title: The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial Comparison of antiepileptic drugs on cognitive function in newly diagnosed epileptic children: a psychometric and neurophysiological study. Side effects of phenobarbital in toddlers; behavioral and cognitive aspects. Randomised controlled trial to assess acceptability of phenobarbital for childhood epilepsy in rural India A Randomized, Double-Blind, Crossover Study of Phenobarbital and Mephobarbital Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Antiepileptic drug treatment in a community health care setting in northern Ecuador: a prospective 12-month assessment Does phenobarbital used for febrile seizures cause sleep disturbances? The first febrile seizure--antipyretic instruction plus either phenobarbital or placebo to prevent recurrence. The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus. Carbamazepine versus phenobarbital for partial onset seizures in children. Prophylactic diazepam or phenobarbitone in febrile convulsions: a prospective, controlled study. Prevention of recurrent febrile convulsions--a randomized therapeutic assay: sodium valproate, phenobarbital and placebo. Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study CYP2C19 polymorphism effect on phenobarbitone. Pharmacokinetics in Japanese patients with epilepsy: analysis by population pharmacokinetics. The value of phenobarbital in the child who has had a single febrile seizure: a controlled prospective study. Long-term effect of phenobarbital on cognitive function in children with febrile convulsions. Analysis of clinical trials by treatment actually received: is it really an option? Phenobarbital for febrile seizures--effects on intelligence and on seizure recurrence. Psychologic and behavioral effects of antiepileptic drugs in children: a double-blind comparison between phenobarbital and valproic acid. PLACEBO-CONTROLLED STUDY OF PHENOBARBITONE AND PHENYTOIN IN THE PROPHYLAXIS OF FEBRILE CONVULSIONS Failure of phenobarbitone to prevent febrile convulsions Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy Comprehensive primary health care antiepileptic drug treatment programme in rural and semi-urban Kenya Phenobarbital compared with carbamazepine in prevention of recurrent febrile convulsions. A double-blind study. INTENTION TO TREAT FEBRILE CONVULSIONS WITH RECTAL DIAZEPAM, VALPROATE OR PHENOBARBITONE A CONTROLLED STUDY OF PROFYLACTIC LONG‐TERM TREATMENT OF FEBRILE CONVULSIONS WITH PHENOBARBITAL
abstract: BACKGROUND Infantile spasms , which comprise a severe infantile seizure disorder , have a high morbidity and are difficult to treat . Hormonal treatments ( adrenocorticotropic hormone and prednisolone ) have been the main therapy for decades , although little evidence supports their use . Vigabatrin has been recorded to have a beneficial effect in this disorder . We aim ed to compare the effects of vigabatrin with those of prednisolone and tetracosactide in the treatment of infantile spasms . METHODS The United Kingdom Infantile Spasms Study assessed these treatments in a multicentre , r and omised controlled trial in 150 hospitals in the UK . The primary outcome was cessation of spasms on days 13 and 14 . Minimum doses were vigabatrin 100 mg/kg per day , oral prednisolone 40 mg per day , or intramuscular tetracosactide depot 0.5 mg ( 40 IU ) on alternate days . Analysis was by intention to treat . FINDINGS Of 208 infants screened and assessed , 107 were r and omly assigned to vigabatrin ( n=52 ) or hormonal treatments ( prednisolone n=30 , tetracosactide n=25 ) . None was lost to follow-up . Proportions with no spasms on days 13 and 14 were : 40 ( 73 % ) of 55 infants assigned hormonal treatments ( prednisolone 21/30 [ 70 % ] , tetracosactide 19/25 [ 76 % ] ) and 28 ( 54 % ) of 52 infants assigned vigabatrin ( difference 19 % , 95 % CI 1%-36 % , p=0.043 ) . Two infants allocated tetracosactide and one allocated vigabatrin received prednisolone .  Adverse events were reported in 30 ( 55 % ) of 55 infants on hormonal treatments and 28 ( 54 % ) of 52 infants on vigabatrin . No deaths were recorded . INTERPRETATION Cessation of spasms was more likely in infants given hormonal treatments than those given vigabatrin .  Adverse events were common with both treatments Using a r and omized parallel group study design , we compared the cognit i ve effects of carbamazepine ( CBZ ) , phenobarbital ( PB ) , and valproate ( VPA ) in children with epilepsy . Seventy-three children with newly diagnosed epilepsy were tested with the Wechsler Intelligence Scale for Children-Revised ( WISC-R ) , Bender-Gestalt test , and auditory event-related potentials ( P 300 ) before and 6 and 12 months after antiepileptic drug ( AED ) treatment . There were no significant differences in WISC-R IQs and Bender-Gestalt scores for children in any group at any of the three sessions . P 300 latencies were increased in the children receiving PB but not in children receiving CBZ and VPA . P 300 amplitudes were significantly reduced in treated children in all three groups , but amplitudes were not significantly different among the three groups . These findings suggest that PB may affect cognitive function of epileptic children and that the P 300 may be a sensitive additional procedure that can be used to assess the cognitive effect of AEDs Cognitive and behavioral effects of phenobarbital in toddlers were assessed in a r and omized , placebo-controlled study of patients who had had a febrile seizure . There were no significant differences in IQ ( Binet or Bayley Scales ) between placebo and phenobarbital groups after eight to 12 months of therapy . However , detrimental effects of phenobarbital were found in memory , for which serum level influenced scores , and in comprehension , in that length of treatment time affected performance . Hyperactivity was not seen . Behavioral changes , reported by parents , were increased fussiness and a characteristic disturbance of sleep . These changes varied in severity and were classified as transient , dose related , or unacceptable . After 12 months in the study , most parents could not distinguish between phenobarbital and placebo . Our data suggest that although most toddlers do not have major side effects from phenobarbital therapy when treated for a year , serum levels and length of time on phenobarbital should be kept at a minimum to reduce negative cognitive and behavioral effects 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 Some pediatric neurologists maintain that mephobarbital ( Mebaral ) causes fewer behavioral side effects than phenobarbital . Because this hypothesis has not been previously tested , we conducted a prospect i ve , double-blind , r and omized , crossover study of these two anticonvulsants . Both drugs were equally effective in reducing the frequency of seizure , although serum phenobarbital levels were significantly higher when the patients were taking phenobarbital compared to mephobarbital . As measured by the Abbott Parent Question naire , there was no significant deterioration of behavior with either phenobarbital or mephobarbital , regardless of which drug was administered first . J Child Neurol 1986;1:361 - 363 Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs ( AEDs ) . As with many AEDs , a broad range of doses is used , with the final " maintenance " dose normally determined by trial and error . Although many genes could influence response to these medicines , there are obvious c and i date s. Both drugs target the alpha-subunit of the sodium channel , encoded by the SCN family of genes . Phenytoin is principally metabolized by CYP2C9 , and both are probable substrates of the drug transporter P-glycoprotein . We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin  in cohorts of 425 and 281 patients , respectively . We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin ( P = 0.0066 ) . We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin ( P = 0.0051 and P = 0.014 , respectively ) . This polymorphism disrupts the consensus sequence of the 5 ' splice donor site of a highly conserved alternative exon ( 5N ) , and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy . These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospect i ve evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine . Although the case made here is compelling , our results can not be considered definitive or ready for clinical application until they are confirmed by independent replication The results of a prospect i ve assessment of antiepileptic drug treatment carried out over a 12-month period , in the context of existing community health care in a rural area of a developing country ( a highl and region of northern Ecuador ) , are reported . A house to house survey defined all patients in the area with a history of epileptic seizures , and 192 patients with active epilepsy were recruited into the programme . These patients were r and omised to treatment with carbamazepine or phenobarbital  , and 139 completed the assessment . Treatment was carried out by health visitors and rural doctors , monitored by a team of neurologists , and st and ard treatment regimens were used . Treatment was effective in controlling seizures , 53 % of the patients were rendered entirely seizure free in the second 6 months of therapy , and a further 14 % had a 50 % or more reduction in seizures . These results were similar to those reported in hospital based studies in developed countries . No significant differences were found between the efficacy and safety of phenobarbital or carbamazepine . Antiepileptic drug levels were monitored during the study , and ranges similar to those found in developed countries were recorded . Compliance was good . In view of the successful treatment in this community control programme , we would recommend that community programmes for the control of epilepsy in rural setting s should be given a higher priority in the planning of health care provision than is commonly the case . Finally , the programme afforded the opportunity to study the efficacy of treatment in patients with chronic long-st and ing epilepsy , who had not been previously treated , and the results of this treatment were good The effect of phenobarbital on total sleep time , night awakenings , and lengthy awakenings was examined as part of a r and omized trial of children with febrile seizures ; information about sleep patterns was gathered by parental observation . Children were between ages 8 - 36 months at enrollment and were examined subsequently for 2 1/2 years .  Night awakenings were not more common in children assigned to phenobarbital except for those who were poor sleepers at the beginning of the study . Total sleep time was no different in children assigned to phenobarbital than in those assigned to placebo . It is concluded that sleep problems reported in most young children with febrile seizures treated with  phenobarbital  did not exceed those reported in children treated with placebo , but a subset of predisposed children did experience an increase in night awakenings A r and omized double-blind study was carried out comparing single daily dose phenobarbital plus antipyretic instruction to a placebo plus antipyretic instruction to prevent a recurrent seizure following an initial simple febrile seizure . Parents of 138 consecutive children presenting to an emergency room with a first simple febrile convulsion received verbal and written instructions about fever control . Seventy-nine then agreed to participate in this study . Children were r and omized to receive either placebo with riboflavin tracer ( n = 40 ) or phenobarbital 5 mg/kg in a single daily dose with a riboflavin tracer ( n = 39 ) for 12 months or until another seizure occurred . Urine fluorescence for riboflavin was used to monitor compliance in all patients . Serum phenobarbital levels were obtained at each follow-up visit and averaged 1.4 mg/dl throughout the study . The significant difference ( P less than 0.02 ) in the incidence of recurrent seizures between patients receiving phenobarbital ( 2/39 ) and those receiving placebo ( 10/40 ) suggests that a single daily dose of phenobarbital is more effective than counseling parents about antipyretic therapy in preventing recurrent seizures following an initial febrile seizure Most systematic review s rely substantially on the assessment of the method ological quality of the individual trials . The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of r and omized clinical trials ( RCTs ) . The invited participants were experts in the field of quality assessment of RCTs . The initial item pool contained all items from existing criteria lists . Subsequently , we reduced the number of items by using the Delphi consensus technique . Each Delphi round comprised a question naire , an analysis , and a feedback report . The feedback report included staff team decisions made on the basis of the analysis and their justification . A total of 33 international experts agreed to participate , of whom 21 completed all question naires . The initial item pool of 206 items was reduced to 9 items in three Delphi rounds . The final criteria list ( the Delphi list ) was satisfactory to all participants . It is a starting point on the way to a minimum reference st and ard for RCTs on many different research topics . This list is not intended to replace , but rather to be used alongside , existing criteria lists Thirty-nine children were treated with either phenobarbital ( PB ) or carbamazepine ( CBZ ) for newly diagnosed partial onset seizures . Drug selection was r and omized in 33 subjects . Parents and the psychologist evaluating the child were blind to drug identity . Psychometric and behavioral evaluations were done at intake and at 6- and 12-month follow-ups . There were no significant differences between drugs in effect on behavior or cognitive function .  CBZ caused more systemic problems . There was a trend toward better seizure control with CBZ , but this was not statistically significant . Although individual children in each group had changes in behavior or cognitive status , neither group changed significantly , in either acute or chronic follow-up After their first episode of febrile convulsions , 195 previously healthy children , aged 6 - -30 months , were given either diazepam or phenobarbitone for a year . Each child was assigned at r and om to one of the two medications : children admitted on even days were given a suppository containing 5 mg diazepam every 8 hours when the rectal temperature was greater than or equal to 38.5 degree C. Children admitted on odd days were given treatment with phenobarbitone , 3.5 + /- 1 mg/kg per day . 156 children completed treatment and outpatient control for a year , 83 in the diazepam and 73 in the phenobarbitone group . The rate of recurrence was independent of the prophylactic and 15 - -16 % of the children in both groups had new febrile convulsions within a year . The recurrence rate after 6 months was also similar , 11 % in the diazepam group and 9 % in the phenobarbitone group . New convulsions were of similar duration and severity in both groups . In both groups 6 % of all febrile episodes led to new convulsions . Long-term treatment with phenobarbitone thus offered no advantage over intermittent diazepam The purpose of this study was to compare three different modes of treatment in the prevention of relapses of febrile convulsions  ( Phenobarbital = PH , Sodium Valproate = SV , Placebo = PO ) in a r and omized therapeutic trial . The patients included in the study had shown their first generalized convulsive seizure during a bout of fever ( greater than or equal to 38.5 degrees C ) and were aged between 6 months and 4 years . They were subsequently followed up as out patients , and Phenobarbital and sodium valproate levels were measured regularly to ascertain compliance with the treatment and to adjust the dosage accordingly . The patients ' families were question ed with respect to the occurrence of feverish bouts and convulsive seizures during the interval between visits , as well as possible adverse reactions . An  EEG  was carried out yearly . Results were as follows : - 69 patients - 35 boys and 34 girls - with an average age of 24 months were divided into 3 groups according to treatment : 21 cases on PH , 22 cases on SV , and 26 cases on PO . - they were followed up for an average duration of 21 months . - the average number of feverish bouts per child and per year was evaluated at 2.5 , no statistically significant difference being noticeable between the various modes of prophylaxis . - 15 relapses of febrile seizures were noted in 14 children , over an average duration of 23 months ; on average , relapses occurred after 9 months ; among the 14 children who had relapsed , one had been treated with SV , 4 with PH and 9 with PO , leading to estimated relapse rates of 4 % , 19 % , and 35 % respectively . There is a statistically significant difference in the relapse rates between the treated groups ( SV and PH ) and the Placebo group , and a particularly significant difference between Sodium Valproate and Placebo . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND Seizures commonly complicate cerebral malaria and are associated with an increased risk of death and neurological sequelae . We undertook a r and omised study to assess the efficacy of intramuscular phenobarbital in preventing seizures in childhood cerebral malaria . METHODS Children with cerebral malaria admitted to one hospital in Kilifi , Kenya , were r and omly assigned a single intramuscular dose of phenobarbital ( 20 mg/kg ) or identical placebo .  Clinical tolerance was assessed at the start of the trial , with particular reference to respiratory depression and hypotension . Seizures were timed and recorded , and treated in a st and ard way . Plasma phenobarbital concentrations were measured . Analyses were by intention to treat . FINDINGS 440 children with cerebral malaria were admitted to the hospital ; 100 were not recruited to the study . Of the remaining 340 , 170 received phenobarbital  and 170 placebo . The drug was adequately absorbed and well tolerated . Seizure frequency was significantly lower in the phenobarbital group than in the placebo group ( 18 [ 11 % ] vs 46 [ 27 % ] children had three or more seizures of any duration ; odds ratio 0.32 [ 95 % CI 0.18 - 0.58 ] ) but mortality was doubled ( 30 [ 18 % ] vs 14 [ 8 % ] deaths ; 2.39 [ 1.28 - 4.64 ] ) . The frequency of respiratory arrest was higher in the phenobarbital group than in the placebo group , and mortality was greatly increased in children who received phenobarbital plus three or more doses of diazepam ( odds ratio 31.7 [ 1.2 - 814 ] ) . INTERPRETATION In children with cerebral malaria , phenobarbital 20 mg/kg provides highly effective seizure prophylaxis but is associated with an unacceptable increase in mortality . Use of this dose can not , therefore , be recommended OBJECTIVE The aim of this study was to clarify the effect of genetic polymorphisms of CYP2C19 on the pharmacokinetics of phenobarbitone ( PB ) using a nonlinear mixed-effects model ( NONMEM ) analysis in Japanese adults with epilepsy . METHODS A total of 144 serum PB concentrations were obtained from 74 subjects treated with both PB and phenytoin but without valproic acid .  All patients were classified into three groups by CYP2C19 genotyping : G1 , G2 and G3 were homozygous for the wild type of CYP2C19 ( * 1/*1 ) , heterozygous extensive metabolizers ( EMs ) , ( * 1/*2 or * 1/*3 ) , and poor metabolizers ( PMs ) , ( * 2/*2 , * 2/*3 ) , respectively . All data were analyzed using NONMEM to estimate pharmacokinetic parameters of PB with respect to the CYP2C19 genotype . RESULTS Thirty-three patients belonged to G1 ( 44.6 % ) , 35 to G2 ( 47.3 % ) , and 6 to G3 ( 8.1 % ) . The total clearance ( CL ) of PB significantly decreased by 18.8 % in PMs ( G3 ) relative to EMs ( G1 and G2 ) . The CL tended to be lower in G2 than in G1 . CONCLUSION In this study , we first demonstrated the effect of the CYP2C19 polymorphism on pharmacokinetics of PB by genotyping . The contribution of other metabolic enzymes in the metabolism of PB in humans remains to be eluci date d ; however , it appears that the disposition of PB is mediated in part by this enzyme . The estimated population clearance values in the three genotype groups can be used to predict the PB dose required to achieve an appropriate serum concentration in an individual patient A group of 355 children who were seen after a first febrile convulsion at the Kaiser Foundation Foundation Hospitals in Southern California from 1970 to 1975 were r and omly assigned to three treatment groups-daily phenobarbital , " intermittent " phenobarbital given at the onset of fever , and no phenobarbital . We found that 42 % had a relative with a febrile seizure and 16 % a relative with an afebrile convulsion . 13 % had seizures which were either lateralized or longer than ten minutes . Parents were unaware of the fever prior to the seizure in about 30 % of the cases . In 81 % the preseizure duration of fever was less than 24 hours . The mean follow-up was 28 months , with a range of 6 to 70 months . There was no significant difference in the recurrence rate between children receiving " intermitent " as compared with no phenobarbital . The recurrence rate in children receiving daily phenobarbital was significantly decreased compared to either of the other two groups . Severe recurrent febrile seizures occurred in no children on daily phenobarbital and in 4.4 % of the children receiving either intermittent or no phenobarbital .  Parental resistance , compliance , and reversible hyperactivity were the main problems encountered with the continuous phenobarbital regimen Psychometric tests were performed on 50 children with a history of febrile convulsions . Twenty-five of these had received daily phenobarbital for a mean of 35 months ; 25 had received no phenobarbital . The two groups were matched for sex , age at the time of testing , race , and socioeconomic status . The tests used were the Wechsler Preschool and Primary Scale of Intelligence ( WPPSI ) , the Matching Familiar Figures Test , and the Children 's Embedded Figures Test . There were no significant differences in test results between the two groups The primary analysis of a r and omized clinical trial should compare patients in their r and omly assigned treatment groups ( intention to treat analysis ) . When a substantial number of subjects fail to take a prescribed medication or are switched to a different study medication , it is tempting to consider treatment comparisons using only those subjects with treatment as actually received rather than as prescribed . There are several arguments against this approach : the prognostic balance brought about by r and omization is likely to be disturbed ; sample size will be reduced ; and the validity of the statistical test procedures will be undermined . Further , results of analysis by treatment actually received may suffer from a bias introduced by using compliance , a factor often related to outcome independently of the treatment received , to determine the groups for comparison . The extent and nature of this bias will be related to the definition of compliance in an as treated analysis , a definition which could be unintentionally self-serving . We have investigated the problem of the definition of actual treatment in the context of a recent clinical trial . We used several definitions to classify patients as  having received or not received treatment as prescribed .  These definitions , when used in as treated analyses , provided results that were at times inconsistent or counter-intuitive , and which neither helped to confirm nor further explain the intention to treat analysis Phenobarbital is widely used in the treatment of children with febrile seizures , although there is concern about possible behavioral and cognitive side effects . In 217 children between 8 and 36 months of age who had had at least one febrile seizure and were at heightened risk of further seizures , we compared the intelligence quotients ( IQs ) of a group r and omly assigned to daily doses of phenobarbital ( 4 to 5 mg per kilogram of body weight per day ) with the IQs of a group r and omly assigned to placebo . After two years , the mean IQ was 7.03 [ corrected ] points lower in the group assigned to phenobarbital than in the placebo group ( 95 percent confidence interval , -11.52 to -2.5 , P = 0.0068 [ corrected ] ) . Six months later , after the medication had been tapered and discontinued , the mean IQ was 5.2 points lower in the group assigned to phenobarbital ( 95 percent confidence interval , -10.5 to 0.04 , P = 0.052 ) . The proportion of children remaining free of subsequent seizures did not differ significantly between the treatment groups . We conclude that phenobarbital depresses cognitive performance in children treated for febrile seizures and that this disadvantage , which may outlast the administration of the drug by several months , is not offset by the benefit of seizure prevention Traditional clinical monitoring of children with epilepsy does not appear to be sufficiently sensitive to cognitive functioning and behavioral problems . Although subtle , these changes may alter a child 's ability to perform well in school and in society . Physicians must prevent seizures without producing intolerable side effects , and ways of more appropriately assessing these side effects must be developed . In this double-blind , counter-balanced , crossover study of 21 children , the effects of phenobarbital and valproic acid on cognitive functioning and behavior were measured . There was no difference in seizure control between the drugs , and each medication was maintained in the therapeutic range for 6 months ( mean phenobarbital level , 21.2 micrograms/mL ; mean valproic acid level , 94.1 micrograms/mL ) . Children were treated with each drug for 6 months . Differences between the drugs were seen on measurements of cognitive function and behavior . On four tests of neuropsychologic function , children performed significantly less well while receiving phenobarbital ( P less than .01 ) . There was no evidence that the patients were se date d or less able to perform continuous performance tasks while receiving phenobarbital .  Parental assessment of behavior indicated significantly worse behavior with the phenobarbital regimen for three items ( P less than .01 ) and children were measurably more " hyperactive " ( P less than .05 ) . Routine clinical assessment of the patients did not reveal differences between the drugs with respect to routine laboratory measurements or side effects as assessed by history or physical examination . Although children may appear to tolerate a medication without clinical ly apparent problems , subtle but significant changes in intellectual function and behavior may be occurring . Additional , more sensitive , methods of monitoring patients while receiving these drugs is necessary Of 138 children who had a first febrile convulsion before their second birthday , 48 were treated with phenobarbitone  , 47 with phenytoin , and 43 with a placebo for 12 months . Drug levels were monitored and adverse effects of the drugs were noted . Compared with placebo , phenobarbitone significantly reduced recurrences among children under 14 months old at the time of their first convulsion , but nor among older children . Phenytoin was an ineffective prophylactic agent . Ideal drug levels were difficult to maintain , and many recurrences occurred when concentrations were suboptimal . Behavioural disturbance in children taking phenobarbitone was not a serious problem . The decision to give continuous prophylaxis for febrile convulsions is complex , and each case must be judged on its merits . For children who have a first seizure before 14 months of age prophylaxis may be advisable and phenobarbitone is effective One-hundred-sixty-five children without known neurological disorder who presented with their first febrile convulsion between the ages of six months and three years were assigned to daily phenobarbitone treatment or to a control group and followed up at a special clinic for six months . One-hundred- and -sixty-one-one children completed the trial , and of the 88 children assigned to phenobarbitone treatment 10 had further convulsions during this period compared with 14 of the 73 control children . Only 49 of those assigned to phenobarbitone took the drug regularly throughout the trial , and four of these had further febrile convulsions , a proportion not significantly different from that in the controls . All four had mean plasma phenobarbitone concentrations over 69 mumol/l ( 16 mug/ml ) during the trial and in three the plasma concentration was at or over this figure within eight hours over 69 mumol/l ( 16 mug/ml ) during the trial and in three the plasma concentration was at or over this figure within eight hours of the repeat convulsion . Regular phenobarbitone does not seem to prevent febrile convulsions . Attention should instead be directed to organising emergency services to allow early termination of fevrile convulsions , whether first or subsequent , to prevent irreversible brain damage BACKGROUND The medical treatment of childhood epilepsy is largely influenced by clinical trials in adult patients . We know of only one r and omised comparative trial ( of two drugs ) in newly diagnosed childhood epilepsy . We have undertaken a long-term , prospect i ve , r and omised , unmasked , pragmatic trial of the comparative efficacy and toxicity of four st and ard antiepileptic drugs used as monotherapy in children with newly diagnosed epilepsy . METHODS Between 1981 and 1987 , 167 children aged 3 - 16 years , who had had at least two previously untreated tonic-clonic or partial seizures , with or without secondary generalisation , were r and omly allocated treatment with phenobarbitone , phenytoin , carbamazepine , or sodium valproate . The protocol was design ed to conform to st and ard clinical practice . Efficacy was assessed by time to first seizure after the start of treatment and time to achieving 1-year remission . FINDINGS The overall outcome with all four drugs was good . 20 % of children remained free of seizures and 73 % had achieved 1-year remission by 3 years of follow-up . We found no significant differences between the drugs for either measure of efficacy at 1 , 2 , or 3 years of follow-up . The overall frequency of unacceptable side-effects necessitating withdrawal of the r and omised drug was 9 % . This total included six of the first ten children assigned phenobarbitone ; no further children were allocated this drug . Of the other three drugs , phenytoin ( 9 % ) was more likely to be withdrawn than carbamazepine ( 4 % ) or sodium valproate ( 4 % ) . INTERPRETATION Our data will inform choice of drug and outcome with four of the st and ard drugs available for newly diagnosed tonic-clonic or partial seizures with or without secondary generalisation in children A programme of antiepileptic treatment in a rural and semi-urban region in Kenya was assessed . Patients with generalised tonic-clonic seizures were treated according to one of two simple drug protocol s. Health workers screened cases reported by key informants in the community . From the 529 patients identified by health workers as having active seizures 302 patients aged 6 - 65 years were recruited by a psychiatrist for therapy with carbamazepine or phenobarbitone . Treatment was supervised largely by primary health workers , and the programme was monitored by a research team , which assessed the effectiveness of treatment . Of the 249 patients who completed the study , 53 % became seizure-free in the second 6 months of therapy , and another 26 % had substantially ( 50 % or more reduction ) fewer seizures than in the 6 months before therapy . The similarity of these findings to those obtained in newly diagnosed patients in the developed world , the low drop-out rate , the low rate of withdrawal due to adverse effects , and the acceptable compliance with therapy indicate that health workers can monitor therapy adequately . Most patients had had several years of delay before starting therapy for their epilepsy , yet they responded well -- a finding that does not support the suggestion that the disorder becomes intractable if not treated early In a double-blind trial , children who had recurrent and /or complex febrile convulsions  were treated with either phenobarbital sodium or carbamazepine .  Forty children were suitable for analysis ; 19 were receiving carbamazepine , and 21 were receiving phenobarbital .  Of the carbamazepine-treated patients , nine ( 47 % ) had recurrent convulsions despite therapeutic levels of the drug , while only two ( 10 % ) of the phenobarbital-treated patients suffered further seizures . These results confirm previous findings suggesting that carbamazepine is not as effective in the prophylactic treatment of febrile convulsions as phenobarbital One hundred and eighty‐six consecutive children aged between six and 72 months admitted to the Manchester Children 's Hospitals with a febrile convulsion in the first year of life , a complicated febrile convulsion , or more than one febrile convulsion within two years , were allocated r and omly to one of three groups who were offered rectal diazepam in the event of a subsequent prolonged febrile convulsion , or prophylactic treatment with sodium valproate or phenobarbitone .  Over‐all risk of recurrence was 30 per cent and adequate prophylaxic treatment did not lessen this risk . Side‐effects in 24 per cent of the valproate group and 61 per cent of the phenobarbitone group did not justify the use of prophylactic treatment An unselected and representative series of 208 children admitted following their first febrile convulsion has been offered a continuous prophylactic treatment with phenobarbital . The treatment was started in 174 of the patients and planned to be given for 2 years . For various reasons – the major one being sideeffects – the drug was discontinued at different times before the end of 2 years in 59 patients , 31 are still in treatment and 84 have completed the course
target: There is no evidence for a difference in antiepileptic efficacy between phenobarbital and any other compared AED , yet no evidence for absolute efficacy .
  No convincing evidence exists for an excess of behavioural adverse effects , over other AEDs , attributable to phenobarbital .
  Masked studies of phenobarbital in childhood epilepsy have shown no significant differences in behavioural or cognitive adverse effects compared to other AEDs .
  This is in contrast to the excess of such adverse effects reported in studies open to observer bias .
  However , the one finding of reduction in cognitive ability associated with phenobarbital treatment for febrile convulsions remains a concern .
background: INTRODUCTION : Against a background of concern about the safety of new pharmaceutical products , there has been renewed interest in one of the oldest antiepileptic drugs ( AEDs ) , phenobarbital .
  Although still in widespread use in developing countries , its popularity has slipped in Western countries over the past century , partly because of controversy about its adverse effect profile .
  This critical review examines the evidence supporting its effectiveness and its associated behavioural adverse effects for febrile convulsions and childhood epilepsy .