[Breath-holding spell or epileptic seizure? A description of three girls with epileptic seizures triggered by anoxia]. / ¿Espasmo del sollozo prolongado o crisis epiléptica?: descripción de tres niñas con crisis epilépticas desencadenadas por anoxia.

TITLE: ¿Espasmo del sollozo prolongado o crisis epiléptica?: descripción de tres niñas con crisis epilépticas desencadenadas por anoxia.

[«Apuntes en Neurologia¼ (Notes in Neurology): a synthesis of the evidence on common paroxysmal neurological disorders and on neurodegenerative disorders]. / «Apuntes en Neurologia¼: una sintesis de la evidencia en trastornos neurologicos comunes paroxisticos y en trastornos neurodegenerativos.

«Apuntes en Neurologia¼ is an initiative in which prominent national and international leaders, with broad academic recognition, came together to synthesise the most outstanding clinical aspects within their area of interest and to discuss the latest developments in a more accessible language. Understanding the factors that affect the onset and progression of any neurological disease through a review is important to be able to develop strategies to reduce the burden of these diseases. Moreover, knowledge of the clinical aspects is essential to solve the problems of daily clinical practice. The data collected here reflect the weight of evidence and some of them anticipate a promising future in the treatment of these diseases. This first edition focuses on common paroxysmal neurological disorders such as migraine, epilepsy and sleep disorders, as well as neurodegenerative disorders such as Parkinson's disease and cognitive impairment. These are clearly different pathologies, although some of them such as migraine and epilepsy, may share clinical symptoms. Sleep disorders, however, are important manifestations of neurodegenerative diseases that are sometimes clinically apparent long before the onset of other neurological symptoms. After recalling pathophysiology and diagnosis, the current review focuses on bringing together the main advances in five of the major neurological diseases.

TITLE: «Apuntes en Neurologia¼: una sintesis de la evidencia en trastornos neurologicos comunes paroxisticos y en trastornos neurodegenerativos.«Apuntes en Neurologia¼ es una iniciativa en la cual lideres de primera linea nacional e internacional, con amplio reconocimiento academico, se reunieron para sintetizar los aspectos clinicos mas destacables dentro de su area de interes y acercar las novedades en una lengua mas proxima. Entender los factores que afectan al inicio y progresion de cualquier enfermedad neurologica a traves de una revision es importante para el desarrollo de estrategias en pro de reducir la carga de estas enfermedades, y conocer los aspectos clinicos es esencial para poder resolver los problemas de la practica clinica diaria. Los datos aqui recogidos reflejan el peso de la evidencia y algunos de ellos anticipan un futuro prometedor en el tratamiento de estas enfermedades. Esta primera edicion se centra en trastornos neurologicos comunes paroxisticos como la migraña, la epilepsia y las alteraciones del sueño, y en trastornos neurodegenerativos como la enfermedad de Parkinson y el deterioro cognitivo. Se trata de patologias claramente diferentes, si bien algunas de ellas, como la migraña y la epilepsia, pueden compartir sintomatologia clinica. Los trastornos del sueño, por su parte, son manifestaciones importantes de enfermedades neurodegenerativas que, en ocasiones, son clinicamente evidentes mucho antes del inicio de otros sintomas neurologicos. Tras recordar la fisiopatologia y el diagnostico, la revision actual se centra en acercar los principales avances en cinco de las principales enfermedades neurologicas.

Efficacy and safety of eslicarbazepine-acetate in elderly patients with focal epilepsy: Case series.

PURPOSE: Eslicarbazepine-acetate (ESL) is a third generation antiepileptic drug licensed as adjunctive therapy in adults with focal seizures. Efficacy and safety of ESL have been established in real-life setting. However, data about outcomes in elderly patients are scarce. Primary endpoint was to evaluate outcomes of ESL in elderly patients. METHOD: This was a retrospective survey that included patients >65years with focal seizures who started ESL between January 2010 and July 2012 at 12 Spanish Hospitals. ESL was prescribed individually according to real-life practice. Efficacy and safety were evaluated over 1year. These patients were included within the bigger study ESLIBASE. RESULTS: We included 29 patients, most of them males (18). Mean age was 71.2 year-old and epilepsy evolution was 20 years. Eighteen were pharmacorresistant at baseline. At 12 months, the mean dose was 850mg/day, the retention rate 69%, the responder rate 62% and 24.1% were seizure-free. At 12 months, 16 patients (55.2%) had ≥1 adverse effect (AE), that led to discontinuation in 7 patients. Dizziness, nausea and ataxia were the most common AEs. The tolerability profile improved in 4/5 patients who switched from carbamazepine (CBZ) or oxcarbazepine (OXC) to ESL due to AEs. CONCLUSIONS: ESL was well-tolerated and effective in elderly patients in a real-life setting over 1year, with a dose around 800mg/day. AE effects improved in most of who switched from CBZ or OXC to ESL.

Safety, efficacy and outcome-related factors of perampanel over 12 months in a real-world setting: The FYDATA study.

BACKGROUND: Real-world data of current antiepileptic drugs (AEDs) used to treat focal seizures is of importance to understand the efficacy and safety outside of the clinical trial setting. Here we report real-world data from a large series of patients treated with perampanel for 1year. METHODS: FYDATA was a multicentre, retrospective, 1-year observational study assessing the efficacy and safety of adjuvant perampanel in patients ≥12 years of age with focal epilepsy in a real-world setting. At 12 months, the proportion of patients who were seizure free, median percentage seizure reduction, proportion of responders, retention rate and proportion of patients with adverse events (AEs) were assessed. Analyses were also performed to identify any patient-, medication- and disease-related factors associated with a large clinical response or carry a risk for AEs. RESULTS: A total of 464 patients were included in the study with a retention rate of 60.6% at 1year. The mean number of prior AEDs was 7.8. The median percentage reduction in overall seizures was 33.3% (75% for secondary generalised seizures) after 1year, with 7.2% of patients achieving seizure freedom. Furthermore, patients on non-enzyme-inducing AEDs were more likely to achieve seizure freedom, and logistic regression revealed that patients aged ≥65 years, those with epilepsy due to a vascular aetiology and those who had received fewer prior AEDs showed a better clinical response to perampanel. A total of 62.9% of the patients experienced AEs at 12 months; dizziness, somnolence and irritability were the most frequent AEs. Patients with prior psychiatric comorbidities (hyperactivity and personality disorder) were more likely to experience psychiatric AEs with perampanel, and slower titration schedules were associated with less AEs overall. CONCLUSION: Perampanel, for the treatment of focal epilepsy in a real-world setting in a refractory population, over 1year, demonstrates a similar efficacy and safety profile to that observed in clinical trials. Our results have implications for the optimisation of perampanel use in a clinical setting.

Novel mutation in STXBP1 gene in a patient with non-lesional Ohtahara syndrome. / Nueva mutación en el gen STXBP1 en un paciente con síndrome de Ohtahara no lesional.

INTRODUCTION: Ohtahara syndrome (OS, OMIM#308350, ORPHA1934) is an early-onset epileptic encephalopathy (EOEE) characterised by spasms, intractable seizures, suppression-burst pattern on the electroencephalogram, and severe psychomotor retardation. Mutations in STXBP1 -a gene that codes for syntaxin binding protein 1 and is involved in synaptic vesicle exocytosis- has been identified in most patients with OS. PATIENT AND RESULTS: We report the case of a 19-month-old child with OS who displays a previously unreported mutation in STXBP1 (c.1249+2T>C, G417AfsX7). This mutation is located in a donor splice site and eliminates exon 14, resulting in a truncated protein. CONCLUSION: This previously unreported STXBP1 mutation in a subject with Ohtahara syndrome and non-lesional magnetic resonance imaging (MRI) broadens the mutational spectrum associated with this devastating epileptic syndrome.

Long-term safety and efficacy of eslicarbazepine acetate in patients with focal seizures: results of the 1-year ESLIBASE retrospective study.

BACKGROUND: Eslicarbazepine acetate (ESL) is a new antiepileptic drug (AED) licensed as adjunctive therapy in adults with partial-onset or focal seizures. OBJECTIVE: To evaluate in a clinical practice setting the long-term efficacy and safety of ESL in patients with focal seizures. METHODS: ESLIBASE was a retrospective study that included all patients with focal seizures who started ESL between January 2010 and July 2012 at 12 hospitals. ESL was prescribed individually according to real-life practice. Efficacy and safety were evaluated over 1 year. Switching from carbamazepine (CBZ) and oxcarbazepine (OXC) was assessed. RESULTS: Three hundred and twenty-seven patients were included; 78% of patients were taking ≥2 other AEDs at baseline. Most (87%) began ESL because of poor seizure control and 13% because of adverse events (AEs) with CBZ or OXC. After 1 year, 237 patients (72.4%) remained on ESL. At 3, 6 and 12 months, the responder rate was 46.3%, 57.9%, and 52.5%, and 21.0%, 28.0%, and 25.3% of patients were seizure free. The responder rate significantly increased when ESL was combined with a non-sodium channel-targeting drug (non-SC drug) (66.7%) versus an SC drug (47.7%; p<0.001). At 12 months, 40.7% of patients had ≥1 AE; AEs led to treatment discontinuation in 16.2%. Dizziness, nausea, and somnolence were the most common AEs. The tolerability profile improved in >50% of the patients who switched from CBZ or OXC to ESL because of AEs. CONCLUSIONS: ESL was well tolerated and effective in a real-world setting over 1 year. Side-effect profile improved when OXC and CBZ recipients were switched to ESL.

Safety and tolerability of perampanel: a review of clinical trial data.

The Phase II and Phase III clinical development program of perampanel is providing a wealth of data on the safety and tolerability of this alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist as an adjuvant treatment for refractory partial-onset seizures. In Phase II dose-finding studies, perampanel was associated with an acceptable tolerability profile up to the maximum evaluated dose of 12 mg/day. Subsequent multinational, multicenter, randomized, double-blind, placebo-controlled Phase III registration studies further supported the tolerability of perampanel across the dose range 2-12 mg/day, with interim data from ongoing extension studies indicating that safety outcomes may be maintained over several years. An analysis of the pooled Phase III data indicated that the frequency of adverse events reported with perampanel generally increased in a dose-dependent manner, and the most common adverse events were dizziness and somnolence. Overall, perampanel has been associated with an acceptable and consistent safety profile that is maintained over long-term settings.

Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures.

OBJECTIVE: To evaluate the efficacy and safety of perampanel 2, 4, and 8 mg/day added to 1-3 concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures. METHODS: During this double-blind, placebo-controlled trial, patients with persisting seizures on 1-3 AEDs were randomized to perampanel 2, 4, and 8 mg/day or placebo following a 6-week baseline phase. Perampanel was titrated weekly by 2 mg/day and maintained at the dose achieved for 13 weeks. Primary endpoints were median percent change in seizure frequency and 50% responder rate. Analysis of covariance was performed on all treated patients with any seizure data (recorded in daily diaries) in the double-blind phase. RESULTS: A total of 706 patients were randomized and received trial medication; 623 completed the trial. Median percent change in seizure frequency-the primary efficacy endpoint-was -10.7%, -13.6%, -23.3%, and -30.8% for placebo, perampanel 2, 4, and 8 mg/day, respectively. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0026) and 8 mg/day (p < 0.0001). The corresponding 50% responder rates were 17.9%, 20.6%, 28.5%, and 34.9%. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0132) and 8 mg/day (p = 0.0003). An apparent dose response was suggested for dizziness, which was the most frequent treatment-emergent adverse event. CONCLUSIONS: This trial demonstrated that adjunctive perampanel effectively reduced seizure frequency and possessed a favorable tolerability profile in patients ≥12 years with partial-onset seizures (with or without secondary generalization), with a minimum effective dose of 4 mg/day. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 4 and 8 mg/day doses of adjunctive perampanel are effective and tolerated in reducing partial-onset seizures.

GLUT1 mutations are a rare cause of familial idiopathic generalized epilepsy.

OBJECTIVE: The idiopathic generalized epilepsies (IGE) are the most common genetically determined epilepsies. However, the underlying genes are largely unknown. We screened the SLC2A1 gene, encoding the glucose transporter type 1 (GLUT1), for mutations in a group of 95 European patients with familial IGE. METHODS: The affected individuals were examined clinically by EEG and brain imaging. The coding regions of SLC2A1 were sequenced in the index cases of all families. Wild-type and mutant transporters were expressed and functionally characterized in Xenopus laevis oocytes. RESULTS: We detected a novel nonsynonymous SLC2A1 mutation (c.694C>T, p.R232C) in one IGE family. Nine family members were affected mainly by absence epilepsies with a variable age at onset, from early childhood to adulthood. Childhood absence epilepsy in one individual evolved into juvenile myoclonic epilepsy. Eight affected and 4 unaffected individuals carried the mutation, revealing a reduced penetrance of 67%. The detected mutation was not found in 846 normal control subjects. Functional analysis revealed a reduced maximum uptake velocity for glucose, whereas the affinity to glucose and the protein expression were not different in wild-type and mutant transporters. CONCLUSION: Our study shows that GLUT1 defects are a rare cause of classic IGE. SLC2A1 screening should be considered in IGE featuring absence epilepsies with onset from early childhood to adult life, because this diagnosis may have important implications for treatment and genetic counseling.

Socio-occupational and employment profile of patients with epilepsy.

OBJECTIVE: Epilepsy has a significant impact on quality of life. Many studies have observed higher unemployment rates among patients with epilepsy. However, unemployment rates vary according to the clinical conditions, country, and group studied. METHODS: Between October 2007 and February 2008, we performed a cross-sectional multicenter epidemiological study to evaluate the socio-occupational and employment profiles of 872 adult patients with epilepsy followed in outpatient epilepsy clinics in Spain. RESULTS: Fifty-eight percent of the patients were employed at the time of the survey, 10.9% of the patients were unemployed, and 12.5% were occupationally incapacitated. CONCLUSION: Patients with epilepsy had employment rates similar to those of the general population, and slightly higher levels of unemployment. The main factors associated with unemployment and incapacity were the presence of refractory epilepsy, the occurrence of a seizure in the last 12 months, level of education, and polytherapy.

Self-reported memory problems in everyday activities in patients with epilepsy treated with antiepileptic drugs.

OBJECTIVE: The goal of this study was to assess everyday memory complaints in a large cohort of patients with epilepsy treated with antiepileptic drugs and to determine demographic, clinical, and emotional state factors associated with patients' self-perception of memory disturbances. METHODS: This cross-sectional epidemiological study was carried out in routine clinical practice using the Questionnaire of Memory Efficiency (QME) and the Hospital Anxiety and Depression Scale (HADS). RESULTS: Six hundred sixty-one patients were recruited. The time since epilepsy diagnosis was 17.3 years (SD=12.5); the number of seizures in the past year 13.8 (SD=4.8); the proportion of patients free of seizures in the last year 42.5%; the proportion of patients with partial seizures 73.2%; and the proportion of patients on monotherapy 56.3%. Total QME score was 110.0 (SD=18.6). Depression and anxiety scores and polytherapy explained 38.7% of the QME variance. CONCLUSIONS: Subjective memory functioning in this cohort of patients with epilepsy was relatively good. Complaints expressed by these patients are explained mainly by the presence of depressive and anxiety symptoms.

Strategies to detect adverse effects of antiepileptic drugs in clinical practice.

OBJECTIVE: The aim was to study the frequency and types of adverse effects (AEs) in patients treated with antiepileptic drugs (AEDs) according to the strategies used by the neurologist to detect them. METHOD: This cross-sectional epidemiological study was carried out in standard clinical practice. Two strategies were used to detect AEs: spontaneous reporting by the patient, and a checklist of possible treatment-related adverse reactions completed by the patient. RESULTS: A total of 579 patients were recruited for the study. Roughly a third (33.7%) reported AEs spontaneously, and 65.2% did so when administered the checklist. The main reason for changing medication was lack of efficacy, but significant side effects were also an important reason for modifying treatment in those patients who reported higher levels of discomfort. CONCLUSIONS: The use of an active approach is recommended for detection of AEs of AED treatment. AEs appear to have a key effect on the decision to change treatment.

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

[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.