Febrile Seizures: Clinical Practice Guideline for the Long-term Management of the Child With Simple Febrile Seizures

INTRODUCTION

Febrile seizures are seizures that occur in febrile children between the ages of 6 and 60 months who do not have an intracranial infection, metabolic disturbance, or history of afebrile seizures. Febrile seizures are subdivided into 2 categories: simple and complex. Simple febrile seizures last for less than 15 minutes, are generalized (without a focal component), and occur once in a 24-hour period, whereas complex febrile seizures are prolonged (>15 minutes), are focal, or occur more than once in 24 hours.¹ Despite the frequency of febrile seizures (2%–5%), there is no unanimity of opinion about management options. This clinical practice guideline addresses potential therapeutic interventions in neurologically normal children with simple febrile seizures. It is not intended for patients with complex febrile seizures and does not pertain to children with previous neurologic insults, known central nervous system abnormalities, or a history of afebrile seizures. This clinical practice guideline is a revision of a 1999 American Academy of Pediatrics (AAP) clinical practice parameter, “The Long-term Treatment of the Child With Simple Febrile Seizures.”²

For a child who has experienced a simple febrile seizure, there are potentially 4 adverse outcomes that theoretically may be altered by an effective therapeutic agent: (1) decline in IQ; (2) increased risk of epilepsy; (3) risk of recurrent febrile seizures; and (4) death. Neither a decline in IQ, academic performance or neurocognitive inattention nor behavioral abnormalities have been shown to be a consequence of recurrent simple febrile seizures.³ Ellenberg and Nelson⁴ studied 431 children who experienced febrile seizures and observed no significant difference in their learning compared with sibling controls. In a similar study by Verity et al,⁵ 303 children with febrile seizures were compared with control children. No difference in learning was identified, except in those children who had neurologic abnormalities before their first seizure.

The second concern, increased risk of epilepsy, is more complex. Children with simple febrile seizures have approximately the same risk of developing epilepsy by the age of 7 years as does the general population (ie, 1%).⁶ However, children who have had multiple simple febrile seizures, are younger than 12 months at the time of their first febrile seizure, and have a family history of epilepsy are at higher risk, with generalized afebrile seizures developing by 25 years of age in 2.4%.⁷ Despite this fact, no study has demonstrated that successful treatment of simple febrile seizures can prevent this later development of epilepsy, and there currently is no evidence that simple febrile seizures cause structural damage to the brain. Indeed, it is most likely that the increased risk of epilepsy in this population is the result of genetic predisposition.

In contrast to the slightly increased risk of developing epilepsy, children with simple febrile seizures have a high rate of recurrence. The risk varies with age. Children younger than 12 months at the time of their first simple febrile seizure have an approximately 50% probability of having recurrent febrile seizures. Children older than 12 months at the time of their first event have an approximately 30% probability of a second febrile seizure; of those who do have a second febrile seizure, 50% have a chance of having at least 1 additional recurrence.⁸

Finally, there is a theoretical risk of a child dying during a simple febrile seizure as a result of documented injury, aspiration, or cardiac arrhythmia, but to the committee's knowledge, it has never been reported.

In summary, with the exception of a high rate of recurrence, no long-term adverse effects of simple febrile seizures have been identified. Because the risks associated with simple febrile seizures, other than recurrence, are so low and because the number of children who have febrile seizures in the first few years of life is so high, to be commensurate, a proposed therapy would need to be exceedingly low in risks and adverse effects, inexpensive, and highly effective.

METHODS

To update the clinical practice guideline on the treatment of children with simple febrile seizures, the AAP reconvened the Subcommittee on Febrile Seizures. The committee was chaired by a child neurologist and consisted of a neuroepidemiologist, 2 additional child neurologists, and a practicing pediatrician. All panel members reviewed and signed the AAP voluntary disclosure and conflict-of-interest form. The guideline was reviewed by members of the AAP Steering Committee on Quality Improvement and Management; members of the AAP Sections on Neurology, Pediatric Emergency Medicine, Developmental and Behavioral Pediatrics, and Epidemiology; members of the AAP Committees on Pediatric Emergency Medicine and Medical Liability and Risk Management; members of the AAP Councils on Children With Disabilities and Community Pediatrics; and members of outside organizations including the Child Neurology Society and the American Academy of Neurology.

A comprehensive review of the evidence-based literature published since 1998 was conducted with the aim of addressing possible therapeutic interventions in the management of children with simple febrile seizures. The review focused on both the efficacy and potential adverse effects of the proposed treatments. Decisions were made on the basis of a systematic grading of the quality of evidence and strength of recommendations.

The AAP established a partnership with the University of Kentucky (Lexington, KY) to develop an evidence report, which served as a major source of information for these practice-guideline recommendations. The specific issues addressed were (1) effectiveness of continuous anticonvulsant therapy in preventing recurrent febrile seizures, (2) effectiveness of intermittent anticonvulsant therapy in preventing recurrent febrile seizures, (3) effectiveness of antipyretics in preventing recurrent febrile seizures, and (4) adverse effects of either continuous or intermittent anticonvulsant therapy.

In the original practice parameter, more than 300 medical journal articles reporting studies of the natural history of simple febrile seizures or the therapy of these seizures were reviewed and abstracted.² An additional 65 articles were reviewed and abstracted for the update. Emphasis was placed on articles that differentiated simple febrile seizures from other types of seizures, that carefully matched treatment and control groups, and that described adherence to the drug regimen. Tables were constructed from the 65 articles that best fit these criteria. A more comprehensive review of the literature on which this report is based can be found in a forthcoming technical report (the initial technical report can be accessed at http://aappolicy.aappublications.org/cgi/content/full/pediatrics;103/6/e86). The technical report also will contain dosing information.

The evidence-based approach to guideline development requires that the evidence in support of a recommendation be identified, appraised, and summarized and that an explicit link between evidence and recommendations be defined. Evidence-based recommendations reflect the quality of evidence and the balance of benefit and harm that is anticipated when the recommendation is followed. The AAP policy statement “Classifying Recommendations for Clinical Practice Guidelines”⁹ was followed in designating levels of recommendations (see Fig 1 and Table 1).

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FIGURE 1

Integrating evidence-quality appraisal with an assessment of the anticipated balance between benefits and harms if a policy is conducted leads to designation of a policy as a strong recommendation, recommendation, option, or no recommendation. RCT indicates randomized, controlled trial.

RECOMMENDATION

On the basis of the risks and benefits of the effective therapies, neither continuous nor intermittent anticonvulsant therapy is recommended for children with 1 or more simple febrile seizures.

• Aggregate evidence quality: B (randomized, controlled trials and diagnostic studies with minor limitations).

• Benefit: prevention of recurrent febrile seizures, which are not harmful and do not significantly increase the risk for development of future epilepsy.

• Harm: adverse effects including rare fatal hepatotoxicity (especially in children younger than 2 years who are also at greatest risk of febrile seizures), thrombocytopenia, weight loss and gain, gastrointestinal disturbances, and pancreatitis with valproic acid and hyperactivity, irritability, lethargy, sleep disturbances, and hypersensitivity reactions with phenobarbital; lethargy, drowsiness, and ataxia for intermittent diazepam as well as the risk of masking an evolving central nervous system infection.

• Benefits/harms assessment: preponderance of harm over benefit.

• Policy level: recommendation.

BENEFITS AND RISKS OF CONTINUOUS ANTICONVULSANT THERAPY

BENEFITS AND RISKS OF INTERMITTENT ANTICONVULSANT THERAPY

BENEFITS AND RISKS OF INTERMITTENT ANTIPYRETICS

No studies have demonstrated that antipyretics, in the absence of anticonvulsants, reduce the recurrence risk of simple febrile seizures. Camfield et al¹¹ treated 79 children who had had a first febrile seizure with either a placebo plus antipyretic instruction (either aspirin or acetaminophen) versus daily phenobarbital plus antipyretic instruction (either aspirin or acetaminophen). Recurrence risk was significantly lower in the phenobarbital-treated group, suggesting that antipyretic instruction, including the use of antipyretics, is ineffective in preventing febrile-seizure recurrence.

Whether antipyretics are given regularly (every 4 hours) or sporadically (contingent on a specific body-temperature elevation) does not influence outcome. Acetaminophen was either given every 4 hours or only for temperature elevations of more than 37.9°C in 104 children. The incidence of febrile episodes did not differ significantly between the 2 groups, nor did the early recurrence of febrile seizures. The authors determined that administering prophylactic acetaminophen during febrile episodes was ineffective in preventing or reducing fever and in preventing febrile-seizure recurrence.³¹

In a randomized double-blind placebo-controlled trial, acetaminophen was administered along with low-dose oral diazepam.³² Febrile-seizure recurrence was not reduced, compared with control groups. As with acetaminophen, ibuprofen also has been shown to be ineffective in preventing recurrence of febrile seizures.^33–35

In general, acetaminophen and ibuprofen are considered to be safe and effective antipyretics for children. However, hepatotoxicity (with acetaminophen) and respiratory failure, metabolic acidosis, renal failure, and coma (with ibuprofen) have been reported in children after overdose or in the presence of risk factors.^36,37

CONCLUSIONS

The subcommittee has determined that a simple febrile seizure is a benign and common event in children between the ages of 6 and 60 months. Nearly all children have an excellent prognosis. The committee concluded that although there is evidence that both continuous antiepileptic therapy with phenobarbital, primidone, or valproic acid and intermittent therapy with oral diazepam are effective in reducing the risk of recurrence, the potential toxicities associated with antiepileptic drugs outweigh the relatively minor risks associated with simple febrile seizures. As such, long-term therapy is not recommended. In situations in which parental anxiety associated with febrile seizures is severe, intermittent oral diazepam at the onset of febrile illness may be effective in preventing recurrence. Although antipyretics may improve the comfort of the child, they will not prevent febrile seizures.

SUBCOMMITTEE ON FEBRILE SEIZURES, 2002–2008

Patricia K. Duffner, MD, Chairperson

Robert J. Baumann, MD, Methodologist

Peter Berman, MD

John L. Green, MD

Sanford Schneider, MD

STEERING COMMITTEE ON QUALITY IMPROVEMENT AND MANAGEMENT, 2007–2008

Elizabeth S. Hodgson, MD, Chairperson

Gordon B. Glade, MD

Norman “Chip” Harbaugh, Jr, MD

Thomas K. McInerny, MD

Marlene R. Miller, MD, MSc

Virginia A. Moyer, MD, MPH

Xavier D. Sevilla, MD

Lisa Simpson, MB, BCh, MPH

Glenn S. Takata, MD

LIAISONS

Denise Dougherty, PhD

Agency for Healthcare Research and Quality

Daniel R. Neuspiel, MD

Section on Epidemiology

Ellen Schwalenstocker, MBA

National Association of Children's Hospitals and Related Institutions

STAFF

Caryn Davidson, MA