Febrile Seizures: Treatment and Prognosis

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1 Epilepia, 41(1):2-9, 2000 Lippincott Williams & Wilkins, Inc., Philadelphia 0 International League Against Epilepsy Progress in Epilepsy Research Febrile Seizures: Treatment and Prognosis Finn Ursin Knudsen Pediutric Department, Glostrup University Hospitul, Glostrup, Denmurk Summary: Recent epidemiologic data indicate that the vast majority of children with febrile seizures have a normal longterm outcome. A precise knowledge of the short- and long-term outcome with or without treatment, and short- and long-term side effects is an important prerequisite for assessing the various treatment strategies. We focus on the impact of short-term or prophylactic treatment on the short- and long-term outcome of various types of febrile seizures. There is universal agreement that daily prophylaxis with antiepileptic agents should never be used routinely in simple febrile seizures, but only in highly selected cases, if at all. Intermittent diazepam (DZP) prophylaxis at times of fever may or may not reduce the recurrence rate, but it does not appear to improve the long-term outcome as compared with short-term seizure control. The treatment may be used to reduce the recurrence rate for a small arbitrarily defined group with multiple simple febrile seizures, complex febrile seizures, especially focal, prolonged or both, febrile status, and when parental anxiety is severe. However, there is no evidence that treatment of simple febrile seizures can prevent the rare cases of later epilepsy, and many children with complex febrile seizures have a benign long-term outcome, even without treatment. Many prefer a wait and see policy. An attractive alternative is to treat new febrile seizures with rectal DZP in solution at seizure onset, given by the parents at home to prevent febrile status. Newer, less well documented short-term strategies include nasal, oral, or rectal administration of other benzodiazepines. Short-term seizure control of febrile status and careful parental counseling are the two most important targets of treatment. Key Words: Febrile seizures-treatment-prophylaxis-prognosis. Our knowledge of the natural history of febrile seizures has increased considerably during the last two decades. Recent epidemiologic studies have confirmed what most pediatricians have thought for decades, that the vast majority of children with febrile seizures have a benign prognosis and a normal long-term outcome (1-7). There are, however, still unsolved problems. We focus on the potential impact of short-term or prophylactic medical intervention on the short- and long-term prognosis. Conflicting data exist as to whether intermittent prophylaxis at times of fever influences the short-term prognosis (i.e., reduces the recurrence rate). Another pertinent problem is as to whether medical intervention, acute or prophylactically, influences the long-term prognosis [i.e., later epilepsy, cognitive dysfunction or other central nervous system (CNS) damage] in multiple simple febrile seizures, in complex febrile seizures, in febrile status, or not at all. Accepted August 5, Address correspondence and reprint requests to Dr. F. U. Knudsen at Pediatric Department, Glostrup University Hospital, Glostrup, DK Denmark. DEFINITIONS Febrile convulsions and febrile seizures are synonymous terms and are defined as an event in neurologically healthy infants and children between 6 months and 5 years of age, associated with fever >38 C, rectal temperature, but without evidence of intracranial infection or a defined cause and with no history of prior afebrile seizures (8). Simple febrile seizures are defined as generalized seizures, lasting <15 min, not recurring within 24 h, and with no postictal neurologic abnormalities. Complex febrile seizures or complicated febrile seizures are focal, prolonged, or recurrent within or associated with postictal neurologic abnormalities, including Todd paresis. Febrile status is seizure duration of >30 min, either one Iong-lasting seizure or a series of shorter seizures, without regaining consciousness interictally. Febrile seizures should be distinguished from seizures with fever (9). The latter include any seizure in any child with fever of any cause. Accordingly, children with meningitis, encephalitis, or cerebral malaria do not have febrile seizures but have seizures with fever. The same is true for children with severe neurologic disorders and/or severe mental retardation. Most febrile seizures are tonic. 2

2 FEBRILE SEIZURES: TREATMENT AND PROGNOSIS 3 clonic, tonic-clonic, or rarely, atonic. Simple febrile seizures are always generalized; the complex variety may be partial or generalized. The number of so-called reflex anoxic seizures presenting as febrile seizures are unknown (10,ll). It seems to be a syncopal type of anoxic seizure resulting from vagal-induced bradycardia or asystolia with reduced cerebral blood flow. The provoking factor may be fever, thus mimicking a febrile seizure. SHORT-TERM OUTCOME The only relevant short-term adverse outcome is new febrile seizures. Death caused by the seizure itself (2) or by the treatment (12) is almost nonexistent, except in developing countries. Seizure-induced acute cerebral damage is not seen in simple febrile seizures but only in some of the rare cases of febrile status (13). Adverse outcome may be more related to an underlying preexisting cerebral condition than to the seizure itself (13,14). Even though febrile status appears to have a much better prognosis than hitherto believed (2,4,14-16) it should still be considered a major pediatric emergency, requiring fast and aggressive treatment. RISK FACTORS FOR NEW FEBRILE SEIZURES The recurrence rate is related to various risk factors, which may include the type of treatment. The determinators for recurrent febrile seizures and for later epilepsy are different. Risk factors for simple and complex recurrences are probably similar (17). The average recurrence rate after a first febrile seizure is 30-40%, but the risk profile differs widely from child to child depending on genetic and environmental factors. Risk assessment is of clinical importance and can be made according to simple clinical available data (I 8). Various short-term riskassessment models are available ( I 9). One study found a total of five risk factors for recurrent febrile seizures when no prophylaxis was given (1 8). In order of predictive power, it included young age at onset (4 5 months), epilepsy in first-degree relatives, febrile seizures in firstdegree relatives, many subsequent febrile episodes (day nursery), and a first complex febrile seizure. The higher the number of risk factors, the higher the recurrence rate and vice versa. The items had independent predictive values, and each factor contributed separately to the recurrence rate. Untreated children with no risk factors had a very low recurrence rate (10%) within 18 months; children with one to two risk factors had an intermediate risk (25-50%), and those with three or more factors had a very high recurrence risk (50-100%). In a similar group of children with febrile seizures, given intermittent diazepam (DZP) prophylaxis at times of fever, all risk groups had a very low recurrence rate (12%). Thus, intermittent prophylaxis reduced the recurrence risk of those with one or more risk factors. The higher the recurrence risk, the better the seizure control during prophylaxis. Berg et al. (20) found that young age at onset (51 year) and a family history of febrile seizures were the only significant determinators. Offringa et al. (17) made a metaanalysis and a reassessment of risk factors for recurrent febrile seizures, pooling a total of 2,496 children from five studies. Besides young age at onset (I 2-24 months), a history of febrile or unprovoked seizures in the firstdegree relatives and a temperature <40 C rectal at the time of the first febrile seizure were associated with a significantly increased recurrence rate. The study specified a detailed risk profile scheme with data for recurrence hazard by attained age in different age groups, thus reflecting the changes in risk over time. Three studies have found that many febrile episodes after the initial febrile seizure appears to be the most powerful risk factor for recurrent febrile seizures (21-23). The most crucial risk factors, those predicting febrile status, include young age at onset, a family history of unprovoked seizures, and an initial partial febrile seizure (1 7,24). Prolonged febrile seizures have a propensity to recur (24). A complex interplay between genetic and environmental factors determines the occurrence of new febrile seizures. The child inherits a low seizure threshold (young age at onset, a family history), which is influenced by environmental factors (many infections and a high temperature). Risk factors for the first febrile seizure comprise the height of the temperature and a family history of febrile seizures (25,26). TREATMENT AND SHORT-TERM OUTCOME Should febrile seizures be prevented, abbreviated, or not treated at all? The available data are conflicting. Treatment options include prolonged daily prophylaxis with phenobarbital (PB) or valproate (VPA), intermittent prophylaxis at times of fever with DZP or other benzodiazepines (BZDs) rectally or orally, antipyretic treatment in case of febrile episodes, immediate treatment with BZDs administered rectally at ongoing seizures, or a wait and see policy. Prolonged daily prophylaxis There is almost universal agreement that long-term prophylaxis with antiepileptic agents because of side effects are justified only in highly selected cases, if at all. Prolonged prophylaxis may or may not be effective (27-30). Long-term PB treatment appears to influence cognition and behavior (drowsiness, sleep problems, aggression, hyperactivity, inattention) (29-33), a large price for the prevention of a benign condition. VPA has in rare cases been associated with hepatotoxicity (34,35). Intermittent diazepam prophylaxis The treatment has been used extensively in many parts of Europe and in Japan for -20 years. In Denmark -30,000 children have been treated with 150,000 DZP doses immediately or prophylactically during this period. Epilepsia, Vol. 41, No. 1, 2000

3 4 F. U. KNUDSEN Only two cases with benign respiratory problems and not a single case of long-term sequelae or fatality has been reported to the authorities (19). If serious side effects had occurred in our tiny little well-monitored country, we would have known. However, conflicting data exist as to whether the treatment is effective. At least 12 studies document that intermittent DZP prophylaxis effectively reduces the recurrence rate (3648). Three double-blind studies exist, and their results are conflicting. Two trials showed no efficacy of intermittent DZP prophylaxis (49,50), and one found the treatment effective (51). A recent meta-analysis based on these three studies concluded that intermittent prophylaxis is ineffective (52). However, the conclusion is open to debate. The metaanalytic process has many problems (53), and the validity of combining these trials may be questioned. The two studies showing no effect have methodologic problems. The study of Autr6t et al. (49) is flawed by severe noncompliance. Only one of the 15 children with a recurrence received DZP as prescribed before the seizure. Thus the lack of efficacy may well have been due to poor adherence to the protocol, a possibility not allowed for if data are analyzed on an intention-to-treat basis. The study of Uhari et al. (50) used low and probably ineffective DZP doses. The recurrence rate in the control group was very low, suggesting that the study group was a very low-risk group, in which DZP prophylaxis has been shown to be ineffective (18). Furthermore, compliance data were not given. The study of Rosman et al. (51) showed that intermittent DZP prophylaxis was effective in children with at high recurrence rate and ineffective in low-risk children, also found by Knudsen (18). A high rate of trivial side effects in the study led to omission of dosage by parents or to reducing the dose to ineffective levels, resulting in a potential underestimation of the true efficacy as compared with an intention-to-treat approach. DZP rectal gel administered as intermittent prophylaxis to children and adults with episodic epilepsy demonstrated significant superiority over placebo in two placebo-controlled double-blind studies (5435). Despite the conflicting evidence, it is justified to conclude that intermittent DZP prophylaxis seems to be effective in reducing the recurrence rate on the premise that sufficient doses are given, compliance problems are minimized, and very low-risk children are left untreated (56). The suggested dosage for prophylaxis is 0.5 mglkg bodyweight DZP administered orally, rectally in solution or in gel, or by suppository every 12 h whenever the rectal temperature is >38.5 C, with a maximum of four consecutive doses to avoid accumulation of the drug. Antipyretic treatment at febrile episodes Three studies have documented that antipyretic treatment during febrile illnesses do not reduce the recurrence rate (50,57,58). Antipyretic agents may be useful in mak- ing the febrile child more comfortable, but cannot be recommended with a view to reduce the recurrence rate. As to whether the antipyretic properties of BZDs has any clinical significance is unknown (59). Short-term treatment of ongoing febrile seizures BZDs given intravenously are the drugs of choice in the immediate situation, but are often unsuccessful in the small child. Rectal tubes containing liquid DZP is a safe, effective, and rational alternative (56). Rectal absorption of liquid DZP is very rapid (60-66), reaches the brain within minutes, has almost i.v. efficacy, and is easy to use at home by the parents and in hospital (67). Anticonvulsant plasma concentrations are obtained within 2-4 min (61), and many uncontrolled studies have documented an effective acute seizure control in febrile and afebrile seizures at home and in a hospital setting (67-73). A newer formulation of DZP rectal gel is now available in the United States, and its prophylactic efficacy has been documented in two clinical trials in children and adults with cluster epilepsy (57,58). Clinical trials with this formulation in children with febrile seizures are not yet available. We also need pediatric pharmacokinetic studies to document how fast single-dose anticonvulsant plasma concentration level of DZP is reached. The effect of short-term treatment with rectal DZP in solution has not been subjected to placebo-controlled doubleblind studies to verify that it is superior to placebo in controlling febrile seizures. A disadvantage of DZP is its short duration of action. Absorption is much slower with a DZP suppository, which is ineffective in the short-term situation. For DZP prophylaxis, rectal solution, rectal gel, suppository, or oral administration may be used. Rectal, oral, or i.v. lorazepam (LZP) (74-77), rectal clonazepam (CZP) (78) nasal midazolam (MDL) (79), and other drugs (80) have also been used, but to a lesser degree. A recent study compared DZP and LZP in the short-term seizure treatment in children with afebrile seizures on an odd and even dates basis. Both drugs acted rapidly, but LZP appeared even more effective than DZP and seemed to have a more protracted duration of action (81). MDL is a water-soluble BZD, which can be given as a liquid by the nasal route. At physiologic ph, the ringstructure closes, the drug becomes lipid soluble, and is rapidly absorbed (79). In a preliminary study, MDL by the nasal route demonstrated effective short-term seizure control in children with epilepsy (79), but has not been used for febrile seizures. TREATMENT AND LONG-TERM OUTCOME Intellectual, cognitive, scholastic and motor outcome Data from large population-based studies document a benign long-term outcome in the vast majority of children with febrile seizures (1-7). The National Collabo- Epilepsia, Vol. 41, No. 1, 2000

4 FEBRILE SEIZURES: TREATMENT AND PROGNOSIS rative Perinatal Project (NCPP) assessed 43 1 pair of siblings discordant for febrile seizure at age 7 years and found no difference in intelligence and academic performance (82). The British CHES cohort identified 398 children with febrile seizures. At the 10-year assessment, the affected children did not differ from controls in terms of academic progress, intelligence, and behavior (83). Children with simple, complex, and recurrent febrile seizures had the same benign prognosis, also found in a hospital-based study (15). The only evidence for a less benign outcome after simple febrile seizures is a twin study (84,85) and older studies from tertiary referral centers, subjected to a high degree of selection bias (86-88). A critical question is whether the type of treatment applied in early childhood has any impact on the longterm outcome. A hospital-based 12-year follow-up study assessed intellectual, cognitive, scholastic, and motor functions in 289 children randomized in early childhood to either intermittent prophylaxis (DZP at fever) or to no prophylaxis (DZP at seizures). At follow-up, both groups had almost identical verbal IQ, performance IQ, and full scale IQ, cognitive abilities, scholastic achievement, and motor function (15). Thus the type of treatment given in early childhood did not influence the long-term prognosis, and prevention of new febrile seizures seemed no better than abbreviating them. Children with simple and complex febrile seizures had the same benign long-term prognosis. Four of the five children with the longest duration of seizures in the series ( min) had normal full IQ (105,106,115,121) (one child was not tested) and a normal academic performance (15). It remains to be seen whether effective short-term anticonvulsant treatment is better than no treatment at all in the long run. Outcome after febrile status Clinic-based studies usually show poorer outcome than population-based studies. In the British CHES cohort with 19 cases of febrile status, one child (5%) had neurologic sequelae, and four developed later afebrile seizures (89). A clinic-based study found no sequelae among 44 children with febrile status (90). A similar study comprising 57 children found 5% severe deficits (9 I ). However, neurologic abnormalities before the seizure are difficult to ascertain in a retrospective study. Risk of epilepsy after febrile seizures Only 3% of children with febrile seizures develop later epilepsy. The NCPP identified three predictive factors for later epilepsy: genetic epilepsy in a first-degree family, abnormal neurologic or developmental status before the febrile seizure, and a complex febrile seizure. At age 7 years, the rate of epilepsy was 0.5% in children without febrile seizures, 1.5% after simple febrile seizures, and 4.0% after the complex form (1). In the British CHES cohort, the risk of subsequent epilepsy was 1% after simple febrile seizures, 4% after multiple seizures, 6% after prolonged seizures, and 29% after febrile seizures with focal features (92). In the Rochester study, the risk of later epilepsy was 2.4% for simple febrile seizures, 6.8% for those with a single complex feature, 17-22% for those with two complex features, and 49% for those with all three features (7). Whereas the spontaneous rate of later epilepsy after febrile seizures is well documented, only a few data exist on the effect of prophylaxis on the rate of later epilepsy. Only a single randomized trial with a long-term followup has addressed this crucial question. In this hospitalbased 12-year follow-up study, the cumulative rate of later epilepsy was very low (2.2%), and the same in children given intermittent DZP prophylaxis (2.1%) or no prophylaxis but short-term anticonvulsant treatment (2.3%) (15). Thus the type of treatment applied in early childhood did not influence the risk of later epilepsy. Prophylaxis was no better in the long run than short-term anticonvulsant treatment. The study showed that prevention of the few cases of later epilepsy is not a realistic target of prophylaxis. However, long-lasting febrile seizures should still be considered a serious pediatric emergency and treated accordingly in the acute situation. Febrile seizures and type of later epilepsy The majority of epilepsies after febrile seizures are generalized, idiopathic epilepsies with tonic-clonic seizures (1-7). A population-based study from Nova Scotia documented that febrile seizures most often precede epilepsy with tonic-clonic seizures, and prolonged febrile seizures rarely precede idiopathic intractable complex partial seizures (93). The febrile seizures plus syndrome provides new insight into the genetic relationship between febrile seizures and generalized epilepsies in childhood (94). In rare cases, multiple febrile recurrences are followed by severe myoclonic epilepsy (95). This is a severe, rare, and well-defined epileptic syndrome with a family history of epilepsy or febrile seizures, onset in early first year of life, with a mixture of febrile and afebrile, generalized or focal seizures, which alternate from side to side, episodes of febrile status, and secondary appearance of myoclonic jerks and partial seizures. It is resistant to treatment, and the course is unfavorable with chaotic hyperactivity, loss of abilities, and mental retardation (96). Contrary to earlier belief, only a small proportion of children with febrile seizures go on to have temporal lobe epilepsy. In the British CHES cohort comprising 382 children with febrile seizures, only 13 (3.4%) developed afebrile seizures, and only six (1.6%) had later epilepsy with complex partial seizures. A higher proportion of children with complex febrile seizures (6.3%) rather than simple febrile seizures (1.O%) developed epilepsy, whereas those with prolonged (9.4%) or focal seizures (29.0%) had the highest risk. In our hospital-based study with a 12-year follow-up of 289 children with fe- Epilepsia, Vol. 41, No. I, 2000

5 6 F. U. KNUDSEN brile seizures, not a single case of partial complex epilepsy with underlying hippocampal sclerosis emerged. Only six cases of later epilepsy were seen, and they were all idiopathic forms, stressing the genetic link between febrile seizures and epilepsy, rather than a cause-andeffect relationship. The association between febrile seizures and temporal lobe epilepsy is recognized (97, review paper), but controversial (95,98,99) and definitely weak from a quantitative point of view (1,2,15,93), even in children with febrile status (3). The estimated risk for developing complex partial epilepsy subsequent to prolonged febrile seizures was 1:75,000 children per year (93). This sequence of events is very rare and was not seen even a single time in the NCPP (3). However, there is no doubt that children with long-lasting lateralized febrile seizures are at risk for developing temporal lobe epilepsy (97), and magnetic resonance (MR) imaging has produced evidence of hippocampal injury after prolonged focal febrile seizures (100). However, another MR study found evidence of a subtle, preexisting hippocampal malformation as a cause of familial febrile seizures and subsequent hippocampal sclerosis (101). There is evidence demonstrating that mesial temporal sclerosis is both a result and a cause of seizures (102). Whether effective short-term or prophylactic seizure control in children with focal or generalized febrile status and at risk for temporal lobe epilepsy with mesial temporal sclerosis can actually prevent subsequent epilepsy is unknown. The more favorable outcomes of complex febrile seizures in recent times is unexplained, but may be related to advances in effective seizure control and supportive treatment. Treatment options The potential goals of treatment are preventing recurrent febrile seizures as well as the rare cases of neurologic seyuelae and later epilepsy. Is it rational to prevent recurrent febrile seizures? Opinion is divided on that topic, but there are strong arguments against routine prophylaxis even in the intermittent form, which may or may not be effective. Recurrences are benign in most cases and do not influence the child s general health. There is no evidence to suggest that prevention of recurrences further reduces the already small risk of later epilepsy or neurologic sequelae (15). Recent data on the long-term outcome indicate that prevention is no better than interruption of recurrent febrile seizures (1 5). Seizures are extremely upsetting for the parents, but that is not an argument for prophylaxis. Parents frightening or even near-death experience is a psychological rather than a medical problem, requiring parental education. What are the available therapeutic options, and how useful are they? PB treatment during febrile episodes, the most widely used prophylaxis for decades, is obsolete and ineffective (103) because of the long half-life of the drug (104,105). Carbamazepine (CBZ) (1 06) and phenytoin (PHT) (107) have not been shown to be effective. VPA treatment of feverish children is of dubious value (108). Consensus has emerged that prolonged daily prophylaxis with PB, mysoline, or VPA should only be used in highly selected cases, if at all. Rectal DZP given at times of fever can prevent some of the recurrences if the dosing and compliance are optimal (19,56). The longterm prognosis in terms of intellectual, cognitive, scholastic, motor, and neurologic performance, as well as subsequent epilepsy, is not influenced by the type of treatment administered in early childhood (1 5). However, only a single long-term study exists. Antipyretic treatment of feverish children does not reduce the recurrence rate (50,57,58), but may be useful in making the child more comfortable (109). The two remaining options are immediate treatment with rectal DZP in solution of ongoing seizures (56,67-73) or a wait and see policy (109,110). I prefer the first option for the following reasons. Immediate anticonvulsant treatment with rectal DZP in solution is effective in aborting recurrent febrile seizures with almost i.v. efficacy. Furthermore it is safe, simple, cost-effective, practical, and useful for nonprofessional personnel including parents and other caretakers (67). In addition it reduces the need for emergency department visits (73). Rectal tubes with liquid DZP empowers parents to apply immediate emergency care and to terminate a potentially CNS-damaging febrile status, even when medical help is unavailable. The possession of rectal tubes reduces family stress and decreases medical expenses related to severe seizures (73). Even though the treatment has not been subjected to placebo-controlled randomized trials, it appears safe and effective and therefore preferable to doing nothing. An attractive routine strategy may be to treat ongoing febrile seizures with rectal DZP in solution to terminate longlasting febrile seizures or febrile status (67). Most seizures stop spontaneously within 2 min and do not require treatment. All affected families should be equipped with a few rectal tubes containing liquid DZP. In Europe, specific liquid DZP preparations for rectal administration (rectal tubes) have been available for 20 years. Newer, less well documented immediate strategies include DZP rectal gel (54,55) and nasal, oral, or rectal administration of other BZDs (74-80,111). Careful parental counseling ( ) and controlling febrile status are the two most important targets of treatment. During the last 20 years, a vast amount of new data on the medical treatment have emerged. A critical evaluation of a rational approach to the short-term and prophylactic-or no-treatment in various clinical settings is needed. Guidelines for the long-term treatment of simple febrile seizures have recently been published by the American Academy of Pediatrics (1 16), together with a technical report. A recent Japanese consensus report also Epilepria, Vol. 41, No. I, 2000

6 I FEBRILE SEIZURES: TREATMENT AND PROGNOSIS 7 is available (1 17). However, we also need consensus recommendations for the treatment of recurrent simple febrile seizures with several or frequent attacks, a first or recurrent complex febrile seizures, a mixture of simple and complex recurrences, an initial or subsequent febrile status, as well as seizures with fever in neurologically abnormal children or with a history of afebrile seizures. The reappraisal should include prolonged and intermittent prophylaxis with antiepileptic agents, intermittent prophylaxis with BZDs given orally, rectally, or by the nasal route, home- and hospital-based emergency anticonvulsive treatment, and a wait and see policy. In addition, all modalities should be put in order of priority. REFERENCES 1. Nelson KB, Ellenberg JH. Predictors of epilepsy in children who have experienced febrile seizures. N Engl J Med 1976;295: Nelson KB, Ellenberg JH. Prognosis in children with febrile seizures. 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