Randomised controlled trial to assess acceptability of phenobarbital for childhood epilepsy in rural India Considerations on Designing Clinical Trials to Evaluate the Place of New Antiepileptic Drugs in the Treatment of Newly Diagnosed and Chronic Patients with Epilepsy Antiepileptic drug treatment in a community health care setting in northern Ecuador: a prospective 12-month assessment Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial Quantifying the response to antiepileptic drugs Intrapatient variation in antiepileptic drug plasma concentration after generic substitution vs stable brand-name drug regimens Side effects of phenobarbital and carbamazepine in childhood epilepsy: randomised controlled trial Magnesium sulphate for pre‐eclampsia and eclampsia: the evidence so far In utero antiepileptic drug exposure Perampanel efficacy and safety by gender: Subanalysis of phase III randomized clinical studies in subjects with partial seizures Tiagabine: the safety landscape. Assessment of Drowsiness in Epilepsy Patients Receiving Chronic Antiepileptic Drug Therapy Long term outcome of prophylaxis for febrile convulsions. Epilepsy, pregnancy, and major birth anomalies: an Italian prospective, controlled study. Phenobarbital Versus Valproate for Generalized Convulsive Status Epilepticus in Adults: A Prospective Randomized Controlled Trial in China Prevention of bone loss and vertebral fractures in patients with chronic epilepsy--antiepileptic drug and osteoporosis prevention trial. A CONTROLLED STUDY OF PROFYLACTIC LONG‐TERM TREATMENT OF FEBRILE CONVULSIONS WITH PHENOBARBITAL Comparison of antiepileptic drugs on cognitive function in newly diagnosed epileptic children: a psychometric and neurophysiological study. Systematic screening allows reduction of adverse antiepileptic drug effects The relationship of depression to antiepileptic drug adherence and quality of life in epilepsy Substitution Monotherapy With Levetiracetam vs Older Antiepileptic Drugs: A Randomized Comparative Trial. Epilepsy diagnosis and localization in patients with antecedent childhood febrile convulsions Levetiracetam: preliminary experience in patients with primary brain tumours
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 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 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 BACKGROUND Almost a third of patients with epilepsy have a treatment-resistant form , which is associated with severe morbidity and increased mortality . Cannabis-based treatments for epilepsy have generated much interest , but scientific data are scarce . We aim ed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe , tolerated , and efficacious in children and young adults with treatment-resistant epilepsy . METHODS In this open-label trial , patients ( aged 1 - 30 years ) with severe , intractable , childhood-onset , treatment-resistant epilepsy , who were receiving stable doses of antiepileptic drugs before study entry , were enrolled in an exp and ed-access programme at 11 epilepsy centres across the USA . Patients were given oral cannabidiol at 2 - 5 mg/kg per day , up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day ( dependent on study site ) . The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks . The efficacy analysis was by modified intention to treat . Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test . RESULTS Between Jan 15 , 2014 , and Jan 15 , 2015 , 214 patients were enrolled ; 162 ( 76 % ) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis , and 137 ( 64 % ) patients were included in the efficacy analysis . In the safety group , 33 ( 20 % ) patients had Dravet syndrome and 31 ( 19 % ) patients had Lennox-Gastaut syndrome . The remaining patients had intractable epilepsies of different causes and type . Adverse events were reported in 128 ( 79 % ) of the 162 patients within the safety group . Adverse events reported in more than 10 % of patients were somnolence ( n=41 [ 25 % ] ) , decreased appetite ( n=31 [ 19 % ] ) , diarrhoea ( n=31 [ 19 % ] ) , fatigue ( n=21 [ 13 % ] ) , and convulsion ( n=18 [ 11 % ] ) . Five ( 3 % ) patients discontinued treatment because of an adverse event . Serious adverse events were reported in 48 ( 30 % ) patients , including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug . 20 ( 12 % ) patients had severe adverse events possibly related to cannabidiol use , the most common of which was status epilepticus ( n=9 [ 6 % ] ) . The median monthly frequency of motor seizures was 30.0 ( IQR 11.0 - 96.0 ) at baseline and 15.8 ( 5.6 - 57.6 ) over the 12 week treatment period . The median reduction in monthly motor seizures was 36.5 % ( IQR 0 - 64.7 ) . INTERPRETATION Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy . R and omised controlled trials are warranted to characterise the safety profile and true efficacy of this compound . FUNDING GW Pharmaceuticals , Epilepsy Therapy Project of the Epilepsy Foundation , Finding A Cure for Epilepsy and Seizures Objective : To quantify the response to treatment with antiepileptic drugs ( AEDs ) as a function of the past treatment history and identify additional prognostic factors for predicting the response to newly administered AED treatments . Methods : A cohort of 478 consecutive patients who received newly administered AED treatments between January 1999 and December 2004 and were followed prospect ively for 1.5 to 7.5 years in a single epilepsy clinic . Results : The response to newly administered AED treatments was highly dependent on the past treatment history . The seizure-free rates decreased from 61.8 % for the first AED to 41.7 % , 16.6 % , and 0 % after one , two to five , and six to seven past AEDs proved inefficient . This response curve corresponded to a mono-exponential function with a maximal response of 61.8 % and half-decay constant of 1.5 AEDs . Likewise the response curve describing a greater than 50 % reduction in seizure frequency corresponded to a mono-exponential function with a maximal response of 85.3 % and half-decay constant of two AEDs . Three additional independent prognostic factors for predicting the response to AEDs were identified : type of epilepsy , duration of epilepsy , and number of seizures in the 3 months prior to AED initiation . Conclusion : Drug resistance is a grade d process that follows a mono-exponential course with a half-decay constant of 1.5 to two antiepileptic drugs ( AEDs ) . Although relative drug-resistant epilepsy can be diagnosed after failure of two past AEDs , absolute drug resistance requires failure of six AEDs , as a significant minority of patients ( 16.6 % ) is rendered seizure-free by addition of newly administered AEDs even after failure of two to five past antiepileptic drugs . GLOSSARY : AED = antiepileptic drug ; CBZ = carbamazepine ; GBP = gabapentin ; LTG = lamotrigine ; TPM = topiramate ; VA = valproic acid Generic substitution of antiepileptic drugs ( AEDs ) is still a matter of controversy and concern among clinicians and patients . We aim ed to assess intrasubject variation in plasma concentrations of lamotrigine ( LTG ) , levetiracetam ( LEV ) and topiramate ( TPM )  after generic substitution compared with a stable br and -name drug regimen in a population of patients with epilepsy . A retrospective analysis was performed on prospect ively collected and stored data from our therapeutic drug monitoring ( TDM ) data base for the years 2009 - 2014 . The main outcome variable was the proportion of patients who , after switching from br and ed to generic formulations , showed a greater than ±20 % change in AED plasma concentrations compared to the proportion of control patients showing a change in AED plasma concentrations of the same extent while receiving stable br and ed formulations over repeated TDM tests . Fifty patients on LTG , 27 on LEV and 16 on TPM showing at least one TDM test while receiving generic products fulfilled the inclusion /exclusion criteria for the analysis and were compared with 200 control patients for LTG , 120 for LEV and 80 for TPM . The proportion of patients showing an intrasubject change greater than ±20 % in AED plasma concentrations was similar in the br and name vs generic group compared with the control one for LTG ( 22 % vs 33 % ) and LEV ( 44 % vs 38 % ) , while it was higher in the control group for TPM ( 41 % vs 6 % , p<0.01 ) . These are the first data in the literature about the within-patient variation in steady-state plasma concentrations of a series of stable treatments with br and -name AEDs in a real clinical setting . In conclusion , a significant interday variability in intrapatient LTG , LEV and TPM plasma concentrations can be observed even in patients stabilized with the same br and name product over time . This suggests that any change in plasma AED concentration and possible related clinical effects after generic substitution may be not necessarily related to the switch . Our results should be confirmed by large , prospect i ve , blinded , r and omized controlled studies in people with epilepsy Objective To compare the behavioural side effects associated with two commonly used antiepilepsy drugs — phenobarbital and carbamazepine — in children in Bangladesh . Design Prospect i ve r and omised controlled single centre trial . Setting Specialist children 's hospital in Dhaka , Bangladesh . Participants 108 children aged 2 - 15 with generalised tonic-clonic ( n=51 ) or partial and secondary generalised seizures ( n=57 ) . Main outcome measures Seizure control and behavioural side effects . Results 91 children were followed up for 12 months . Six required a change of antiepilepsy drug . Side effects were compared in 85 children . In the last quarter of the 12 month follow-up , 71 children were seizure free after one year 's treatment . Thirty two in the phenobarbital group and 39 in the carbamazepine group had no seizures in 74 and 102 days after r and omisation , respectively . Ten children had increased behavioural problems , which were unacceptable in four ( one in the phenobarbital group and three in the carbamazepine group ) . Independent t tests , however , showed no difference between the two trial drugs . Conclusion There was no excess in behavioural side effects with phenobarbital in children with epilepsy in a country with limited re sources . Trial registration NCT00381537 Eclampsia remains a rare , but serious , complication of pregnancy , estimated to complicate around 1 in 2000 deliveries in Europe and other developed countries ( Douglas & Redman 1992 ) , and from 1 in 100 to 1700 deliveries in developing countries ( Crowther 1985 ; WHO lnternational Collaborative Study of Hypertensive Disorders of Pregnancy 1988 ) ; eclampsia is associated with 10 % of maternal deaths and approximately 50000 women die each year having had an eclamptic convulsion ( Duley 1992 ) . Much of the recent debate about management of women with eclampsia has focused on control of convulsions .  Anticonvulsants are given to prevent the first fit in women who have fulminating pre-eclampsia and to prevent further convulsions in women who already have had an eclamptic fit . Although these indications are related , women who have pre-eclampsia are likely to be less sick than those with eclampsia . The potential for benefit or for harm will , therefore , be different , and the effectiveness of anticonvulsants should be evaluated separately for these two situations . For well over half a century , magnesium sulphate has been advocated for the care of women with pre-eclampsia and eclampsia , yet its use remains controversial ( Donaldson 1992 ) . In the past , the lack of a sound hypothesis for the mechanism by which magnesium sulphate might act as an anticonvulsant has contributed to this . Recent plausible suggestions are that it may act by vasodilatation and subsequent reduction of cerebral ischaemia ( Belfort & Moise 1992 ) ; an alternative is by blocking some of the neuronal damage associated with cerebral ischaemia ( Goldman & Finkbeiner 1988 ) . Reflecting ongoing uncertainty about its role , use of magnesium sulphate continues to vary enormously . In the United States , for example , magnesium sulphate is the anticonvulsant of choice for women with either eclampsia or pre-eclampsia ( Consensus Report 1990 ) , while in the United Kingdom it is used by only 2 % of obstetricians ( Hutton et al. 1992 ) . What is the evidence that magnesium sulphate given to women with either pre-eclampsia or eclampsia does more good than harm ? The popularity of . magnesium sulphate in North America ( and elsewhere ) is largely based on reports of a few hundred women with eclampsia who were treated with magnesium sulphate  ( Pritchard et al. 1984 ) . Whilst sometimes impressive in the number of women included , none of these reports included any form of comparison or control group . Without comparison , it is impossible to know whether the good or bad outcome for the women was due to magnesium sulphate or to a combination of other factors , such as the severity of disease , health status of the women , or to additional interventions . The effectiveness of an intervention , such as magnesium sulphate , is best evaluated by systematic review of all relevant r and omised trials . In the perinatal field , a system for preparing and maintaining review s of the effects of health care already exists ( Cochrane Pregnancy and Childbirth Data base 1993 ) . The evidence presented here is derived from review s published on this data base Background : Pregnancy outcomes following in utero exposure to antiepileptic drugs ( AEDs ) are uncertain , limiting an evidence d-based approach . Objective : To determine if fetal outcomes vary as a function of different in utero AED exposures . Methods : This ongoing prospect i ve observational study across 25 epilepsy centers in the USA and UK enrolled pregnant women with epilepsy from October 1999 to February 2004 to determine if differential long-term cognitive and behavioral neurodevelopmental effects exist across the four most commonly used AEDs . This initial report focuses on the incidence of serious adverse outcomes including major congenital malformations ( which could be attributable to AEDs ) or fetal death .  A total of 333 mother/child pairs were analyzed for monotherapy exposures : carbamazepine ( n = 110 ) , lamotrigine ( n = 98 ) , phenytoin ( n = 56 ) , and valproate ( n = 69 ) . Results : Response frequencies of pregnancies result ing in serious adverse outcomes for each AED were as follows : carbamazepine 8.2 % , lamotrigine 1.0 % , phenytoin 10.7 % , and valproate 20.3 % . Distribution of serious adverse outcomes differed significantly across AEDs and was not explained by factors other than in utero AED exposure . Valproate exhibited a dose-dependent effect . Conclusions : More adverse outcomes were observed in pregnancies with in utero valproate exposure vs the other antiepileptic drugs ( AEDs ) . These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus . For women who fail other AEDs and require valproate , the dose should be limited if possible The antiepileptic drug ( AED ) perampanel is approved in ≥40 countries as adjunctive therapy for drug‐resistant partial seizures in patients with epilepsy . This post hoc analysis of pooled data from three phase III , double‐blind , r and omized studies of perampanel examines between‐gender differences in perampanel efficacy and safety . Of the 1,478 subjects in the pooled analysis ( 719 male , 759 female ) , 1,109 were included in the pharmacokinetic/pharmacodynamic analysis .  Perampanel oral clearance was 17 % lower in female than in male patients not receiving enzyme‐inducing AEDs . Pooled efficacy analysis revealed that seizure frequency was reduced with perampanel treatment regardless of gender ; a greater numerical reduction in seizure frequency and increased responder rates occurred in female participants at perampanel doses of 4 , 8 , and 12 mg . Tolerability was similar between groups , although common adverse events such as dizziness and headache occurred more frequently in female subjects . Modest elevations in perampanel exposure in female patients may result in meaningful between‐gender differences in efficacy and safety ; therefore , dosing should be individualized and clinical response monitored Tiagabine ( TGB ) hydrochloride is a potential new antiepileptic drug ( AED ) undergoing clinical development . Experience in humans amounts to 1,810 patient-years of exposure . TGB was found to be tolerated in an integrated safety analysis of five double-blind , add-on therapy trials involving approximately 1,000 patients with epilepsy with difficult-to-control seizures with existing AEDs . Discontinuation result ing from adverse events were infrequent , occurring in 15 % of patients receiving TGB compared to 5 % receiving placebo . The most frequently reported adverse event was dizziness , which was usually transient and did not require medical intervention . Adverse events that were statistically significantly more common with TGB than placebo were dizziness , asthenia , nervousness , tremor , diarrhea , and depression ( not major depression ) . Adverse events were usually mild to moderate in severity and transient , and most were associated with dose titration . The incidence , type , and severity of adverse events in long-term studies were comparable with those in short-term studies . Serious adverse events were uncommon and no idiosyncratic events were reported Drowsiness is a common complaint among patients with epilepsy taking antiepileptic drugs ( AEDs )  and may be of particular importance because of the potential effects on cognitive abilities . We used a novel EEG‐based measure ( the Awake Maintenance Task , AMT ) to determine objective ly whether patients on chronic , stable AED therapy had impaired ability to maintain wakefulness . Thirty patients receiving AEDs [ carbamazepine ( CBZ ) , phenytoin ( PHT ) , phenobarbital ( PB ) , valproate ( VPA ) ] were compared to 35 healthy controls , 12 seizure patients not taking AEDs , and 16 patients with multiple sclerosis . A structured EEG recording was conducted under controlled conditions , and subjects were tested to determine their ability to maintain wakefulness during a 6‐min unstimulated trial . Testing also included Digit Symbol , auditory reaction time , and subjective measures of fatigue or sleepiness [ Profile of Mood States ( POMS ) , Stanford Sleepiness Scale ( SSS ) ] . Patients receiving AEDs had a mean total drowsiness score of 101 s compared with ≤ 12 s for each of the three control groups ( p < 0.001 ) . One third of the AED‐treated patients had > 120 s of drowsiness , in contrast to only 1 of 63 controls ( p < 0.001 ) . Among patients receiving AEDs , objective EEG drowsiness did not correlate with AED levels or performance measures . Untreated seizure patients had significantly greater complaints of lack of vigor despite a near absence of objective drowsiness on the AMT . These results suggest that epilepsy patients receiving chronic AED therapy have impaired ability to maintain wakefulness . Patient self‐reports of AED‐related sleepiness may not accurately represent this problem A cohort of 289 children with febrile convulsions who had been r and omised in early childhood to either intermittent prophylaxis ( diazepam at fever ) or no prophylaxis ( diazepam at seizures )  was followed up 12 years later . The study focused on the occurrence of epilepsy and on neurological , motor , intellectual , cognitive , and scholastic achievements in the cohort . At follow up the two groups were of almost identical age ( 14.0 v 14.1 years ) , body weight ( 58.2 v 57.2 kg ) , height ( 168.2 v 167.7 cm ) , and head circumference ( 55.9 v 56.2 cm ) . The occurrence of epilepsy ( 0.7 % v 0.8 % ) , neurological examination , fine and gross motor development on the Stott motor test , intellectual performance on the Wechsler intelligence scale for children verbal IQ ( 105 v 105 ) , performance IQ ( 114 v 111 ) , and full scale IQ ( 110 v 108 ) , cognitive abilities on a neuropsychological test battery , including short and long term , auditory and visual memory , visuomotor tempo , computer reaction time , reading test , and scholastic achievement were also very similar . Children with simple and complex febrile convulsions had the same benign outcome . The long term prognosis in terms of subsequent epilepsy , neurological , motor , intellectual , cognitive , and scholastic ability was not influenced by the type of treatment applied in early childhood . Preventing new febrile convulsions appears no better in the long run than abbreviating them We followed prospect ively 97 women with epilepsy during 138 pregnancies and 88 women without epilepsy , matched for age , during 140 pregnancies . We evaluated seizure frequency , pregnancy outcome , and presence of major congenital malformations , and correlated them with the type of epilepsy , antiepileptic drugs ( AEDs ) implicated , plasma AED levels during pregnancy , and maternal age . We compared the two groups regarding type and number of pregnancies ; complications during gestation , labor , and delivery ; prevalence of abortions ( spontaneous or induced ) ; perinatal deaths ; and type and prevalence of major malformations . No change in seizure frequency during pregnancy was seen in 79.7 % of cases . Pregnancy complications and incidence of major congenital malformations were only slightly higher in women with epilepsy than in women without epilepsy . No single AED used as monotherapy correlated with increased risk of malformations , but polypharmacy with phenobarbital and phenytoin seemed to represent a risk factor . Low socioeconomic status , older age at delivery , and family history of malformations were other risk factors for neonatal malformations Objective Although generalized convulsive status epilepticus ( GCSE ) is a life-threatening emergency , evidence -based data to guide initial drug treatment choices are lacking in the Chinese population . We conducted this prospect i ve , r and omized , controlled trial to evaluate the relative efficacy and safety of intravenous phenobarbital and valproate in patients with GCSE . Methods After the failure of first-line diazepam treatment , Chinese adult patients with GCSE were r and omized to receive either intravenous phenobarbital ( st and ard doses , low rate ) or valproate ( st and ard ) . Successful treatment was considered when clinical and electroencephalographic seizure activity ceased . Adverse events following treatment , as well as the neurological outcomes at discharge and 3 months later , were also evaluated . Results Overall , 73 cases were enrolled in the study . Intravenous phenobarbital was successful in 81.1 % of patients , and intravenous valproate was successful in 44.4 % of patients ( p < 0.05 ) . The relapse rate of status epilepticus within 24 h of receiving phenobarbital ( 6.7 % ) was significantly lower than that in patients receiving valproate ( 31.3 % ) , and the total number of adverse events did not differ significantly between the two groups ( p > 0.05 ) . In the phenobarbital group , two patients ( 5.4 % ) required ventilation and two patients ( 5.4 % ) developed serious hypotension . The neurological outcomes of the phenobarbital group were generally better than those of the valproate group ; however , no significant differences were observed between phenobarbital and valproate with respect to mortality ( 8.1 vs. 16.6 % ) at discharge , or mortality ( 16.2 vs. 30.5 % ) and post-symptomatic epilepsy ( 26.3 vs. 42.8 % ) at 3-month follow-up . Conclusions Intravenous phenobarbital appears to be more effective than intravenous valproate for Chinese adult patients with GCSE . The occurrence of serious respiratory depression and hypotension caused by phenobarbital was reduced by decreasing the intravenous infusion rate ; however , even at a lower infusion rate than typically used in other institutions , intravenous phenobarbital result ed in more serious adverse events than intravenous valproate . The better outcomes in the phenobarbital group compared with the valproate group suggest that phenobarbital should be considered for the early successful treatment of GCSE PURPOSE To evaluate whether use of a bisphosphonate ( risedronate ) in addition to calcium and vitamin D in male veterans with epilepsy who were taking antiepileptic drugs ( AEDs ) long term can prevent the loss of bone mass ( BMD , bone mineral density ) associated with AED use compared to patients who were treated with a placebo plus calcium and vitamin D. As a secondary end point we studied the incidence of new morphometric vertebral and nonvertebral fractures . METHODS Antiepileptic drug and osteoporosis prevention trial ( ADOPT ) was design ed as a prospect i ve 2-year double-blind , r and omized placebo controlled study involving 80 male veterans with epilepsy who were being treated with AEDs such as phenytoin , phenobarbital , sodium valproate , or carbamazepine for a minimum of 2 years . All enrolled participants received calcium and vitamin D supplementation , and were r and omized to risedronate or matching placebo .  Total body , bilateral proximal femora , and anteroposterior ( AP ) lumbar spine BMDs in addition to morphometric lateral vertebral assessment s ( LVAs ) were evaluated by a dual energy x-ray absorptiometry ( DXA ) instrument . Comparisons of BMDs were made between baseline , 1 year , and after 2 years of enrollment in the study . The incidence of new vertebral and nonvertebral fractures was secondary end point . KEY FINDINGS Of the 80 patients initially enrolled in the study , 53 patients completed the study . Baseline characteristics of the two groups were similar . At the end of the study , in the placebo plus calcium and vitamin D group , we observed a significant improvement in BMD at any of the evaluated sites when compared to their baseline scans in 69 % ( 18/26 ) of the participants . In the risedronate plus calcium and vitamin D group , we observed significant improvement of BMDs in 70 % ( 19/27 ) of the participants . At the end of the study , the risedronate group experienced a significant increase of BMD at the lumbar spine L1 - 4 ( 1.267 - 1.332 g/cm(2 ) ) , which was significantly larger than that seen in the placebo group ) ( 1.229 g/cm(2 ) vs. 1.245 g/cm(2 ) ; p = 0.0066).There were nonsignificant differences between the two groups regarding changes of total body BMD or at the proximal bilateral femora . Five new vertebral fractures and one nonvertebral fracture were observed only in the placebo group . SIGNIFICANCE Calcium and vitamin D supplementation or calcium and vitamin D supplementation in addition to risedronate improved BMD in more than 69 % of male veterans with epilepsy who were taking AEDs . In the group receiving risedronate plus calcium and vitamin D there was a significant improvement of BMD at the lumbar spine as compared to the placebo group , which also received calcium and vitamin D. The use of risedronate plus calcium and vitamin D prevented the incidence of new vertebral fractures and one nonvertebral fracture in this cohort 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 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 Objective : To determine the effectiveness of systematic screening with a brief 19-item self-report instrument , the Adverse Events Profile ( AEP ) , to reduce adverse effects of antiepileptic drugs ( AEDs ) and improve subjective health status . Methods : The authors performed a prospect i ve r and omized trial comparing the use of the AEP with usual care without the AEP .  Sixty-two patients with an AEP score of ≥45 were enrolled from a consecutive group of 200 consenting adults with epilepsy . Results : The mean percent improvement in AEP scores was greater in the patient group for which clinicians received the AEP compared with the usual care group ( 25 % vs 5 % ; p < 0.01 ) . Mean change in Quality of Life in Epilepsy Inventory (QOLIE)-89 total scores was not different between groups , but for the entire sample QOLIE-89 change was greater for patients having a 15-point improvement in AEP scores than for those with a 0- to 15-point improvement or a worsened score ( 24 vs 12 vs 3 ; analysis of variance , p < 0.008 ) . More patients in the AEP group had a > 15-point improvement in QOLIE-89 score ( p < 0.03 ) . Use of the AEP was associated with a 2.8-fold increase ( 95 % CI , 1.7 to 4.8 ) in AED modifications . No difference in seizure rates was observed . Conclusions : Systematic screening for antiepileptic drug side effects may increase identification of toxicity and guide medication changes to reduce adverse effects and possibly improve subjective health status We sought to examine the impact of depression upon antiepileptic drug ( AED ) adherence in patients with epilepsy . We administered the Center for Epidemiologic Studies Depression Scale ( CES-D ) , Neurological Disorders Depression Inventory for Epilepsy ( NDDI-E ) , Seizure Severity Question naire ( SSQ ) , and Quality of Life in Epilepsy-10 ( QOLIE-10 ) and measured AED adherence by utilizing the medication possession ratio ( MPR ) in adult patients with epilepsy identified through a pharmacy cl aims data base . From a sampling frame of over 10,000 patients identified in cl aims , 2750 were r and omly selected and contacted directly by mail to participate in the cross-sectional survey . A total of 465 eligible patients completed a survey . Survey data were combined with administrative cl aims data for analysis . We conducted a path analysis to assess the relationships between depression , adherence , seizure severity , and quality of life ( QOL ) .  Patients with depression scored significantly worse on measures of seizure severity ( p=.003 ) , QOL ( p<.001 ) , and adherence ( p=.001 ) . On path analysis , depression and QOL and seizure severity and QOL were related , but only the NDDI-E scores had a significant relationship with medication adherence ( p=.001 ) . Depression as measured by the NDDI-E was correlated with an increased risk of AED nonadherence . Depression or seizure severity adversely impacted QOL . These results demonstrate yet another important reason to screen for depression in epilepsy OBJECTIVE To determine whether patients who fail their first antiepileptic drug ( AED ) have better neuropsychiatric and quality -of-life ( QOL ) outcomes if substituted to levetiracetam monotherapy compared with a second older AED . DESIGN R and omized comparative trial . Participants with partial epilepsy who had failed monotherapy with phenytoin sodium , carbamazepine , or valproate sodium  were r and omized to substitution monotherapy with levetiracetam or a different older AED . Assessment s were performed at baseline , 3 months , and 12 months using question naires measuring neuropsychiatric , QOL , seizure control , AED adverse effects , and neurocognitive outcomes . SETTING Epilepsy service of a teaching hospital . PATIENTS Fifty-one patients were r and omized to levetiracetam and 48 were r and omized to a second older AED ( 25 to valproate and 23 to carbamazepine ) . MAIN OUTCOME MEASURES Proportions showing improvements in depression ( on the Hospital Anxiety and Depression Scale ) and QOL scores ( on the 89-item Quality of Life in Epilepsy Inventory ) at 3 months . RESULTS There were no differences between the groups in depression scores at 3 months ( improvement in 17 of 43 patients [ 39.5 % ] in the levetiracetam group and 15 of 44 patients [ 34.1 % ] in the older AED group ; P = .60 ) , but a greater proportion of the older AED group improved on the 89-item Quality of Life in Epilepsy Inventory compared with the levetiracetam group ( 27 of 38 patients [ 71.1 % ] vs 21 of 43 patients [ 48.8 % ] , respectively ; P = .04 ) . The QOL , anxiety , and AED adverse effects scores were improved in both groups at 3 and 12 months after r and omization . CONCLUSIONS Substitution monotherapy in a patient experiencing ongoing seizures or tolerability issues is associated with sustained improvements in measures of QOL , psychiatric , and adverse events outcomes . Patients switched to levetiracetam do not have better outcomes than those switched to a second older AED . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12606000102572 Purpose : A history of febrile convulsions ( FC ) is often obtained in patients presenting for surgical treatment of temporal lobe epilepsy ( TLE ) , but it is not clear that preferential temporal localization of epilepsy is associated with antecedent FC . Methods : We prospect ively inquired about FC and their characteristics in all patients presenting to an epilepsy clinic through a patient question naire and interview .  We studied the incidence of antecedent childhood febrile convulsions in relation to epilepsy diagnosis . Results : FC were reported by 133 of 1005 study patients ( 13.2 % ) . TLE was more likely to be preceded by FC ( 78/310 , 25.2 % ) than extratemporal epilepsy (ETE)(12/216 , 5.6 % ) ( p < 0.000001 ) or generalized epilepsy (GE)(16/146 , 11.0 % ) ( p < 0.001 ) . Patients with GE were more likely than patients with TLE to have had simple FC ( p < 0.00005 ) . Prolonged duration was the most common FC complex feature in TLE patients . Conclusions : We demonstrated a preferential association of FC with temporal lobe foci and a weaker association between FC and GE . FC does not appear to be a clear risk factor for ETE Epilepsy in patients with brain tumours is common . The incidence of seizures varies from 20 to 70 % with the highest incidence in low- grade gliomas ( 60–70 % ) 1 . There is an increasing use of systemic chemotherapy in patients with brain tumours , and this raises the concern on the potential of substantial interactions between AEDs and anti-neoplastic agents . Phenytoin , carbamazepine , phenobarbital , and to a lesser extent valproate , oxcarbazepine and topiramate , are metabolised by the hepatic cytochrome P-450 system , especially the CYP 2C9 , CYP 2C19 , CYP 3A4 and CYP 2B1 iso-enzyme 2 , 3 . To a more or lesser extent , all these AEDs have inductory or inhibitory effects on one or more iso-enzymes . Many chemotherapeutic agents also are metabolised by the hepatic CYP system4 . Glucocorticoids are of special interest in patients with brain tumours .  Dexamethasone is metabolised by CYP 3A4 , and mostly induces it 5 .  Levetiracetam ( LEV ) , a novel AED , has no known pharmacological interactions as it has no effect on mixed function oxidase liver enzymes and has no protein-binding properties 6 . Therefore , LEV may be a particularly useful drug in this group of patients . We performed a prospect i ve feasibility study to evaluate the safety and efficacy of LEV in this patient group
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 .
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 .