***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: The Fifth Commission on Antiepileptic Drugs of the International League Against Epilepsy was asked to advise the ILAE Executive on the place of new drugs in the treatment of patients with newly diagnosed or chronic epilepsy . With the licensing of a significant number of new antiepileptic drugs ( AEDs ) in the last 5 - 10 years , there is an obvious need for these new treatments to be introduced efficiently and effectively to benefit the care and management of people with epilepsy . Implicit in this will be a determination of the comparative efficacy , tolerability , and overall effectiveness against st and ard ( existing ) AEDs and against other new drugs . Although many of the issues relating to comparative studies were addressed in Guidelines for the Clinical Evaluation of Antiepileptic Drugs , produced by the Fourth Commission , several complex ethical and method ological problems remain that would benefit from further discussion aim ed at the establishment of some form of consensus . Although determination of the relative risks of rare but potentially serious idiosyncratic adverse reactions and teratogenicity can be determined only by adequate postmarketing surveillance , other issues concerning the efficacy , tolerability , and effectiveness of new drugs can best be determined within the context of well- design ed r and omized ( or otherwise controlled ) clinical trials ( RCTs ) . It is the design , structure , and outcomes of such comparative RCTs that dem and further consideration . Many of the difficulties arise because the most meaningful and satisfactory comparative studies will essentially be those that compare monotherapy with a new agent with monotherapy with alternative agents . The Commission recognizes that several different parties have interests in comparative studies . First and foremost patients and their doctors require adequate information to guide daily practice in an “ evidence -based ” way so that patients can make fully informed decisions about their drug treatment . Individual pharmaceutical manufacturers need to know how their drug compares with other products so that a drug can be appropriately positioned in the market . Licensing authorities have traditionally ignored issues of comparative Background The choice of antiepileptic drug for an individual should be based upon the highest quality evidence regarding potential benefits and harms of the available treatments . Systematic review s and meta- analysis of r and omised controlled trials should be a major source of evidence supporting this decision making process . We summarise all available individual patient data evidence from r and omised controlled trials that compared at least two out of eight antiepileptic drugs given as monotherapy . Methods Multiple treatment comparisons from epilepsy monotherapy trials were synthesized in a single stratified Cox regression model adjusted for treatment by epilepsy type interactions and making use of direct and indirect evidence . Primary outcomes were time to treatment failure and time to 12 month remission from seizures . A secondary outcome was time to first seizure . Results Individual patient data for 6418 patients from 20 r and omised trials comparing eight antiepileptic drugs were synthesized . For partial onset seizures ( 4628 ( 72 % ) patients ) , lamotrigine , carbamazepine and oxcarbazepine provide the best combination of seizure control and treatment failure .  Lamotrigine is clinical ly superior to all other drugs for treatment failure but estimates suggest a disadvantage compared to carbamazepine for time to 12 month remission [ Hazard Ratio ( 95 % Confidence Interval ) = 0.87(0.73 to 1.04 ) ] and time to first seizure [ 1.29(1.13 to 1.48 ) ] . Phenobarbitone may delay time to first seizure [ 0.77(0.61 to 0.96 ) ] but at the expense of increased treatment failure [ 1.60(1.22 to 2.10 ) ] . For generalized onset tonic clonic seizures ( 1790 ( 28 % ) patients ) estimates suggest valproate or phenytoin may provide the best combination of seizure control and treatment failure but some uncertainty remains about the relative effectiveness of other drugs . Conclusion For patients with partial onset seizures , results favour carbamazepine , oxcarbazepine and lamotrigine . For generalized onset tonic clonic seizures , results favour valproate and phenytoin Objective To examine the prevalence of outcome reporting bias — the selection for publication of a subset of the original recorded outcome variables on the basis of the results — and its impact on Cochrane review s. Design A nine point classification system for missing outcome data in r and omised trials was developed and applied to the trials assessed in a large , unselected cohort of Cochrane systematic review s. Research ers who conducted the trials were contacted and the reason sought for the non-reporting of data . A sensitivity analysis was undertaken to assess the impact of outcome reporting bias on review s that included a single meta- analysis of the review primary outcome . Results More than half ( 157/283 ( 55 % ) ) the review s did not include full data for the review primary outcome of interest from all eligible trials . The median amount of review outcome data missing for any reason was 10 % , whereas 50 % or more of the potential data were missing in 70 ( 25 % ) review s. It was clear from the publications for 155 ( 6 % ) of the 2486 assessable trials that the research ers had measured and analysed the review primary outcome but did not report or only partially reported the results . For reports that did not mention the review primary outcome , our classification regarding the presence of outcome reporting bias was shown to have a sensitivity of 88 % ( 95 % CI 65 % to 100 % ) and specificity of 80 % ( 95 % CI 69 % to 90 % ) on the basis of responses from 62 trialists . A third of Cochrane review s ( 96/283 ( 34 % ) ) contained at least one trial with high suspicion of outcome reporting bias for the review primary outcome . In a sensitivity analysis undertaken for 81 review s with a single meta- analysis of the primary outcome of interest , the treatment effect estimate was reduced by 20 % or more in 19 ( 23 % ) . Of the 42 meta-analyses with a statistically significant result only , eight ( 19 % ) became non-significant after adjustment for outcome reporting bias and 11 ( 26 % ) would have overestimated the treatment effect by 20 % or more . Conclusions Outcome reporting bias is an under-recognised problem that affects the conclusions in a substantial proportion of Cochrane review s. Individuals conducting systematic review s need to address explicitly the issue of missing outcome data for their review to be considered a reliable source of evidence . Extra care is required during data extraction , review ers should identify when a trial reports that an outcome was measured but no results were reported or events observed , and contact with trialists should be encouraged BACKGROUND The use of phenobarbital for childhood epilepsy is controversial because of reported behavioural side-effects ; however , whether this research can validly be extrapolated to developing countries is not clear . We undertook a r and omised comparison of phenobarbital and phenytoin to assess the acceptability and efficacy of phenobarbital as monotherapy for childhood epilepsy in rural India . METHODS Between August , 1995 , and February , 1996 , 109 unselected children aged 2 - 18 years with partial and generalised tonic-clonic epilepsy were identified by population screening . 15 families declined to take part . 94 children were r and omly allocated treatment with phenobarbital ( 1.5 mg/kg daily for 2 weeks ; maintenance dose 3.0 mg/kg daily ; n = 47 ) or phenytoin ( 2.5 mg/kg daily then 5.0 mg/kg daily ; n = 47 ) . Children were followed up for 12 months . The primary outcome measure was the frequency of behavioural side-effects ; behaviour was assessed by the Conners parent rating scale for children aged 6 years and older , and by the preschool behaviour screening question naire ( BSQ ) for those aged 2 - 5 years , at 12 months or at withdrawal from treatment . Analysis was by intention to treat . FINDINGS The mean log-transformed scores on the behaviour rating scales did not differ significantly between the phenobarbital and phenytoin groups ( Conners 2.64 [ SD 0.71 ] vs 2.65 [ 0.89 ] , p = 0.97 ; n = 32 in each group : BSQ 2.12 [ 1.31 ] vs 2.18 [ 1.02 ] , p = 0.94 ; n = 4 vs 3 ) . The odds ratio for behavioural problems  ( phenobarbital vs phenytoin ) was 0.51 ( 95 % CI 0.16 - 1.59 ) . There was no excess in parental reports of side-effects for phenobarbital . We found no difference in efficacy between the study drugs ( adjusted hazard ratio for time to first seizure from r and omisation 0.97 [ 0.28 - 3.30 ] ) . INTERPRETATION This evidence supports the acceptability of phenobarbital as a first-line drug for childhood epilepsy in rural setting s in developing countries PRIMIDONE ( Mysoline ) has been shown to be an effective anticonvulsant drug . 1 - 6 It has been stated that primidone is exceptionally valuable in the control of focal seizures and the " drug of choice " for the treatment of psychomotor seizures . 7 - 9 Previous clinical comparative studies have not contradicted this cl aim . 4,5 One study found that phenobarbital and primidone were equally effective as anticonvulsants with 50 mg of phenobarbital being equivalent to 250 mg of primidone . Another similar study 5 revealed that primidone and phenobarbital are about equally effective as anticonvulsants but more effective than  diphenylhydantoin ( Dilantin ) .  However , as the authors of that study point out , the five day medication trial was not sufficient for maximal anticonvulsant effect of diphenylhydantoin  to occur . Their data revealed a sharp increase in effectiveness of diphenylhydantoin  on the fifth treatment day , while primidone and phenobarbital were relatively more effective on the first and second days . Recent studies have shown that most newly diagnosed epileptic patients can be satisfactorily treated with a single antiepileptic drug . We therefore undertook a prospect i ve r and omised pragmatic trial of the comparative efficacy and toxicity of four major antiepileptic drugs , utilised as monotherapy in newly diagnosed epileptic patients . Between 1981 and 1987 243 adult patients aged 16 years or over , newly referred to two district general hospitals with a minimum of two previously untreated tonic-clonic or partial with or without secondary generalised seizures were r and omly allocated to treatment with phenobarbitone , phenytoin , carbamazepine , or sodium valproate . The protocol was design ed to conform with st and ard clinical practice . Efficacy was assessed by time to first seizure after the start of treatment and time to enter one year remission . The overall outcome with all of the four drugs was good with 27 % remaining seizure free and 75 % entering one year of remission by three years of follow up . No significant differences between the four drugs were found for either measure of efficacy at one , two , or three years of follow up . The overall incidence of unacceptable side effects , necessitating withdrawal of the r and omised drug , was 10 % . For the individual drugs phenobarbitone ( 22 % ) was more likely to be withdrawn than phenytoin ( 3 % ) , carbamazepine ( 11 % ) , and sodium valproate ( 5 % ) . In patients with newly diagnosed tonic-clonic or partial with or without secondary generalised seizures , the choice of drug will be more influenced by considerations of toxicity and costs Objective : To assess the relative risk of major congenital malformation ( MCM ) from in utero exposure to antiepileptic drug ( AEDs ) . Methods : Prospect i ve data collected by the UK Epilepsy and Pregnancy Register were analysed . The presence of MCMs recorded within the first three months of life was the main outcome measure . Results : Full outcome data were collected on 3607 cases . The overall MCM rate for all AED exposed cases was 4.2 % ( 95 % confidence interval ( CI ) , 3.6 % to 5.0 % ) . The MCM rate was higher for polytherapy ( 6.0 % ) ( n = 770 ) than for monotherapy ( 3.7 % ) ( n = 2598 ) ( crude odds ratio ( OR ) = 1.63 ( p = 0.010 ) , adjusted OR = 1.83 ( p = 0.002 ) ) . The MCM rate for women with epilepsy who had not taken AEDs during pregnancy ( n = 239 ) was 3.5 % ( 1.8 % to 6.8 % ) . The MCM rate was greater for pregnancies exposed only to valproate ( 6.2 % ( 95 % CI , 4.6 % to 8.2 % ) than only to carbamazepine ( 2.2 % ( 1.4 % to 3.4 % ) ( OR = 2.78 ( p<0.001 ) ; adjusted OR = 2.97 ( p<0.001 ) ) . There were fewer MCMs for pregnancies exposed only to lamotrigine than only to valproate . A positive dose response for MCMs was found for lamotrigine ( p = 0.006 ) . Polytherapy combinations containing valproate carried a higher risk of MCM than combinations not containing valproate ( OR = 2.49 ( 1.31 to 4.70 ) ) . Conclusions : Only 4.2 % of live births to women with epilepsy had an MCM . The MCM rate for polytherapy exposure was greater than for monotherapy exposure . Polyther 
    Output:
    
Several confounding factors , most notably the differences in design of the trials with respect to blinding , were likely to have impacted on the results of the primary outcome ' time to treatment failure ' , and in turn , the treatment failure rates may have impacted on the secondary efficacy outcomes of time to first seizure and time to 12-month and six-month remission .
AUTHORS ' CONCLUSIONS Low-certainty evidence from this review suggests that phenytoin may be a more effective drug than phenobarbitone in terms of treatment retention ( treatment failures due to lack of efficacy or adverse events or both ) .
Moderate-certainty evidence from this review also indicates no differences between the drugs in terms of time to seizure recurrence and seizure remission .