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Prevention of recurrent febrile seizures
EDITOR'S COLUMN
Prevention of recurrent febrile seizures Disorders of high prevalence but low morbidity rates, such as febrile seizures, are rich sources of controversy. Four percent of children will have a first febrile seizure, and 30% to 40% will have at least one recurrence. I, 2 There is nearly universal agreement that the vast majority of febrile seizures cause no physical harm to the child. The most impressive evidence has come from the National Collaborative Perinatal Project. 3 This prospective cohort study identified 431 sibling pairs who were discordant for febrile seizures. When they were assessed at age 7 years, there was no difference in intelligence or academic achievement. On the other hand, most parents are extremely upset by what they perceive as a near-death event for their child.4 To date, studies of the risks and benefits of medical treatment designed to prevent recurrent febrile seizures have failed to address the effect of these treatments on parental anxiety. We suspect that the most common medical treatment aimed at reducing febrile seizure recurrences is the use of antipyretic agents. The essential precursor of a febrile seizure is fever, usually a high fever. Therefore physicians have intuitively concluded that antipyretic measures should prevent recurrences, but there is abundant evidence to the contrary. Because sponging febrile children with cool water is ineffective for fever reduction, the use of acetylsalicylic acid or acetaminophen is the only logical potential intervention. 5 The recurrence rate in the first year after a first "simple" febrile seizure was 25% in a group of children receiving intensive antipyretic instruction and placebo. 6 In a British study of 89 children with a febrile seizure, half had received an appropriate dose of antipyretics within an hour of a febrile seizure. 7 In this issue of THE JOURNAL, Uhari et al. 8 report a randomized trial of alternating acetaminophen versus placebo during subsequent illnesses, for Finnish children who had had a first febrile seizure. The authors observed no reduction in recurrences with acetaminophen. Acetaminophen was prescribed as 10 mg/kg per dose, a reasonable though not enormous dose. 9 From this study we also learn that after a first febrile seizure the risk of a recurrence appears to be 5.6% to 11.1% per febrile illness. Intuition is therefore misguided, and there is no evidence that the usual methods of Reprint requests: Peter Camfield, MD, FRCP(C), IWK Children's Hospital, Box 3070, Halifax, Nova Scotia B3J 3G9, Canada. THE JOURNALOF PEDIATRICS1995;126:929-30 Copyright © 1995 by Mosby-Year Book, Inc. 0022-3476/95/$3.00 + 0 9121164615
fever control have any effect on recurrences of febrile seizures. For physicians to continue to recommend meticulous documentation of fever and abundant use of antipyretic agents seems destined to increase parental anxiety and '"fever phobia." 10 Prescription of anticonvulsant medications is the alternative approach to the prevention of recurrences. Daily administration of phenobarbital may or may not be efficacious but does appear to alter cognitive abilities and behavior frequently--a large price for the prevention of a benign disorder. 1113 Anticonvulsant medication administered only at the time of illness might be more acceptable. Intermittent use of phenobarbital at the time of illness appears ineffective, probably because of the delay in achieving appropriate serum levels. The only placebo=controlled trials of intermittent administration of medication have been with orally administered diazepam. 8, ~4, 15 Again, the meticulous Uhari studys showed no benefit in recurrence when orally administered diazepam, 0.2 mg/kg per dose, was given every 8 hours See related article, p. 991. while the child was "feverish." Furthermore, the investigators examined the combined effect of this dose of diazepam plus acetaminophen and found the combination no better than placebo. A French randomized study of 185 patients treated with orally administered diazepam at the time of illness also found the drug to be ineffectivel4; the dose was 0.5 mg/kg as an initial dose, and then 0.2 mg/kg every 12 hours if the temperature was greater than 38 ° C. The authors concluded that the failure was related to the difficulties of early recognition of fever and the logistics of administering medication intermittently to children with multiple caretakers, asopposed to the ineffectiveness of orally administered diazepam. Some investigators have noted that febrile seizures may be the initial manifestation of fever, an observation that predicts some failures for all intermittent regimens. I6 A randomized, placebo-controlled American study of 406 children with febrile seizures found intermittent oral administration of diazepam at a dosage of 0.33 mg/kg per dose to reduce the incidence of recurrent febrile seizures "significantly.''15 On the basis of an intention-to-treat survival curve analysis, the percentage of children with at least one recurrence who received diazepam was 23% compared
929
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Camfieldetal.
with 31% of those given placebo (p = 0.064). This represents a rather modest reduction in the risk of recurrence of 26%. The way that results are presented may influence the perception of utility of a treatment. ~719 An alternative and perhaps more practical technique is to calculate the number of patients requiring treatment for one successful outcome.2719 Using the data from the U.S. study, one can calculate that 12 children would have to be treated with intermittent oral administration of diazepam to prevent a single recurrent febrile seizure. In addition, the use of intermittent diazepam could be viewed as self-defeating because 40% of the children treated with a 0.33 mg/kg dose had "moderately severe" side effects, including somnolence and ataxia. Although these side effects were apparently eliminated by dose reduction, we now know that a lower dose, 0.2 mg/kg, is ineffective.s We conclude that physicians must counsel parents that currently available oral intermittent medication regimens (diazepam or acetaminophen or both) will not prevent recurrent febrile seizures in most children. Antipyretic agents may be useful in making a febrile child more comfortable, but this is the only benefit in relation to febrile seizures. Our efforts should focus on strategies to reduce parental anxiety about this benign disorder, rather than offering children ineffective medication.
Peter R. Camfield, MD, FRCP(C) Carol S. Camfield, MD, FRCP(C) Kevin Gordon, MD, FRCP(C) Joseph M. Dooley, MB, FRCP(C) Department of Pediatrics, Division of Neurology Isaak Walton Killam Children's Hospital and Dalhousie University Halifax, Nova Scotia B3J 3G9, Canada REFERENCES 1. Nelson K, Ellenberg J. Prognosis in children with febrile seizures. Pediatrics 1978;61:720-7. 2. Annegers JF, Hauser WA, Shirto S, et al. Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med 1987;316:493-8.
The Journal of Pediatrics June 1995 3. EllenbergJH, Nelson KB. Febrile seizuresand later intellectual performance. Arch Neurol 1978;35:17-21. 4. Baumer JH, David TJ, Valentine SJ, Roberts JE, Hughes BR. Many parents think their child is dying when having a first febrile convulsion. Dev Med Child Neurol 1981;23:462-4. 5. Newman J. Evaluation of spongingto reduce body temperature in febrile children. Can Med Assoc J 1985;t32:641-2. 6. CarnfieldPR, CarnfieldCS, Shapiro S, Cummings C. The first febrile seizure: antipyreticinstructionplus either phenobarbital or placebo to prevent a recurrence. J I~DIATR1980; 97:1621. 7. Rutter N, Metcalfe DH. Febrile convulsions: what do parents do? BMJ 1978;2:1345-6. 8. UhariM, Rantala H, Vainionp~, Kurttila R. Effect of acetaminophen and of low intermittent doses of diazepam on prevention of recurrences of febrile seizures. J PEDIATR 1995; 126:991-5. 9. Compendiumofpharmaceuticalsand specialities;Toronto:CK Productions, 1994;12:15-6. 10. Schmitt BD. Fever phobia. Am J Dis Child 1980;134:176-81. 11. Newton RW. Randomized controlled trials of phenobarbitone and valproate in febrile convulsions. Arch Dis Child 1988; 63:1189-92. 12. Camfield CS, Chaplin S, Doyle AB, et al. Side effects of phenobarhital in toddlers: behavioral and cognitive aspects. J PZDIATR1979;95:361-5. 13. Farwell J, Lee YJ, Hirtz DG, Sulzbacher SI, Ellenberg JH, Nelson KB. Phenobarbitalfor febrile seizures: effects on intelligence and on seizure recurrence. N Engl J Med 1990; 322:364-9. 14. AutretE, BiUardC, Bertrand P, Motte J, Pouplard F, Jonville AP. Double-blindrandomizedtrial of diazepam versus placebo for prevention of recurrence of febrile seizures. J PEDIATR 1990;117:490-5. 15. Rosman NP, Colton T, Labazzo J, et al. A controlled trial of diazeparn administered during febrile illnesses to prevent recurrence of febrile seizures. N Engl J Med 1993;329:79-85. 16. Woff SM, Can"A, David DC, et al. The value of phenobarbital in the child who has had a single febrile seizure: a controlled prospective study. Pediatrics 1977;59:378-85. 17. Naylor CD, Chen E, Strauss B. Measured enthusiasm:does the method of reporting trial results alter perceptions of therapeutic effectiveness?Ann Intern Med 1992;117:916-21. 18. Forrow L, Taylor WC. Absolutely relative: how research results are summarized can affect treatment decisions. Am J Med 1992;92:121-4. 19. Sackett DL, Cook RJ. Understanding clinical trials. BMJ 1994;309:755-6.
Prevention of recurrent febrile seizures Disorders of high prevalence but low morbidity rates, such as febrile seizures, are rich sources of controversy. Four percent of children will have a first febrile seizure, and 30% to 40% will have at least one recurrence. I, 2 There is nearly universal agreement that the vast majority of febrile seizures cause no physical harm to the child. The most impressive evidence has come from the National Collaborative Perinatal Project. 3 This prospective cohort study identified 431 sibling pairs who were discordant for febrile seizures. When they were assessed at age 7 years, there was no difference in intelligence or academic achievement. On the other hand, most parents are extremely upset by what they perceive as a near-death event for their child.4 To date, studies of the risks and benefits of medical treatment designed to prevent recurrent febrile seizures have failed to address the effect of these treatments on parental anxiety. We suspect that the most common medical treatment aimed at reducing febrile seizure recurrences is the use of antipyretic agents. The essential precursor of a febrile seizure is fever, usually a high fever. Therefore physicians have intuitively concluded that antipyretic measures should prevent recurrences, but there is abundant evidence to the contrary. Because sponging febrile children with cool water is ineffective for fever reduction, the use of acetylsalicylic acid or acetaminophen is the only logical potential intervention. 5 The recurrence rate in the first year after a first "simple" febrile seizure was 25% in a group of children receiving intensive antipyretic instruction and placebo. 6 In a British study of 89 children with a febrile seizure, half had received an appropriate dose of antipyretics within an hour of a febrile seizure. 7 In this issue of THE JOURNAL, Uhari et al. 8 report a randomized trial of alternating acetaminophen versus placebo during subsequent illnesses, for Finnish children who had had a first febrile seizure. The authors observed no reduction in recurrences with acetaminophen. Acetaminophen was prescribed as 10 mg/kg per dose, a reasonable though not enormous dose. 9 From this study we also learn that after a first febrile seizure the risk of a recurrence appears to be 5.6% to 11.1% per febrile illness. Intuition is therefore misguided, and there is no evidence that the usual methods of Reprint requests: Peter Camfield, MD, FRCP(C), IWK Children's Hospital, Box 3070, Halifax, Nova Scotia B3J 3G9, Canada. THE JOURNALOF PEDIATRICS1995;126:929-30 Copyright © 1995 by Mosby-Year Book, Inc. 0022-3476/95/$3.00 + 0 9121164615
fever control have any effect on recurrences of febrile seizures. For physicians to continue to recommend meticulous documentation of fever and abundant use of antipyretic agents seems destined to increase parental anxiety and '"fever phobia." 10 Prescription of anticonvulsant medications is the alternative approach to the prevention of recurrences. Daily administration of phenobarbital may or may not be efficacious but does appear to alter cognitive abilities and behavior frequently--a large price for the prevention of a benign disorder. 1113 Anticonvulsant medication administered only at the time of illness might be more acceptable. Intermittent use of phenobarbital at the time of illness appears ineffective, probably because of the delay in achieving appropriate serum levels. The only placebo=controlled trials of intermittent administration of medication have been with orally administered diazepam. 8, ~4, 15 Again, the meticulous Uhari studys showed no benefit in recurrence when orally administered diazepam, 0.2 mg/kg per dose, was given every 8 hours See related article, p. 991. while the child was "feverish." Furthermore, the investigators examined the combined effect of this dose of diazepam plus acetaminophen and found the combination no better than placebo. A French randomized study of 185 patients treated with orally administered diazepam at the time of illness also found the drug to be ineffectivel4; the dose was 0.5 mg/kg as an initial dose, and then 0.2 mg/kg every 12 hours if the temperature was greater than 38 ° C. The authors concluded that the failure was related to the difficulties of early recognition of fever and the logistics of administering medication intermittently to children with multiple caretakers, asopposed to the ineffectiveness of orally administered diazepam. Some investigators have noted that febrile seizures may be the initial manifestation of fever, an observation that predicts some failures for all intermittent regimens. I6 A randomized, placebo-controlled American study of 406 children with febrile seizures found intermittent oral administration of diazepam at a dosage of 0.33 mg/kg per dose to reduce the incidence of recurrent febrile seizures "significantly.''15 On the basis of an intention-to-treat survival curve analysis, the percentage of children with at least one recurrence who received diazepam was 23% compared
929
930
Camfieldetal.
with 31% of those given placebo (p = 0.064). This represents a rather modest reduction in the risk of recurrence of 26%. The way that results are presented may influence the perception of utility of a treatment. ~719 An alternative and perhaps more practical technique is to calculate the number of patients requiring treatment for one successful outcome.2719 Using the data from the U.S. study, one can calculate that 12 children would have to be treated with intermittent oral administration of diazepam to prevent a single recurrent febrile seizure. In addition, the use of intermittent diazepam could be viewed as self-defeating because 40% of the children treated with a 0.33 mg/kg dose had "moderately severe" side effects, including somnolence and ataxia. Although these side effects were apparently eliminated by dose reduction, we now know that a lower dose, 0.2 mg/kg, is ineffective.s We conclude that physicians must counsel parents that currently available oral intermittent medication regimens (diazepam or acetaminophen or both) will not prevent recurrent febrile seizures in most children. Antipyretic agents may be useful in making a febrile child more comfortable, but this is the only benefit in relation to febrile seizures. Our efforts should focus on strategies to reduce parental anxiety about this benign disorder, rather than offering children ineffective medication.
Peter R. Camfield, MD, FRCP(C) Carol S. Camfield, MD, FRCP(C) Kevin Gordon, MD, FRCP(C) Joseph M. Dooley, MB, FRCP(C) Department of Pediatrics, Division of Neurology Isaak Walton Killam Children's Hospital and Dalhousie University Halifax, Nova Scotia B3J 3G9, Canada REFERENCES 1. Nelson K, Ellenberg J. Prognosis in children with febrile seizures. Pediatrics 1978;61:720-7. 2. Annegers JF, Hauser WA, Shirto S, et al. Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med 1987;316:493-8.
The Journal of Pediatrics June 1995 3. EllenbergJH, Nelson KB. Febrile seizuresand later intellectual performance. Arch Neurol 1978;35:17-21. 4. Baumer JH, David TJ, Valentine SJ, Roberts JE, Hughes BR. Many parents think their child is dying when having a first febrile convulsion. Dev Med Child Neurol 1981;23:462-4. 5. Newman J. Evaluation of spongingto reduce body temperature in febrile children. Can Med Assoc J 1985;t32:641-2. 6. CarnfieldPR, CarnfieldCS, Shapiro S, Cummings C. The first febrile seizure: antipyreticinstructionplus either phenobarbital or placebo to prevent a recurrence. J I~DIATR1980; 97:1621. 7. Rutter N, Metcalfe DH. Febrile convulsions: what do parents do? BMJ 1978;2:1345-6. 8. UhariM, Rantala H, Vainionp~, Kurttila R. Effect of acetaminophen and of low intermittent doses of diazepam on prevention of recurrences of febrile seizures. J PEDIATR 1995; 126:991-5. 9. Compendiumofpharmaceuticalsand specialities;Toronto:CK Productions, 1994;12:15-6. 10. Schmitt BD. Fever phobia. Am J Dis Child 1980;134:176-81. 11. Newton RW. Randomized controlled trials of phenobarbitone and valproate in febrile convulsions. Arch Dis Child 1988; 63:1189-92. 12. Camfield CS, Chaplin S, Doyle AB, et al. Side effects of phenobarhital in toddlers: behavioral and cognitive aspects. J PZDIATR1979;95:361-5. 13. Farwell J, Lee YJ, Hirtz DG, Sulzbacher SI, Ellenberg JH, Nelson KB. Phenobarbitalfor febrile seizures: effects on intelligence and on seizure recurrence. N Engl J Med 1990; 322:364-9. 14. AutretE, BiUardC, Bertrand P, Motte J, Pouplard F, Jonville AP. Double-blindrandomizedtrial of diazepam versus placebo for prevention of recurrence of febrile seizures. J PEDIATR 1990;117:490-5. 15. Rosman NP, Colton T, Labazzo J, et al. A controlled trial of diazeparn administered during febrile illnesses to prevent recurrence of febrile seizures. N Engl J Med 1993;329:79-85. 16. Woff SM, Can"A, David DC, et al. The value of phenobarbital in the child who has had a single febrile seizure: a controlled prospective study. Pediatrics 1977;59:378-85. 17. Naylor CD, Chen E, Strauss B. Measured enthusiasm:does the method of reporting trial results alter perceptions of therapeutic effectiveness?Ann Intern Med 1992;117:916-21. 18. Forrow L, Taylor WC. Absolutely relative: how research results are summarized can affect treatment decisions. Am J Med 1992;92:121-4. 19. Sackett DL, Cook RJ. Understanding clinical trials. BMJ 1994;309:755-6.