[Preventing the recurrence of febrile seizures: intermittent prevention with rectal diazepam compared with continuous treatment with sodium valproate]. Double-blind, randomized trial of diazepam versus placebo for prevention of recurrence of febrile seizures. Diazepam versus clobazam for intermittent prophylaxis of febrile seizures. Effect of acetaminophen and of low intermittent doses of diazepam on prevention of recurrences of febrile seizures. Comparison of phenobarbitone, phenytoin with sodium valproate: randomized, double-blind study. A controlled trial of diazepam administered during febrile illnesses to prevent recurrence of febrile seizures. Placebo-controlled study of phenobarbitone and phenytoin in the prophylaxis of febrile convulsions. Intention to treat febrile convulsions with rectal diazepam, valproate or phenobarbitone. Prevention of recurrent febrile convulsions--a randomized therapeutic assay: sodium valproate, phenobarbital and placebo. Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. The first febrile seizure--antipyretic instruction plus either phenobarbital or placebo to prevent recurrence. The value of phenobarbital in the child who has had a single febrile seizure: a controlled prospective study. Effectiveness of intermittent diazepam prophylaxis in febrile seizures: long-term prospective controlled study. Intermittent oral diazepam prophylaxis in febrile convulsions: its effectiveness for febrile seizure recurrence. Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial. Randomized, controlled trial of ibuprofen syrup administered during febrile illnesses to prevent febrile seizure recurrences. Antipyretic agents for preventing recurrences of febrile seizures: randomized controlled trial. Intermittent prophylaxis in febrile convulsions: diazepam or valproic acid? Effective short-term diazepam prophylaxis in febrile convulsions. Late cognitive effects of early treatment with phenobarbital. Role of phenobarbitone in preventing recurrence of febrile convulsions. Continuous sodium valproate or phenobarbitone in the prevention of 'simple' febrile convulsions. Comparison by a double-blind trial. Phenobarbital for febrile seizures--effects on intelligence and on seizure recurrence. Continuous midazolam versus diazepam infusion for refractory convulsive status epilepticus. Comparative double blind clinical trial of phenytoin and sodium valproate as anticonvulsant prophylaxis after craniotomy: efficacy, tolerability, and cognitive effects. Behavior disturbance, phenobarbital, and febrile seizures. Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. Randomised controlled trial to assess acceptability of phenobarbital for childhood epilepsy in rural India. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. A controlled trial of pyridoxine supplementation in children with febrile convulsions. Rectal diazepam gel for treatment of acute repetitive seizures in adults. Recurrence risk after first febrile seizure and effect of short term diazepam prophylaxis. Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study.
Sixty nine children suffering from a first febrile seizure without evidence of neurologic disorder or associated risk factors were randomly assigned to one of three groups: no treatment; intermittent rectal diazepam; or continuous oral sodium valproate. All patients were followed for two years. Periodical controls were performed every three months in order to record febrile episodes, recurrent seizures, and treatment side affects. Rate of recurrent febrile seizures was 16% in control group, and 5.5% in diazepam group. Sodium valproate group showed no recurrences in the follow-up period. The low relapsing rate in control group suggests that prophylaxis should not be established even if it is requested by certain parental attitudes. The aim of this study was to evaluate the efficacy and tolerance of intermittent oral administration of diazepam during hyperthermia for reducing the recurrence of febrile seizure: 185 children, between 8 months and 3 years of age, with a first febrile seizure and normal neurologic development, were randomly assigned in a double-blind fashion to receive orally administered diazepam (0.5 mg/kg, then 0.20 mg/kg, every 12 hours) or placebo, whenever the rectal temperature was more than 38 degrees C. The main criterion of efficacy was the seizure recurrence rate 1 year after the first seizure. The duration of the study was 3 years; eight different centers in France participated. There were 462 febrile episodes and 1000 days with prophylactic treatment. The recurrence rates did not differ between the diazepam group (16%) and the placebo (19.5%) group. The children with recurrent seizures were significantly younger at the time of the first seizure (17 +/- 6.9 months) than children without a recurrent seizure (21 +/- 8.5 months). In children with recurrent seizures, prophylactic treatment was correctly administered to only 1 of 15 children in the diazepam group and to 7 of 18 children in the placebo group. The following were the reasons for this poor cooperation: convulsion being the first manifestation of the fever (seven cases in each group), parents neglecting to give treatment (nine cases), and refusal to take treatment by two children. Side effects were similar in the two groups except for hyperactivity, which was more frequent in the diazepam (138 days) than in the placebo (34 days) group. Intermittent oral administration of diazepam at the onset of fever offered no advantage over placebo in preventing recurrence of seizure. This finding probably reflects a lack of efficacy of the intermittent method rather than of diazepam itself. To compare the effectiveness of intermittent clobazam versus diazepam therapy in preventing the recurrence of febrile seizures and assess adverse effects of each drug.
                This prospective randomized controlled trial was performed on neurologically normal children aged from 6 months to 5 years with a history of simple febrile seizures and normal electroencephalogram without any evidence of acute central nervous system infection. The patients were randomly prescribed with oral clobazam (37 cases) or diazepam (35 cases) when they developed a febrile disease. They were advised to use the medications during the first 48 h of the onset of fever. All the patients were monitored regarding developing seizure and adverse effects of the drugs. All patients were followed for 12 months.
                Overall, 243 episodes of fever occurred during the period, including 116 episodes in the clobazam group and 127 episodes in the diazepam group. Recurrence of seizures occurred in 2 (1.7%) subjects in the clobazam group, and in 4(3.1%) cases in the diazepam group. (P value=0.474). Twenty cases (54%) in the diazepam group and 5 (14.2%) cases in the clobazam group developed drowsiness and sedation during the follow-up period (P value=0.0001).
                Intermittent clobazam therapy seems advantageous to diazepam due to similar efficacy but significantly lower adverse effects such as drowsiness and sedation. Acetaminophen and low doses of diazepam were evaluated for the prevention of recurrences of febrile seizures in a placebo-controlled, double-blind trial. Children after their first febrile seizure were assigned to receive either one dose of rectally administered diazepam, and then, after 6 hours, oral doses of 0.2 mg/kg three times a day for the first 2 days if the fever stayed greater than 38.5 degrees C, or a placebo similarly during forthcoming febrile episodes. In addition, each febrile episode was randomly assigned to be treated with acetaminophen or the placebo. Thus four groups were examined for 2 years: patients receiving two kinds of placebo, patients receiving diazepam and a placebo, patients receiving acetaminophen and a placebo, and patients receiving both diazepam and acetaminophen. Of a total of 180 patients (102 boys), 161 were followed for the 2-year period and 157 were seen at the last outpatient examination: 80 in the diazepam group and 77 in the placebo group. The final analysis of the efficacy of the drugs was made on the basis of the data from 153 patients who had had at least one febrile episode during follow-up. There were 641 fever events during this period, and 38 children (21.1%) had 55 recurrences of febrile seizures. Acetaminophen had no effect on the recurrence rate. Seizures recurred at least once in 21 patients (28.4%) receiving diazepam and 17 (21.5%) receiving a placebo (p = 0.4138, log-rank test). The combination of antipyretic agents with anticonvulsant medication did not reduce the recurrence of febrile seizures. Our results show that low doses of acetaminophen or diazepam or both are ineffective for preventing febrile seizures. To compare the efficacy and side effects of phenobarbitone (PB), phenytoin (PHT) and sodium valproate (SVP) in controlling generalized tonic-clonic convulsions (GTC).
                Randomized, double blind clinical trial.
                Out-Patients in a tertiary care hospital.
                151 children with GTC, aged 4-12 yrs, from Madras city were enrolled. At the end of 2 yrs, 127 children remained in the study.
                Each child was given one active drug and 2 placebo tablets. Clinical, hematological and biochemical evaluations were done every month. Serum drug levels were assessed periodically.
                Recurrence of convulsion and side effects.
                The proportion of children with recurrence did not differ among the 3 groups. More than one side effect was observed in 16 (32%) children on PB, 20 (40%) children on PHT and 9 (19%) children on SVP and this difference was statistically significant (p < 0.05). Hyperactivity was the major side effect of PB, observed in 22% of children.
                All 3 drugs were equally effective in controlling seizures. Side effects were minimal with SVP followed by PB. Though side effects were more frequent with PHT, most of them disappeared on adjusting drug dosage. Least expensive phenobarbitone may be preferred as the first drug of choice but, only for pre-school children. SVP is advised for school going children. Phenobarbital, once widely prescribed to prevent febrile seizures, is now in disfavor because of its side effects and lack of efficacy. Diazepam, administered only during episodes of fever, may be a safe, effective agent to prevent the recurrence of febrile seizures.
                We conducted a randomized, double-blind, placebo-controlled trial among 406 children (mean age, 24 months) who had at least one febrile seizure. Diazepam (0.33 mg per kilogram of body weight) or placebo was administered orally every eight hours during all febrile illnesses.
                During a mean follow-up of 1.9 years (a period during which 90 percent of febrile seizures recur), our intention-to-treat analysis showed a reduction of 44 percent in the risk of febrile seizures per person-year with diazepam (relative risk = 0.56; 95 percent confidence interval, 0.38 to 0.81; P = 0.002). A survival analysis of the length of time to the first recurrent febrile seizure did not show a significant difference between the treatment groups (P = 0.064 by the log-rank test), but after adjustment for covariates, diazepam was found to have a benefit (P = 0.027 by Cox regression analysis). An analysis restricted to children who had seizures while actually receiving the study medication (7 in the diazepam group and 29 in the placebo group) showed an 82 percent reduction in the risk of febrile seizures with diazepam (relative risk = 0.18; 95 percent confidence interval, 0.09 to 0.37; P < 0.001). Of the 153 children who took at least one dose of diazepam, 39 percent had ataxia, lethargy, or irritability or at least one other moderate side effect that was reversed after a reduction in the dose. There were no severe side effects.
                Oral diazepam, given only when fever is present, is safe and reduces the risk of recurrent febrile seizures. 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 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 randomly 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 prophylactic 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. 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 randomized 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 outpatients, 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 questioned 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) The medical treatment of childhood epilepsy is largely influenced by clinical trials in adult patients. We know of only one randomised comparative trial (of two drugs) in newly diagnosed childhood epilepsy. We have undertaken a long-term, prospective, randomised, unmasked, pragmatic trial of the comparative efficacy and toxicity of four standard antiepileptic drugs used as monotherapy in children with newly diagnosed epilepsy.
                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 randomly allocated treatment with phenobarbitone, phenytoin, carbamazepine, or sodium valproate. The protocol was designed to conform to standard clinical practice. Efficacy was assessed by time to first seizure after the start of treatment and time to achieving 1-year remission.
                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 randomised 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 standard drugs available for newly diagnosed tonic-clonic or partial seizures with or without secondary generalisation in children. A randomized 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 randomized 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. 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 randomly 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. The efficacy of intermittent rectal diazepam prophylaxis is assessed in the prevention of febrile seizures. In a prospective randomized cohort trial, 139 children (77 girls, 62 boys) who experienced a first febrile seizure were allocated to two groups: group A, which received intermittent diazepam (n = 68), and group B, which received no prophylaxis (n = 71). All children had a 3-year follow-up. The inclusion criteria were no personal history of afebrile seizures, normal neurodevelopment, no previous anticonvulsant therapy, and age between 6 months and 3 years. Each group was stratified to low, intermediate, and high risk according to the available clinical data. The 36-month recurrence rates in the no-prophylaxis group were 83% in high-risk patients, 55% in intermediate-risk patients, and 46% in low-risk patients. In the prophylaxis group, the recurrence rates were reduced in all risk groups: 38%, 35%, and 33%, respectively. Intermittent diazepam prophylaxis reduces the recurrence rate mainly in high-risk children provided that sufficient doses are given on time and adequately. In order to evaluate the effectiveness of diazepam for the reduction in the recurrence of febrile seizures we carried out a prospective study in two groups of children; Group A: 45 children (25 female, 20 male), receiving oral prophylaxis with diazepam, and Group B: 65 children (35 female, 30 male) who did not receive any oral prophylaxis. All subjects of both groups were followed for at least 4 years and finally re-evaluated at the mean age of 6.7+/-1.4 years. Among the patients of Group A, recurrent febrile seizures (FS) occurred in five of the 45 children (11.1%). Among the 65 children of Group B, 20 (30.7%) went on to have one or more additional episodes. In conclusion, our study demonstrates that oral diazepam, given only when fever is present, is an effective means of reducing the risk of recurrences of FS. Recent studies have shown that most newly diagnosed epileptic patients can be satisfactorily treated with a single antiepileptic drug. We therefore undertook a prospective randomised 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 randomly allocated to treatment with phenobarbitone, phenytoin, carbamazepine, or sodium valproate. The protocol was designed to conform with standard 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 randomised 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. Febrile seizures recur frequently. Factors increasing the risk of febrile seizure recurrence include young age at onset, family history of febrile seizures, previous recurrent febrile seizures, time lapse since previous seizure <6 months, relative low temperature at the initial seizure, multiple type initial seizure, and frequent febrile illnesses. Prevention of seizure recurrences serves two useful purposes: meeting parental fear of recurrent febrile seizures in general and reducing the (small) risk of a long-lasting and eventually injurious recurrent seizure. In daily practice, children with febrile seizures often are treated with antipyretics during fever to prevent febrile seizure recurrences. Thus far, no randomized placebo-controlled trial has been performed to assess the efficacy of intermittent antipyretic treatment in the prevention of seizure recurrence.
                We performed a randomized, double-blind, placebo-controlled trial. Children 1 to 4 years of age who had had at least one risk factor for febrile seizure recurrence were enrolled. They were randomly assigned to either ibuprofen syrup, 20 mg/mL, 0.25 mL (= 5 mg) per kilogram of body weight per dose, or matching placebo, to be administered every 6 hours during fever (temperature, >/=38.5 degrees C). Parents were instructed to take the child's rectal temperature immediately when the child seemed ill or feverish and to promptly administer the study medication when the temperature was >/=38.5 degrees C. Doses were to be administered every 6 hours until the child was afebrile for 24 hours. The parents were instructed not to administer any other antipyretic drug to the child. For measuring rectal temperature, a Philips HP5316 digital thermometer (Philips, Eindhoven, The Netherlands) was distributed. During subsequent treatment of the fever episode, parents had to call the investigator at least once each day to notify the investigator in case of febrile seizure recurrence. The investigator could be contacted by parents 24 hours per day. The primary outcome was the first recurrence of a febrile seizure. Kaplan-Meier curves and Cox regression were used for the statistical analysis. The treatment effect on the course of the temperature was assessed using analysis of covariance, with temperature at fever onset as covariate. Two analyses were performed. In an intention-to-treat analysis, all first recurrences were considered regardless of study medication compliance. A per-protocol analysis was limited to those recurrences that occurred in the context of study medication compliance.
                Between October 1, 1994, and April 1, 1996, 230 children were randomly assigned to ibuprofen syrup (111 children) or placebo (119 children). Median follow-up time was 1.04 years (25th-75th percentiles; 0.7-1.8 years) in the ibuprofen group and 0.98 years (0.7-1.6 years) in the placebo group. Of all children, 67 had a first febrile seizure recurrence, with 31 in the ibuprofen group and 36 in the placebo group. The 2-year recurrence probabilities were 32% and 39%, respectively. The recurrence risk in the ibuprofen group was 0.9 (95% confidence interval: 0.6-1.5) times the recurrence risk in the placebo group (intention to treat). Adjustment for baseline characteristics did not affect the risk-reduction estimate. Of the 67 recurrences, 30 occurred in the context of study medication compliance (13 ibuprofen, 17 placebo). The per-protocol analysis, which was limited to these events, showed similar results. A significant reduction in temperature (0.7 degrees C) after fever onset in the ibuprofen group compared with the placebo group was demonstrated if all 555 fever episodes were considered. In the fever episodes with a seizure recurrence, a similar temperature increase was shown in both groups, with no significant difference between the intention-to-treat and the per-protocol analysis.
                (ABSTRACT TRUNCATED) To evaluate the efficacy of different antipyretic agents and their highest recommended doses for preventing febrile seizures.
                Randomized, placebo-controlled, double-blind trial.
                Five hospitals, each working as the only pediatric hospital in its region.
                A total of 231 children who experienced their first febrile seizure between January 1, 1997, and December 31, 2003. The children were observed for 2 years.
                All febrile episodes during follow-up were treated first with either rectal diclofenac or placebo. After 8 hours, treatment was continued with oral ibuprofen, acetaminophen, or placebo.
                Recurrence of febrile seizures.
                The children experienced 851 febrile episodes, and 89 of these included a febrile seizure. Febrile seizure recurrences occurred in 54 of the 231 children (23.4%). There were no significant differences between the groups in the main measure of effect, and the effect estimates were similar, as the rate was 23.4% (46 of 197) in those receiving antipyretic agents and 23.5% (8 of 34) in those receiving placebo (difference, 0.2; 95% confidence interval, -12.8 to 17.6; P = .99). Fever was significantly higher during the episodes with seizure than in those without seizure (39.7 degrees C vs 38.9 degrees C; difference, 0.7 degrees C; 95% confidence interval, -0.9 degrees C to -0.6 degrees C; P < .001), and this phenomenon was independent of the medication given.
                Antipyretic agents are ineffective for the prevention of recurrences of febrile seizures and for the lowering of body temperature in patients with a febrile episode that leads to a recurrent febrile seizure. In an open, prospective, randomized, and hospital-based study, comprising 219 consecutive children, 169 were given intermittent prophylaxis for one year, receiving either diazepam or valproic acid after their first febrile convulsion. Children admitted on odd dates (n = 89) were given rectal diazepam in solution every 12 h, whenever the temperature was 38.5 degrees C or more. Children admitted on even dates (n = 80) were given valproic acid as suppositories at times of fever. Twenty-three children in the diazepam group had a recurrence within 1 year versus 14 in the valproic acid group. On an intention-to-treat basis the 12-month recurrence rates in the 2 groups were similar, 27% vs 20%. The latter is well below figures for untreated controls from Denmark (32%), suggesting that intermittent valproic acid at times of fever may be effective, but further studies are needed. The number of complex recurrences, however, were significantly higher in the valproic acid group than in the diazepam group. Parental non-compliance was a major problem, and in the 2 study groups only 5 and 12 children, respectively, with recurrences were treated adequately. Sixty-nine children receiving diazepam had side-effects vs 37 receiving valproic acid. None were serious. The efficacy of short-term diazepam prophylaxis in febrile convulsions was evaluated in a prospective, controlled study. A total of 289 consecutive children admitted with their first febrile seizure were randomized into two groups. One group received short-term prophylaxis for 18 months with rectally administered diazepam in solution whenever the temperature was greater than or equal to 38.5 degrees C. The control group received no prophylaxis, but diazepam rectally in the event of new seizures. The short-term prophylaxis, a mean of five doses of diazepam per child per year, afforded effective seizure control; the 18-month recurrence rate was reduced from 39% to 12% (P less than 0.001), the total number of recurrences from 77 to 23 (P less than 0.001), the long-lasting recurrences from 5.0% to 0.7% (P less than 0.05). The risk of subsequent epilepsy within the first 2 years was the same, regardless of receiving prophylaxis (3%) or not (3%); it was low after simple febrile convulsions (no cases of epilepsy in 230 children) but considerable after complex febrile seizures (20%) or seizures associated with severe interictal EEG abnormalities (50%). We previously reported that IQ was significantly lowered in a group of toddler-aged children randomly assigned to receive phenobarbital or placebo for febrile seizures and there was no difference in the febrile seizure recurrence rate. We retested these children 3-5 years later, after they had entered school, to determine whether those effects persisted over the longer term and whether later school performance might be affected. On follow-up testing of 139 (of the original n = 217) Western Washington children who had experienced febrile seizures, we found that the phenobarbital group scored significantly lower than the placebo group on the Wide Range Achievement Test (WRAT-R) reading achievement standard score (87.6 vs 95.6; p = 0.007). There was a nonsignificant mean difference of 3.71 IQ points on the Stanford-Binet, with the phenobarbital-treated group scoring lower (102.2 vs 105.7; p = 0.09). There were five children in our sample with afebrile seizures during the 5-year period after the end of the medication trial. Two had been assigned to phenobarbital, and three had been in the placebo group. We conclude there may be a long-term adverse cognitive effect of phenobarbital on the developmental skills (language/verbal) being acquired during the period of treatment and no beneficial effect on the rate of febrile seizure recurrences or later nonfebrile seizures. A randomized double blind placebo controlled trial was carried out to study the effect of phenobarbitone (PB) in preventing recurrences of simple and atypical febrile convulsions among children in the age group 6 months to 6 years. Children with simple febrile convulsions were randomly allocated to receive either phenobarbitone or placebo. Children with atypical convulsions were treated with phenobarbitone, as a third group. Thirty children were admitted in each group. All the children were followed up for a period of twelve months. Recurrence of convulsions and side effects of PB were recorded. Recurrence occurred in only 7% (95% confidence interval: 1-22) of children on Phenobarbitone, suffering from either simple or atypical febrile convulsions, compared to 53% (95% confidence interval: 34-72) of children on placebo, suffering from simple febrile convulsions. With Phenobarbitone, 5% of children had intolerable side effects. These results suggest that long term prophylaxis with phenobarbitone, even in simple febrile convulsions will be useful. Of the 265 children aged between 6 and 18 months admitted to hospital in a 26-month period each with his first febrile convulsion, there were 64 who satisfied our criteria for a simple febrile convulsion. Of these, 43 (random) were entered into a double-blind trial of continuous sodium valproate versus phenobarbitone, and 21 were untreated. The dosage was phenobarbitone 3-6 mg/kg per day; sodium valproate 30-60 mg/kg per day. 39 completed treatment (21 phenobarbitone, 18 sodium valproate), 2 in each group being withdrawn because of unacceptable side effects. Close supervision and random serum drug estimations showed compliance to be good. After a mean treatment period of 12 months (mean age 25 months) there had been one recurrence in the sodium valproate group compared with 7 in the untreated group (P less than 0.05), and 4 recurrences in the phenobarbitone group. The difference between treatment and no treatment was significant (P less than 0.05). These results suggest that in simple febrile convulsions occurring between 6 and 18 months of age sodium valproate is as effective as phenobarbitone in preventing recurrence and that either treatment is better than none. 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 randomly assigned to daily doses of phenobarbital (4 to 5 mg per kilogram of body weight per day) with the IQs of a group randomly 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. The objective of this study was to compare the efficacy of continuous midazolam and diazepam infusion for the control of refractory status epilepticus. An open-label, randomized control study was undertaken at the Pediatric Emergency and Intensive Care Service of a multidisciplinary teaching and referral hospital. Subjects included 40 children, 2 to 12 years of age, with refractory status epilepticus (motor seizures uncontrolled after two doses of diazepam, 0.3 mg/kg per dose, and phenytoin infusion, 20 mg/kg). Either continuous midazolam (n = 21) or diazepam infusion (n = 19) in incremental doses was administered. The primary outcome measure was the proportion of children in each group with successful control of refractory status epilepticus. The secondary outcome measure was the time to control seizure activity, recurrence of seizure after initial control, if any, the frequency of hypotension, and the need for ventilation. The two groups were similar in age (mean +/- SD = 4.9 +/- 43.6 months) and etiology. Twenty-three (57.5%) patients had acute central nervous system infection. Refractory status epilepticus was controlled in 18 (86%) and 17 (89%) patients in the midazolam and diazepam groups, respectively (P = not significant). The median time to seizure control was 16 minutes in both groups, but in the midazolam group, seizures recurred in more children (57% versus 16% in diazepam group; P < .05). The maximum dose (mean +/- SD) of midazolam and diazepam required was 5.3 +/- 2.6 microg/kg/min and 0.04 +/- 0.02 mg/kg/min, respectively. About half of the patients needed mechanical ventilation and 40% had hypotension in both groups, but the mortality was higher in the midazolam group (38%) as compared to the diazepam group (10.5%, P < .1 > .05). Continuous midazolam and diazepam infusions were equally effective for control of refractory status epilepticus. However, midazolam was associated with more seizure recurrence and higher mortality in refractory status epilepticus predominantly caused by central nervous system infections. To determine the efficacy, tolerability, and impact on quality of life and cognitive functioning of anticonvulsant prophylaxis with phenytoin or sodium valproate in patients after craniotomy.
                A prospective, stratified, randomised, double blind single centre clinical trial was performed, comparing two groups of 50 patients each, who underwent craniotomy for different pathological conditions and who were treated for 1 year after surgery with either 300 mg phenytoin/day or 1500 mg sodium valproate/day. During the study period patients were seen in the outpatient clinic at 1.5, 3, 6, and 12 months, when medical history, adverse events, and drug plasma concentrations were evaluated. Neuropsychological functioning and quality of life were assessed on the last three visits. In cases of a seizure an EEG was performed, drug plasma concentration assessed, and medication subsequently increased.
                Of the 100 included patients 14 (seven in each group) experienced one or more postoperative seizures. Severity of the seizures was comparable in the two groups. In all patients, drug plasma concentrations were in the low or subtherapeutic ranges at the time of the first postoperative seizure. Five patients in the phenytoin group and two in the valproate group had to stop their treatment due to drug related adverse events. Sixty patients completed the 12 month period. Analysis of neuropsychological and quality of life data showed no significant differences.
                For efficacy, tolerability, impact on cognitive functioning, and quality of life, no major differences were found between phenytoin and valproate prophylaxis. Valproate is an alternative for anticonvulsant prophylaxis in patients after craniotomy. Of 109 children treated daily with phenobarbital following the first fibrile convulsion, 42% developed a behavior disorder, usually hyperactivity. Daily phenobarbital therapy was prematurely discontinued in 54% of the children with behavior abnormality (20% of those treated). The behavior disturbance usually appeared within several months, was no correlated with high blood barbiturate levels, disappeared in 73%, and improved in all children when barbiturate therapy was discontinued. No characteristics of the child, the initial febrile seizure, or recurrence of febrile seizures were significantly correlated with the occurrence of the behavior disorder except for behavioral abnormality preceding the initial febrile convulsion. Eighteen percent of the children who received no phenobarbital developed behavior disorder, most often hyperactivity. The behavior disturbance spontaneously disappeared in 52%. Among these children not given phenobarbital, the group with normal behavior had a greater frequency of family history of seizures, especially febrile convulsions, and a lower frequency of preseizure behavior disturbance; abnormalities of pregnancy, labor, delivery, and neonatal period; delayed milestones; long seizures; abnormal results of neurological examination; abnormal EEG; and recurrent febrile seizures. In a randomized, nonblinded clinical trial, 36 consecutive patients with generalized convulsive status epilepticus were treated with either combination diazepam and phenytoin (DZ/DPH) or phenobarbital (PB). Phenytoin was added to the PB regimen if seizures persisted for 10 minutes after beginning therapy. The cumulative convulsion time (total time spent in active convulsive movements) was shorter for the PB group than for the DZ/DPH group (median, 5 versus 9 minutes, p less than 0.06); the response latency (elapsed time from initiation of therapy to the end of the last convulsion) was also shorter for the PB group (median, 5.5 versus 15 minutes, p less than 0.10). The median cumulative convulsion time is between 0 and 14 minutes shorter for the PB regimen than for the DZ/DPH regimen (95% confidence interval). Similarly, the median response latency for the PB regimen is between 1 minute longer and 20 minutes shorter than that for the DZ/DPH regimen (95% confidence interval). The frequencies of intubation, hypotension, and arrhythmias were similar in the two groups. Eleven of 18 patients in the PB group responded to phenobarbital monotherapy. We conclude that the PB regimen is rapidly effective, comparable in safety, and enjoys certain practical advantages in comparison with the DZ/DPH regimen. We conducted a 10-center, double-blind trial to compare the efficacy and toxicity of four antiepileptic drugs in the treatment of partial and secondarily generalized tonic-clonic seizures in 622 adults. Patients were randomly assigned to treatment with carbamazepine, phenobarbital, phenytoin, or primidone and were followed for two years or until the drug failed to control seizures or caused unacceptable side effects. Overall treatment success was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest with primidone (P less than 0.002). Differences in failure rates of the drugs were explained primarily by the fact that primidone caused more intolerable acute toxic effects, such as nausea, vomiting, dizziness, and sedation. Decreased libido and impotence were more common in patients given primidone. Phenytoin caused more dysmorphic effects and hypersensitivity. Control of tonic-clonic seizures did not differ significantly with the various drugs. Carbamazepine provided complete control of partial seizures more often than primidone or phenobarbital (P less than 0.03). Overall, carbamazepine and phenytoin are recommended drugs of first choice for single-drug therapy of adults with partial or generalized tonic-clonic seizures or with both. 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 randomised comparison of phenobarbital and phenytoin to assess the acceptability and efficacy of phenobarbital as monotherapy for childhood epilepsy in rural India.
                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 randomly 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 questionnaire (BSQ) for those aged 2-5 years, at 12 months or at withdrawal from treatment. Analysis was by intention to treat.
                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 randomisation 0.97 [0.28-3.30]).
                This evidence supports the acceptability of phenobarbital as a first-line drug for childhood epilepsy in rural settings in developing countries. Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled.
                Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days.
                As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use. A total of 107 children who had been hospitalized following a febrile convulsion were enrolled into the trial. By random allocation, 55 children were treated with pyridoxine hydrochloride (20 mgs twice daily) and the remaining 52 children were treated with a placebo until there had been either a further convulsion or a year had passed without recurrence. Eighty children were adequately followed up and of these, 17 had a recurrent febrile convulsion while receiving medication. Recurrences occurrences occurred in 7 of the 38 children receiving pyridoxine and in 10 of the 42 children receiving placebo (X2 = .346, p greater than 0.5). Initial tryptophan load tests had been abnormal in 34 children, and of these, recurrences occurred in 3 of the 17 who received pyridoxine and in 3 of the 17 who received placebo. It has yet to be shown that pyridoxine supplementation protects children from recurrent febrile convulsions. To evaluate the efficacy and tolerability of diazepam (DZP) rectal gel (Diastat; Elan Pharmaceuticals, Dublin, Ireland) for the treatment of acute repetitive seizures in adult patients in 2 multicenter, double-blind, placebo-controlled parallel studies.
                Ninety-six adults 18 years or older with acute repetitive seizures, 70 of whom received treatment, were randomized into the 2 studies. Active and placebo medications were supplied in prefilled, identical-appearing delivery systems. In study 001, patients received a second dose 4 hours after the initial treatment. Patients in study 003 received only 1 treatment. Patients were observed for 12 hours after the first dose.
                There was a significant reduction in seizure frequency in patients who received DZP compared with the placebo group. The median number of seizures per hour in the group treated with DZP rectal gel was 0.00, vs 0.13 in the placebo group (P =.002). In addition, significantly more DZP rectal gel-treated patients remained seizure-free during the 12-hour observation period (71% [22/31] vs 28% [11/39]). Using Kaplan-Meier life-table analysis, time to the next seizure was found to be significantly longer in DZP rectal gel-treated than placebo-treated patients (P<.001). Global assessment as provided by the caregivers was in favor of DZP rectal gel for both study 001 (P =.17) and study 003 (P =.02). Dizziness and somnolence were the only central nervous system adverse events that occurred more frequently in patients receiving DZP rectal gel than in those receiving placebo.
                In adults, rectal DZP formulated as Diastat significantly reduced the likelihood of seizure recurrence during an episode of acute repetitive seizures, with minimal safety concerns. In a prospective randomised study, 289 children admitted consecutively to hospital with their first febrile seizure were allocated, by date of admission, to short term diazepam prophylaxis (n = 152) or to no prophylaxis (n = 137) and followed for 18 months. In untreated children, five major risk factors for recurrent febrile convulsions were identified: age 15 months or less at the time of the first febrile seizure, epilepsy in first degree relatives, febrile convulsions in first degree relatives, a first complex febrile seizure, and day nursery care. The 18 month recurrence rate was 80 to 100% if three to five risk factors were present, 50% if two factors were identified, 25% where one factor was found, and 12% if there were no predictors. During prophylaxis the recurrence rate was uniformly low (mean 12%) in all risk groups. In high (three or more factors) and intermediate (two factors) risk children prophylaxis provided effective seizure control and reduced the recurrence rate from 80%, or more, to 12% and 50% to 12%, respectively. In children with one risk factor 50% of all recurrences were prevented (25% to 12%). Prophylaxis was ineffective in very low risk children (12% to 12%). Seizures commonly complicate cerebral malaria and are associated with an increased risk of death and neurological sequelae. We undertook a randomised study to assess the efficacy of intramuscular phenobarbital in preventing seizures in childhood cerebral malaria.
                Children with cerebral malaria admitted to one hospital in Kilifi, Kenya, were randomly 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 standard way. Plasma phenobarbital concentrations were measured. Analyses were by intention to treat.
                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]).
                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 cannot, therefore, be recommended.
No clinically important benefits for children with febrile seizures were found for intermittent oral diazepam, phenytoin, phenobarbitone, intermittent rectal diazepam, valproate, pyridoxine, intermittent phenobarbitone or intermittent ibuprofen, nor for diclofenac versus placebo followed by ibuprofen, acetominophen or placebo. Adverse effects were reported in up to 30% of children. Apparent benefit for clobazam treatment in one recent trial needs to be replicated to be judged reliable. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management and, most importantly, the benign nature of the phenomenon.