con levetiracetam en condiciones de práctica clínica.Métodos. Se realizó un estudio abierto, observacional y prospectivo, con período de seguimiento de 1 año. Fueron incluidos todos los pacientes en los que se inició tratamiento con levetiracetam entre enero de 2002 y enero de 2004 en el centro donde se realizó el estudio. Los pacientes fueron evaluados en una visita basal y en los meses 1, 3, 6 y 12. En la visita basal se recogieron: edad, sexo, edad al inicio de las crisis, tipos de crisis, tipo de epilepsia, etiología, frecuencia mensual de crisis y número de fármacos antiepilépticos (FAE) utilizados. Durante las visitas de seguimiento se recogió un recuento de crisis, efectos adversos y FAE concomitantes. El análisis se realizó por intención de tratar (AIT) y en los pacientes que completaron el año de seguimiento.Resultados. Ciento ocho pacientes fueron incluidos en el estudio. La mayoría presentaban crisis parciales complejas (63,1 %) y epilepsia parcial (88 %). Ochenta y un pacientes completaron el año de seguimiento (75 %). En relación al AIT, el porcentaje de respondedores fue del 63% y el porcentaje de pacientes libres de crisis del 35,2 %. Estos porcentajes permanecieron estables durante el estudio. Los efectos secundarios fueron mantenidos en 21 pacientes (19,4 %) y en 9 pacientes (8,3 %) llevaron a la retirada. El efecto adverso más frecuente fue la somnolencia. Alcanzaron monoterapia con levetiracetam al final del año de seguimiento 18 pacientes (16,7%)Conclusiones. Este estudio demuestra la eficacia y la tolerabilidad, que rara vez llevó a la retirada, del levetiracetam en condiciones de práctica clínica

Objective. Analyze efficacy and tolerability of levetiracetam under clinical practice conditions.Methods. An open-label, observational and prospective study with a one-year follow-up period, was conducted. All the patients in whom treatment was initiated with levetiracetam between January 2002 and January 2004 in the site where the study was conducted were included. The patients were evaluated in the baseline visit and months 1, 3, 6 and 12. The following were collected in the baseline visit: age, gender, age at onset of the episode, types of episodes, type of epilepsy, etiology, monthly rate of episodes and number of anti-epileptic drugs (AED) used. During the follow-up visits, episodes, adverse effects and concomitant AED were counted. Analysis was conducted by intention-to-treat (ITT) and in the patients who completed one year of follow-up.Results. One hundred eight patients were enrolled in the study. Most had partial complex seizures (63.1 %) and partial epilepsy (88 %). Eighty-one patients completed the one year of follow-up (75 %). In relationship to the ITT, the percentage of responders was 63 % and the percentage of seizure-free patients 35.2 %. These percentages remained stable during the study. Secondary effects were maintained in 21 patients (19.4 %), resulting in withdrawal in 9 patients (8.3 %). The most frequent adverse event was somnolence. Monotherapy was achieved with levetiracetam at the end of the one year of follow-up in 18 patients (16.7%)Conclusions. This study shows the efficacy and tolerability, which rarely led to withdrawal, of levetiracetam under conditions of clinical practice