Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child.

BACKGROUND: Prenatal exposure to certain anti-seizure medications (ASMs) is associated with an increased risk of major congenital malformations (MCM). The majority of women with epilepsy continue taking ASMs throughout pregnancy and, therefore, information on the potential risks associated with ASM treatment is required. OBJECTIVES: To assess the effects of prenatal exposure to ASMs on the prevalence of MCM in the child. SEARCH METHODS: For the latest update of this review, we searched the following databases on 17 February 2022: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to February 16, 2022), SCOPUS (1823 onwards), and ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP). No language restrictions were imposed. SELECTION CRITERIA: We included prospective cohort controlled studies, cohort studies set within pregnancy registries, randomised controlled trials and epidemiological studies using routine health record data. Participants were women with epilepsy taking ASMs; the two control groups were women without epilepsy and untreated women with epilepsy. DATA COLLECTION AND ANALYSIS: Five authors independently selected studies for inclusion. Eight authors completed data extraction and/or risk of bias assessments. The primary outcome was the presence of an MCM. Secondary outcomes included specific types of MCM. Where meta-analysis was not possible, we reviewed included studies narratively. MAIN RESULTS: From 12,296 abstracts, we reviewed 283 full-text publications which identified 49 studies with 128 publications between them. Data from ASM-exposed pregnancies were more numerous for prospective cohort studies (n = 17,963), than data currently available for epidemiological health record studies (n = 7913). The MCM risk for children of women without epilepsy was 2.1% (95% CI 1.5 to 3.0) in cohort studies and 3.3% (95% CI 1.5 to 7.1) in health record studies. The known risk associated with sodium valproate exposure was clear across comparisons with a pooled prevalence of 9.8% (95% CI 8.1 to 11.9) from cohort data and 9.7% (95% CI 7.1 to 13.4) from routine health record studies. This was elevated across almost all comparisons to other monotherapy ASMs, with the absolute risk differences ranging from 5% to 9%. Multiple studies found that the MCM risk is dose-dependent. Children exposed to carbamazepine had an increased MCM prevalence in both cohort studies (4.7%, 95% CI 3.7 to 5.9) and routine health record studies (4.0%, 95% CI 2.9 to 5.4) which was significantly higher than that for the children born to women without epilepsy for both cohort (RR 2.30, 95% CI 1.47 to 3.59) and routine health record studies (RR 1.14, 95% CI 0.80 to 1.64); with similar significant results in comparison to the children of women with untreated epilepsy for both cohort studies (RR 1.44, 95% CI 1.05 to 1.96) and routine health record studies (RR 1.42, 95% CI 1.10 to 1.83). For phenobarbital exposure, the prevalence was 6.3% (95% CI 4.8 to 8.3) and 8.8% (95% CI 0.0 to 9277.0) from cohort and routine health record data, respectively. This increased risk was significant in comparison to the children of women without epilepsy (RR 3.22, 95% CI 1.84 to 5.65) and those born to women with untreated epilepsy (RR 1.64, 95% CI 0.94 to 2.83) in cohort studies; data from routine health record studies was limited. For phenytoin exposure, the prevalence of MCM was elevated for cohort study data (5.4%, 95% CI 3.6 to 8.1) and routine health record data (6.8%, 95% CI 0.1 to 701.2). The prevalence of MCM was higher for phenytoin-exposed children in comparison to children of women without epilepsy (RR 3.81, 95% CI 1.91 to 7.57) and the children of women with untreated epilepsy (RR 2.01. 95% CI 1.29 to 3.12); there were no data from routine health record studies. Pooled data from cohort studies indicated a significantly increased MCM risk for children exposed to lamotrigine in comparison to children born to women without epilepsy (RR 1.99, 95% CI 1.16 to 3.39); with a risk difference (RD) indicating a 1% increased risk of MCM (RD 0.01. 95% CI 0.00 to 0.03). This was not replicated in the comparison to the children of women with untreated epilepsy (RR 1.04, 95% CI 0.66 to 1.63), which contained the largest group of lamotrigine-exposed children (> 2700). Further, a non-significant difference was also found both in comparison to the children of women without epilepsy (RR 1.19, 95% CI 0.86 to 1.64) and children born to women with untreated epilepsy (RR 1.00, 95% CI 0.79 to 1.28) from routine data studies. For levetiracetam exposure, pooled data provided similar risk ratios to women without epilepsy in cohort (RR 2.20, 95% CI 0.98 to 4.93) and routine health record studies (RR 0.67, 95% CI 0.17 to 2.66). This was supported by the pooled results from both cohort (RR 0.71, 95% CI 0.39 to 1.28) and routine health record studies (RR 0.82, 95% CI 0.39 to 1.71) when comparisons were made to the offspring of women with untreated epilepsy. For topiramate, the prevalence of MCM was 3.9% (95% CI 2.3 to 6.5) from cohort study data and 4.1% (0.0 to 27,050.1) from routine health record studies. Risk ratios were significantly higher for children exposed to topiramate in comparison to the children of women without epilepsy in cohort studies (RR 4.07, 95% CI 1.64 to 10.14) but not in a smaller comparison to the children of women with untreated epilepsy (RR 1.37, 95% CI 0.57 to 3.27); few data are currently available from routine health record studies. Exposure in utero to topiramate was also associated with significantly higher RRs in comparison to other ASMs for oro-facial clefts. Data for all other ASMs were extremely limited. Given the observational designs, all studies were at high risk of certain biases, but the biases observed across primary data collection studies and secondary use of routine health records were different and were, in part, complementary. Biases were balanced across the ASMs investigated, and it is unlikely that the differential results observed across the ASMs are solely explained by these biases. AUTHORS' CONCLUSIONS: Exposure in the womb to certain ASMs was associated with an increased risk of certain MCMs which, for many, is dose-dependent.

ANTECEDENTES: La exposición prenatal a determinados fármacos anticonvulsivos (FAC) se asocia con un mayor riesgo de malformaciones congénitas graves (MCG). La mayoría de las mujeres con epilepsia continúan tomando FAC durante todo el embarazo y, por lo tanto, se requiere información sobre los riesgos potenciales asociados con el tratamiento con FAC. OBJETIVOS: Evaluar los efectos de la exposición prenatal a los FAC sobre la prevalencia de MCG en el niño. MÉTODOS DE BÚSQUEDA: Para la última actualización de esta revisión se hicieron búsquedas el 17 de febrero de 2022 en las siguientes bases de datos: Registro Cochrane de Estudios (Cochrane Register of Studies [CRS Web]), MEDLINE (Ovid, 1946 hasta el 16 de febrero de 2022), SCOPUS (1823 en adelante) y ClinicalTrials.gov , Plataforma de registros internacionales de ensayos clínicos (ICTRP). No se impusieron restricciones de idioma. CRITERIOS DE SELECCIÓN: Se incluyeron estudios prospectivos controlados de cohortes, estudios de cohortes establecidos dentro de registros de embarazos, ensayos controlados aleatorizados y estudios epidemiológicos que utilizaron datos rutinarios de los historiales médicos. Las participantes fueron mujeres con epilepsia que tomaban FAC; los dos grupos de control fueron mujeres sin epilepsia y mujeres con epilepsia que no recibían tratamiento. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Cinco autores seleccionaron de forma independiente los estudios para inclusión. Ocho autores completaron la extracción de los datos y las evaluaciones del riesgo de sesgo. El desenlace principal fue la presencia de una MCG. Los desenlaces secundarios incluyeron tipos específicos de MCG. Cuando no fue posible realizar un metanálisis, los estudios incluidos se examinaron de forma narrativa. RESULTADOS PRINCIPALES: De 12 296 resúmenes, se revisaron 283 publicaciones a texto completo que identificaron 49 estudios con 128 publicaciones entre ellos. Los datos de los embarazos expuestos a FAC fueron más numerosos en el caso de los estudios prospectivos de cohortes (n = 17 963), que los datos actualmente disponibles de estudios de registros sanitarios epidemiológicos (n = 7913). El riesgo de MCG en los hijos de mujeres sin epilepsia fue del 2,1% (IC del 95%: 1,5 a 3,0) en los estudios de cohortes y del 3,3% (IC del 95%: 1,5 a 7,1) en los estudios de registros sanitarios. El riesgo conocido asociado con la exposición al valproato de sodio fue evidente en todas las comparaciones, con una prevalencia agrupada del 9,8% (IC del 95%: 8,1 a 11,9) a partir de los datos de los estudios de cohortes y del 9,7% (IC del 95%: 7,1 a 13,4) a partir de los estudios con datos rutinarios de los historiales médicos. Este fue elevado en casi todas las comparaciones con otros FAC como monoterapia, con diferencias absolutas de riesgo que variaron entre el 5% y el 9%. Múltiples estudios han constatado que el riesgo de MCG depende de la dosis. Los niños expuestos a la carbamazepina tuvieron una mayor prevalencia de MCG tanto en los estudios de cohortes (4,7%; IC del 95%: 3,7 a 5,9) como en los estudios con datos rutinarios de los historiales médicos (4,0%; IC del 95%: 2,9 a 5,4), que fue significativamente superior a la de los niños nacidos de mujeres sin epilepsia tanto en los estudios de cohortes (RR 2,30; IC del 95%: 1,47 a 3,59) como en los estudios de historias clínicas habituales (RR 1,14; IC del 95%: 0,80 a 1,64), con resultados significativos similares en comparación con los hijos de mujeres con epilepsia que no reciben tratamiento tanto en los estudios de cohortes (RR 1,44; IC del 95%: 1,05 a 1,96) como en los estudios con datos rutinarios de los historiales médicos (RR 1,42; IC del 95%: 1,10 a 1,83). Para la exposición al fenobarbital, la prevalencia fue del 6,3% (IC del 95%: 4,8 a 8,3) y del 8,8% IC del 95%: 0,0 a 9277,0) a partir de los datos de estudios de cohortes y los datos de estudios con datos rutinarios de los historiales médicos, respectivamente. Este aumento del riesgo fue significativo en comparación con los hijos de mujeres sin epilepsia (RR 3,22; IC del 95%: 1,84 a 5,65) y los nacidos de mujeres con epilepsia que no reciben tratamiento (RR 1,64; IC del 95%: 0,94 a 2,83) en estudios de cohortes; los datos procedentes de estudios con datos rutinarios de los historiales médicos fueron limitados. En cuanto a la exposición a la fenitoína, la prevalencia de MCG fue elevada en los datos de los estudios de cohortes (5,4%; IC del 95%: 3,6 a 8,1) y en los datos rutinarios de los historiales médicos (6,8%; IC del 95%: 0,1 a 701,2). La prevalencia de MCG fue mayor en los niños expuestos a la fenitoína en comparación con los hijos de mujeres sin epilepsia (RR 3,81; IC del 95%: 1,91 a 7,57) y los hijos de mujeres con epilepsia que no reciben tratamiento (RR 2,01; IC del 95%: 1,29 a 3,12); no hubo datos procedentes de estudios con datos rutinarios de los historiales médicos. Los datos agrupados de los estudios de cohortes indicaron un riesgo significativamente mayor de MCG en los niños expuestos a lamotrigina en comparación con los niños nacidos de mujeres sin epilepsia (RR 1,99; IC del 95%: 1,16 a 3,39); con una diferencia de riesgos (DR) que indica un riesgo 1% mayor de MCG (DR 0,01. IC del 95%: 0,00 a 0,03). Esto no se repitió en la comparación con los hijos de las mujeres con epilepsia que no reciben tratamiento (RR 1,04; IC del 95%: 0,66 a 1,63), que contenía el mayor grupo de niños expuestos a la lamotrigina (> 2700). Además, también se encontró una diferencia no significativa tanto en comparación con los hijos de mujeres sin epilepsia (RR 1,19; IC del 95%: 0,86 a 1,64) como con los hijos de mujeres con epilepsia que no reciben tratamiento (RR 1,00; IC del 95%: 0,79 a 1,28) a partir de los estudios con datos rutinarios. Para la exposición al levetiracetam, los datos agrupados proporcionaron razones de riesgos similares a las de las mujeres sin epilepsia en los estudios de cohortes (RR 2,20; IC del 95%: 0,98 a 4,93) y en los estudios con datos rutinarios de los historiales médicos (RR 0,67; IC del 95%: 0,17 a 2,66). Los resultados agrupados de los estudios de cohortes (RR: 0,71; IC del 95%: 0,39 a 1,28) y de los estudios con datos rutinarios de los historiales médicos (RR: 0,82; IC del 95%: 0,39 a 1,71) respaldan esta afirmación cuando se comparan con los hijos de las mujeres con epilepsia que no reciben tratamiento. En el caso del topiramato, la prevalencia de MCG fue del 3,9% (IC del 95%: 2,3 a 6,5) a partir de los datos de los estudios de cohortes y del 4,1% (0,0 a 27.050,1) a partir de los estudios con datos rutinarios de los historiales médicos. Las razones de riesgos fueron significativamente más altas para los niños expuestos al topiramato en comparación con los hijos de mujeres sin epilepsia en estudios de cohortes (RR 4,07; IC del 95%: 1,64 a 10,14), pero no en una comparación más pequeña con los hijos de mujeres con epilepsia que no reciben tratamiento (RR 1,37; IC del 95%: 0,57 a 3,27); actualmente se dispone de pocos datos a partir de estudios con datos rutinarios de los historiales médicos. La exposición en el útero al topiramato también se asoció con RR significativamente mayores en comparación con otros FAC para las hendiduras orofaciales. Los datos de todos las demás FAC fueron extremadamente limitados. Debido a los diseños observacionales, todos los estudios presentaron un alto riesgo de ciertos sesgos, pero los sesgos observados en los estudios de obtención de datos primarios y el uso secundario de historiales médicos rutinarios fueron diferentes y, en parte, complementarios. Los sesgos estaban equilibrados entre los FAC investigados, y es poco probable que los resultados diferenciales observados entre los FAC se expliquen únicamente por estos sesgos. CONCLUSIONES DE LOS AUTORES: La exposición en el útero a ciertos FAC se asoció con un mayor riesgo de ciertos MCG que, para muchos, depende de la dosis.

Pregabalin add-on for drug-resistant partial epilepsy.

BACKGROUND: Epilepsy is a common chronic neurological disease with an estimated prevalence of 1% in the UK. Approximately one third of these people continue to have seizures despite drug treatment. In order to try to improve outcomes a number of new antiepileptic drugs have been developed and pregabalin is one of these. This review is an update of a previous Cochrane review (Pulman 2008); no further studies have been added since the previous update in 2012 and only one study has been identified as an ongoing trial. OBJECTIVES: To summarise evidence from randomised controlled trials regarding the efficacy and tolerability of pregabalin when used as an add-on antiepileptic treatment in drug-resistant partial epilepsy. The definitions of drug resistance used were those employed by the authors of the included trials. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (Jan 2014), CENTRAL (the Cochrane Central Register of Controlled Trials, The Cochrane Library 2013, Issue 12), MEDLINE (Ovid, 1946 to 09/01/2014) and contacted Pfizer Ltd. (the manufacturers of pregabalin) to identify published, unpublished and ongoing trials. SELECTION CRITERIA: We included randomised controlled trials comparing pregabalin with placebo or an alternative antiepileptic drug for people with drug-resistant partial epilepsy. Outcomes included 50% or greater reduction in seizure frequency, seizure freedom, treatment withdrawal for any reason, treatment withdrawal for adverse events and nature of adverse events. DATA COLLECTION AND ANALYSIS: Two review authors (JP and AGM) independently selected and assessed suitable trials and extracted data. Primary analyses were by intention-to-treat (ITT). Results are presented as risk ratios (RR) with 95% confidence intervals (CI). Included studies were assessed for risk of bias by two authors using the Cochrane 'Risk of bias' tool. MAIN RESULTS: Six suitable industry-sponsored trials (2009 participants) were identified and included in the analysis. Trials tested doses of pregabalin ranging from 50 mg/day to 600 mg/day. For the primary outcome, 50% or higher seizure reduction was significantly more likely in patients randomised to pregabalin than to placebo (RR 2.61; 95% CI 1.70 to 4.01). A dose-response analysis suggested increasing effect with increasing dose. Pregabalin was significantly associated with seizure freedom (RR 2.59; 95% CI 1.05 to 6.36). Patients were significantly more likely to have withdrawn from pregabalin treatment than placebo treatment for any reason (RR 1.39; 95% CI 1.13 to 1.72) or for adverse effects (RR 2.69; 95% CI 1.88 to 3.86). Ataxia, dizziness, somnolence and weight gain were significantly associated with pregabalin. The odds of response doubled with an increase in dose from 300 mg/day to 600 mg/day (OR 2.12; 95% CI 1.76 to 2.54). Overall, the evidence was rated as low/unclear risk of bias due to the possibility of publication bias. The quality of the evidence was rated as moderate using the GRADE approach. AUTHORS' CONCLUSIONS: Pregabalin, when used as an add-on drug for treatment-resistant partial epilepsy, is significantly more effective than placebo at achieving a 50% or greater seizure reduction and significantly increasing seizure freedom. Results demonstrate efficacy for doses from 150 mg/day to 600 mg/day, with increasing effectiveness at 600 mg doses. The trials included in this review were of short duration and longer-term trials are needed to inform clinical decision making better.

Psychological and behavioural treatments for adults with non-epileptic attack disorder.

BACKGROUND: Psychogenic non-epileptic seizures, also known as non-epileptic attack disorder (NEAD), have the outward appearance of epilepsy in the absence of physiological or electroencephalographic correlates. Non-epileptic seizures can occur in isolation or in combination with epileptic seizures. The development and maintenance of non-epileptic seizures has been well documented and there is a growing literature on the treatment of non-epileptic seizures which includes non-psychological (including anti-anxiety and antidepressant pharmacological treatment) and psychological therapies (including cognitive behavioural therapy (CBT), hypnotherapy and paradoxical therapy). Various treatment methodologies have been tried with variable success. The purpose of this Cochrane review was to establish the evidence base for the treatment of non-epileptic seizures with behavioural and psychological therapies only. OBJECTIVES: To assess whether behavioural or psychological treatments for non-epileptic seizures or NEAD result in a reduction in the frequency of seizures or improvement in quality of life, or both, and whether any treatment is significantly more effective than others. SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialised Register (4 February 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 1) (January 2013), MEDLINE (1946 to 4 February 2013), PsycINFO (4 February 2013) and SCOPUS (4 February 2013). No language restrictions were imposed. We checked the reference lists of retrieved studies for additional reports of relevant studies SELECTION CRITERIA: Randomised controlled trials (RCTs) and before and after controlled and non-controlled studies were eligible for inclusion. Studies were required to assess one or more types of behavioural or psychological interventions, or both, for the treatment of non-epileptic seizures. Studies of childhood non-epileptic seizures were excluded from our review. DATA COLLECTION AND ANALYSIS: Two review authors (JM, JP) independently assessed the trials for inclusion and extracted data. Outcomes included reduction in seizure frequency and improvements in quality of life. MAIN RESULTS: Twelve studies, with a total of 343 participants, met our inclusion criteria (four RCTs and eight before and after non-controlled studies). Of the four RCTs, one examined patients with non-epileptic seizures and three had a mixed diagnosis (pseudoseizures, conversion disorder and somatisation disorder). Most of the non-randomised studies used non-epileptic seizure patients exclusively. Overall, five studies examined the effectiveness of psychotherapy, three examined CBT, two investigated hypnosis, one assessed paradoxical intention and one had a mixed intervention design. We classified two included studies as low risk of bias, one as unclear and nine as high risk of bias. Meta-analysis could not be undertaken due to the heterogeneity of design and interventions. Most included studies reported improved outcomes for the intervention under investigation. One RCT investigating the effectiveness of CBT in this patient group found a significant reduction in seizure frequency compared to controls (P < 0.001). AUTHORS' CONCLUSIONS: There is little reliable evidence to support the use of any treatment, including CBT, in the treatment of non-epileptic seizures. Further randomised controlled trials of CBT and other interventions are needed.

Tiagabine add-on for drug-resistant partial epilepsy.

BACKGROUND: Epilepsy is a common neurological condition that affects almost 0.5% to 1% of the population. Nearly 30% of people with epilepsy are resistant to currently available drugs. Tiagabine is one of the newer antiepileptic drugs; its effects as an adjunct (add-on) to standard drugs are assessed in this review. OBJECTIVES: To evaluate the effects of add-on treatment with tiagabine on seizures, adverse effects, cognition and quality of life for people with drug-resistant localisation-related seizures. SEARCH METHODS: This is an updated version of the original Cochrane review published in 2012 (Issue 5). We searched the Cochrane Epilepsy Group Specialised Register (November 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, 2013, Issue 10) and MEDLINE (1946 to November 2013). No language restrictions were imposed. We also contacted the manufacturers of tiagabine and experts in the field to seek any ongoing or unpublished studies. SELECTION CRITERIA: Randomised placebo-controlled add-on trials of people of any age with localisation-related seizures in which an adequate method of concealment of randomisation was used were included. The studies could be double-blind, single-blind or unblinded and of parallel or cross-over design. They had to have a minimum treatment period of eight weeks. Trials using an active drug control group were also included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted data. Disagreements were resolved by discussion. Outcomes investigated included 50% or greater reduction in seizure frequency, treatment withdrawal, adverse effects, effects on cognition and quality of life. The primary analyses were performed by intention-to-treat. Worst-case and best-case analyses were calculated for seizure outcomes. Dose response was evaluated in regression models. Risk of bias in each study was assessed by two review authors using the Cochrane 'Risk of bias' tool. MAIN RESULTS: Four parallel-group and two cross-over group trials were included. The overall risk ratio (RR) with 95% confidence intervals (CIs) for a 50% or greater reduction in seizure frequency (tiagabine vs placebo) was 3.16 (95% CI 1.97 to 5.07). Because of differences in response rates among trials, regression models were unable to provide reliable estimates of response to individual doses. The RR for treatment withdrawal was 1.81 (95% CI 1.25 to 2.62). The 99% CIs for the adverse effects of dizziness, fatigue, nervousness and tremor did not include unity, indicating that they are significantly associated with tiagabine. For cognitive and quality of life outcomes, the limited available data suggested no significant effects on cognition and mood and adjustment. Two of the five studies were judged as having low risk of bias, three studies unclear risk of bias and one study high risk of bias. Overall study quality was rated as high using the GRADE approach. AUTHORS' CONCLUSIONS: Tiagabine reduces seizure frequency but is associated with some adverse effects when used as an add-on treatment for people with drug-resistant localisation-related seizures.

Topiramate add-on for drug-resistant partial epilepsy.

BACKGROUND: The majority of people with epilepsy have a good prognosis and their seizures are controlled by a single antiepileptic drug. However, up to 20% of patients from population-based studies and up to 30% from clinical series (not population-based) develop drug-resistant epilepsy, especially those with partial onset seizures. In this review we summarise the current evidence regarding topiramate, an antiepileptic drug first marketed in 1996, when used as an add-on treatment for drug-resistant partial epilepsy. This is an updated version of the original Cochrane review published in Issue 3, 1999. OBJECTIVES: To evaluate the efficacy and safety of topiramate when used as an add-on treatment for people with drug-resistant partial epilepsy. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (June 2013); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 5); MEDLINE (1946 to 2013); SCOPUS (1823 to 2013); ClinicalTrials.gov and ICTRP. We imposed no language restrictions. We also contacted the manufacturers of topiramate and researchers in the field to identify any ongoing or unpublished studies. SELECTION CRITERIA: Randomised, placebo-controlled or active drug controlled add-on trials of topiramate, recruiting people with drug-resistant partial epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: (a) 50% or greater reduction in seizure frequency; (b) seizure freedom; (c) treatment withdrawal (any reason); (d) side effects. Primary analyses were intention-to-treat and summary risk ratios (RR) with 95% confidence intervals (95% CI) are presented. We evaluated dose response in regression models. We carried out a 'Risk of bias' assessment for each included study using the Cochrane 'Risk of bias' tool and assessed the overall quality of evidence using the GRADE approach, which we presented in a 'Summary of findings' table. MAIN RESULTS: Eleven trials were included, representing 1401 randomised participants. Baseline phases ranged from 4 to 12 weeks and double-blind phases from 11 to 19 weeks. The RR for a 50% or greater reduction in seizure frequency compared to placebo was 2.97 (95% CI 2.38 to 3.72). Dose regression analysis shows increasing effect with increasing dose, but found no advantage for doses over 300 or 400 mg per day. The RR for seizure freedom (95% CI) compared to placebo was 3.41 (95% CI 1.37 to 8.51). The RR for treatment withdrawal compared to placebo was 2.44 (95% CI 1.64 to 3.62). The RRs for the following side effects indicate that they are significantly associated with topiramate: ataxia 2.29 (99% CI 1.10 to 4.77); concentration difficulties 7.81 (2.08 to 29.29); dizziness 1.54 (99% CI 1.07 to 2.22); fatigue 2.19 (99% CI 1.42 to 3.40); paraesthesia 3.91 (1.51 to 10.12); somnolence 2.29 (99% CI 1.49 to 3.51); 'thinking abnormally' 5.70 (99% CI 2.26 to 14.38) and weight loss 3.47 (1.55 to 7.79). Evidence of publication bias was found (P-value from the Egger test was P=0.003). We rated all studies included in the review as having either low or unclear risk of bias. Overall, we assessed the evidence as moderate quality due to the evidence of publication bias. AUTHORS' CONCLUSIONS: Topiramate has efficacy as an add-on treatment for drug-resistant partial epilepsy in that it is three times more effective compared to a placebo in reducing seizures. However, the trials reviewed were of relatively short duration and provide no evidence for the long-term efficacy of topiramate. In the short term topiramate as an add-on has been shown to be associated with several adverse events. The results of this review cannot be extrapolated to monotherapy or treatment of other epilepsy types and future research should consider examining the effect of dose.

Zonisamide add-on for drug-resistant partial epilepsy.

BACKGROUND: The majority of people with epilepsy have a good prognosis and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with partial seizures. In this review we summarise the current evidence regarding zonisamide, when used as an add-on treatment for drug-resistant partial epilepsy. OBJECTIVES: To evaluate the efficacy and tolerability of zonisamide when used as an add-on treatment for people with drug-resistant partial epilepsy. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (12 February 2013), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 1) (January 2013), MEDLINE (Ovid, 1946 to 12 February 2013), SCOPUS (13 February 2013), ClinicalTrials.gov (12 February 2013) and the WHO International Clinical Trials Registry Platform ICTRP (13 February 2013). In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field to seek any ongoing/unpublished studies. SELECTION CRITERIA: Randomised, placebo-controlled, add-on trials of zonisamide in people with drug-resistant partial epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted data. Outcomes were: (1) 50% or greater reduction in total seizure frequency; (2) treatment withdrawal; (3) adverse effects. Primary analyses were intention-to-treat. We estimated summary risk ratios (RRs) for each outcome. All studies were assessed for risk of bias using the Cochrane risk of bias tool and the quality of evidence was assessed using the GRADE approach and presented in a summary of findings table. MAIN RESULTS: Five trials (949 participants) were included. The overall RR with 95% confidence interval (CI) for 50% reduction in seizure frequency compared to placebo for 300 to 500 mg/day of zonisamide was 2.00 (95% CI 1.58 to 2.54). The RR for 50% reduction in seizure frequency compared to placebo for any dose of zonisamide (100 to 500 mg per day) was 1.92 (95% CI 1.52 to 2.42). The number needed to treat (NNT) was 6 for this outcome. Two trials provide evidence of a dose response relationship for this outcome. The RR for treatment withdrawal for 300 to 500 mg/day of zonisamide compared to placebo was 1.64 (95% CI 1.20 to 2.25) and for 100 to 500 mg per day was 1.47 (95% CI 1.07 to 2.01). NNT for this outcome was 21. The CIs of the following adverse effects indicate that they are significantly associated with zonisamide: ataxia 3.77 (99% CI 1.28 to 11.11); somnolence 1.83 (99% CI 1.08 to 3.11); agitation 2.35 (99% CI 1.05 to 5.27) and anorexia 2.71 (99% CI 1.29 to 5.69). Across the 5 studies, risk of bias domains were rated as low is bias or unclear. None of the evidence for outcomes was downgraded for quality. AUTHORS' CONCLUSIONS: Zonisamide has efficacy as an add-on treatment in people with drug-resistant partial epilepsy. In this review minimum effective and maximum tolerated doses cannot be identified. The trials reviewed were of a maximum stable-dose phase of 18 weeks in duration and results cannot be used to confirm longer periods of effectiveness in seizure control. The results cannot be extrapolated to monotherapy or to people with other seizure types or epilepsy syndromes.

Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic-clonic seizures.

BACKGROUND: This is an updated version of the previously published Cochrane review (Issue 4, 2009)Worldwide, phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset seizures, and that valproate is more effective for generalised onset tonic-clonic seizures with or without other generalised seizure types. OBJECTIVES: To review the best evidence comparing phenytoin and valproate when used as monotherapy in individuals with partial onset seizures or generalised onset tonic-clonic seizures with or without other generalised seizure types. SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialised Register (19 February 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, The Cochrane Library, January 2013), MEDLINE (1946 to 18 February 2013), SCOPUS (19 February 2013), ClinicalTrials.gov (19 February 2013), and WHO International Clinical Trials Registry Platform ICTRP (19 February 2013). We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field. SELECTION CRITERIA: Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of valproate monotherapy versus phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual patient data review. Outcomes were time to (a) treatment withdrawal (b) 12-month remission (c) six-month remission and (d) first seizure post randomisation. Cox proportional hazards regression models were used to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) with the generic inverse variance method used to obtain the overall pooled HR and 95% CI. MAIN RESULTS: Individual patient data were available for 669 individuals out of 1119 eligible individuals from five out of 11 trials, 60% of the potential data. Results apply to generalised tonic-clonic seizures, but not absence or myoclonus seizure types. For remission outcomes, HR > 1 indicates an advantage for phenytoin and for first seizure and withdrawal outcomes HR > 1 indicates an advantage for valproateThe main overall results (pooled HR adjusted for seizure type, 95% CI) were time to (a) withdrawal of allocated treatment 1.09 (0.76 to 1.55); (b) 12-month remission 0.98 (0.78 to 1.23); (c) six-month remission 0.95 (0.78 to 1.15) and (d) first seizure 0.93 (0.75 to 1.14). The results suggest no overall difference between the drugs for these outcomes. No statistical interaction between treatment and seizure type (partial versus generalised) was found, but misclassification of seizure type may have confounded the results of this review. AUTHORS' CONCLUSIONS: We have not found evidence that a significant difference exists between phenytoin and valproate for the outcomes examined in this review. However misclassification of seizure type may have confounded the results of this review. Results do not apply to absence or myoclonus seizure types. No outright evidence was found to support or refute current treatment policies.

Gabapentin add-on for drug-resistant partial epilepsy.

BACKGROUND: The majority of people with epilepsy have a good prognosis and their seizures are well controlled by a single antiepileptic drug, but up to 30% develop drug-resistant epilepsy, especially those with partial seizures. In this review we summarise the current evidence regarding the antiepileptic drug gabapentin, when used as an add-on treatment for drug-resistant partial epilepsy. OBJECTIVES: To evaluate the efficacy and tolerability of gabapentin when used as an add-on treatment for people with drug-resistant partial epilepsy. SEARCH METHODS: This is an updated version of the original Cochrane review published in The Cochrane Library 2009, Issue 4. We searched the Cochrane Epilepsy Group's Specialised Register (14 May 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 4, The Cochrane Library) (April 2013) and MEDLINE (1946 to 14 May 2013). We imposed no language restrictions. SELECTION CRITERIA: Randomised, placebo-controlled, double-blind, add-on trials of gabapentin in people with drug-resistant partial epilepsy. Trials using an active drug control group or which compared doses of gabapentin were also included in the review. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: (a) seizure frequency and seizure freedom; (b) treatment withdrawal (any reason); (c) adverse effects. Primary analyses were intention-to-treat. We also undertook sensitivity best and worst-case analyses. We estimated summary risk ratios for each outcome and evaluated dose-response in regression models. MAIN RESULTS: Eleven trials were included representing 2125 randomised participants. We combined data from six trials in meta-analyses of 1206 randomised participants. The overall risk ratio (RR) for 50% or greater reduction in seizure frequency compared to placebo was 1.89 (95% confidence interval (CI) 1.40 to 2.55). Dose regression analysis (for trials in adults) shows increasing efficacy with increasing dose, with 25.3% (19.3 to 32.3) of people responding to 1800 mg of gabapentin compared to 9.7% on placebo, a 15.5% increase in response rate (8.5 to 22.5). The RR for treatment withdrawal compared to placebo was 1.05 (95% CI 0.74 to 1.49). Adverse effects were significantly associated with gabapentin compared to placebo. Risk ratios were as follows: ataxia 2.01 (99% CI 0.98 to 4.11), dizziness 2.43 (99% CI 1.44 to 4.12), fatigue 1.95 (99% CI 0.99 to 3.82) and somnolence 1.93 (99% CI 1.22 to 3.06). No significant differences were found for the adverse effects of headache (RR 0.79, 99% CI 0.46 to 1.35) or nausea (RR 0.95, 99% CI 0.52 to 1.73). Overall the studies together are rated as low/unclear risk of bias due to information on each risk of bias domain not being available. AUTHORS' CONCLUSIONS: Gabapentin has efficacy as an add-on treatment in people with drug-resistant partial epilepsy. However, the trials reviewed were of relatively short duration and provide no evidence for the long-term efficacy of gabapentin beyond a three-month period. The results cannot be extrapolated to monotherapy or to people with other epilepsy types.

A meta-analysis evaluating the effectiveness of two different upper limb hemiparesis interventions on improving health-related quality of life following stroke.

PURPOSE: The aim of this article is to quantitatively assess the efficacy of different upper limb interventions on health-related quality of life (QOL) in stroke patients. METHOD: Two botulinum type A injection (BTX-A) studies and 4 constraint-induced movement therapy (CIMT) studies were separately combined in a meta-analysis using a fixed effects model. QOL mean scores were extracted and transformed into weighted mean differences. RESULTS: Combined, the BTX-A studies showed no significant improvements in overall health-related QOL. Similarly, a meta-analysis of 4 CIMT studies revealed nonsignificant findings for the domains of activities of daily living, communication, and hand function. A separate meta-analysis of 3 CIMT studies showed a significant increase in strength scores (P = .007); however, sensitivity analysis for this domain due to significant heterogeneity led to a newP value of .078, showing a nonsignificant increase in strength. Further results for memory, mobility, mood, participation, and overall recovery were all nonsignificant. CONCLUSION: This report did not show these types of upper limb interventions to be effective in improving health-related QOL in the poststroke population.

Assessing the efficacy of different upper limb hemiparesis interventions on improving health-related quality of life in stroke patients: a systematic review.

BACKGROUND: This review aims to assess the efficacy of upper limb interventions on stroke survivors' health-related quality of life (QOL). METHOD: Published studies were identified following a systematic search of the literature from 10 electronic databases, 3 subject-relevant journals, a Web search via a popular search engine, and reference lists of the included articles. In total, 22 articles met the inclusion criteria and were subjected to data extraction to establish the effectiveness of the intervention on QOL scores. Interventions varied according to their content, including acupuncture treatment, botulinum toxin type A (BTX-A) injections, constraint-induced movement therapy (CIMT), task training, and therapeutic exercise. Studies were required to have at least 1 quantitative outcome QOL measure. RESULTS: Of the 22 studies, 12 reported significant findings within groups and between control groups. Interventions including BTX-A injections, CIMT, exercise programs, baclofen pump, robotic-assisted therapy, electrical stimulation, and acupuncture were reported to significantly improve either overall health-related QOL or certain individual QOL domains, such as strength, hand function, memory, mood, activities of daily living, mobility, social participation, communication, energy, pain, and sleep. CONCLUSION: The review demonstrates the need for upper limb intervention studies to focus on QOL as a primary outcome measure in addition to the functional outcomes currently used.

Calcium antagonists as an add-on therapy for drug-resistant epilepsy.

BACKGROUND: This is an updated version of the original Cochrane review published in The Cochrane Library 2001, Issue 4.Nearly a third of people with epilepsy do not have their seizures controlled with current treatments. Continuous attempts have been made to find new antiepileptic drugs based on increasing knowledge of the cellular and molecular biology involved in the genesis of epilepsy and seizures. Therefore, calcium antagonists that can alter the effects of calcium on brain cells have been investigated for their effect on epileptic seizures. OBJECTIVES: To evaluate the effects of calcium antagonists when used as an add-on therapy for people with drug-resistant epilepsy. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (29 January 2013), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 12), MEDLINE (1948 to 29 January 2013) and SCOPUS (all years to 29 January 2013). SELECTION CRITERIA: Randomised placebo-controlled or active-controlled add-on trials of any calcium antagonist in people with drug-resistant epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors (MH and JP) independently selected trials for inclusion and extracted data. Outcomes investigated included 50% or greater reduction in seizure frequency, treatment withdrawal, adverse effects, cognition and quality of life. Analyses were by intention to treat. MAIN RESULTS: Eleven trials were included with a total of 424 participants, one parallel-group and seven cross-over trials of flunarizine, two cross-over trials of nimodipine and one cross-over trial of nifedipine.For flunarizine, the risk ratio (RR) with 95% confidence interval (CI) for a 50% or greater reduction in seizure frequency in a single parallel trial was 1.53 (95% CI 0.59 to 3.96) indicating a non-significant advantage of flunarizine. We were unable to acquire data for this outcome from the other seven cross-over trials. The overall RR for treatment withdrawal of flunarizine was 7.11 (95% CI 1.73 to 29.30) indicating individuals were significantly more likely to have flunarizine withdrawn than placebo. No adverse effects were associated statistically with flunarizine.For nifedipine, we were unable to acquire the data we required for our specified outcomes.For nimodipine, we had data only from the first treatment period from one of the two cross-over trials (17 participants). The RR for a 50% or greater reduction in seizure frequency was 7.78 (99% CI 0.46 to 130.88) and for treatment withdrawal the RR was 2.25 (99% CI 0.25 to 20.38). AUTHORS' CONCLUSIONS: Flunarizine may have a weak effect on seizure frequency but had a significant withdrawal rate, probably due to adverse effects, and should not be recommended for use as an add-on treatment. Similarly, there is no convincing evidence to support the use of nifedipine or nimodipine as add-on treatments for epilepsy.

Antiepileptic drugs as prophylaxis for post-craniotomy seizures.

BACKGROUND: The incidence of seizures following supratentorial craniotomy for non-traumatic pathology has been estimated to be 15% to 20%; however, the risk of experiencing a seizure may vary from 3% to 92% over a five-year period. Postoperative seizures can precipitate the development of epilepsy; seizures are most likely to occur within the first month of cranial surgery. The use of antiepileptic drugs (AEDs) administered pre- or postoperatively to prevent seizures following cranial surgery has been investigated in a number of randomised controlled trials. OBJECTIVES: To determine the efficacy and safety of AEDs when used prophylactically in people undergoing craniotomy and to examine which AEDs are most effective. SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialized Register (September 2012), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 9, 2012), and MEDLINE (1946 to September 2012). No language restrictions were imposed. SELECTION CRITERIA: Randomised controlled trials of people with no history of epilepsy who were undergoing craniotomy for either therapeutic or diagnostic reasons were included. Trials with adequate randomisation methods and concealment were included; these could either be blinded or unblinded parallel trials. No minimum treatment period was stipulated, trials using active drugs or placebo as a control group were included. DATA COLLECTION AND ANALYSIS: Two review authors (JP and JG) independently selected trials for inclusion and carried out data extraction and risk of bias assessments. Any disagreements were resolved through discussion. Outcomes investigated included the number of patients experiencing seizures (early - occurring within first week following craniotomy and late - occurring after first week following craniotomy), the number of deaths and the number of people experiencing disability and adverse effects. Due to the heterogeneous nature of the trials, data from the trials were not combined in a meta-analysis; the findings of the review are presented in narrative format. MAIN RESULTS: Six RCTs (N = 1398) were eligible for inclusion within the review with publication dates ranging between 1983 and 1999. Two trials compared a single AED (phenytoin) with a placebo. One three-arm trial compared two AEDs (carbamazepine, phenytoin) with no treatment. A second three-arm trial compared phenytoin, phenobarbital and no treatment. Two other trials were head-to-head trials of AEDs (phenytoin vs. valproate and zonisamide vs. phenobarbital). Of the four trials comparing AEDs with controls only one trial reported a significant difference between AED treatment and controls for early seizure occurrence. All other comparisons were non-significant. Of the head-to-head trials, none reported statistically significant differences between treatments for either early or late seizures. One head-to-head trial showed an increase in the number of deaths following one AED treatment compared to another AED treatment. Incidences of adverse effects of treatment were poorly reported, no significant differences between treatment groups were found due to the limited number of reported occurrences. AUTHORS' CONCLUSIONS: There is little evidence to suggest that AED treatment administered prophylactically is effective or not effective in preventing post-craniotomy seizures. The current evidence base is limited due to the differing methodologies employed in the trials and inconsistencies in reporting of outcomes. Further evidence from good-quality, contemporary trials is required in order to assess the effectiveness of prophylactic AED treatment compared to control groups or other AEDs in preventing post-craniotomy seizures properly.

Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalised onset tonic-clonic seizures.

BACKGROUND: This is an updated version of the original Cochrane review published in The Cochrane Library 2001, Issue 4.Worldwide, particularly in the developing world, phenytoin and phenobarbitone are commonly used antiepileptic drugs, primarily because they are inexpensive. The aim of this review is to summarise data from existing trials comparing phenytoin and phenobarbitone. OBJECTIVES: To review the best evidence comparing phenobarbitone and phenytoin when used as monotherapy in participants with partial onset seizures or generalised tonic-clonic seizures with or without other generalised seizure types. SEARCH METHODS: We searched the Cochrane Epilepsy Group trials register (31 May 2012), the Cochrane Central Register of Controlled Trials (CENTRAL Issue 5 of 12, The Cochrane Library 2012) and MEDLINE (1946 to May week 4, 2012). We hand-searched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field.   SELECTION CRITERIA: Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of phenobarbitone monotherapy with phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Outcomes were time to (a) treatment withdrawal (b) 12-month remission (c) six-month remission and (d) first seizure post randomisation. Cox proportional hazards regression models were used to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) with the generic inverse variance method used to obtain the overall pooled estimate of HRs and 95% CIs. MAIN RESULTS: Data have been obtained for four of eight studies meeting the inclusion criteria, amounting to 599 individuals, or approximately 63% of the potential data.The main overall results (pooled HR, 95% CI) were (a) time to treatment withdrawal 1.62 (1.23 to 2.14); (b) time to 12-month remission 0.90 (0.69 to 1.18) (c) time to six-month remission 0.92 (0.73 to 1.16) and (d) time to first seizure 0.85 (0.68 to 1.05). These results indicate a statistically significant clinical advantage for phenytoin in terms of treatment withdrawal. However, this result may have been confounded by several factors including substantial statistical heterogeneity between studies and lack of blinding in two studies. AUTHORS' CONCLUSIONS: The results of this review show that phenobarbitone was significantly more likely to be withdrawn than phenytoin. Given that no significant differences for seizure outcomes were found, the higher withdrawal rate with phenobarbitone may be due to adverse effects. Several factors may have confounded the results of this review.  

Tiagabine add-on for drug-resistant partial epilepsy.

BACKGROUND: Epilepsy is a common neurological condition, affecting almost 0.5 to 1% of the population. Nearly 30% of people with epilepsy are resistant to currently available drugs. Tiagabine is one of the newer antiepileptic drugs and its effects as an adjunct (add-on) to standard drugs are assessed in this review. OBJECTIVES: To evaluate the effects of add-on treatment with tiagabine upon seizures, adverse effects, cognition and quality of life for people with drug-resistant localisation related seizures. SEARCH METHODS: This is an updated version of the original Cochrane review published in issue 10, 2010. We searched the Cochrane Epilepsy Group's Specialised Register (December 2011), the Cochrane Central Register of Controlled Trials (CENTRAL, issue 4, 2011 of The Cochrane Library), and MEDLINE (1948 to November 2011). No language restrictions were imposed. We also contacted the manufacturers of tiagabine and experts in the field to seek any ongoing or unpublished studies. SELECTION CRITERIA: Randomised placebo controlled add-on trials of people of any age with localisation related seizures, in which an adequate method of concealment of randomisation was used were included. The studies could be double, single or unblinded and be of parallel or crossover design. They had to have a minimum treatment period of eight weeks. Trials using an active drug control group were also included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted data. Any disagreements were resolved by discussion. Outcomes investigated included 50% or greater reduction in seizure frequency; treatment withdrawal; adverse effects; effects on cognition and quality of life. The primary analyses were by intention-to-treat. Worst case and best case analyses were also calculated for seizure outcomes. Dose response was evaluated in regression models. MAIN RESULTS: Four parallel group and two crossover group trials were included. The overall relative risk (RR) with 95% confidence intervals (CIs) for a 50% or greater reduction in seizure frequency (tiagabine versus placebo) was 3.16 (95% CI 1.97 to 5.07). Due to differences in response rates among trials, regression models were unable to provide reliable estimates of responses to individual doses. The RR for treatment withdrawal was 1.81 (95% CI 1.25 to 2.62). The 99% CIs for the following adverse effects: dizziness; fatigue; nervousness and tremor did not include unity, indicating that they are significantly associated with tiagabine. For cognitive and quality of life outcomes the limited data available suggested that there were no significant effects on cognition and mood and adjustment. AUTHORS' CONCLUSIONS: Tiagabine reduces seizure frequency but is associated with some adverse effects when used as an add-on for people with drug-resistant localisation-related seizures.